STOWE, VERMONT—Rather than greater headache frequency, a systemic endocrine–metabolic disorder that is associated with frequent headaches may distinguish chronic migraine from episodic migraine, said Egilius L. H. Spierings, MD, PhD, at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England.

Egilius L. H. Spierings, MD, PhD

According to the International Headache Society (IHS), a patient with headache on 15 or more days per month for more than three months, and whose headache has the features of migraine on at least eight days per month, fulfills the diagnostic criteria for chronic migraine. A migraineur with headache on 14 or fewer days per month has episodic migraine. The neurology community has accepted this distinction.

The IHS classification is “extremely simple” and “highly arbitrarily defined,” said Dr. Spierings, Director of the Headache and Face Pain Program at Tufts Medical Center in Boston and Clinical Professor of Craniofacial Pain at Tufts University. “There must be more behind that distinction, especially when you look at the question of why Botox works preventively in chronic migraine and not in episodic migraine.”

Taking the perspective of a general practitioner, rather than that of a headache specialist, may clarify the distinction between chronic and episodic migraine, according to Dr. Spierings. A general review of systems suggests that patients with episodic migraine tend to be healthy overall, while patients with chronic migraine tend to have many psychiatric and medical comorbidities. In an exploratory study, Dr. Spierings and colleagues found that women with chronic migraine had a significantly higher prevalence of menstrual cycle disorders (eg, oligomenorrhea and polymenorrhea) and dysmenorrhea, compared with women with episodic migraine.

These findings appear to be consistent with those of previous research. In 2002, Bigal and colleagues found that asthma, allergies, hypertension, and hypothyroidism were significantly more common in patients with chronic migraine than in those with episodic migraine. In 2006, Tietjen et al observed that endometriosis was significantly more common in women with chronic migraine than in women with episodic migraine.

In the most extensive study in this area, Ferrari et al found that psychiatric, gastrointestinal, musculoskeletal, ocular, genitourinary, hematologic, cerebrovascular, and cardiac comorbidities were significantly more common in patients with chronic migraine than in those with episodic migraine. Hypertension, constipation, and insomnia also were more prevalent in chronic migraine.

In addition, data from various studies show that patients with chronic migraine tend to be, on average, 10 to 20 years older than those with episodic migraine. About two-thirds of patients with chronic migraine develop their condition gradually over time out of episodic migraine, a transition that takes, on average, 11.6 years. During this period, these patients may develop the comorbidities that are more frequent in chronic migraine, said Dr. Spierings.

But younger patients with chronic migraine also have more comorbidities than patients of the same age with episodic migraine. One patient of Dr. Spierings was an 18-year-old woman who had had chronic migraine since menarche and whose mother had migraine. The woman’s comorbidities included fatigue, insomnia, anxiety, depression, tight and sore neck and shoulder muscles, reflux disease, and diarrhea. Another patient of Dr. Spierings was a 20-year-old woman who had had chronic migraine since menarche and whose mother had migraine. Among her comorbidities were fatigue, insomnia, depression, tight and sore neck and shoulder muscles, lumbago, polymenorrhea, dysmenorrhea, and hypermenorrhea.

Dr. Spierings also examined a 34-year-old woman without a family history of migraine. She developed a pressure sensation in the temples, but not headaches or migraine, after pregnancy. The woman’s comorbidities included fatigue, anxiety, tight and sore neck and shoulder muscles, fibromyalgia, gastritis, constipation, endometriosis, and hypermenorrhea.

All three patients have a disorder of multiple systems that affects the nervous system, the musculoskeletal system, the gastrointestinal system, and the genitourinary system. “The only unifying diagnosis … is somatic symptom disorder,” said Dr. Spierings. Yet this diagnosis is unsatisfying, he added.

“These people have a systemic endocrine–metabolic disorder centered around energy metabolism that causes the multitude of medical and psychiatric conditions that we tend to see in patients [with chronic migraine] .… It is a syndrome with multiple etiologies, either endocrine or metabolic, genetic or acquired.” The first two patients may have a “genetically determined headache amplifier” that contributed to the development of chronic migraine, Dr. Spierings added. The third patient, who has no family history of migraine, does not have this genetically determined headache amplifier.

In previous research, Dr. Spierings and colleagues concluded that stress, tension, irregular eating times, fatigue, and insufficient sleep were general headache triggers to which everyone is susceptible. “When we do not have that headache amplifier, we get regular headaches that we can combat with a couple of aspirin. When we have that headache amplifier inherited from one or both parents, we need specific antimigraine medications to take care of it,” he said. The inherited headache amplifier “is the essence of migraine” and is related to the threshold at which neurogenic inflammation occurs, said Dr. Spierings. Patients with chronic migraine have the headache amplifier and a systemic disorder not shared by patients with episodic migraine, he concluded.

—Erik Greb

STOWE, VERMONT—Rather than greater headache frequency, a systemic endocrine–metabolic disorder that is associated with frequent headaches may distinguish chronic migraine from episodic migraine, said Egilius L. H. Spierings, MD, PhD, at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England.

Egilius L. H. Spierings, MD, PhD

According to the International Headache Society (IHS), a patient with headache on 15 or more days per month for more than three months, and whose headache has the features of migraine on at least eight days per month, fulfills the diagnostic criteria for chronic migraine. A migraineur with headache on 14 or fewer days per month has episodic migraine. The neurology community has accepted this distinction.

The IHS classification is “extremely simple” and “highly arbitrarily defined,” said Dr. Spierings, Director of the Headache and Face Pain Program at Tufts Medical Center in Boston and Clinical Professor of Craniofacial Pain at Tufts University. “There must be more behind that distinction, especially when you look at the question of why Botox works preventively in chronic migraine and not in episodic migraine.”

Taking the perspective of a general practitioner, rather than that of a headache specialist, may clarify the distinction between chronic and episodic migraine, according to Dr. Spierings. A general review of systems suggests that patients with episodic migraine tend to be healthy overall, while patients with chronic migraine tend to have many psychiatric and medical comorbidities. In an exploratory study, Dr. Spierings and colleagues found that women with chronic migraine had a significantly higher prevalence of menstrual cycle disorders (eg, oligomenorrhea and polymenorrhea) and dysmenorrhea, compared with women with episodic migraine.

These findings appear to be consistent with those of previous research. In 2002, Bigal and colleagues found that asthma, allergies, hypertension, and hypothyroidism were significantly more common in patients with chronic migraine than in those with episodic migraine. In 2006, Tietjen et al observed that endometriosis was significantly more common in women with chronic migraine than in women with episodic migraine.

In the most extensive study in this area, Ferrari et al found that psychiatric, gastrointestinal, musculoskeletal, ocular, genitourinary, hematologic, cerebrovascular, and cardiac comorbidities were significantly more common in patients with chronic migraine than in those with episodic migraine. Hypertension, constipation, and insomnia also were more prevalent in chronic migraine.

In addition, data from various studies show that patients with chronic migraine tend to be, on average, 10 to 20 years older than those with episodic migraine. About two-thirds of patients with chronic migraine develop their condition gradually over time out of episodic migraine, a transition that takes, on average, 11.6 years. During this period, these patients may develop the comorbidities that are more frequent in chronic migraine, said Dr. Spierings.

But younger patients with chronic migraine also have more comorbidities than patients of the same age with episodic migraine. One patient of Dr. Spierings was an 18-year-old woman who had had chronic migraine since menarche and whose mother had migraine. The woman’s comorbidities included fatigue, insomnia, anxiety, depression, tight and sore neck and shoulder muscles, reflux disease, and diarrhea. Another patient of Dr. Spierings was a 20-year-old woman who had had chronic migraine since menarche and whose mother had migraine. Among her comorbidities were fatigue, insomnia, depression, tight and sore neck and shoulder muscles, lumbago, polymenorrhea, dysmenorrhea, and hypermenorrhea.

Dr. Spierings also examined a 34-year-old woman without a family history of migraine. She developed a pressure sensation in the temples, but not headaches or migraine, after pregnancy. The woman’s comorbidities included fatigue, anxiety, tight and sore neck and shoulder muscles, fibromyalgia, gastritis, constipation, endometriosis, and hypermenorrhea.

All three patients have a disorder of multiple systems that affects the nervous system, the musculoskeletal system, the gastrointestinal system, and the genitourinary system. “The only unifying diagnosis … is somatic symptom disorder,” said Dr. Spierings. Yet this diagnosis is unsatisfying, he added.

“These people have a systemic endocrine–metabolic disorder centered around energy metabolism that causes the multitude of medical and psychiatric conditions that we tend to see in patients [with chronic migraine] .… It is a syndrome with multiple etiologies, either endocrine or metabolic, genetic or acquired.” The first two patients may have a “genetically determined headache amplifier” that contributed to the development of chronic migraine, Dr. Spierings added. The third patient, who has no family history of migraine, does not have this genetically determined headache amplifier.

In previous research, Dr. Spierings and colleagues concluded that stress, tension, irregular eating times, fatigue, and insufficient sleep were general headache triggers to which everyone is susceptible. “When we do not have that headache amplifier, we get regular headaches that we can combat with a couple of aspirin. When we have that headache amplifier inherited from one or both parents, we need specific antimigraine medications to take care of it,” he said. The inherited headache amplifier “is the essence of migraine” and is related to the threshold at which neurogenic inflammation occurs, said Dr. Spierings. Patients with chronic migraine have the headache amplifier and a systemic disorder not shared by patients with episodic migraine, he concluded.

—Erik Greb

STOWE, VERMONT—Rather than greater headache frequency, a systemic endocrine–metabolic disorder that is associated with frequent headaches may distinguish chronic migraine from episodic migraine, said Egilius L. H. Spierings, MD, PhD, at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England.

Egilius L. H. Spierings, MD, PhD

According to the International Headache Society (IHS), a patient with headache on 15 or more days per month for more than three months, and whose headache has the features of migraine on at least eight days per month, fulfills the diagnostic criteria for chronic migraine. A migraineur with headache on 14 or fewer days per month has episodic migraine. The neurology community has accepted this distinction.

The IHS classification is “extremely simple” and “highly arbitrarily defined,” said Dr. Spierings, Director of the Headache and Face Pain Program at Tufts Medical Center in Boston and Clinical Professor of Craniofacial Pain at Tufts University. “There must be more behind that distinction, especially when you look at the question of why Botox works preventively in chronic migraine and not in episodic migraine.”

Taking the perspective of a general practitioner, rather than that of a headache specialist, may clarify the distinction between chronic and episodic migraine, according to Dr. Spierings. A general review of systems suggests that patients with episodic migraine tend to be healthy overall, while patients with chronic migraine tend to have many psychiatric and medical comorbidities. In an exploratory study, Dr. Spierings and colleagues found that women with chronic migraine had a significantly higher prevalence of menstrual cycle disorders (eg, oligomenorrhea and polymenorrhea) and dysmenorrhea, compared with women with episodic migraine.

These findings appear to be consistent with those of previous research. In 2002, Bigal and colleagues found that asthma, allergies, hypertension, and hypothyroidism were significantly more common in patients with chronic migraine than in those with episodic migraine. In 2006, Tietjen et al observed that endometriosis was significantly more common in women with chronic migraine than in women with episodic migraine.

In the most extensive study in this area, Ferrari et al found that psychiatric, gastrointestinal, musculoskeletal, ocular, genitourinary, hematologic, cerebrovascular, and cardiac comorbidities were significantly more common in patients with chronic migraine than in those with episodic migraine. Hypertension, constipation, and insomnia also were more prevalent in chronic migraine.

In addition, data from various studies show that patients with chronic migraine tend to be, on average, 10 to 20 years older than those with episodic migraine. About two-thirds of patients with chronic migraine develop their condition gradually over time out of episodic migraine, a transition that takes, on average, 11.6 years. During this period, these patients may develop the comorbidities that are more frequent in chronic migraine, said Dr. Spierings.

But younger patients with chronic migraine also have more comorbidities than patients of the same age with episodic migraine. One patient of Dr. Spierings was an 18-year-old woman who had had chronic migraine since menarche and whose mother had migraine. The woman’s comorbidities included fatigue, insomnia, anxiety, depression, tight and sore neck and shoulder muscles, reflux disease, and diarrhea. Another patient of Dr. Spierings was a 20-year-old woman who had had chronic migraine since menarche and whose mother had migraine. Among her comorbidities were fatigue, insomnia, depression, tight and sore neck and shoulder muscles, lumbago, polymenorrhea, dysmenorrhea, and hypermenorrhea.

Dr. Spierings also examined a 34-year-old woman without a family history of migraine. She developed a pressure sensation in the temples, but not headaches or migraine, after pregnancy. The woman’s comorbidities included fatigue, anxiety, tight and sore neck and shoulder muscles, fibromyalgia, gastritis, constipation, endometriosis, and hypermenorrhea.

All three patients have a disorder of multiple systems that affects the nervous system, the musculoskeletal system, the gastrointestinal system, and the genitourinary system. “The only unifying diagnosis … is somatic symptom disorder,” said Dr. Spierings. Yet this diagnosis is unsatisfying, he added.

“These people have a systemic endocrine–metabolic disorder centered around energy metabolism that causes the multitude of medical and psychiatric conditions that we tend to see in patients [with chronic migraine] .… It is a syndrome with multiple etiologies, either endocrine or metabolic, genetic or acquired.” The first two patients may have a “genetically determined headache amplifier” that contributed to the development of chronic migraine, Dr. Spierings added. The third patient, who has no family history of migraine, does not have this genetically determined headache amplifier.

In previous research, Dr. Spierings and colleagues concluded that stress, tension, irregular eating times, fatigue, and insufficient sleep were general headache triggers to which everyone is susceptible. “When we do not have that headache amplifier, we get regular headaches that we can combat with a couple of aspirin. When we have that headache amplifier inherited from one or both parents, we need specific antimigraine medications to take care of it,” he said. The inherited headache amplifier “is the essence of migraine” and is related to the threshold at which neurogenic inflammation occurs, said Dr. Spierings. Patients with chronic migraine have the headache amplifier and a systemic disorder not shared by patients with episodic migraine, he concluded.

—Erik Greb

In the age of technology, parents denying their teens a smartphone is blatant child abuse, at least in the eyes of the teen. Between Twitter, Instagram, and Snapchat, a teen’s entire life revolves around minute-to-minute check-ins. Smartphones have opened the door for sexual predators, bullying, and complete withdrawal from the world that surrounds them. But, with every bad there is a good and it’s knowing how to make the technology takeover work for you.

The smartphone is the best bargaining chip ever created. A teen would sooner die than lose his or her phone. Parents need to use this upper hand to get just about anything done: “You will get your phone back when XYZ is done.” Teens should understand that a phone is a privilege and not a right, so if they don’t want to cooperate, then there is a consequence.

Second, there is no greater source of information than a teen’s phone. From information in text, to locations, to the dreaded selfies, teens cannot help themselves when it comes to sharing every aspect of their lives. There are countless stories of teens getting busted because they posted a picture on Instagram with the person they were not supposed to be with or from a place they were not supposed to be. There are several great apps that allow parents to see deleted texts, and track locations and websites visited. These same apps allow parents to add controls that block X-rated websites, and notify them when the teen leaves a location or signs up for social media apps.

Accidents are the leading cause of death among teens and smartphones have only increased that. A recent study showed that 34% admitted to texting and driving. Another study reported that 11 teens die per day* because of distracted driver accidents. Not only are teens distracted, they also are inexperienced and are increasing their risk of injury. Teens are 23 times more likely to be in an accident as a result of distracted driving.

©ponsulak/ThinkStock.com

Now, there are apps that will alert parents when the teen is driving above the speed limit or has left the restricted area designated by the parent. These apps can silence incoming texts and prevent texts from being sent if the teen is in motion. Some of the apps will read the text out loud and respond with an automated response, letting the caller know that they are unavailable. Canary, My Mobile Watchdog, and Drivesafe.ly are examples, but both Sprint and Verizon have similar apps available. This is an excellent way for parents to monitor teen driving habits. The cost varies from $7.99/month to $99/month but the information provided is priceless.

Whether we like it or not, smartphones are here and have totally changed how teens interact and give them limitless exposure. Many parents, even if they own a smartphone, only use it for its basic functions and may have no idea these types of controls exist. Educating parents that they can use the phone as a tool to monitor and protect their teens is an important part of the well visit, and could very well save a life.

Dr. Pearce is a pediatrician in Frankfort, Ill. Email her at [email protected].

*Correction, 6/1/2016: The frequency of teen deaths due to distracted driver accidents was misquoted.

In the age of technology, parents denying their teens a smartphone is blatant child abuse, at least in the eyes of the teen. Between Twitter, Instagram, and Snapchat, a teen’s entire life revolves around minute-to-minute check-ins. Smartphones have opened the door for sexual predators, bullying, and complete withdrawal from the world that surrounds them. But, with every bad there is a good and it’s knowing how to make the technology takeover work for you.

The smartphone is the best bargaining chip ever created. A teen would sooner die than lose his or her phone. Parents need to use this upper hand to get just about anything done: “You will get your phone back when XYZ is done.” Teens should understand that a phone is a privilege and not a right, so if they don’t want to cooperate, then there is a consequence.

Second, there is no greater source of information than a teen’s phone. From information in text, to locations, to the dreaded selfies, teens cannot help themselves when it comes to sharing every aspect of their lives. There are countless stories of teens getting busted because they posted a picture on Instagram with the person they were not supposed to be with or from a place they were not supposed to be. There are several great apps that allow parents to see deleted texts, and track locations and websites visited. These same apps allow parents to add controls that block X-rated websites, and notify them when the teen leaves a location or signs up for social media apps.

Accidents are the leading cause of death among teens and smartphones have only increased that. A recent study showed that 34% admitted to texting and driving. Another study reported that 11 teens die per day* because of distracted driver accidents. Not only are teens distracted, they also are inexperienced and are increasing their risk of injury. Teens are 23 times more likely to be in an accident as a result of distracted driving.

©ponsulak/ThinkStock.com

Now, there are apps that will alert parents when the teen is driving above the speed limit or has left the restricted area designated by the parent. These apps can silence incoming texts and prevent texts from being sent if the teen is in motion. Some of the apps will read the text out loud and respond with an automated response, letting the caller know that they are unavailable. Canary, My Mobile Watchdog, and Drivesafe.ly are examples, but both Sprint and Verizon have similar apps available. This is an excellent way for parents to monitor teen driving habits. The cost varies from $7.99/month to $99/month but the information provided is priceless.

Whether we like it or not, smartphones are here and have totally changed how teens interact and give them limitless exposure. Many parents, even if they own a smartphone, only use it for its basic functions and may have no idea these types of controls exist. Educating parents that they can use the phone as a tool to monitor and protect their teens is an important part of the well visit, and could very well save a life.

Dr. Pearce is a pediatrician in Frankfort, Ill. Email her at [email protected].

*Correction, 6/1/2016: The frequency of teen deaths due to distracted driver accidents was misquoted.

In the age of technology, parents denying their teens a smartphone is blatant child abuse, at least in the eyes of the teen. Between Twitter, Instagram, and Snapchat, a teen’s entire life revolves around minute-to-minute check-ins. Smartphones have opened the door for sexual predators, bullying, and complete withdrawal from the world that surrounds them. But, with every bad there is a good and it’s knowing how to make the technology takeover work for you.

The smartphone is the best bargaining chip ever created. A teen would sooner die than lose his or her phone. Parents need to use this upper hand to get just about anything done: “You will get your phone back when XYZ is done.” Teens should understand that a phone is a privilege and not a right, so if they don’t want to cooperate, then there is a consequence.

Second, there is no greater source of information than a teen’s phone. From information in text, to locations, to the dreaded selfies, teens cannot help themselves when it comes to sharing every aspect of their lives. There are countless stories of teens getting busted because they posted a picture on Instagram with the person they were not supposed to be with or from a place they were not supposed to be. There are several great apps that allow parents to see deleted texts, and track locations and websites visited. These same apps allow parents to add controls that block X-rated websites, and notify them when the teen leaves a location or signs up for social media apps.

Accidents are the leading cause of death among teens and smartphones have only increased that. A recent study showed that 34% admitted to texting and driving. Another study reported that 11 teens die per day* because of distracted driver accidents. Not only are teens distracted, they also are inexperienced and are increasing their risk of injury. Teens are 23 times more likely to be in an accident as a result of distracted driving.

©ponsulak/ThinkStock.com

Now, there are apps that will alert parents when the teen is driving above the speed limit or has left the restricted area designated by the parent. These apps can silence incoming texts and prevent texts from being sent if the teen is in motion. Some of the apps will read the text out loud and respond with an automated response, letting the caller know that they are unavailable. Canary, My Mobile Watchdog, and Drivesafe.ly are examples, but both Sprint and Verizon have similar apps available. This is an excellent way for parents to monitor teen driving habits. The cost varies from $7.99/month to $99/month but the information provided is priceless.

Whether we like it or not, smartphones are here and have totally changed how teens interact and give them limitless exposure. Many parents, even if they own a smartphone, only use it for its basic functions and may have no idea these types of controls exist. Educating parents that they can use the phone as a tool to monitor and protect their teens is an important part of the well visit, and could very well save a life.

Dr. Pearce is a pediatrician in Frankfort, Ill. Email her at [email protected].

*Correction, 6/1/2016: The frequency of teen deaths due to distracted driver accidents was misquoted.

Treating multiple myeloma cells with panobinostat and FK506 reduced their viability by inhibiting expression of the PPP3CA catalytic subunit of calcineurin, according to researchers.

“The development of new calcineurin-targeted therapies, which inhibit PPP3CA–NF-kappaB signaling by small molecules, is expected to profoundly improve the treatment of multiple myeloma. This will overcome drug resistance and improve osteolytic lesions in a wide range of patients, including those receiving reduced intensity–conditioned allogeneic stem cell transplantation, who may be treated with panobinostat and FK506,” wrote Dr. Yoichi Imai of Tokyo Women’s Medical University in Japan, and his associates (JCI Insight 2016 doi: 10.1172/jci.insight.85061). .

Adding panobinostat to bortezomib and dexamethasone has been shown to improve progression-free survival in relapsed and refractory multiple myeloma, the researchers noted. Other studies have linked calcineurin activation to the pathogenesis of T-cell cancers, and calcineurin inhibition seems to be involved in defective B-cell activation, they added.

Eight candidate oncogenes were identified by use of the Gene Expression Omnibus. PPP3CA was expressed at significantly higher levels in multiple myeloma cells from patients with stage III disease compared with those with stage I disease (P = .016). Furthermore, levels of serum lactate dehydrogenase correlated with PPP3CA expression and with poor overall and progression-free survival. Patients with high PPP3CA expression also had high levels of alpha₄ integrins, which mediate resistance to bortezomib and conventional chemotherapy, the researchers noted.

When multiple myeloma cells were exposed to either panobinostat or a control agent, PPP3CA dropped in the panobinostat-treated cells. Adding the proteasome inhibitor lactacystin to the mixture counteracted this effect, “supporting the possibility that PPP3CA expression was reduced through protein degradation by panobinostat,” they said.

Levels of PPP3CA expression were lower in multiple myeloma cells that were cotreated with an HDAC inhibitor (panobinostat or ACY-1215) and the immunosuppressive agent FK506 than in multiple myeloma cells that were exposed only to an HDAC inhibitor. In addition, the combination regimen blocked the formation of osteoclasts, which are involved in osteolytic lesions, the researchers noted.

Also, significantly higher PPP3CA expression, which correlated with worse progression-free survival, was noted in bortezomib-resistant patients, compared with bortezomib-sensitive patients.

“The cytotoxic effect exerted by panobinostat on CD20+ cells was subtle, while the addition of FK506 did not increase their viability,” the researchers reported. “Moreover, development of T and B lineage cells was normal in PPP3CA-deficient mice, and panobinostat did not compromise donor lymphocyte reconstitution in a mouse BM transplantation model. These results suggest that calcineurin-targeting therapy exerts an antimyeloma effect without inducing significant side effects in normal lymphoid systems.”

The Japan Society for the Promotion of Science, the Takeda Science Foundation, the International Myeloma Foundation, and the Japan Leukemia Research Fund funded the study. The investigators had no disclosures.

Treating multiple myeloma cells with panobinostat and FK506 reduced their viability by inhibiting expression of the PPP3CA catalytic subunit of calcineurin, according to researchers.

“The development of new calcineurin-targeted therapies, which inhibit PPP3CA–NF-kappaB signaling by small molecules, is expected to profoundly improve the treatment of multiple myeloma. This will overcome drug resistance and improve osteolytic lesions in a wide range of patients, including those receiving reduced intensity–conditioned allogeneic stem cell transplantation, who may be treated with panobinostat and FK506,” wrote Dr. Yoichi Imai of Tokyo Women’s Medical University in Japan, and his associates (JCI Insight 2016 doi: 10.1172/jci.insight.85061). .

Adding panobinostat to bortezomib and dexamethasone has been shown to improve progression-free survival in relapsed and refractory multiple myeloma, the researchers noted. Other studies have linked calcineurin activation to the pathogenesis of T-cell cancers, and calcineurin inhibition seems to be involved in defective B-cell activation, they added.

Eight candidate oncogenes were identified by use of the Gene Expression Omnibus. PPP3CA was expressed at significantly higher levels in multiple myeloma cells from patients with stage III disease compared with those with stage I disease (P = .016). Furthermore, levels of serum lactate dehydrogenase correlated with PPP3CA expression and with poor overall and progression-free survival. Patients with high PPP3CA expression also had high levels of alpha₄ integrins, which mediate resistance to bortezomib and conventional chemotherapy, the researchers noted.

When multiple myeloma cells were exposed to either panobinostat or a control agent, PPP3CA dropped in the panobinostat-treated cells. Adding the proteasome inhibitor lactacystin to the mixture counteracted this effect, “supporting the possibility that PPP3CA expression was reduced through protein degradation by panobinostat,” they said.

Levels of PPP3CA expression were lower in multiple myeloma cells that were cotreated with an HDAC inhibitor (panobinostat or ACY-1215) and the immunosuppressive agent FK506 than in multiple myeloma cells that were exposed only to an HDAC inhibitor. In addition, the combination regimen blocked the formation of osteoclasts, which are involved in osteolytic lesions, the researchers noted.

Also, significantly higher PPP3CA expression, which correlated with worse progression-free survival, was noted in bortezomib-resistant patients, compared with bortezomib-sensitive patients.

“The cytotoxic effect exerted by panobinostat on CD20+ cells was subtle, while the addition of FK506 did not increase their viability,” the researchers reported. “Moreover, development of T and B lineage cells was normal in PPP3CA-deficient mice, and panobinostat did not compromise donor lymphocyte reconstitution in a mouse BM transplantation model. These results suggest that calcineurin-targeting therapy exerts an antimyeloma effect without inducing significant side effects in normal lymphoid systems.”

The Japan Society for the Promotion of Science, the Takeda Science Foundation, the International Myeloma Foundation, and the Japan Leukemia Research Fund funded the study. The investigators had no disclosures.

Treating multiple myeloma cells with panobinostat and FK506 reduced their viability by inhibiting expression of the PPP3CA catalytic subunit of calcineurin, according to researchers.

“The development of new calcineurin-targeted therapies, which inhibit PPP3CA–NF-kappaB signaling by small molecules, is expected to profoundly improve the treatment of multiple myeloma. This will overcome drug resistance and improve osteolytic lesions in a wide range of patients, including those receiving reduced intensity–conditioned allogeneic stem cell transplantation, who may be treated with panobinostat and FK506,” wrote Dr. Yoichi Imai of Tokyo Women’s Medical University in Japan, and his associates (JCI Insight 2016 doi: 10.1172/jci.insight.85061). .

Adding panobinostat to bortezomib and dexamethasone has been shown to improve progression-free survival in relapsed and refractory multiple myeloma, the researchers noted. Other studies have linked calcineurin activation to the pathogenesis of T-cell cancers, and calcineurin inhibition seems to be involved in defective B-cell activation, they added.

Eight candidate oncogenes were identified by use of the Gene Expression Omnibus. PPP3CA was expressed at significantly higher levels in multiple myeloma cells from patients with stage III disease compared with those with stage I disease (P = .016). Furthermore, levels of serum lactate dehydrogenase correlated with PPP3CA expression and with poor overall and progression-free survival. Patients with high PPP3CA expression also had high levels of alpha₄ integrins, which mediate resistance to bortezomib and conventional chemotherapy, the researchers noted.

When multiple myeloma cells were exposed to either panobinostat or a control agent, PPP3CA dropped in the panobinostat-treated cells. Adding the proteasome inhibitor lactacystin to the mixture counteracted this effect, “supporting the possibility that PPP3CA expression was reduced through protein degradation by panobinostat,” they said.

Levels of PPP3CA expression were lower in multiple myeloma cells that were cotreated with an HDAC inhibitor (panobinostat or ACY-1215) and the immunosuppressive agent FK506 than in multiple myeloma cells that were exposed only to an HDAC inhibitor. In addition, the combination regimen blocked the formation of osteoclasts, which are involved in osteolytic lesions, the researchers noted.

Also, significantly higher PPP3CA expression, which correlated with worse progression-free survival, was noted in bortezomib-resistant patients, compared with bortezomib-sensitive patients.

“The cytotoxic effect exerted by panobinostat on CD20+ cells was subtle, while the addition of FK506 did not increase their viability,” the researchers reported. “Moreover, development of T and B lineage cells was normal in PPP3CA-deficient mice, and panobinostat did not compromise donor lymphocyte reconstitution in a mouse BM transplantation model. These results suggest that calcineurin-targeting therapy exerts an antimyeloma effect without inducing significant side effects in normal lymphoid systems.”

The Japan Society for the Promotion of Science, the Takeda Science Foundation, the International Myeloma Foundation, and the Japan Leukemia Research Fund funded the study. The investigators had no disclosures.

CHICAGO – Just over one-half of all sudden deaths in a large pediatric case series were due to a primary arrhythmia syndrome, Dr. Grazia Delle Donne reported at the annual meeting of the American College of Cardiology.

She presented an analysis of all patients under the age of 18 years who were referred to London’s Royal Brompton Hospital for post mortem examination following presumed sudden cardiac death during 1991-2013. Royal Brompton is a national referral center for sudden cardiac death.

The review was undertaken because sudden cardiac death in the pediatric population occurs infrequently. Little is known about the prevalence of the various causes, noted Dr. Delle Donne of Royal Brompton.

Bruce Jancin/Frontline Medical News

Of the 398 subjects, 266 (67%) were female. The median age at death was 14 years. Twenty-two percent of the fatalities occurred during or immediately after exercise. Thirty-nine percent occurred while at rest.

Thirty-one percent of subjects had a family history of sudden cardiac death, another 14% had a family history of cardiomyopathy, and in 5% of cases there was a significant family history of arrhythmia.

Five percent of the children were known to have congenital heart disease. Eighteen percent of the children had a history of syncope.

Investigators determined that a primary arrhythmia syndrome such as long QT or Brugada syndrome was the cause of sudden death in 54% of cases. Death was attributed to cardiomyopathy in 15% cases, congenital heart disease in 8%, myocarditis in 6%, and coronary anomalies in 5%, with miscellaneous causes accounting for the remainder.

Dr. Delle Donne reported having no financial conflicts of interest regarding her presentation.

[email protected]

CHICAGO – Just over one-half of all sudden deaths in a large pediatric case series were due to a primary arrhythmia syndrome, Dr. Grazia Delle Donne reported at the annual meeting of the American College of Cardiology.

She presented an analysis of all patients under the age of 18 years who were referred to London’s Royal Brompton Hospital for post mortem examination following presumed sudden cardiac death during 1991-2013. Royal Brompton is a national referral center for sudden cardiac death.

The review was undertaken because sudden cardiac death in the pediatric population occurs infrequently. Little is known about the prevalence of the various causes, noted Dr. Delle Donne of Royal Brompton.

Bruce Jancin/Frontline Medical News

Of the 398 subjects, 266 (67%) were female. The median age at death was 14 years. Twenty-two percent of the fatalities occurred during or immediately after exercise. Thirty-nine percent occurred while at rest.

Thirty-one percent of subjects had a family history of sudden cardiac death, another 14% had a family history of cardiomyopathy, and in 5% of cases there was a significant family history of arrhythmia.

Five percent of the children were known to have congenital heart disease. Eighteen percent of the children had a history of syncope.

Investigators determined that a primary arrhythmia syndrome such as long QT or Brugada syndrome was the cause of sudden death in 54% of cases. Death was attributed to cardiomyopathy in 15% cases, congenital heart disease in 8%, myocarditis in 6%, and coronary anomalies in 5%, with miscellaneous causes accounting for the remainder.

Dr. Delle Donne reported having no financial conflicts of interest regarding her presentation.

[email protected]

CHICAGO – Just over one-half of all sudden deaths in a large pediatric case series were due to a primary arrhythmia syndrome, Dr. Grazia Delle Donne reported at the annual meeting of the American College of Cardiology.

She presented an analysis of all patients under the age of 18 years who were referred to London’s Royal Brompton Hospital for post mortem examination following presumed sudden cardiac death during 1991-2013. Royal Brompton is a national referral center for sudden cardiac death.

The review was undertaken because sudden cardiac death in the pediatric population occurs infrequently. Little is known about the prevalence of the various causes, noted Dr. Delle Donne of Royal Brompton.

Bruce Jancin/Frontline Medical News

Of the 398 subjects, 266 (67%) were female. The median age at death was 14 years. Twenty-two percent of the fatalities occurred during or immediately after exercise. Thirty-nine percent occurred while at rest.

Thirty-one percent of subjects had a family history of sudden cardiac death, another 14% had a family history of cardiomyopathy, and in 5% of cases there was a significant family history of arrhythmia.

Five percent of the children were known to have congenital heart disease. Eighteen percent of the children had a history of syncope.

Investigators determined that a primary arrhythmia syndrome such as long QT or Brugada syndrome was the cause of sudden death in 54% of cases. Death was attributed to cardiomyopathy in 15% cases, congenital heart disease in 8%, myocarditis in 6%, and coronary anomalies in 5%, with miscellaneous causes accounting for the remainder.

Dr. Delle Donne reported having no financial conflicts of interest regarding her presentation.

[email protected]

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes management today: Issues in achieving glycemic goals
M. Cecilia Lansang

The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk
Courtney Nagel Sandler and Marie E. McDonnell

Antihyperglycemic drugs and cardiovascular outcomes in type 2 diabetes
Om P. Ganda

Newer oral and noninsulin therapies to treat type 2 diabetes mellitus
Kathie L. Hermayer and Andrew Dake

New insulin preparations: A primer for the clinician
Luigi Meneghini

Inpatient hyperglycemia management: A practical review for primary medical and surgical teams
M. Cecilia Lansang and Guillermo E. Umpierrez

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes management today: Issues in achieving glycemic goals
M. Cecilia Lansang

The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk
Courtney Nagel Sandler and Marie E. McDonnell

Antihyperglycemic drugs and cardiovascular outcomes in type 2 diabetes
Om P. Ganda

Newer oral and noninsulin therapies to treat type 2 diabetes mellitus
Kathie L. Hermayer and Andrew Dake

New insulin preparations: A primer for the clinician
Luigi Meneghini

Inpatient hyperglycemia management: A practical review for primary medical and surgical teams
M. Cecilia Lansang and Guillermo E. Umpierrez

Supplement Editor:
M. Cecilia Lansang, MD, MPH

Contents

Diabetes management today: Issues in achieving glycemic goals
M. Cecilia Lansang

The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk
Courtney Nagel Sandler and Marie E. McDonnell

Antihyperglycemic drugs and cardiovascular outcomes in type 2 diabetes
Om P. Ganda

Newer oral and noninsulin therapies to treat type 2 diabetes mellitus
Kathie L. Hermayer and Andrew Dake

New insulin preparations: A primer for the clinician
Luigi Meneghini

Inpatient hyperglycemia management: A practical review for primary medical and surgical teams
M. Cecilia Lansang and Guillermo E. Umpierrez

Guest Editor
Andrew M. Kaunitz, MD

Authors
Sheryl Kingsberg, PhD; Michael Krychman, MD; Juliana M. Kling, MD, MPH; JoAnn E. Manson, MD, DrPH; James H. Liu, MD; Gretchen Collins, MD; Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

The object of this special issue is to enhance how you respond to and manage patients' menopausal and sexuality symptom concerns. The articles aim to alert women's health professionals to:

• the effects of sexual dysfunction, genitourinary syndrome of menopause in particular, on women emotionally and physically, and the available treatment options
• current nonhormonal treatment for hot flashes
• latest data on SERMs' role in managing menopausal symptoms, considering matching patients' symptoms to agents
• recommendations for intimacy counseling.

Articles included:

Image

Not enough women are receiving treatment for bothersome menopausal symptoms
Andrew M. Kaunitz, MD
Mitigating the impact of genitourinary syndrome of menopause on sexuality
Sheryl Kingsberg, PhD, and Michael Krychman, MD
Nonhormonal treatment options for vasomotor symptoms of menopause
Juliana M. Kling, MD, MPH, and JoAnn E. Manson, MD, DrPH
SERMs in menopause: Matching agents to patients' symptoms and attributes
James H. Liu, MD, and Gretchen Collins, MD

Tips for counseling women about intimacy after menopause
Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

Guest Editor
Andrew M. Kaunitz, MD

Authors
Sheryl Kingsberg, PhD; Michael Krychman, MD; Juliana M. Kling, MD, MPH; JoAnn E. Manson, MD, DrPH; James H. Liu, MD; Gretchen Collins, MD; Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

The object of this special issue is to enhance how you respond to and manage patients' menopausal and sexuality symptom concerns. The articles aim to alert women's health professionals to:

• the effects of sexual dysfunction, genitourinary syndrome of menopause in particular, on women emotionally and physically, and the available treatment options
• current nonhormonal treatment for hot flashes
• latest data on SERMs' role in managing menopausal symptoms, considering matching patients' symptoms to agents
• recommendations for intimacy counseling.

Articles included:

Image

Not enough women are receiving treatment for bothersome menopausal symptoms
Andrew M. Kaunitz, MD
Mitigating the impact of genitourinary syndrome of menopause on sexuality
Sheryl Kingsberg, PhD, and Michael Krychman, MD
Nonhormonal treatment options for vasomotor symptoms of menopause
Juliana M. Kling, MD, MPH, and JoAnn E. Manson, MD, DrPH
SERMs in menopause: Matching agents to patients' symptoms and attributes
James H. Liu, MD, and Gretchen Collins, MD

Tips for counseling women about intimacy after menopause
Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

Guest Editor
Andrew M. Kaunitz, MD

Authors
Sheryl Kingsberg, PhD; Michael Krychman, MD; Juliana M. Kling, MD, MPH; JoAnn E. Manson, MD, DrPH; James H. Liu, MD; Gretchen Collins, MD; Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

The object of this special issue is to enhance how you respond to and manage patients' menopausal and sexuality symptom concerns. The articles aim to alert women's health professionals to:

• the effects of sexual dysfunction, genitourinary syndrome of menopause in particular, on women emotionally and physically, and the available treatment options
• current nonhormonal treatment for hot flashes
• latest data on SERMs' role in managing menopausal symptoms, considering matching patients' symptoms to agents
• recommendations for intimacy counseling.

Articles included:

Image

Not enough women are receiving treatment for bothersome menopausal symptoms
Andrew M. Kaunitz, MD
Mitigating the impact of genitourinary syndrome of menopause on sexuality
Sheryl Kingsberg, PhD, and Michael Krychman, MD
Nonhormonal treatment options for vasomotor symptoms of menopause
Juliana M. Kling, MD, MPH, and JoAnn E. Manson, MD, DrPH
SERMs in menopause: Matching agents to patients' symptoms and attributes
James H. Liu, MD, and Gretchen Collins, MD

Tips for counseling women about intimacy after menopause
Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC

In 2001, it was projected that nearly 20 million Americans would have diabetes by 2025.¹ But in 2015, 29 million Americans had been diagnosed with diabetes, exceeding the 2001 projection by 9 million. Newer projections are sobering—the prevalence of diabetes is estimated to increase from 9.3% of the population in 2012 to between 21% and 30% by 2050.²

As a result, most healthcare providers will face patients with diabetes or at risk for diabetes. Patients with diabetes today differ from those in the past in that increasing numbers of them are insulin resistant with impaired insulin secretion. Elements of metabolic syndrome including obesity, hypertension, high triglyceride levels, and low high-density lipoprotein levels increase the risk of diabetes and cardiovascular disease.

With the medications and treatments available today, how well are we practitioners doing in managing hyperglycemia? National Health and Nutrition Examination Survey data from 2005 to 2010 show that among patients taking diabetes medication, only 55% had controlled hemoglobin A1c (HbA1c) levels.³ The role of HbA1c in the assessment and management of patients with diabetes is discussed in this supplement by Marie E. McDonnell, MD, and Courtney Nagel Sandler, MD. Though an essential tool in blood glucose control, appropriate HbA1c target levels and reliability vary among patients. Interpretation of HbA1c may be difficult in some patients, and HbA1c levels should be tailored by balancing risks and benefits.

Diabetes management is complicated by the existence of comorbid cardiovascular disease. While a number of studies link intense glycemic control to improved cardiovascular outcomes in patients with diabetes, other studies have demonstrated higher morbidity and mortality associated with antihyperglycemic drugs. Om P. Ganda, MD, reviews the sometimes perplexing and confusing research on the effect of glucose-lowering drugs on cardiovascular outcomes, including results from a recently completed trial evaluating empagliflozin.

Further reflecting the complexity of the biologic mechanisms associated with treating diabetes, today we have 12 classes of drugs approved by the US Food and Drug Administration (FDA) for diabetes compared with the two classes (insulin and sulfonylureas) available in the 1980s. In the last decade, the FDA approved 14 noninsulin drugs in 5 classes. In this supplement, Kathie L. Hermayer, MD, MS, and Andrew Dake, MD, discuss the various noninsulin therapies and their use in achieving the balance of blood glucose control and reduced adverse events and hypoglycemia in patients with type 2 diabetes.

For patients with profound insulin deficiency, insulin remains the most important therapeutic option. Insulin is available in four general classes: rapid-, short-, intermediate-, and long-acting (and in premixed variations). The latest in insulin formulations include ultra-long-acting insulin, new concentrated insulin (glargine U-300 and lispro U-200), and inhaled insulin. A primer on these new insulin preparations and how they fit into clinical practice is provided by Luigi Meneghini, MD, MBA.

Finally, despite the availability of new medications for outpatient management of patients with diabetes, inpatient care represents the largest proportion of healthcare dollars spent on these patients. In inpatients, hyperglycemia is associated with a higher risk of complications, higher utilization of healthcare resources, and increased mortality rates. Guillermo E. Umpierrez, MD, CDE, and I outline best practices to achieve glycemic control and avoid hypogly­cemia in critically and noncritically ill inpatients.

The growing number of patients with diabetes and the variety of therapeutic options available present physicians with many considerations in achieving glycemic goals. With great enthusiasm, I invite you to read this supplement on diabetes and hope you find it worthwhile and useful in elucidating issues in the management of diabetes today.

In 2001, it was projected that nearly 20 million Americans would have diabetes by 2025.¹ But in 2015, 29 million Americans had been diagnosed with diabetes, exceeding the 2001 projection by 9 million. Newer projections are sobering—the prevalence of diabetes is estimated to increase from 9.3% of the population in 2012 to between 21% and 30% by 2050.²

As a result, most healthcare providers will face patients with diabetes or at risk for diabetes. Patients with diabetes today differ from those in the past in that increasing numbers of them are insulin resistant with impaired insulin secretion. Elements of metabolic syndrome including obesity, hypertension, high triglyceride levels, and low high-density lipoprotein levels increase the risk of diabetes and cardiovascular disease.

With the medications and treatments available today, how well are we practitioners doing in managing hyperglycemia? National Health and Nutrition Examination Survey data from 2005 to 2010 show that among patients taking diabetes medication, only 55% had controlled hemoglobin A1c (HbA1c) levels.³ The role of HbA1c in the assessment and management of patients with diabetes is discussed in this supplement by Marie E. McDonnell, MD, and Courtney Nagel Sandler, MD. Though an essential tool in blood glucose control, appropriate HbA1c target levels and reliability vary among patients. Interpretation of HbA1c may be difficult in some patients, and HbA1c levels should be tailored by balancing risks and benefits.

Diabetes management is complicated by the existence of comorbid cardiovascular disease. While a number of studies link intense glycemic control to improved cardiovascular outcomes in patients with diabetes, other studies have demonstrated higher morbidity and mortality associated with antihyperglycemic drugs. Om P. Ganda, MD, reviews the sometimes perplexing and confusing research on the effect of glucose-lowering drugs on cardiovascular outcomes, including results from a recently completed trial evaluating empagliflozin.

Further reflecting the complexity of the biologic mechanisms associated with treating diabetes, today we have 12 classes of drugs approved by the US Food and Drug Administration (FDA) for diabetes compared with the two classes (insulin and sulfonylureas) available in the 1980s. In the last decade, the FDA approved 14 noninsulin drugs in 5 classes. In this supplement, Kathie L. Hermayer, MD, MS, and Andrew Dake, MD, discuss the various noninsulin therapies and their use in achieving the balance of blood glucose control and reduced adverse events and hypoglycemia in patients with type 2 diabetes.

For patients with profound insulin deficiency, insulin remains the most important therapeutic option. Insulin is available in four general classes: rapid-, short-, intermediate-, and long-acting (and in premixed variations). The latest in insulin formulations include ultra-long-acting insulin, new concentrated insulin (glargine U-300 and lispro U-200), and inhaled insulin. A primer on these new insulin preparations and how they fit into clinical practice is provided by Luigi Meneghini, MD, MBA.

Finally, despite the availability of new medications for outpatient management of patients with diabetes, inpatient care represents the largest proportion of healthcare dollars spent on these patients. In inpatients, hyperglycemia is associated with a higher risk of complications, higher utilization of healthcare resources, and increased mortality rates. Guillermo E. Umpierrez, MD, CDE, and I outline best practices to achieve glycemic control and avoid hypogly­cemia in critically and noncritically ill inpatients.

The growing number of patients with diabetes and the variety of therapeutic options available present physicians with many considerations in achieving glycemic goals. With great enthusiasm, I invite you to read this supplement on diabetes and hope you find it worthwhile and useful in elucidating issues in the management of diabetes today.

In 2001, it was projected that nearly 20 million Americans would have diabetes by 2025.¹ But in 2015, 29 million Americans had been diagnosed with diabetes, exceeding the 2001 projection by 9 million. Newer projections are sobering—the prevalence of diabetes is estimated to increase from 9.3% of the population in 2012 to between 21% and 30% by 2050.²

As a result, most healthcare providers will face patients with diabetes or at risk for diabetes. Patients with diabetes today differ from those in the past in that increasing numbers of them are insulin resistant with impaired insulin secretion. Elements of metabolic syndrome including obesity, hypertension, high triglyceride levels, and low high-density lipoprotein levels increase the risk of diabetes and cardiovascular disease.

With the medications and treatments available today, how well are we practitioners doing in managing hyperglycemia? National Health and Nutrition Examination Survey data from 2005 to 2010 show that among patients taking diabetes medication, only 55% had controlled hemoglobin A1c (HbA1c) levels.³ The role of HbA1c in the assessment and management of patients with diabetes is discussed in this supplement by Marie E. McDonnell, MD, and Courtney Nagel Sandler, MD. Though an essential tool in blood glucose control, appropriate HbA1c target levels and reliability vary among patients. Interpretation of HbA1c may be difficult in some patients, and HbA1c levels should be tailored by balancing risks and benefits.

Diabetes management is complicated by the existence of comorbid cardiovascular disease. While a number of studies link intense glycemic control to improved cardiovascular outcomes in patients with diabetes, other studies have demonstrated higher morbidity and mortality associated with antihyperglycemic drugs. Om P. Ganda, MD, reviews the sometimes perplexing and confusing research on the effect of glucose-lowering drugs on cardiovascular outcomes, including results from a recently completed trial evaluating empagliflozin.

Further reflecting the complexity of the biologic mechanisms associated with treating diabetes, today we have 12 classes of drugs approved by the US Food and Drug Administration (FDA) for diabetes compared with the two classes (insulin and sulfonylureas) available in the 1980s. In the last decade, the FDA approved 14 noninsulin drugs in 5 classes. In this supplement, Kathie L. Hermayer, MD, MS, and Andrew Dake, MD, discuss the various noninsulin therapies and their use in achieving the balance of blood glucose control and reduced adverse events and hypoglycemia in patients with type 2 diabetes.

For patients with profound insulin deficiency, insulin remains the most important therapeutic option. Insulin is available in four general classes: rapid-, short-, intermediate-, and long-acting (and in premixed variations). The latest in insulin formulations include ultra-long-acting insulin, new concentrated insulin (glargine U-300 and lispro U-200), and inhaled insulin. A primer on these new insulin preparations and how they fit into clinical practice is provided by Luigi Meneghini, MD, MBA.

Finally, despite the availability of new medications for outpatient management of patients with diabetes, inpatient care represents the largest proportion of healthcare dollars spent on these patients. In inpatients, hyperglycemia is associated with a higher risk of complications, higher utilization of healthcare resources, and increased mortality rates. Guillermo E. Umpierrez, MD, CDE, and I outline best practices to achieve glycemic control and avoid hypogly­cemia in critically and noncritically ill inpatients.

The growing number of patients with diabetes and the variety of therapeutic options available present physicians with many considerations in achieving glycemic goals. With great enthusiasm, I invite you to read this supplement on diabetes and hope you find it worthwhile and useful in elucidating issues in the management of diabetes today.

Since its widespread introduction into routine clinical practice nearly 2 decades ago, hemoglobin A1c (HbA1c) measurement has become an integral tool for the diagnosis and management of diabetes mellitus. It is frequently used in both the care of individuals and in landmark population-based clinical trials. It also serves as a surro­gate marker of glycemic control and is a key risk indicator for diabetes-associated microvascular and macrovascular complications and mortality.

With so much importance placed on one labora­tory value, it is imperative to remember that the test is imperfect, with pitfalls both in accuracy and interpretation. The purpose of this review is to provide a broad understanding of HbA1c and how it can be optimally applied to patient management and the assessment of diabetes and cardiovascular (CV) risk.

HbA1c TESTING, BACKGROUND

HbA1c was first discovered in 1955, but elevated HbA1c levels in diabetes patients were not noted until 1968.¹ Another 8 years passed before HbA1c was correlated with blood glucose values in hospitalized patients with diabetes and was proposed for monitoring glycemia.²

Biochemically, HbA1c forms through a nonenzymatic reaction in which glucose attaches to the valine amino terminal of one or both beta chains of hemoglobin A. This compound can be separated out from nonglycated hemoglobin and from other glycated hemoglobin molecules through various methods, such as high performance liquid chromatography or immunoassay.³

During the first few years of clinical use, HbA1c measures were inconsistent. The publication of the Diabetes Control and Complications Trial (DCCT) in 1993³ made the importance of precise HbA1c measurement apparent. This study found that the approximate 2% difference in HbA1c between standard- and intensive-insulin therapy groups resulted in dramatically reduced risk of microvascular disease in patients with type 1 diabetes. The continuation of the DCCT, the Epidemiology of Diabetes Interventions and Complications trial,⁴ and a study of patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS),⁵ further supported the relationship between sustaining a lower average HbA1c over time and improved patient outcomes, including CV events and mortality. Given the implications of small changes in HbA1c on morbidity, the need to reduce error margins in measurement became apparent.

The NGSP (formerly the National Glycohemoglobin Standardization Program) was founded in 1996 to regulate HbA1c measurements to DCCT standards.⁶ This program, now international in scope through involvement with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), calibrates HbA1c measurements by outside laboratories and manufacturers to reference standards. Laboratories and manufacturers that measure HbA1c certify through IFCC/NGSP and participate in yearly surveys to ensure inter-laboratory reproducibility. Through this successful program, standardization and accuracy of HbA1c measurements greatly improved from 1993 to 2012 (Figure 1).^1,6,7 Largely owing to this fact, HbA1c was approved as a diagnostic tool by the American Diabetes Association (ADA) in 2009;⁸ the test has become a key measure for diagnosing, screening, and monitoring diabetes.

The HbA1c level is affected by the blood glucose concentration, the duration of red blood cell (RBC) exposure to varying concentrations, and RBC quantity. HbA1c most accurately reflects the previous 2 to 3 months of glycemic control in the setting of the usual RBC life span of 120 days.⁹ As a relatively long-term indicator of glycemic control, it may not accurately represent acute improvements or deteriorations in glycemia. Recent factors affecting glycemia must be considered, as HbA1c represents a weighted average glucose with 50% contribution from the preceding month.¹⁰

HbA1c must be interpreted with caution. In nonpregnant adults, HbA1c is often falsely low in conditions that reduce the number of glycosylated RBCs, such as hemolysis, splenomegaly, chronic kidney disease, cirrhosis, hemorrhage, blood transfusions, use of erythropoiesis-stimulating agents, and certain hemoglobinopathies (ie, HbS, HbC, HbF). Alternately, HbA1c is elevated in other hemoglobinopathies and in conditions that result in decreased RBC turnover such as iron or vitamin B12-deficiency anemia.^11–13

The 2008 A1c-Derived Average Glucose study group (507 participants from 10 international centers) used linear regression analysis to correlate HbA1c drawn every 3 months with average blood glucose readings taken during those 3 months. Results from participants without diabetes were compared with patients with type 1 or type 2 diabetes.¹⁴ The resulting significant correlation between HbA1c and average blood glucose readings (coefficient of determination 0.84, P <.0001) became the standard for estimating glycemia from HbA1c (Table 1).

DIAGNOSIS, SCREENING FOR DIABETES

HbA1c was accepted by the ADA as a diagnostic test for diabetes in 2009⁴ and the World Health Organization (WHO) in 2011,¹³ although the WHO recommended alternate methods for diagnosis given concerns about test availability, cost, and accuracy in the developing world.¹⁵

Advantages to HbA1c use in diagnosis include standardization of measurement, convenience as a single blood-draw that does not require fasting, minimal day-to-day variability, and preanalytic sample stability. Although point-of-care testing for HbA1c is widely available, it is not recommended for diagnostic use because these assays are generally not IFCC/NGSP certified and do not undergo the same proficiency testing as laboratory samples.^12,16

The 1997 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus¹⁷ encouraged that diagnosis be based on the glycemic level at which microvascular complications develop. Using fasting plasma glucose (FPG), 2-hour postprandial plasma glucose, and funduscopic data from several large epidemiologic studies, the committee established that increased risk of diabetic retinopathy occurs at FPG levels greater than or equal to 126 mg/dL (7.0 mmol/L). Subsequent studies analyzed sensitivity and specificity correlations between FPG levels above 126 mg/dL and HbA1c in an effort to define cutoffs for HbA1c as a diagnostic tool; however, their results lacked clear clinical relevance.^18–20

In 2003, the DETECT-2 trial analyzed HbA1c levels in more than 28,000 participants to determine HbA1c diagnostic definitions based on microvascular complications.²¹ Evaluating HbA1c in 0.5% increments, investigators found that the incidence of diabetic retinopathy rose above baseline at HbA1c of 6.5%, the now accepted diagnostic value. It is important to note that this cutoff makes HbA1c less sensitive than other diagnostic indicators, which if applied to the same number of individuals, would result in up to one-third more patients diagnosed with diabetes. However, the lower sensitivity is balanced by higher screening rates given HbA1c accessibility.¹⁶

Diabetes can be diagnosed according to the criteria in Table 2, using venous plasma samples for HbA1c and glucose measurements. FPG assessment, both alone and as part of a 2-hour oral glucose tolerance test (OGTT), requires a minimum 8-hour fast. Although it is more cumbersome for both patients and practitioners, the 2-hour OGTT remains the technical standard diagnostic test for diabetes. It can formally identify patients with impaired fasting glucose and impaired glucose tolerance, which are markers of impaired beta cell function and future progression to frank diabetes mellitus.

In the presence of clear symptoms of hyperglycemia such as blurry vision, polyuria, polydipsia, weight loss, and a random plasma glucose value ≥ 200 mg/dL (11.1 mmol/L), a single laboratory measurement fitting any of the three diagnostic criteria confirms the diagnosis of diabetes. In the absence of these symptoms, one positive test must be repeated and remain positive in order to confirm diabetes. As an alternative to repeating the original diagnostic test, two of the three criteria may be positive at any one time to make the diagnosis.^13,16

Routine screening for diabetes using HbA1c should be based on risk in the absence of symptoms (Table 3). The ADA recommends screening at 3-year intervals if an initial screen is within normal limits or yearly in individuals with prediabetes or a change in risk status.¹⁶ Screening also is recommended for patients on medications that increase the risk of hyperglycemia (eg, glucocorticoids, thiazides, and atypical antipsychotics).

Individuals with prediabetes are identified as having impaired fasting glucose and impaired glucose tolerance based on 2-hour OGTT, FPG, or HbA1c (Table 4). Those with HbA1c values 6.00% to 6.49% are considered by the ADA and WHO to have the highest risk of developing diabetes.^13,15,16 This range is based primarily on a 2010 systematic review²² evaluating the relationship between HbA1c and progression to diabetes in studies involving more than 44,000 participants. Patients with HbA1c of 6.0% or above had a 5-year risk of progression to diabetes between 25% and 50%, 20 times higher than those with HbA1c less than 5%.²² The ADA-defined lower limit for diagnosing prediabetes (HbA1c ≥ 5.7%) is based on a 2011 analysis of National Health and Nutrition Examination Survey data.²³ In that study, adults with HbA1c levels at or above 5.7% were at similar risk of developing frank type 2 diabetes and CV disease (41.3% over 7.5 years and 13.3% over 10 years, respectively) as the 3,234 participants in the Diabetes Prevention Program, a prospective, population-based study evaluating the risk of incident diabetes.^23,24

MONITORING PATIENTS WITH DIABETES

HbA1c should be performed every 3 months in patients with known diabetes and can be spaced to twice yearly in patients meeting treatment goals on stable therapy.

While not recommended for diagnosis, point-of-care testing of HbA1c has been endorsed by the ADA for monitoring patients with diabetes. Studies have shown that a higher percentage of patients achieve HbA1c targets with treatment adjustment based on point-of-care testing of HbA1c at the time of visit vs usual laboratory monitoring.^16,25

Goal HbA1c levels in patients with diabetes should be patient-tailored, as outlined in Figure 2. For example, stricter control with HbA1c (≤ 6.5%) may be desired in a young, otherwise healthy individual, whereas an HbA1c of 8% may be appropriate in a patient with multiple comorbidities.²⁶

HbA1c AND CARDIOVASCULAR RISK

HbA1c has been established as a strong predictor of CV events and mortality in patients with diabetes despite the absence of firm evidence that glycemic control modifies this risk substantially over time.²⁷ Results from the UKPDS and DCCT trials lend strong support to the hypothesis that glycemic control early in the course of disease provides preventive benefit.^3–5 In contrast, three major trials that enrolled older patients at higher baseline risk showed no mortality or CV benefit of tighter glycemic control.^28–30 One of these, the Action to Control Cardiovascular Risk in Diabetes trial,²⁸ found increased mortality risk in the intensive glycemic-control arm among those who did not achieve the HbA1c target, illustrating the complexity of interpreting HbA1c in clinical practice.

While HbA1c may predict the risk of mortality and CV events in diabetes populations, it is unlikely to be a strong predictor in patients without established diabetes. Analysis of data from the Emerging Risk Factors Collaboration indicates that below the HbA1c diagnostic threshold of diabetes (< 6.5%), HbA1c is less predictive than stronger risk factors such as lipids.³¹ In this retrospective analysis, which included a cohort of more than 200,000 individuals without diabetes, the risk model to predict CV events was not enhanced significantly by the addition of HbA1c information.

MISREPRESENTING THE GLYCEMIC ‘BIG PICTURE’

Aside from the previously discussed medical conditions that may affect HbA1c accuracy, other factors may complicate HbA1c interpretation. Recent studies raised concern about the generalizability of HbA1c across racial and ethnic groups. A 2010 study of non-Hispanic black and white participants without diabetes revealed that black participants had higher HbA1c levels across the glycemic continuum.³² In the past, concern was raised that these HbA1c elevations were related simply to poorer glycemic management and healthcare disparities. However, a study using data from the Diabetes Prevention Program compared HbA1c in five racial and ethnic groups and found that racial and ethnic minorities had higher HbA1c levels after adjusting for demographics, socioeconomics, and anthropometrics.³³ This suggests that racial-genetic differences in RBC survival or glycation of hemoglobin may affect HbA1c. These studies did not assess for the presence of hemoglobinopathies despite higher prevalence in certain ethnic groups.

One critique of the HbA1c assay is that HbA1c does not reflect glycemic variability. A 2007 study analyzing DCCT data found that participants with similar HbA1c levels had dissimilar mean plasma glucose (MPG) levels and glucose variability (standard deviation of MPG).³⁴ The authors provided an example of two patients with identical HbA1c and MPG but disparate glucose variability. The patient with higher glucose variability had a 35% to 45% excess risk of hypoglycemia. Failure of HbA1c to clearly define those at risk for frequent hypoglycemic events is problematic, since hypoglycemia is an identified risk factor for CV disease and morbidity.^35,36 Of perhaps greatest concern is that an elevated HbA1c may be a common presentation of variability in the elderly. One study showed that more than 60% of elderly patients taking insulin with an average HbA1c above 8% had several hypoglycemic events per week, and based on elevated HbA1c, they may be advised to increase insulin dosing.³⁷

Glucose variability itself, including wide postprandial excursions, may be a risk factor for CV disease. The recent FLAT-SUGAR trial used HbA1c and continuous glucose monitoring to assess glycemic control and CV risk markers in participants on basal-bolus insulin therapy plus metformin versus subjects on basal insulin, metformin, and a GLP-1 agonist intended to reduce postprandial glucose excursions.³⁸ Although groups achieved similar target HbA1c levels, the intervention group had fewer glycemic excursions as well as reductions in some CV risk markers.

Alternatives to HbA1c are available for monitoring glycemic control. The monosaccharide 1,5-anhydroglucitol, a short-term marker of glycemia, competes with glucose for reabsorption in the kidney. In patients with normal renal function, low serum levels represent short-term hyperglycemia. Fructosamine and glycated albumin, formed by the glycation of proteins, reflect glycemia over the 2- to 4-week protein half-life.³⁹ Fructosamine measurement is confounded by the presence of low molecular weight substances such as bilirubin and uric acid; therefore, it may not be useful in medically complex patients. Glycated albumin is not affected by these substances; it may also be useful in patients in whom variations in RBC survival make HbA1c unreliable.^11,40 Despite the growing body of research about their usefulness, these tests lack the stringent standardization of HbA1c and have not been vetted for use in large clinical trials. Thus, their use in routine clinical practice remains controversial.

CONCLUSION

The focus on HbA1c during the last 40 years has resulted in enhanced test accuracy, availability, and use among patients and providers in the care of diabetes. Because HbA1c has become the standard in how population-based studies evaluate the effects of glycemic control on disease progression and complications, it serves as the basis for guidelines that address diabetes and CV risk definition and management. Although HbA1c may seem familiar, there is much not known about test interpretation and how it may actually miss the mark. As HbA1c use continues, these concerns need to be clarified to optimize the screening, diagnosis, and care of patients with diabetes and CV disease.

Since its widespread introduction into routine clinical practice nearly 2 decades ago, hemoglobin A1c (HbA1c) measurement has become an integral tool for the diagnosis and management of diabetes mellitus. It is frequently used in both the care of individuals and in landmark population-based clinical trials. It also serves as a surro­gate marker of glycemic control and is a key risk indicator for diabetes-associated microvascular and macrovascular complications and mortality.

With so much importance placed on one labora­tory value, it is imperative to remember that the test is imperfect, with pitfalls both in accuracy and interpretation. The purpose of this review is to provide a broad understanding of HbA1c and how it can be optimally applied to patient management and the assessment of diabetes and cardiovascular (CV) risk.

HbA1c TESTING, BACKGROUND

HbA1c was first discovered in 1955, but elevated HbA1c levels in diabetes patients were not noted until 1968.¹ Another 8 years passed before HbA1c was correlated with blood glucose values in hospitalized patients with diabetes and was proposed for monitoring glycemia.²

Biochemically, HbA1c forms through a nonenzymatic reaction in which glucose attaches to the valine amino terminal of one or both beta chains of hemoglobin A. This compound can be separated out from nonglycated hemoglobin and from other glycated hemoglobin molecules through various methods, such as high performance liquid chromatography or immunoassay.³

During the first few years of clinical use, HbA1c measures were inconsistent. The publication of the Diabetes Control and Complications Trial (DCCT) in 1993³ made the importance of precise HbA1c measurement apparent. This study found that the approximate 2% difference in HbA1c between standard- and intensive-insulin therapy groups resulted in dramatically reduced risk of microvascular disease in patients with type 1 diabetes. The continuation of the DCCT, the Epidemiology of Diabetes Interventions and Complications trial,⁴ and a study of patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS),⁵ further supported the relationship between sustaining a lower average HbA1c over time and improved patient outcomes, including CV events and mortality. Given the implications of small changes in HbA1c on morbidity, the need to reduce error margins in measurement became apparent.

The NGSP (formerly the National Glycohemoglobin Standardization Program) was founded in 1996 to regulate HbA1c measurements to DCCT standards.⁶ This program, now international in scope through involvement with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), calibrates HbA1c measurements by outside laboratories and manufacturers to reference standards. Laboratories and manufacturers that measure HbA1c certify through IFCC/NGSP and participate in yearly surveys to ensure inter-laboratory reproducibility. Through this successful program, standardization and accuracy of HbA1c measurements greatly improved from 1993 to 2012 (Figure 1).^1,6,7 Largely owing to this fact, HbA1c was approved as a diagnostic tool by the American Diabetes Association (ADA) in 2009;⁸ the test has become a key measure for diagnosing, screening, and monitoring diabetes.

The HbA1c level is affected by the blood glucose concentration, the duration of red blood cell (RBC) exposure to varying concentrations, and RBC quantity. HbA1c most accurately reflects the previous 2 to 3 months of glycemic control in the setting of the usual RBC life span of 120 days.⁹ As a relatively long-term indicator of glycemic control, it may not accurately represent acute improvements or deteriorations in glycemia. Recent factors affecting glycemia must be considered, as HbA1c represents a weighted average glucose with 50% contribution from the preceding month.¹⁰

HbA1c must be interpreted with caution. In nonpregnant adults, HbA1c is often falsely low in conditions that reduce the number of glycosylated RBCs, such as hemolysis, splenomegaly, chronic kidney disease, cirrhosis, hemorrhage, blood transfusions, use of erythropoiesis-stimulating agents, and certain hemoglobinopathies (ie, HbS, HbC, HbF). Alternately, HbA1c is elevated in other hemoglobinopathies and in conditions that result in decreased RBC turnover such as iron or vitamin B12-deficiency anemia.^11–13

The 2008 A1c-Derived Average Glucose study group (507 participants from 10 international centers) used linear regression analysis to correlate HbA1c drawn every 3 months with average blood glucose readings taken during those 3 months. Results from participants without diabetes were compared with patients with type 1 or type 2 diabetes.¹⁴ The resulting significant correlation between HbA1c and average blood glucose readings (coefficient of determination 0.84, P <.0001) became the standard for estimating glycemia from HbA1c (Table 1).

DIAGNOSIS, SCREENING FOR DIABETES

HbA1c was accepted by the ADA as a diagnostic test for diabetes in 2009⁴ and the World Health Organization (WHO) in 2011,¹³ although the WHO recommended alternate methods for diagnosis given concerns about test availability, cost, and accuracy in the developing world.¹⁵

Advantages to HbA1c use in diagnosis include standardization of measurement, convenience as a single blood-draw that does not require fasting, minimal day-to-day variability, and preanalytic sample stability. Although point-of-care testing for HbA1c is widely available, it is not recommended for diagnostic use because these assays are generally not IFCC/NGSP certified and do not undergo the same proficiency testing as laboratory samples.^12,16

The 1997 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus¹⁷ encouraged that diagnosis be based on the glycemic level at which microvascular complications develop. Using fasting plasma glucose (FPG), 2-hour postprandial plasma glucose, and funduscopic data from several large epidemiologic studies, the committee established that increased risk of diabetic retinopathy occurs at FPG levels greater than or equal to 126 mg/dL (7.0 mmol/L). Subsequent studies analyzed sensitivity and specificity correlations between FPG levels above 126 mg/dL and HbA1c in an effort to define cutoffs for HbA1c as a diagnostic tool; however, their results lacked clear clinical relevance.^18–20

In 2003, the DETECT-2 trial analyzed HbA1c levels in more than 28,000 participants to determine HbA1c diagnostic definitions based on microvascular complications.²¹ Evaluating HbA1c in 0.5% increments, investigators found that the incidence of diabetic retinopathy rose above baseline at HbA1c of 6.5%, the now accepted diagnostic value. It is important to note that this cutoff makes HbA1c less sensitive than other diagnostic indicators, which if applied to the same number of individuals, would result in up to one-third more patients diagnosed with diabetes. However, the lower sensitivity is balanced by higher screening rates given HbA1c accessibility.¹⁶

Diabetes can be diagnosed according to the criteria in Table 2, using venous plasma samples for HbA1c and glucose measurements. FPG assessment, both alone and as part of a 2-hour oral glucose tolerance test (OGTT), requires a minimum 8-hour fast. Although it is more cumbersome for both patients and practitioners, the 2-hour OGTT remains the technical standard diagnostic test for diabetes. It can formally identify patients with impaired fasting glucose and impaired glucose tolerance, which are markers of impaired beta cell function and future progression to frank diabetes mellitus.

In the presence of clear symptoms of hyperglycemia such as blurry vision, polyuria, polydipsia, weight loss, and a random plasma glucose value ≥ 200 mg/dL (11.1 mmol/L), a single laboratory measurement fitting any of the three diagnostic criteria confirms the diagnosis of diabetes. In the absence of these symptoms, one positive test must be repeated and remain positive in order to confirm diabetes. As an alternative to repeating the original diagnostic test, two of the three criteria may be positive at any one time to make the diagnosis.^13,16

Routine screening for diabetes using HbA1c should be based on risk in the absence of symptoms (Table 3). The ADA recommends screening at 3-year intervals if an initial screen is within normal limits or yearly in individuals with prediabetes or a change in risk status.¹⁶ Screening also is recommended for patients on medications that increase the risk of hyperglycemia (eg, glucocorticoids, thiazides, and atypical antipsychotics).

Individuals with prediabetes are identified as having impaired fasting glucose and impaired glucose tolerance based on 2-hour OGTT, FPG, or HbA1c (Table 4). Those with HbA1c values 6.00% to 6.49% are considered by the ADA and WHO to have the highest risk of developing diabetes.^13,15,16 This range is based primarily on a 2010 systematic review²² evaluating the relationship between HbA1c and progression to diabetes in studies involving more than 44,000 participants. Patients with HbA1c of 6.0% or above had a 5-year risk of progression to diabetes between 25% and 50%, 20 times higher than those with HbA1c less than 5%.²² The ADA-defined lower limit for diagnosing prediabetes (HbA1c ≥ 5.7%) is based on a 2011 analysis of National Health and Nutrition Examination Survey data.²³ In that study, adults with HbA1c levels at or above 5.7% were at similar risk of developing frank type 2 diabetes and CV disease (41.3% over 7.5 years and 13.3% over 10 years, respectively) as the 3,234 participants in the Diabetes Prevention Program, a prospective, population-based study evaluating the risk of incident diabetes.^23,24

MONITORING PATIENTS WITH DIABETES

HbA1c should be performed every 3 months in patients with known diabetes and can be spaced to twice yearly in patients meeting treatment goals on stable therapy.

While not recommended for diagnosis, point-of-care testing of HbA1c has been endorsed by the ADA for monitoring patients with diabetes. Studies have shown that a higher percentage of patients achieve HbA1c targets with treatment adjustment based on point-of-care testing of HbA1c at the time of visit vs usual laboratory monitoring.^16,25

Goal HbA1c levels in patients with diabetes should be patient-tailored, as outlined in Figure 2. For example, stricter control with HbA1c (≤ 6.5%) may be desired in a young, otherwise healthy individual, whereas an HbA1c of 8% may be appropriate in a patient with multiple comorbidities.²⁶

HbA1c AND CARDIOVASCULAR RISK

HbA1c has been established as a strong predictor of CV events and mortality in patients with diabetes despite the absence of firm evidence that glycemic control modifies this risk substantially over time.²⁷ Results from the UKPDS and DCCT trials lend strong support to the hypothesis that glycemic control early in the course of disease provides preventive benefit.^3–5 In contrast, three major trials that enrolled older patients at higher baseline risk showed no mortality or CV benefit of tighter glycemic control.^28–30 One of these, the Action to Control Cardiovascular Risk in Diabetes trial,²⁸ found increased mortality risk in the intensive glycemic-control arm among those who did not achieve the HbA1c target, illustrating the complexity of interpreting HbA1c in clinical practice.

While HbA1c may predict the risk of mortality and CV events in diabetes populations, it is unlikely to be a strong predictor in patients without established diabetes. Analysis of data from the Emerging Risk Factors Collaboration indicates that below the HbA1c diagnostic threshold of diabetes (< 6.5%), HbA1c is less predictive than stronger risk factors such as lipids.³¹ In this retrospective analysis, which included a cohort of more than 200,000 individuals without diabetes, the risk model to predict CV events was not enhanced significantly by the addition of HbA1c information.

MISREPRESENTING THE GLYCEMIC ‘BIG PICTURE’

Aside from the previously discussed medical conditions that may affect HbA1c accuracy, other factors may complicate HbA1c interpretation. Recent studies raised concern about the generalizability of HbA1c across racial and ethnic groups. A 2010 study of non-Hispanic black and white participants without diabetes revealed that black participants had higher HbA1c levels across the glycemic continuum.³² In the past, concern was raised that these HbA1c elevations were related simply to poorer glycemic management and healthcare disparities. However, a study using data from the Diabetes Prevention Program compared HbA1c in five racial and ethnic groups and found that racial and ethnic minorities had higher HbA1c levels after adjusting for demographics, socioeconomics, and anthropometrics.³³ This suggests that racial-genetic differences in RBC survival or glycation of hemoglobin may affect HbA1c. These studies did not assess for the presence of hemoglobinopathies despite higher prevalence in certain ethnic groups.

One critique of the HbA1c assay is that HbA1c does not reflect glycemic variability. A 2007 study analyzing DCCT data found that participants with similar HbA1c levels had dissimilar mean plasma glucose (MPG) levels and glucose variability (standard deviation of MPG).³⁴ The authors provided an example of two patients with identical HbA1c and MPG but disparate glucose variability. The patient with higher glucose variability had a 35% to 45% excess risk of hypoglycemia. Failure of HbA1c to clearly define those at risk for frequent hypoglycemic events is problematic, since hypoglycemia is an identified risk factor for CV disease and morbidity.^35,36 Of perhaps greatest concern is that an elevated HbA1c may be a common presentation of variability in the elderly. One study showed that more than 60% of elderly patients taking insulin with an average HbA1c above 8% had several hypoglycemic events per week, and based on elevated HbA1c, they may be advised to increase insulin dosing.³⁷

Glucose variability itself, including wide postprandial excursions, may be a risk factor for CV disease. The recent FLAT-SUGAR trial used HbA1c and continuous glucose monitoring to assess glycemic control and CV risk markers in participants on basal-bolus insulin therapy plus metformin versus subjects on basal insulin, metformin, and a GLP-1 agonist intended to reduce postprandial glucose excursions.³⁸ Although groups achieved similar target HbA1c levels, the intervention group had fewer glycemic excursions as well as reductions in some CV risk markers.

Alternatives to HbA1c are available for monitoring glycemic control. The monosaccharide 1,5-anhydroglucitol, a short-term marker of glycemia, competes with glucose for reabsorption in the kidney. In patients with normal renal function, low serum levels represent short-term hyperglycemia. Fructosamine and glycated albumin, formed by the glycation of proteins, reflect glycemia over the 2- to 4-week protein half-life.³⁹ Fructosamine measurement is confounded by the presence of low molecular weight substances such as bilirubin and uric acid; therefore, it may not be useful in medically complex patients. Glycated albumin is not affected by these substances; it may also be useful in patients in whom variations in RBC survival make HbA1c unreliable.^11,40 Despite the growing body of research about their usefulness, these tests lack the stringent standardization of HbA1c and have not been vetted for use in large clinical trials. Thus, their use in routine clinical practice remains controversial.

CONCLUSION

The focus on HbA1c during the last 40 years has resulted in enhanced test accuracy, availability, and use among patients and providers in the care of diabetes. Because HbA1c has become the standard in how population-based studies evaluate the effects of glycemic control on disease progression and complications, it serves as the basis for guidelines that address diabetes and CV risk definition and management. Although HbA1c may seem familiar, there is much not known about test interpretation and how it may actually miss the mark. As HbA1c use continues, these concerns need to be clarified to optimize the screening, diagnosis, and care of patients with diabetes and CV disease.

Since its widespread introduction into routine clinical practice nearly 2 decades ago, hemoglobin A1c (HbA1c) measurement has become an integral tool for the diagnosis and management of diabetes mellitus. It is frequently used in both the care of individuals and in landmark population-based clinical trials. It also serves as a surro­gate marker of glycemic control and is a key risk indicator for diabetes-associated microvascular and macrovascular complications and mortality.

With so much importance placed on one labora­tory value, it is imperative to remember that the test is imperfect, with pitfalls both in accuracy and interpretation. The purpose of this review is to provide a broad understanding of HbA1c and how it can be optimally applied to patient management and the assessment of diabetes and cardiovascular (CV) risk.

HbA1c TESTING, BACKGROUND

HbA1c was first discovered in 1955, but elevated HbA1c levels in diabetes patients were not noted until 1968.¹ Another 8 years passed before HbA1c was correlated with blood glucose values in hospitalized patients with diabetes and was proposed for monitoring glycemia.²

Biochemically, HbA1c forms through a nonenzymatic reaction in which glucose attaches to the valine amino terminal of one or both beta chains of hemoglobin A. This compound can be separated out from nonglycated hemoglobin and from other glycated hemoglobin molecules through various methods, such as high performance liquid chromatography or immunoassay.³

During the first few years of clinical use, HbA1c measures were inconsistent. The publication of the Diabetes Control and Complications Trial (DCCT) in 1993³ made the importance of precise HbA1c measurement apparent. This study found that the approximate 2% difference in HbA1c between standard- and intensive-insulin therapy groups resulted in dramatically reduced risk of microvascular disease in patients with type 1 diabetes. The continuation of the DCCT, the Epidemiology of Diabetes Interventions and Complications trial,⁴ and a study of patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS),⁵ further supported the relationship between sustaining a lower average HbA1c over time and improved patient outcomes, including CV events and mortality. Given the implications of small changes in HbA1c on morbidity, the need to reduce error margins in measurement became apparent.

The NGSP (formerly the National Glycohemoglobin Standardization Program) was founded in 1996 to regulate HbA1c measurements to DCCT standards.⁶ This program, now international in scope through involvement with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), calibrates HbA1c measurements by outside laboratories and manufacturers to reference standards. Laboratories and manufacturers that measure HbA1c certify through IFCC/NGSP and participate in yearly surveys to ensure inter-laboratory reproducibility. Through this successful program, standardization and accuracy of HbA1c measurements greatly improved from 1993 to 2012 (Figure 1).^1,6,7 Largely owing to this fact, HbA1c was approved as a diagnostic tool by the American Diabetes Association (ADA) in 2009;⁸ the test has become a key measure for diagnosing, screening, and monitoring diabetes.

The HbA1c level is affected by the blood glucose concentration, the duration of red blood cell (RBC) exposure to varying concentrations, and RBC quantity. HbA1c most accurately reflects the previous 2 to 3 months of glycemic control in the setting of the usual RBC life span of 120 days.⁹ As a relatively long-term indicator of glycemic control, it may not accurately represent acute improvements or deteriorations in glycemia. Recent factors affecting glycemia must be considered, as HbA1c represents a weighted average glucose with 50% contribution from the preceding month.¹⁰

HbA1c must be interpreted with caution. In nonpregnant adults, HbA1c is often falsely low in conditions that reduce the number of glycosylated RBCs, such as hemolysis, splenomegaly, chronic kidney disease, cirrhosis, hemorrhage, blood transfusions, use of erythropoiesis-stimulating agents, and certain hemoglobinopathies (ie, HbS, HbC, HbF). Alternately, HbA1c is elevated in other hemoglobinopathies and in conditions that result in decreased RBC turnover such as iron or vitamin B12-deficiency anemia.^11–13

The 2008 A1c-Derived Average Glucose study group (507 participants from 10 international centers) used linear regression analysis to correlate HbA1c drawn every 3 months with average blood glucose readings taken during those 3 months. Results from participants without diabetes were compared with patients with type 1 or type 2 diabetes.¹⁴ The resulting significant correlation between HbA1c and average blood glucose readings (coefficient of determination 0.84, P <.0001) became the standard for estimating glycemia from HbA1c (Table 1).

DIAGNOSIS, SCREENING FOR DIABETES

HbA1c was accepted by the ADA as a diagnostic test for diabetes in 2009⁴ and the World Health Organization (WHO) in 2011,¹³ although the WHO recommended alternate methods for diagnosis given concerns about test availability, cost, and accuracy in the developing world.¹⁵

Advantages to HbA1c use in diagnosis include standardization of measurement, convenience as a single blood-draw that does not require fasting, minimal day-to-day variability, and preanalytic sample stability. Although point-of-care testing for HbA1c is widely available, it is not recommended for diagnostic use because these assays are generally not IFCC/NGSP certified and do not undergo the same proficiency testing as laboratory samples.^12,16

The 1997 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus¹⁷ encouraged that diagnosis be based on the glycemic level at which microvascular complications develop. Using fasting plasma glucose (FPG), 2-hour postprandial plasma glucose, and funduscopic data from several large epidemiologic studies, the committee established that increased risk of diabetic retinopathy occurs at FPG levels greater than or equal to 126 mg/dL (7.0 mmol/L). Subsequent studies analyzed sensitivity and specificity correlations between FPG levels above 126 mg/dL and HbA1c in an effort to define cutoffs for HbA1c as a diagnostic tool; however, their results lacked clear clinical relevance.^18–20

In 2003, the DETECT-2 trial analyzed HbA1c levels in more than 28,000 participants to determine HbA1c diagnostic definitions based on microvascular complications.²¹ Evaluating HbA1c in 0.5% increments, investigators found that the incidence of diabetic retinopathy rose above baseline at HbA1c of 6.5%, the now accepted diagnostic value. It is important to note that this cutoff makes HbA1c less sensitive than other diagnostic indicators, which if applied to the same number of individuals, would result in up to one-third more patients diagnosed with diabetes. However, the lower sensitivity is balanced by higher screening rates given HbA1c accessibility.¹⁶

Diabetes can be diagnosed according to the criteria in Table 2, using venous plasma samples for HbA1c and glucose measurements. FPG assessment, both alone and as part of a 2-hour oral glucose tolerance test (OGTT), requires a minimum 8-hour fast. Although it is more cumbersome for both patients and practitioners, the 2-hour OGTT remains the technical standard diagnostic test for diabetes. It can formally identify patients with impaired fasting glucose and impaired glucose tolerance, which are markers of impaired beta cell function and future progression to frank diabetes mellitus.

In the presence of clear symptoms of hyperglycemia such as blurry vision, polyuria, polydipsia, weight loss, and a random plasma glucose value ≥ 200 mg/dL (11.1 mmol/L), a single laboratory measurement fitting any of the three diagnostic criteria confirms the diagnosis of diabetes. In the absence of these symptoms, one positive test must be repeated and remain positive in order to confirm diabetes. As an alternative to repeating the original diagnostic test, two of the three criteria may be positive at any one time to make the diagnosis.^13,16

Routine screening for diabetes using HbA1c should be based on risk in the absence of symptoms (Table 3). The ADA recommends screening at 3-year intervals if an initial screen is within normal limits or yearly in individuals with prediabetes or a change in risk status.¹⁶ Screening also is recommended for patients on medications that increase the risk of hyperglycemia (eg, glucocorticoids, thiazides, and atypical antipsychotics).

Individuals with prediabetes are identified as having impaired fasting glucose and impaired glucose tolerance based on 2-hour OGTT, FPG, or HbA1c (Table 4). Those with HbA1c values 6.00% to 6.49% are considered by the ADA and WHO to have the highest risk of developing diabetes.^13,15,16 This range is based primarily on a 2010 systematic review²² evaluating the relationship between HbA1c and progression to diabetes in studies involving more than 44,000 participants. Patients with HbA1c of 6.0% or above had a 5-year risk of progression to diabetes between 25% and 50%, 20 times higher than those with HbA1c less than 5%.²² The ADA-defined lower limit for diagnosing prediabetes (HbA1c ≥ 5.7%) is based on a 2011 analysis of National Health and Nutrition Examination Survey data.²³ In that study, adults with HbA1c levels at or above 5.7% were at similar risk of developing frank type 2 diabetes and CV disease (41.3% over 7.5 years and 13.3% over 10 years, respectively) as the 3,234 participants in the Diabetes Prevention Program, a prospective, population-based study evaluating the risk of incident diabetes.^23,24

MONITORING PATIENTS WITH DIABETES

HbA1c should be performed every 3 months in patients with known diabetes and can be spaced to twice yearly in patients meeting treatment goals on stable therapy.

While not recommended for diagnosis, point-of-care testing of HbA1c has been endorsed by the ADA for monitoring patients with diabetes. Studies have shown that a higher percentage of patients achieve HbA1c targets with treatment adjustment based on point-of-care testing of HbA1c at the time of visit vs usual laboratory monitoring.^16,25

Goal HbA1c levels in patients with diabetes should be patient-tailored, as outlined in Figure 2. For example, stricter control with HbA1c (≤ 6.5%) may be desired in a young, otherwise healthy individual, whereas an HbA1c of 8% may be appropriate in a patient with multiple comorbidities.²⁶

HbA1c AND CARDIOVASCULAR RISK

HbA1c has been established as a strong predictor of CV events and mortality in patients with diabetes despite the absence of firm evidence that glycemic control modifies this risk substantially over time.²⁷ Results from the UKPDS and DCCT trials lend strong support to the hypothesis that glycemic control early in the course of disease provides preventive benefit.^3–5 In contrast, three major trials that enrolled older patients at higher baseline risk showed no mortality or CV benefit of tighter glycemic control.^28–30 One of these, the Action to Control Cardiovascular Risk in Diabetes trial,²⁸ found increased mortality risk in the intensive glycemic-control arm among those who did not achieve the HbA1c target, illustrating the complexity of interpreting HbA1c in clinical practice.

While HbA1c may predict the risk of mortality and CV events in diabetes populations, it is unlikely to be a strong predictor in patients without established diabetes. Analysis of data from the Emerging Risk Factors Collaboration indicates that below the HbA1c diagnostic threshold of diabetes (< 6.5%), HbA1c is less predictive than stronger risk factors such as lipids.³¹ In this retrospective analysis, which included a cohort of more than 200,000 individuals without diabetes, the risk model to predict CV events was not enhanced significantly by the addition of HbA1c information.

MISREPRESENTING THE GLYCEMIC ‘BIG PICTURE’

Aside from the previously discussed medical conditions that may affect HbA1c accuracy, other factors may complicate HbA1c interpretation. Recent studies raised concern about the generalizability of HbA1c across racial and ethnic groups. A 2010 study of non-Hispanic black and white participants without diabetes revealed that black participants had higher HbA1c levels across the glycemic continuum.³² In the past, concern was raised that these HbA1c elevations were related simply to poorer glycemic management and healthcare disparities. However, a study using data from the Diabetes Prevention Program compared HbA1c in five racial and ethnic groups and found that racial and ethnic minorities had higher HbA1c levels after adjusting for demographics, socioeconomics, and anthropometrics.³³ This suggests that racial-genetic differences in RBC survival or glycation of hemoglobin may affect HbA1c. These studies did not assess for the presence of hemoglobinopathies despite higher prevalence in certain ethnic groups.

One critique of the HbA1c assay is that HbA1c does not reflect glycemic variability. A 2007 study analyzing DCCT data found that participants with similar HbA1c levels had dissimilar mean plasma glucose (MPG) levels and glucose variability (standard deviation of MPG).³⁴ The authors provided an example of two patients with identical HbA1c and MPG but disparate glucose variability. The patient with higher glucose variability had a 35% to 45% excess risk of hypoglycemia. Failure of HbA1c to clearly define those at risk for frequent hypoglycemic events is problematic, since hypoglycemia is an identified risk factor for CV disease and morbidity.^35,36 Of perhaps greatest concern is that an elevated HbA1c may be a common presentation of variability in the elderly. One study showed that more than 60% of elderly patients taking insulin with an average HbA1c above 8% had several hypoglycemic events per week, and based on elevated HbA1c, they may be advised to increase insulin dosing.³⁷

Glucose variability itself, including wide postprandial excursions, may be a risk factor for CV disease. The recent FLAT-SUGAR trial used HbA1c and continuous glucose monitoring to assess glycemic control and CV risk markers in participants on basal-bolus insulin therapy plus metformin versus subjects on basal insulin, metformin, and a GLP-1 agonist intended to reduce postprandial glucose excursions.³⁸ Although groups achieved similar target HbA1c levels, the intervention group had fewer glycemic excursions as well as reductions in some CV risk markers.

Alternatives to HbA1c are available for monitoring glycemic control. The monosaccharide 1,5-anhydroglucitol, a short-term marker of glycemia, competes with glucose for reabsorption in the kidney. In patients with normal renal function, low serum levels represent short-term hyperglycemia. Fructosamine and glycated albumin, formed by the glycation of proteins, reflect glycemia over the 2- to 4-week protein half-life.³⁹ Fructosamine measurement is confounded by the presence of low molecular weight substances such as bilirubin and uric acid; therefore, it may not be useful in medically complex patients. Glycated albumin is not affected by these substances; it may also be useful in patients in whom variations in RBC survival make HbA1c unreliable.^11,40 Despite the growing body of research about their usefulness, these tests lack the stringent standardization of HbA1c and have not been vetted for use in large clinical trials. Thus, their use in routine clinical practice remains controversial.

CONCLUSION

The focus on HbA1c during the last 40 years has resulted in enhanced test accuracy, availability, and use among patients and providers in the care of diabetes. Because HbA1c has become the standard in how population-based studies evaluate the effects of glycemic control on disease progression and complications, it serves as the basis for guidelines that address diabetes and CV risk definition and management. Although HbA1c may seem familiar, there is much not known about test interpretation and how it may actually miss the mark. As HbA1c use continues, these concerns need to be clarified to optimize the screening, diagnosis, and care of patients with diabetes and CV disease.

The essential value of glycemic control in preventing microvascular and neuropathic complications was established in the Diabetes Control and Complications Trial (DCCT)¹ and the United Kingdom Prospective Diabetes Study (UKPDS),² conducted in patients with type 1 and type 2 diabetes, respectively. However, it took another 10 or more years of observational follow-up of those cohorts to demonstrate statistically significant atherosclerotic cardiovascular (CV) disease benefits resulting from the intensive glycemic control achieved during those trials, as reported in the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC)³ and the UKPDS follow-up studies.⁴ Overall, it took more than 20 years of observational follow-up of the original intensive glucose-treatment cohort of DCCT/EDIC to show a significant decline in total deaths compared with the conventional treatment cohort.⁵

In patients with type 2 diabetes, the relationship between intensive glycemic control and CV benefits is somewhat controversial, particularly in view of negative CV outcomes from several long-term clinical trials in subjects older than the UKPDS subjects and with longer duration of diabetes:

• ACCORD trial (Action to Control Cardiovascular Risk in Diabetes)^6,7
• ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation)^8,9
• VADT: (Veteran Affairs Diabetes Trial).^10,11

The controversy was spurred by an unexplained increase in total deaths in ACCORD,^6,7 despite a reduction in ischemic coronary events. In the VADT,^10,11 a significant decline was reported for major CV events, but not total deaths, after a median of 9.8 years of observational follow-up.¹¹ In the ADVANCE cohort,^8,9 a reduction in total deaths or CV events was not seen after 5.4 years of additional follow-up.⁹ Some of these differences in outcomes between the UKPDS and these other long-term trials may well reflect the younger aged and the newly diagnosed patients in the UKPDS population, and differences in specific glucose-lowering strategies. Nevertheless, this remains an unsettled issue.

CV OUTCOMES WITH SPECIFIC ANTIHYPERGLYCEMIC AGENTS

Another poorly understood question relates to the impact of specific glucose-lowering agents on CV events, regardless of the glucose control. Table 1 lists the studies of the currently available agents. Studies such as the UKPDS have investigated the question of intensive hyperglycemia control compared with standard, less intensive control.

The question of CV safety with glucose-lowering agents was highlighted in a 2007 meta-analysis of 42 short-term studies with rosiglitazone that reported significantly worse myocardial infarction (MI) risks along with increased mortality from all CV causes that was borderline significant (P = .06).¹² This finding, however, was not confirmed in the only randomized controlled trial (RCT) completed with rosiglitazone.¹³ The controversy led the US Food and Drug Administration (FDA) to issue a 2008 guidance statement recommending that all new diabetes drugs undergo a long-term, noninferiority RCT to prove their CV safety vs an active comparator.¹⁴ Before the FDA mandate, few clinical trials had addressed the long-term effects of glucose-lowering drugs on CV outcomes in patients with type 2 diabetes.

In the UKPDS, the only primary prevention trial thus far, investigators used first-generation sulfonylureas (glyburide and chlorpropamide) with or without insulin as the intensive control strategy in 3,867 patients newly diagnosed with type 2 diabetes.² After a median follow-up of 10 years, the active treatment group had a borderline benefit in fatal and nonfatal MI (16% reduction in relative risk for MI; P = .052) compared with the nondrug treatment.

Additionally, a small subgroup of overweight patients in the UKPDS who were randomized to metformin (N = 342) had 36% (P = .010) lower risk of all-cause mortality and 39% (P = .011) lower risk of MI compared with conventional treatment.¹⁵ This benefit occurred despite a more modest hemoglobin A1c (HbA1c) reduction (0.6%) in the metformin group than in the entire UKPDS trial (0.9%).

The mechanism underlying these impressive CV benefits remains unclear in view of the nonglucose effects of metformin, such as lack of weight gain. Metformin also has been reported to reduce generation of advanced glycosylation end products and oxidative damage to apolipoprotein B100 in patients with type 2 diabetes.¹⁶

One curious but unexplained finding in the UKPDS was an increase in both diabetes-related deaths (relative risk [RR], 1.96; P = .039) and total deaths (RR, 1.60; P = .04) in a subgroup of 268 patients in whom metformin was added to sulfonylurea therapy; however, the number of total deaths was relatively small, 47 deaths in the metformin added group and 31 deaths in the sulfonylurea group.¹⁵ Because of the absence of proven CV benefits with any other diabetes drug thus far, metformin is generally the preferred initial drug in all treatment guidelines.

The relative effects of metformin and sulfonylureas when used as the initial monotherapy regimen have been studied in several large observational studies.^17–20 In general, there appears to be a consistent pattern of significantly increased CV events and total mortality—by 20% to 50%—in those treated with sulfonylureas, with or without prior CV disease. However, these analyses were not based on RCTs.

In two RCTs—NAVIGATOR Study Group²¹ and STOP-NIDDM Trial²²—patients with impaired glucose tolerance were recruited with the primary aim of preventing progression to diabetes. In the NAVIGATOR trial, the short-acting insulin secretagogue nateglinide did not reduce CV events or the progression to diabetes.²¹ In the other study, acarbose, an alpha-glucosidase inhibitor, significantly reduced CV events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28–0.85; P = .03)²² and also prevented progression to diabetes. (P < .002).²³ Although the number of CV events in that 3-year study was small, a meta-analyses of seven studies using acarbose therapy in patients with diabetes also found a significant reduction in composite CV events (HR, 0.65; P < .007), including MIs.²⁴ A long-term, much larger RCT with acarbose is in progress.²⁵

Following the demonstration of strikingly protective effects of metformin on CV events in the UKPDS,¹⁶ two major trials of thiazolidinediones (TZDs) investigated the effects of insulin sensitization on CV events.^13,26 Pioglitazone in patients with long duration type 2 diabetes mellitus and pre-existing CV disease was reported to marginally reduce major CV outcomes (HR, 0.84; 95% CI, 0.72–98; P < .03),²⁶ whereas rosiglitazone in patients with a shorter duration of diabetes was found to be noninferior to the control group.¹³ In both trials, however, there was a twofold increased risk for hospitalization for heart failure and increased risk for bone fractures in women,^13,26 but without an increased risk for mortality.²⁷ Furthermore, in the BARI 2D trial in patients with diabetes and established CV disease, adding rosiglitazone did not significantly reduce propensity-matched CV outcomes, compared with insulin secretagogues or insulin.²⁸ Thus, while TZDs appear to have no major adverse effects on CV outcomes, the other associated adverse effects limit their use.

In a 1-year study of the efficacy and CV safety of the dopaminergic agent quick-release bromocriptine, an FDA-approved drug for diabetes, there was a marked decrease in incidence of composite CV end points (HR, 0.60; 95% CI, 0.37–0.96).²⁹ However, there also was a 47% dropout rate and a small number of total events; thus, the implications remain inconclusive.

Incretin-mimetic agents and CV outcomes

Following the FDA guidance,¹⁴ all newer agents, including incretin-mimetic agents (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been undergoing well-designed, long-term, noninferiority trials with the comparison group receiving the standard of diabetes and CV care. The goal of these trials, unlike that of most of the studies discussed in this article, was to investigate the safety of individual agents rather than different levels of glycemic control.

Since 2013, such trials with three of the available DPP-4 inhibitors have been completed (Table 2).^30–34 Each trial was conducted in patients with pre-existing CV disease or high risk of it. The mean duration of follow-up in these trials was 1.5 to 3.0 years. There were significant, but only marginal, differences in HbA1c compared with the control groups receiving standard care. In each trial, the primary CV end points showed noninferiority, thus documenting their CV safety. One important difference in secondary end points was a significant increase in hospitalization rates for heart failure with saxagliptin^31,33 that was not observed in the trials with alogliptin^30,34 or sitagliptin.³² Another secondary end point—hospitalization for heart failure plus CV mortality—also was not increased in the alogliptin³⁴ and sitagliptin³² trials (rates not reported for saxagliptin); however, there was no increase in total deaths from any cause in these trials.

The mechanisms underlying the increased rates of heart failure with saxagliptin are unclear. The baseline characteristics of patients in these three trials were similar (Table 2). Patients with type 2 diabetes have higher rates of heart failure in general, but the effects of concomitant drug therapy on risk of heart failure, other than with TZDs, have not been well studied. In an extensive meta-analysis of 84 RTCs of various durations, the overall risk (OR) of heart failure was higher in patients treated with DPP-4 inhibitors than in those treated with placebo or active comparators (OR, 1.19; 95% CI, 1.03–1.37; P = .015), suggesting that DPP-4 inhibitors as a class could be associated with an increased risk of heart failure.³⁵ A case-control study, however, found no increase in rates of heart failure with DPP-4 inhibitors, although there were very few patients on saxagliptin.³⁶ Yet another large retrospective, propensity-adjusted observational analysis of more than 112,000 patients, which compared those on saxagliptin and sitagliptin, reported no difference in rates of heart failure; however, the median follow-up period was less than 6 months.³⁷

In comparative observational analyses,^18,37,38 the risks of heart failure with TZDs and sulfonylureas were increased, compared with DPP-4 inhibitors, particularly with TZDs. On the other hand, a large population-based analysis from Italy found that DPP-4 inhibitors were associated with a propensity-matched 36% lower rate of hospitalization for heart failure compared with sulfonylureas.³⁹ These data point to a need for more well-designed comparative studies to investigate valid differences between drugs in this class.

In the only GLP-1 receptor agonist trial completed thus far, ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome), there were no differences in primary and major secondary CV outcomes in 6,068 very high-risk patients randomized to lixisenatide or placebo after a 25-month follow-up (HR, 1.02; 95%, CI, 0.89–1.17).⁴⁰ Moreover, the hospitalization rates for heart failure were not increased (HR, 0.96; 95% CI, 0.75–1.23). The earlier meta-analyses of short-term studies with DPP-4 inhibitors reporting significant reductions in CV events^41,42 also underscore the need for well-designed long-term RCTs to accurately interpret drug effects.

SGLT-2 inhibitors and CV outcomes

The first CV outcome RCT with the SGLT-2 inhibitor empagliflozin, the EMPA-REG OUTCOME trial,⁴³ was recently reported. Of great importance in this 7,020-patient trial comparing empagliflozin with placebo were the following results:

• 14% reduction in the primary end point (composite of death from CV causes, nonfatal MI, or nonfatal stroke) (P = .04)
• 32% reduction in all-cause deaths (P < .001)
• 35% reduction in hospitalization for heart failure (P = .002).

The mechanism underlying these impressive benefits is not known, although there were modest reductions in HbA1c levels, body weight (~2 kg), waist circumference (~2 cm), and systolic blood pressure (~4 mm Hg) with empagliflozin. The main adverse effects were related to a 3 to 4 times increased incidence of genital infections. Trials with other agents in this class are currently ongoing.

Insulin and CV outcomes

The UKPDS trial is the only primary prevention trial that provided evidence of significant benefits from intensive glucose control (with insulin, with or without sulfonylurea therapy) on CV outcomes and mortality, but only after 10 additional years of follow-up after the end of the trial.⁴ A few other trials have investigated the long-term effects of insulin compared with conventional therapy in patients with CV disease.

The DIGAMI-1 (Diabetes Insulin-Glucose in Acute Myocardial Infarction) was a RCT conducted between 1990 and 1993 in 620 patients with type 2 diabetes and acute MI randomized to short-term, intensive insulin-based glucose therapy or to conventional glucose-lowering therapy.⁴⁴ Results showed the intensive treatment group had an 11% decrease in mortality rate at 3.4 years. A 20-year follow-up reassessment showed the overall survival was improved by a mean of 2.3 years at 8 years, particularly in those at lower risk at baseline.⁴⁵ However, none of these patients were on statin therapy at baseline; thus, the implications of that study with current standards of care are quite uncertain. Subsequent studies—DIGAMI-2 (N = 1,253)⁴⁶ and the HI-5 (Hyperglycemia: Intensive Insulin Infusion in Infarction) study (N = 240),⁴⁷ both investigating the effects of intensive insulin therapy in patients with type 2 diabetes and MI—showed no significant effects on mortality in patients at 1 year (DIGAMI-2) and 6 months (HI-5).

The HEART2D trial (Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus), an RCT of 1,115 post-MI patients, investigated the effects of targeting prandial insulin compared with basal insulin. During a mean follow-up of 2.7 years, there were no between-group differences in CV outcomes (HR, 0.98; 95% CI, 0.8–1.21) or glycemic control.⁴⁸ Also, there was no impact of glycemic variability.⁴⁹ Finally, the ORIGIN trial (Outcome Reduction With an Initial Glargine Intervention), an RCT of more than 12,000 patients at high risk for CV disease but with relatively recent onset of either type 2 diabetes or prediabetes, randomized patients to basal insulin glargine or noninsulin treatments.⁵⁰ The baseline HbA1c was relatively low at 6.4%, but it significantly declined by 0.3% by the end of trial, compared with the control group. There was no effect on CV outcomes (HR, 1.02; 95% CI, 0.94–1.11) after a median follow-up of 6.2 years.

However, it remains a perplexing question regarding whether long-term treatment with increasing insulin dosages in a subset of obese patients with poorly controlled type 2 diabetes and increasing insulin resistance could be potentially harmful to the CV system.⁵¹

CONCLUSION

The long-term RCTs with antihyperglycemic agents, including DCCT/EDIC in type 1 diabetes and UKPDS, ACCORD, and VADT in type 2 diabetes, with the exception of ADVANCE, have established the value of intensive glycemic control in reducing CV outcomes but only after many years of follow-up. However, the effects of intensive glycemic control on CV disease in type 2 diabetes are inconsistent, with only the primary prevention cohorts of UKPDS showing significant effects on mortality after prolonged follow-up. This is in contrast to the positive effects of statins in relatively short-term trials.

While it is difficult to interpret the CV results of specific drugs from the degree of glycemic control, it is reassuring that the large RCTs with several individual agents, including TZDs (both pioglitazone and rosiglitazone), several DPP-4 inhibitors, and one GLP-1 receptor agonist, have demonstrated no appreciable harm. The increase in the secondary outcome of heart failure but with no increase in mortality observed with saxagliptin requires further mechanistic studies while awaiting the results of other ongoing trials with newer agents including other incretin-based drugs and SGLT-2 inhibitors.

With SGLT-2 inhibitors, the recently published results of the empagliflozin trail (EMPA-REG OUTCOME trial) with type 2 diabetes revealed a significant reduction in CV end points and mortality. Before those data were published, metformin was the only antihyperglycemic drug that had shown a significant effect on CV events and mortality, but it was studied in only a small subgroup of the UKPDS cohort, and there are no RCTs of the relative impact of metformin or other agents as compared to sulfonylureas. The results of ongoing CV trials with SGLT-2 inhibitors are eagerly awaited.

The essential value of glycemic control in preventing microvascular and neuropathic complications was established in the Diabetes Control and Complications Trial (DCCT)¹ and the United Kingdom Prospective Diabetes Study (UKPDS),² conducted in patients with type 1 and type 2 diabetes, respectively. However, it took another 10 or more years of observational follow-up of those cohorts to demonstrate statistically significant atherosclerotic cardiovascular (CV) disease benefits resulting from the intensive glycemic control achieved during those trials, as reported in the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC)³ and the UKPDS follow-up studies.⁴ Overall, it took more than 20 years of observational follow-up of the original intensive glucose-treatment cohort of DCCT/EDIC to show a significant decline in total deaths compared with the conventional treatment cohort.⁵

In patients with type 2 diabetes, the relationship between intensive glycemic control and CV benefits is somewhat controversial, particularly in view of negative CV outcomes from several long-term clinical trials in subjects older than the UKPDS subjects and with longer duration of diabetes:

• ACCORD trial (Action to Control Cardiovascular Risk in Diabetes)^6,7
• ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation)^8,9
• VADT: (Veteran Affairs Diabetes Trial).^10,11

The controversy was spurred by an unexplained increase in total deaths in ACCORD,^6,7 despite a reduction in ischemic coronary events. In the VADT,^10,11 a significant decline was reported for major CV events, but not total deaths, after a median of 9.8 years of observational follow-up.¹¹ In the ADVANCE cohort,^8,9 a reduction in total deaths or CV events was not seen after 5.4 years of additional follow-up.⁹ Some of these differences in outcomes between the UKPDS and these other long-term trials may well reflect the younger aged and the newly diagnosed patients in the UKPDS population, and differences in specific glucose-lowering strategies. Nevertheless, this remains an unsettled issue.

CV OUTCOMES WITH SPECIFIC ANTIHYPERGLYCEMIC AGENTS

Another poorly understood question relates to the impact of specific glucose-lowering agents on CV events, regardless of the glucose control. Table 1 lists the studies of the currently available agents. Studies such as the UKPDS have investigated the question of intensive hyperglycemia control compared with standard, less intensive control.

The question of CV safety with glucose-lowering agents was highlighted in a 2007 meta-analysis of 42 short-term studies with rosiglitazone that reported significantly worse myocardial infarction (MI) risks along with increased mortality from all CV causes that was borderline significant (P = .06).¹² This finding, however, was not confirmed in the only randomized controlled trial (RCT) completed with rosiglitazone.¹³ The controversy led the US Food and Drug Administration (FDA) to issue a 2008 guidance statement recommending that all new diabetes drugs undergo a long-term, noninferiority RCT to prove their CV safety vs an active comparator.¹⁴ Before the FDA mandate, few clinical trials had addressed the long-term effects of glucose-lowering drugs on CV outcomes in patients with type 2 diabetes.

In the UKPDS, the only primary prevention trial thus far, investigators used first-generation sulfonylureas (glyburide and chlorpropamide) with or without insulin as the intensive control strategy in 3,867 patients newly diagnosed with type 2 diabetes.² After a median follow-up of 10 years, the active treatment group had a borderline benefit in fatal and nonfatal MI (16% reduction in relative risk for MI; P = .052) compared with the nondrug treatment.

Additionally, a small subgroup of overweight patients in the UKPDS who were randomized to metformin (N = 342) had 36% (P = .010) lower risk of all-cause mortality and 39% (P = .011) lower risk of MI compared with conventional treatment.¹⁵ This benefit occurred despite a more modest hemoglobin A1c (HbA1c) reduction (0.6%) in the metformin group than in the entire UKPDS trial (0.9%).

The mechanism underlying these impressive CV benefits remains unclear in view of the nonglucose effects of metformin, such as lack of weight gain. Metformin also has been reported to reduce generation of advanced glycosylation end products and oxidative damage to apolipoprotein B100 in patients with type 2 diabetes.¹⁶

One curious but unexplained finding in the UKPDS was an increase in both diabetes-related deaths (relative risk [RR], 1.96; P = .039) and total deaths (RR, 1.60; P = .04) in a subgroup of 268 patients in whom metformin was added to sulfonylurea therapy; however, the number of total deaths was relatively small, 47 deaths in the metformin added group and 31 deaths in the sulfonylurea group.¹⁵ Because of the absence of proven CV benefits with any other diabetes drug thus far, metformin is generally the preferred initial drug in all treatment guidelines.

The relative effects of metformin and sulfonylureas when used as the initial monotherapy regimen have been studied in several large observational studies.^17–20 In general, there appears to be a consistent pattern of significantly increased CV events and total mortality—by 20% to 50%—in those treated with sulfonylureas, with or without prior CV disease. However, these analyses were not based on RCTs.

In two RCTs—NAVIGATOR Study Group²¹ and STOP-NIDDM Trial²²—patients with impaired glucose tolerance were recruited with the primary aim of preventing progression to diabetes. In the NAVIGATOR trial, the short-acting insulin secretagogue nateglinide did not reduce CV events or the progression to diabetes.²¹ In the other study, acarbose, an alpha-glucosidase inhibitor, significantly reduced CV events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28–0.85; P = .03)²² and also prevented progression to diabetes. (P < .002).²³ Although the number of CV events in that 3-year study was small, a meta-analyses of seven studies using acarbose therapy in patients with diabetes also found a significant reduction in composite CV events (HR, 0.65; P < .007), including MIs.²⁴ A long-term, much larger RCT with acarbose is in progress.²⁵

Following the demonstration of strikingly protective effects of metformin on CV events in the UKPDS,¹⁶ two major trials of thiazolidinediones (TZDs) investigated the effects of insulin sensitization on CV events.^13,26 Pioglitazone in patients with long duration type 2 diabetes mellitus and pre-existing CV disease was reported to marginally reduce major CV outcomes (HR, 0.84; 95% CI, 0.72–98; P < .03),²⁶ whereas rosiglitazone in patients with a shorter duration of diabetes was found to be noninferior to the control group.¹³ In both trials, however, there was a twofold increased risk for hospitalization for heart failure and increased risk for bone fractures in women,^13,26 but without an increased risk for mortality.²⁷ Furthermore, in the BARI 2D trial in patients with diabetes and established CV disease, adding rosiglitazone did not significantly reduce propensity-matched CV outcomes, compared with insulin secretagogues or insulin.²⁸ Thus, while TZDs appear to have no major adverse effects on CV outcomes, the other associated adverse effects limit their use.

In a 1-year study of the efficacy and CV safety of the dopaminergic agent quick-release bromocriptine, an FDA-approved drug for diabetes, there was a marked decrease in incidence of composite CV end points (HR, 0.60; 95% CI, 0.37–0.96).²⁹ However, there also was a 47% dropout rate and a small number of total events; thus, the implications remain inconclusive.

Incretin-mimetic agents and CV outcomes

Following the FDA guidance,¹⁴ all newer agents, including incretin-mimetic agents (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been undergoing well-designed, long-term, noninferiority trials with the comparison group receiving the standard of diabetes and CV care. The goal of these trials, unlike that of most of the studies discussed in this article, was to investigate the safety of individual agents rather than different levels of glycemic control.

Since 2013, such trials with three of the available DPP-4 inhibitors have been completed (Table 2).^30–34 Each trial was conducted in patients with pre-existing CV disease or high risk of it. The mean duration of follow-up in these trials was 1.5 to 3.0 years. There were significant, but only marginal, differences in HbA1c compared with the control groups receiving standard care. In each trial, the primary CV end points showed noninferiority, thus documenting their CV safety. One important difference in secondary end points was a significant increase in hospitalization rates for heart failure with saxagliptin^31,33 that was not observed in the trials with alogliptin^30,34 or sitagliptin.³² Another secondary end point—hospitalization for heart failure plus CV mortality—also was not increased in the alogliptin³⁴ and sitagliptin³² trials (rates not reported for saxagliptin); however, there was no increase in total deaths from any cause in these trials.

The mechanisms underlying the increased rates of heart failure with saxagliptin are unclear. The baseline characteristics of patients in these three trials were similar (Table 2). Patients with type 2 diabetes have higher rates of heart failure in general, but the effects of concomitant drug therapy on risk of heart failure, other than with TZDs, have not been well studied. In an extensive meta-analysis of 84 RTCs of various durations, the overall risk (OR) of heart failure was higher in patients treated with DPP-4 inhibitors than in those treated with placebo or active comparators (OR, 1.19; 95% CI, 1.03–1.37; P = .015), suggesting that DPP-4 inhibitors as a class could be associated with an increased risk of heart failure.³⁵ A case-control study, however, found no increase in rates of heart failure with DPP-4 inhibitors, although there were very few patients on saxagliptin.³⁶ Yet another large retrospective, propensity-adjusted observational analysis of more than 112,000 patients, which compared those on saxagliptin and sitagliptin, reported no difference in rates of heart failure; however, the median follow-up period was less than 6 months.³⁷

In comparative observational analyses,^18,37,38 the risks of heart failure with TZDs and sulfonylureas were increased, compared with DPP-4 inhibitors, particularly with TZDs. On the other hand, a large population-based analysis from Italy found that DPP-4 inhibitors were associated with a propensity-matched 36% lower rate of hospitalization for heart failure compared with sulfonylureas.³⁹ These data point to a need for more well-designed comparative studies to investigate valid differences between drugs in this class.

In the only GLP-1 receptor agonist trial completed thus far, ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome), there were no differences in primary and major secondary CV outcomes in 6,068 very high-risk patients randomized to lixisenatide or placebo after a 25-month follow-up (HR, 1.02; 95%, CI, 0.89–1.17).⁴⁰ Moreover, the hospitalization rates for heart failure were not increased (HR, 0.96; 95% CI, 0.75–1.23). The earlier meta-analyses of short-term studies with DPP-4 inhibitors reporting significant reductions in CV events^41,42 also underscore the need for well-designed long-term RCTs to accurately interpret drug effects.

SGLT-2 inhibitors and CV outcomes

The first CV outcome RCT with the SGLT-2 inhibitor empagliflozin, the EMPA-REG OUTCOME trial,⁴³ was recently reported. Of great importance in this 7,020-patient trial comparing empagliflozin with placebo were the following results:

• 14% reduction in the primary end point (composite of death from CV causes, nonfatal MI, or nonfatal stroke) (P = .04)
• 32% reduction in all-cause deaths (P < .001)
• 35% reduction in hospitalization for heart failure (P = .002).

The mechanism underlying these impressive benefits is not known, although there were modest reductions in HbA1c levels, body weight (~2 kg), waist circumference (~2 cm), and systolic blood pressure (~4 mm Hg) with empagliflozin. The main adverse effects were related to a 3 to 4 times increased incidence of genital infections. Trials with other agents in this class are currently ongoing.

Insulin and CV outcomes

The UKPDS trial is the only primary prevention trial that provided evidence of significant benefits from intensive glucose control (with insulin, with or without sulfonylurea therapy) on CV outcomes and mortality, but only after 10 additional years of follow-up after the end of the trial.⁴ A few other trials have investigated the long-term effects of insulin compared with conventional therapy in patients with CV disease.

The DIGAMI-1 (Diabetes Insulin-Glucose in Acute Myocardial Infarction) was a RCT conducted between 1990 and 1993 in 620 patients with type 2 diabetes and acute MI randomized to short-term, intensive insulin-based glucose therapy or to conventional glucose-lowering therapy.⁴⁴ Results showed the intensive treatment group had an 11% decrease in mortality rate at 3.4 years. A 20-year follow-up reassessment showed the overall survival was improved by a mean of 2.3 years at 8 years, particularly in those at lower risk at baseline.⁴⁵ However, none of these patients were on statin therapy at baseline; thus, the implications of that study with current standards of care are quite uncertain. Subsequent studies—DIGAMI-2 (N = 1,253)⁴⁶ and the HI-5 (Hyperglycemia: Intensive Insulin Infusion in Infarction) study (N = 240),⁴⁷ both investigating the effects of intensive insulin therapy in patients with type 2 diabetes and MI—showed no significant effects on mortality in patients at 1 year (DIGAMI-2) and 6 months (HI-5).

The HEART2D trial (Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus), an RCT of 1,115 post-MI patients, investigated the effects of targeting prandial insulin compared with basal insulin. During a mean follow-up of 2.7 years, there were no between-group differences in CV outcomes (HR, 0.98; 95% CI, 0.8–1.21) or glycemic control.⁴⁸ Also, there was no impact of glycemic variability.⁴⁹ Finally, the ORIGIN trial (Outcome Reduction With an Initial Glargine Intervention), an RCT of more than 12,000 patients at high risk for CV disease but with relatively recent onset of either type 2 diabetes or prediabetes, randomized patients to basal insulin glargine or noninsulin treatments.⁵⁰ The baseline HbA1c was relatively low at 6.4%, but it significantly declined by 0.3% by the end of trial, compared with the control group. There was no effect on CV outcomes (HR, 1.02; 95% CI, 0.94–1.11) after a median follow-up of 6.2 years.

However, it remains a perplexing question regarding whether long-term treatment with increasing insulin dosages in a subset of obese patients with poorly controlled type 2 diabetes and increasing insulin resistance could be potentially harmful to the CV system.⁵¹

CONCLUSION

The long-term RCTs with antihyperglycemic agents, including DCCT/EDIC in type 1 diabetes and UKPDS, ACCORD, and VADT in type 2 diabetes, with the exception of ADVANCE, have established the value of intensive glycemic control in reducing CV outcomes but only after many years of follow-up. However, the effects of intensive glycemic control on CV disease in type 2 diabetes are inconsistent, with only the primary prevention cohorts of UKPDS showing significant effects on mortality after prolonged follow-up. This is in contrast to the positive effects of statins in relatively short-term trials.

While it is difficult to interpret the CV results of specific drugs from the degree of glycemic control, it is reassuring that the large RCTs with several individual agents, including TZDs (both pioglitazone and rosiglitazone), several DPP-4 inhibitors, and one GLP-1 receptor agonist, have demonstrated no appreciable harm. The increase in the secondary outcome of heart failure but with no increase in mortality observed with saxagliptin requires further mechanistic studies while awaiting the results of other ongoing trials with newer agents including other incretin-based drugs and SGLT-2 inhibitors.

With SGLT-2 inhibitors, the recently published results of the empagliflozin trail (EMPA-REG OUTCOME trial) with type 2 diabetes revealed a significant reduction in CV end points and mortality. Before those data were published, metformin was the only antihyperglycemic drug that had shown a significant effect on CV events and mortality, but it was studied in only a small subgroup of the UKPDS cohort, and there are no RCTs of the relative impact of metformin or other agents as compared to sulfonylureas. The results of ongoing CV trials with SGLT-2 inhibitors are eagerly awaited.

The essential value of glycemic control in preventing microvascular and neuropathic complications was established in the Diabetes Control and Complications Trial (DCCT)¹ and the United Kingdom Prospective Diabetes Study (UKPDS),² conducted in patients with type 1 and type 2 diabetes, respectively. However, it took another 10 or more years of observational follow-up of those cohorts to demonstrate statistically significant atherosclerotic cardiovascular (CV) disease benefits resulting from the intensive glycemic control achieved during those trials, as reported in the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC)³ and the UKPDS follow-up studies.⁴ Overall, it took more than 20 years of observational follow-up of the original intensive glucose-treatment cohort of DCCT/EDIC to show a significant decline in total deaths compared with the conventional treatment cohort.⁵

In patients with type 2 diabetes, the relationship between intensive glycemic control and CV benefits is somewhat controversial, particularly in view of negative CV outcomes from several long-term clinical trials in subjects older than the UKPDS subjects and with longer duration of diabetes:

• ACCORD trial (Action to Control Cardiovascular Risk in Diabetes)^6,7
• ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation)^8,9
• VADT: (Veteran Affairs Diabetes Trial).^10,11

The controversy was spurred by an unexplained increase in total deaths in ACCORD,^6,7 despite a reduction in ischemic coronary events. In the VADT,^10,11 a significant decline was reported for major CV events, but not total deaths, after a median of 9.8 years of observational follow-up.¹¹ In the ADVANCE cohort,^8,9 a reduction in total deaths or CV events was not seen after 5.4 years of additional follow-up.⁹ Some of these differences in outcomes between the UKPDS and these other long-term trials may well reflect the younger aged and the newly diagnosed patients in the UKPDS population, and differences in specific glucose-lowering strategies. Nevertheless, this remains an unsettled issue.

CV OUTCOMES WITH SPECIFIC ANTIHYPERGLYCEMIC AGENTS

Another poorly understood question relates to the impact of specific glucose-lowering agents on CV events, regardless of the glucose control. Table 1 lists the studies of the currently available agents. Studies such as the UKPDS have investigated the question of intensive hyperglycemia control compared with standard, less intensive control.

The question of CV safety with glucose-lowering agents was highlighted in a 2007 meta-analysis of 42 short-term studies with rosiglitazone that reported significantly worse myocardial infarction (MI) risks along with increased mortality from all CV causes that was borderline significant (P = .06).¹² This finding, however, was not confirmed in the only randomized controlled trial (RCT) completed with rosiglitazone.¹³ The controversy led the US Food and Drug Administration (FDA) to issue a 2008 guidance statement recommending that all new diabetes drugs undergo a long-term, noninferiority RCT to prove their CV safety vs an active comparator.¹⁴ Before the FDA mandate, few clinical trials had addressed the long-term effects of glucose-lowering drugs on CV outcomes in patients with type 2 diabetes.

In the UKPDS, the only primary prevention trial thus far, investigators used first-generation sulfonylureas (glyburide and chlorpropamide) with or without insulin as the intensive control strategy in 3,867 patients newly diagnosed with type 2 diabetes.² After a median follow-up of 10 years, the active treatment group had a borderline benefit in fatal and nonfatal MI (16% reduction in relative risk for MI; P = .052) compared with the nondrug treatment.

Additionally, a small subgroup of overweight patients in the UKPDS who were randomized to metformin (N = 342) had 36% (P = .010) lower risk of all-cause mortality and 39% (P = .011) lower risk of MI compared with conventional treatment.¹⁵ This benefit occurred despite a more modest hemoglobin A1c (HbA1c) reduction (0.6%) in the metformin group than in the entire UKPDS trial (0.9%).

The mechanism underlying these impressive CV benefits remains unclear in view of the nonglucose effects of metformin, such as lack of weight gain. Metformin also has been reported to reduce generation of advanced glycosylation end products and oxidative damage to apolipoprotein B100 in patients with type 2 diabetes.¹⁶

One curious but unexplained finding in the UKPDS was an increase in both diabetes-related deaths (relative risk [RR], 1.96; P = .039) and total deaths (RR, 1.60; P = .04) in a subgroup of 268 patients in whom metformin was added to sulfonylurea therapy; however, the number of total deaths was relatively small, 47 deaths in the metformin added group and 31 deaths in the sulfonylurea group.¹⁵ Because of the absence of proven CV benefits with any other diabetes drug thus far, metformin is generally the preferred initial drug in all treatment guidelines.

The relative effects of metformin and sulfonylureas when used as the initial monotherapy regimen have been studied in several large observational studies.^17–20 In general, there appears to be a consistent pattern of significantly increased CV events and total mortality—by 20% to 50%—in those treated with sulfonylureas, with or without prior CV disease. However, these analyses were not based on RCTs.

In two RCTs—NAVIGATOR Study Group²¹ and STOP-NIDDM Trial²²—patients with impaired glucose tolerance were recruited with the primary aim of preventing progression to diabetes. In the NAVIGATOR trial, the short-acting insulin secretagogue nateglinide did not reduce CV events or the progression to diabetes.²¹ In the other study, acarbose, an alpha-glucosidase inhibitor, significantly reduced CV events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28–0.85; P = .03)²² and also prevented progression to diabetes. (P < .002).²³ Although the number of CV events in that 3-year study was small, a meta-analyses of seven studies using acarbose therapy in patients with diabetes also found a significant reduction in composite CV events (HR, 0.65; P < .007), including MIs.²⁴ A long-term, much larger RCT with acarbose is in progress.²⁵

Following the demonstration of strikingly protective effects of metformin on CV events in the UKPDS,¹⁶ two major trials of thiazolidinediones (TZDs) investigated the effects of insulin sensitization on CV events.^13,26 Pioglitazone in patients with long duration type 2 diabetes mellitus and pre-existing CV disease was reported to marginally reduce major CV outcomes (HR, 0.84; 95% CI, 0.72–98; P < .03),²⁶ whereas rosiglitazone in patients with a shorter duration of diabetes was found to be noninferior to the control group.¹³ In both trials, however, there was a twofold increased risk for hospitalization for heart failure and increased risk for bone fractures in women,^13,26 but without an increased risk for mortality.²⁷ Furthermore, in the BARI 2D trial in patients with diabetes and established CV disease, adding rosiglitazone did not significantly reduce propensity-matched CV outcomes, compared with insulin secretagogues or insulin.²⁸ Thus, while TZDs appear to have no major adverse effects on CV outcomes, the other associated adverse effects limit their use.

In a 1-year study of the efficacy and CV safety of the dopaminergic agent quick-release bromocriptine, an FDA-approved drug for diabetes, there was a marked decrease in incidence of composite CV end points (HR, 0.60; 95% CI, 0.37–0.96).²⁹ However, there also was a 47% dropout rate and a small number of total events; thus, the implications remain inconclusive.

Incretin-mimetic agents and CV outcomes

Following the FDA guidance,¹⁴ all newer agents, including incretin-mimetic agents (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been undergoing well-designed, long-term, noninferiority trials with the comparison group receiving the standard of diabetes and CV care. The goal of these trials, unlike that of most of the studies discussed in this article, was to investigate the safety of individual agents rather than different levels of glycemic control.

Since 2013, such trials with three of the available DPP-4 inhibitors have been completed (Table 2).^30–34 Each trial was conducted in patients with pre-existing CV disease or high risk of it. The mean duration of follow-up in these trials was 1.5 to 3.0 years. There were significant, but only marginal, differences in HbA1c compared with the control groups receiving standard care. In each trial, the primary CV end points showed noninferiority, thus documenting their CV safety. One important difference in secondary end points was a significant increase in hospitalization rates for heart failure with saxagliptin^31,33 that was not observed in the trials with alogliptin^30,34 or sitagliptin.³² Another secondary end point—hospitalization for heart failure plus CV mortality—also was not increased in the alogliptin³⁴ and sitagliptin³² trials (rates not reported for saxagliptin); however, there was no increase in total deaths from any cause in these trials.

The mechanisms underlying the increased rates of heart failure with saxagliptin are unclear. The baseline characteristics of patients in these three trials were similar (Table 2). Patients with type 2 diabetes have higher rates of heart failure in general, but the effects of concomitant drug therapy on risk of heart failure, other than with TZDs, have not been well studied. In an extensive meta-analysis of 84 RTCs of various durations, the overall risk (OR) of heart failure was higher in patients treated with DPP-4 inhibitors than in those treated with placebo or active comparators (OR, 1.19; 95% CI, 1.03–1.37; P = .015), suggesting that DPP-4 inhibitors as a class could be associated with an increased risk of heart failure.³⁵ A case-control study, however, found no increase in rates of heart failure with DPP-4 inhibitors, although there were very few patients on saxagliptin.³⁶ Yet another large retrospective, propensity-adjusted observational analysis of more than 112,000 patients, which compared those on saxagliptin and sitagliptin, reported no difference in rates of heart failure; however, the median follow-up period was less than 6 months.³⁷

In comparative observational analyses,^18,37,38 the risks of heart failure with TZDs and sulfonylureas were increased, compared with DPP-4 inhibitors, particularly with TZDs. On the other hand, a large population-based analysis from Italy found that DPP-4 inhibitors were associated with a propensity-matched 36% lower rate of hospitalization for heart failure compared with sulfonylureas.³⁹ These data point to a need for more well-designed comparative studies to investigate valid differences between drugs in this class.

In the only GLP-1 receptor agonist trial completed thus far, ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome), there were no differences in primary and major secondary CV outcomes in 6,068 very high-risk patients randomized to lixisenatide or placebo after a 25-month follow-up (HR, 1.02; 95%, CI, 0.89–1.17).⁴⁰ Moreover, the hospitalization rates for heart failure were not increased (HR, 0.96; 95% CI, 0.75–1.23). The earlier meta-analyses of short-term studies with DPP-4 inhibitors reporting significant reductions in CV events^41,42 also underscore the need for well-designed long-term RCTs to accurately interpret drug effects.

SGLT-2 inhibitors and CV outcomes

The first CV outcome RCT with the SGLT-2 inhibitor empagliflozin, the EMPA-REG OUTCOME trial,⁴³ was recently reported. Of great importance in this 7,020-patient trial comparing empagliflozin with placebo were the following results:

• 14% reduction in the primary end point (composite of death from CV causes, nonfatal MI, or nonfatal stroke) (P = .04)
• 32% reduction in all-cause deaths (P < .001)
• 35% reduction in hospitalization for heart failure (P = .002).

The mechanism underlying these impressive benefits is not known, although there were modest reductions in HbA1c levels, body weight (~2 kg), waist circumference (~2 cm), and systolic blood pressure (~4 mm Hg) with empagliflozin. The main adverse effects were related to a 3 to 4 times increased incidence of genital infections. Trials with other agents in this class are currently ongoing.

Insulin and CV outcomes

The UKPDS trial is the only primary prevention trial that provided evidence of significant benefits from intensive glucose control (with insulin, with or without sulfonylurea therapy) on CV outcomes and mortality, but only after 10 additional years of follow-up after the end of the trial.⁴ A few other trials have investigated the long-term effects of insulin compared with conventional therapy in patients with CV disease.

The DIGAMI-1 (Diabetes Insulin-Glucose in Acute Myocardial Infarction) was a RCT conducted between 1990 and 1993 in 620 patients with type 2 diabetes and acute MI randomized to short-term, intensive insulin-based glucose therapy or to conventional glucose-lowering therapy.⁴⁴ Results showed the intensive treatment group had an 11% decrease in mortality rate at 3.4 years. A 20-year follow-up reassessment showed the overall survival was improved by a mean of 2.3 years at 8 years, particularly in those at lower risk at baseline.⁴⁵ However, none of these patients were on statin therapy at baseline; thus, the implications of that study with current standards of care are quite uncertain. Subsequent studies—DIGAMI-2 (N = 1,253)⁴⁶ and the HI-5 (Hyperglycemia: Intensive Insulin Infusion in Infarction) study (N = 240),⁴⁷ both investigating the effects of intensive insulin therapy in patients with type 2 diabetes and MI—showed no significant effects on mortality in patients at 1 year (DIGAMI-2) and 6 months (HI-5).

The HEART2D trial (Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus), an RCT of 1,115 post-MI patients, investigated the effects of targeting prandial insulin compared with basal insulin. During a mean follow-up of 2.7 years, there were no between-group differences in CV outcomes (HR, 0.98; 95% CI, 0.8–1.21) or glycemic control.⁴⁸ Also, there was no impact of glycemic variability.⁴⁹ Finally, the ORIGIN trial (Outcome Reduction With an Initial Glargine Intervention), an RCT of more than 12,000 patients at high risk for CV disease but with relatively recent onset of either type 2 diabetes or prediabetes, randomized patients to basal insulin glargine or noninsulin treatments.⁵⁰ The baseline HbA1c was relatively low at 6.4%, but it significantly declined by 0.3% by the end of trial, compared with the control group. There was no effect on CV outcomes (HR, 1.02; 95% CI, 0.94–1.11) after a median follow-up of 6.2 years.

However, it remains a perplexing question regarding whether long-term treatment with increasing insulin dosages in a subset of obese patients with poorly controlled type 2 diabetes and increasing insulin resistance could be potentially harmful to the CV system.⁵¹

CONCLUSION

The long-term RCTs with antihyperglycemic agents, including DCCT/EDIC in type 1 diabetes and UKPDS, ACCORD, and VADT in type 2 diabetes, with the exception of ADVANCE, have established the value of intensive glycemic control in reducing CV outcomes but only after many years of follow-up. However, the effects of intensive glycemic control on CV disease in type 2 diabetes are inconsistent, with only the primary prevention cohorts of UKPDS showing significant effects on mortality after prolonged follow-up. This is in contrast to the positive effects of statins in relatively short-term trials.

While it is difficult to interpret the CV results of specific drugs from the degree of glycemic control, it is reassuring that the large RCTs with several individual agents, including TZDs (both pioglitazone and rosiglitazone), several DPP-4 inhibitors, and one GLP-1 receptor agonist, have demonstrated no appreciable harm. The increase in the secondary outcome of heart failure but with no increase in mortality observed with saxagliptin requires further mechanistic studies while awaiting the results of other ongoing trials with newer agents including other incretin-based drugs and SGLT-2 inhibitors.

With SGLT-2 inhibitors, the recently published results of the empagliflozin trail (EMPA-REG OUTCOME trial) with type 2 diabetes revealed a significant reduction in CV end points and mortality. Before those data were published, metformin was the only antihyperglycemic drug that had shown a significant effect on CV events and mortality, but it was studied in only a small subgroup of the UKPDS cohort, and there are no RCTs of the relative impact of metformin or other agents as compared to sulfonylureas. The results of ongoing CV trials with SGLT-2 inhibitors are eagerly awaited.

Type 2 diabetes mellitus (DM) is caused by hyperglycemia and metabolic alterations due to abnormalities in insulin secretion or insulin action, or both. To achieve desired glycemic targets, different antihyperglycemic drugs are used alone or in combination with other agents, including insulin. First-line options for diabetes treatment are weight loss, lifestyle modification, and metformin. The American Diabetes Association and the European Association for the Study of Diabetes recommend a patient-specific treatment approach to enhance glycemic control while avoiding weight gain and hypoglycemia.¹ This review will focus on the newer oral agents and injectable noninsulin agents that are used to achieve glycemic control. Table 1 lists the noninsulin drugs approved since 2005.

INCRETIN-BASED THERAPIES

The incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the gastrointestinal (GI) tract in response to food intake. Both GLP-1 and GIP stimulate beta cells of the pancreas, which contribute 60% of the insulin secretion after a meal. Type 2 DM is associated with decreased secretion of GLP-1 and lowered responsiveness to GIP. Benefits of the incretin hormones on glycemic control include enhanced satiety, decreased GI motility, increased glucose-dependent insulin secretion, reduced glucagon secretion, and decreased hepatic glucose release.² Two incretin-based drug classes are used to treat patients with type 2 DM—oral dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.

DPP-4 inhibitors

The oral DPP-4 inhibitors block the degradation of the enzyme DPP-4 active site and thus increase the GLP-1 and GIP concentrations by two to three times. Their primary effectiveness centers on controlling insulin and glucagon secretion without increasing weight.

Four DPP-4 inhibitors are approved by the US Food and Drug Administration (FDA) in once-daily oral formulations: sitagliptin, saxagliptin, linagliptin, and alogliptin. Another DPP-4 inhibitor, vildagliptin, is not licensed in the United States but is approved for use in Europe and Japan.³ Another DPP-4 inhibitor, teneligliptin, is also marketed in Japan.

The DPP-4 inhibitors are indicated for use as monotherapy or in combination with other agents such as metformin, sulfonylureas, thiazolidinediones, and insulin. Generally, DPP-4 inhibitors do not cause hypoglycemia when used as monotherapy.¹ When adding a DPP-4 inhibitor to a sulfonylurea or insulin, it is recommended to decrease the sulfonylurea or insulin dose to reduce the risk of hypoglycemia. The potential of these agents to lower the hemoglobin A1c (HbA1c) when used as monotherapy and in combination with metformin, sulfonylureas, or thiazolidine­diones is 0.3% to 0.71%.⁴

The DPP-4 inhibitors are not known to cause adverse GI effects. Sitagliptin, alogliptin, vildagliptin, and saxagliptin need dosing adjustments for renal insufficiency; however, linagliptin is not renally eliminated and does not require dosing adjustment. Common adverse events (> 5%) are nasopharyngitis, upper-respiratory infection, and headache. Sitagliptin and saxagliptin have been associated with urinary tract infection. Sitagliptin also has been associated with more extremity pain, back pain, and osteoarthritis.⁴

The DPP-4 inhibitors are primarily excreted by the renal or fecal route and, therefore, have few drug interactions. All DPP-4 inhibitors are partially metabolized through cytochrome P450 enzymes, except saxagliptin.⁴ Their pharmacokinetic profiles are shown on Table 2.

In keeping with the FDA guidelines, sitagliptin, saxagliptin, linagliptin, and alogliptin have been evaluated for cardiovascular (CV) outcomes. The SAVOR-TIMI 53 clinical trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) was a 2-year CV safety and efficacy trial.⁵ This trial demonstrated no statistically significant difference in the primary end point as a composite of CV death, myocardial infarction (MI), and ischemic stroke. Additionally, the secondary end points, including hospitalization for unstable angina, coronary revascularization, and heart failure, also did not show significant difference. However, based on a subgroup analysis, there was a statistically significant increase in patients in the saxagliptin group vs the placebo group who were hospitalized for heart failure.

A 2-year trial comparing linagliptin with glimepiride, a second-generation sulfonylurea, showed significantly fewer CV events with linagliptin.⁶ This trial found a relative risk reduction of 54% in the end points of CV death, nonfatal MI or stroke, and unstable angina during hospitalization.^4,6 Another trial reviewed the incidence of CV events (CV death, nonfatal MI, and nonfatal stroke) in patients treated with alogliptin, placebo, or comparator antihyperglycemic drugs and found no increased incidence of major adverse CV events vs comparator therapies.⁷

The recently published TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin), reported no increase in major atherosclerotic CV events, no difference in all-cause mortality, and no difference in heart failure for hospitalization or other adverse events in patients with type 2 DM.⁸ Other clinical trials such as the CAROLINA study (linagliptin compared with glimepiride),⁹ the EXAMINE study (alogliptin),¹⁰ and the CARMALINA study (linagliptin)¹¹ are also reviewing the CV safety of DPP-4 inhibitors in the United States.

Concern has been raised about the association between incretin-based therapies and adverse pancreatic effects. CV outcomes trials using saxagliptin and alogliptin found similar rates of pancreatitis and fewer pancreatic cancer cases in comparison with placebo.^5,7,10 TECOS demonstrated that with sitagliptin, acute pancreatitis occurred more in the sitagliptin group, but there was no statistical significance reported. However, pancreatic cancer occurred more in the placebo group, although the difference was not statistically significant.⁸ Neither the FDA nor the European Medicines Agency (EMA) has reached a firm conclusion about the possible association between incretin-based therapies and pancreatitis or pancreatic cancer.¹²

GLP-1 agonists

The GLP-1 drugs mimic the action of native GLP-1. Several GLP-1 agents are available in the United States, and several more are in development.^11,13 The drug class is divided into three groups:

• Short-acting (4–6 hours): exenatide, lixisenatide
• Intermediate-acting (24 hours): liraglutide
• Long-acting (7 days): exenatide extended-release (ER), dulaglutide, and albiglutide (semaglutide is in phase 3 study).

The GLP-1 receptor agonists heighten glucose homeostasis by the following mechanisms of action: stimulate insulin secretion, suppress glucagon secretion, directly and indirectly inhibit endogenous glucose production, promote satiety, heighten insulin sensitivity due to weight loss, and slow gastric emptying time. Table 3 lists dosing and pharmacokinetic profiles for GLP-1 agonists. When GLP-1 agonists are used as monotherapy, the HbA1c is reduced by 0.7% to 1.51%.¹³ When GLP-1 agonists are used in combination with metformin, sulfonylureas, thiazolidinediones, or as three-drug therapy with other oral antidiabetic medications, the HbA1c is lowered by 0.4% to 1.9%.^13–17

A notable advantage of GLP-1 agonists is their effect on weight loss separate from GI side effects. Weight reductions of 0.2 to 3.6 kg in 26 weeks have been seen with the exenatide formulations, liraglutide, albiglutide, and dulaglutide.^13,18 Liraglutide has demonstrated a greater weight reduction than exenatide, exenatide ER, or albiglutide.^13,16,17 There were similar weight reductions of 1.5 kg in 26 weeks in a comparator trial involving liraglutide and dulaglutide (3.6 vs 2.9 kg).¹⁹

Common adverse effects of the GLP-1 agonists are nausea (8% to 44%), diarrhea (6% to 20%), and vomiting (4% to 18%), which may occur initially and diminish with continued use.^13,14 There have been more GI side effects with liraglutide than with exenatide ER or albiglutide.²⁰ Increased rates of injection site reactions, such as transient small nodule formations, were seen with exenatide ER (5.4% to 17.6%) and albiglutide, the once-weekly GLP-1 agonist therapies, vs exenatide, liraglutide, and insulin glargine.^13,14 Dulaglutide, another once-weekly GLP-1 agonist, does not have this finding; however, there is enhanced patient satisfaction with the once-weekly preparations in comparison with the twice-daily preparations.^14,16 Patients who received albiglutide have noted hypersensitivity reactions such as pruritus, rash, and dyspnea (10% to 18%).¹³ Hypoglycemia is not seen with the GLP-1 agonists, unless they are used in conjunction with a sulfonylurea or insulin.

Exenatide and exenatide ER are excreted by the renal route; therefore, it is not recommended to use these agonists in patients with renal impairment or end-stage renal disease (creatinine clearance [CrCl] < 30 mL/min). Liraglutide is not excreted by the renal route; however, it should be used with caution in patients with renal impairment.²¹ No renal dose adjustment is required when using albiglutide or dulaglutide.²¹

Clinical trials have demonstrated the short-term CV outcomes of GLP-1 agonists. The CV benefits include a decrease in blood pressure, reduction of lipid levels, enhanced endothelial function, and improved myocardial function.¹³ One meta-analysis reported a tendency for lowering the rate of major CV events, stroke, MI, CV mortality, and all-cause mortality.²² Several ongoing trials are evaluating the safety of GLP-1 agonists and CV safety: LEADER (liraglutide), EXSCEL (exenatide LR), ELIXA (lixisenatide), SUSTAIN 6 (semaglutide), and REWIND (dulaglutide).¹¹

The GLP-1 agonists have been linked to an increased incidence of thyroid cancer. There was a potential increased risk of thyroid cancer in preclinical rodent studies involving liraglutide and exenatide ER, but this risk was not demonstrated for the exenatide twice-daily preparation.¹³ The FDA noted that the findings from rodent studies, which demonstrated a possible heightened risk for thyroid cancer, should not be conveyed to the outcomes for humans. Nevertheless, when liraglutide was approved in January 2010, the FDA issued a boxed warning about the risk of thyroid C-cell hyperplasia. The package inserts list a thyroid carcinoma risk for exenatide ER, liraglutide, albiglutide, and dulaglutide in those patients with a personal or family history of medullary thyroid cancer.

There is controversy about the incidence of pancreatitis and pancreatic cancer with the use of the incretin-based therapies. Published studies and case reports seem to support speculation that there is an increased incidence of acute pancreatitis associated with type 2 DM.²¹ The FDA and the EMA have independently reviewed postmarketing reports about pancreatitis and pancreatic cancer among more than 28,000 patients who received some form of incretin-based therapy.¹² They independently agreed that a causal association between incretin-based drugs and pancreatitis or pancreatic cancer is inconsistent with the current data.¹² At this time, there is no final conclusion about a causal relationship between the use of incretin-based drugs and possible pancreatitis and pancreatic cancer.

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

In 2013, canagliflozin became the first sodium-glucose cotransporter-2 (SGLT-2) inhibitor to be FDA-approved for treating patients with type 2 DM, followed in 2014 by dapagliflozin and empagliflozin. Several other drugs in this class are available outside the US or are currently undergoing clinical development, including ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin. Currently, no SGLT-2 inhibitors are FDA-approved for type 1 DM, although they have been used off-label and in trials in this patient population.

These drugs work by targeting the SGLT-2 protein in the kidney. In healthy individuals, 99% of filtered glucose is reabsorbed by the kidney with a filtered load of approximately 180 g/day.²³ Glucosuria occurs with glucose concentrations above this threshold. In patients with type 2 DM, this threshold and the ability to reabsorb glucose is increased, contributing to hyperglycemia.²⁴ Located in the proximal tubule, the SGLT-2 protein is responsible for 80% to 90% of glucose reabsorption, with SGLT-1 responsible for the other 10% to 20%.²⁵ Inhibition of SGLT-2 reduces the renal threshold for glucose, thus leading to glucosuria and reduction in serum glucose levels.²⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for the SGLT-2 inhibitors.

As a monotherapy, SGLT-2 inhibitors significantly reduce HbA1c levels by 0.4% to 1.1% when compared with placebo.^26–28 Reductions may be more significant in patients with HbA1c levels greater than 8.5%, and even more so in patients with HbA1c levels above 10%.²⁹ When compared with other therapeutic options for type 2 DM, SGLT-2 inhibitors have efficacy similar to metformin, sitagliptin, and glipizide; however, some studies have shown superiority to glimepiride and sitagliptin at reducing HbA1c, depending on the dose and duration of treatment.^26,27

The SGLT-2 inhibitors do not rely on insulin activity, allowing for their use at any stage of type 2 DM and in combination with other therapies, including insulin. As an add-on medication, SGLT-2 inhibitors reduce HbA1c by 0.5% to 0.7%.^27,28 Given that the mechanism of action depends on the filtered load of glucose, they are less effective in patients with a reduced glomerular filtration rate (GFR).

The SGLT-2 inhibitors have bene­fits beyond that of glycemic control. Studies report weight loss of 1 to 3 kg, which is maintained up to 104 weeks.^27–31 Sustained weight loss is secondary to glucosuria, which amounts to a caloric loss of 200 to 300 kcal/day.³⁰ Also, SGLT-2 inhibitors lead to modest reductions in systolic and diastolic blood pressure of approximately 3 to 6 mm Hg and 1 to 2 mm Hg, respectively, due to their diuretic effect.^27,31 The risk of hypoglycemia is low—similar to that of metformin and DPP-4 inhibitors—and only slightly higher than placebo when used as monotherapy.^26,31 When added to sulfonylureas or insulin, however, the risk of hypoglycemia is increased.^26,29

Meta-analyses of SGLT-2 inhibitors showed rates of death and other serious adverse effects were no different than placebo.^26,27 A 2015 study on the CV safety of empagliflozin showed lower rates of CV death (38% relative risk [RR] reduction), lower rates of hospitalization due to heart failure (35% RR reduction), and lower rates of all-cause mortality (32% RR reduction) when compared with placebo, with no difference in nonfatal stroke and MI.³² CV safety trials for dapagliflozin and canagliflozin are ongoing, although some trials have shown an increased incidence in CV events in the first 30 days of treatment with canagliflozin.⁴

Common side effects include genital infections, such as vaginitis and balanitis, as well as urinary tract infections. In a 2013 meta-analysis,²⁷ genital infections carried an odds ratio of 3.5 for SGLT-2 inhibitors compared with placebo, while urinary tract infections carried a 1.34 odds ratio. The increased risk of infection is thought to be secondary to glucosuria combined with immune dysfunction and altered glycosylation uroepithelium cells.³⁰

During clinical trials, more cases of bladder cancer were diagnosed in patients on dapagliflozin than on placebo, leading to a delay in FDA approval. No causal relationship was established, but dapagliflozin is not recommended in patients with active bladder cancer.³⁰

Treatment with SGLT-2 inhibitors can lead to a decrease in GFR, likely secondary to the diuretic effect. In patients with GFR greater than 60 mL/min, this decrease is transient. In patients with GFR below 60 mL/min (moderate renal impairment) who were treated with dapagliflozin, GFR did not quite return to baseline, and they did not show an improvement in HbA1c relative to placebo.³³ Canagliflozin at a dose of 300 mg/day caused renal-related adverse events with GFR 45 to 60 mL/min, but a lower dose of 100 mg/day did not.²⁷ A decrease in GFR also occurred in patients with chronic kidney disease treated with empagliflozin, which returned to baseline after discontinuing the drug.³¹ Despite these findings, renal function stabilizes in patients on SGLT-2 inhibitors over time, whereas it continues to decrease with placebo, suggesting there may be a renal protective effect.³⁰ Their diuretic effect can also lead to volume depletion in patients at risk such as elderly patients or those already taking diuretics.³¹

Some studies have shown mild increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels with no change in triglycerides, though long-term effects of this are unknown.³¹

There are case reports of euglycemic diabetic ketoacidosis occurring in patients with type 1 DM and type 2 DM treated with SGLT-2 inhibitors, which led the FDA in May 2015 to issue a warning that SGLT-2 inhibitors may increase the risk of ketoacidosis.³⁴ There are several possible mechanisms for this increased risk. The SGLT-2 inhibitors may decrease renal clearance of ketones, stimulate glucagon secretion leading to hepatic ketogenesis, or suppress glucose-mediated insulin secretion leading practitioners to decrease insulin doses thus resulting in increased ketone production via lipolysis.³⁴ More studies are needed, but patients and healthcare providers should be aware of potential euglycemic ketoacidosis associated with SGLT-2-inhibitors, as the lack of hyperglycemia can delay the diagnosis.

BILE ACID SEQUESTRANTS

Bile acid sequestrants have been used for years in hyperlipidemia to reduce LDL concentration; however, colesevelam is the only drug in this class approved (2009) for treating type 2 DM, after studies showed colesevelam improves glycemic control.^35–37 Though several possibilities have been proposed, the precise mechanism of action for lowering blood glucose levels is unknown.³⁵ Colesevelam is not absorbed systemically and does not affect endogenous insulin levels.⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for colesevelam.

As monotherapy, studies have shown varying effectiveness in reducing HbA1c relative to placebo ranging from no statistical difference to 0.54% reduction.^36,37 As an add-on to other diabetic medications, a Cochrane review of six randomized controlled trials showed a decrease in HbA1c by 0.3% to 0.5% and decrease in fasting glucose of 15 mg/dL.³⁷ Additional benefits of colesevelam include low risk for hypoglycemia, weight neutrality, and reduction in LDL.⁴ No serious adverse events or deaths have been associated with colesevelam, including CV events; however, more trials on macrovascular outcomes are needed to clarify its side-effect profile.³⁵

Common side effects include constipation, flatulence, and dyspepsia.³⁵ Colesevelam has shown a statistically significant increase in triglycerides, so its use in patients with triglycerides above 500 mg/dL or with hypertriglyceridemia-induced pancreatitis is contraindicated.⁴ Caution should be used prior to starting treatment in patients with triglyceride levels above 200 mg/dL.³⁵ Colesevelam is contraindicated in patients with a history of small-bowel obstruction, and caution is recommended in patients with decreased gastric motility. This drug may reduce absorption of fat-soluble vitamins and some medications.⁴

Although further research into the long-term effects of colesevelam is needed, its relatively good safety profile makes it a reasonable choice in diabetic patients with hyperlipidemia not controlled with statins.

DOPAMINE-RECEPTOR AGONIST

Bromocriptine, a dopamine-receptor agonist, was FDA-approved for the treatment of Parkinson disease, hyperprolactinemia, and acromegaly in the 1970s. In 2009, a quick-release formulation of bromocriptine (bromocriptine QR) was approved for treatment of type 2 DM. Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for bromocriptine.

The precise mechanism of action is unclear, but an American Association of Clinical Endocrinologists expert panel recommendation suggests that it may lower glucose levels by improving hypothalamic-mediated, postprandial insulin sensitivity via increasing morning dopaminergic activity (decreased in patients with type 2 DM) and by reducing hypothalamic adrenergic tone.³⁸ It is not currently recommended as monotherapy, although a study of 154 patients showed monotherapy reduced HbA1c by 0.55%.³⁹ When added to other diabetic medications, it reduced HbA1c by 0.4% to 0.7%.^4,38

Bromocriptine QR is weight neutral and carries a low risk of hypoglycemia.⁴ A safety trial with 3,095 patients showed fewer adverse CV events in patients treated with bromocriptine QR compared with placebo, which may be secondary to reduced sympathetic tone or to reduced systemic inflammation.⁴⁰ Some studies have shown reductions in blood pressure, free fatty acid levels, and triglycerides, with no change in LDL or HDL.³⁸

Common side effects include nausea, headache, dizziness, diarrhea, and fatigue. Administration is recommended with food to reduce GI side effects. It is contraindicated in women who are nursing and those with syncopal migraines. Furthermore, it may be prudent to avoid this medication in patients with a history of psychosis, those currently treated with dopamine agonists or antagonists, or those at risk for hypotension.⁴

CONCLUSION

The pathophysiology of type 2 DM involves at least seven organs and tissues—the brain, liver, pancreas, intestines, kidneys, fat, and muscle—and no single medication addresses all seven of them. Most patients require more than one medication to adequately treat their diabetes, making availability and development of drugs with unique and complementary mechanisms of action of paramount importance. The medications described here—DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, colesevelam, and bromocriptine QR—provide therapeutic options with novel mechanisms of action, all while avoiding weight gain and providing a low risk of hypoglycemia. While not appropriate for every patient, these medications give healthcare providers additional options to individualize treatment and optimize care for patients.
 

Acknowledgments. The authors gratefully thank Julie Benke-Bennett for assistance with manuscript formatting and transcription. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

Type 2 diabetes mellitus (DM) is caused by hyperglycemia and metabolic alterations due to abnormalities in insulin secretion or insulin action, or both. To achieve desired glycemic targets, different antihyperglycemic drugs are used alone or in combination with other agents, including insulin. First-line options for diabetes treatment are weight loss, lifestyle modification, and metformin. The American Diabetes Association and the European Association for the Study of Diabetes recommend a patient-specific treatment approach to enhance glycemic control while avoiding weight gain and hypoglycemia.¹ This review will focus on the newer oral agents and injectable noninsulin agents that are used to achieve glycemic control. Table 1 lists the noninsulin drugs approved since 2005.

INCRETIN-BASED THERAPIES

The incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the gastrointestinal (GI) tract in response to food intake. Both GLP-1 and GIP stimulate beta cells of the pancreas, which contribute 60% of the insulin secretion after a meal. Type 2 DM is associated with decreased secretion of GLP-1 and lowered responsiveness to GIP. Benefits of the incretin hormones on glycemic control include enhanced satiety, decreased GI motility, increased glucose-dependent insulin secretion, reduced glucagon secretion, and decreased hepatic glucose release.² Two incretin-based drug classes are used to treat patients with type 2 DM—oral dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.

DPP-4 inhibitors

The oral DPP-4 inhibitors block the degradation of the enzyme DPP-4 active site and thus increase the GLP-1 and GIP concentrations by two to three times. Their primary effectiveness centers on controlling insulin and glucagon secretion without increasing weight.

Four DPP-4 inhibitors are approved by the US Food and Drug Administration (FDA) in once-daily oral formulations: sitagliptin, saxagliptin, linagliptin, and alogliptin. Another DPP-4 inhibitor, vildagliptin, is not licensed in the United States but is approved for use in Europe and Japan.³ Another DPP-4 inhibitor, teneligliptin, is also marketed in Japan.

The DPP-4 inhibitors are indicated for use as monotherapy or in combination with other agents such as metformin, sulfonylureas, thiazolidinediones, and insulin. Generally, DPP-4 inhibitors do not cause hypoglycemia when used as monotherapy.¹ When adding a DPP-4 inhibitor to a sulfonylurea or insulin, it is recommended to decrease the sulfonylurea or insulin dose to reduce the risk of hypoglycemia. The potential of these agents to lower the hemoglobin A1c (HbA1c) when used as monotherapy and in combination with metformin, sulfonylureas, or thiazolidine­diones is 0.3% to 0.71%.⁴

The DPP-4 inhibitors are not known to cause adverse GI effects. Sitagliptin, alogliptin, vildagliptin, and saxagliptin need dosing adjustments for renal insufficiency; however, linagliptin is not renally eliminated and does not require dosing adjustment. Common adverse events (> 5%) are nasopharyngitis, upper-respiratory infection, and headache. Sitagliptin and saxagliptin have been associated with urinary tract infection. Sitagliptin also has been associated with more extremity pain, back pain, and osteoarthritis.⁴

The DPP-4 inhibitors are primarily excreted by the renal or fecal route and, therefore, have few drug interactions. All DPP-4 inhibitors are partially metabolized through cytochrome P450 enzymes, except saxagliptin.⁴ Their pharmacokinetic profiles are shown on Table 2.

In keeping with the FDA guidelines, sitagliptin, saxagliptin, linagliptin, and alogliptin have been evaluated for cardiovascular (CV) outcomes. The SAVOR-TIMI 53 clinical trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) was a 2-year CV safety and efficacy trial.⁵ This trial demonstrated no statistically significant difference in the primary end point as a composite of CV death, myocardial infarction (MI), and ischemic stroke. Additionally, the secondary end points, including hospitalization for unstable angina, coronary revascularization, and heart failure, also did not show significant difference. However, based on a subgroup analysis, there was a statistically significant increase in patients in the saxagliptin group vs the placebo group who were hospitalized for heart failure.

A 2-year trial comparing linagliptin with glimepiride, a second-generation sulfonylurea, showed significantly fewer CV events with linagliptin.⁶ This trial found a relative risk reduction of 54% in the end points of CV death, nonfatal MI or stroke, and unstable angina during hospitalization.^4,6 Another trial reviewed the incidence of CV events (CV death, nonfatal MI, and nonfatal stroke) in patients treated with alogliptin, placebo, or comparator antihyperglycemic drugs and found no increased incidence of major adverse CV events vs comparator therapies.⁷

The recently published TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin), reported no increase in major atherosclerotic CV events, no difference in all-cause mortality, and no difference in heart failure for hospitalization or other adverse events in patients with type 2 DM.⁸ Other clinical trials such as the CAROLINA study (linagliptin compared with glimepiride),⁹ the EXAMINE study (alogliptin),¹⁰ and the CARMALINA study (linagliptin)¹¹ are also reviewing the CV safety of DPP-4 inhibitors in the United States.

Concern has been raised about the association between incretin-based therapies and adverse pancreatic effects. CV outcomes trials using saxagliptin and alogliptin found similar rates of pancreatitis and fewer pancreatic cancer cases in comparison with placebo.^5,7,10 TECOS demonstrated that with sitagliptin, acute pancreatitis occurred more in the sitagliptin group, but there was no statistical significance reported. However, pancreatic cancer occurred more in the placebo group, although the difference was not statistically significant.⁸ Neither the FDA nor the European Medicines Agency (EMA) has reached a firm conclusion about the possible association between incretin-based therapies and pancreatitis or pancreatic cancer.¹²

GLP-1 agonists

The GLP-1 drugs mimic the action of native GLP-1. Several GLP-1 agents are available in the United States, and several more are in development.^11,13 The drug class is divided into three groups:

• Short-acting (4–6 hours): exenatide, lixisenatide
• Intermediate-acting (24 hours): liraglutide
• Long-acting (7 days): exenatide extended-release (ER), dulaglutide, and albiglutide (semaglutide is in phase 3 study).

The GLP-1 receptor agonists heighten glucose homeostasis by the following mechanisms of action: stimulate insulin secretion, suppress glucagon secretion, directly and indirectly inhibit endogenous glucose production, promote satiety, heighten insulin sensitivity due to weight loss, and slow gastric emptying time. Table 3 lists dosing and pharmacokinetic profiles for GLP-1 agonists. When GLP-1 agonists are used as monotherapy, the HbA1c is reduced by 0.7% to 1.51%.¹³ When GLP-1 agonists are used in combination with metformin, sulfonylureas, thiazolidinediones, or as three-drug therapy with other oral antidiabetic medications, the HbA1c is lowered by 0.4% to 1.9%.^13–17

A notable advantage of GLP-1 agonists is their effect on weight loss separate from GI side effects. Weight reductions of 0.2 to 3.6 kg in 26 weeks have been seen with the exenatide formulations, liraglutide, albiglutide, and dulaglutide.^13,18 Liraglutide has demonstrated a greater weight reduction than exenatide, exenatide ER, or albiglutide.^13,16,17 There were similar weight reductions of 1.5 kg in 26 weeks in a comparator trial involving liraglutide and dulaglutide (3.6 vs 2.9 kg).¹⁹

Common adverse effects of the GLP-1 agonists are nausea (8% to 44%), diarrhea (6% to 20%), and vomiting (4% to 18%), which may occur initially and diminish with continued use.^13,14 There have been more GI side effects with liraglutide than with exenatide ER or albiglutide.²⁰ Increased rates of injection site reactions, such as transient small nodule formations, were seen with exenatide ER (5.4% to 17.6%) and albiglutide, the once-weekly GLP-1 agonist therapies, vs exenatide, liraglutide, and insulin glargine.^13,14 Dulaglutide, another once-weekly GLP-1 agonist, does not have this finding; however, there is enhanced patient satisfaction with the once-weekly preparations in comparison with the twice-daily preparations.^14,16 Patients who received albiglutide have noted hypersensitivity reactions such as pruritus, rash, and dyspnea (10% to 18%).¹³ Hypoglycemia is not seen with the GLP-1 agonists, unless they are used in conjunction with a sulfonylurea or insulin.

Exenatide and exenatide ER are excreted by the renal route; therefore, it is not recommended to use these agonists in patients with renal impairment or end-stage renal disease (creatinine clearance [CrCl] < 30 mL/min). Liraglutide is not excreted by the renal route; however, it should be used with caution in patients with renal impairment.²¹ No renal dose adjustment is required when using albiglutide or dulaglutide.²¹

Clinical trials have demonstrated the short-term CV outcomes of GLP-1 agonists. The CV benefits include a decrease in blood pressure, reduction of lipid levels, enhanced endothelial function, and improved myocardial function.¹³ One meta-analysis reported a tendency for lowering the rate of major CV events, stroke, MI, CV mortality, and all-cause mortality.²² Several ongoing trials are evaluating the safety of GLP-1 agonists and CV safety: LEADER (liraglutide), EXSCEL (exenatide LR), ELIXA (lixisenatide), SUSTAIN 6 (semaglutide), and REWIND (dulaglutide).¹¹

The GLP-1 agonists have been linked to an increased incidence of thyroid cancer. There was a potential increased risk of thyroid cancer in preclinical rodent studies involving liraglutide and exenatide ER, but this risk was not demonstrated for the exenatide twice-daily preparation.¹³ The FDA noted that the findings from rodent studies, which demonstrated a possible heightened risk for thyroid cancer, should not be conveyed to the outcomes for humans. Nevertheless, when liraglutide was approved in January 2010, the FDA issued a boxed warning about the risk of thyroid C-cell hyperplasia. The package inserts list a thyroid carcinoma risk for exenatide ER, liraglutide, albiglutide, and dulaglutide in those patients with a personal or family history of medullary thyroid cancer.

There is controversy about the incidence of pancreatitis and pancreatic cancer with the use of the incretin-based therapies. Published studies and case reports seem to support speculation that there is an increased incidence of acute pancreatitis associated with type 2 DM.²¹ The FDA and the EMA have independently reviewed postmarketing reports about pancreatitis and pancreatic cancer among more than 28,000 patients who received some form of incretin-based therapy.¹² They independently agreed that a causal association between incretin-based drugs and pancreatitis or pancreatic cancer is inconsistent with the current data.¹² At this time, there is no final conclusion about a causal relationship between the use of incretin-based drugs and possible pancreatitis and pancreatic cancer.

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

In 2013, canagliflozin became the first sodium-glucose cotransporter-2 (SGLT-2) inhibitor to be FDA-approved for treating patients with type 2 DM, followed in 2014 by dapagliflozin and empagliflozin. Several other drugs in this class are available outside the US or are currently undergoing clinical development, including ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin. Currently, no SGLT-2 inhibitors are FDA-approved for type 1 DM, although they have been used off-label and in trials in this patient population.

These drugs work by targeting the SGLT-2 protein in the kidney. In healthy individuals, 99% of filtered glucose is reabsorbed by the kidney with a filtered load of approximately 180 g/day.²³ Glucosuria occurs with glucose concentrations above this threshold. In patients with type 2 DM, this threshold and the ability to reabsorb glucose is increased, contributing to hyperglycemia.²⁴ Located in the proximal tubule, the SGLT-2 protein is responsible for 80% to 90% of glucose reabsorption, with SGLT-1 responsible for the other 10% to 20%.²⁵ Inhibition of SGLT-2 reduces the renal threshold for glucose, thus leading to glucosuria and reduction in serum glucose levels.²⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for the SGLT-2 inhibitors.

As a monotherapy, SGLT-2 inhibitors significantly reduce HbA1c levels by 0.4% to 1.1% when compared with placebo.^26–28 Reductions may be more significant in patients with HbA1c levels greater than 8.5%, and even more so in patients with HbA1c levels above 10%.²⁹ When compared with other therapeutic options for type 2 DM, SGLT-2 inhibitors have efficacy similar to metformin, sitagliptin, and glipizide; however, some studies have shown superiority to glimepiride and sitagliptin at reducing HbA1c, depending on the dose and duration of treatment.^26,27

The SGLT-2 inhibitors do not rely on insulin activity, allowing for their use at any stage of type 2 DM and in combination with other therapies, including insulin. As an add-on medication, SGLT-2 inhibitors reduce HbA1c by 0.5% to 0.7%.^27,28 Given that the mechanism of action depends on the filtered load of glucose, they are less effective in patients with a reduced glomerular filtration rate (GFR).

The SGLT-2 inhibitors have bene­fits beyond that of glycemic control. Studies report weight loss of 1 to 3 kg, which is maintained up to 104 weeks.^27–31 Sustained weight loss is secondary to glucosuria, which amounts to a caloric loss of 200 to 300 kcal/day.³⁰ Also, SGLT-2 inhibitors lead to modest reductions in systolic and diastolic blood pressure of approximately 3 to 6 mm Hg and 1 to 2 mm Hg, respectively, due to their diuretic effect.^27,31 The risk of hypoglycemia is low—similar to that of metformin and DPP-4 inhibitors—and only slightly higher than placebo when used as monotherapy.^26,31 When added to sulfonylureas or insulin, however, the risk of hypoglycemia is increased.^26,29

Meta-analyses of SGLT-2 inhibitors showed rates of death and other serious adverse effects were no different than placebo.^26,27 A 2015 study on the CV safety of empagliflozin showed lower rates of CV death (38% relative risk [RR] reduction), lower rates of hospitalization due to heart failure (35% RR reduction), and lower rates of all-cause mortality (32% RR reduction) when compared with placebo, with no difference in nonfatal stroke and MI.³² CV safety trials for dapagliflozin and canagliflozin are ongoing, although some trials have shown an increased incidence in CV events in the first 30 days of treatment with canagliflozin.⁴

Common side effects include genital infections, such as vaginitis and balanitis, as well as urinary tract infections. In a 2013 meta-analysis,²⁷ genital infections carried an odds ratio of 3.5 for SGLT-2 inhibitors compared with placebo, while urinary tract infections carried a 1.34 odds ratio. The increased risk of infection is thought to be secondary to glucosuria combined with immune dysfunction and altered glycosylation uroepithelium cells.³⁰

During clinical trials, more cases of bladder cancer were diagnosed in patients on dapagliflozin than on placebo, leading to a delay in FDA approval. No causal relationship was established, but dapagliflozin is not recommended in patients with active bladder cancer.³⁰

Treatment with SGLT-2 inhibitors can lead to a decrease in GFR, likely secondary to the diuretic effect. In patients with GFR greater than 60 mL/min, this decrease is transient. In patients with GFR below 60 mL/min (moderate renal impairment) who were treated with dapagliflozin, GFR did not quite return to baseline, and they did not show an improvement in HbA1c relative to placebo.³³ Canagliflozin at a dose of 300 mg/day caused renal-related adverse events with GFR 45 to 60 mL/min, but a lower dose of 100 mg/day did not.²⁷ A decrease in GFR also occurred in patients with chronic kidney disease treated with empagliflozin, which returned to baseline after discontinuing the drug.³¹ Despite these findings, renal function stabilizes in patients on SGLT-2 inhibitors over time, whereas it continues to decrease with placebo, suggesting there may be a renal protective effect.³⁰ Their diuretic effect can also lead to volume depletion in patients at risk such as elderly patients or those already taking diuretics.³¹

Some studies have shown mild increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels with no change in triglycerides, though long-term effects of this are unknown.³¹

There are case reports of euglycemic diabetic ketoacidosis occurring in patients with type 1 DM and type 2 DM treated with SGLT-2 inhibitors, which led the FDA in May 2015 to issue a warning that SGLT-2 inhibitors may increase the risk of ketoacidosis.³⁴ There are several possible mechanisms for this increased risk. The SGLT-2 inhibitors may decrease renal clearance of ketones, stimulate glucagon secretion leading to hepatic ketogenesis, or suppress glucose-mediated insulin secretion leading practitioners to decrease insulin doses thus resulting in increased ketone production via lipolysis.³⁴ More studies are needed, but patients and healthcare providers should be aware of potential euglycemic ketoacidosis associated with SGLT-2-inhibitors, as the lack of hyperglycemia can delay the diagnosis.

BILE ACID SEQUESTRANTS

Bile acid sequestrants have been used for years in hyperlipidemia to reduce LDL concentration; however, colesevelam is the only drug in this class approved (2009) for treating type 2 DM, after studies showed colesevelam improves glycemic control.^35–37 Though several possibilities have been proposed, the precise mechanism of action for lowering blood glucose levels is unknown.³⁵ Colesevelam is not absorbed systemically and does not affect endogenous insulin levels.⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for colesevelam.

As monotherapy, studies have shown varying effectiveness in reducing HbA1c relative to placebo ranging from no statistical difference to 0.54% reduction.^36,37 As an add-on to other diabetic medications, a Cochrane review of six randomized controlled trials showed a decrease in HbA1c by 0.3% to 0.5% and decrease in fasting glucose of 15 mg/dL.³⁷ Additional benefits of colesevelam include low risk for hypoglycemia, weight neutrality, and reduction in LDL.⁴ No serious adverse events or deaths have been associated with colesevelam, including CV events; however, more trials on macrovascular outcomes are needed to clarify its side-effect profile.³⁵

Common side effects include constipation, flatulence, and dyspepsia.³⁵ Colesevelam has shown a statistically significant increase in triglycerides, so its use in patients with triglycerides above 500 mg/dL or with hypertriglyceridemia-induced pancreatitis is contraindicated.⁴ Caution should be used prior to starting treatment in patients with triglyceride levels above 200 mg/dL.³⁵ Colesevelam is contraindicated in patients with a history of small-bowel obstruction, and caution is recommended in patients with decreased gastric motility. This drug may reduce absorption of fat-soluble vitamins and some medications.⁴

Although further research into the long-term effects of colesevelam is needed, its relatively good safety profile makes it a reasonable choice in diabetic patients with hyperlipidemia not controlled with statins.

DOPAMINE-RECEPTOR AGONIST

Bromocriptine, a dopamine-receptor agonist, was FDA-approved for the treatment of Parkinson disease, hyperprolactinemia, and acromegaly in the 1970s. In 2009, a quick-release formulation of bromocriptine (bromocriptine QR) was approved for treatment of type 2 DM. Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for bromocriptine.

The precise mechanism of action is unclear, but an American Association of Clinical Endocrinologists expert panel recommendation suggests that it may lower glucose levels by improving hypothalamic-mediated, postprandial insulin sensitivity via increasing morning dopaminergic activity (decreased in patients with type 2 DM) and by reducing hypothalamic adrenergic tone.³⁸ It is not currently recommended as monotherapy, although a study of 154 patients showed monotherapy reduced HbA1c by 0.55%.³⁹ When added to other diabetic medications, it reduced HbA1c by 0.4% to 0.7%.^4,38

Bromocriptine QR is weight neutral and carries a low risk of hypoglycemia.⁴ A safety trial with 3,095 patients showed fewer adverse CV events in patients treated with bromocriptine QR compared with placebo, which may be secondary to reduced sympathetic tone or to reduced systemic inflammation.⁴⁰ Some studies have shown reductions in blood pressure, free fatty acid levels, and triglycerides, with no change in LDL or HDL.³⁸

Common side effects include nausea, headache, dizziness, diarrhea, and fatigue. Administration is recommended with food to reduce GI side effects. It is contraindicated in women who are nursing and those with syncopal migraines. Furthermore, it may be prudent to avoid this medication in patients with a history of psychosis, those currently treated with dopamine agonists or antagonists, or those at risk for hypotension.⁴

CONCLUSION

The pathophysiology of type 2 DM involves at least seven organs and tissues—the brain, liver, pancreas, intestines, kidneys, fat, and muscle—and no single medication addresses all seven of them. Most patients require more than one medication to adequately treat their diabetes, making availability and development of drugs with unique and complementary mechanisms of action of paramount importance. The medications described here—DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, colesevelam, and bromocriptine QR—provide therapeutic options with novel mechanisms of action, all while avoiding weight gain and providing a low risk of hypoglycemia. While not appropriate for every patient, these medications give healthcare providers additional options to individualize treatment and optimize care for patients.
 

Acknowledgments. The authors gratefully thank Julie Benke-Bennett for assistance with manuscript formatting and transcription. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

Type 2 diabetes mellitus (DM) is caused by hyperglycemia and metabolic alterations due to abnormalities in insulin secretion or insulin action, or both. To achieve desired glycemic targets, different antihyperglycemic drugs are used alone or in combination with other agents, including insulin. First-line options for diabetes treatment are weight loss, lifestyle modification, and metformin. The American Diabetes Association and the European Association for the Study of Diabetes recommend a patient-specific treatment approach to enhance glycemic control while avoiding weight gain and hypoglycemia.¹ This review will focus on the newer oral agents and injectable noninsulin agents that are used to achieve glycemic control. Table 1 lists the noninsulin drugs approved since 2005.

INCRETIN-BASED THERAPIES

The incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the gastrointestinal (GI) tract in response to food intake. Both GLP-1 and GIP stimulate beta cells of the pancreas, which contribute 60% of the insulin secretion after a meal. Type 2 DM is associated with decreased secretion of GLP-1 and lowered responsiveness to GIP. Benefits of the incretin hormones on glycemic control include enhanced satiety, decreased GI motility, increased glucose-dependent insulin secretion, reduced glucagon secretion, and decreased hepatic glucose release.² Two incretin-based drug classes are used to treat patients with type 2 DM—oral dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.

DPP-4 inhibitors

The oral DPP-4 inhibitors block the degradation of the enzyme DPP-4 active site and thus increase the GLP-1 and GIP concentrations by two to three times. Their primary effectiveness centers on controlling insulin and glucagon secretion without increasing weight.

Four DPP-4 inhibitors are approved by the US Food and Drug Administration (FDA) in once-daily oral formulations: sitagliptin, saxagliptin, linagliptin, and alogliptin. Another DPP-4 inhibitor, vildagliptin, is not licensed in the United States but is approved for use in Europe and Japan.³ Another DPP-4 inhibitor, teneligliptin, is also marketed in Japan.

The DPP-4 inhibitors are indicated for use as monotherapy or in combination with other agents such as metformin, sulfonylureas, thiazolidinediones, and insulin. Generally, DPP-4 inhibitors do not cause hypoglycemia when used as monotherapy.¹ When adding a DPP-4 inhibitor to a sulfonylurea or insulin, it is recommended to decrease the sulfonylurea or insulin dose to reduce the risk of hypoglycemia. The potential of these agents to lower the hemoglobin A1c (HbA1c) when used as monotherapy and in combination with metformin, sulfonylureas, or thiazolidine­diones is 0.3% to 0.71%.⁴

The DPP-4 inhibitors are not known to cause adverse GI effects. Sitagliptin, alogliptin, vildagliptin, and saxagliptin need dosing adjustments for renal insufficiency; however, linagliptin is not renally eliminated and does not require dosing adjustment. Common adverse events (> 5%) are nasopharyngitis, upper-respiratory infection, and headache. Sitagliptin and saxagliptin have been associated with urinary tract infection. Sitagliptin also has been associated with more extremity pain, back pain, and osteoarthritis.⁴

The DPP-4 inhibitors are primarily excreted by the renal or fecal route and, therefore, have few drug interactions. All DPP-4 inhibitors are partially metabolized through cytochrome P450 enzymes, except saxagliptin.⁴ Their pharmacokinetic profiles are shown on Table 2.

In keeping with the FDA guidelines, sitagliptin, saxagliptin, linagliptin, and alogliptin have been evaluated for cardiovascular (CV) outcomes. The SAVOR-TIMI 53 clinical trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) was a 2-year CV safety and efficacy trial.⁵ This trial demonstrated no statistically significant difference in the primary end point as a composite of CV death, myocardial infarction (MI), and ischemic stroke. Additionally, the secondary end points, including hospitalization for unstable angina, coronary revascularization, and heart failure, also did not show significant difference. However, based on a subgroup analysis, there was a statistically significant increase in patients in the saxagliptin group vs the placebo group who were hospitalized for heart failure.

A 2-year trial comparing linagliptin with glimepiride, a second-generation sulfonylurea, showed significantly fewer CV events with linagliptin.⁶ This trial found a relative risk reduction of 54% in the end points of CV death, nonfatal MI or stroke, and unstable angina during hospitalization.^4,6 Another trial reviewed the incidence of CV events (CV death, nonfatal MI, and nonfatal stroke) in patients treated with alogliptin, placebo, or comparator antihyperglycemic drugs and found no increased incidence of major adverse CV events vs comparator therapies.⁷

The recently published TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin), reported no increase in major atherosclerotic CV events, no difference in all-cause mortality, and no difference in heart failure for hospitalization or other adverse events in patients with type 2 DM.⁸ Other clinical trials such as the CAROLINA study (linagliptin compared with glimepiride),⁹ the EXAMINE study (alogliptin),¹⁰ and the CARMALINA study (linagliptin)¹¹ are also reviewing the CV safety of DPP-4 inhibitors in the United States.

Concern has been raised about the association between incretin-based therapies and adverse pancreatic effects. CV outcomes trials using saxagliptin and alogliptin found similar rates of pancreatitis and fewer pancreatic cancer cases in comparison with placebo.^5,7,10 TECOS demonstrated that with sitagliptin, acute pancreatitis occurred more in the sitagliptin group, but there was no statistical significance reported. However, pancreatic cancer occurred more in the placebo group, although the difference was not statistically significant.⁸ Neither the FDA nor the European Medicines Agency (EMA) has reached a firm conclusion about the possible association between incretin-based therapies and pancreatitis or pancreatic cancer.¹²

GLP-1 agonists

The GLP-1 drugs mimic the action of native GLP-1. Several GLP-1 agents are available in the United States, and several more are in development.^11,13 The drug class is divided into three groups:

• Short-acting (4–6 hours): exenatide, lixisenatide
• Intermediate-acting (24 hours): liraglutide
• Long-acting (7 days): exenatide extended-release (ER), dulaglutide, and albiglutide (semaglutide is in phase 3 study).

The GLP-1 receptor agonists heighten glucose homeostasis by the following mechanisms of action: stimulate insulin secretion, suppress glucagon secretion, directly and indirectly inhibit endogenous glucose production, promote satiety, heighten insulin sensitivity due to weight loss, and slow gastric emptying time. Table 3 lists dosing and pharmacokinetic profiles for GLP-1 agonists. When GLP-1 agonists are used as monotherapy, the HbA1c is reduced by 0.7% to 1.51%.¹³ When GLP-1 agonists are used in combination with metformin, sulfonylureas, thiazolidinediones, or as three-drug therapy with other oral antidiabetic medications, the HbA1c is lowered by 0.4% to 1.9%.^13–17

A notable advantage of GLP-1 agonists is their effect on weight loss separate from GI side effects. Weight reductions of 0.2 to 3.6 kg in 26 weeks have been seen with the exenatide formulations, liraglutide, albiglutide, and dulaglutide.^13,18 Liraglutide has demonstrated a greater weight reduction than exenatide, exenatide ER, or albiglutide.^13,16,17 There were similar weight reductions of 1.5 kg in 26 weeks in a comparator trial involving liraglutide and dulaglutide (3.6 vs 2.9 kg).¹⁹

Common adverse effects of the GLP-1 agonists are nausea (8% to 44%), diarrhea (6% to 20%), and vomiting (4% to 18%), which may occur initially and diminish with continued use.^13,14 There have been more GI side effects with liraglutide than with exenatide ER or albiglutide.²⁰ Increased rates of injection site reactions, such as transient small nodule formations, were seen with exenatide ER (5.4% to 17.6%) and albiglutide, the once-weekly GLP-1 agonist therapies, vs exenatide, liraglutide, and insulin glargine.^13,14 Dulaglutide, another once-weekly GLP-1 agonist, does not have this finding; however, there is enhanced patient satisfaction with the once-weekly preparations in comparison with the twice-daily preparations.^14,16 Patients who received albiglutide have noted hypersensitivity reactions such as pruritus, rash, and dyspnea (10% to 18%).¹³ Hypoglycemia is not seen with the GLP-1 agonists, unless they are used in conjunction with a sulfonylurea or insulin.

Exenatide and exenatide ER are excreted by the renal route; therefore, it is not recommended to use these agonists in patients with renal impairment or end-stage renal disease (creatinine clearance [CrCl] < 30 mL/min). Liraglutide is not excreted by the renal route; however, it should be used with caution in patients with renal impairment.²¹ No renal dose adjustment is required when using albiglutide or dulaglutide.²¹

Clinical trials have demonstrated the short-term CV outcomes of GLP-1 agonists. The CV benefits include a decrease in blood pressure, reduction of lipid levels, enhanced endothelial function, and improved myocardial function.¹³ One meta-analysis reported a tendency for lowering the rate of major CV events, stroke, MI, CV mortality, and all-cause mortality.²² Several ongoing trials are evaluating the safety of GLP-1 agonists and CV safety: LEADER (liraglutide), EXSCEL (exenatide LR), ELIXA (lixisenatide), SUSTAIN 6 (semaglutide), and REWIND (dulaglutide).¹¹

The GLP-1 agonists have been linked to an increased incidence of thyroid cancer. There was a potential increased risk of thyroid cancer in preclinical rodent studies involving liraglutide and exenatide ER, but this risk was not demonstrated for the exenatide twice-daily preparation.¹³ The FDA noted that the findings from rodent studies, which demonstrated a possible heightened risk for thyroid cancer, should not be conveyed to the outcomes for humans. Nevertheless, when liraglutide was approved in January 2010, the FDA issued a boxed warning about the risk of thyroid C-cell hyperplasia. The package inserts list a thyroid carcinoma risk for exenatide ER, liraglutide, albiglutide, and dulaglutide in those patients with a personal or family history of medullary thyroid cancer.

There is controversy about the incidence of pancreatitis and pancreatic cancer with the use of the incretin-based therapies. Published studies and case reports seem to support speculation that there is an increased incidence of acute pancreatitis associated with type 2 DM.²¹ The FDA and the EMA have independently reviewed postmarketing reports about pancreatitis and pancreatic cancer among more than 28,000 patients who received some form of incretin-based therapy.¹² They independently agreed that a causal association between incretin-based drugs and pancreatitis or pancreatic cancer is inconsistent with the current data.¹² At this time, there is no final conclusion about a causal relationship between the use of incretin-based drugs and possible pancreatitis and pancreatic cancer.

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

In 2013, canagliflozin became the first sodium-glucose cotransporter-2 (SGLT-2) inhibitor to be FDA-approved for treating patients with type 2 DM, followed in 2014 by dapagliflozin and empagliflozin. Several other drugs in this class are available outside the US or are currently undergoing clinical development, including ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin. Currently, no SGLT-2 inhibitors are FDA-approved for type 1 DM, although they have been used off-label and in trials in this patient population.

These drugs work by targeting the SGLT-2 protein in the kidney. In healthy individuals, 99% of filtered glucose is reabsorbed by the kidney with a filtered load of approximately 180 g/day.²³ Glucosuria occurs with glucose concentrations above this threshold. In patients with type 2 DM, this threshold and the ability to reabsorb glucose is increased, contributing to hyperglycemia.²⁴ Located in the proximal tubule, the SGLT-2 protein is responsible for 80% to 90% of glucose reabsorption, with SGLT-1 responsible for the other 10% to 20%.²⁵ Inhibition of SGLT-2 reduces the renal threshold for glucose, thus leading to glucosuria and reduction in serum glucose levels.²⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for the SGLT-2 inhibitors.

As a monotherapy, SGLT-2 inhibitors significantly reduce HbA1c levels by 0.4% to 1.1% when compared with placebo.^26–28 Reductions may be more significant in patients with HbA1c levels greater than 8.5%, and even more so in patients with HbA1c levels above 10%.²⁹ When compared with other therapeutic options for type 2 DM, SGLT-2 inhibitors have efficacy similar to metformin, sitagliptin, and glipizide; however, some studies have shown superiority to glimepiride and sitagliptin at reducing HbA1c, depending on the dose and duration of treatment.^26,27

The SGLT-2 inhibitors do not rely on insulin activity, allowing for their use at any stage of type 2 DM and in combination with other therapies, including insulin. As an add-on medication, SGLT-2 inhibitors reduce HbA1c by 0.5% to 0.7%.^27,28 Given that the mechanism of action depends on the filtered load of glucose, they are less effective in patients with a reduced glomerular filtration rate (GFR).

The SGLT-2 inhibitors have bene­fits beyond that of glycemic control. Studies report weight loss of 1 to 3 kg, which is maintained up to 104 weeks.^27–31 Sustained weight loss is secondary to glucosuria, which amounts to a caloric loss of 200 to 300 kcal/day.³⁰ Also, SGLT-2 inhibitors lead to modest reductions in systolic and diastolic blood pressure of approximately 3 to 6 mm Hg and 1 to 2 mm Hg, respectively, due to their diuretic effect.^27,31 The risk of hypoglycemia is low—similar to that of metformin and DPP-4 inhibitors—and only slightly higher than placebo when used as monotherapy.^26,31 When added to sulfonylureas or insulin, however, the risk of hypoglycemia is increased.^26,29

Meta-analyses of SGLT-2 inhibitors showed rates of death and other serious adverse effects were no different than placebo.^26,27 A 2015 study on the CV safety of empagliflozin showed lower rates of CV death (38% relative risk [RR] reduction), lower rates of hospitalization due to heart failure (35% RR reduction), and lower rates of all-cause mortality (32% RR reduction) when compared with placebo, with no difference in nonfatal stroke and MI.³² CV safety trials for dapagliflozin and canagliflozin are ongoing, although some trials have shown an increased incidence in CV events in the first 30 days of treatment with canagliflozin.⁴

Common side effects include genital infections, such as vaginitis and balanitis, as well as urinary tract infections. In a 2013 meta-analysis,²⁷ genital infections carried an odds ratio of 3.5 for SGLT-2 inhibitors compared with placebo, while urinary tract infections carried a 1.34 odds ratio. The increased risk of infection is thought to be secondary to glucosuria combined with immune dysfunction and altered glycosylation uroepithelium cells.³⁰

During clinical trials, more cases of bladder cancer were diagnosed in patients on dapagliflozin than on placebo, leading to a delay in FDA approval. No causal relationship was established, but dapagliflozin is not recommended in patients with active bladder cancer.³⁰

Treatment with SGLT-2 inhibitors can lead to a decrease in GFR, likely secondary to the diuretic effect. In patients with GFR greater than 60 mL/min, this decrease is transient. In patients with GFR below 60 mL/min (moderate renal impairment) who were treated with dapagliflozin, GFR did not quite return to baseline, and they did not show an improvement in HbA1c relative to placebo.³³ Canagliflozin at a dose of 300 mg/day caused renal-related adverse events with GFR 45 to 60 mL/min, but a lower dose of 100 mg/day did not.²⁷ A decrease in GFR also occurred in patients with chronic kidney disease treated with empagliflozin, which returned to baseline after discontinuing the drug.³¹ Despite these findings, renal function stabilizes in patients on SGLT-2 inhibitors over time, whereas it continues to decrease with placebo, suggesting there may be a renal protective effect.³⁰ Their diuretic effect can also lead to volume depletion in patients at risk such as elderly patients or those already taking diuretics.³¹

Some studies have shown mild increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels with no change in triglycerides, though long-term effects of this are unknown.³¹

There are case reports of euglycemic diabetic ketoacidosis occurring in patients with type 1 DM and type 2 DM treated with SGLT-2 inhibitors, which led the FDA in May 2015 to issue a warning that SGLT-2 inhibitors may increase the risk of ketoacidosis.³⁴ There are several possible mechanisms for this increased risk. The SGLT-2 inhibitors may decrease renal clearance of ketones, stimulate glucagon secretion leading to hepatic ketogenesis, or suppress glucose-mediated insulin secretion leading practitioners to decrease insulin doses thus resulting in increased ketone production via lipolysis.³⁴ More studies are needed, but patients and healthcare providers should be aware of potential euglycemic ketoacidosis associated with SGLT-2-inhibitors, as the lack of hyperglycemia can delay the diagnosis.

BILE ACID SEQUESTRANTS

Bile acid sequestrants have been used for years in hyperlipidemia to reduce LDL concentration; however, colesevelam is the only drug in this class approved (2009) for treating type 2 DM, after studies showed colesevelam improves glycemic control.^35–37 Though several possibilities have been proposed, the precise mechanism of action for lowering blood glucose levels is unknown.³⁵ Colesevelam is not absorbed systemically and does not affect endogenous insulin levels.⁴ Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for colesevelam.

As monotherapy, studies have shown varying effectiveness in reducing HbA1c relative to placebo ranging from no statistical difference to 0.54% reduction.^36,37 As an add-on to other diabetic medications, a Cochrane review of six randomized controlled trials showed a decrease in HbA1c by 0.3% to 0.5% and decrease in fasting glucose of 15 mg/dL.³⁷ Additional benefits of colesevelam include low risk for hypoglycemia, weight neutrality, and reduction in LDL.⁴ No serious adverse events or deaths have been associated with colesevelam, including CV events; however, more trials on macrovascular outcomes are needed to clarify its side-effect profile.³⁵

Common side effects include constipation, flatulence, and dyspepsia.³⁵ Colesevelam has shown a statistically significant increase in triglycerides, so its use in patients with triglycerides above 500 mg/dL or with hypertriglyceridemia-induced pancreatitis is contraindicated.⁴ Caution should be used prior to starting treatment in patients with triglyceride levels above 200 mg/dL.³⁵ Colesevelam is contraindicated in patients with a history of small-bowel obstruction, and caution is recommended in patients with decreased gastric motility. This drug may reduce absorption of fat-soluble vitamins and some medications.⁴

Although further research into the long-term effects of colesevelam is needed, its relatively good safety profile makes it a reasonable choice in diabetic patients with hyperlipidemia not controlled with statins.

DOPAMINE-RECEPTOR AGONIST

Bromocriptine, a dopamine-receptor agonist, was FDA-approved for the treatment of Parkinson disease, hyperprolactinemia, and acromegaly in the 1970s. In 2009, a quick-release formulation of bromocriptine (bromocriptine QR) was approved for treatment of type 2 DM. Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for bromocriptine.

The precise mechanism of action is unclear, but an American Association of Clinical Endocrinologists expert panel recommendation suggests that it may lower glucose levels by improving hypothalamic-mediated, postprandial insulin sensitivity via increasing morning dopaminergic activity (decreased in patients with type 2 DM) and by reducing hypothalamic adrenergic tone.³⁸ It is not currently recommended as monotherapy, although a study of 154 patients showed monotherapy reduced HbA1c by 0.55%.³⁹ When added to other diabetic medications, it reduced HbA1c by 0.4% to 0.7%.^4,38

Bromocriptine QR is weight neutral and carries a low risk of hypoglycemia.⁴ A safety trial with 3,095 patients showed fewer adverse CV events in patients treated with bromocriptine QR compared with placebo, which may be secondary to reduced sympathetic tone or to reduced systemic inflammation.⁴⁰ Some studies have shown reductions in blood pressure, free fatty acid levels, and triglycerides, with no change in LDL or HDL.³⁸

Common side effects include nausea, headache, dizziness, diarrhea, and fatigue. Administration is recommended with food to reduce GI side effects. It is contraindicated in women who are nursing and those with syncopal migraines. Furthermore, it may be prudent to avoid this medication in patients with a history of psychosis, those currently treated with dopamine agonists or antagonists, or those at risk for hypotension.⁴

CONCLUSION

The pathophysiology of type 2 DM involves at least seven organs and tissues—the brain, liver, pancreas, intestines, kidneys, fat, and muscle—and no single medication addresses all seven of them. Most patients require more than one medication to adequately treat their diabetes, making availability and development of drugs with unique and complementary mechanisms of action of paramount importance. The medications described here—DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, colesevelam, and bromocriptine QR—provide therapeutic options with novel mechanisms of action, all while avoiding weight gain and providing a low risk of hypoglycemia. While not appropriate for every patient, these medications give healthcare providers additional options to individualize treatment and optimize care for patients.
 

Acknowledgments. The authors gratefully thank Julie Benke-Bennett for assistance with manuscript formatting and transcription. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.