A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8 Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³ E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39 Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8 Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³ E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39 Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8 Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³ E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39 Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

The transition from hospital to home can be overwhelming for caregivers.¹ Stress of hospitalization coupled with the expectation of families to execute postdischarge care plans make understandable discharge communication critical. Communication failures, inadequate education, absence of caregiver confidence, and lack of clarity regarding care plans may prohibit smooth transitions and lead to adverse postdischarge outcomes.^2-4

Health literacy plays a pivotal role in caregivers’ capacity to navigate the healthcare system, comprehend, and execute care plans. An estimated 90 million Americans have limited health literacy that may negatively impact the provision of safe and quality care^5,6 and be a risk factor for poor outcomes, including increased emergency department (ED) utilization and readmission rates.^7-9 Readability strongly influences the effectiveness of written materials.¹⁰ However, written medical information for patients and families are frequently between the 10^th and 12^th grade reading levels; more than 75% of all pediatric health information is written at or above 10^th grade reading level.¹¹ Government agencies recommend between a 6^th and 8^th grade reading level, for written material;^5,12,13 written discharge instructions have been identified as an important quality metric for hospital-to-home transitions.^14-16

At our center, we found that discharge instructions were commonly written at high reading levels and often incomplete.¹⁷ Poor discharge instructions may contribute to increased readmission rates and unnecessary ED visits.^9,18 Our global aim targeted improved health-literate written information, including understandability and completeness.

Our specific aim was to increase the percentage of discharge instructions written at or below the 7th grade level for hospital medicine (HM) patients on a community hospital pediatric unit from 13% to 80% in 6 months.

Context

The improvement work took place at a 42-bed inpatient pediatric unit at a community satellite of our large, urban, academic hospital. The unit is staffed by medical providers including attendings, fellows, nurse practitioners (NPs), and senior pediatric residents, and had more than 1000 HM discharges in fiscal year 2016. Children with common general pediatric diagnoses are admitted to this service; postsurgical patients are not admitted primarily to the HM service. In Cincinnati, the neighborhood-level high school drop-out rates are as high as 64%.¹⁹ Discharge instructions are written by medical providers in the electronic health record (EHR). A printed copy is given to families and verbally reviewed by a bedside nurse prior to discharge. Quality improvement (QI) efforts focused on discharge instructions were ignited by a prior review of 200 discharge instructions that showed they were difficult to read (median reading level of 10^th grade), poorly understandable (36% of instructions met the threshold of understandability as measured by the Patient Education Materials Assessment Tool²⁰) and were missing key elements of information.¹⁷

Improvement Team

The improvement team consisted of 4 pediatric hospitalists, 2 NPs, 1 nurse educator with health literacy expertise, 1 pediatric resident, 1 fourth-year medical student, 1 QI consultant, and 2 parents who had first-hand experience on the HM service. The improvement team observed the discharge process, including roles of the provider, nurse and family, outlined a process map, and created a modified failure mode and effect analysis.²¹ Prior to our work, discharge instructions written by providers often occurred as a last step, and the content was created as free text or from nonstandardized templates. Key drivers that informed interventions were determined and revised over time (Figure 1). The study was reviewed by our institutional review board and deemed not human subjects research.

Improvement Activities

Key drivers were identified, and interventions were executed using Plan-Do Study-Act cycles.²² The key drivers thought to be critical for the success of the QI efforts were family engagement; standardization of discharge instructions; medical staff engagement; and audit and feedback of data. The corresponding interventions were as follows:

Family Engagement

Understanding the discharge information families desired. Prior to testing, 10 families admitted to the HM service were asked about the discharge experience. We asked families about information they wanted in written discharge instructions: 1) reasons to call your primary doctor or return to the hospital; 2) when to see your primary doctor for a follow-up visit; 3) the phone number to reach your child’s doctor; 4) more information about why your child was admitted; 5) information about new medications; and 6) what to do to help your child continue to recover at home.

Development of templates. We engaged families throughout the process of creating general and disease-specific discharge templates. After a specific template was created and reviewed by the parents on our team, it was sent to members of the institutional Patient Education Committee, which includes parents and local health literacy experts, to review and critique. Feedback from the reviewers was incorporated into the templates prior to use in the EHR.

Postdischarge phone calls.A convenience sample of families discharged from the satellite campus was called 24 to 48 hours after discharge over a 2-week period in January, 2016. A member of our improvement team solicited feedback from families about the quality of the discharge instructions. Families were asked if discharge instructions were reviewed with them prior to going home, if they were given a copy of the instructions, how they would rate the ability to read and use the information, and if there were additional pieces of information that would have improved the instructions.

Standardization of Instructions

Education. A presentation was created and shared with medical providers; it was re-disseminated monthly to new residents rotating onto the service and to the attendings, fellows, and NPs scheduled for shifts during the month. This education continued for the duration of the study. The presentation included the definition of health literacy, scope of the problem, examples of poorly written discharge instructions, and tips on how to write readable and understandable instructions. Laminated cards that included tips on how to write instructions were also placed on work stations.

While the general template was an important first step, the content relied heavily on free text by providers, which could still lead to instructions written at a high reading level. Thus, disease-specific discharge instruction templates were created with prepopulated information that was written at a reading level at or below 7^th grade level (Figure 2). The diseases were prioritized based on the most common diagnoses on our HM service. Each template included information under each of the subheadings noted in the general template. Twelve disease-specific templates were tested and ultimately embedded in the EHR; the general template remained for use when the discharge diagnosis was not covered by a disease-specific template.

Medical Staff Engagement

Previously described tests of change also aimed to enhance staff engagement. These included frequent e-mails, discussion of the QI efforts at specific team meetings, and the creation of visual cues posted at computer work stations, which prompted staff to begin to work on discharge instructions soon after admission.

Audit and Feedback of Data

Weekly phone calls. One team updated clinicians through a regularly scheduled bi-weekly phone conference. The phone conference was established prior to our work and was designed to relay pertinent information to attendings and NPs who work at the satellite hospital. During the phone conferences, clinicians were notified of current performance on discharge instruction readability and specific tests of change for the week. Additionally, providers gave feedback about the improvement efforts. These updates continued for the first 6 months of the project until sustained improvements were observed.

E-mails. Weekly e-mails were sent to all providers scheduled for clinical time at the satellite campus. The e-mail contained information on current tests of change, a list of discharge instruction templates that were available in the EHR, and the annotated run chart illustrating readability levels over time.

Additionally, individual e-mails were sent to each provider after review of the written discharge instructions for the week. Providers were given information on the number of discharge instructions they personally composed, the percentage of those instructions that were written at or below 7^th grade level, and specific feedback on how their written instructions could be improved. We also encouraged feedback from each provider to better identify barriers to achieving our goal.

Study of the Interventions

Baseline data included a review of all instructions for patients discharged from the satellite campus from the end of April 2015 through mid-September 2015. The time period for testing of interventions during the fall and winter months allowed for rapid cycle learning due to higher patient census and predictability of admissions for specific diagnosis (ie, asthma and bronchiolitis). An automated report was generated from the EHR weekly with specific demographics and identifiers for patient discharged over the past 7 days, including patient age, gender, length of stay, discharge diagnosis, and insurance classification. Data was collected during the intervention period via structured review of the discharge instructions in the EHR by the principal investigator or a trained research coordinator. Discharge instructions for medically cleared mental health patients admitted to hospital medicine while awaiting psychiatric bed availability and patients and parents who were non-English speaking were excluded from review. All other instructions for patients discharged from the HM service at our Liberty Campus were included for review.

Measures

Readability, our primary measure of interest, was calculated using the mean score from the following formulas: Flesch Kincaid Grade Level,²³ Simple Measure of Gobbledygook Index,²⁴ Coleman-Liau Index,²⁵ Gunning-Fog Index,²⁶ and Automated Readability Index²⁷ by means of an online platform (https://readability-score.com).²⁸ This platform was chosen because it incorporated a variety of formulas, was user-friendly, and required minimal data cleaning. Each of the readability formulas have been used to assesses readability of health information given to patients and families.^29,30 The threshold of 7th grade is in alignment with our institutional policy for educational materials and with recommendations from several government agencies.^5,12

Analysis

A statistical process control p-chart was used to analyze our primary measure of readability, dichotomized as percent discharge instructions written at or below 7th grade level. Run charts were used to follow mean reading level of discharge instructions and our process measure of percent of discharge instruction written with a general or disease-specific standardized template. Run chart and control chart rules for identifying special cause were used for midline shifts.³¹

The Table includes the demographic and clinical information of patients included in our analyses. Through sequential interventions, the percentage of discharge instructions written at or below 7th grade readability level increased from a mean of 13% to more than 80% in 3 months (Figure 3). Furthermore, the mean was sustained above 90% for 10 months and at 98% for the last 4 months. The use of 1 of the 13 EHR templates increased from 0% to 96% and was associated with the largest impact on the overall improvements (Supplemental Figure 1). Additionally, the average reading level of the discharge instructions decreased from 10th grade to 6th grade level (Supplemental Figure 2).

Qualitative comments from providers about the discharge instructions included:

“Are these [discharge instructions] available at base??  Great resource for interns.”
“These [discharge] instructions make the [discharge] process so easy!!! Love these...”
“Also feel like they have helped my discharge teaching in the room!”

Qualitative comments from families postdischarge included:
“I thought the instructions were very clear and easy to read. I especially thought that highlighting the important areas really helped.”
“I think this form looks great, and I really like the idea of having your child’s name on it.”

Through sequential Plan-Do Study-Act cycles, we increased the percentage of discharge instructions written at or below 7^th grade reading level from 13% to 98%. Our most impactful intervention was the creation and dissemination of standardized disease-specific discharge instruction templates. Our findings complement evidence in the adult and pediatric literature that the use of standardized, disease-specific discharge instruction templates may improve readability of instructions.^32,33 And, while quality improvement efforts have been employed to improve the discharge process for patients,^34-36 this is the first study in the inpatient setting that, to our knowledge, specifically addresses discharge instructions using quality improvement methods.

Our work targeted the critical intersection between individual health literacy, an individual’s capacity to acquire, interpret, and use health information, and the necessary changes needed within our healthcare system to ensure that appropriately written instructions are given to patients and families.^17,37 Our efforts focused on improving discharge instructions answer the call to consider health literacy a modifiable clinical risk factor.³⁷ Furthermore, we address the 6 aims for quality healthcare delivery: 1) safe, timely, efficient and equitable delivery of care through the creation and dissemination of standardized instructions that are written at the appropriate reading level for families to ease hospital-to-home transitions and streamline the workflow of medical providers; 2) effective education of medical providers on health literacy concepts; and 3) family-centeredness through the involvement of families in our QI efforts. While previous QI efforts to improve hospital-to-home transitions have focused on medication reconciliation, communication with primary care physicians, follow-up appointments, and timely discharges of patients, none have specifically focused on the quality of discharge instructions.^34-36

Most physicians do not receive education about how to write information that is readable and understandable; more than half of providers desired more education in this area.³⁸ Furthermore, pediatric providers may overestimate parental health literacy levels,³⁹ which may contribute to variability in the readability of written health materials. While education alone can contribute to a provider’s ability to create readable instructions, we note the improvement after the introduction of disease templates to demonstrate the importance of workflow-integrated higher reliability interventions to sustain improvements.

Our baseline poor readability rates were due to limited knowledge by frontline providers composing the instructions and a system in which an important element for successful hospital-to-home transitions was not tackled until patients were ready for discharge. Streamlining of the discharge process, including the creation of discharge instructions, may lead to improved efficiency, fewer discrepancies, more effective communication, and an enhanced family experience. Moreover, the success of our improvement work was due to key stakeholders, including parents, being a part of the team and the notable buy-in from providers.

Our work was not without limitations. We excluded non-English speaking families from the study. We were unable to measure reading level of our population directly and instead based our goals on national estimates. Our primary measure was readability, which is only 1 piece contributing to quality discharge instructions. Understandability and actionability are also important considerations; ^17,20,29,40 however, improvements in these areas were limited by our design options within the EHR. Our efforts focused on children with common general pediatric diagnoses, and it is unclear how our interventions would generalize to medically complex patients with more volume of information to communicate at discharge and with uncommon diagnoses that are less readily incorporated into standardized templates. Relatedly, our work occurred at the satellite campus of our tertiary care center and may not represent generalizable material or methods to implement templates at our main campus location or at other hospitals. To begin to better understand this, we have spread to HM patients at our main campus, including medically complex patients with technology dependence and/or neurological impairments. Standardized, disease-specific templates most relevant to this population as well as several patient specific templates, for those with frequent readmissions due to medical complexity, have been created and are actively being tested.

In conclusion, in using interventions targeted at standardization of discharge instructions and timely feedback to staff, we saw rapid, dramatic, and sustained improvement in the readability of discharge instructions. Next steps include adaptation and spread to other patient populations and care teams, collaborations with other centers, and assessing the impact of effectively written discharge instructions on patient outcomes, such as adverse drug events, readmission rates, and family experience.

Disclosure

No external funding was secured for this study. Dr. Brady is supported by a Patient-Centered Outcomes Research Mentored Clinical Investigator Award from the Agency for Healthcare Research and Quality, Award Number K08HS023827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. The funding organization had no role in the design, preparation, review, or approval of this paper; nor the decision to submit the manuscript for publication. The authors have no financial relationships relevant to this article to disclose.

The transition from hospital to home can be overwhelming for caregivers.¹ Stress of hospitalization coupled with the expectation of families to execute postdischarge care plans make understandable discharge communication critical. Communication failures, inadequate education, absence of caregiver confidence, and lack of clarity regarding care plans may prohibit smooth transitions and lead to adverse postdischarge outcomes.^2-4

Health literacy plays a pivotal role in caregivers’ capacity to navigate the healthcare system, comprehend, and execute care plans. An estimated 90 million Americans have limited health literacy that may negatively impact the provision of safe and quality care^5,6 and be a risk factor for poor outcomes, including increased emergency department (ED) utilization and readmission rates.^7-9 Readability strongly influences the effectiveness of written materials.¹⁰ However, written medical information for patients and families are frequently between the 10^th and 12^th grade reading levels; more than 75% of all pediatric health information is written at or above 10^th grade reading level.¹¹ Government agencies recommend between a 6^th and 8^th grade reading level, for written material;^5,12,13 written discharge instructions have been identified as an important quality metric for hospital-to-home transitions.^14-16

At our center, we found that discharge instructions were commonly written at high reading levels and often incomplete.¹⁷ Poor discharge instructions may contribute to increased readmission rates and unnecessary ED visits.^9,18 Our global aim targeted improved health-literate written information, including understandability and completeness.

Our specific aim was to increase the percentage of discharge instructions written at or below the 7th grade level for hospital medicine (HM) patients on a community hospital pediatric unit from 13% to 80% in 6 months.

Context

The improvement work took place at a 42-bed inpatient pediatric unit at a community satellite of our large, urban, academic hospital. The unit is staffed by medical providers including attendings, fellows, nurse practitioners (NPs), and senior pediatric residents, and had more than 1000 HM discharges in fiscal year 2016. Children with common general pediatric diagnoses are admitted to this service; postsurgical patients are not admitted primarily to the HM service. In Cincinnati, the neighborhood-level high school drop-out rates are as high as 64%.¹⁹ Discharge instructions are written by medical providers in the electronic health record (EHR). A printed copy is given to families and verbally reviewed by a bedside nurse prior to discharge. Quality improvement (QI) efforts focused on discharge instructions were ignited by a prior review of 200 discharge instructions that showed they were difficult to read (median reading level of 10^th grade), poorly understandable (36% of instructions met the threshold of understandability as measured by the Patient Education Materials Assessment Tool²⁰) and were missing key elements of information.¹⁷

Improvement Team

The improvement team consisted of 4 pediatric hospitalists, 2 NPs, 1 nurse educator with health literacy expertise, 1 pediatric resident, 1 fourth-year medical student, 1 QI consultant, and 2 parents who had first-hand experience on the HM service. The improvement team observed the discharge process, including roles of the provider, nurse and family, outlined a process map, and created a modified failure mode and effect analysis.²¹ Prior to our work, discharge instructions written by providers often occurred as a last step, and the content was created as free text or from nonstandardized templates. Key drivers that informed interventions were determined and revised over time (Figure 1). The study was reviewed by our institutional review board and deemed not human subjects research.

Improvement Activities

Key drivers were identified, and interventions were executed using Plan-Do Study-Act cycles.²² The key drivers thought to be critical for the success of the QI efforts were family engagement; standardization of discharge instructions; medical staff engagement; and audit and feedback of data. The corresponding interventions were as follows:

Family Engagement

Understanding the discharge information families desired. Prior to testing, 10 families admitted to the HM service were asked about the discharge experience. We asked families about information they wanted in written discharge instructions: 1) reasons to call your primary doctor or return to the hospital; 2) when to see your primary doctor for a follow-up visit; 3) the phone number to reach your child’s doctor; 4) more information about why your child was admitted; 5) information about new medications; and 6) what to do to help your child continue to recover at home.

Development of templates. We engaged families throughout the process of creating general and disease-specific discharge templates. After a specific template was created and reviewed by the parents on our team, it was sent to members of the institutional Patient Education Committee, which includes parents and local health literacy experts, to review and critique. Feedback from the reviewers was incorporated into the templates prior to use in the EHR.

Postdischarge phone calls.A convenience sample of families discharged from the satellite campus was called 24 to 48 hours after discharge over a 2-week period in January, 2016. A member of our improvement team solicited feedback from families about the quality of the discharge instructions. Families were asked if discharge instructions were reviewed with them prior to going home, if they were given a copy of the instructions, how they would rate the ability to read and use the information, and if there were additional pieces of information that would have improved the instructions.

Standardization of Instructions

Education. A presentation was created and shared with medical providers; it was re-disseminated monthly to new residents rotating onto the service and to the attendings, fellows, and NPs scheduled for shifts during the month. This education continued for the duration of the study. The presentation included the definition of health literacy, scope of the problem, examples of poorly written discharge instructions, and tips on how to write readable and understandable instructions. Laminated cards that included tips on how to write instructions were also placed on work stations.

While the general template was an important first step, the content relied heavily on free text by providers, which could still lead to instructions written at a high reading level. Thus, disease-specific discharge instruction templates were created with prepopulated information that was written at a reading level at or below 7^th grade level (Figure 2). The diseases were prioritized based on the most common diagnoses on our HM service. Each template included information under each of the subheadings noted in the general template. Twelve disease-specific templates were tested and ultimately embedded in the EHR; the general template remained for use when the discharge diagnosis was not covered by a disease-specific template.

Medical Staff Engagement

Previously described tests of change also aimed to enhance staff engagement. These included frequent e-mails, discussion of the QI efforts at specific team meetings, and the creation of visual cues posted at computer work stations, which prompted staff to begin to work on discharge instructions soon after admission.

Audit and Feedback of Data

Weekly phone calls. One team updated clinicians through a regularly scheduled bi-weekly phone conference. The phone conference was established prior to our work and was designed to relay pertinent information to attendings and NPs who work at the satellite hospital. During the phone conferences, clinicians were notified of current performance on discharge instruction readability and specific tests of change for the week. Additionally, providers gave feedback about the improvement efforts. These updates continued for the first 6 months of the project until sustained improvements were observed.

E-mails. Weekly e-mails were sent to all providers scheduled for clinical time at the satellite campus. The e-mail contained information on current tests of change, a list of discharge instruction templates that were available in the EHR, and the annotated run chart illustrating readability levels over time.

Additionally, individual e-mails were sent to each provider after review of the written discharge instructions for the week. Providers were given information on the number of discharge instructions they personally composed, the percentage of those instructions that were written at or below 7^th grade level, and specific feedback on how their written instructions could be improved. We also encouraged feedback from each provider to better identify barriers to achieving our goal.

Study of the Interventions

Baseline data included a review of all instructions for patients discharged from the satellite campus from the end of April 2015 through mid-September 2015. The time period for testing of interventions during the fall and winter months allowed for rapid cycle learning due to higher patient census and predictability of admissions for specific diagnosis (ie, asthma and bronchiolitis). An automated report was generated from the EHR weekly with specific demographics and identifiers for patient discharged over the past 7 days, including patient age, gender, length of stay, discharge diagnosis, and insurance classification. Data was collected during the intervention period via structured review of the discharge instructions in the EHR by the principal investigator or a trained research coordinator. Discharge instructions for medically cleared mental health patients admitted to hospital medicine while awaiting psychiatric bed availability and patients and parents who were non-English speaking were excluded from review. All other instructions for patients discharged from the HM service at our Liberty Campus were included for review.

Measures

Readability, our primary measure of interest, was calculated using the mean score from the following formulas: Flesch Kincaid Grade Level,²³ Simple Measure of Gobbledygook Index,²⁴ Coleman-Liau Index,²⁵ Gunning-Fog Index,²⁶ and Automated Readability Index²⁷ by means of an online platform (https://readability-score.com).²⁸ This platform was chosen because it incorporated a variety of formulas, was user-friendly, and required minimal data cleaning. Each of the readability formulas have been used to assesses readability of health information given to patients and families.^29,30 The threshold of 7th grade is in alignment with our institutional policy for educational materials and with recommendations from several government agencies.^5,12

Analysis

A statistical process control p-chart was used to analyze our primary measure of readability, dichotomized as percent discharge instructions written at or below 7th grade level. Run charts were used to follow mean reading level of discharge instructions and our process measure of percent of discharge instruction written with a general or disease-specific standardized template. Run chart and control chart rules for identifying special cause were used for midline shifts.³¹

The Table includes the demographic and clinical information of patients included in our analyses. Through sequential interventions, the percentage of discharge instructions written at or below 7th grade readability level increased from a mean of 13% to more than 80% in 3 months (Figure 3). Furthermore, the mean was sustained above 90% for 10 months and at 98% for the last 4 months. The use of 1 of the 13 EHR templates increased from 0% to 96% and was associated with the largest impact on the overall improvements (Supplemental Figure 1). Additionally, the average reading level of the discharge instructions decreased from 10th grade to 6th grade level (Supplemental Figure 2).

Qualitative comments from providers about the discharge instructions included:

“Are these [discharge instructions] available at base??  Great resource for interns.”
“These [discharge] instructions make the [discharge] process so easy!!! Love these...”
“Also feel like they have helped my discharge teaching in the room!”

Qualitative comments from families postdischarge included:
“I thought the instructions were very clear and easy to read. I especially thought that highlighting the important areas really helped.”
“I think this form looks great, and I really like the idea of having your child’s name on it.”

Through sequential Plan-Do Study-Act cycles, we increased the percentage of discharge instructions written at or below 7^th grade reading level from 13% to 98%. Our most impactful intervention was the creation and dissemination of standardized disease-specific discharge instruction templates. Our findings complement evidence in the adult and pediatric literature that the use of standardized, disease-specific discharge instruction templates may improve readability of instructions.^32,33 And, while quality improvement efforts have been employed to improve the discharge process for patients,^34-36 this is the first study in the inpatient setting that, to our knowledge, specifically addresses discharge instructions using quality improvement methods.

Our work targeted the critical intersection between individual health literacy, an individual’s capacity to acquire, interpret, and use health information, and the necessary changes needed within our healthcare system to ensure that appropriately written instructions are given to patients and families.^17,37 Our efforts focused on improving discharge instructions answer the call to consider health literacy a modifiable clinical risk factor.³⁷ Furthermore, we address the 6 aims for quality healthcare delivery: 1) safe, timely, efficient and equitable delivery of care through the creation and dissemination of standardized instructions that are written at the appropriate reading level for families to ease hospital-to-home transitions and streamline the workflow of medical providers; 2) effective education of medical providers on health literacy concepts; and 3) family-centeredness through the involvement of families in our QI efforts. While previous QI efforts to improve hospital-to-home transitions have focused on medication reconciliation, communication with primary care physicians, follow-up appointments, and timely discharges of patients, none have specifically focused on the quality of discharge instructions.^34-36

Most physicians do not receive education about how to write information that is readable and understandable; more than half of providers desired more education in this area.³⁸ Furthermore, pediatric providers may overestimate parental health literacy levels,³⁹ which may contribute to variability in the readability of written health materials. While education alone can contribute to a provider’s ability to create readable instructions, we note the improvement after the introduction of disease templates to demonstrate the importance of workflow-integrated higher reliability interventions to sustain improvements.

Our baseline poor readability rates were due to limited knowledge by frontline providers composing the instructions and a system in which an important element for successful hospital-to-home transitions was not tackled until patients were ready for discharge. Streamlining of the discharge process, including the creation of discharge instructions, may lead to improved efficiency, fewer discrepancies, more effective communication, and an enhanced family experience. Moreover, the success of our improvement work was due to key stakeholders, including parents, being a part of the team and the notable buy-in from providers.

Our work was not without limitations. We excluded non-English speaking families from the study. We were unable to measure reading level of our population directly and instead based our goals on national estimates. Our primary measure was readability, which is only 1 piece contributing to quality discharge instructions. Understandability and actionability are also important considerations; ^17,20,29,40 however, improvements in these areas were limited by our design options within the EHR. Our efforts focused on children with common general pediatric diagnoses, and it is unclear how our interventions would generalize to medically complex patients with more volume of information to communicate at discharge and with uncommon diagnoses that are less readily incorporated into standardized templates. Relatedly, our work occurred at the satellite campus of our tertiary care center and may not represent generalizable material or methods to implement templates at our main campus location or at other hospitals. To begin to better understand this, we have spread to HM patients at our main campus, including medically complex patients with technology dependence and/or neurological impairments. Standardized, disease-specific templates most relevant to this population as well as several patient specific templates, for those with frequent readmissions due to medical complexity, have been created and are actively being tested.

In conclusion, in using interventions targeted at standardization of discharge instructions and timely feedback to staff, we saw rapid, dramatic, and sustained improvement in the readability of discharge instructions. Next steps include adaptation and spread to other patient populations and care teams, collaborations with other centers, and assessing the impact of effectively written discharge instructions on patient outcomes, such as adverse drug events, readmission rates, and family experience.

Disclosure

No external funding was secured for this study. Dr. Brady is supported by a Patient-Centered Outcomes Research Mentored Clinical Investigator Award from the Agency for Healthcare Research and Quality, Award Number K08HS023827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. The funding organization had no role in the design, preparation, review, or approval of this paper; nor the decision to submit the manuscript for publication. The authors have no financial relationships relevant to this article to disclose.

The transition from hospital to home can be overwhelming for caregivers.¹ Stress of hospitalization coupled with the expectation of families to execute postdischarge care plans make understandable discharge communication critical. Communication failures, inadequate education, absence of caregiver confidence, and lack of clarity regarding care plans may prohibit smooth transitions and lead to adverse postdischarge outcomes.^2-4

Health literacy plays a pivotal role in caregivers’ capacity to navigate the healthcare system, comprehend, and execute care plans. An estimated 90 million Americans have limited health literacy that may negatively impact the provision of safe and quality care^5,6 and be a risk factor for poor outcomes, including increased emergency department (ED) utilization and readmission rates.^7-9 Readability strongly influences the effectiveness of written materials.¹⁰ However, written medical information for patients and families are frequently between the 10^th and 12^th grade reading levels; more than 75% of all pediatric health information is written at or above 10^th grade reading level.¹¹ Government agencies recommend between a 6^th and 8^th grade reading level, for written material;^5,12,13 written discharge instructions have been identified as an important quality metric for hospital-to-home transitions.^14-16

At our center, we found that discharge instructions were commonly written at high reading levels and often incomplete.¹⁷ Poor discharge instructions may contribute to increased readmission rates and unnecessary ED visits.^9,18 Our global aim targeted improved health-literate written information, including understandability and completeness.

Our specific aim was to increase the percentage of discharge instructions written at or below the 7th grade level for hospital medicine (HM) patients on a community hospital pediatric unit from 13% to 80% in 6 months.

Context

The improvement work took place at a 42-bed inpatient pediatric unit at a community satellite of our large, urban, academic hospital. The unit is staffed by medical providers including attendings, fellows, nurse practitioners (NPs), and senior pediatric residents, and had more than 1000 HM discharges in fiscal year 2016. Children with common general pediatric diagnoses are admitted to this service; postsurgical patients are not admitted primarily to the HM service. In Cincinnati, the neighborhood-level high school drop-out rates are as high as 64%.¹⁹ Discharge instructions are written by medical providers in the electronic health record (EHR). A printed copy is given to families and verbally reviewed by a bedside nurse prior to discharge. Quality improvement (QI) efforts focused on discharge instructions were ignited by a prior review of 200 discharge instructions that showed they were difficult to read (median reading level of 10^th grade), poorly understandable (36% of instructions met the threshold of understandability as measured by the Patient Education Materials Assessment Tool²⁰) and were missing key elements of information.¹⁷

Improvement Team

The improvement team consisted of 4 pediatric hospitalists, 2 NPs, 1 nurse educator with health literacy expertise, 1 pediatric resident, 1 fourth-year medical student, 1 QI consultant, and 2 parents who had first-hand experience on the HM service. The improvement team observed the discharge process, including roles of the provider, nurse and family, outlined a process map, and created a modified failure mode and effect analysis.²¹ Prior to our work, discharge instructions written by providers often occurred as a last step, and the content was created as free text or from nonstandardized templates. Key drivers that informed interventions were determined and revised over time (Figure 1). The study was reviewed by our institutional review board and deemed not human subjects research.

Improvement Activities

Key drivers were identified, and interventions were executed using Plan-Do Study-Act cycles.²² The key drivers thought to be critical for the success of the QI efforts were family engagement; standardization of discharge instructions; medical staff engagement; and audit and feedback of data. The corresponding interventions were as follows:

Family Engagement

Understanding the discharge information families desired. Prior to testing, 10 families admitted to the HM service were asked about the discharge experience. We asked families about information they wanted in written discharge instructions: 1) reasons to call your primary doctor or return to the hospital; 2) when to see your primary doctor for a follow-up visit; 3) the phone number to reach your child’s doctor; 4) more information about why your child was admitted; 5) information about new medications; and 6) what to do to help your child continue to recover at home.

Development of templates. We engaged families throughout the process of creating general and disease-specific discharge templates. After a specific template was created and reviewed by the parents on our team, it was sent to members of the institutional Patient Education Committee, which includes parents and local health literacy experts, to review and critique. Feedback from the reviewers was incorporated into the templates prior to use in the EHR.

Postdischarge phone calls.A convenience sample of families discharged from the satellite campus was called 24 to 48 hours after discharge over a 2-week period in January, 2016. A member of our improvement team solicited feedback from families about the quality of the discharge instructions. Families were asked if discharge instructions were reviewed with them prior to going home, if they were given a copy of the instructions, how they would rate the ability to read and use the information, and if there were additional pieces of information that would have improved the instructions.

Standardization of Instructions

Education. A presentation was created and shared with medical providers; it was re-disseminated monthly to new residents rotating onto the service and to the attendings, fellows, and NPs scheduled for shifts during the month. This education continued for the duration of the study. The presentation included the definition of health literacy, scope of the problem, examples of poorly written discharge instructions, and tips on how to write readable and understandable instructions. Laminated cards that included tips on how to write instructions were also placed on work stations.

While the general template was an important first step, the content relied heavily on free text by providers, which could still lead to instructions written at a high reading level. Thus, disease-specific discharge instruction templates were created with prepopulated information that was written at a reading level at or below 7^th grade level (Figure 2). The diseases were prioritized based on the most common diagnoses on our HM service. Each template included information under each of the subheadings noted in the general template. Twelve disease-specific templates were tested and ultimately embedded in the EHR; the general template remained for use when the discharge diagnosis was not covered by a disease-specific template.

Medical Staff Engagement

Previously described tests of change also aimed to enhance staff engagement. These included frequent e-mails, discussion of the QI efforts at specific team meetings, and the creation of visual cues posted at computer work stations, which prompted staff to begin to work on discharge instructions soon after admission.

Audit and Feedback of Data

Weekly phone calls. One team updated clinicians through a regularly scheduled bi-weekly phone conference. The phone conference was established prior to our work and was designed to relay pertinent information to attendings and NPs who work at the satellite hospital. During the phone conferences, clinicians were notified of current performance on discharge instruction readability and specific tests of change for the week. Additionally, providers gave feedback about the improvement efforts. These updates continued for the first 6 months of the project until sustained improvements were observed.

E-mails. Weekly e-mails were sent to all providers scheduled for clinical time at the satellite campus. The e-mail contained information on current tests of change, a list of discharge instruction templates that were available in the EHR, and the annotated run chart illustrating readability levels over time.

Additionally, individual e-mails were sent to each provider after review of the written discharge instructions for the week. Providers were given information on the number of discharge instructions they personally composed, the percentage of those instructions that were written at or below 7^th grade level, and specific feedback on how their written instructions could be improved. We also encouraged feedback from each provider to better identify barriers to achieving our goal.

Study of the Interventions

Baseline data included a review of all instructions for patients discharged from the satellite campus from the end of April 2015 through mid-September 2015. The time period for testing of interventions during the fall and winter months allowed for rapid cycle learning due to higher patient census and predictability of admissions for specific diagnosis (ie, asthma and bronchiolitis). An automated report was generated from the EHR weekly with specific demographics and identifiers for patient discharged over the past 7 days, including patient age, gender, length of stay, discharge diagnosis, and insurance classification. Data was collected during the intervention period via structured review of the discharge instructions in the EHR by the principal investigator or a trained research coordinator. Discharge instructions for medically cleared mental health patients admitted to hospital medicine while awaiting psychiatric bed availability and patients and parents who were non-English speaking were excluded from review. All other instructions for patients discharged from the HM service at our Liberty Campus were included for review.

Measures

Readability, our primary measure of interest, was calculated using the mean score from the following formulas: Flesch Kincaid Grade Level,²³ Simple Measure of Gobbledygook Index,²⁴ Coleman-Liau Index,²⁵ Gunning-Fog Index,²⁶ and Automated Readability Index²⁷ by means of an online platform (https://readability-score.com).²⁸ This platform was chosen because it incorporated a variety of formulas, was user-friendly, and required minimal data cleaning. Each of the readability formulas have been used to assesses readability of health information given to patients and families.^29,30 The threshold of 7th grade is in alignment with our institutional policy for educational materials and with recommendations from several government agencies.^5,12

Analysis

A statistical process control p-chart was used to analyze our primary measure of readability, dichotomized as percent discharge instructions written at or below 7th grade level. Run charts were used to follow mean reading level of discharge instructions and our process measure of percent of discharge instruction written with a general or disease-specific standardized template. Run chart and control chart rules for identifying special cause were used for midline shifts.³¹

The Table includes the demographic and clinical information of patients included in our analyses. Through sequential interventions, the percentage of discharge instructions written at or below 7th grade readability level increased from a mean of 13% to more than 80% in 3 months (Figure 3). Furthermore, the mean was sustained above 90% for 10 months and at 98% for the last 4 months. The use of 1 of the 13 EHR templates increased from 0% to 96% and was associated with the largest impact on the overall improvements (Supplemental Figure 1). Additionally, the average reading level of the discharge instructions decreased from 10th grade to 6th grade level (Supplemental Figure 2).

Qualitative comments from providers about the discharge instructions included:

“Are these [discharge instructions] available at base??  Great resource for interns.”
“These [discharge] instructions make the [discharge] process so easy!!! Love these...”
“Also feel like they have helped my discharge teaching in the room!”

Qualitative comments from families postdischarge included:
“I thought the instructions were very clear and easy to read. I especially thought that highlighting the important areas really helped.”
“I think this form looks great, and I really like the idea of having your child’s name on it.”

Through sequential Plan-Do Study-Act cycles, we increased the percentage of discharge instructions written at or below 7^th grade reading level from 13% to 98%. Our most impactful intervention was the creation and dissemination of standardized disease-specific discharge instruction templates. Our findings complement evidence in the adult and pediatric literature that the use of standardized, disease-specific discharge instruction templates may improve readability of instructions.^32,33 And, while quality improvement efforts have been employed to improve the discharge process for patients,^34-36 this is the first study in the inpatient setting that, to our knowledge, specifically addresses discharge instructions using quality improvement methods.

Our work targeted the critical intersection between individual health literacy, an individual’s capacity to acquire, interpret, and use health information, and the necessary changes needed within our healthcare system to ensure that appropriately written instructions are given to patients and families.^17,37 Our efforts focused on improving discharge instructions answer the call to consider health literacy a modifiable clinical risk factor.³⁷ Furthermore, we address the 6 aims for quality healthcare delivery: 1) safe, timely, efficient and equitable delivery of care through the creation and dissemination of standardized instructions that are written at the appropriate reading level for families to ease hospital-to-home transitions and streamline the workflow of medical providers; 2) effective education of medical providers on health literacy concepts; and 3) family-centeredness through the involvement of families in our QI efforts. While previous QI efforts to improve hospital-to-home transitions have focused on medication reconciliation, communication with primary care physicians, follow-up appointments, and timely discharges of patients, none have specifically focused on the quality of discharge instructions.^34-36

Most physicians do not receive education about how to write information that is readable and understandable; more than half of providers desired more education in this area.³⁸ Furthermore, pediatric providers may overestimate parental health literacy levels,³⁹ which may contribute to variability in the readability of written health materials. While education alone can contribute to a provider’s ability to create readable instructions, we note the improvement after the introduction of disease templates to demonstrate the importance of workflow-integrated higher reliability interventions to sustain improvements.

Our baseline poor readability rates were due to limited knowledge by frontline providers composing the instructions and a system in which an important element for successful hospital-to-home transitions was not tackled until patients were ready for discharge. Streamlining of the discharge process, including the creation of discharge instructions, may lead to improved efficiency, fewer discrepancies, more effective communication, and an enhanced family experience. Moreover, the success of our improvement work was due to key stakeholders, including parents, being a part of the team and the notable buy-in from providers.

Our work was not without limitations. We excluded non-English speaking families from the study. We were unable to measure reading level of our population directly and instead based our goals on national estimates. Our primary measure was readability, which is only 1 piece contributing to quality discharge instructions. Understandability and actionability are also important considerations; ^17,20,29,40 however, improvements in these areas were limited by our design options within the EHR. Our efforts focused on children with common general pediatric diagnoses, and it is unclear how our interventions would generalize to medically complex patients with more volume of information to communicate at discharge and with uncommon diagnoses that are less readily incorporated into standardized templates. Relatedly, our work occurred at the satellite campus of our tertiary care center and may not represent generalizable material or methods to implement templates at our main campus location or at other hospitals. To begin to better understand this, we have spread to HM patients at our main campus, including medically complex patients with technology dependence and/or neurological impairments. Standardized, disease-specific templates most relevant to this population as well as several patient specific templates, for those with frequent readmissions due to medical complexity, have been created and are actively being tested.

In conclusion, in using interventions targeted at standardization of discharge instructions and timely feedback to staff, we saw rapid, dramatic, and sustained improvement in the readability of discharge instructions. Next steps include adaptation and spread to other patient populations and care teams, collaborations with other centers, and assessing the impact of effectively written discharge instructions on patient outcomes, such as adverse drug events, readmission rates, and family experience.

Disclosure

No external funding was secured for this study. Dr. Brady is supported by a Patient-Centered Outcomes Research Mentored Clinical Investigator Award from the Agency for Healthcare Research and Quality, Award Number K08HS023827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. The funding organization had no role in the design, preparation, review, or approval of this paper; nor the decision to submit the manuscript for publication. The authors have no financial relationships relevant to this article to disclose.

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes and obesity: Managing dual epidemics
M. Cecilia Lansang, MD, MPH

Diabetes with obesity—Is there an ideal diet?
Zahrae Sandouk and M. Cecilia Lansang

The essential role of exercise in the management of type 2 diabetes
John P. Kirwan, Jessica Sacks, and Stephan Nieuwoudt

Optimizing diabetes treatment in the presence of obesity
Mary Angelynne Esquivel and M. Cecilia Lansang

Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?
Bartolome Burguera, Khawla F. Ali, and Juan P. Brito

Metabolic surgery for treating type 2 diabetes mellitus: Now supported by the world's leading diabetes organizations
Philip R. Schauer, Zubaidah Nor Hanipah, and Francesco Rubino

— Bonus Article —Medical Treatment of Diabetes Mellitus
Mario Skugor

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes and obesity: Managing dual epidemics
M. Cecilia Lansang, MD, MPH

Diabetes with obesity—Is there an ideal diet?
Zahrae Sandouk and M. Cecilia Lansang

The essential role of exercise in the management of type 2 diabetes
John P. Kirwan, Jessica Sacks, and Stephan Nieuwoudt

Optimizing diabetes treatment in the presence of obesity
Mary Angelynne Esquivel and M. Cecilia Lansang

Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?
Bartolome Burguera, Khawla F. Ali, and Juan P. Brito

Metabolic surgery for treating type 2 diabetes mellitus: Now supported by the world's leading diabetes organizations
Philip R. Schauer, Zubaidah Nor Hanipah, and Francesco Rubino

— Bonus Article —Medical Treatment of Diabetes Mellitus
Mario Skugor

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes and obesity: Managing dual epidemics
M. Cecilia Lansang, MD, MPH

Diabetes with obesity—Is there an ideal diet?
Zahrae Sandouk and M. Cecilia Lansang

The essential role of exercise in the management of type 2 diabetes
John P. Kirwan, Jessica Sacks, and Stephan Nieuwoudt

Optimizing diabetes treatment in the presence of obesity
Mary Angelynne Esquivel and M. Cecilia Lansang

Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?
Bartolome Burguera, Khawla F. Ali, and Juan P. Brito

Metabolic surgery for treating type 2 diabetes mellitus: Now supported by the world's leading diabetes organizations
Philip R. Schauer, Zubaidah Nor Hanipah, and Francesco Rubino

— Bonus Article —Medical Treatment of Diabetes Mellitus
Mario Skugor

The odds are high that practitioners who manage patients with diabetes are also managing patients who are overweight or obese. The numbers are staggering: more than two-thirds of American adults with type 2 diabetes are obese, and the need to address these dual epidemics is clear. Many strategies exist, but how does a practitioner select the best option for an individual patient? This Cleveland Clinic Journal of Medicine supplement on diabetes and obesity includes articles by experts who review the evidence on the impact of different diets and exercise and the use of “weight-friendly” diabetes medications, drug therapy, and metabolic surgery in managing obesity in patients with diabetes.

For some patients with type 2 diabetes, changes in diet and exercise are beneficial in managing the disease and can lead to weight loss. Diets abound, but what diets are best, particularly for patients with obesity? Zahrae Sandouk, MD, and I review several popular diets and what is known about their effects on weight loss, glycemic control, and cardiovascular risk.

As for exercise, both aerobic and resistance training are essential to improve glucose regulation and cardiovascular health. John P. Kirwan, PhD, Jessica Sacks, and Stephan Nieuwoudt review exercise recommendations, modalities, and the metabolic benefits of exercise for this patient population.

Drug therapy typically focuses on the diabetes side of the coin and not necessarily the obesity side; however, practitioners are increasingly helping patients establish goals on both fronts. To that end, Mary Angelynne Esquivel, MD, and I discuss medications for treatment of type 2 diabetes that also have weight loss as a side effect, including glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin.

The heightened focus on addressing obesity warrants consideration of medications for weight loss. Bartolome Burguera, MD, PhD, Khawla F. Ali, MD, and Juan P. Brito, MD, discuss a potential shift in thinking: using antiobesity drugs to manage type 2 diabetes. The authors review pharmacologic therapies approved for managing obesity in the context of diabetes.

While initially used for patients with severe obesity, bariatric surgery is now called metabolic surgery when used for type 2 diabetes because of its dramatic impact in reversing type 2 diabetes. Philip R. Schauer, MD, Zubaidah Nor Hanipah, MD, and Francesco Rubino, MD, describe the benefits of metabolic surgery and review the evidence that led diabetes organizations to set new guidelines with a lower body mass index threshold than previously recommended.

The dual epidemics of diabetes and obesity present physicians with a complex set of considerations to help patients achieve their treatment goals on both fronts in the battle. I hope you find this supplement on diabetes and obesity informative and useful to you to enhance patient care.

The odds are high that practitioners who manage patients with diabetes are also managing patients who are overweight or obese. The numbers are staggering: more than two-thirds of American adults with type 2 diabetes are obese, and the need to address these dual epidemics is clear. Many strategies exist, but how does a practitioner select the best option for an individual patient? This Cleveland Clinic Journal of Medicine supplement on diabetes and obesity includes articles by experts who review the evidence on the impact of different diets and exercise and the use of “weight-friendly” diabetes medications, drug therapy, and metabolic surgery in managing obesity in patients with diabetes.

For some patients with type 2 diabetes, changes in diet and exercise are beneficial in managing the disease and can lead to weight loss. Diets abound, but what diets are best, particularly for patients with obesity? Zahrae Sandouk, MD, and I review several popular diets and what is known about their effects on weight loss, glycemic control, and cardiovascular risk.

As for exercise, both aerobic and resistance training are essential to improve glucose regulation and cardiovascular health. John P. Kirwan, PhD, Jessica Sacks, and Stephan Nieuwoudt review exercise recommendations, modalities, and the metabolic benefits of exercise for this patient population.

Drug therapy typically focuses on the diabetes side of the coin and not necessarily the obesity side; however, practitioners are increasingly helping patients establish goals on both fronts. To that end, Mary Angelynne Esquivel, MD, and I discuss medications for treatment of type 2 diabetes that also have weight loss as a side effect, including glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin.

The heightened focus on addressing obesity warrants consideration of medications for weight loss. Bartolome Burguera, MD, PhD, Khawla F. Ali, MD, and Juan P. Brito, MD, discuss a potential shift in thinking: using antiobesity drugs to manage type 2 diabetes. The authors review pharmacologic therapies approved for managing obesity in the context of diabetes.

While initially used for patients with severe obesity, bariatric surgery is now called metabolic surgery when used for type 2 diabetes because of its dramatic impact in reversing type 2 diabetes. Philip R. Schauer, MD, Zubaidah Nor Hanipah, MD, and Francesco Rubino, MD, describe the benefits of metabolic surgery and review the evidence that led diabetes organizations to set new guidelines with a lower body mass index threshold than previously recommended.

The dual epidemics of diabetes and obesity present physicians with a complex set of considerations to help patients achieve their treatment goals on both fronts in the battle. I hope you find this supplement on diabetes and obesity informative and useful to you to enhance patient care.

The odds are high that practitioners who manage patients with diabetes are also managing patients who are overweight or obese. The numbers are staggering: more than two-thirds of American adults with type 2 diabetes are obese, and the need to address these dual epidemics is clear. Many strategies exist, but how does a practitioner select the best option for an individual patient? This Cleveland Clinic Journal of Medicine supplement on diabetes and obesity includes articles by experts who review the evidence on the impact of different diets and exercise and the use of “weight-friendly” diabetes medications, drug therapy, and metabolic surgery in managing obesity in patients with diabetes.

For some patients with type 2 diabetes, changes in diet and exercise are beneficial in managing the disease and can lead to weight loss. Diets abound, but what diets are best, particularly for patients with obesity? Zahrae Sandouk, MD, and I review several popular diets and what is known about their effects on weight loss, glycemic control, and cardiovascular risk.

As for exercise, both aerobic and resistance training are essential to improve glucose regulation and cardiovascular health. John P. Kirwan, PhD, Jessica Sacks, and Stephan Nieuwoudt review exercise recommendations, modalities, and the metabolic benefits of exercise for this patient population.

Drug therapy typically focuses on the diabetes side of the coin and not necessarily the obesity side; however, practitioners are increasingly helping patients establish goals on both fronts. To that end, Mary Angelynne Esquivel, MD, and I discuss medications for treatment of type 2 diabetes that also have weight loss as a side effect, including glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin.

The heightened focus on addressing obesity warrants consideration of medications for weight loss. Bartolome Burguera, MD, PhD, Khawla F. Ali, MD, and Juan P. Brito, MD, discuss a potential shift in thinking: using antiobesity drugs to manage type 2 diabetes. The authors review pharmacologic therapies approved for managing obesity in the context of diabetes.

While initially used for patients with severe obesity, bariatric surgery is now called metabolic surgery when used for type 2 diabetes because of its dramatic impact in reversing type 2 diabetes. Philip R. Schauer, MD, Zubaidah Nor Hanipah, MD, and Francesco Rubino, MD, describe the benefits of metabolic surgery and review the evidence that led diabetes organizations to set new guidelines with a lower body mass index threshold than previously recommended.

The dual epidemics of diabetes and obesity present physicians with a complex set of considerations to help patients achieve their treatment goals on both fronts in the battle. I hope you find this supplement on diabetes and obesity informative and useful to you to enhance patient care.

According to National Health and Nutrition Examination Survey data, more than one-third of adults in the United States are obese and more than two-thirds of adults with type 2 diabetes mellitus (DM) are obese.¹ In light of overall increased life expectancy, the Centers for Disease Control and Prevention estimates that adults in the United States have a 40% lifetime risk of developing diabetes, as diabetes and obesity remain at epidemic levels.²

Weight loss in individuals who are overweight or obese is effective in preventing type 2 DM and improving management of the disease.^3,4 Dietary changes play a central role in achieving weight loss, as do other important lifestyle interventions such as exercise, behavior modification, and pharmacotherapy. Achieving glycemic goals with diet alone is difficult, and for patients with DM who are also obese, it may be even more challenging.

Medical nutrition therapy, a term coined by the American Dietetic Association, describes an approach to treating medical conditions using specific diets. As developed and monitored by a physician and registered dietitian, diet can result in beneficial outcomes and is a front-line approach for patients with noninsulin-dependent diabetes.⁵ Medical nutrition therapy for patients with type 2 DM is most effective when used within 1 year of diagnosis and is associated with a 0.5% to 2% decrease in hemoglobin A1c (HbA1c) levels.⁶ This article reviews the role of diet in managing patients with both type 2 DM and obesity. Several diets are presented including what is known about their effect on weight loss, glycemic control, and cardiovascular risk prevention in patients with diabetes and obesity.

WEIGHT LOSS AND DIET FOR PATIENTS WITH OBESITY AND DIABETES

A person is overweight or obese if he or she weighs more than the ideal weight for their height as calculated by the body mass index (BMI; weight in kg/height in meters squared). A BMI of 25 to 30 is overweight and a BMI of 30 or greater is obese.⁷ The recommended daily caloric intake for adults is based on sex, age, and daily activity level and ranges from 1,600 to 2,000 calories per day for women and 2,000 to 2,600 calories per day for men. The lower end of the range is for sedentary adults, and the higher end is for active adults (walking 1.5 to 3 miles per day at 3 to 4 miles per hour, in addition to independent living).⁸

According to the American Diabetes Association (ADA), weight loss requires reducing dietary intake by 500 to 750 calories per day, or roughly 1,200 to 1,500 kcal/day for women and 1,500 to 1,800 kcal/day for men.³ For patients with obesity and type 2 DM, sustained, modest weight loss of 5% of initial body weight improves glycemic control and reduces the need for diabetes medications.⁹ Weight loss of greater than 5% body weight also improves lipid and blood pressure status in patients with obesity and diabetes, though ideally, patients are encouraged to achieve weight reduction of 7% or greater.¹⁰

Evidence of benefits from lifestyle and dietary modifications

The fact that patients with obesity and type 2 DM have increased risk of cardiovascular morbidity and mortality is well established.¹¹ Multiple studies considered the effects of weight loss on cardiovascular morbidity and mortality. Our article focuses on dietary modifications, though most large, multicenter trials used both diet and increased physical activity to achieve weight loss. It is difficult to determine if diet or physical activity had the most effect on outcomes; however, results show that weight loss from dietary and other lifestyle interventions leads to change in outcomes.

Look AHEAD (Action for Health in Diabetes) trial. This large, multicenter, randomized controlled trial evaluated the effect of weight loss on cardiovascular morbidity and mortality in overweight or obese adults with type 2 DM. The 5,145 participants were assigned either to a long-term weight reduction intensive lifestyle intervention of diet, physical activity, and behavior modification or to usual care of support and education. At 1 year, the lifestyle intervention group had greater weight loss, improved fitness, decreased number of diabetes medications, decreased blood pressure, and improved biomarkers of glucose and lipid control compared with the usual care group.¹² No significant reductions in cardiovascular morbidity and mortality were found, though an observational post hoc analysis of the Look AHEAD data suggested an association between the magnitude of weight loss and the incidence of cardiovascular disease.¹³

The diet portion of the intensive lifestyle intervention consisted of self-selected, conventional foods while recording dietary intake during week 1. In week 2, patients weighing less than 114 kg (250 lbs) restricted their intake to 1,200 to 1,500 kcal/day, and patients weighing 114 kg or more restricted their intake to 1,500 to 1,800 kcal/day. Fewer than 30% of calories were from fat, with less than 10% from saturated fat. During week 3 through week 9, meal replacement options and conventional foods were used to reach caloric goals. Participants then decreased the use of meal replacement and increased the use of conventional foods during week 20 through week 22.¹⁴

The mean weight loss for participants in the intensive lifestyle intervention group was 8.6% compared with 0.7% in the support and education group (P < .001). HbA1c decreased by 0.7% in the intervention group compared with 0.1% the support and education group (P < .001).¹²

Finnish Diabetes Prevention Study. This study evaluated lifestyle changes in diet and physical activity in the prevention of type 2 DM in participants with impaired glucose intolerance. Participants (N = 552) were randomly assigned to the control group or the intervention group where detailed instruction was provided to achieve weight loss of greater than 5%.¹⁵ The dietary goals included fewer than 30% of total calories from fat, with fewer than 10% from saturated fat, increased fiber consumption (15 g per 1,000 kcal), and physical activity of 30 minutes daily.¹⁵ During the trial (mean duration of follow-up 3.2 years), the risk of type 2 DM was reduced by 58% in the intervention group compared with the control group.¹⁵

Diabetes Prevention Program Research Group. A landmark study by the Diabetes Prevention Program Research Group randomized 3,234 participates with elevated plasma glucose levels to placebo, metformin, and lifestyle intervention arms.⁴ Those in the lifestyle intervention arm were educated about ways to achieve and maintain a 7% or greater reduction in body weight using a low-calorie, low-fat diet and moderate physical activity. Results based on a mean follow-up of 2.8 years found a 58% reduction in the incidence of diabetes for those in the lifestyle intervention arm.⁴

 

 

DIETS AND THEIR EFFECTS ON OBESITY, DIABETES, AND CARDIOVASCULAR RISK

When patients seek consultation about diet, they frequently ask about specific types of popular diets, not the very controlled diets employed in research studies. Dietary preferences are personal, so patients may have researched a particular diet or feel that they will be more adherent if only 1 or 2 components of their meals are changed. There is no single optimal dietary strategy for patients with both obesity and type 2 DM. In general, diets are categorized based on the 3 basic macronutrients: carbohydrate, fat, and protein. We will review several popular diets, delineating content, effects on weight loss, glycemic control, and cardiovascular factors.

LOW-CARBOHYDRATE DIET

In practice, the median intake of carbohydrates for US adults is much higher, at 220 to 330 g per day for men and 180 to 230 g per day for women.¹⁶ The ADA recommends that all Americans consume fewer refined carbohydrates and added sugars in favor of whole grains, legumes, vegetables, and fruit.¹⁸

Low-carbohydrate diets focus on reducing carbo­hydrate intake with the thought that fewer carbohydrates are better. However, the definition of a low-carbohydrate diet varies. In most studies, carbohydrate intake was limited to less than 20 g to 120 g daily or fewer than 4% to 45% of the total calories consumed.^17,19 Intake of fat and total calories is unlimited, though unsaturated fats are preferred over saturated or trans fats.

Limiting the intake of disaccharide sugar in the form of sucrose and high-fructose corn syrup is endorsed because of concerns that these sugars are rapidly digested, absorbed, and fully metabolized. However, several randomized trials showed that substituting sucrose for equal amounts of other types of carbohydrates in individuals with type 2 DM showed no difference in glycemic response.²⁰ The resulting conclusion is that the postprandial glycemic response is mainly driven by the amount rather than the type of carbohydrates. The consumption of sugar-sweetened beverages is associated with obesity and an increased risk of diabetes, attributed to the high caloric intake and decreased insulin sensitivity associated with these beverages.²¹

Of the 2 monosaccharides, glucose and fructose, that make up sucrose, fructose is metabolized in the liver. The rapid metabolism of fructose may lead to alterations in lipid metabolism and affect insulin sensitivity.²² While the ADA does not advise against consuming fructose, it does advise limiting its use due to the caloric density of many foods containing fructose.

Multiple studies have investigated the effect of a low-carbohydrate diet on weight loss, glucose control, and cardiovascular risk, but comparing the results is difficult due to the varying definitions of a low-carbohydrate diet.

Low-carbohydrate diets are associated with rapid weight loss. A 6-month study of 31 patients with obesity and type 2 DM found a mean weight change of −11.4 kg (± 4 kg) in the low-carbohydrate group compared with −1.8 kg (± 3.8 kg) in the high-carbo­hydrate control group, a loss maintained up to 1 year.²³ Another study of 88 patients with type 2 DM who consumed less than 40 g/day of carbohydrate had a weight loss of 7.2 kg over 12 months.²⁴ Samaha et al²⁵ compared a low-carbohydrate diet with a low-fat diet in 132 participants with obesity (mean BMI 43), of which 39% had diabetes and 43% had metabolic syndrome. Those in the low-carbohydrate diet group had significantly more weight loss over a period of 6 months (−5.8 kg mean, ± 8.6 kg standard deviation [SD] vs −1.9 kg mean ± 4.2 kg SD, P = .002). However, at 1 year, there was no significant difference in weight loss between groups. At 36 months, weight regain was 2.2 kg (SD 12.3 kg) less than baseline in the low-carbohydrate group compared with 4.3 kg (SD 12.2 kg) less than baseline in the low-fat group
(P = .071).^25,26  On the other hand, a meta-analysis of 23 randomized trials involving 2,788 participants found no difference in weight loss at 6 months between those on a low-carbohydrate diet and those on a low-fat diet.¹⁹

With respect to glucose control, low-carbohydrate diets have been associated with a 1.4% (SD ± 1.1%)decrease in HbA1c during a 6-month period in 31 patients with obesity and type 2 DM.²³ Another 6-month study of 206 patients with obesity and diabetes comparing a low-carbohydrate diet with a low-calorie diet found no significant difference in HbA1c (−0.48% vs −0.24%, respectively) and a weight loss of 1.34 kg vs 3.77 kg, respectively (P < .001).²⁷ The change in glycemic control did not persist over time, perhaps due to the weight regain associated with this diet. A meta-analysis concluded that HbA1c was reduced more in patients with type 2 DM randomized to a lower-carbohydrate diet compared with a higher-carbohydrate diet (mean change from baseline 0% to −2.2%).¹⁷

No studies of the effects of a low-carbohydrate diet on overall cardiovascular morbidity or mortality exist. However, Kirk et al¹⁷ reported results of a low-carbohydrate diet on cardiovascular risk factors such as lipid profiles and showed a significant reduction in triglyceride levels but no effect on total cholesterol, high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol (LDL-C) levels.

The ADA has reported that low-carbohydrate diets may be effective in the management of type 2 DM in the short term. Caution is warranted because they could eliminate important sources of energy, fiber, vitamins, and minerals. It is also important to monitor lipid profile, renal function, and protein intake in certain patients, especially those with renal dysfunction.⁶

 

 

LOW-GLYCEMIC DIET

Various factors affect the GI including the type of carbohydrate, fat content, protein content, and acidity of the food consumed, as well as the rate of intestinal reaction to the food. The faster the digestion of a food, the higher the GI. High-GI foods (> 70), such as those highly processed and with high starch content, produce higher peak glucose levels when compared with low-GI foods (< 55). Low-GI foods include lentils, beans, oats, and nonstarchy vegetables.

Low-GI foods curb the large and rapid rise of blood glucose, insulin response, and glucagon inhibition that occur with high-GI foods. Many low-GI foods have high amounts of fiber, which prolongs distention of the gastrointestinal tract, increases secretion of cholecystokinin and incretins, and extends statiety.²⁸

In a meta-analysis of 19 randomized trials of overweight or obese patients (BMI > 25), a low-glycemic diet did not show weight loss when compared with an isocaloric control diet (mean difference −0.32 kg; 95% confidence interval [CI] −0.86 kg, 0.23 kg).²⁹ On the other hand, the effect on glycemic control is more pronounced. Another meta-analysis that included 11 studies of patients with DM who followed a low-glycemic diet for less than 3 months to over 6 months showed that those who followed a low-glycemic diet had a significant reduction of HbA1c (6 studies had HbA1c as the primary outcome, HbA1c weighted mean difference  −0.5%; 95% CI, −0.8 to −0.2; P = .001). Five studies reported on parameters related to insulin action, and 1 showed increased sensitivity measured by euglycemic-hyperinsulinemic clamp in a low-glycemic diet (glucose disposal 7.0 ± 1.3 mg glucose/kg/min) vs a high-glycemic diet (4.8 mg glucose/kg/min ± 0.9, P < .001).²⁸

There are no large trials of cardiovascular mortality or morbidity of low-glycemic diets, but some studies have included cardiovascular parameters. A randomized study of 210 patients with type 2 DM evaluated cardiovascular risk factors after 6 months of a low-glycemic diet and high-glycemic diet. The low-glycemic diet group had an increase in HDL-C compared with the high-glycemic diet group (1.7 mg/dL; 95% CI, 0.8 to 2.6 mg/dL vs −0.2 mg/dL; 95% CI, −0.9 to –0.5 mg/dL, P = .005).³⁰ Another crossover study of 20 patients with type 2 DM on a low-glycemic diet over 2 consecutive 24-day periods revealed a 53% reduction of the activity of plasminogen activator inhibitor-1, a thrombolytic factor that increases plaque formation.³¹ Most studies were of short duration; thus, weight regain was not clearly established.

The GI of low-GI foods differs based on the cooking method, presence of other macronutrients, and metabolic variations among individuals. Low-glycemic diets can reduce the intake of important dietary nutrients. The ADA notes that low-glycemic diets may provide only modest benefit in controlling postprandial hyperglycemia.³²

LOW-FAT DIET

Different types of fats have different effects on metabolism. LDL-C is mostly derived from saturated fats.³⁴ Consuming 2% of energy intake from trans fat substantially increases the risk of coronary heart disease.³⁵ Though the ideal total amount of fat for people with diabetes is unknown, the amount consumed still has important consequences, especially since patients with type 2 DM are at risk for coronary artery disease. The Institute of Medicine states that fat intake of 20% to 35% of energy is acceptable for all adults.¹⁶

Low-fat diets along with reduced caloric intake induce weight loss, but this cannot compete with the rapid weight loss that patients experience with the low-carbohydrate diet. This was shown in multiple studies including a meta-analysis of 5 randomized clinical trials of 447 patients with obesity who lost less weight in the low-fat diet group compared with low-carbohydrate diet group (weighted mean difference −3.3 kg; 95% CI, −5.3 to −1.4 kg) at 6 months.³⁶ Interestingly, the difference between diets was nonexistent after 12 months (weighted mean difference −1.0 kg; 95% CI, −3.5 to 1.5 kg), which may be due to weight regain in the low-carbohydrate diet group.³⁶

Foster et al³⁷ studied 307 participants with obesity assigned to a low-fat or low-carbohydrate diet. Both groups lost 11% in 1 year, and with regain, lost 7% from baseline at 2 years. There was no statistically significant difference between groups during the 2 years, but there was a trend for more weight loss in the low-carbohydrate group in the first 3 months (P = .019).³⁷

The low-fat diet has no to minimal improvement in glycemic control in patients with diabetes and obesity, regardless of the weight loss achieved. However, a low-fat diet is associated with some beneficial effects on cardiovascular risks. Nordmann et al³⁶ found no difference in blood pressure between low-carbohydrate and low-fat diets. The low-fat diet was associated with lower total cholesterol and LDL-C levels (weighted mean difference 5.4 mg/dL [0.14 mmol/L]; 95% CI, 1.2 mg/dL to 10.1 mg/dL [0.03–0.26 mmol/L]).³⁶  Triglyceride and HDL-C levels were more favorably changed in the low-carbohydrate diet (for triglycerides, weighted mean difference −22.1 mg/dL [−0.25 mmol/L]; 95% CI, −38.1 to −5.3 mg/dL [−0.43 to −0.06 mmol/L]; and for HDL-C, weighted mean difference 4.6 mg/dL [0.12 mmol/L]; 95% CI, 1.5 mg/dL to 8.1 mg/dL [0.04–0.21 mmol/L]).³⁶

 

 

VERY-LOW-CALORIE DIET

Saris et al³⁸ reported results from 8 randomized clinical trials ranging from 10 to 32 patients with obesity comparing very-low-calorie diets with a low-calorie diet of 800 to 1,200 calories a day. Over the first 4 to 6 weeks, weight loss was between 1.4 kg and 2.5 kg per week and was higher with the very-low-calorie diet when compared with the low-calorie diet though not statistically significant. Interestingly, when followed for 16 to 26 weeks, the difference in weight loss was again not statistically significant with no trend for more weight loss in the very-low-calorie diet group. Another meta-analysis looking at 6 randomized clinical trials in patients with obesity showed that weight loss with very-low-calorie diets was statistically significant when compared with low-calorie diets (16.1% ± 1.6% vs 9.7% ± 2.4% weight loss over a period of 12.7 ± 6.4 weeks).³⁹

In general, it is believed that when individuals lose a large amount of weight in a short period, a larger weight regain will occur, resulting in a higher weight than before the initial loss. This was refuted by Tsai et al,³⁹ who found that long-term data (1 to 5 years) showed the percentage of weight regained is higher with a very-low-calorie diet (62%) vs a low-calorie diet (41%) but the overall weight lost remains superior with the very-low-calorie diet, though not statistically significant (6.3% ± 3.2% and 5.0% ± 4.0% loss of initial weight, respectively).

Toubro et al⁴⁰ looked at 43 obese individuals who followed the very-low-calorie diet for 8 weeks compared with 17 weeks of a conventional diet (1,200 kcal/day) followed by a year of unrestricted calories, low-fat, high-carbohydrate diet or fixed calorie group (1,800 kcal/day). The very-low-calorie diet group lost weight at a more rapid rate, but the rate had no effect on weight maintenance after 6 or 12 months. Interestingly, the group that followed the “unrestricted calories, low-fat, high-carbohydrate diet” for a year maintained 13.2 kg (8.1 kg to 18.3 kg) of the initial 13.8 kg (11.8 kg to 15.7 kg) weight loss, while the fixed-calorie group maintained less weight loss (9.7 kg [6.1 kg to 13.3 kg]). Saris³⁸ concluded that the rapid weight loss by very-low-calorie diet has better long-term results when followed up with a program that includes nutritional education, behavioral therapy, and increased physical activity.

Very-low-calorie diets achieve glycemic control by reducing hepatic glucose output, increasing insulin action in the liver and peripheral tissues, and enhancing insulin secretion. These benefits occur soon after starting the diet, which suggests that caloric restriction plays a critical role. A study at the University of Michigan showed that the use of very-low-calorie diets in addition to moderate-intensity exercise resulted in a reduction of HbA1c from 7.4% (± 1.3%) to 6.5% (± 1.2%) in 66 patients with established type 2 DM.⁴¹ HbA1c of less than 7% occurred in 76% of patients with established diabetes and 100% of patients with newly diagnosed diabetes.⁴¹ Improvement in HbA1c over 12 weeks was associated with higher baseline HbA1c and greater reduction in BMI.⁴¹

Long-term cardiovascular risk reduction of very-low-calorie diets is small. One study showed that serum total cholesterol decreased at 2 weeks but did not differ at 3 months from baseline.⁴² A large reduction was observed in serum triglycerides at 3 months (4.57 mmol/L ± 1.0 mmol/L vs 2.18 mmol/L ± .26 mmol/L, P = .012) while HDL-C increased (0.96 mmol/L ± .06 mmol/L vs 1.11 mmol/L ± .05 mmol/L, P = .009).⁴² Blood pressure was also reduced in both systolic pressure (152 mm Hg ± 6 mm Hg vs 133 mm Hg ± 3 mm Hg, P = .004) and diastolic pressure (92 mm Hg ± 3 mm Hg vs 81 mm Hg ± 3 mm Hg, P = .007).⁴²

Challenges with this diet include significant weight regain and safety concerns for patients with obesity and type 2 DM, especially those who are taking insulin, since this diet will lead to significant rapid lowering of insulin levels.³⁸ Finally, very-low-calorie diets require a multidisciplinary approach with frequent health professional visits.

MEDITERRANEAN DIET

This diet also has a positive impact on glycemic control and has been shown to reduce the incidence of diabetes. Estruch et al⁴⁵ conducted a randomized controlled trial on 772 adults at high risk for cardiovascular disease, of which 421 had type 2 DM, assigned to Mediterranean diet supplemented either with extra-virgin olive oil or mixed nuts compared with a control group receiving advice on a low-fat diet. Their primary prevention trial, PREDIMED, looked mainly at the rate of total cardiovascular events (stroke, myocardial infarction, cardiovascular death); however, a subgroup analysis showed that the incidence of new-onset diabetes was reduced by 52% with the Mediterranean diet compared with the control group after 4 years of follow-up. Multivariate-adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the Mediterranean diet supplemented with olive oil and nuts groups, respectively, compared with the control group. Intuitively, they also showed that the higher the adherence, the lower the incidence rate.⁴⁶ This occurred despite no difference in weight loss between the groups and may indicate that the components of the diet itself could have anti-inflammatory and antioxidative effects. Esposito et al⁴⁷ showed that after 1 year of intervention in 215 patients with type 2 DM, HbA1c was lower in those assigned to the Mediterranean diet vs those assigned to a low-fat diet (difference: −0.6%; 95% CI, −0.9 to −0.3). Similarly, in a 12-month trial, Elhayany et al⁴³ found a significant difference in the reduction in HbA1c in those on the Mediterranean diet compared with a low-fat diet (0.4%, P = .02).

Many studies have shown a beneficial effect of the Mediterranean diet on cardiovascular health. Estruch et al⁴⁵ showed that 772 patients (143 with type 2 DM) at high risk of cardiovascular disease who followed a Mediterranean diet with nuts for 3 months had a reduced systolic blood pressure of −7.1 mm Hg (CI, −10.0 mm Hg to −4.1 mm Hg) and reduced HDL-C ratio of −0.26 (CI, −0.42 to −0.10) compared with a low-fat diet. There was also a reduction in fasting plasma glucose of −0.30 mmol/L (CI, −0.58 mmol/L to −0.01 mmol/L).⁴⁵

 

 

PROTEIN-SPARING MODIFIED FAST

One of the earlier studies on protein-sparing modified fast showed that weight loss was as high as 21 kg ± 13 kg during the initial phase and 19 kg ± 13 kg during the refeeding phase.⁴⁹ Weight regain is high: in the protein-sparing modified fast, most patients return to their baseline weight in 5 years.⁵⁰

A study comparing 6 patients who were put on a protein-sparing modified fast diet with 6 patients who underwent gastric bypass surgery showed that the mean steady-state plasma glucose fell from 377 mg/dL to 208 mg/dL (P < .008) and mean fasting insulin values fell from 31.0 to 17.0 µU/mL (P < .004).⁵¹ There were also changes in cardiovascular risk factors: mean HDL-C values increased from 33.8 mg/dL to 40.5 mg/dL (P < .008), and factor VIII coagulant activity decreased from 194% to 140% (P < .005).⁵¹ Total cholesterol and LDL-C levels were also improved, but these changes were not always maintained at follow-up visits.⁵²

VEGETARIAN AND VEGAN DIETS

In 2013, Mishra et al⁵³ conducted a randomized clinical trial of employees with obesity and type 2 DM (N = 291) assigned to a low-fat vegan diet or no intervention for 18 weeks. Weight decreased in the low-fat vegan diet group compared with the control group (2.9 kg vs 0.06 kg, respectively, P < .001). Statistically significant reductions in total cholesterol (8 mg/dL vs 0.01 mg/dL, P < .01), LDL-C (8.1 mg/dL vs 0.9 mg/dL, P < .01), and HbA1c (0.6% vs 0.08%, P < .01) occurred in the intervention group compared with the control group.⁵³

Many studies of vegetarian and vegan diets have been of short duration and used a combination of low-fat and vegetarian or vegan diets on people that were not all considered obese. Research is limited for vegan and vegetarian diets, and not enough information exists about the effects on glycemic control and cardiovascular risk. Vegan and vegetarian diets may reduce the intake of many essential nutrients. Vegans who exclude dairy products, for example, have low bone mineral density and higher risk of fractures due to inadequate intake of calcium.

HIGH-PROTEIN DIET

Parker et al⁵⁴ reported a weight loss of 5.2 kg ± 1.8 kg in 12 weeks in 54 patients with obesity and type 2 DM irrespective of a diet with high or low protein content. Women on a high-protein diet lost more total fat and abdominal fat compared with women on a low-protein diet. Total lean mass decreased in all patients irrespective of diet.

Studies have shown that high-protein diets can improve glucose control. Ajala et al⁵⁵ reviewed 20 clinical trials of patients with type 2 DM randomized to various diets for more than 6 months. In the trials that used a high-protein diet as an intervention, HbA1c levels decreased as much as 0.28% compared with the control diets (P < .001). A small study of 8 men with untreated type 2 DM compared a high-protein low-carbohydrate diet (nonketogenic, protein 30%, carbohydrate content 20%, fat 50%) with a control diet (protein 15%, carbohydrate 55%, fat 30%).⁵⁶ The high-protein low-carbohydrate diet group had lower HbA1c levels (7.6 mg/dL ± 0.3 mg/dL vs 9.8 mg/dL ± 0.5 mg/dL) and mean 24-hour integrated serum glucose (126 mg/dL vs 198 mg/dL) compared with the control diet. Most of the studies of high-protein diets have been small and of short duration, and have used a combination of macronutrients (high protein and low carbohydrate), limiting the ability to identify the dietary component that had the most effect.

There are no studies evaluating cardiovascular outcomes, but some studies have included cardiovascular risk factors such as LDL-C levels and body fat composition. Parker et al⁵⁴ showed that women on a high-protein diet lost more total fat (5.3 kg vs 2.8 kg, P = .009) and abdominal fat (1.3 kg vs 0.7 kg, P = .006) compared with a low-protein diet. Interestingly, no difference in total fat and abdominal fat was found in men. LDL-C reduction was greater in a high-protein diet compared with a low-protein diet (5.7% vs 2.7%, P < .01).⁵⁴ In a review by Ajala et al,⁵⁵ the high-protein diet was the only diet that did not show a rise in HDL-C levels after interventions of more than 6 months.

The ADA does not recommend high-protein diets as a method for weight loss because the long-term effects are unknown. ADA recommendations include an individualized approach based on a patient’s cardiometabolic risk and renal profiles. Protein content should be 0.8 g/kg to 1.0 g/kg of weight per day in patients with early chronic kidney disease, and 0.8 g/kg of weight per day in patients with advanced kidney disease.⁶

COMPARISONS AMONG DIETS

Studies comparing diets have reached varying conclusions and have been limited by inconsistent diet definitions, small sample sizes, and high participant dropout rates. A meta-analysis conducted by Ajala et al⁵⁵ included 20 randomized controlled trials that lasted 6 months or more with 3,073 individuals in the analysis. Low-carbohydrate, vegetarian, vegan, low-glycemic, high-fiber, Mediterranean, and high-protein diets were compared with low-fat, high-glycemic, ADA, European Association for the Study of Diabetes, and low-protein diets as controls. The greatest weight loss occurred with the low-carbohydrate (−0.69 kg, P = .21) and Mediterranean diets (−1.84 kg, P < .001). Compared with the control diets, the greatest reductions in HbA1c were with the low-carbohydrate (−0.12%, P = .04), low-glycemic (−0.14%, P = .008), Mediterranean (−0.47%, P < .001), and high-protein diets (−0.28%, P < .001). HDL-C levels increased in all the diets except the high-protein diet.⁵⁵

CONCLUSION

The optimal macronutrient intake for patients with obesity and type 2 DM is unknown. Diets with equivalent caloric intakes result in similar weight loss and glucose control regardless of the macronutrient contents. It is important that total caloric intake be appropriate for weight management and glucose control goals. The metabolic status of the patient as determined by lipid profiles, and renal and liver function is the main driver for the macronutrient composition of the diet.

Current trends favor the low-carbohydrate, low-glycemic, Mediterranean, and low-caloric intake diets, though there is no evidence that one is best for weight loss and optimal glycemic control in patients with obesity and type 2 DM. Studies are limited by varying definitions, high dropout rates, and poor adherence. In addition, for many patients, weight regain often follows successful short-term weight loss, indicative of a low durability of results with many diet interventions. Medical nutrition therapy and a multidisciplinary lifestyle approach remain essential components in managing weight and type 2 DM. The ideal diet is one that achieves the best adherence when tailored to a patient’s preferences, energy needs, and health status.

According to National Health and Nutrition Examination Survey data, more than one-third of adults in the United States are obese and more than two-thirds of adults with type 2 diabetes mellitus (DM) are obese.¹ In light of overall increased life expectancy, the Centers for Disease Control and Prevention estimates that adults in the United States have a 40% lifetime risk of developing diabetes, as diabetes and obesity remain at epidemic levels.²

Weight loss in individuals who are overweight or obese is effective in preventing type 2 DM and improving management of the disease.^3,4 Dietary changes play a central role in achieving weight loss, as do other important lifestyle interventions such as exercise, behavior modification, and pharmacotherapy. Achieving glycemic goals with diet alone is difficult, and for patients with DM who are also obese, it may be even more challenging.

Medical nutrition therapy, a term coined by the American Dietetic Association, describes an approach to treating medical conditions using specific diets. As developed and monitored by a physician and registered dietitian, diet can result in beneficial outcomes and is a front-line approach for patients with noninsulin-dependent diabetes.⁵ Medical nutrition therapy for patients with type 2 DM is most effective when used within 1 year of diagnosis and is associated with a 0.5% to 2% decrease in hemoglobin A1c (HbA1c) levels.⁶ This article reviews the role of diet in managing patients with both type 2 DM and obesity. Several diets are presented including what is known about their effect on weight loss, glycemic control, and cardiovascular risk prevention in patients with diabetes and obesity.

WEIGHT LOSS AND DIET FOR PATIENTS WITH OBESITY AND DIABETES

A person is overweight or obese if he or she weighs more than the ideal weight for their height as calculated by the body mass index (BMI; weight in kg/height in meters squared). A BMI of 25 to 30 is overweight and a BMI of 30 or greater is obese.⁷ The recommended daily caloric intake for adults is based on sex, age, and daily activity level and ranges from 1,600 to 2,000 calories per day for women and 2,000 to 2,600 calories per day for men. The lower end of the range is for sedentary adults, and the higher end is for active adults (walking 1.5 to 3 miles per day at 3 to 4 miles per hour, in addition to independent living).⁸

According to the American Diabetes Association (ADA), weight loss requires reducing dietary intake by 500 to 750 calories per day, or roughly 1,200 to 1,500 kcal/day for women and 1,500 to 1,800 kcal/day for men.³ For patients with obesity and type 2 DM, sustained, modest weight loss of 5% of initial body weight improves glycemic control and reduces the need for diabetes medications.⁹ Weight loss of greater than 5% body weight also improves lipid and blood pressure status in patients with obesity and diabetes, though ideally, patients are encouraged to achieve weight reduction of 7% or greater.¹⁰

Evidence of benefits from lifestyle and dietary modifications

The fact that patients with obesity and type 2 DM have increased risk of cardiovascular morbidity and mortality is well established.¹¹ Multiple studies considered the effects of weight loss on cardiovascular morbidity and mortality. Our article focuses on dietary modifications, though most large, multicenter trials used both diet and increased physical activity to achieve weight loss. It is difficult to determine if diet or physical activity had the most effect on outcomes; however, results show that weight loss from dietary and other lifestyle interventions leads to change in outcomes.

Look AHEAD (Action for Health in Diabetes) trial. This large, multicenter, randomized controlled trial evaluated the effect of weight loss on cardiovascular morbidity and mortality in overweight or obese adults with type 2 DM. The 5,145 participants were assigned either to a long-term weight reduction intensive lifestyle intervention of diet, physical activity, and behavior modification or to usual care of support and education. At 1 year, the lifestyle intervention group had greater weight loss, improved fitness, decreased number of diabetes medications, decreased blood pressure, and improved biomarkers of glucose and lipid control compared with the usual care group.¹² No significant reductions in cardiovascular morbidity and mortality were found, though an observational post hoc analysis of the Look AHEAD data suggested an association between the magnitude of weight loss and the incidence of cardiovascular disease.¹³

The diet portion of the intensive lifestyle intervention consisted of self-selected, conventional foods while recording dietary intake during week 1. In week 2, patients weighing less than 114 kg (250 lbs) restricted their intake to 1,200 to 1,500 kcal/day, and patients weighing 114 kg or more restricted their intake to 1,500 to 1,800 kcal/day. Fewer than 30% of calories were from fat, with less than 10% from saturated fat. During week 3 through week 9, meal replacement options and conventional foods were used to reach caloric goals. Participants then decreased the use of meal replacement and increased the use of conventional foods during week 20 through week 22.¹⁴

The mean weight loss for participants in the intensive lifestyle intervention group was 8.6% compared with 0.7% in the support and education group (P < .001). HbA1c decreased by 0.7% in the intervention group compared with 0.1% the support and education group (P < .001).¹²

Finnish Diabetes Prevention Study. This study evaluated lifestyle changes in diet and physical activity in the prevention of type 2 DM in participants with impaired glucose intolerance. Participants (N = 552) were randomly assigned to the control group or the intervention group where detailed instruction was provided to achieve weight loss of greater than 5%.¹⁵ The dietary goals included fewer than 30% of total calories from fat, with fewer than 10% from saturated fat, increased fiber consumption (15 g per 1,000 kcal), and physical activity of 30 minutes daily.¹⁵ During the trial (mean duration of follow-up 3.2 years), the risk of type 2 DM was reduced by 58% in the intervention group compared with the control group.¹⁵

Diabetes Prevention Program Research Group. A landmark study by the Diabetes Prevention Program Research Group randomized 3,234 participates with elevated plasma glucose levels to placebo, metformin, and lifestyle intervention arms.⁴ Those in the lifestyle intervention arm were educated about ways to achieve and maintain a 7% or greater reduction in body weight using a low-calorie, low-fat diet and moderate physical activity. Results based on a mean follow-up of 2.8 years found a 58% reduction in the incidence of diabetes for those in the lifestyle intervention arm.⁴

 

 

DIETS AND THEIR EFFECTS ON OBESITY, DIABETES, AND CARDIOVASCULAR RISK

When patients seek consultation about diet, they frequently ask about specific types of popular diets, not the very controlled diets employed in research studies. Dietary preferences are personal, so patients may have researched a particular diet or feel that they will be more adherent if only 1 or 2 components of their meals are changed. There is no single optimal dietary strategy for patients with both obesity and type 2 DM. In general, diets are categorized based on the 3 basic macronutrients: carbohydrate, fat, and protein. We will review several popular diets, delineating content, effects on weight loss, glycemic control, and cardiovascular factors.

LOW-CARBOHYDRATE DIET

In practice, the median intake of carbohydrates for US adults is much higher, at 220 to 330 g per day for men and 180 to 230 g per day for women.¹⁶ The ADA recommends that all Americans consume fewer refined carbohydrates and added sugars in favor of whole grains, legumes, vegetables, and fruit.¹⁸

Low-carbohydrate diets focus on reducing carbo­hydrate intake with the thought that fewer carbohydrates are better. However, the definition of a low-carbohydrate diet varies. In most studies, carbohydrate intake was limited to less than 20 g to 120 g daily or fewer than 4% to 45% of the total calories consumed.^17,19 Intake of fat and total calories is unlimited, though unsaturated fats are preferred over saturated or trans fats.

Limiting the intake of disaccharide sugar in the form of sucrose and high-fructose corn syrup is endorsed because of concerns that these sugars are rapidly digested, absorbed, and fully metabolized. However, several randomized trials showed that substituting sucrose for equal amounts of other types of carbohydrates in individuals with type 2 DM showed no difference in glycemic response.²⁰ The resulting conclusion is that the postprandial glycemic response is mainly driven by the amount rather than the type of carbohydrates. The consumption of sugar-sweetened beverages is associated with obesity and an increased risk of diabetes, attributed to the high caloric intake and decreased insulin sensitivity associated with these beverages.²¹

Of the 2 monosaccharides, glucose and fructose, that make up sucrose, fructose is metabolized in the liver. The rapid metabolism of fructose may lead to alterations in lipid metabolism and affect insulin sensitivity.²² While the ADA does not advise against consuming fructose, it does advise limiting its use due to the caloric density of many foods containing fructose.

Multiple studies have investigated the effect of a low-carbohydrate diet on weight loss, glucose control, and cardiovascular risk, but comparing the results is difficult due to the varying definitions of a low-carbohydrate diet.

Low-carbohydrate diets are associated with rapid weight loss. A 6-month study of 31 patients with obesity and type 2 DM found a mean weight change of −11.4 kg (± 4 kg) in the low-carbohydrate group compared with −1.8 kg (± 3.8 kg) in the high-carbo­hydrate control group, a loss maintained up to 1 year.²³ Another study of 88 patients with type 2 DM who consumed less than 40 g/day of carbohydrate had a weight loss of 7.2 kg over 12 months.²⁴ Samaha et al²⁵ compared a low-carbohydrate diet with a low-fat diet in 132 participants with obesity (mean BMI 43), of which 39% had diabetes and 43% had metabolic syndrome. Those in the low-carbohydrate diet group had significantly more weight loss over a period of 6 months (−5.8 kg mean, ± 8.6 kg standard deviation [SD] vs −1.9 kg mean ± 4.2 kg SD, P = .002). However, at 1 year, there was no significant difference in weight loss between groups. At 36 months, weight regain was 2.2 kg (SD 12.3 kg) less than baseline in the low-carbohydrate group compared with 4.3 kg (SD 12.2 kg) less than baseline in the low-fat group
(P = .071).^25,26  On the other hand, a meta-analysis of 23 randomized trials involving 2,788 participants found no difference in weight loss at 6 months between those on a low-carbohydrate diet and those on a low-fat diet.¹⁹

With respect to glucose control, low-carbohydrate diets have been associated with a 1.4% (SD ± 1.1%)decrease in HbA1c during a 6-month period in 31 patients with obesity and type 2 DM.²³ Another 6-month study of 206 patients with obesity and diabetes comparing a low-carbohydrate diet with a low-calorie diet found no significant difference in HbA1c (−0.48% vs −0.24%, respectively) and a weight loss of 1.34 kg vs 3.77 kg, respectively (P < .001).²⁷ The change in glycemic control did not persist over time, perhaps due to the weight regain associated with this diet. A meta-analysis concluded that HbA1c was reduced more in patients with type 2 DM randomized to a lower-carbohydrate diet compared with a higher-carbohydrate diet (mean change from baseline 0% to −2.2%).¹⁷

No studies of the effects of a low-carbohydrate diet on overall cardiovascular morbidity or mortality exist. However, Kirk et al¹⁷ reported results of a low-carbohydrate diet on cardiovascular risk factors such as lipid profiles and showed a significant reduction in triglyceride levels but no effect on total cholesterol, high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol (LDL-C) levels.

The ADA has reported that low-carbohydrate diets may be effective in the management of type 2 DM in the short term. Caution is warranted because they could eliminate important sources of energy, fiber, vitamins, and minerals. It is also important to monitor lipid profile, renal function, and protein intake in certain patients, especially those with renal dysfunction.⁶

 

 

LOW-GLYCEMIC DIET

Various factors affect the GI including the type of carbohydrate, fat content, protein content, and acidity of the food consumed, as well as the rate of intestinal reaction to the food. The faster the digestion of a food, the higher the GI. High-GI foods (> 70), such as those highly processed and with high starch content, produce higher peak glucose levels when compared with low-GI foods (< 55). Low-GI foods include lentils, beans, oats, and nonstarchy vegetables.

Low-GI foods curb the large and rapid rise of blood glucose, insulin response, and glucagon inhibition that occur with high-GI foods. Many low-GI foods have high amounts of fiber, which prolongs distention of the gastrointestinal tract, increases secretion of cholecystokinin and incretins, and extends statiety.²⁸

In a meta-analysis of 19 randomized trials of overweight or obese patients (BMI > 25), a low-glycemic diet did not show weight loss when compared with an isocaloric control diet (mean difference −0.32 kg; 95% confidence interval [CI] −0.86 kg, 0.23 kg).²⁹ On the other hand, the effect on glycemic control is more pronounced. Another meta-analysis that included 11 studies of patients with DM who followed a low-glycemic diet for less than 3 months to over 6 months showed that those who followed a low-glycemic diet had a significant reduction of HbA1c (6 studies had HbA1c as the primary outcome, HbA1c weighted mean difference  −0.5%; 95% CI, −0.8 to −0.2; P = .001). Five studies reported on parameters related to insulin action, and 1 showed increased sensitivity measured by euglycemic-hyperinsulinemic clamp in a low-glycemic diet (glucose disposal 7.0 ± 1.3 mg glucose/kg/min) vs a high-glycemic diet (4.8 mg glucose/kg/min ± 0.9, P < .001).²⁸

There are no large trials of cardiovascular mortality or morbidity of low-glycemic diets, but some studies have included cardiovascular parameters. A randomized study of 210 patients with type 2 DM evaluated cardiovascular risk factors after 6 months of a low-glycemic diet and high-glycemic diet. The low-glycemic diet group had an increase in HDL-C compared with the high-glycemic diet group (1.7 mg/dL; 95% CI, 0.8 to 2.6 mg/dL vs −0.2 mg/dL; 95% CI, −0.9 to –0.5 mg/dL, P = .005).³⁰ Another crossover study of 20 patients with type 2 DM on a low-glycemic diet over 2 consecutive 24-day periods revealed a 53% reduction of the activity of plasminogen activator inhibitor-1, a thrombolytic factor that increases plaque formation.³¹ Most studies were of short duration; thus, weight regain was not clearly established.

The GI of low-GI foods differs based on the cooking method, presence of other macronutrients, and metabolic variations among individuals. Low-glycemic diets can reduce the intake of important dietary nutrients. The ADA notes that low-glycemic diets may provide only modest benefit in controlling postprandial hyperglycemia.³²

LOW-FAT DIET

Different types of fats have different effects on metabolism. LDL-C is mostly derived from saturated fats.³⁴ Consuming 2% of energy intake from trans fat substantially increases the risk of coronary heart disease.³⁵ Though the ideal total amount of fat for people with diabetes is unknown, the amount consumed still has important consequences, especially since patients with type 2 DM are at risk for coronary artery disease. The Institute of Medicine states that fat intake of 20% to 35% of energy is acceptable for all adults.¹⁶

Low-fat diets along with reduced caloric intake induce weight loss, but this cannot compete with the rapid weight loss that patients experience with the low-carbohydrate diet. This was shown in multiple studies including a meta-analysis of 5 randomized clinical trials of 447 patients with obesity who lost less weight in the low-fat diet group compared with low-carbohydrate diet group (weighted mean difference −3.3 kg; 95% CI, −5.3 to −1.4 kg) at 6 months.³⁶ Interestingly, the difference between diets was nonexistent after 12 months (weighted mean difference −1.0 kg; 95% CI, −3.5 to 1.5 kg), which may be due to weight regain in the low-carbohydrate diet group.³⁶

Foster et al³⁷ studied 307 participants with obesity assigned to a low-fat or low-carbohydrate diet. Both groups lost 11% in 1 year, and with regain, lost 7% from baseline at 2 years. There was no statistically significant difference between groups during the 2 years, but there was a trend for more weight loss in the low-carbohydrate group in the first 3 months (P = .019).³⁷

The low-fat diet has no to minimal improvement in glycemic control in patients with diabetes and obesity, regardless of the weight loss achieved. However, a low-fat diet is associated with some beneficial effects on cardiovascular risks. Nordmann et al³⁶ found no difference in blood pressure between low-carbohydrate and low-fat diets. The low-fat diet was associated with lower total cholesterol and LDL-C levels (weighted mean difference 5.4 mg/dL [0.14 mmol/L]; 95% CI, 1.2 mg/dL to 10.1 mg/dL [0.03–0.26 mmol/L]).³⁶  Triglyceride and HDL-C levels were more favorably changed in the low-carbohydrate diet (for triglycerides, weighted mean difference −22.1 mg/dL [−0.25 mmol/L]; 95% CI, −38.1 to −5.3 mg/dL [−0.43 to −0.06 mmol/L]; and for HDL-C, weighted mean difference 4.6 mg/dL [0.12 mmol/L]; 95% CI, 1.5 mg/dL to 8.1 mg/dL [0.04–0.21 mmol/L]).³⁶

 

 

VERY-LOW-CALORIE DIET

Saris et al³⁸ reported results from 8 randomized clinical trials ranging from 10 to 32 patients with obesity comparing very-low-calorie diets with a low-calorie diet of 800 to 1,200 calories a day. Over the first 4 to 6 weeks, weight loss was between 1.4 kg and 2.5 kg per week and was higher with the very-low-calorie diet when compared with the low-calorie diet though not statistically significant. Interestingly, when followed for 16 to 26 weeks, the difference in weight loss was again not statistically significant with no trend for more weight loss in the very-low-calorie diet group. Another meta-analysis looking at 6 randomized clinical trials in patients with obesity showed that weight loss with very-low-calorie diets was statistically significant when compared with low-calorie diets (16.1% ± 1.6% vs 9.7% ± 2.4% weight loss over a period of 12.7 ± 6.4 weeks).³⁹

In general, it is believed that when individuals lose a large amount of weight in a short period, a larger weight regain will occur, resulting in a higher weight than before the initial loss. This was refuted by Tsai et al,³⁹ who found that long-term data (1 to 5 years) showed the percentage of weight regained is higher with a very-low-calorie diet (62%) vs a low-calorie diet (41%) but the overall weight lost remains superior with the very-low-calorie diet, though not statistically significant (6.3% ± 3.2% and 5.0% ± 4.0% loss of initial weight, respectively).

Toubro et al⁴⁰ looked at 43 obese individuals who followed the very-low-calorie diet for 8 weeks compared with 17 weeks of a conventional diet (1,200 kcal/day) followed by a year of unrestricted calories, low-fat, high-carbohydrate diet or fixed calorie group (1,800 kcal/day). The very-low-calorie diet group lost weight at a more rapid rate, but the rate had no effect on weight maintenance after 6 or 12 months. Interestingly, the group that followed the “unrestricted calories, low-fat, high-carbohydrate diet” for a year maintained 13.2 kg (8.1 kg to 18.3 kg) of the initial 13.8 kg (11.8 kg to 15.7 kg) weight loss, while the fixed-calorie group maintained less weight loss (9.7 kg [6.1 kg to 13.3 kg]). Saris³⁸ concluded that the rapid weight loss by very-low-calorie diet has better long-term results when followed up with a program that includes nutritional education, behavioral therapy, and increased physical activity.

Very-low-calorie diets achieve glycemic control by reducing hepatic glucose output, increasing insulin action in the liver and peripheral tissues, and enhancing insulin secretion. These benefits occur soon after starting the diet, which suggests that caloric restriction plays a critical role. A study at the University of Michigan showed that the use of very-low-calorie diets in addition to moderate-intensity exercise resulted in a reduction of HbA1c from 7.4% (± 1.3%) to 6.5% (± 1.2%) in 66 patients with established type 2 DM.⁴¹ HbA1c of less than 7% occurred in 76% of patients with established diabetes and 100% of patients with newly diagnosed diabetes.⁴¹ Improvement in HbA1c over 12 weeks was associated with higher baseline HbA1c and greater reduction in BMI.⁴¹

Long-term cardiovascular risk reduction of very-low-calorie diets is small. One study showed that serum total cholesterol decreased at 2 weeks but did not differ at 3 months from baseline.⁴² A large reduction was observed in serum triglycerides at 3 months (4.57 mmol/L ± 1.0 mmol/L vs 2.18 mmol/L ± .26 mmol/L, P = .012) while HDL-C increased (0.96 mmol/L ± .06 mmol/L vs 1.11 mmol/L ± .05 mmol/L, P = .009).⁴² Blood pressure was also reduced in both systolic pressure (152 mm Hg ± 6 mm Hg vs 133 mm Hg ± 3 mm Hg, P = .004) and diastolic pressure (92 mm Hg ± 3 mm Hg vs 81 mm Hg ± 3 mm Hg, P = .007).⁴²

Challenges with this diet include significant weight regain and safety concerns for patients with obesity and type 2 DM, especially those who are taking insulin, since this diet will lead to significant rapid lowering of insulin levels.³⁸ Finally, very-low-calorie diets require a multidisciplinary approach with frequent health professional visits.

MEDITERRANEAN DIET

This diet also has a positive impact on glycemic control and has been shown to reduce the incidence of diabetes. Estruch et al⁴⁵ conducted a randomized controlled trial on 772 adults at high risk for cardiovascular disease, of which 421 had type 2 DM, assigned to Mediterranean diet supplemented either with extra-virgin olive oil or mixed nuts compared with a control group receiving advice on a low-fat diet. Their primary prevention trial, PREDIMED, looked mainly at the rate of total cardiovascular events (stroke, myocardial infarction, cardiovascular death); however, a subgroup analysis showed that the incidence of new-onset diabetes was reduced by 52% with the Mediterranean diet compared with the control group after 4 years of follow-up. Multivariate-adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the Mediterranean diet supplemented with olive oil and nuts groups, respectively, compared with the control group. Intuitively, they also showed that the higher the adherence, the lower the incidence rate.⁴⁶ This occurred despite no difference in weight loss between the groups and may indicate that the components of the diet itself could have anti-inflammatory and antioxidative effects. Esposito et al⁴⁷ showed that after 1 year of intervention in 215 patients with type 2 DM, HbA1c was lower in those assigned to the Mediterranean diet vs those assigned to a low-fat diet (difference: −0.6%; 95% CI, −0.9 to −0.3). Similarly, in a 12-month trial, Elhayany et al⁴³ found a significant difference in the reduction in HbA1c in those on the Mediterranean diet compared with a low-fat diet (0.4%, P = .02).

Many studies have shown a beneficial effect of the Mediterranean diet on cardiovascular health. Estruch et al⁴⁵ showed that 772 patients (143 with type 2 DM) at high risk of cardiovascular disease who followed a Mediterranean diet with nuts for 3 months had a reduced systolic blood pressure of −7.1 mm Hg (CI, −10.0 mm Hg to −4.1 mm Hg) and reduced HDL-C ratio of −0.26 (CI, −0.42 to −0.10) compared with a low-fat diet. There was also a reduction in fasting plasma glucose of −0.30 mmol/L (CI, −0.58 mmol/L to −0.01 mmol/L).⁴⁵

 

 

PROTEIN-SPARING MODIFIED FAST

One of the earlier studies on protein-sparing modified fast showed that weight loss was as high as 21 kg ± 13 kg during the initial phase and 19 kg ± 13 kg during the refeeding phase.⁴⁹ Weight regain is high: in the protein-sparing modified fast, most patients return to their baseline weight in 5 years.⁵⁰

A study comparing 6 patients who were put on a protein-sparing modified fast diet with 6 patients who underwent gastric bypass surgery showed that the mean steady-state plasma glucose fell from 377 mg/dL to 208 mg/dL (P < .008) and mean fasting insulin values fell from 31.0 to 17.0 µU/mL (P < .004).⁵¹ There were also changes in cardiovascular risk factors: mean HDL-C values increased from 33.8 mg/dL to 40.5 mg/dL (P < .008), and factor VIII coagulant activity decreased from 194% to 140% (P < .005).⁵¹ Total cholesterol and LDL-C levels were also improved, but these changes were not always maintained at follow-up visits.⁵²

VEGETARIAN AND VEGAN DIETS

In 2013, Mishra et al⁵³ conducted a randomized clinical trial of employees with obesity and type 2 DM (N = 291) assigned to a low-fat vegan diet or no intervention for 18 weeks. Weight decreased in the low-fat vegan diet group compared with the control group (2.9 kg vs 0.06 kg, respectively, P < .001). Statistically significant reductions in total cholesterol (8 mg/dL vs 0.01 mg/dL, P < .01), LDL-C (8.1 mg/dL vs 0.9 mg/dL, P < .01), and HbA1c (0.6% vs 0.08%, P < .01) occurred in the intervention group compared with the control group.⁵³

Many studies of vegetarian and vegan diets have been of short duration and used a combination of low-fat and vegetarian or vegan diets on people that were not all considered obese. Research is limited for vegan and vegetarian diets, and not enough information exists about the effects on glycemic control and cardiovascular risk. Vegan and vegetarian diets may reduce the intake of many essential nutrients. Vegans who exclude dairy products, for example, have low bone mineral density and higher risk of fractures due to inadequate intake of calcium.

HIGH-PROTEIN DIET

Parker et al⁵⁴ reported a weight loss of 5.2 kg ± 1.8 kg in 12 weeks in 54 patients with obesity and type 2 DM irrespective of a diet with high or low protein content. Women on a high-protein diet lost more total fat and abdominal fat compared with women on a low-protein diet. Total lean mass decreased in all patients irrespective of diet.

Studies have shown that high-protein diets can improve glucose control. Ajala et al⁵⁵ reviewed 20 clinical trials of patients with type 2 DM randomized to various diets for more than 6 months. In the trials that used a high-protein diet as an intervention, HbA1c levels decreased as much as 0.28% compared with the control diets (P < .001). A small study of 8 men with untreated type 2 DM compared a high-protein low-carbohydrate diet (nonketogenic, protein 30%, carbohydrate content 20%, fat 50%) with a control diet (protein 15%, carbohydrate 55%, fat 30%).⁵⁶ The high-protein low-carbohydrate diet group had lower HbA1c levels (7.6 mg/dL ± 0.3 mg/dL vs 9.8 mg/dL ± 0.5 mg/dL) and mean 24-hour integrated serum glucose (126 mg/dL vs 198 mg/dL) compared with the control diet. Most of the studies of high-protein diets have been small and of short duration, and have used a combination of macronutrients (high protein and low carbohydrate), limiting the ability to identify the dietary component that had the most effect.

There are no studies evaluating cardiovascular outcomes, but some studies have included cardiovascular risk factors such as LDL-C levels and body fat composition. Parker et al⁵⁴ showed that women on a high-protein diet lost more total fat (5.3 kg vs 2.8 kg, P = .009) and abdominal fat (1.3 kg vs 0.7 kg, P = .006) compared with a low-protein diet. Interestingly, no difference in total fat and abdominal fat was found in men. LDL-C reduction was greater in a high-protein diet compared with a low-protein diet (5.7% vs 2.7%, P < .01).⁵⁴ In a review by Ajala et al,⁵⁵ the high-protein diet was the only diet that did not show a rise in HDL-C levels after interventions of more than 6 months.

The ADA does not recommend high-protein diets as a method for weight loss because the long-term effects are unknown. ADA recommendations include an individualized approach based on a patient’s cardiometabolic risk and renal profiles. Protein content should be 0.8 g/kg to 1.0 g/kg of weight per day in patients with early chronic kidney disease, and 0.8 g/kg of weight per day in patients with advanced kidney disease.⁶

COMPARISONS AMONG DIETS

Studies comparing diets have reached varying conclusions and have been limited by inconsistent diet definitions, small sample sizes, and high participant dropout rates. A meta-analysis conducted by Ajala et al⁵⁵ included 20 randomized controlled trials that lasted 6 months or more with 3,073 individuals in the analysis. Low-carbohydrate, vegetarian, vegan, low-glycemic, high-fiber, Mediterranean, and high-protein diets were compared with low-fat, high-glycemic, ADA, European Association for the Study of Diabetes, and low-protein diets as controls. The greatest weight loss occurred with the low-carbohydrate (−0.69 kg, P = .21) and Mediterranean diets (−1.84 kg, P < .001). Compared with the control diets, the greatest reductions in HbA1c were with the low-carbohydrate (−0.12%, P = .04), low-glycemic (−0.14%, P = .008), Mediterranean (−0.47%, P < .001), and high-protein diets (−0.28%, P < .001). HDL-C levels increased in all the diets except the high-protein diet.⁵⁵

CONCLUSION

The optimal macronutrient intake for patients with obesity and type 2 DM is unknown. Diets with equivalent caloric intakes result in similar weight loss and glucose control regardless of the macronutrient contents. It is important that total caloric intake be appropriate for weight management and glucose control goals. The metabolic status of the patient as determined by lipid profiles, and renal and liver function is the main driver for the macronutrient composition of the diet.

Current trends favor the low-carbohydrate, low-glycemic, Mediterranean, and low-caloric intake diets, though there is no evidence that one is best for weight loss and optimal glycemic control in patients with obesity and type 2 DM. Studies are limited by varying definitions, high dropout rates, and poor adherence. In addition, for many patients, weight regain often follows successful short-term weight loss, indicative of a low durability of results with many diet interventions. Medical nutrition therapy and a multidisciplinary lifestyle approach remain essential components in managing weight and type 2 DM. The ideal diet is one that achieves the best adherence when tailored to a patient’s preferences, energy needs, and health status.

According to National Health and Nutrition Examination Survey data, more than one-third of adults in the United States are obese and more than two-thirds of adults with type 2 diabetes mellitus (DM) are obese.¹ In light of overall increased life expectancy, the Centers for Disease Control and Prevention estimates that adults in the United States have a 40% lifetime risk of developing diabetes, as diabetes and obesity remain at epidemic levels.²

Weight loss in individuals who are overweight or obese is effective in preventing type 2 DM and improving management of the disease.^3,4 Dietary changes play a central role in achieving weight loss, as do other important lifestyle interventions such as exercise, behavior modification, and pharmacotherapy. Achieving glycemic goals with diet alone is difficult, and for patients with DM who are also obese, it may be even more challenging.

Medical nutrition therapy, a term coined by the American Dietetic Association, describes an approach to treating medical conditions using specific diets. As developed and monitored by a physician and registered dietitian, diet can result in beneficial outcomes and is a front-line approach for patients with noninsulin-dependent diabetes.⁵ Medical nutrition therapy for patients with type 2 DM is most effective when used within 1 year of diagnosis and is associated with a 0.5% to 2% decrease in hemoglobin A1c (HbA1c) levels.⁶ This article reviews the role of diet in managing patients with both type 2 DM and obesity. Several diets are presented including what is known about their effect on weight loss, glycemic control, and cardiovascular risk prevention in patients with diabetes and obesity.

WEIGHT LOSS AND DIET FOR PATIENTS WITH OBESITY AND DIABETES

A person is overweight or obese if he or she weighs more than the ideal weight for their height as calculated by the body mass index (BMI; weight in kg/height in meters squared). A BMI of 25 to 30 is overweight and a BMI of 30 or greater is obese.⁷ The recommended daily caloric intake for adults is based on sex, age, and daily activity level and ranges from 1,600 to 2,000 calories per day for women and 2,000 to 2,600 calories per day for men. The lower end of the range is for sedentary adults, and the higher end is for active adults (walking 1.5 to 3 miles per day at 3 to 4 miles per hour, in addition to independent living).⁸

According to the American Diabetes Association (ADA), weight loss requires reducing dietary intake by 500 to 750 calories per day, or roughly 1,200 to 1,500 kcal/day for women and 1,500 to 1,800 kcal/day for men.³ For patients with obesity and type 2 DM, sustained, modest weight loss of 5% of initial body weight improves glycemic control and reduces the need for diabetes medications.⁹ Weight loss of greater than 5% body weight also improves lipid and blood pressure status in patients with obesity and diabetes, though ideally, patients are encouraged to achieve weight reduction of 7% or greater.¹⁰

Evidence of benefits from lifestyle and dietary modifications

The fact that patients with obesity and type 2 DM have increased risk of cardiovascular morbidity and mortality is well established.¹¹ Multiple studies considered the effects of weight loss on cardiovascular morbidity and mortality. Our article focuses on dietary modifications, though most large, multicenter trials used both diet and increased physical activity to achieve weight loss. It is difficult to determine if diet or physical activity had the most effect on outcomes; however, results show that weight loss from dietary and other lifestyle interventions leads to change in outcomes.

Look AHEAD (Action for Health in Diabetes) trial. This large, multicenter, randomized controlled trial evaluated the effect of weight loss on cardiovascular morbidity and mortality in overweight or obese adults with type 2 DM. The 5,145 participants were assigned either to a long-term weight reduction intensive lifestyle intervention of diet, physical activity, and behavior modification or to usual care of support and education. At 1 year, the lifestyle intervention group had greater weight loss, improved fitness, decreased number of diabetes medications, decreased blood pressure, and improved biomarkers of glucose and lipid control compared with the usual care group.¹² No significant reductions in cardiovascular morbidity and mortality were found, though an observational post hoc analysis of the Look AHEAD data suggested an association between the magnitude of weight loss and the incidence of cardiovascular disease.¹³

The diet portion of the intensive lifestyle intervention consisted of self-selected, conventional foods while recording dietary intake during week 1. In week 2, patients weighing less than 114 kg (250 lbs) restricted their intake to 1,200 to 1,500 kcal/day, and patients weighing 114 kg or more restricted their intake to 1,500 to 1,800 kcal/day. Fewer than 30% of calories were from fat, with less than 10% from saturated fat. During week 3 through week 9, meal replacement options and conventional foods were used to reach caloric goals. Participants then decreased the use of meal replacement and increased the use of conventional foods during week 20 through week 22.¹⁴

The mean weight loss for participants in the intensive lifestyle intervention group was 8.6% compared with 0.7% in the support and education group (P < .001). HbA1c decreased by 0.7% in the intervention group compared with 0.1% the support and education group (P < .001).¹²

Finnish Diabetes Prevention Study. This study evaluated lifestyle changes in diet and physical activity in the prevention of type 2 DM in participants with impaired glucose intolerance. Participants (N = 552) were randomly assigned to the control group or the intervention group where detailed instruction was provided to achieve weight loss of greater than 5%.¹⁵ The dietary goals included fewer than 30% of total calories from fat, with fewer than 10% from saturated fat, increased fiber consumption (15 g per 1,000 kcal), and physical activity of 30 minutes daily.¹⁵ During the trial (mean duration of follow-up 3.2 years), the risk of type 2 DM was reduced by 58% in the intervention group compared with the control group.¹⁵

Diabetes Prevention Program Research Group. A landmark study by the Diabetes Prevention Program Research Group randomized 3,234 participates with elevated plasma glucose levels to placebo, metformin, and lifestyle intervention arms.⁴ Those in the lifestyle intervention arm were educated about ways to achieve and maintain a 7% or greater reduction in body weight using a low-calorie, low-fat diet and moderate physical activity. Results based on a mean follow-up of 2.8 years found a 58% reduction in the incidence of diabetes for those in the lifestyle intervention arm.⁴

 

 

DIETS AND THEIR EFFECTS ON OBESITY, DIABETES, AND CARDIOVASCULAR RISK

When patients seek consultation about diet, they frequently ask about specific types of popular diets, not the very controlled diets employed in research studies. Dietary preferences are personal, so patients may have researched a particular diet or feel that they will be more adherent if only 1 or 2 components of their meals are changed. There is no single optimal dietary strategy for patients with both obesity and type 2 DM. In general, diets are categorized based on the 3 basic macronutrients: carbohydrate, fat, and protein. We will review several popular diets, delineating content, effects on weight loss, glycemic control, and cardiovascular factors.

LOW-CARBOHYDRATE DIET

In practice, the median intake of carbohydrates for US adults is much higher, at 220 to 330 g per day for men and 180 to 230 g per day for women.¹⁶ The ADA recommends that all Americans consume fewer refined carbohydrates and added sugars in favor of whole grains, legumes, vegetables, and fruit.¹⁸

Low-carbohydrate diets focus on reducing carbo­hydrate intake with the thought that fewer carbohydrates are better. However, the definition of a low-carbohydrate diet varies. In most studies, carbohydrate intake was limited to less than 20 g to 120 g daily or fewer than 4% to 45% of the total calories consumed.^17,19 Intake of fat and total calories is unlimited, though unsaturated fats are preferred over saturated or trans fats.

Limiting the intake of disaccharide sugar in the form of sucrose and high-fructose corn syrup is endorsed because of concerns that these sugars are rapidly digested, absorbed, and fully metabolized. However, several randomized trials showed that substituting sucrose for equal amounts of other types of carbohydrates in individuals with type 2 DM showed no difference in glycemic response.²⁰ The resulting conclusion is that the postprandial glycemic response is mainly driven by the amount rather than the type of carbohydrates. The consumption of sugar-sweetened beverages is associated with obesity and an increased risk of diabetes, attributed to the high caloric intake and decreased insulin sensitivity associated with these beverages.²¹

Of the 2 monosaccharides, glucose and fructose, that make up sucrose, fructose is metabolized in the liver. The rapid metabolism of fructose may lead to alterations in lipid metabolism and affect insulin sensitivity.²² While the ADA does not advise against consuming fructose, it does advise limiting its use due to the caloric density of many foods containing fructose.

Multiple studies have investigated the effect of a low-carbohydrate diet on weight loss, glucose control, and cardiovascular risk, but comparing the results is difficult due to the varying definitions of a low-carbohydrate diet.

Low-carbohydrate diets are associated with rapid weight loss. A 6-month study of 31 patients with obesity and type 2 DM found a mean weight change of −11.4 kg (± 4 kg) in the low-carbohydrate group compared with −1.8 kg (± 3.8 kg) in the high-carbo­hydrate control group, a loss maintained up to 1 year.²³ Another study of 88 patients with type 2 DM who consumed less than 40 g/day of carbohydrate had a weight loss of 7.2 kg over 12 months.²⁴ Samaha et al²⁵ compared a low-carbohydrate diet with a low-fat diet in 132 participants with obesity (mean BMI 43), of which 39% had diabetes and 43% had metabolic syndrome. Those in the low-carbohydrate diet group had significantly more weight loss over a period of 6 months (−5.8 kg mean, ± 8.6 kg standard deviation [SD] vs −1.9 kg mean ± 4.2 kg SD, P = .002). However, at 1 year, there was no significant difference in weight loss between groups. At 36 months, weight regain was 2.2 kg (SD 12.3 kg) less than baseline in the low-carbohydrate group compared with 4.3 kg (SD 12.2 kg) less than baseline in the low-fat group
(P = .071).^25,26  On the other hand, a meta-analysis of 23 randomized trials involving 2,788 participants found no difference in weight loss at 6 months between those on a low-carbohydrate diet and those on a low-fat diet.¹⁹

With respect to glucose control, low-carbohydrate diets have been associated with a 1.4% (SD ± 1.1%)decrease in HbA1c during a 6-month period in 31 patients with obesity and type 2 DM.²³ Another 6-month study of 206 patients with obesity and diabetes comparing a low-carbohydrate diet with a low-calorie diet found no significant difference in HbA1c (−0.48% vs −0.24%, respectively) and a weight loss of 1.34 kg vs 3.77 kg, respectively (P < .001).²⁷ The change in glycemic control did not persist over time, perhaps due to the weight regain associated with this diet. A meta-analysis concluded that HbA1c was reduced more in patients with type 2 DM randomized to a lower-carbohydrate diet compared with a higher-carbohydrate diet (mean change from baseline 0% to −2.2%).¹⁷

No studies of the effects of a low-carbohydrate diet on overall cardiovascular morbidity or mortality exist. However, Kirk et al¹⁷ reported results of a low-carbohydrate diet on cardiovascular risk factors such as lipid profiles and showed a significant reduction in triglyceride levels but no effect on total cholesterol, high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol (LDL-C) levels.

The ADA has reported that low-carbohydrate diets may be effective in the management of type 2 DM in the short term. Caution is warranted because they could eliminate important sources of energy, fiber, vitamins, and minerals. It is also important to monitor lipid profile, renal function, and protein intake in certain patients, especially those with renal dysfunction.⁶

 

 

LOW-GLYCEMIC DIET

Various factors affect the GI including the type of carbohydrate, fat content, protein content, and acidity of the food consumed, as well as the rate of intestinal reaction to the food. The faster the digestion of a food, the higher the GI. High-GI foods (> 70), such as those highly processed and with high starch content, produce higher peak glucose levels when compared with low-GI foods (< 55). Low-GI foods include lentils, beans, oats, and nonstarchy vegetables.

Low-GI foods curb the large and rapid rise of blood glucose, insulin response, and glucagon inhibition that occur with high-GI foods. Many low-GI foods have high amounts of fiber, which prolongs distention of the gastrointestinal tract, increases secretion of cholecystokinin and incretins, and extends statiety.²⁸

In a meta-analysis of 19 randomized trials of overweight or obese patients (BMI > 25), a low-glycemic diet did not show weight loss when compared with an isocaloric control diet (mean difference −0.32 kg; 95% confidence interval [CI] −0.86 kg, 0.23 kg).²⁹ On the other hand, the effect on glycemic control is more pronounced. Another meta-analysis that included 11 studies of patients with DM who followed a low-glycemic diet for less than 3 months to over 6 months showed that those who followed a low-glycemic diet had a significant reduction of HbA1c (6 studies had HbA1c as the primary outcome, HbA1c weighted mean difference  −0.5%; 95% CI, −0.8 to −0.2; P = .001). Five studies reported on parameters related to insulin action, and 1 showed increased sensitivity measured by euglycemic-hyperinsulinemic clamp in a low-glycemic diet (glucose disposal 7.0 ± 1.3 mg glucose/kg/min) vs a high-glycemic diet (4.8 mg glucose/kg/min ± 0.9, P < .001).²⁸

There are no large trials of cardiovascular mortality or morbidity of low-glycemic diets, but some studies have included cardiovascular parameters. A randomized study of 210 patients with type 2 DM evaluated cardiovascular risk factors after 6 months of a low-glycemic diet and high-glycemic diet. The low-glycemic diet group had an increase in HDL-C compared with the high-glycemic diet group (1.7 mg/dL; 95% CI, 0.8 to 2.6 mg/dL vs −0.2 mg/dL; 95% CI, −0.9 to –0.5 mg/dL, P = .005).³⁰ Another crossover study of 20 patients with type 2 DM on a low-glycemic diet over 2 consecutive 24-day periods revealed a 53% reduction of the activity of plasminogen activator inhibitor-1, a thrombolytic factor that increases plaque formation.³¹ Most studies were of short duration; thus, weight regain was not clearly established.

The GI of low-GI foods differs based on the cooking method, presence of other macronutrients, and metabolic variations among individuals. Low-glycemic diets can reduce the intake of important dietary nutrients. The ADA notes that low-glycemic diets may provide only modest benefit in controlling postprandial hyperglycemia.³²

LOW-FAT DIET

Different types of fats have different effects on metabolism. LDL-C is mostly derived from saturated fats.³⁴ Consuming 2% of energy intake from trans fat substantially increases the risk of coronary heart disease.³⁵ Though the ideal total amount of fat for people with diabetes is unknown, the amount consumed still has important consequences, especially since patients with type 2 DM are at risk for coronary artery disease. The Institute of Medicine states that fat intake of 20% to 35% of energy is acceptable for all adults.¹⁶

Low-fat diets along with reduced caloric intake induce weight loss, but this cannot compete with the rapid weight loss that patients experience with the low-carbohydrate diet. This was shown in multiple studies including a meta-analysis of 5 randomized clinical trials of 447 patients with obesity who lost less weight in the low-fat diet group compared with low-carbohydrate diet group (weighted mean difference −3.3 kg; 95% CI, −5.3 to −1.4 kg) at 6 months.³⁶ Interestingly, the difference between diets was nonexistent after 12 months (weighted mean difference −1.0 kg; 95% CI, −3.5 to 1.5 kg), which may be due to weight regain in the low-carbohydrate diet group.³⁶

Foster et al³⁷ studied 307 participants with obesity assigned to a low-fat or low-carbohydrate diet. Both groups lost 11% in 1 year, and with regain, lost 7% from baseline at 2 years. There was no statistically significant difference between groups during the 2 years, but there was a trend for more weight loss in the low-carbohydrate group in the first 3 months (P = .019).³⁷

The low-fat diet has no to minimal improvement in glycemic control in patients with diabetes and obesity, regardless of the weight loss achieved. However, a low-fat diet is associated with some beneficial effects on cardiovascular risks. Nordmann et al³⁶ found no difference in blood pressure between low-carbohydrate and low-fat diets. The low-fat diet was associated with lower total cholesterol and LDL-C levels (weighted mean difference 5.4 mg/dL [0.14 mmol/L]; 95% CI, 1.2 mg/dL to 10.1 mg/dL [0.03–0.26 mmol/L]).³⁶  Triglyceride and HDL-C levels were more favorably changed in the low-carbohydrate diet (for triglycerides, weighted mean difference −22.1 mg/dL [−0.25 mmol/L]; 95% CI, −38.1 to −5.3 mg/dL [−0.43 to −0.06 mmol/L]; and for HDL-C, weighted mean difference 4.6 mg/dL [0.12 mmol/L]; 95% CI, 1.5 mg/dL to 8.1 mg/dL [0.04–0.21 mmol/L]).³⁶

 

 

VERY-LOW-CALORIE DIET

Saris et al³⁸ reported results from 8 randomized clinical trials ranging from 10 to 32 patients with obesity comparing very-low-calorie diets with a low-calorie diet of 800 to 1,200 calories a day. Over the first 4 to 6 weeks, weight loss was between 1.4 kg and 2.5 kg per week and was higher with the very-low-calorie diet when compared with the low-calorie diet though not statistically significant. Interestingly, when followed for 16 to 26 weeks, the difference in weight loss was again not statistically significant with no trend for more weight loss in the very-low-calorie diet group. Another meta-analysis looking at 6 randomized clinical trials in patients with obesity showed that weight loss with very-low-calorie diets was statistically significant when compared with low-calorie diets (16.1% ± 1.6% vs 9.7% ± 2.4% weight loss over a period of 12.7 ± 6.4 weeks).³⁹

In general, it is believed that when individuals lose a large amount of weight in a short period, a larger weight regain will occur, resulting in a higher weight than before the initial loss. This was refuted by Tsai et al,³⁹ who found that long-term data (1 to 5 years) showed the percentage of weight regained is higher with a very-low-calorie diet (62%) vs a low-calorie diet (41%) but the overall weight lost remains superior with the very-low-calorie diet, though not statistically significant (6.3% ± 3.2% and 5.0% ± 4.0% loss of initial weight, respectively).

Toubro et al⁴⁰ looked at 43 obese individuals who followed the very-low-calorie diet for 8 weeks compared with 17 weeks of a conventional diet (1,200 kcal/day) followed by a year of unrestricted calories, low-fat, high-carbohydrate diet or fixed calorie group (1,800 kcal/day). The very-low-calorie diet group lost weight at a more rapid rate, but the rate had no effect on weight maintenance after 6 or 12 months. Interestingly, the group that followed the “unrestricted calories, low-fat, high-carbohydrate diet” for a year maintained 13.2 kg (8.1 kg to 18.3 kg) of the initial 13.8 kg (11.8 kg to 15.7 kg) weight loss, while the fixed-calorie group maintained less weight loss (9.7 kg [6.1 kg to 13.3 kg]). Saris³⁸ concluded that the rapid weight loss by very-low-calorie diet has better long-term results when followed up with a program that includes nutritional education, behavioral therapy, and increased physical activity.

Very-low-calorie diets achieve glycemic control by reducing hepatic glucose output, increasing insulin action in the liver and peripheral tissues, and enhancing insulin secretion. These benefits occur soon after starting the diet, which suggests that caloric restriction plays a critical role. A study at the University of Michigan showed that the use of very-low-calorie diets in addition to moderate-intensity exercise resulted in a reduction of HbA1c from 7.4% (± 1.3%) to 6.5% (± 1.2%) in 66 patients with established type 2 DM.⁴¹ HbA1c of less than 7% occurred in 76% of patients with established diabetes and 100% of patients with newly diagnosed diabetes.⁴¹ Improvement in HbA1c over 12 weeks was associated with higher baseline HbA1c and greater reduction in BMI.⁴¹

Long-term cardiovascular risk reduction of very-low-calorie diets is small. One study showed that serum total cholesterol decreased at 2 weeks but did not differ at 3 months from baseline.⁴² A large reduction was observed in serum triglycerides at 3 months (4.57 mmol/L ± 1.0 mmol/L vs 2.18 mmol/L ± .26 mmol/L, P = .012) while HDL-C increased (0.96 mmol/L ± .06 mmol/L vs 1.11 mmol/L ± .05 mmol/L, P = .009).⁴² Blood pressure was also reduced in both systolic pressure (152 mm Hg ± 6 mm Hg vs 133 mm Hg ± 3 mm Hg, P = .004) and diastolic pressure (92 mm Hg ± 3 mm Hg vs 81 mm Hg ± 3 mm Hg, P = .007).⁴²

Challenges with this diet include significant weight regain and safety concerns for patients with obesity and type 2 DM, especially those who are taking insulin, since this diet will lead to significant rapid lowering of insulin levels.³⁸ Finally, very-low-calorie diets require a multidisciplinary approach with frequent health professional visits.

MEDITERRANEAN DIET

This diet also has a positive impact on glycemic control and has been shown to reduce the incidence of diabetes. Estruch et al⁴⁵ conducted a randomized controlled trial on 772 adults at high risk for cardiovascular disease, of which 421 had type 2 DM, assigned to Mediterranean diet supplemented either with extra-virgin olive oil or mixed nuts compared with a control group receiving advice on a low-fat diet. Their primary prevention trial, PREDIMED, looked mainly at the rate of total cardiovascular events (stroke, myocardial infarction, cardiovascular death); however, a subgroup analysis showed that the incidence of new-onset diabetes was reduced by 52% with the Mediterranean diet compared with the control group after 4 years of follow-up. Multivariate-adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the Mediterranean diet supplemented with olive oil and nuts groups, respectively, compared with the control group. Intuitively, they also showed that the higher the adherence, the lower the incidence rate.⁴⁶ This occurred despite no difference in weight loss between the groups and may indicate that the components of the diet itself could have anti-inflammatory and antioxidative effects. Esposito et al⁴⁷ showed that after 1 year of intervention in 215 patients with type 2 DM, HbA1c was lower in those assigned to the Mediterranean diet vs those assigned to a low-fat diet (difference: −0.6%; 95% CI, −0.9 to −0.3). Similarly, in a 12-month trial, Elhayany et al⁴³ found a significant difference in the reduction in HbA1c in those on the Mediterranean diet compared with a low-fat diet (0.4%, P = .02).

Many studies have shown a beneficial effect of the Mediterranean diet on cardiovascular health. Estruch et al⁴⁵ showed that 772 patients (143 with type 2 DM) at high risk of cardiovascular disease who followed a Mediterranean diet with nuts for 3 months had a reduced systolic blood pressure of −7.1 mm Hg (CI, −10.0 mm Hg to −4.1 mm Hg) and reduced HDL-C ratio of −0.26 (CI, −0.42 to −0.10) compared with a low-fat diet. There was also a reduction in fasting plasma glucose of −0.30 mmol/L (CI, −0.58 mmol/L to −0.01 mmol/L).⁴⁵

 

 

PROTEIN-SPARING MODIFIED FAST

One of the earlier studies on protein-sparing modified fast showed that weight loss was as high as 21 kg ± 13 kg during the initial phase and 19 kg ± 13 kg during the refeeding phase.⁴⁹ Weight regain is high: in the protein-sparing modified fast, most patients return to their baseline weight in 5 years.⁵⁰

A study comparing 6 patients who were put on a protein-sparing modified fast diet with 6 patients who underwent gastric bypass surgery showed that the mean steady-state plasma glucose fell from 377 mg/dL to 208 mg/dL (P < .008) and mean fasting insulin values fell from 31.0 to 17.0 µU/mL (P < .004).⁵¹ There were also changes in cardiovascular risk factors: mean HDL-C values increased from 33.8 mg/dL to 40.5 mg/dL (P < .008), and factor VIII coagulant activity decreased from 194% to 140% (P < .005).⁵¹ Total cholesterol and LDL-C levels were also improved, but these changes were not always maintained at follow-up visits.⁵²

VEGETARIAN AND VEGAN DIETS

In 2013, Mishra et al⁵³ conducted a randomized clinical trial of employees with obesity and type 2 DM (N = 291) assigned to a low-fat vegan diet or no intervention for 18 weeks. Weight decreased in the low-fat vegan diet group compared with the control group (2.9 kg vs 0.06 kg, respectively, P < .001). Statistically significant reductions in total cholesterol (8 mg/dL vs 0.01 mg/dL, P < .01), LDL-C (8.1 mg/dL vs 0.9 mg/dL, P < .01), and HbA1c (0.6% vs 0.08%, P < .01) occurred in the intervention group compared with the control group.⁵³

Many studies of vegetarian and vegan diets have been of short duration and used a combination of low-fat and vegetarian or vegan diets on people that were not all considered obese. Research is limited for vegan and vegetarian diets, and not enough information exists about the effects on glycemic control and cardiovascular risk. Vegan and vegetarian diets may reduce the intake of many essential nutrients. Vegans who exclude dairy products, for example, have low bone mineral density and higher risk of fractures due to inadequate intake of calcium.

HIGH-PROTEIN DIET

Parker et al⁵⁴ reported a weight loss of 5.2 kg ± 1.8 kg in 12 weeks in 54 patients with obesity and type 2 DM irrespective of a diet with high or low protein content. Women on a high-protein diet lost more total fat and abdominal fat compared with women on a low-protein diet. Total lean mass decreased in all patients irrespective of diet.

Studies have shown that high-protein diets can improve glucose control. Ajala et al⁵⁵ reviewed 20 clinical trials of patients with type 2 DM randomized to various diets for more than 6 months. In the trials that used a high-protein diet as an intervention, HbA1c levels decreased as much as 0.28% compared with the control diets (P < .001). A small study of 8 men with untreated type 2 DM compared a high-protein low-carbohydrate diet (nonketogenic, protein 30%, carbohydrate content 20%, fat 50%) with a control diet (protein 15%, carbohydrate 55%, fat 30%).⁵⁶ The high-protein low-carbohydrate diet group had lower HbA1c levels (7.6 mg/dL ± 0.3 mg/dL vs 9.8 mg/dL ± 0.5 mg/dL) and mean 24-hour integrated serum glucose (126 mg/dL vs 198 mg/dL) compared with the control diet. Most of the studies of high-protein diets have been small and of short duration, and have used a combination of macronutrients (high protein and low carbohydrate), limiting the ability to identify the dietary component that had the most effect.

There are no studies evaluating cardiovascular outcomes, but some studies have included cardiovascular risk factors such as LDL-C levels and body fat composition. Parker et al⁵⁴ showed that women on a high-protein diet lost more total fat (5.3 kg vs 2.8 kg, P = .009) and abdominal fat (1.3 kg vs 0.7 kg, P = .006) compared with a low-protein diet. Interestingly, no difference in total fat and abdominal fat was found in men. LDL-C reduction was greater in a high-protein diet compared with a low-protein diet (5.7% vs 2.7%, P < .01).⁵⁴ In a review by Ajala et al,⁵⁵ the high-protein diet was the only diet that did not show a rise in HDL-C levels after interventions of more than 6 months.

The ADA does not recommend high-protein diets as a method for weight loss because the long-term effects are unknown. ADA recommendations include an individualized approach based on a patient’s cardiometabolic risk and renal profiles. Protein content should be 0.8 g/kg to 1.0 g/kg of weight per day in patients with early chronic kidney disease, and 0.8 g/kg of weight per day in patients with advanced kidney disease.⁶

COMPARISONS AMONG DIETS

Studies comparing diets have reached varying conclusions and have been limited by inconsistent diet definitions, small sample sizes, and high participant dropout rates. A meta-analysis conducted by Ajala et al⁵⁵ included 20 randomized controlled trials that lasted 6 months or more with 3,073 individuals in the analysis. Low-carbohydrate, vegetarian, vegan, low-glycemic, high-fiber, Mediterranean, and high-protein diets were compared with low-fat, high-glycemic, ADA, European Association for the Study of Diabetes, and low-protein diets as controls. The greatest weight loss occurred with the low-carbohydrate (−0.69 kg, P = .21) and Mediterranean diets (−1.84 kg, P < .001). Compared with the control diets, the greatest reductions in HbA1c were with the low-carbohydrate (−0.12%, P = .04), low-glycemic (−0.14%, P = .008), Mediterranean (−0.47%, P < .001), and high-protein diets (−0.28%, P < .001). HDL-C levels increased in all the diets except the high-protein diet.⁵⁵

CONCLUSION

The optimal macronutrient intake for patients with obesity and type 2 DM is unknown. Diets with equivalent caloric intakes result in similar weight loss and glucose control regardless of the macronutrient contents. It is important that total caloric intake be appropriate for weight management and glucose control goals. The metabolic status of the patient as determined by lipid profiles, and renal and liver function is the main driver for the macronutrient composition of the diet.

Current trends favor the low-carbohydrate, low-glycemic, Mediterranean, and low-caloric intake diets, though there is no evidence that one is best for weight loss and optimal glycemic control in patients with obesity and type 2 DM. Studies are limited by varying definitions, high dropout rates, and poor adherence. In addition, for many patients, weight regain often follows successful short-term weight loss, indicative of a low durability of results with many diet interventions. Medical nutrition therapy and a multidisciplinary lifestyle approach remain essential components in managing weight and type 2 DM. The ideal diet is one that achieves the best adherence when tailored to a patient’s preferences, energy needs, and health status.

Type 2 diabetes has emerged as a major public health and economic burden of the 21st century. Recent statistics from the Centers for Disease Control and Prevention suggest that diabetes affects 29.1 million people in the United States,¹ and the International Diabetes Federation estimates diabetes effects 366 million people worldwide.²

As these shocking numbers continue to increase, the cost of caring for patients with diabetes is placing enormous strain on the economies of the US and other countries. In order to manage and treat a disease on the scale of diabetes, the approaches need to be efficacious, sustainable, scalable, and affordable.

Of all the treatment options available, including multiple new medications and bariatric surgery (for patients who meet the criteria, discussed elsewhere in this supplement),^3–5 exercise as part of a lifestyle approach⁶ is a strategy that meets the majority of these criteria.

The health benefits of exercise have a long and storied history. Hippocrates, the father of scientific medicine, was the first physician on record to recognize the value of exercise for a patient with “consumption.”⁷ Today, exercise is recommended as one of the first management strategies for patients newly diagnosed with type 2 diabetes and, together with diet and behavior modification, is a central component of all type 2 diabetes and obesity prevention programs.

The evidence base for the efficacy, scalability, and affordability of exercise includes multiple large randomized controlled trials; and these data were used to create the recently updated exercise guidelines for the prevention and treatment of type 2 diabetes, published by the American Diabetes Association (ADA), American College of Sports Medicine (ACSM), and other national organizations.^8–10

Herein, we highlight the literature surrounding the metabolic effects and clinical outcomes in patients with type 2 diabetes following exercise intervention, and point to future directions for translational research in the field of exercise and diabetes.

It is known that adults who maintain a physically active lifestyle can reduce their risk of developing impaired glucose tolerance, insulin resistance, and type 2 diabetes.⁸ It has also been established that low cardiovascular fitness is a strong and independent predictor of all-cause mortality in patients with type 2 diabetes.^11,12 Indeed, patients with diabetes are 2 to 4 times more likely than healthy individuals to suffer from cardiovascular disease, due to the metabolic complexity and underlying comorbidities of type 2 diabetes including obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension.^13,14

Additionally, elevated hemoglobin A1c (HbA1c) levels are predictive of vascular complications in patients with diabetes, and regular exercise has been shown to reduce HbA1c levels, both alone and in conjunction with dietary intervention. In a meta-analysis of 9 randomized trials comprising 266 adults with type 2 diabetes, patients randomized to 20 weeks of regular exercise at 50% to 75% of their maximal aerobic capacity (VO_2max) demonstrated marked improvements in HbA1c and cardiorespiratory fitness.¹¹ Importantly, larger reductions in HbA1c were observed with more intense exercise, reflecting greater improvements in blood glucose control with increasing exercise intensity.

In addition to greater energy expenditure, which aids in reversing obesity-associated type 2 diabetes, exercise also boosts insulin action through short-term effects, mainly via insulin-independent glucose transport. For example, our laboratory and others have shown that as little as 7 days of vigorous aerobic exercise training in adults with type 2 diabetes results in improved glycemic control, without any effect on body weight.^15,16 Specifically, we observed decreased fasting plasma insulin, a 45% increase in insulin-stimulated glucose disposal, and suppressed hepatic glucose production (HGP) during carefully controlled euglycemic hyperinsulinemic clamps.¹⁵

Although the metabolic benefits of exercise are striking, the effects are short-lived and begin to fade within 48 to 96 hours.¹⁷ Therefore, an ongoing exercise program is required to maintain the favorable metabolic milieu that can be derived through exercise.

EXERCISE MODALITIES

Aerobic exercise

Notably, aerobic exercise is a well-established way to improve HbA1c, and strong evidence exists with regard to the effects of aerobic activity on weight loss and the enhanced regulation of lipid and lipoprotein metabolism.⁸ For example, in a 2007 report, 6 months of aerobic exercise training in 60 adults with type 2 diabetes led to reductions in HbA1c (−0.63% ± 0.41 vs 0.31% ± 0.10, P < .001), fasting plasma glucose (−18.6 mg/dL ± 4.4 vs 4.28 mg/dL ± 2.57, P < .001), insulin resistance (−1.52 ± 0.6 vs 0.56 ± 0.44, P = .023; as measured by homeostatic model assessment), fasting insulin (−2.91 mU/L ± 0.4 vs 0.94 mU/L ± 0.21, P = .031), and systolic blood pressure (−6.9 mm Hg ± 5.19 vs 1.22 mm Hg ± 1.09, P = .010) compared with the control group.¹⁴

Furthermore, meta-analyses reviewing the benefits of aerobic activity for patients with type 2 diabetes have repeatedly confirmed that compared with patients in sedentary control groups, aerobic exercise improves glycemic control, insulin sensitivity, oxidative capacity, and important related metabolic parameters.¹¹ Taken together, there is ample evidence that aerobic exercise is a tried-and-true exercise modality for managing and preventing type 2 diabetes.

Resistance training

During the last 2 decades, resistance training has gained considerable recognition as a viable exercise training option for patients with type 2 diabetes. Synonymous with strength training, resistance exercise involves movements utilizing free weights, weight machines, body weight exercises, or elastic resistance bands.

Primary outcomes in studies evaluating the effects of resistance training in type 2 diabetes have found improvements that range from 10% to 15% in strength, bone mineral density, blood pressure, lipid profiles, cardiovascular health, insulin sensitivity, and muscle mass.^18,20 Furthermore, because of the increased prevalence of type 2 diabetes with aging, coupled with age-related decline in muscle mass, known as sarcopenia,²¹ resistance training can provide additional health benefits in older adults.

Dunstan et al²¹ reported a threefold greater reduction in HbA1c in patients with type 2 diabetes ages 60 to 80 compared with nonexercising patients in a control group. They also noted an increase in lean body mass in the resistance-training group, while those in the nonexercising control group lost lean mass after 6 months. In a shorter, 8-week circuit weight training study performed by the same research group, patients with type 2 diabetes had improved glucose and insulin responses during an oral glucose tolerance test.²²

These findings support the use of resistance training as part of a diabetes management plan. In addition, key opinion leaders advocate that the resistance-training-induced increase in skeletal muscle mass and the associated reductions in HbA1c may indicate that skeletal muscle is a “sink” for glucose; thus, the improved glycemic control in response to resistance training may be at least in part the result of enhanced muscle glycogen storage.^21,23

Based on increasing evidence supporting the role of resistance training in glycemic control, the ADA and ACSM recently updated their exercise guidelines for treatment and prevention of type 2 diabetes to include resistance training.⁹

 

 

Combining aerobic and resistance training

The combination of aerobic and resistance training, as recommended by current ADA guidelines, may be the most effective exercise modality for controlling glucose and lipids in type 2 diabetes.

Cuff et al²⁴ evaluated whether a combined training program could improve insulin sensitivity beyond that of aerobic exercise alone in 28 postmenopausal women with type 2 diabetes. Indeed, 16 weeks of combined training led to significantly increased insulin-mediated glucose uptake compared with a group performing only aerobic exercise, reflecting greater insulin sensitivity.

Balducci et al²⁵ demonstrated that combined aerobic and resistance training markedly improved HbA1c (from 8.31% ± 1.73 to 7.1% ± 1.16, P < .001) compared with the control group and globally improved risk factors for cardiovascular disease, supporting the notion that combined training for patients with type 2 diabetes may have additive benefits.

Of note, Snowling and Hopkins²⁶ performed a head-to-head meta-analysis of 27 controlled trials on the metabolic effects of aerobic, resistance, and combination training in a total of 1,003 patients with diabetes. All 3 exercise modes provided favorable effects on HbA1c, fasting and postprandial glucose levels, insulin sensitivity, and fasting insulin levels, and the differences between exercise modalities were trivial.

In contrast, Schwingshackl and colleagues²⁷ performed a systematic review of 14 randomized controlled trials for the same 3 exercise modalities in 915 adults with diabetes and reported that combined training produced a significantly greater reduction in HbA1c than aerobic or resistance training alone.

Future research is necessary to quantify the additive and synergistic clinical benefits of combined exercise compared with aerobic or resistance training regimens alone; however, evidence suggests that combination exercise may be the optimal strategy for managing diabetes.

High-intensity interval training

High-intensity interval training (HIIT) has emerged as one of the fastest growing exercise programs in recent years. HIIT consists of 4 to 6 repeated, short (30-second) bouts of maximal effort interspersed with brief periods (30 to 60 seconds) of rest or active recovery. Exercise is typically performed on a stationary bike, and a single session lasts about 10 minutes.

HIIT increases skeletal muscle oxidative capacity, glycemic control, and insulin sensitivity in adults with type 2 diabetes.^28,29 A recent meta-analysis that quantified the effects of HIIT programs on glucose regulation and insulin resistance reported superior effects for HIIT compared with aerobic training or no exercise as a control.²⁸ Specifically, in 50 trials with interventions lasting at least 2 weeks, participants in HIIT groups had a 0.19% decrease in HbA1c and a 1.3-kg decrease in body weight compared with control groups.

Alternative high-intensity exercise programs have also emerged in recent years such as CrossFit, which we evaluated in a group of 12 patients with type 2 diabetes. Our proof-of-concept study found that a 6-week CrossFit program reduced body fat, diastolic blood pressure, lipids, and metabolic syndrome Z-score, and increased insulin sensitivity to glucose, basal fat oxidation, VO_2max, and high-molecular-weight adiponectin.³⁰ HIIT appears to be another effective way to improve metabolic health; and for patients with type 2 diabetes who can tolerate HIIT, it may be a time-efficient, alternative approach to continuous aerobic exercise.

BENEFITS OF EXERCISE FOR SPECIFIC METABOLIC TISSUES

Within 5 years of the discovery of insulin by Banting and Best in 1921, the first report of exercise-induced improvements in insulin action was published, though the specific cellular and molecular mechanisms that underpin these effects remain unknown.³¹

Skeletal muscle

Following a meal, skeletal muscle is the primary site for glucose disposal and uptake. Peripheral insulin resistance originating in skeletal muscle is a major driver for the development and progression of type 2 diabetes.

Exercise enhances skeletal muscle glucose uptake using both insulin-dependent and insulin-independent mechanisms, and regular exercise results in sustained improvements in insulin sensitivity and glucose disposal.³²

Of note, acute bouts of exercise can also temporarily enhance glucose uptake by the skeletal muscle up to fivefold via increased (insulin-independent) glucose transport.³³ As this transient effect fades, it is replaced by increased insulin sensitivity, and over time, these 2 adaptations to exercise result in improvements in both the insulin responsiveness and insulin sensitivity of skeletal muscle.³⁴

The fuel-sensing enzyme adenosine monophosphate-activated protein kinase (AMPK) is the major insulin-independent regulator of glucose uptake, and its activation in skeletal muscle by exercise induces glucose transport, lipid and protein synthesis, and nutrient metabolism.³⁵ AMPK remains transiently activated after exercise and regulates several downstream targets involved in mitochondrial biogenesis and function and oxidative capacity.³⁶

In this regard, aerobic training has been shown to increase skeletal muscle mitochondrial content and oxidative enzymes, resulting in dramatic improvements in glucose and fatty acid oxidation¹⁰ and increased expression of proteins involved in insulin signaling.³⁷

Adipose tissue

Exercise confers numerous positive effects in adipose tissue, namely, reduced fat mass, enhanced insulin sensitivity, and decreased inflammation. Chronic low-grade inflammation has been integrally linked to type 2 diabetes and increases the risk of cardiovascular disease.³⁸

Several inflammatory adipokines have emerged as novel predictors for the development of atherosclerosis,³⁹ and fat-cell enlargement from excessive caloric intake leads to increased production of pro-inflammatory cytokines, altered adipokine secretion, increased circulating fatty acids, and lipotoxicity concomitant with insulin resistance.⁴⁰

It has been suggested that exercise may suppress cytokine production through reduced inflammatory cell infiltration and improved adipocyte function.⁴¹ Levels of the key pro-inflammatory marker C-reactive protein is markedly reduced by exercise,^14,42 and normalization of adipokine signaling and related cytokine secretion has been validated for multiple exercise modalities.⁴²

Moreover, Ibañez et al⁴³ demonstrated that in addition to significant improvements in insulin sensitivity, resistance exercise training reduced visceral and subcutaneous fat mass in patients with type 2 diabetes.

 

 

Liver

The liver regulates fasting glucose through gluconeogenesis and glycogen storage. The liver is also the primary site of action for pancreatic hormones during the transition from pre- to postprandial states.

As with skeletal muscle and adipose tissue, insulin resistance is also present within the liver in patients with type 2 diabetes. Specifically, impaired suppression of HGP by insulin is a hallmark of type 2 diabetes, leading to sustained hyperglycemia.⁴⁴

Approaches using fasting measures of glucose and insulin do not distinguish between peripheral and hepatic insulin resistance.⁴⁵ Instead, hepatic insulin sensitivity and HGP are best assessed by the hyperinsulinemic-euglycemic clamp technique, along with isotopic glucose tracers.¹⁵

Although more elaborate, magnetic resonance spectroscopy may also be used to assess intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.⁴⁶ Indirect measures of hepatic dysfunction may be made from increased levels of the circulating hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.¹⁶

From an exercise perspective, we have shown that 7 days of aerobic training, in the absence of weight loss, improves hepatic insulin sensitivity.¹⁵ It has also been shown that hepatic AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to exercise may facilitate improved suppression of HGP.⁴⁷ We have also shown that a longer 12-week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted caloric intake.⁴⁸ Further, HGP correlated with reduced visceral fat, suggesting that this fat depot may play an important mechanistic role in improved hepatic function.

Pancreas

Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin secretion from pancreatic beta cells. For many, this hypersecretory state is unsustainable, and the subsequent loss of beta-cell function marks the onset of type 2 diabetes.⁴⁹ Fasting plasma glucose, insulin, and glucagon levels are generally poor indicators of beta-cell function.

Clinical research studies typically use the oral glucose tolerance test and hyperglycemic clamp technique to more accurately measure the dynamic regulation of glucose homeostasis by the pancreas.⁵⁰ However, few studies have examined the effects of exercise on beta-cell function in type 2 diabetes.

Dela and colleagues⁵¹ showed that 3 months of aerobic training improved beta-cell function in type 2 diabetes, but only in those who had some residual function and were less severely diabetic. We have shown that a 12-week aerobic exercise intervention improves beta-cell function in older obese adults and in patients with type 2 diabetes.^52,53 We have also found that improvements in glycemic control that occur with exercise are better predicted by changes in insulin secretion as opposed to peripheral insulin sensitivity.⁵⁴ It has also been shown that a relatively short (8-week) HIIT program improved beta-cell function in patients with type 2 diabetes.⁵⁵ And we recently found that a 6-week CrossFit training program improved beta-cell function in adults with type 2 diabetes.³⁰

SUMMARY, CONCLUSIONS, AND FUTURE DIRECTIONS

Regular exercise produces health benefits beyond improvements in cardiovascular fitness. These include enhanced glycemic control, insulin signaling, and blood lipids, as well as reduced low-grade inflammation, improved vascular function, and weight loss.

Both aerobic and resistance training programs promote healthier skeletal muscle, adipose tissue, liver, and pancreatic function.¹⁸ Greater whole-body insulin sensitivity is seen immediately after exercise and persists for up to 96 hours. While a discrete bout of exercise provides substantial metabolic benefits in diabetic cohorts, maintenance of glucose control and insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months, and years of exercise training.^15,33

Exercise intensity,¹¹ volume, and frequency⁵⁶ are associated with reductions in HbA1c; however, a consensus has not been reached on whether one is a better determinant than the other.

The most important consideration when recommending exercise to patients with type 2 diabetes is that the intensity and volume be optimized for the greatest metabolic benefit while avoiding injury or cardiovascular risk. In general, the risk of exercise-induced adverse events is low, even in adults with type 2 diabetes, and there is no current evidence that screening procedures beyond usual diabetes care are needed to safely prescribe exercise in asymptomatic patients in this population.¹⁸

Future clinical research in this area will provide a broader appreciation for the interactions (positive and negative) between exercise and diabetes medications, the synergy between exercise and bariatric surgery, and the potential to use exercise to reduce the health burden of diabetes complications, including nephropathy, retinopathy, neuropathy, and peripheral arterial disease.

Moreover, basic research will likely identify the detailed molecular defects that contribute to diabetes in insulin-targeted tissues. The emerging science surrounding cytokines, adipokines, myokines, and, most recently, exerkines is likely to deepen our understanding of the mechanistic links between exercise and diabetes management.

Finally, although we have ample evidence that exercise is an effective, scalable, and affordable approach to prevent and manage type 2 diabetes, we still need to overcome the challenge of discovering how to make exercise sustainable for patients.

Type 2 diabetes has emerged as a major public health and economic burden of the 21st century. Recent statistics from the Centers for Disease Control and Prevention suggest that diabetes affects 29.1 million people in the United States,¹ and the International Diabetes Federation estimates diabetes effects 366 million people worldwide.²

As these shocking numbers continue to increase, the cost of caring for patients with diabetes is placing enormous strain on the economies of the US and other countries. In order to manage and treat a disease on the scale of diabetes, the approaches need to be efficacious, sustainable, scalable, and affordable.

Of all the treatment options available, including multiple new medications and bariatric surgery (for patients who meet the criteria, discussed elsewhere in this supplement),^3–5 exercise as part of a lifestyle approach⁶ is a strategy that meets the majority of these criteria.

The health benefits of exercise have a long and storied history. Hippocrates, the father of scientific medicine, was the first physician on record to recognize the value of exercise for a patient with “consumption.”⁷ Today, exercise is recommended as one of the first management strategies for patients newly diagnosed with type 2 diabetes and, together with diet and behavior modification, is a central component of all type 2 diabetes and obesity prevention programs.

The evidence base for the efficacy, scalability, and affordability of exercise includes multiple large randomized controlled trials; and these data were used to create the recently updated exercise guidelines for the prevention and treatment of type 2 diabetes, published by the American Diabetes Association (ADA), American College of Sports Medicine (ACSM), and other national organizations.^8–10

Herein, we highlight the literature surrounding the metabolic effects and clinical outcomes in patients with type 2 diabetes following exercise intervention, and point to future directions for translational research in the field of exercise and diabetes.

It is known that adults who maintain a physically active lifestyle can reduce their risk of developing impaired glucose tolerance, insulin resistance, and type 2 diabetes.⁸ It has also been established that low cardiovascular fitness is a strong and independent predictor of all-cause mortality in patients with type 2 diabetes.^11,12 Indeed, patients with diabetes are 2 to 4 times more likely than healthy individuals to suffer from cardiovascular disease, due to the metabolic complexity and underlying comorbidities of type 2 diabetes including obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension.^13,14

Additionally, elevated hemoglobin A1c (HbA1c) levels are predictive of vascular complications in patients with diabetes, and regular exercise has been shown to reduce HbA1c levels, both alone and in conjunction with dietary intervention. In a meta-analysis of 9 randomized trials comprising 266 adults with type 2 diabetes, patients randomized to 20 weeks of regular exercise at 50% to 75% of their maximal aerobic capacity (VO_2max) demonstrated marked improvements in HbA1c and cardiorespiratory fitness.¹¹ Importantly, larger reductions in HbA1c were observed with more intense exercise, reflecting greater improvements in blood glucose control with increasing exercise intensity.

In addition to greater energy expenditure, which aids in reversing obesity-associated type 2 diabetes, exercise also boosts insulin action through short-term effects, mainly via insulin-independent glucose transport. For example, our laboratory and others have shown that as little as 7 days of vigorous aerobic exercise training in adults with type 2 diabetes results in improved glycemic control, without any effect on body weight.^15,16 Specifically, we observed decreased fasting plasma insulin, a 45% increase in insulin-stimulated glucose disposal, and suppressed hepatic glucose production (HGP) during carefully controlled euglycemic hyperinsulinemic clamps.¹⁵

Although the metabolic benefits of exercise are striking, the effects are short-lived and begin to fade within 48 to 96 hours.¹⁷ Therefore, an ongoing exercise program is required to maintain the favorable metabolic milieu that can be derived through exercise.

EXERCISE MODALITIES

Aerobic exercise

Notably, aerobic exercise is a well-established way to improve HbA1c, and strong evidence exists with regard to the effects of aerobic activity on weight loss and the enhanced regulation of lipid and lipoprotein metabolism.⁸ For example, in a 2007 report, 6 months of aerobic exercise training in 60 adults with type 2 diabetes led to reductions in HbA1c (−0.63% ± 0.41 vs 0.31% ± 0.10, P < .001), fasting plasma glucose (−18.6 mg/dL ± 4.4 vs 4.28 mg/dL ± 2.57, P < .001), insulin resistance (−1.52 ± 0.6 vs 0.56 ± 0.44, P = .023; as measured by homeostatic model assessment), fasting insulin (−2.91 mU/L ± 0.4 vs 0.94 mU/L ± 0.21, P = .031), and systolic blood pressure (−6.9 mm Hg ± 5.19 vs 1.22 mm Hg ± 1.09, P = .010) compared with the control group.¹⁴

Furthermore, meta-analyses reviewing the benefits of aerobic activity for patients with type 2 diabetes have repeatedly confirmed that compared with patients in sedentary control groups, aerobic exercise improves glycemic control, insulin sensitivity, oxidative capacity, and important related metabolic parameters.¹¹ Taken together, there is ample evidence that aerobic exercise is a tried-and-true exercise modality for managing and preventing type 2 diabetes.

Resistance training

During the last 2 decades, resistance training has gained considerable recognition as a viable exercise training option for patients with type 2 diabetes. Synonymous with strength training, resistance exercise involves movements utilizing free weights, weight machines, body weight exercises, or elastic resistance bands.

Primary outcomes in studies evaluating the effects of resistance training in type 2 diabetes have found improvements that range from 10% to 15% in strength, bone mineral density, blood pressure, lipid profiles, cardiovascular health, insulin sensitivity, and muscle mass.^18,20 Furthermore, because of the increased prevalence of type 2 diabetes with aging, coupled with age-related decline in muscle mass, known as sarcopenia,²¹ resistance training can provide additional health benefits in older adults.

Dunstan et al²¹ reported a threefold greater reduction in HbA1c in patients with type 2 diabetes ages 60 to 80 compared with nonexercising patients in a control group. They also noted an increase in lean body mass in the resistance-training group, while those in the nonexercising control group lost lean mass after 6 months. In a shorter, 8-week circuit weight training study performed by the same research group, patients with type 2 diabetes had improved glucose and insulin responses during an oral glucose tolerance test.²²

These findings support the use of resistance training as part of a diabetes management plan. In addition, key opinion leaders advocate that the resistance-training-induced increase in skeletal muscle mass and the associated reductions in HbA1c may indicate that skeletal muscle is a “sink” for glucose; thus, the improved glycemic control in response to resistance training may be at least in part the result of enhanced muscle glycogen storage.^21,23

Based on increasing evidence supporting the role of resistance training in glycemic control, the ADA and ACSM recently updated their exercise guidelines for treatment and prevention of type 2 diabetes to include resistance training.⁹

 

 

Combining aerobic and resistance training

The combination of aerobic and resistance training, as recommended by current ADA guidelines, may be the most effective exercise modality for controlling glucose and lipids in type 2 diabetes.

Cuff et al²⁴ evaluated whether a combined training program could improve insulin sensitivity beyond that of aerobic exercise alone in 28 postmenopausal women with type 2 diabetes. Indeed, 16 weeks of combined training led to significantly increased insulin-mediated glucose uptake compared with a group performing only aerobic exercise, reflecting greater insulin sensitivity.

Balducci et al²⁵ demonstrated that combined aerobic and resistance training markedly improved HbA1c (from 8.31% ± 1.73 to 7.1% ± 1.16, P < .001) compared with the control group and globally improved risk factors for cardiovascular disease, supporting the notion that combined training for patients with type 2 diabetes may have additive benefits.

Of note, Snowling and Hopkins²⁶ performed a head-to-head meta-analysis of 27 controlled trials on the metabolic effects of aerobic, resistance, and combination training in a total of 1,003 patients with diabetes. All 3 exercise modes provided favorable effects on HbA1c, fasting and postprandial glucose levels, insulin sensitivity, and fasting insulin levels, and the differences between exercise modalities were trivial.

In contrast, Schwingshackl and colleagues²⁷ performed a systematic review of 14 randomized controlled trials for the same 3 exercise modalities in 915 adults with diabetes and reported that combined training produced a significantly greater reduction in HbA1c than aerobic or resistance training alone.

Future research is necessary to quantify the additive and synergistic clinical benefits of combined exercise compared with aerobic or resistance training regimens alone; however, evidence suggests that combination exercise may be the optimal strategy for managing diabetes.

High-intensity interval training

High-intensity interval training (HIIT) has emerged as one of the fastest growing exercise programs in recent years. HIIT consists of 4 to 6 repeated, short (30-second) bouts of maximal effort interspersed with brief periods (30 to 60 seconds) of rest or active recovery. Exercise is typically performed on a stationary bike, and a single session lasts about 10 minutes.

HIIT increases skeletal muscle oxidative capacity, glycemic control, and insulin sensitivity in adults with type 2 diabetes.^28,29 A recent meta-analysis that quantified the effects of HIIT programs on glucose regulation and insulin resistance reported superior effects for HIIT compared with aerobic training or no exercise as a control.²⁸ Specifically, in 50 trials with interventions lasting at least 2 weeks, participants in HIIT groups had a 0.19% decrease in HbA1c and a 1.3-kg decrease in body weight compared with control groups.

Alternative high-intensity exercise programs have also emerged in recent years such as CrossFit, which we evaluated in a group of 12 patients with type 2 diabetes. Our proof-of-concept study found that a 6-week CrossFit program reduced body fat, diastolic blood pressure, lipids, and metabolic syndrome Z-score, and increased insulin sensitivity to glucose, basal fat oxidation, VO_2max, and high-molecular-weight adiponectin.³⁰ HIIT appears to be another effective way to improve metabolic health; and for patients with type 2 diabetes who can tolerate HIIT, it may be a time-efficient, alternative approach to continuous aerobic exercise.

BENEFITS OF EXERCISE FOR SPECIFIC METABOLIC TISSUES

Within 5 years of the discovery of insulin by Banting and Best in 1921, the first report of exercise-induced improvements in insulin action was published, though the specific cellular and molecular mechanisms that underpin these effects remain unknown.³¹

Skeletal muscle

Following a meal, skeletal muscle is the primary site for glucose disposal and uptake. Peripheral insulin resistance originating in skeletal muscle is a major driver for the development and progression of type 2 diabetes.

Exercise enhances skeletal muscle glucose uptake using both insulin-dependent and insulin-independent mechanisms, and regular exercise results in sustained improvements in insulin sensitivity and glucose disposal.³²

Of note, acute bouts of exercise can also temporarily enhance glucose uptake by the skeletal muscle up to fivefold via increased (insulin-independent) glucose transport.³³ As this transient effect fades, it is replaced by increased insulin sensitivity, and over time, these 2 adaptations to exercise result in improvements in both the insulin responsiveness and insulin sensitivity of skeletal muscle.³⁴

The fuel-sensing enzyme adenosine monophosphate-activated protein kinase (AMPK) is the major insulin-independent regulator of glucose uptake, and its activation in skeletal muscle by exercise induces glucose transport, lipid and protein synthesis, and nutrient metabolism.³⁵ AMPK remains transiently activated after exercise and regulates several downstream targets involved in mitochondrial biogenesis and function and oxidative capacity.³⁶

In this regard, aerobic training has been shown to increase skeletal muscle mitochondrial content and oxidative enzymes, resulting in dramatic improvements in glucose and fatty acid oxidation¹⁰ and increased expression of proteins involved in insulin signaling.³⁷

Adipose tissue

Exercise confers numerous positive effects in adipose tissue, namely, reduced fat mass, enhanced insulin sensitivity, and decreased inflammation. Chronic low-grade inflammation has been integrally linked to type 2 diabetes and increases the risk of cardiovascular disease.³⁸

Several inflammatory adipokines have emerged as novel predictors for the development of atherosclerosis,³⁹ and fat-cell enlargement from excessive caloric intake leads to increased production of pro-inflammatory cytokines, altered adipokine secretion, increased circulating fatty acids, and lipotoxicity concomitant with insulin resistance.⁴⁰

It has been suggested that exercise may suppress cytokine production through reduced inflammatory cell infiltration and improved adipocyte function.⁴¹ Levels of the key pro-inflammatory marker C-reactive protein is markedly reduced by exercise,^14,42 and normalization of adipokine signaling and related cytokine secretion has been validated for multiple exercise modalities.⁴²

Moreover, Ibañez et al⁴³ demonstrated that in addition to significant improvements in insulin sensitivity, resistance exercise training reduced visceral and subcutaneous fat mass in patients with type 2 diabetes.

 

 

Liver

The liver regulates fasting glucose through gluconeogenesis and glycogen storage. The liver is also the primary site of action for pancreatic hormones during the transition from pre- to postprandial states.

As with skeletal muscle and adipose tissue, insulin resistance is also present within the liver in patients with type 2 diabetes. Specifically, impaired suppression of HGP by insulin is a hallmark of type 2 diabetes, leading to sustained hyperglycemia.⁴⁴

Approaches using fasting measures of glucose and insulin do not distinguish between peripheral and hepatic insulin resistance.⁴⁵ Instead, hepatic insulin sensitivity and HGP are best assessed by the hyperinsulinemic-euglycemic clamp technique, along with isotopic glucose tracers.¹⁵

Although more elaborate, magnetic resonance spectroscopy may also be used to assess intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.⁴⁶ Indirect measures of hepatic dysfunction may be made from increased levels of the circulating hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.¹⁶

From an exercise perspective, we have shown that 7 days of aerobic training, in the absence of weight loss, improves hepatic insulin sensitivity.¹⁵ It has also been shown that hepatic AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to exercise may facilitate improved suppression of HGP.⁴⁷ We have also shown that a longer 12-week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted caloric intake.⁴⁸ Further, HGP correlated with reduced visceral fat, suggesting that this fat depot may play an important mechanistic role in improved hepatic function.

Pancreas

Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin secretion from pancreatic beta cells. For many, this hypersecretory state is unsustainable, and the subsequent loss of beta-cell function marks the onset of type 2 diabetes.⁴⁹ Fasting plasma glucose, insulin, and glucagon levels are generally poor indicators of beta-cell function.

Clinical research studies typically use the oral glucose tolerance test and hyperglycemic clamp technique to more accurately measure the dynamic regulation of glucose homeostasis by the pancreas.⁵⁰ However, few studies have examined the effects of exercise on beta-cell function in type 2 diabetes.

Dela and colleagues⁵¹ showed that 3 months of aerobic training improved beta-cell function in type 2 diabetes, but only in those who had some residual function and were less severely diabetic. We have shown that a 12-week aerobic exercise intervention improves beta-cell function in older obese adults and in patients with type 2 diabetes.^52,53 We have also found that improvements in glycemic control that occur with exercise are better predicted by changes in insulin secretion as opposed to peripheral insulin sensitivity.⁵⁴ It has also been shown that a relatively short (8-week) HIIT program improved beta-cell function in patients with type 2 diabetes.⁵⁵ And we recently found that a 6-week CrossFit training program improved beta-cell function in adults with type 2 diabetes.³⁰

SUMMARY, CONCLUSIONS, AND FUTURE DIRECTIONS

Regular exercise produces health benefits beyond improvements in cardiovascular fitness. These include enhanced glycemic control, insulin signaling, and blood lipids, as well as reduced low-grade inflammation, improved vascular function, and weight loss.

Both aerobic and resistance training programs promote healthier skeletal muscle, adipose tissue, liver, and pancreatic function.¹⁸ Greater whole-body insulin sensitivity is seen immediately after exercise and persists for up to 96 hours. While a discrete bout of exercise provides substantial metabolic benefits in diabetic cohorts, maintenance of glucose control and insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months, and years of exercise training.^15,33

Exercise intensity,¹¹ volume, and frequency⁵⁶ are associated with reductions in HbA1c; however, a consensus has not been reached on whether one is a better determinant than the other.

The most important consideration when recommending exercise to patients with type 2 diabetes is that the intensity and volume be optimized for the greatest metabolic benefit while avoiding injury or cardiovascular risk. In general, the risk of exercise-induced adverse events is low, even in adults with type 2 diabetes, and there is no current evidence that screening procedures beyond usual diabetes care are needed to safely prescribe exercise in asymptomatic patients in this population.¹⁸

Future clinical research in this area will provide a broader appreciation for the interactions (positive and negative) between exercise and diabetes medications, the synergy between exercise and bariatric surgery, and the potential to use exercise to reduce the health burden of diabetes complications, including nephropathy, retinopathy, neuropathy, and peripheral arterial disease.

Moreover, basic research will likely identify the detailed molecular defects that contribute to diabetes in insulin-targeted tissues. The emerging science surrounding cytokines, adipokines, myokines, and, most recently, exerkines is likely to deepen our understanding of the mechanistic links between exercise and diabetes management.

Finally, although we have ample evidence that exercise is an effective, scalable, and affordable approach to prevent and manage type 2 diabetes, we still need to overcome the challenge of discovering how to make exercise sustainable for patients.

Type 2 diabetes has emerged as a major public health and economic burden of the 21st century. Recent statistics from the Centers for Disease Control and Prevention suggest that diabetes affects 29.1 million people in the United States,¹ and the International Diabetes Federation estimates diabetes effects 366 million people worldwide.²

As these shocking numbers continue to increase, the cost of caring for patients with diabetes is placing enormous strain on the economies of the US and other countries. In order to manage and treat a disease on the scale of diabetes, the approaches need to be efficacious, sustainable, scalable, and affordable.

Of all the treatment options available, including multiple new medications and bariatric surgery (for patients who meet the criteria, discussed elsewhere in this supplement),^3–5 exercise as part of a lifestyle approach⁶ is a strategy that meets the majority of these criteria.

The health benefits of exercise have a long and storied history. Hippocrates, the father of scientific medicine, was the first physician on record to recognize the value of exercise for a patient with “consumption.”⁷ Today, exercise is recommended as one of the first management strategies for patients newly diagnosed with type 2 diabetes and, together with diet and behavior modification, is a central component of all type 2 diabetes and obesity prevention programs.

The evidence base for the efficacy, scalability, and affordability of exercise includes multiple large randomized controlled trials; and these data were used to create the recently updated exercise guidelines for the prevention and treatment of type 2 diabetes, published by the American Diabetes Association (ADA), American College of Sports Medicine (ACSM), and other national organizations.^8–10

Herein, we highlight the literature surrounding the metabolic effects and clinical outcomes in patients with type 2 diabetes following exercise intervention, and point to future directions for translational research in the field of exercise and diabetes.

It is known that adults who maintain a physically active lifestyle can reduce their risk of developing impaired glucose tolerance, insulin resistance, and type 2 diabetes.⁸ It has also been established that low cardiovascular fitness is a strong and independent predictor of all-cause mortality in patients with type 2 diabetes.^11,12 Indeed, patients with diabetes are 2 to 4 times more likely than healthy individuals to suffer from cardiovascular disease, due to the metabolic complexity and underlying comorbidities of type 2 diabetes including obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension.^13,14

Additionally, elevated hemoglobin A1c (HbA1c) levels are predictive of vascular complications in patients with diabetes, and regular exercise has been shown to reduce HbA1c levels, both alone and in conjunction with dietary intervention. In a meta-analysis of 9 randomized trials comprising 266 adults with type 2 diabetes, patients randomized to 20 weeks of regular exercise at 50% to 75% of their maximal aerobic capacity (VO_2max) demonstrated marked improvements in HbA1c and cardiorespiratory fitness.¹¹ Importantly, larger reductions in HbA1c were observed with more intense exercise, reflecting greater improvements in blood glucose control with increasing exercise intensity.

In addition to greater energy expenditure, which aids in reversing obesity-associated type 2 diabetes, exercise also boosts insulin action through short-term effects, mainly via insulin-independent glucose transport. For example, our laboratory and others have shown that as little as 7 days of vigorous aerobic exercise training in adults with type 2 diabetes results in improved glycemic control, without any effect on body weight.^15,16 Specifically, we observed decreased fasting plasma insulin, a 45% increase in insulin-stimulated glucose disposal, and suppressed hepatic glucose production (HGP) during carefully controlled euglycemic hyperinsulinemic clamps.¹⁵

Although the metabolic benefits of exercise are striking, the effects are short-lived and begin to fade within 48 to 96 hours.¹⁷ Therefore, an ongoing exercise program is required to maintain the favorable metabolic milieu that can be derived through exercise.

EXERCISE MODALITIES

Aerobic exercise

Notably, aerobic exercise is a well-established way to improve HbA1c, and strong evidence exists with regard to the effects of aerobic activity on weight loss and the enhanced regulation of lipid and lipoprotein metabolism.⁸ For example, in a 2007 report, 6 months of aerobic exercise training in 60 adults with type 2 diabetes led to reductions in HbA1c (−0.63% ± 0.41 vs 0.31% ± 0.10, P < .001), fasting plasma glucose (−18.6 mg/dL ± 4.4 vs 4.28 mg/dL ± 2.57, P < .001), insulin resistance (−1.52 ± 0.6 vs 0.56 ± 0.44, P = .023; as measured by homeostatic model assessment), fasting insulin (−2.91 mU/L ± 0.4 vs 0.94 mU/L ± 0.21, P = .031), and systolic blood pressure (−6.9 mm Hg ± 5.19 vs 1.22 mm Hg ± 1.09, P = .010) compared with the control group.¹⁴

Furthermore, meta-analyses reviewing the benefits of aerobic activity for patients with type 2 diabetes have repeatedly confirmed that compared with patients in sedentary control groups, aerobic exercise improves glycemic control, insulin sensitivity, oxidative capacity, and important related metabolic parameters.¹¹ Taken together, there is ample evidence that aerobic exercise is a tried-and-true exercise modality for managing and preventing type 2 diabetes.

Resistance training

During the last 2 decades, resistance training has gained considerable recognition as a viable exercise training option for patients with type 2 diabetes. Synonymous with strength training, resistance exercise involves movements utilizing free weights, weight machines, body weight exercises, or elastic resistance bands.

Primary outcomes in studies evaluating the effects of resistance training in type 2 diabetes have found improvements that range from 10% to 15% in strength, bone mineral density, blood pressure, lipid profiles, cardiovascular health, insulin sensitivity, and muscle mass.^18,20 Furthermore, because of the increased prevalence of type 2 diabetes with aging, coupled with age-related decline in muscle mass, known as sarcopenia,²¹ resistance training can provide additional health benefits in older adults.

Dunstan et al²¹ reported a threefold greater reduction in HbA1c in patients with type 2 diabetes ages 60 to 80 compared with nonexercising patients in a control group. They also noted an increase in lean body mass in the resistance-training group, while those in the nonexercising control group lost lean mass after 6 months. In a shorter, 8-week circuit weight training study performed by the same research group, patients with type 2 diabetes had improved glucose and insulin responses during an oral glucose tolerance test.²²

These findings support the use of resistance training as part of a diabetes management plan. In addition, key opinion leaders advocate that the resistance-training-induced increase in skeletal muscle mass and the associated reductions in HbA1c may indicate that skeletal muscle is a “sink” for glucose; thus, the improved glycemic control in response to resistance training may be at least in part the result of enhanced muscle glycogen storage.^21,23

Based on increasing evidence supporting the role of resistance training in glycemic control, the ADA and ACSM recently updated their exercise guidelines for treatment and prevention of type 2 diabetes to include resistance training.⁹

 

 

Combining aerobic and resistance training

The combination of aerobic and resistance training, as recommended by current ADA guidelines, may be the most effective exercise modality for controlling glucose and lipids in type 2 diabetes.

Cuff et al²⁴ evaluated whether a combined training program could improve insulin sensitivity beyond that of aerobic exercise alone in 28 postmenopausal women with type 2 diabetes. Indeed, 16 weeks of combined training led to significantly increased insulin-mediated glucose uptake compared with a group performing only aerobic exercise, reflecting greater insulin sensitivity.

Balducci et al²⁵ demonstrated that combined aerobic and resistance training markedly improved HbA1c (from 8.31% ± 1.73 to 7.1% ± 1.16, P < .001) compared with the control group and globally improved risk factors for cardiovascular disease, supporting the notion that combined training for patients with type 2 diabetes may have additive benefits.

Of note, Snowling and Hopkins²⁶ performed a head-to-head meta-analysis of 27 controlled trials on the metabolic effects of aerobic, resistance, and combination training in a total of 1,003 patients with diabetes. All 3 exercise modes provided favorable effects on HbA1c, fasting and postprandial glucose levels, insulin sensitivity, and fasting insulin levels, and the differences between exercise modalities were trivial.

In contrast, Schwingshackl and colleagues²⁷ performed a systematic review of 14 randomized controlled trials for the same 3 exercise modalities in 915 adults with diabetes and reported that combined training produced a significantly greater reduction in HbA1c than aerobic or resistance training alone.

Future research is necessary to quantify the additive and synergistic clinical benefits of combined exercise compared with aerobic or resistance training regimens alone; however, evidence suggests that combination exercise may be the optimal strategy for managing diabetes.

High-intensity interval training

High-intensity interval training (HIIT) has emerged as one of the fastest growing exercise programs in recent years. HIIT consists of 4 to 6 repeated, short (30-second) bouts of maximal effort interspersed with brief periods (30 to 60 seconds) of rest or active recovery. Exercise is typically performed on a stationary bike, and a single session lasts about 10 minutes.

HIIT increases skeletal muscle oxidative capacity, glycemic control, and insulin sensitivity in adults with type 2 diabetes.^28,29 A recent meta-analysis that quantified the effects of HIIT programs on glucose regulation and insulin resistance reported superior effects for HIIT compared with aerobic training or no exercise as a control.²⁸ Specifically, in 50 trials with interventions lasting at least 2 weeks, participants in HIIT groups had a 0.19% decrease in HbA1c and a 1.3-kg decrease in body weight compared with control groups.

Alternative high-intensity exercise programs have also emerged in recent years such as CrossFit, which we evaluated in a group of 12 patients with type 2 diabetes. Our proof-of-concept study found that a 6-week CrossFit program reduced body fat, diastolic blood pressure, lipids, and metabolic syndrome Z-score, and increased insulin sensitivity to glucose, basal fat oxidation, VO_2max, and high-molecular-weight adiponectin.³⁰ HIIT appears to be another effective way to improve metabolic health; and for patients with type 2 diabetes who can tolerate HIIT, it may be a time-efficient, alternative approach to continuous aerobic exercise.

BENEFITS OF EXERCISE FOR SPECIFIC METABOLIC TISSUES

Within 5 years of the discovery of insulin by Banting and Best in 1921, the first report of exercise-induced improvements in insulin action was published, though the specific cellular and molecular mechanisms that underpin these effects remain unknown.³¹

Skeletal muscle

Following a meal, skeletal muscle is the primary site for glucose disposal and uptake. Peripheral insulin resistance originating in skeletal muscle is a major driver for the development and progression of type 2 diabetes.

Exercise enhances skeletal muscle glucose uptake using both insulin-dependent and insulin-independent mechanisms, and regular exercise results in sustained improvements in insulin sensitivity and glucose disposal.³²

Of note, acute bouts of exercise can also temporarily enhance glucose uptake by the skeletal muscle up to fivefold via increased (insulin-independent) glucose transport.³³ As this transient effect fades, it is replaced by increased insulin sensitivity, and over time, these 2 adaptations to exercise result in improvements in both the insulin responsiveness and insulin sensitivity of skeletal muscle.³⁴

The fuel-sensing enzyme adenosine monophosphate-activated protein kinase (AMPK) is the major insulin-independent regulator of glucose uptake, and its activation in skeletal muscle by exercise induces glucose transport, lipid and protein synthesis, and nutrient metabolism.³⁵ AMPK remains transiently activated after exercise and regulates several downstream targets involved in mitochondrial biogenesis and function and oxidative capacity.³⁶

In this regard, aerobic training has been shown to increase skeletal muscle mitochondrial content and oxidative enzymes, resulting in dramatic improvements in glucose and fatty acid oxidation¹⁰ and increased expression of proteins involved in insulin signaling.³⁷

Adipose tissue

Exercise confers numerous positive effects in adipose tissue, namely, reduced fat mass, enhanced insulin sensitivity, and decreased inflammation. Chronic low-grade inflammation has been integrally linked to type 2 diabetes and increases the risk of cardiovascular disease.³⁸

Several inflammatory adipokines have emerged as novel predictors for the development of atherosclerosis,³⁹ and fat-cell enlargement from excessive caloric intake leads to increased production of pro-inflammatory cytokines, altered adipokine secretion, increased circulating fatty acids, and lipotoxicity concomitant with insulin resistance.⁴⁰

It has been suggested that exercise may suppress cytokine production through reduced inflammatory cell infiltration and improved adipocyte function.⁴¹ Levels of the key pro-inflammatory marker C-reactive protein is markedly reduced by exercise,^14,42 and normalization of adipokine signaling and related cytokine secretion has been validated for multiple exercise modalities.⁴²

Moreover, Ibañez et al⁴³ demonstrated that in addition to significant improvements in insulin sensitivity, resistance exercise training reduced visceral and subcutaneous fat mass in patients with type 2 diabetes.

 

 

Liver

The liver regulates fasting glucose through gluconeogenesis and glycogen storage. The liver is also the primary site of action for pancreatic hormones during the transition from pre- to postprandial states.

As with skeletal muscle and adipose tissue, insulin resistance is also present within the liver in patients with type 2 diabetes. Specifically, impaired suppression of HGP by insulin is a hallmark of type 2 diabetes, leading to sustained hyperglycemia.⁴⁴

Approaches using fasting measures of glucose and insulin do not distinguish between peripheral and hepatic insulin resistance.⁴⁵ Instead, hepatic insulin sensitivity and HGP are best assessed by the hyperinsulinemic-euglycemic clamp technique, along with isotopic glucose tracers.¹⁵

Although more elaborate, magnetic resonance spectroscopy may also be used to assess intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.⁴⁶ Indirect measures of hepatic dysfunction may be made from increased levels of the circulating hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.¹⁶

From an exercise perspective, we have shown that 7 days of aerobic training, in the absence of weight loss, improves hepatic insulin sensitivity.¹⁵ It has also been shown that hepatic AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to exercise may facilitate improved suppression of HGP.⁴⁷ We have also shown that a longer 12-week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted caloric intake.⁴⁸ Further, HGP correlated with reduced visceral fat, suggesting that this fat depot may play an important mechanistic role in improved hepatic function.

Pancreas

Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin secretion from pancreatic beta cells. For many, this hypersecretory state is unsustainable, and the subsequent loss of beta-cell function marks the onset of type 2 diabetes.⁴⁹ Fasting plasma glucose, insulin, and glucagon levels are generally poor indicators of beta-cell function.

Clinical research studies typically use the oral glucose tolerance test and hyperglycemic clamp technique to more accurately measure the dynamic regulation of glucose homeostasis by the pancreas.⁵⁰ However, few studies have examined the effects of exercise on beta-cell function in type 2 diabetes.

Dela and colleagues⁵¹ showed that 3 months of aerobic training improved beta-cell function in type 2 diabetes, but only in those who had some residual function and were less severely diabetic. We have shown that a 12-week aerobic exercise intervention improves beta-cell function in older obese adults and in patients with type 2 diabetes.^52,53 We have also found that improvements in glycemic control that occur with exercise are better predicted by changes in insulin secretion as opposed to peripheral insulin sensitivity.⁵⁴ It has also been shown that a relatively short (8-week) HIIT program improved beta-cell function in patients with type 2 diabetes.⁵⁵ And we recently found that a 6-week CrossFit training program improved beta-cell function in adults with type 2 diabetes.³⁰

SUMMARY, CONCLUSIONS, AND FUTURE DIRECTIONS

Regular exercise produces health benefits beyond improvements in cardiovascular fitness. These include enhanced glycemic control, insulin signaling, and blood lipids, as well as reduced low-grade inflammation, improved vascular function, and weight loss.

Both aerobic and resistance training programs promote healthier skeletal muscle, adipose tissue, liver, and pancreatic function.¹⁸ Greater whole-body insulin sensitivity is seen immediately after exercise and persists for up to 96 hours. While a discrete bout of exercise provides substantial metabolic benefits in diabetic cohorts, maintenance of glucose control and insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months, and years of exercise training.^15,33

Exercise intensity,¹¹ volume, and frequency⁵⁶ are associated with reductions in HbA1c; however, a consensus has not been reached on whether one is a better determinant than the other.

The most important consideration when recommending exercise to patients with type 2 diabetes is that the intensity and volume be optimized for the greatest metabolic benefit while avoiding injury or cardiovascular risk. In general, the risk of exercise-induced adverse events is low, even in adults with type 2 diabetes, and there is no current evidence that screening procedures beyond usual diabetes care are needed to safely prescribe exercise in asymptomatic patients in this population.¹⁸

Future clinical research in this area will provide a broader appreciation for the interactions (positive and negative) between exercise and diabetes medications, the synergy between exercise and bariatric surgery, and the potential to use exercise to reduce the health burden of diabetes complications, including nephropathy, retinopathy, neuropathy, and peripheral arterial disease.

Moreover, basic research will likely identify the detailed molecular defects that contribute to diabetes in insulin-targeted tissues. The emerging science surrounding cytokines, adipokines, myokines, and, most recently, exerkines is likely to deepen our understanding of the mechanistic links between exercise and diabetes management.

Finally, although we have ample evidence that exercise is an effective, scalable, and affordable approach to prevent and manage type 2 diabetes, we still need to overcome the challenge of discovering how to make exercise sustainable for patients.

Diabesity was a term coined by Sims et al¹ in the 1970s to describe diabetes occurring in the setting of obesity. Today, the link between type 2 diabetes mellitus (DM), obesity, and insulin resistance is well recognized, and 80% of people with type 2 DM are overweight or obese.^2,3 Unfortunately, weight gain is a known side effect of most agents used to treat type 2 DM (eg, insulin, sulfonylureas, thiazolidinediones), and this often leads to nonadherence, poor glycemic control, and further weight gain.

During the past several years, evidence has emerged of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes.² This has led to research for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c (HbA1c), but also have weight loss as a potential side effect.

In this paper, we review medications approved for the treatment of type 2 DM (including pramlintide, also approved for type 1 DM) that also have weight loss as a side effect. Drugs we will discuss include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, we also comment on the effects of the drugs on cardiovascular outcomes.

GLP-1 RECEPTOR AGONISTS

Mechanism of action

GLP-1 is a hormone produced from the proglucagon gene in the alpha cells of the pancreas, in the L cells of intestinal mucosa (predominantly in the ileum and distal colon), and in structures of the nervous system including the brainstem, hypothalamus, and vagal afferent nerves.⁴ Food in the gastrointestinal tract, especially if high in fats and carbohydrates, stimulates secretion of GLP-1 in the L cells, which in turn amplifies insulin secretion in a glucose-dependent manner (the incretin effect).⁴ Glucagon secretion is inhibited by GLP-1 during times of hyperglycemia but not hypoglycemia, thereby preventing inappropriately high levels of the hormone.⁵ Peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility.⁵ Lastly, GLP-1 exerts an anorexic effect by acting on central pathways that mediate satiation.⁶

Bioactive forms of GLP-1 are rapidly degraded in the circulation by the dipeptidyl peptidase-4 enzyme. GLP-1 receptor agonists have slightly altered molecular structure and longer duration of action than native GLP-1. Short-acting GLP-1 agonists (eg, exenatide, lixisenatide) have more effect on gastric emptying and lower postprandial blood glucose levels, whereas long-acting GLP-1 agonists (eg, liraglutide, albiglutide, dulaglutide, semaglutide, exenatide) have a greater effect on fasting glucose levels.⁴

Effects on HbA1c and weight loss

Of the current GLP-1 agonists, exenatide and liraglutide have been on the market the longest, thus studied more in terms of weight reduction.

Exenatide. Exenatide BID was the first GLP-1 agonist, approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of type 2 DM. In a 30-week triple-blind, placebo-controlled study of 336 patients already on background therapy with metformin, progressive weight loss was noted with exenatide 5 μg (−1.6 ± 0.4 kg) and exenatide 10 μg (−2.8 ± 0.5 kg) compared with placebo (−0.3 ± 0.3 kg; P < .001).¹⁵ A meta-analysis of 14 trials with 2,583 patients showed significant weight reduction with both exenatide 5 μg twice daily (a difference of −0.56 kg, 95% confidence interval [CI] −1.07 to −0.06, P = .0002) in 8 trials and exenatide 10 μg twice daily (a difference of −1.24 kg, 95% CI −1.69 to −0.78, P < .001) in 12 trials, after treatment for more than 16 weeks.¹⁶

Liraglutide. Liraglutide has a longer half-life than exenatide and is administered once daily. It is not a first-line therapy for type 2 DM and is recommended as an add-on. Approved daily doses for type 2 DM are 1.2 mg and 1.8 mg.

Multiple studies of glycemic control and weight loss with liraglutide have been conducted since its introduction to the US market in 2010. In the Liraglutide Effect and Action in Diabetes (LEAD) series of trials, liraglutide use as monotherapy or in combination with oral agents was associated with significant dose-dependent weight loss.¹⁷ Liraglutide monotherapy (at 1.2 mg and 1.8 mg) compared with glimepiride in the LEAD-3 trial led to significant weight reduction (2.1 kg and 2.5 kg, respectively, P < .001) after 16 weeks, and was sustained up to 52 weeks.¹⁸ Addition of liraglutide (at 1.2 mg and 1.8 mg) to metformin plus rosiglitazone resulted in significant weight loss (1.02 kg and 2.02 kg, respectively) whereas the addition of placebo caused a 0.6-kg weight gain (P < .001).¹⁹ The SCALE study randomized 846 adults with type 2 DM who were overweight to obese (body mass index [BMI] ≥ 27 kg/m²), were taking 0 to 3 oral antihyperglycemic agents (metformin, thiazolidinedione, and a sulfonylurea), and had stable body weight and an HbA1c of 7% to 10% to liraglutide 1.8 mg, liraglutide 3.0 mg, or placebo. Mean weight loss after 56 weeks was 6.0% (6.4 kg) with liraglutide 1.8 mg, 4.7% (5.0 kg) with liraglutide 3.0 mg, and 2.0% (2.2 kg) with placebo.²⁰

In 2016, high-dose once-daily liraglutide 3.0 mg (Saxenda) was approved by the FDA for weight loss. In a double-blind randomized trial of liraglutide 3.0 mg vs placebo in patients who had a BMI of at least 30 or who had a BMI of at least 27 plus treated or untreated dyslipidemia or hypertension, Pi-Sunyer et al²¹ reported a mean weight reduction of 8.4 ± 7.3 kg with liraglutide vs 2.8 ± 6.5 kg with placebo (a difference of −5.6 kg, 95% CI −6.0 to −5.1, P < .001) after 56 weeks. Furthermore, 63.2% of patients in the liraglutide group lost at least 5% of body weight vs 27.1% with placebo, and 33.1% in the liraglutide group lost 10% or more of body weight vs 10.6% in the placebo group (P < .001).²¹ Of note, liraglutide 3.0 mg is not indicated for type 2 DM per se.

In a 2012 meta-analysis of randomized controlled trials of adults with and without type 2 DM, with a BMI of 25 or greater, and who received GLP-1 receptor agonists at clinically rele­vant doses (exenatide ≥ 10 μg/day, exenatide ≥ 2 mg/week, or liraglutide ≥ 1.2 mg/day), those taking GLP-1 receptor agonists had more weight loss than those on a control intervention (oral antihyperglycemic, insulin, or placebo) at a minimum of 20 weeks, with a weighted mean difference −2.9 kg (95% CI −3.6 to −2.2) in 21 trials and 6,411 participants.²²

GLP-1 agonists currently being investigated for obesity treatment are lixisenatide, albiglutide, taspoglutide, and oxyntomodulin.²³

 

 

Cardiovascular outcomes

The presence of GLP-1 receptors in blood vessels and myocardium has led to the hypothesis that GLP-1 receptor agonists can improve cardiovascular disease outcomes.²⁴ In the pivotal Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, 9,340 patients with type 2 DM and increased cardiovascular disease risk were randomized to liraglutide vs placebo.²⁵ The hazard ratio (HR) for time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was 0.87 (P = .01 for superiority, P < .001 for noninferiority) for liraglutide compared with placebo after 3.8 years. The incidence of death from any cause or cardiovascular cause was also lower with liraglutide.²⁵

Adverse effects

Tolerable transient nausea and vomiting are reported adverse effects; these symptoms occur early in therapy, usually resolve in 4 to 8 weeks, and appear to be associated with greater weight loss.²⁶ Although no causal relationship between GLP-1 receptor agonist use and pancreatitis or pancreatic cancer has been established to date, several cases of acute pancreatitis have been reported.²⁵ Alternative therapies should be considered in patients with a history of or risk factors for pancreatitis.

Combined with insulin

A product that combines insulin glargine and lixisenatide (Soliqua) is FDA-approved for patients with type 2 DM. In a 30-week randomized controlled trial of the combination product vs insulin glargine alone in patients with type 2 DM not controlled on basal insulin with or without up to 2 oral agents, the combination product resulted in an HbA1c reduction from baseline of 1.1% vs 0.6% for insulin glargine alone (P < .001).²⁷ Mean body weight decreased by 0.7 kg with the combination product and increased by 0.7 kg with insulin glargine (P < .001).²⁷ In a 24-week study of a lixisenatide-insulin glargine combination vs insulin glargine in insulin-naïve patients taking metformin, there was a reduction in HbA1c of about −1.7% from baseline in both groups, while the combination group had a 1-kg weight reduction compared with a 0.5-kg weight increase in the insulin glargine group (P < .001).²⁸

SGLT-2 INHIBITORS

Mechanism of action

In a healthy normoglycemic person, about 180 g of glucose per day is filtered into the glomerular filtrate and reabsorbed into the circulation.²⁹ SGLT-2 facilitates the reabsorption of glucose in the proximal convoluted tubule of the kidneys. Approximately 90% of glucose reabsorption is mediated by SGLT-2 found in the S1 and S2 segments of the proximal convoluted tubule, and the remaining 10% by SGLT-1 in the S3 segment. At serum glucose levels above 180 g, the reabsorptive capacity of the nephron is overwhelmed, resulting in glycosuria.³⁰ SGLT-2 expression is also increased in patients with diabetes, thus leading to increased glucose reabsorption into the circulation, further contributing to hyperglycemia.³⁰ Inhibition of SGLT-2 alleviates hyperglycemia by decreasing glucose reabsorption (30% to 50% of filtered glucose) in the kidneys and by increasing excretion (50 mg to 80 mg of glucose) in the urine.³¹ SGLT-2 inhibitors currently FDA-approved are canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance).

HbA1c 

SGLT-2 inhibitors have relatively weak glycemic efficacy. A meta-analysis of SGLT-2 inhibitors vs other antidiabetic medications or placebo found that SGLT-2 inhibitors appeared to have a “favorable effect” on HbA1c, with a mean difference vs placebo of −0.66% (95% CI −0.73% to −0.58%) and a mean difference vs other antihyperglycemic medications of −0.06% (95% CI 0.18% to 0.05%).³²

Weight loss

The same meta-analysis found that SGLT-2 inhibitors reduced body weight (mean difference −1.8 kg, 95% CI −3.50 kg to −0.11 kg).³² And in a randomized controlled trial, monotherapy with canagliflozin 100 mg/day and 300 mg/day resulted in body weight reduction of 2.2% (1.9 kg) and 3.3% (−2.9 kg), respectively, after 26 weeks.³³ A Japanese study showed a dose-related total body weight loss with empagliflozin vs placebo ranging from 2.5 ± 0.2 kg (5-mg dose) to 3.1 ± 0.2 kg (50-mg dose) after 12 weeks.³⁴ Bolinder et al³⁵ reported that adding dapagliflozin 10 mg to metformin in patients with type 2 DM reduced total body weight by −2.96 kg (95% CI −3.51 to −2.41, P < .001) at week 24. Whole-body dual-energy x-ray absorptiometry and magnetic resonance imaging findings in this study revealed a decrease in fat mass and visceral and subcutaneous adipose tissue after treatment with dapagliflozin, thus suggesting urinary loss of glucose (and hence caloric loss) contributing to weight reduction in addition to initial weight loss from fluid loss due to osmotic diuresis.³⁵ A continuous decline in total body weight was observed in a 78-week extension study resulting in −4.54 kg (95% CI −5.43 to −3.66 kg) at week 102, along with further reduction in total body fat mass as measured by dual-energy x-ray absorptiometry.³⁶

Cardiovascular outcomes

The landmark study Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG) involving 7,020 patients was the first large cardiovascular outcomes trial in patients with type 2 DM and overt cardiovascular disease. A relative risk reduction of 14% (12.1% to 10.5%, HR 0.86, 95% CI 0.74 to 0.99) in major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was observed with empagliflozin.³⁷ Rates of all-cause mortality and hospitalization for heart failure relative risk reductions were 32% (8.3% to 5.7%; HR 0.68 [0.57, 0.8]) and 35% (4.1% to 2.7%; HR 0.65 [0.50, 0.85]), respectively, with empagliflozin. The mechanism behind this cardiovascular benefit is unknown but is currently being explored.³⁷

Adverse effects

Increased risk of urinary tract and genital infections are known adverse effects of SGLT-2s. Other effects noted include postural hypotension from volume depletion and a transient increase in serum creatinine and decrease in glomerular filtration.²⁹

NEUROENDOCRINE PEPTIDE HORMONE: AMYLIN ANALOGUES

Mechanism of action

Amylin is a 37-amino-acid neuroendocrine peptide hormone secreted primarily by pancreatic beta cells. It promotes early satiety, and its anorexigenic effects are mediated by its action on the neurons of the area postrema in the brain.³⁸ After a meal, amylin decreases gastric acid secretion and slows gastric emptying. It is co-secreted with insulin in a 1:20 amylin-to-insulin ratio and inhibits glucagon secretion via a centrally mediated mechanism.³⁹

Pramlintide (Symlin) is an amylin analogue administered subcutaneously immediately before major meals. It decreases postprandial glucose levels and has been approved by the FDA as an adjunct to prandial insulin in patients with type 1 and type 2 DM.⁴⁰

HbA1c

Amylin secretion is impaired in type 1 and type 2 DM, and small but significant reductions in HbA1c have been observed with addition of pramlintide to usual insulin regimens. In patients with type 1 DM, HbA1c levels were reduced by 0.4% to 0.6% after 26 weeks on 30 μg 3 times daily to 60 μg 4 times daily of pramlintide added to insulin.^41,42 And pramlintide 120 μg added to usual antihyperglycemic therapy in patients with type 2 DM has been reported to decrease HbA1c by 0.7% at week 16 or 26.^43,44

Weight loss

A meta-analysis of 8 randomized controlled trials assessed the effects of pramlintide on glycemic control and weight in patients with type 2 DM treated with insulin and in obese patients without diabetes.⁴⁵ In these trials, patients took at least 120 μg of pramlintide before 2 to 3 meals for at least 12 weeks; a total of 1,616 participants were included. In the type 2 DM group, pramlintide reduced body weight by 2.57 kg (95% CI −3.44 to −1.70 kg, P < .001) vs control, over 16 to 52 weeks.⁴⁵ The nondiabetic obese group had a weight loss of −2.27 kg (95%CI −2.88 to −1.66 kg, P < .001) vs control.⁴⁵

Pramlintide and a pramlintide-phentermine combination are currently under investigation for treatment of obesity.²³

Cardiovascular outcomes

Cardiovascular outcomes in patients treated with pramlintide have not been studied to date, but reductions have been observed in markers of cardiovascular risk including high-sensitivity C-reactive protein and triglycerides.⁴⁶

Adverse effects

Transient mild-to-moderate nausea is the most common adverse effect of pramlintide. Hypoglycemia has also been reported, more frequently in patients with type 1 DM, which is possibly associated with inadequate reduction in insulin.

 

 

ALPHA-GLUCOSIDASE INHIBITORS

Mechanism of action

Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes at the brush border of the small intestine. Taken orally before meals, these drugs mitigate postprandial hyperglycemia by preventing the breakdown of complex carbohydrates into simpler monosaccharides, thus delaying their absorption.⁴⁷ These agents may be used as monotherapy or in combination with other antihyperglycemic agents. They work independently from insulin, although they have been shown to potentiate GLP-1 secretion.⁴⁸ Acarbose and miglitol are currently approved in the United States. Acarbose has been more extensively studied worldwide.

HbA1c

Alpha-glucosidase inhibitors have been reported to reduce mean HbA1c by 0.8% (95% CI −0.9% to −0.7%), as well as fasting and postprandial glucose, and postprandial insulin levels.⁴⁹

Weight loss

There is conflicting evidence on whether alpha-glucosidase inhibitor therapy has a neutral or beneficial effect on body weight. A Cochrane meta-analysis observed significant BMI reduction with acarbose, although no effect on body weight was noted,⁴⁹ whereas in another meta-analysis, body weight was significantly reduced by 0.96 kg (95% CI −1.80 to −0.12 kg) when acarbose was added to metformin.⁵⁰ A review of pooled data from worldwide post-marketing studies for acarbose reported a weight reduction after 3 months of 0.98 ± 2.11 kg in overweight patients and 1.67 ± 3.02 kg in obese patients.⁵¹

Cardiovascular outcomes

In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), when compared with placebo, treatment of patients with impaired glucose tolerance with acarbose significantly reduced the incidence of cardiovascular events (HR 0.51, 95% CI 0.28 to 0.95, P = .03), myocardial infarction (HR 0.09, 95% CI 0.01 to 0.72, P = .02), and newly diagnosed hypertension (HR 0.66, 95% CI 0.49 to 0.89, P = .006).⁵²

Adverse effects

Although mild, gastrointestinal effects of flatulence and diarrhea can be bothersome and result in discontinuation of the drug in most patients.

METFORMIN

Mechanism of action

Metformin is the first-line antihyperglycemic agent for type 2 DM recommended by the American Diabetes Association and European Association for the Study of Diabetes.^53,54 The main action of metformin is to decrease glucose production in the liver. In the small intestine, metformin stimulates the L cells to produce GLP-1, and in skeletal muscle, it increases glucose uptake and disposal.⁵⁵

HbA1c

As monotherapy, metformin has resulted in HbA1c reductions of 0.88% to 1.2%.⁵⁵

Weight loss

Reduced food intake^56,57 and gastrointestinal intolerance⁵⁸ occurring early in therapy have been noted to account for weight loss in short-term studies of non-diabetic obese patients treated with metformin.⁵⁹ Long-term trials of patients with and without diabetes have yielded mixed results on weight reduction from metformin as monotherapy or adjunct therapy. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin had resulted in approximately 1.5 kg of weight gain (slightly less than the 4-kg weight gain in the glibenclamide group).⁶⁰ Improved antihyperglycemic efficacy of other antihyperglycemic agents (insulin, sulfonylureas, and thiazolidinediones) with addition of metformin led to dose-lowering of the antihyperglycemic agents, ultimately resulting in amelioration of weight gain; this has also led to small weight reductions in some studies.⁵⁹ In the Diabetes Prevention Program study of patients with impaired glucose tolerance, metformin treatment resulted in an average weight loss of 2.1 kg compared with placebo (−0.1 kg) and lifestyle intervention (−5.6 kg; P <.001).⁶¹

Cardiovascular outcomes

Metformin has been observed to decrease micro- and macrovascular complications. Compared with diet alone, metformin was associated with a 39% reduction in the risk of myocardial infarction, and a 30% lower risk of a composite of macrovascular diseases (myocardial infarction, sudden death, angina, stroke, and peripheral disease).⁶⁰

Adverse effects

The most common adverse effect of metformin is gastrointestinal intolerance from abdominal pain, flatulence, and diarrhea.⁶² Metformin-associated lactic acidosis is a serious and potentially life-threatening effect; and vitamin B₁₂ deficiency may occur with long-term treatment.⁶²

TAKE-HOME POINTS

As more medications and interventions are being developed to counter obesity, it also makes sense to select diabetes medications that do not contribute to weight gain in patients who are already overweight or obese. The effects of available medications can be maximized and treatment regimens individualized (based on patients’ needs and preferences, within the limitations of drug costs and side effects), along with lifestyle modification, to target diabesity.

Diabesity was a term coined by Sims et al¹ in the 1970s to describe diabetes occurring in the setting of obesity. Today, the link between type 2 diabetes mellitus (DM), obesity, and insulin resistance is well recognized, and 80% of people with type 2 DM are overweight or obese.^2,3 Unfortunately, weight gain is a known side effect of most agents used to treat type 2 DM (eg, insulin, sulfonylureas, thiazolidinediones), and this often leads to nonadherence, poor glycemic control, and further weight gain.

During the past several years, evidence has emerged of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes.² This has led to research for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c (HbA1c), but also have weight loss as a potential side effect.

In this paper, we review medications approved for the treatment of type 2 DM (including pramlintide, also approved for type 1 DM) that also have weight loss as a side effect. Drugs we will discuss include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, we also comment on the effects of the drugs on cardiovascular outcomes.

GLP-1 RECEPTOR AGONISTS

Mechanism of action

GLP-1 is a hormone produced from the proglucagon gene in the alpha cells of the pancreas, in the L cells of intestinal mucosa (predominantly in the ileum and distal colon), and in structures of the nervous system including the brainstem, hypothalamus, and vagal afferent nerves.⁴ Food in the gastrointestinal tract, especially if high in fats and carbohydrates, stimulates secretion of GLP-1 in the L cells, which in turn amplifies insulin secretion in a glucose-dependent manner (the incretin effect).⁴ Glucagon secretion is inhibited by GLP-1 during times of hyperglycemia but not hypoglycemia, thereby preventing inappropriately high levels of the hormone.⁵ Peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility.⁵ Lastly, GLP-1 exerts an anorexic effect by acting on central pathways that mediate satiation.⁶

Bioactive forms of GLP-1 are rapidly degraded in the circulation by the dipeptidyl peptidase-4 enzyme. GLP-1 receptor agonists have slightly altered molecular structure and longer duration of action than native GLP-1. Short-acting GLP-1 agonists (eg, exenatide, lixisenatide) have more effect on gastric emptying and lower postprandial blood glucose levels, whereas long-acting GLP-1 agonists (eg, liraglutide, albiglutide, dulaglutide, semaglutide, exenatide) have a greater effect on fasting glucose levels.⁴

Effects on HbA1c and weight loss

Of the current GLP-1 agonists, exenatide and liraglutide have been on the market the longest, thus studied more in terms of weight reduction.

Exenatide. Exenatide BID was the first GLP-1 agonist, approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of type 2 DM. In a 30-week triple-blind, placebo-controlled study of 336 patients already on background therapy with metformin, progressive weight loss was noted with exenatide 5 μg (−1.6 ± 0.4 kg) and exenatide 10 μg (−2.8 ± 0.5 kg) compared with placebo (−0.3 ± 0.3 kg; P < .001).¹⁵ A meta-analysis of 14 trials with 2,583 patients showed significant weight reduction with both exenatide 5 μg twice daily (a difference of −0.56 kg, 95% confidence interval [CI] −1.07 to −0.06, P = .0002) in 8 trials and exenatide 10 μg twice daily (a difference of −1.24 kg, 95% CI −1.69 to −0.78, P < .001) in 12 trials, after treatment for more than 16 weeks.¹⁶

Liraglutide. Liraglutide has a longer half-life than exenatide and is administered once daily. It is not a first-line therapy for type 2 DM and is recommended as an add-on. Approved daily doses for type 2 DM are 1.2 mg and 1.8 mg.

Multiple studies of glycemic control and weight loss with liraglutide have been conducted since its introduction to the US market in 2010. In the Liraglutide Effect and Action in Diabetes (LEAD) series of trials, liraglutide use as monotherapy or in combination with oral agents was associated with significant dose-dependent weight loss.¹⁷ Liraglutide monotherapy (at 1.2 mg and 1.8 mg) compared with glimepiride in the LEAD-3 trial led to significant weight reduction (2.1 kg and 2.5 kg, respectively, P < .001) after 16 weeks, and was sustained up to 52 weeks.¹⁸ Addition of liraglutide (at 1.2 mg and 1.8 mg) to metformin plus rosiglitazone resulted in significant weight loss (1.02 kg and 2.02 kg, respectively) whereas the addition of placebo caused a 0.6-kg weight gain (P < .001).¹⁹ The SCALE study randomized 846 adults with type 2 DM who were overweight to obese (body mass index [BMI] ≥ 27 kg/m²), were taking 0 to 3 oral antihyperglycemic agents (metformin, thiazolidinedione, and a sulfonylurea), and had stable body weight and an HbA1c of 7% to 10% to liraglutide 1.8 mg, liraglutide 3.0 mg, or placebo. Mean weight loss after 56 weeks was 6.0% (6.4 kg) with liraglutide 1.8 mg, 4.7% (5.0 kg) with liraglutide 3.0 mg, and 2.0% (2.2 kg) with placebo.²⁰

In 2016, high-dose once-daily liraglutide 3.0 mg (Saxenda) was approved by the FDA for weight loss. In a double-blind randomized trial of liraglutide 3.0 mg vs placebo in patients who had a BMI of at least 30 or who had a BMI of at least 27 plus treated or untreated dyslipidemia or hypertension, Pi-Sunyer et al²¹ reported a mean weight reduction of 8.4 ± 7.3 kg with liraglutide vs 2.8 ± 6.5 kg with placebo (a difference of −5.6 kg, 95% CI −6.0 to −5.1, P < .001) after 56 weeks. Furthermore, 63.2% of patients in the liraglutide group lost at least 5% of body weight vs 27.1% with placebo, and 33.1% in the liraglutide group lost 10% or more of body weight vs 10.6% in the placebo group (P < .001).²¹ Of note, liraglutide 3.0 mg is not indicated for type 2 DM per se.

In a 2012 meta-analysis of randomized controlled trials of adults with and without type 2 DM, with a BMI of 25 or greater, and who received GLP-1 receptor agonists at clinically rele­vant doses (exenatide ≥ 10 μg/day, exenatide ≥ 2 mg/week, or liraglutide ≥ 1.2 mg/day), those taking GLP-1 receptor agonists had more weight loss than those on a control intervention (oral antihyperglycemic, insulin, or placebo) at a minimum of 20 weeks, with a weighted mean difference −2.9 kg (95% CI −3.6 to −2.2) in 21 trials and 6,411 participants.²²

GLP-1 agonists currently being investigated for obesity treatment are lixisenatide, albiglutide, taspoglutide, and oxyntomodulin.²³

 

 

Cardiovascular outcomes

The presence of GLP-1 receptors in blood vessels and myocardium has led to the hypothesis that GLP-1 receptor agonists can improve cardiovascular disease outcomes.²⁴ In the pivotal Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, 9,340 patients with type 2 DM and increased cardiovascular disease risk were randomized to liraglutide vs placebo.²⁵ The hazard ratio (HR) for time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was 0.87 (P = .01 for superiority, P < .001 for noninferiority) for liraglutide compared with placebo after 3.8 years. The incidence of death from any cause or cardiovascular cause was also lower with liraglutide.²⁵

Adverse effects

Tolerable transient nausea and vomiting are reported adverse effects; these symptoms occur early in therapy, usually resolve in 4 to 8 weeks, and appear to be associated with greater weight loss.²⁶ Although no causal relationship between GLP-1 receptor agonist use and pancreatitis or pancreatic cancer has been established to date, several cases of acute pancreatitis have been reported.²⁵ Alternative therapies should be considered in patients with a history of or risk factors for pancreatitis.

Combined with insulin

A product that combines insulin glargine and lixisenatide (Soliqua) is FDA-approved for patients with type 2 DM. In a 30-week randomized controlled trial of the combination product vs insulin glargine alone in patients with type 2 DM not controlled on basal insulin with or without up to 2 oral agents, the combination product resulted in an HbA1c reduction from baseline of 1.1% vs 0.6% for insulin glargine alone (P < .001).²⁷ Mean body weight decreased by 0.7 kg with the combination product and increased by 0.7 kg with insulin glargine (P < .001).²⁷ In a 24-week study of a lixisenatide-insulin glargine combination vs insulin glargine in insulin-naïve patients taking metformin, there was a reduction in HbA1c of about −1.7% from baseline in both groups, while the combination group had a 1-kg weight reduction compared with a 0.5-kg weight increase in the insulin glargine group (P < .001).²⁸

SGLT-2 INHIBITORS

Mechanism of action

In a healthy normoglycemic person, about 180 g of glucose per day is filtered into the glomerular filtrate and reabsorbed into the circulation.²⁹ SGLT-2 facilitates the reabsorption of glucose in the proximal convoluted tubule of the kidneys. Approximately 90% of glucose reabsorption is mediated by SGLT-2 found in the S1 and S2 segments of the proximal convoluted tubule, and the remaining 10% by SGLT-1 in the S3 segment. At serum glucose levels above 180 g, the reabsorptive capacity of the nephron is overwhelmed, resulting in glycosuria.³⁰ SGLT-2 expression is also increased in patients with diabetes, thus leading to increased glucose reabsorption into the circulation, further contributing to hyperglycemia.³⁰ Inhibition of SGLT-2 alleviates hyperglycemia by decreasing glucose reabsorption (30% to 50% of filtered glucose) in the kidneys and by increasing excretion (50 mg to 80 mg of glucose) in the urine.³¹ SGLT-2 inhibitors currently FDA-approved are canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance).

HbA1c 

SGLT-2 inhibitors have relatively weak glycemic efficacy. A meta-analysis of SGLT-2 inhibitors vs other antidiabetic medications or placebo found that SGLT-2 inhibitors appeared to have a “favorable effect” on HbA1c, with a mean difference vs placebo of −0.66% (95% CI −0.73% to −0.58%) and a mean difference vs other antihyperglycemic medications of −0.06% (95% CI 0.18% to 0.05%).³²

Weight loss

The same meta-analysis found that SGLT-2 inhibitors reduced body weight (mean difference −1.8 kg, 95% CI −3.50 kg to −0.11 kg).³² And in a randomized controlled trial, monotherapy with canagliflozin 100 mg/day and 300 mg/day resulted in body weight reduction of 2.2% (1.9 kg) and 3.3% (−2.9 kg), respectively, after 26 weeks.³³ A Japanese study showed a dose-related total body weight loss with empagliflozin vs placebo ranging from 2.5 ± 0.2 kg (5-mg dose) to 3.1 ± 0.2 kg (50-mg dose) after 12 weeks.³⁴ Bolinder et al³⁵ reported that adding dapagliflozin 10 mg to metformin in patients with type 2 DM reduced total body weight by −2.96 kg (95% CI −3.51 to −2.41, P < .001) at week 24. Whole-body dual-energy x-ray absorptiometry and magnetic resonance imaging findings in this study revealed a decrease in fat mass and visceral and subcutaneous adipose tissue after treatment with dapagliflozin, thus suggesting urinary loss of glucose (and hence caloric loss) contributing to weight reduction in addition to initial weight loss from fluid loss due to osmotic diuresis.³⁵ A continuous decline in total body weight was observed in a 78-week extension study resulting in −4.54 kg (95% CI −5.43 to −3.66 kg) at week 102, along with further reduction in total body fat mass as measured by dual-energy x-ray absorptiometry.³⁶

Cardiovascular outcomes

The landmark study Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG) involving 7,020 patients was the first large cardiovascular outcomes trial in patients with type 2 DM and overt cardiovascular disease. A relative risk reduction of 14% (12.1% to 10.5%, HR 0.86, 95% CI 0.74 to 0.99) in major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was observed with empagliflozin.³⁷ Rates of all-cause mortality and hospitalization for heart failure relative risk reductions were 32% (8.3% to 5.7%; HR 0.68 [0.57, 0.8]) and 35% (4.1% to 2.7%; HR 0.65 [0.50, 0.85]), respectively, with empagliflozin. The mechanism behind this cardiovascular benefit is unknown but is currently being explored.³⁷

Adverse effects

Increased risk of urinary tract and genital infections are known adverse effects of SGLT-2s. Other effects noted include postural hypotension from volume depletion and a transient increase in serum creatinine and decrease in glomerular filtration.²⁹

NEUROENDOCRINE PEPTIDE HORMONE: AMYLIN ANALOGUES

Mechanism of action

Amylin is a 37-amino-acid neuroendocrine peptide hormone secreted primarily by pancreatic beta cells. It promotes early satiety, and its anorexigenic effects are mediated by its action on the neurons of the area postrema in the brain.³⁸ After a meal, amylin decreases gastric acid secretion and slows gastric emptying. It is co-secreted with insulin in a 1:20 amylin-to-insulin ratio and inhibits glucagon secretion via a centrally mediated mechanism.³⁹

Pramlintide (Symlin) is an amylin analogue administered subcutaneously immediately before major meals. It decreases postprandial glucose levels and has been approved by the FDA as an adjunct to prandial insulin in patients with type 1 and type 2 DM.⁴⁰

HbA1c

Amylin secretion is impaired in type 1 and type 2 DM, and small but significant reductions in HbA1c have been observed with addition of pramlintide to usual insulin regimens. In patients with type 1 DM, HbA1c levels were reduced by 0.4% to 0.6% after 26 weeks on 30 μg 3 times daily to 60 μg 4 times daily of pramlintide added to insulin.^41,42 And pramlintide 120 μg added to usual antihyperglycemic therapy in patients with type 2 DM has been reported to decrease HbA1c by 0.7% at week 16 or 26.^43,44

Weight loss

A meta-analysis of 8 randomized controlled trials assessed the effects of pramlintide on glycemic control and weight in patients with type 2 DM treated with insulin and in obese patients without diabetes.⁴⁵ In these trials, patients took at least 120 μg of pramlintide before 2 to 3 meals for at least 12 weeks; a total of 1,616 participants were included. In the type 2 DM group, pramlintide reduced body weight by 2.57 kg (95% CI −3.44 to −1.70 kg, P < .001) vs control, over 16 to 52 weeks.⁴⁵ The nondiabetic obese group had a weight loss of −2.27 kg (95%CI −2.88 to −1.66 kg, P < .001) vs control.⁴⁵

Pramlintide and a pramlintide-phentermine combination are currently under investigation for treatment of obesity.²³

Cardiovascular outcomes

Cardiovascular outcomes in patients treated with pramlintide have not been studied to date, but reductions have been observed in markers of cardiovascular risk including high-sensitivity C-reactive protein and triglycerides.⁴⁶

Adverse effects

Transient mild-to-moderate nausea is the most common adverse effect of pramlintide. Hypoglycemia has also been reported, more frequently in patients with type 1 DM, which is possibly associated with inadequate reduction in insulin.

 

 

ALPHA-GLUCOSIDASE INHIBITORS

Mechanism of action

Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes at the brush border of the small intestine. Taken orally before meals, these drugs mitigate postprandial hyperglycemia by preventing the breakdown of complex carbohydrates into simpler monosaccharides, thus delaying their absorption.⁴⁷ These agents may be used as monotherapy or in combination with other antihyperglycemic agents. They work independently from insulin, although they have been shown to potentiate GLP-1 secretion.⁴⁸ Acarbose and miglitol are currently approved in the United States. Acarbose has been more extensively studied worldwide.

HbA1c

Alpha-glucosidase inhibitors have been reported to reduce mean HbA1c by 0.8% (95% CI −0.9% to −0.7%), as well as fasting and postprandial glucose, and postprandial insulin levels.⁴⁹

Weight loss

There is conflicting evidence on whether alpha-glucosidase inhibitor therapy has a neutral or beneficial effect on body weight. A Cochrane meta-analysis observed significant BMI reduction with acarbose, although no effect on body weight was noted,⁴⁹ whereas in another meta-analysis, body weight was significantly reduced by 0.96 kg (95% CI −1.80 to −0.12 kg) when acarbose was added to metformin.⁵⁰ A review of pooled data from worldwide post-marketing studies for acarbose reported a weight reduction after 3 months of 0.98 ± 2.11 kg in overweight patients and 1.67 ± 3.02 kg in obese patients.⁵¹

Cardiovascular outcomes

In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), when compared with placebo, treatment of patients with impaired glucose tolerance with acarbose significantly reduced the incidence of cardiovascular events (HR 0.51, 95% CI 0.28 to 0.95, P = .03), myocardial infarction (HR 0.09, 95% CI 0.01 to 0.72, P = .02), and newly diagnosed hypertension (HR 0.66, 95% CI 0.49 to 0.89, P = .006).⁵²

Adverse effects

Although mild, gastrointestinal effects of flatulence and diarrhea can be bothersome and result in discontinuation of the drug in most patients.

METFORMIN

Mechanism of action

Metformin is the first-line antihyperglycemic agent for type 2 DM recommended by the American Diabetes Association and European Association for the Study of Diabetes.^53,54 The main action of metformin is to decrease glucose production in the liver. In the small intestine, metformin stimulates the L cells to produce GLP-1, and in skeletal muscle, it increases glucose uptake and disposal.⁵⁵

HbA1c

As monotherapy, metformin has resulted in HbA1c reductions of 0.88% to 1.2%.⁵⁵

Weight loss

Reduced food intake^56,57 and gastrointestinal intolerance⁵⁸ occurring early in therapy have been noted to account for weight loss in short-term studies of non-diabetic obese patients treated with metformin.⁵⁹ Long-term trials of patients with and without diabetes have yielded mixed results on weight reduction from metformin as monotherapy or adjunct therapy. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin had resulted in approximately 1.5 kg of weight gain (slightly less than the 4-kg weight gain in the glibenclamide group).⁶⁰ Improved antihyperglycemic efficacy of other antihyperglycemic agents (insulin, sulfonylureas, and thiazolidinediones) with addition of metformin led to dose-lowering of the antihyperglycemic agents, ultimately resulting in amelioration of weight gain; this has also led to small weight reductions in some studies.⁵⁹ In the Diabetes Prevention Program study of patients with impaired glucose tolerance, metformin treatment resulted in an average weight loss of 2.1 kg compared with placebo (−0.1 kg) and lifestyle intervention (−5.6 kg; P <.001).⁶¹

Cardiovascular outcomes

Metformin has been observed to decrease micro- and macrovascular complications. Compared with diet alone, metformin was associated with a 39% reduction in the risk of myocardial infarction, and a 30% lower risk of a composite of macrovascular diseases (myocardial infarction, sudden death, angina, stroke, and peripheral disease).⁶⁰

Adverse effects

The most common adverse effect of metformin is gastrointestinal intolerance from abdominal pain, flatulence, and diarrhea.⁶² Metformin-associated lactic acidosis is a serious and potentially life-threatening effect; and vitamin B₁₂ deficiency may occur with long-term treatment.⁶²

TAKE-HOME POINTS

As more medications and interventions are being developed to counter obesity, it also makes sense to select diabetes medications that do not contribute to weight gain in patients who are already overweight or obese. The effects of available medications can be maximized and treatment regimens individualized (based on patients’ needs and preferences, within the limitations of drug costs and side effects), along with lifestyle modification, to target diabesity.

Diabesity was a term coined by Sims et al¹ in the 1970s to describe diabetes occurring in the setting of obesity. Today, the link between type 2 diabetes mellitus (DM), obesity, and insulin resistance is well recognized, and 80% of people with type 2 DM are overweight or obese.^2,3 Unfortunately, weight gain is a known side effect of most agents used to treat type 2 DM (eg, insulin, sulfonylureas, thiazolidinediones), and this often leads to nonadherence, poor glycemic control, and further weight gain.

During the past several years, evidence has emerged of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes.² This has led to research for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c (HbA1c), but also have weight loss as a potential side effect.

In this paper, we review medications approved for the treatment of type 2 DM (including pramlintide, also approved for type 1 DM) that also have weight loss as a side effect. Drugs we will discuss include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, we also comment on the effects of the drugs on cardiovascular outcomes.

GLP-1 RECEPTOR AGONISTS

Mechanism of action

GLP-1 is a hormone produced from the proglucagon gene in the alpha cells of the pancreas, in the L cells of intestinal mucosa (predominantly in the ileum and distal colon), and in structures of the nervous system including the brainstem, hypothalamus, and vagal afferent nerves.⁴ Food in the gastrointestinal tract, especially if high in fats and carbohydrates, stimulates secretion of GLP-1 in the L cells, which in turn amplifies insulin secretion in a glucose-dependent manner (the incretin effect).⁴ Glucagon secretion is inhibited by GLP-1 during times of hyperglycemia but not hypoglycemia, thereby preventing inappropriately high levels of the hormone.⁵ Peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility.⁵ Lastly, GLP-1 exerts an anorexic effect by acting on central pathways that mediate satiation.⁶

Bioactive forms of GLP-1 are rapidly degraded in the circulation by the dipeptidyl peptidase-4 enzyme. GLP-1 receptor agonists have slightly altered molecular structure and longer duration of action than native GLP-1. Short-acting GLP-1 agonists (eg, exenatide, lixisenatide) have more effect on gastric emptying and lower postprandial blood glucose levels, whereas long-acting GLP-1 agonists (eg, liraglutide, albiglutide, dulaglutide, semaglutide, exenatide) have a greater effect on fasting glucose levels.⁴

Effects on HbA1c and weight loss

Of the current GLP-1 agonists, exenatide and liraglutide have been on the market the longest, thus studied more in terms of weight reduction.

Exenatide. Exenatide BID was the first GLP-1 agonist, approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of type 2 DM. In a 30-week triple-blind, placebo-controlled study of 336 patients already on background therapy with metformin, progressive weight loss was noted with exenatide 5 μg (−1.6 ± 0.4 kg) and exenatide 10 μg (−2.8 ± 0.5 kg) compared with placebo (−0.3 ± 0.3 kg; P < .001).¹⁵ A meta-analysis of 14 trials with 2,583 patients showed significant weight reduction with both exenatide 5 μg twice daily (a difference of −0.56 kg, 95% confidence interval [CI] −1.07 to −0.06, P = .0002) in 8 trials and exenatide 10 μg twice daily (a difference of −1.24 kg, 95% CI −1.69 to −0.78, P < .001) in 12 trials, after treatment for more than 16 weeks.¹⁶

Liraglutide. Liraglutide has a longer half-life than exenatide and is administered once daily. It is not a first-line therapy for type 2 DM and is recommended as an add-on. Approved daily doses for type 2 DM are 1.2 mg and 1.8 mg.

Multiple studies of glycemic control and weight loss with liraglutide have been conducted since its introduction to the US market in 2010. In the Liraglutide Effect and Action in Diabetes (LEAD) series of trials, liraglutide use as monotherapy or in combination with oral agents was associated with significant dose-dependent weight loss.¹⁷ Liraglutide monotherapy (at 1.2 mg and 1.8 mg) compared with glimepiride in the LEAD-3 trial led to significant weight reduction (2.1 kg and 2.5 kg, respectively, P < .001) after 16 weeks, and was sustained up to 52 weeks.¹⁸ Addition of liraglutide (at 1.2 mg and 1.8 mg) to metformin plus rosiglitazone resulted in significant weight loss (1.02 kg and 2.02 kg, respectively) whereas the addition of placebo caused a 0.6-kg weight gain (P < .001).¹⁹ The SCALE study randomized 846 adults with type 2 DM who were overweight to obese (body mass index [BMI] ≥ 27 kg/m²), were taking 0 to 3 oral antihyperglycemic agents (metformin, thiazolidinedione, and a sulfonylurea), and had stable body weight and an HbA1c of 7% to 10% to liraglutide 1.8 mg, liraglutide 3.0 mg, or placebo. Mean weight loss after 56 weeks was 6.0% (6.4 kg) with liraglutide 1.8 mg, 4.7% (5.0 kg) with liraglutide 3.0 mg, and 2.0% (2.2 kg) with placebo.²⁰

In 2016, high-dose once-daily liraglutide 3.0 mg (Saxenda) was approved by the FDA for weight loss. In a double-blind randomized trial of liraglutide 3.0 mg vs placebo in patients who had a BMI of at least 30 or who had a BMI of at least 27 plus treated or untreated dyslipidemia or hypertension, Pi-Sunyer et al²¹ reported a mean weight reduction of 8.4 ± 7.3 kg with liraglutide vs 2.8 ± 6.5 kg with placebo (a difference of −5.6 kg, 95% CI −6.0 to −5.1, P < .001) after 56 weeks. Furthermore, 63.2% of patients in the liraglutide group lost at least 5% of body weight vs 27.1% with placebo, and 33.1% in the liraglutide group lost 10% or more of body weight vs 10.6% in the placebo group (P < .001).²¹ Of note, liraglutide 3.0 mg is not indicated for type 2 DM per se.

In a 2012 meta-analysis of randomized controlled trials of adults with and without type 2 DM, with a BMI of 25 or greater, and who received GLP-1 receptor agonists at clinically rele­vant doses (exenatide ≥ 10 μg/day, exenatide ≥ 2 mg/week, or liraglutide ≥ 1.2 mg/day), those taking GLP-1 receptor agonists had more weight loss than those on a control intervention (oral antihyperglycemic, insulin, or placebo) at a minimum of 20 weeks, with a weighted mean difference −2.9 kg (95% CI −3.6 to −2.2) in 21 trials and 6,411 participants.²²

GLP-1 agonists currently being investigated for obesity treatment are lixisenatide, albiglutide, taspoglutide, and oxyntomodulin.²³

 

 

Cardiovascular outcomes

The presence of GLP-1 receptors in blood vessels and myocardium has led to the hypothesis that GLP-1 receptor agonists can improve cardiovascular disease outcomes.²⁴ In the pivotal Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, 9,340 patients with type 2 DM and increased cardiovascular disease risk were randomized to liraglutide vs placebo.²⁵ The hazard ratio (HR) for time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was 0.87 (P = .01 for superiority, P < .001 for noninferiority) for liraglutide compared with placebo after 3.8 years. The incidence of death from any cause or cardiovascular cause was also lower with liraglutide.²⁵

Adverse effects

Tolerable transient nausea and vomiting are reported adverse effects; these symptoms occur early in therapy, usually resolve in 4 to 8 weeks, and appear to be associated with greater weight loss.²⁶ Although no causal relationship between GLP-1 receptor agonist use and pancreatitis or pancreatic cancer has been established to date, several cases of acute pancreatitis have been reported.²⁵ Alternative therapies should be considered in patients with a history of or risk factors for pancreatitis.

Combined with insulin

A product that combines insulin glargine and lixisenatide (Soliqua) is FDA-approved for patients with type 2 DM. In a 30-week randomized controlled trial of the combination product vs insulin glargine alone in patients with type 2 DM not controlled on basal insulin with or without up to 2 oral agents, the combination product resulted in an HbA1c reduction from baseline of 1.1% vs 0.6% for insulin glargine alone (P < .001).²⁷ Mean body weight decreased by 0.7 kg with the combination product and increased by 0.7 kg with insulin glargine (P < .001).²⁷ In a 24-week study of a lixisenatide-insulin glargine combination vs insulin glargine in insulin-naïve patients taking metformin, there was a reduction in HbA1c of about −1.7% from baseline in both groups, while the combination group had a 1-kg weight reduction compared with a 0.5-kg weight increase in the insulin glargine group (P < .001).²⁸

SGLT-2 INHIBITORS

Mechanism of action

In a healthy normoglycemic person, about 180 g of glucose per day is filtered into the glomerular filtrate and reabsorbed into the circulation.²⁹ SGLT-2 facilitates the reabsorption of glucose in the proximal convoluted tubule of the kidneys. Approximately 90% of glucose reabsorption is mediated by SGLT-2 found in the S1 and S2 segments of the proximal convoluted tubule, and the remaining 10% by SGLT-1 in the S3 segment. At serum glucose levels above 180 g, the reabsorptive capacity of the nephron is overwhelmed, resulting in glycosuria.³⁰ SGLT-2 expression is also increased in patients with diabetes, thus leading to increased glucose reabsorption into the circulation, further contributing to hyperglycemia.³⁰ Inhibition of SGLT-2 alleviates hyperglycemia by decreasing glucose reabsorption (30% to 50% of filtered glucose) in the kidneys and by increasing excretion (50 mg to 80 mg of glucose) in the urine.³¹ SGLT-2 inhibitors currently FDA-approved are canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance).

HbA1c 

SGLT-2 inhibitors have relatively weak glycemic efficacy. A meta-analysis of SGLT-2 inhibitors vs other antidiabetic medications or placebo found that SGLT-2 inhibitors appeared to have a “favorable effect” on HbA1c, with a mean difference vs placebo of −0.66% (95% CI −0.73% to −0.58%) and a mean difference vs other antihyperglycemic medications of −0.06% (95% CI 0.18% to 0.05%).³²

Weight loss

The same meta-analysis found that SGLT-2 inhibitors reduced body weight (mean difference −1.8 kg, 95% CI −3.50 kg to −0.11 kg).³² And in a randomized controlled trial, monotherapy with canagliflozin 100 mg/day and 300 mg/day resulted in body weight reduction of 2.2% (1.9 kg) and 3.3% (−2.9 kg), respectively, after 26 weeks.³³ A Japanese study showed a dose-related total body weight loss with empagliflozin vs placebo ranging from 2.5 ± 0.2 kg (5-mg dose) to 3.1 ± 0.2 kg (50-mg dose) after 12 weeks.³⁴ Bolinder et al³⁵ reported that adding dapagliflozin 10 mg to metformin in patients with type 2 DM reduced total body weight by −2.96 kg (95% CI −3.51 to −2.41, P < .001) at week 24. Whole-body dual-energy x-ray absorptiometry and magnetic resonance imaging findings in this study revealed a decrease in fat mass and visceral and subcutaneous adipose tissue after treatment with dapagliflozin, thus suggesting urinary loss of glucose (and hence caloric loss) contributing to weight reduction in addition to initial weight loss from fluid loss due to osmotic diuresis.³⁵ A continuous decline in total body weight was observed in a 78-week extension study resulting in −4.54 kg (95% CI −5.43 to −3.66 kg) at week 102, along with further reduction in total body fat mass as measured by dual-energy x-ray absorptiometry.³⁶

Cardiovascular outcomes

The landmark study Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG) involving 7,020 patients was the first large cardiovascular outcomes trial in patients with type 2 DM and overt cardiovascular disease. A relative risk reduction of 14% (12.1% to 10.5%, HR 0.86, 95% CI 0.74 to 0.99) in major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was observed with empagliflozin.³⁷ Rates of all-cause mortality and hospitalization for heart failure relative risk reductions were 32% (8.3% to 5.7%; HR 0.68 [0.57, 0.8]) and 35% (4.1% to 2.7%; HR 0.65 [0.50, 0.85]), respectively, with empagliflozin. The mechanism behind this cardiovascular benefit is unknown but is currently being explored.³⁷

Adverse effects

Increased risk of urinary tract and genital infections are known adverse effects of SGLT-2s. Other effects noted include postural hypotension from volume depletion and a transient increase in serum creatinine and decrease in glomerular filtration.²⁹

NEUROENDOCRINE PEPTIDE HORMONE: AMYLIN ANALOGUES

Mechanism of action

Amylin is a 37-amino-acid neuroendocrine peptide hormone secreted primarily by pancreatic beta cells. It promotes early satiety, and its anorexigenic effects are mediated by its action on the neurons of the area postrema in the brain.³⁸ After a meal, amylin decreases gastric acid secretion and slows gastric emptying. It is co-secreted with insulin in a 1:20 amylin-to-insulin ratio and inhibits glucagon secretion via a centrally mediated mechanism.³⁹

Pramlintide (Symlin) is an amylin analogue administered subcutaneously immediately before major meals. It decreases postprandial glucose levels and has been approved by the FDA as an adjunct to prandial insulin in patients with type 1 and type 2 DM.⁴⁰

HbA1c

Amylin secretion is impaired in type 1 and type 2 DM, and small but significant reductions in HbA1c have been observed with addition of pramlintide to usual insulin regimens. In patients with type 1 DM, HbA1c levels were reduced by 0.4% to 0.6% after 26 weeks on 30 μg 3 times daily to 60 μg 4 times daily of pramlintide added to insulin.^41,42 And pramlintide 120 μg added to usual antihyperglycemic therapy in patients with type 2 DM has been reported to decrease HbA1c by 0.7% at week 16 or 26.^43,44

Weight loss

A meta-analysis of 8 randomized controlled trials assessed the effects of pramlintide on glycemic control and weight in patients with type 2 DM treated with insulin and in obese patients without diabetes.⁴⁵ In these trials, patients took at least 120 μg of pramlintide before 2 to 3 meals for at least 12 weeks; a total of 1,616 participants were included. In the type 2 DM group, pramlintide reduced body weight by 2.57 kg (95% CI −3.44 to −1.70 kg, P < .001) vs control, over 16 to 52 weeks.⁴⁵ The nondiabetic obese group had a weight loss of −2.27 kg (95%CI −2.88 to −1.66 kg, P < .001) vs control.⁴⁵

Pramlintide and a pramlintide-phentermine combination are currently under investigation for treatment of obesity.²³

Cardiovascular outcomes

Cardiovascular outcomes in patients treated with pramlintide have not been studied to date, but reductions have been observed in markers of cardiovascular risk including high-sensitivity C-reactive protein and triglycerides.⁴⁶

Adverse effects

Transient mild-to-moderate nausea is the most common adverse effect of pramlintide. Hypoglycemia has also been reported, more frequently in patients with type 1 DM, which is possibly associated with inadequate reduction in insulin.

 

 

ALPHA-GLUCOSIDASE INHIBITORS

Mechanism of action

Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes at the brush border of the small intestine. Taken orally before meals, these drugs mitigate postprandial hyperglycemia by preventing the breakdown of complex carbohydrates into simpler monosaccharides, thus delaying their absorption.⁴⁷ These agents may be used as monotherapy or in combination with other antihyperglycemic agents. They work independently from insulin, although they have been shown to potentiate GLP-1 secretion.⁴⁸ Acarbose and miglitol are currently approved in the United States. Acarbose has been more extensively studied worldwide.

HbA1c

Alpha-glucosidase inhibitors have been reported to reduce mean HbA1c by 0.8% (95% CI −0.9% to −0.7%), as well as fasting and postprandial glucose, and postprandial insulin levels.⁴⁹

Weight loss

There is conflicting evidence on whether alpha-glucosidase inhibitor therapy has a neutral or beneficial effect on body weight. A Cochrane meta-analysis observed significant BMI reduction with acarbose, although no effect on body weight was noted,⁴⁹ whereas in another meta-analysis, body weight was significantly reduced by 0.96 kg (95% CI −1.80 to −0.12 kg) when acarbose was added to metformin.⁵⁰ A review of pooled data from worldwide post-marketing studies for acarbose reported a weight reduction after 3 months of 0.98 ± 2.11 kg in overweight patients and 1.67 ± 3.02 kg in obese patients.⁵¹

Cardiovascular outcomes

In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), when compared with placebo, treatment of patients with impaired glucose tolerance with acarbose significantly reduced the incidence of cardiovascular events (HR 0.51, 95% CI 0.28 to 0.95, P = .03), myocardial infarction (HR 0.09, 95% CI 0.01 to 0.72, P = .02), and newly diagnosed hypertension (HR 0.66, 95% CI 0.49 to 0.89, P = .006).⁵²

Adverse effects

Although mild, gastrointestinal effects of flatulence and diarrhea can be bothersome and result in discontinuation of the drug in most patients.

METFORMIN

Mechanism of action

Metformin is the first-line antihyperglycemic agent for type 2 DM recommended by the American Diabetes Association and European Association for the Study of Diabetes.^53,54 The main action of metformin is to decrease glucose production in the liver. In the small intestine, metformin stimulates the L cells to produce GLP-1, and in skeletal muscle, it increases glucose uptake and disposal.⁵⁵

HbA1c

As monotherapy, metformin has resulted in HbA1c reductions of 0.88% to 1.2%.⁵⁵

Weight loss

Reduced food intake^56,57 and gastrointestinal intolerance⁵⁸ occurring early in therapy have been noted to account for weight loss in short-term studies of non-diabetic obese patients treated with metformin.⁵⁹ Long-term trials of patients with and without diabetes have yielded mixed results on weight reduction from metformin as monotherapy or adjunct therapy. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin had resulted in approximately 1.5 kg of weight gain (slightly less than the 4-kg weight gain in the glibenclamide group).⁶⁰ Improved antihyperglycemic efficacy of other antihyperglycemic agents (insulin, sulfonylureas, and thiazolidinediones) with addition of metformin led to dose-lowering of the antihyperglycemic agents, ultimately resulting in amelioration of weight gain; this has also led to small weight reductions in some studies.⁵⁹ In the Diabetes Prevention Program study of patients with impaired glucose tolerance, metformin treatment resulted in an average weight loss of 2.1 kg compared with placebo (−0.1 kg) and lifestyle intervention (−5.6 kg; P <.001).⁶¹

Cardiovascular outcomes

Metformin has been observed to decrease micro- and macrovascular complications. Compared with diet alone, metformin was associated with a 39% reduction in the risk of myocardial infarction, and a 30% lower risk of a composite of macrovascular diseases (myocardial infarction, sudden death, angina, stroke, and peripheral disease).⁶⁰

Adverse effects

The most common adverse effect of metformin is gastrointestinal intolerance from abdominal pain, flatulence, and diarrhea.⁶² Metformin-associated lactic acidosis is a serious and potentially life-threatening effect; and vitamin B₁₂ deficiency may occur with long-term treatment.⁶²

TAKE-HOME POINTS

As more medications and interventions are being developed to counter obesity, it also makes sense to select diabetes medications that do not contribute to weight gain in patients who are already overweight or obese. The effects of available medications can be maximized and treatment regimens individualized (based on patients’ needs and preferences, within the limitations of drug costs and side effects), along with lifestyle modification, to target diabesity.