Acne is the most common skin condition, affecting up to 50 million individuals annually. Self-esteem is affected, and scarring can result if left untreated or inadequately treated. Although still somewhat controversial in some circles, available data have linked acne to dairy products, refined sugar ingestion, and high glycemic loads.

Acne has been linked to insulin levels and insulin-like growth factor (IGF-1). Glycemic loads are associated with both insulin and IGF-1. Metformin reduces glucose release from the liver while increasing glucose uptake in muscles and adipocytes.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article.

Acne is the most common skin condition, affecting up to 50 million individuals annually. Self-esteem is affected, and scarring can result if left untreated or inadequately treated. Although still somewhat controversial in some circles, available data have linked acne to dairy products, refined sugar ingestion, and high glycemic loads.

Acne has been linked to insulin levels and insulin-like growth factor (IGF-1). Glycemic loads are associated with both insulin and IGF-1. Metformin reduces glucose release from the liver while increasing glucose uptake in muscles and adipocytes.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article.

Acne is the most common skin condition, affecting up to 50 million individuals annually. Self-esteem is affected, and scarring can result if left untreated or inadequately treated. Although still somewhat controversial in some circles, available data have linked acne to dairy products, refined sugar ingestion, and high glycemic loads.

Acne has been linked to insulin levels and insulin-like growth factor (IGF-1). Glycemic loads are associated with both insulin and IGF-1. Metformin reduces glucose release from the liver while increasing glucose uptake in muscles and adipocytes.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article.

ORLANDO – In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over 5 or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the annual International AF Symposium.

“The risk of stroke is high among patients after unsuccessful catheter ablation,” confirmed Mihran Martirosyan, MD, Erasmus Medical Center, Rotterdam, the Netherlands. He asserted that this is the first study to investigate long-term clinical outcomes of AF patients with unsuccessful rhythm control following repeated catheter ablation.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least 5 years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke over the course of follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66 years. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, catheter ablation failure was defined as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at 1 year (Europace 2014 Oct 21;17[3]:403-8). When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only 4 occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

Dr. Martirosyan reports no relevant financial relationships.

ORLANDO – In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over 5 or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the annual International AF Symposium.

“The risk of stroke is high among patients after unsuccessful catheter ablation,” confirmed Mihran Martirosyan, MD, Erasmus Medical Center, Rotterdam, the Netherlands. He asserted that this is the first study to investigate long-term clinical outcomes of AF patients with unsuccessful rhythm control following repeated catheter ablation.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least 5 years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke over the course of follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66 years. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, catheter ablation failure was defined as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at 1 year (Europace 2014 Oct 21;17[3]:403-8). When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only 4 occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

Dr. Martirosyan reports no relevant financial relationships.

ORLANDO – In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over 5 or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the annual International AF Symposium.

“The risk of stroke is high among patients after unsuccessful catheter ablation,” confirmed Mihran Martirosyan, MD, Erasmus Medical Center, Rotterdam, the Netherlands. He asserted that this is the first study to investigate long-term clinical outcomes of AF patients with unsuccessful rhythm control following repeated catheter ablation.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least 5 years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke over the course of follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66 years. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, catheter ablation failure was defined as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at 1 year (Europace 2014 Oct 21;17[3]:403-8). When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only 4 occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

Dr. Martirosyan reports no relevant financial relationships.

NEW ORLEANS – Thromboprophylaxis for 35-42 days with the new oral anticoagulant betrixaban led to a significant reduction in all-cause and ischemic strokes in medically ill patients who required hospitalization as compared with conventional prophylaxis for 10 days, based on a post-hoc analysis of data from a randomized trial with more than 7,500 patients.

But the trial’s unusual design left it unclear whether the incremental benefit seen from prolonged prophylaxis with a NOAC resulted primarily from a longer period of treatment, the drug used, or both.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW ORLEANS – Thromboprophylaxis for 35-42 days with the new oral anticoagulant betrixaban led to a significant reduction in all-cause and ischemic strokes in medically ill patients who required hospitalization as compared with conventional prophylaxis for 10 days, based on a post-hoc analysis of data from a randomized trial with more than 7,500 patients.

But the trial’s unusual design left it unclear whether the incremental benefit seen from prolonged prophylaxis with a NOAC resulted primarily from a longer period of treatment, the drug used, or both.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW ORLEANS – Thromboprophylaxis for 35-42 days with the new oral anticoagulant betrixaban led to a significant reduction in all-cause and ischemic strokes in medically ill patients who required hospitalization as compared with conventional prophylaxis for 10 days, based on a post-hoc analysis of data from a randomized trial with more than 7,500 patients.

But the trial’s unusual design left it unclear whether the incremental benefit seen from prolonged prophylaxis with a NOAC resulted primarily from a longer period of treatment, the drug used, or both.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Lurasidone HCl, marketed as Latuda, has received approval from the Food and Drug Administration for the treatment of schizophrenia in adolescents aged 13-17 years old, according to a press release from Sunovion Pharmaceuticals.

FDA approval of Latuda is based on results of a 6-week study in which adolescents with schizophrenia received either 40 mg of lurasidone per day, 80 mg per day, or a placebo. Patients who received lurasidone HCI showed statistical and clinical improvements in schizophrenia symptoms, compared with the placebo group. The drug was well tolerated with no significant adverse events reported.

[email protected]

Lurasidone HCl, marketed as Latuda, has received approval from the Food and Drug Administration for the treatment of schizophrenia in adolescents aged 13-17 years old, according to a press release from Sunovion Pharmaceuticals.

FDA approval of Latuda is based on results of a 6-week study in which adolescents with schizophrenia received either 40 mg of lurasidone per day, 80 mg per day, or a placebo. Patients who received lurasidone HCI showed statistical and clinical improvements in schizophrenia symptoms, compared with the placebo group. The drug was well tolerated with no significant adverse events reported.

[email protected]

Lurasidone HCl, marketed as Latuda, has received approval from the Food and Drug Administration for the treatment of schizophrenia in adolescents aged 13-17 years old, according to a press release from Sunovion Pharmaceuticals.

FDA approval of Latuda is based on results of a 6-week study in which adolescents with schizophrenia received either 40 mg of lurasidone per day, 80 mg per day, or a placebo. Patients who received lurasidone HCI showed statistical and clinical improvements in schizophrenia symptoms, compared with the placebo group. The drug was well tolerated with no significant adverse events reported.

[email protected]

SAN FRANCISCO – “If one is going to say ‘you need 6 months of abstinence from cannabis before I am going to treat your ADHD,’ that’s absurd. If [kids] are stoned all the time, no, but if it’s intermittent, it’s really not a factor,” according to James J. McGough, MD, director of the Attention Deficit Disorder Clinic at the University of California, Los Angeles.

There’s no evidence that ongoing stimulant treatment increases the risk of substance abuse, and “we must admit to ourselves that substance use among adolescents and young adults is normative. It happens,” even among well-adapted kids. “Think of your own past histories,” he said to an audience of psychiatrists and other medical professionals at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

[email protected]

SAN FRANCISCO – “If one is going to say ‘you need 6 months of abstinence from cannabis before I am going to treat your ADHD,’ that’s absurd. If [kids] are stoned all the time, no, but if it’s intermittent, it’s really not a factor,” according to James J. McGough, MD, director of the Attention Deficit Disorder Clinic at the University of California, Los Angeles.

There’s no evidence that ongoing stimulant treatment increases the risk of substance abuse, and “we must admit to ourselves that substance use among adolescents and young adults is normative. It happens,” even among well-adapted kids. “Think of your own past histories,” he said to an audience of psychiatrists and other medical professionals at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

[email protected]

SAN FRANCISCO – “If one is going to say ‘you need 6 months of abstinence from cannabis before I am going to treat your ADHD,’ that’s absurd. If [kids] are stoned all the time, no, but if it’s intermittent, it’s really not a factor,” according to James J. McGough, MD, director of the Attention Deficit Disorder Clinic at the University of California, Los Angeles.

There’s no evidence that ongoing stimulant treatment increases the risk of substance abuse, and “we must admit to ourselves that substance use among adolescents and young adults is normative. It happens,” even among well-adapted kids. “Think of your own past histories,” he said to an audience of psychiatrists and other medical professionals at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

[email protected]

WAILEA, HAWAII – Several patterns can provide clues to diagnoses of rheumatologic diseases, according to Daniel E. Furst, MD, professor of rheumatology, University of Washington, Seattle.

Dermatology and rheumatology share the use of pattern recognition when making a diagnosis, he said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation. An important pattern is the idea of polyarticular versus monoarticular disease. Rheumatoid arthritis, osteoarthritis, autoimmune diseases, and gout and crystalline diseases, he said, encompass “about 80% of the cases with polyarticular arthritis.”

Another pattern to consider is symmetry versus asymmetry. Osteoarthritis and gout will be asymmetric, while autoimmune diseases and RA will be symmetrical, Dr. Furst pointed out. Also consider areas of involvement, such as upper and lower parts of the body. “Lower tends to be more gout and more OA,” while upper-extremity involvement is more likely to be autoimmune diseases and RA, he said.

“You don’t have to be Einstein to be a rheumatologist; just remember some simple stuff,” added Dr. Furst, who also discusses the use of lab tests in the interview.

Dr. Furst is also professor emeritus, University of California, Los Angeles, and is affiliated with the University of Florence (Italy) Medical School.

He disclosed financial relationships with companies including AbbVie, Actelion, Amgen, BMS, Cytori, Genentech/Roche, Novartis, and Pfizer.

SDEF and this news organization are owned by the same parent company.

WAILEA, HAWAII – Several patterns can provide clues to diagnoses of rheumatologic diseases, according to Daniel E. Furst, MD, professor of rheumatology, University of Washington, Seattle.

Dermatology and rheumatology share the use of pattern recognition when making a diagnosis, he said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation. An important pattern is the idea of polyarticular versus monoarticular disease. Rheumatoid arthritis, osteoarthritis, autoimmune diseases, and gout and crystalline diseases, he said, encompass “about 80% of the cases with polyarticular arthritis.”

Another pattern to consider is symmetry versus asymmetry. Osteoarthritis and gout will be asymmetric, while autoimmune diseases and RA will be symmetrical, Dr. Furst pointed out. Also consider areas of involvement, such as upper and lower parts of the body. “Lower tends to be more gout and more OA,” while upper-extremity involvement is more likely to be autoimmune diseases and RA, he said.

“You don’t have to be Einstein to be a rheumatologist; just remember some simple stuff,” added Dr. Furst, who also discusses the use of lab tests in the interview.

Dr. Furst is also professor emeritus, University of California, Los Angeles, and is affiliated with the University of Florence (Italy) Medical School.

He disclosed financial relationships with companies including AbbVie, Actelion, Amgen, BMS, Cytori, Genentech/Roche, Novartis, and Pfizer.

SDEF and this news organization are owned by the same parent company.

WAILEA, HAWAII – Several patterns can provide clues to diagnoses of rheumatologic diseases, according to Daniel E. Furst, MD, professor of rheumatology, University of Washington, Seattle.

Dermatology and rheumatology share the use of pattern recognition when making a diagnosis, he said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation. An important pattern is the idea of polyarticular versus monoarticular disease. Rheumatoid arthritis, osteoarthritis, autoimmune diseases, and gout and crystalline diseases, he said, encompass “about 80% of the cases with polyarticular arthritis.”

Another pattern to consider is symmetry versus asymmetry. Osteoarthritis and gout will be asymmetric, while autoimmune diseases and RA will be symmetrical, Dr. Furst pointed out. Also consider areas of involvement, such as upper and lower parts of the body. “Lower tends to be more gout and more OA,” while upper-extremity involvement is more likely to be autoimmune diseases and RA, he said.

“You don’t have to be Einstein to be a rheumatologist; just remember some simple stuff,” added Dr. Furst, who also discusses the use of lab tests in the interview.

Dr. Furst is also professor emeritus, University of California, Los Angeles, and is affiliated with the University of Florence (Italy) Medical School.

He disclosed financial relationships with companies including AbbVie, Actelion, Amgen, BMS, Cytori, Genentech/Roche, Novartis, and Pfizer.

SDEF and this news organization are owned by the same parent company.

Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).

The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.

For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).

Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.

Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.

Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.

Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).

The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.

For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).

Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.

Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.

Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.

Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).

The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.

For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).

Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.

Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.

Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.

SAN DIEGO—A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s disease who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test, an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

ANAVEX 2-73 (Anavex Life Sciences, New York) also conferred an unexpected benefit upon subjects with insomnia. “Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane, MBBS, said at the Clinical Trials on Alzheimer’s Disease conference.

The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional end points were secondary. It comprised 32 patients at baseline, 25 of whom completed both a five-week, randomized, dose-finding, crossover trial and a 52-week, open-label, extension study. There was no placebo comparator. Instead, researchers used three different sets of historical control data.

Investigators will continue to treat and follow the extension study cohort, and plan to launch a placebo-controlled study in 2017, said Dr. Macfarlane, Head of Clinical Governance for the Dementia Centre in Melbourne.

The five-week, randomized, dose-finding, crossover trial started one group of patients on 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial two-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days. This trial was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last six months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.

An Attractive Drug Target

The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the CNS. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.

The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins—a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

In preclinical testing, ANAVEX 2-73 seemed to enhance cognition in wild-type and Alzheimer’s disease–model mice.

The mean age of patients in the extension study was 71. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of an acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable.

The primary end points were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.

The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By the study’s end, it had decreased to a mean of 1 point. Patients also reported improvements in their ability to work or do other activities, and in anxiety, agitation, hypochondriasis, and insight.

Electrophysiologic Measures

The P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter, it steadily improved to about 8 microvolts by 57 weeks—a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s disease cohort, which decreased to about 4 microvolts over a 52-week period while patients were taking donepezil.

Researchers used a second historical control group to assess changes on the Computerized Cogstate Alzheimer’s Battery. All subjects in a large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to improve.

At 57 weeks, patients’ mean MMSE score was near the baseline mean score of 20. ADCS-ADL scores declined slightly, from a mean of about 70 to approximately 65.

Finally, the investigators used another historical cohort to assess projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point benefit on the MMSE and a 4-point benefit on the ADCS-ADL.

“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”

Nearly all patients (98%) experienced an adverse event. Most events were mild, transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out of the trial because of adverse events (ie, delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care Alzheimer’s disease medications.

—Michelle G. Sullivan

SAN DIEGO—A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s disease who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test, an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

ANAVEX 2-73 (Anavex Life Sciences, New York) also conferred an unexpected benefit upon subjects with insomnia. “Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane, MBBS, said at the Clinical Trials on Alzheimer’s Disease conference.

The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional end points were secondary. It comprised 32 patients at baseline, 25 of whom completed both a five-week, randomized, dose-finding, crossover trial and a 52-week, open-label, extension study. There was no placebo comparator. Instead, researchers used three different sets of historical control data.

Investigators will continue to treat and follow the extension study cohort, and plan to launch a placebo-controlled study in 2017, said Dr. Macfarlane, Head of Clinical Governance for the Dementia Centre in Melbourne.

The five-week, randomized, dose-finding, crossover trial started one group of patients on 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial two-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days. This trial was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last six months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.

An Attractive Drug Target

The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the CNS. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.

The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins—a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

In preclinical testing, ANAVEX 2-73 seemed to enhance cognition in wild-type and Alzheimer’s disease–model mice.

The mean age of patients in the extension study was 71. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of an acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable.

The primary end points were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.

The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By the study’s end, it had decreased to a mean of 1 point. Patients also reported improvements in their ability to work or do other activities, and in anxiety, agitation, hypochondriasis, and insight.

Electrophysiologic Measures

The P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter, it steadily improved to about 8 microvolts by 57 weeks—a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s disease cohort, which decreased to about 4 microvolts over a 52-week period while patients were taking donepezil.

Researchers used a second historical control group to assess changes on the Computerized Cogstate Alzheimer’s Battery. All subjects in a large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to improve.

At 57 weeks, patients’ mean MMSE score was near the baseline mean score of 20. ADCS-ADL scores declined slightly, from a mean of about 70 to approximately 65.

Finally, the investigators used another historical cohort to assess projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point benefit on the MMSE and a 4-point benefit on the ADCS-ADL.

“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”

Nearly all patients (98%) experienced an adverse event. Most events were mild, transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out of the trial because of adverse events (ie, delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care Alzheimer’s disease medications.

—Michelle G. Sullivan

SAN DIEGO—A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s disease who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test, an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

ANAVEX 2-73 (Anavex Life Sciences, New York) also conferred an unexpected benefit upon subjects with insomnia. “Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane, MBBS, said at the Clinical Trials on Alzheimer’s Disease conference.

The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional end points were secondary. It comprised 32 patients at baseline, 25 of whom completed both a five-week, randomized, dose-finding, crossover trial and a 52-week, open-label, extension study. There was no placebo comparator. Instead, researchers used three different sets of historical control data.

Investigators will continue to treat and follow the extension study cohort, and plan to launch a placebo-controlled study in 2017, said Dr. Macfarlane, Head of Clinical Governance for the Dementia Centre in Melbourne.

The five-week, randomized, dose-finding, crossover trial started one group of patients on 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial two-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days. This trial was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last six months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.

An Attractive Drug Target

The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the CNS. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.

The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins—a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

In preclinical testing, ANAVEX 2-73 seemed to enhance cognition in wild-type and Alzheimer’s disease–model mice.

The mean age of patients in the extension study was 71. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of an acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable.

The primary end points were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.

The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By the study’s end, it had decreased to a mean of 1 point. Patients also reported improvements in their ability to work or do other activities, and in anxiety, agitation, hypochondriasis, and insight.

Electrophysiologic Measures

The P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter, it steadily improved to about 8 microvolts by 57 weeks—a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s disease cohort, which decreased to about 4 microvolts over a 52-week period while patients were taking donepezil.

Researchers used a second historical control group to assess changes on the Computerized Cogstate Alzheimer’s Battery. All subjects in a large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to improve.

At 57 weeks, patients’ mean MMSE score was near the baseline mean score of 20. ADCS-ADL scores declined slightly, from a mean of about 70 to approximately 65.

Finally, the investigators used another historical cohort to assess projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point benefit on the MMSE and a 4-point benefit on the ADCS-ADL.

“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”

Nearly all patients (98%) experienced an adverse event. Most events were mild, transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out of the trial because of adverse events (ie, delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care Alzheimer’s disease medications.

—Michelle G. Sullivan

In 2012, 29.1 million Americans, or 9.3% of the population, had diabetes. Of this number, 21 million were diagnosed, and 8.1 million were undiagnosed. Each year almost 1.5 million Americans receive a new diagnosis of diabetes. The management of diabetes relies upon excellent primary care. Each year the American Diabetes Association reviews new evidence and publishes an updated Standards of Care in the January issue of Diabetes Care. Here we give a short overview of the guidelines with emphasis on fundamentals and changes in the standards over the past year.

Self-management education and support, nutrition therapy, and physical activity

All patients should participate in ongoing diabetes self-management education (DSME) to facilitate the knowledge, skills, and abilities necessary to obtain optimal self-care and incorporate the needs, goals, and life experiences of the person with diabetes as they face new challenges throughout a lifetime of diabetes.

In addition, each patient should receive individualized medical nutrition therapy (MNT) provided by a registered dietitian with knowledge regarding diabetes-specific MNT. Most patients should increase aerobic physical activity to 150 min/week. Providers should encourage patients to reduce the amount of time spent sedentary by briefly standing, walking, or performing other light physical activities every 30 minutes.
 

Glycemic targets

A reasonable hemoglobin A_1c goal for many diabetic nonpregnant adults is less than 7%. A less stringent goal under 8% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular and macrovascular complications, and extensive comorbid conditions. HbA_1c measurements should be done at diagnosis and routinely to monitor glycemic control. To aid in achieving glycemic targets, self-monitoring blood glucose (SMBG) allows patients to evaluate their individual response to therapy. Integrating SMBG data into diabetes management can help guide MNT, adjust medications, determine physical activity requirements, and prevent hypoglycemia. Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter and counseled regarding treatment of hypoglycemic events.

Obesity management

There is strong and consistent evidence that obesity management may be beneficial in the treatment of type 2 diabetes. For overweight and obese patients with type 2 diabetes, interventions should be high intensity (more than 16 sessions in 6 months) and focus on diet, physical activity, and behavioral therapy designed to achieve a greater than 5% weight loss (energy deficit of 500-750 kcal/day).

For select patients, weight loss medications may be effective as adjuncts to lifestyle changes. When choosing additional pharmacologic interventions to improve glycemic control in overweight or obese patients, providers should use medications that promote weight loss or are weight neutral including metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 inhibitors (DPP-4) versus those that cause weight gain such as insulin secretagogues, thiazolidinediones, and insulin.

Metabolic surgery should be recommended to patients with type 2 diabetes and body mass index above 40 kg/m² (BMI above 37.5 kg/m² in Asian Americans), regardless of adequate glycemic control and for patients with BMI above 35 kg/m² (more than 32.5 kg/m² in Asian Americans) without adequate glycemic control despite lifestyle modifications and optimal medical therapy. Metabolic surgery should be considered for appropriate candidates with BMIs as low as 30 if hyperglycemia is inadequately controlled despite optical medical control by either oral or injectable medications.
 

CV disease and risk management: BP, lipids, antiplatelet therapy, and glycemic medication management

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for individuals with diabetes. Screening for atherosclerotic cardiovascular disease is not recommended; rather, the emphasis is on careful risk factor management.

If systolic blood pressure (SBP) is confirmed to be above 140 mm Hg and/or the diastolic blood pressure (DBP) is confirmed to be above 90 mm Hg, pharmacologic therapy should be initiated. A meta-analysis of randomized trials of adults with type 2 diabetes comparing intensive blood pressure targets (upper limit of 130 mm Hg SBP and 80 mm Hg DBP) with standard targets (upper limit of 140-160 mm Hg SBP and 85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MI. There was a statistically significant, 35% relative risk (RR) reduction in stroke with intensive targets, but intensive targets were associated with an increased risk for adverse events such as hypotension and syncope. Recommendations suggest that antihypertension treatment in adults with diabetes without albuminuria should include any of the classes of medication demonstrated to reduce cardiovascular events in patients with diabetes, such as ACE inhibitors, angiotensin receptor blockers (ARBs), thiazide-like diuretics, or dihydropyridine calcium-channel blockers. ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and elevated urine albumin/creatinine ratios (above 30 mg/g creatinine). The standards also suggest consideration of administering one or more antihypertensive medications at bedtime, which may improve cardiovascular outcomes.

For patients aged 40-75 years who have diabetes without additional atherosclerotic CV disease risk factors, a moderate-intensity statin should be considered. If there are additional cardiovascular risk factors, then a high-intensity statin should be considered. For patients who are younger than 40 years of age and have diabetes with additional atherosclerotic CV disease risk factors, a less strong recommendation is to consider using moderate-intensity or high-intensity statins. For patients older than 75 years with diabetes without additional atherosclerotic CV disease risk factors, consider using moderate-intensity statin therapy; high-intensity statin therapy may be considered in older adults with risk factors for atherosclerotic cardiovascular disease.

Both women and men who are at least 50 years old and have diabetes with at least one additional cardiovascular risk factor should consider taking daily aspirin therapy (75-162 mg/day) if they do not have any risk for excessive bleeding.

In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic CV disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

Microvascular disease and foot care

Large prospective studies have demonstrated that optimized glucose control can reduce the onset and progression of diabetic microvascular complications. Diabetic kidney disease occurs in about 20%-40% of persons with diabetes. Annual screening includes estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio. Treatment includes ACE inhibitors or ARBs in addition to a target blood pressure of under 140/90 mm Hg.

Diabetic retinopathy screening includes a dilated eye exam by an eye care professional. Treatment includes laser photocoagulation therapy for high risk nonproliferative retinopathy or proliferative retinopathy, or intravitreal injections of antivascular endothelial growth factor agents for central-involved diabetic macular edema.

Diabetic peripheral neuropathy screening includes annual 10-g monofilament and 128-HZ tuning fork vibration sensation. Medications for painful diabetic neuropathy may include gabapentin, pregabalin, duloxetine, and other agents.

Neuropathy and vascular disease are contributors to diabetic foot ulcers and amputation. A comprehensive foot examination along with appropriate risk factor oriented history to include neuropathic and vascular components (pulses, claudication) should be performed annually, while all patients with diabetes should have their feet checked at every visit.
 

Older adults

Prioritizing treatment goals in older adults is important in this heterogeneous population. Cardiovascular risk factor treatment is likely to be beneficial.

In setting HbA_1c goals, functional status, and comorbid conditions should be considered. Metformin can still be a first-line agent for many older adults with type 2 diabetes, with consideration to renal status (creatinine clearance above 30 mL/min per 1.73 m²) and heart failure. DPP-4s have few side effects and low risk of hypoglycemia. GLP-1 receptor agonists have a low risk of hypoglycemia but may be associated with GI side effects and weight loss. SGLT-2 inhibitors have a low risk of hypoglycemia, and attention should be paid to renal thresholds for use. Thiazolidinediones should be used cautiously in those with heart failure or at elevated fracture risk. Sulfonylureas should be used cautiously because of their elevated risk of hypoglycemia. When used, a short-acting sulfonylurea – such as glipizide – is preferred, as long-acting sulfonylureas are contraindicated because of even greater hypoglycemic risk. Single-injection basal insulin may be appropriate for many with ease of use and efficacy.
 

The bottom line

Diabetes is a rapidly changing field and each year the American Diabetes Association updates the Standards of Medical Care document to be consistent with the latest evidence. Highlights of the standards include emphasis on diabetes self-management education, individualized glycemic goal setting, obesity management, setting blood pressure targets to less than 140/90 mm Hg, as well as statins and daily aspirin for most people with diabetes. In addition, ADA now recommends the use of specific antihyperglycemic medications to reduce cardiovascular and all-cause mortality in patients with diabetes and established cardiovascular disease.

Reference

American Diabetes Association Standards of Medical Care in Diabetes – 2017. Diabetes Care 2017; 40 (sup 1):S1-S138

Dr. Skolnik is professor of family and community medicine, Temple University School of Medicine, Philadelphia, and associate director, Family Medicine Residency Program, Abington-Jefferson Health, Abington, Pa. Dr. Johnson is associate professor at the University of North Dakota School of Medicine and Health Sciences, and practices at the Altru Diabetes Center, Grand Forks. Ms. Neuman practices at St. Mark’s Hospital, Salt Lake City.

In 2012, 29.1 million Americans, or 9.3% of the population, had diabetes. Of this number, 21 million were diagnosed, and 8.1 million were undiagnosed. Each year almost 1.5 million Americans receive a new diagnosis of diabetes. The management of diabetes relies upon excellent primary care. Each year the American Diabetes Association reviews new evidence and publishes an updated Standards of Care in the January issue of Diabetes Care. Here we give a short overview of the guidelines with emphasis on fundamentals and changes in the standards over the past year.

Self-management education and support, nutrition therapy, and physical activity

All patients should participate in ongoing diabetes self-management education (DSME) to facilitate the knowledge, skills, and abilities necessary to obtain optimal self-care and incorporate the needs, goals, and life experiences of the person with diabetes as they face new challenges throughout a lifetime of diabetes.

In addition, each patient should receive individualized medical nutrition therapy (MNT) provided by a registered dietitian with knowledge regarding diabetes-specific MNT. Most patients should increase aerobic physical activity to 150 min/week. Providers should encourage patients to reduce the amount of time spent sedentary by briefly standing, walking, or performing other light physical activities every 30 minutes.
 

Glycemic targets

A reasonable hemoglobin A_1c goal for many diabetic nonpregnant adults is less than 7%. A less stringent goal under 8% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular and macrovascular complications, and extensive comorbid conditions. HbA_1c measurements should be done at diagnosis and routinely to monitor glycemic control. To aid in achieving glycemic targets, self-monitoring blood glucose (SMBG) allows patients to evaluate their individual response to therapy. Integrating SMBG data into diabetes management can help guide MNT, adjust medications, determine physical activity requirements, and prevent hypoglycemia. Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter and counseled regarding treatment of hypoglycemic events.

Obesity management

There is strong and consistent evidence that obesity management may be beneficial in the treatment of type 2 diabetes. For overweight and obese patients with type 2 diabetes, interventions should be high intensity (more than 16 sessions in 6 months) and focus on diet, physical activity, and behavioral therapy designed to achieve a greater than 5% weight loss (energy deficit of 500-750 kcal/day).

For select patients, weight loss medications may be effective as adjuncts to lifestyle changes. When choosing additional pharmacologic interventions to improve glycemic control in overweight or obese patients, providers should use medications that promote weight loss or are weight neutral including metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 inhibitors (DPP-4) versus those that cause weight gain such as insulin secretagogues, thiazolidinediones, and insulin.

Metabolic surgery should be recommended to patients with type 2 diabetes and body mass index above 40 kg/m² (BMI above 37.5 kg/m² in Asian Americans), regardless of adequate glycemic control and for patients with BMI above 35 kg/m² (more than 32.5 kg/m² in Asian Americans) without adequate glycemic control despite lifestyle modifications and optimal medical therapy. Metabolic surgery should be considered for appropriate candidates with BMIs as low as 30 if hyperglycemia is inadequately controlled despite optical medical control by either oral or injectable medications.
 

CV disease and risk management: BP, lipids, antiplatelet therapy, and glycemic medication management

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for individuals with diabetes. Screening for atherosclerotic cardiovascular disease is not recommended; rather, the emphasis is on careful risk factor management.

If systolic blood pressure (SBP) is confirmed to be above 140 mm Hg and/or the diastolic blood pressure (DBP) is confirmed to be above 90 mm Hg, pharmacologic therapy should be initiated. A meta-analysis of randomized trials of adults with type 2 diabetes comparing intensive blood pressure targets (upper limit of 130 mm Hg SBP and 80 mm Hg DBP) with standard targets (upper limit of 140-160 mm Hg SBP and 85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MI. There was a statistically significant, 35% relative risk (RR) reduction in stroke with intensive targets, but intensive targets were associated with an increased risk for adverse events such as hypotension and syncope. Recommendations suggest that antihypertension treatment in adults with diabetes without albuminuria should include any of the classes of medication demonstrated to reduce cardiovascular events in patients with diabetes, such as ACE inhibitors, angiotensin receptor blockers (ARBs), thiazide-like diuretics, or dihydropyridine calcium-channel blockers. ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and elevated urine albumin/creatinine ratios (above 30 mg/g creatinine). The standards also suggest consideration of administering one or more antihypertensive medications at bedtime, which may improve cardiovascular outcomes.

For patients aged 40-75 years who have diabetes without additional atherosclerotic CV disease risk factors, a moderate-intensity statin should be considered. If there are additional cardiovascular risk factors, then a high-intensity statin should be considered. For patients who are younger than 40 years of age and have diabetes with additional atherosclerotic CV disease risk factors, a less strong recommendation is to consider using moderate-intensity or high-intensity statins. For patients older than 75 years with diabetes without additional atherosclerotic CV disease risk factors, consider using moderate-intensity statin therapy; high-intensity statin therapy may be considered in older adults with risk factors for atherosclerotic cardiovascular disease.

Both women and men who are at least 50 years old and have diabetes with at least one additional cardiovascular risk factor should consider taking daily aspirin therapy (75-162 mg/day) if they do not have any risk for excessive bleeding.

In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic CV disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

Microvascular disease and foot care

Large prospective studies have demonstrated that optimized glucose control can reduce the onset and progression of diabetic microvascular complications. Diabetic kidney disease occurs in about 20%-40% of persons with diabetes. Annual screening includes estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio. Treatment includes ACE inhibitors or ARBs in addition to a target blood pressure of under 140/90 mm Hg.

Diabetic retinopathy screening includes a dilated eye exam by an eye care professional. Treatment includes laser photocoagulation therapy for high risk nonproliferative retinopathy or proliferative retinopathy, or intravitreal injections of antivascular endothelial growth factor agents for central-involved diabetic macular edema.

Diabetic peripheral neuropathy screening includes annual 10-g monofilament and 128-HZ tuning fork vibration sensation. Medications for painful diabetic neuropathy may include gabapentin, pregabalin, duloxetine, and other agents.

Neuropathy and vascular disease are contributors to diabetic foot ulcers and amputation. A comprehensive foot examination along with appropriate risk factor oriented history to include neuropathic and vascular components (pulses, claudication) should be performed annually, while all patients with diabetes should have their feet checked at every visit.
 

Older adults

Prioritizing treatment goals in older adults is important in this heterogeneous population. Cardiovascular risk factor treatment is likely to be beneficial.

In setting HbA_1c goals, functional status, and comorbid conditions should be considered. Metformin can still be a first-line agent for many older adults with type 2 diabetes, with consideration to renal status (creatinine clearance above 30 mL/min per 1.73 m²) and heart failure. DPP-4s have few side effects and low risk of hypoglycemia. GLP-1 receptor agonists have a low risk of hypoglycemia but may be associated with GI side effects and weight loss. SGLT-2 inhibitors have a low risk of hypoglycemia, and attention should be paid to renal thresholds for use. Thiazolidinediones should be used cautiously in those with heart failure or at elevated fracture risk. Sulfonylureas should be used cautiously because of their elevated risk of hypoglycemia. When used, a short-acting sulfonylurea – such as glipizide – is preferred, as long-acting sulfonylureas are contraindicated because of even greater hypoglycemic risk. Single-injection basal insulin may be appropriate for many with ease of use and efficacy.
 

The bottom line

Diabetes is a rapidly changing field and each year the American Diabetes Association updates the Standards of Medical Care document to be consistent with the latest evidence. Highlights of the standards include emphasis on diabetes self-management education, individualized glycemic goal setting, obesity management, setting blood pressure targets to less than 140/90 mm Hg, as well as statins and daily aspirin for most people with diabetes. In addition, ADA now recommends the use of specific antihyperglycemic medications to reduce cardiovascular and all-cause mortality in patients with diabetes and established cardiovascular disease.

Reference

American Diabetes Association Standards of Medical Care in Diabetes – 2017. Diabetes Care 2017; 40 (sup 1):S1-S138

Dr. Skolnik is professor of family and community medicine, Temple University School of Medicine, Philadelphia, and associate director, Family Medicine Residency Program, Abington-Jefferson Health, Abington, Pa. Dr. Johnson is associate professor at the University of North Dakota School of Medicine and Health Sciences, and practices at the Altru Diabetes Center, Grand Forks. Ms. Neuman practices at St. Mark’s Hospital, Salt Lake City.

In 2012, 29.1 million Americans, or 9.3% of the population, had diabetes. Of this number, 21 million were diagnosed, and 8.1 million were undiagnosed. Each year almost 1.5 million Americans receive a new diagnosis of diabetes. The management of diabetes relies upon excellent primary care. Each year the American Diabetes Association reviews new evidence and publishes an updated Standards of Care in the January issue of Diabetes Care. Here we give a short overview of the guidelines with emphasis on fundamentals and changes in the standards over the past year.

Self-management education and support, nutrition therapy, and physical activity

All patients should participate in ongoing diabetes self-management education (DSME) to facilitate the knowledge, skills, and abilities necessary to obtain optimal self-care and incorporate the needs, goals, and life experiences of the person with diabetes as they face new challenges throughout a lifetime of diabetes.

In addition, each patient should receive individualized medical nutrition therapy (MNT) provided by a registered dietitian with knowledge regarding diabetes-specific MNT. Most patients should increase aerobic physical activity to 150 min/week. Providers should encourage patients to reduce the amount of time spent sedentary by briefly standing, walking, or performing other light physical activities every 30 minutes.
 

Glycemic targets

A reasonable hemoglobin A_1c goal for many diabetic nonpregnant adults is less than 7%. A less stringent goal under 8% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular and macrovascular complications, and extensive comorbid conditions. HbA_1c measurements should be done at diagnosis and routinely to monitor glycemic control. To aid in achieving glycemic targets, self-monitoring blood glucose (SMBG) allows patients to evaluate their individual response to therapy. Integrating SMBG data into diabetes management can help guide MNT, adjust medications, determine physical activity requirements, and prevent hypoglycemia. Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter and counseled regarding treatment of hypoglycemic events.

Obesity management

There is strong and consistent evidence that obesity management may be beneficial in the treatment of type 2 diabetes. For overweight and obese patients with type 2 diabetes, interventions should be high intensity (more than 16 sessions in 6 months) and focus on diet, physical activity, and behavioral therapy designed to achieve a greater than 5% weight loss (energy deficit of 500-750 kcal/day).

For select patients, weight loss medications may be effective as adjuncts to lifestyle changes. When choosing additional pharmacologic interventions to improve glycemic control in overweight or obese patients, providers should use medications that promote weight loss or are weight neutral including metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 inhibitors (DPP-4) versus those that cause weight gain such as insulin secretagogues, thiazolidinediones, and insulin.

Metabolic surgery should be recommended to patients with type 2 diabetes and body mass index above 40 kg/m² (BMI above 37.5 kg/m² in Asian Americans), regardless of adequate glycemic control and for patients with BMI above 35 kg/m² (more than 32.5 kg/m² in Asian Americans) without adequate glycemic control despite lifestyle modifications and optimal medical therapy. Metabolic surgery should be considered for appropriate candidates with BMIs as low as 30 if hyperglycemia is inadequately controlled despite optical medical control by either oral or injectable medications.
 

CV disease and risk management: BP, lipids, antiplatelet therapy, and glycemic medication management

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for individuals with diabetes. Screening for atherosclerotic cardiovascular disease is not recommended; rather, the emphasis is on careful risk factor management.

If systolic blood pressure (SBP) is confirmed to be above 140 mm Hg and/or the diastolic blood pressure (DBP) is confirmed to be above 90 mm Hg, pharmacologic therapy should be initiated. A meta-analysis of randomized trials of adults with type 2 diabetes comparing intensive blood pressure targets (upper limit of 130 mm Hg SBP and 80 mm Hg DBP) with standard targets (upper limit of 140-160 mm Hg SBP and 85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MI. There was a statistically significant, 35% relative risk (RR) reduction in stroke with intensive targets, but intensive targets were associated with an increased risk for adverse events such as hypotension and syncope. Recommendations suggest that antihypertension treatment in adults with diabetes without albuminuria should include any of the classes of medication demonstrated to reduce cardiovascular events in patients with diabetes, such as ACE inhibitors, angiotensin receptor blockers (ARBs), thiazide-like diuretics, or dihydropyridine calcium-channel blockers. ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and elevated urine albumin/creatinine ratios (above 30 mg/g creatinine). The standards also suggest consideration of administering one or more antihypertensive medications at bedtime, which may improve cardiovascular outcomes.

For patients aged 40-75 years who have diabetes without additional atherosclerotic CV disease risk factors, a moderate-intensity statin should be considered. If there are additional cardiovascular risk factors, then a high-intensity statin should be considered. For patients who are younger than 40 years of age and have diabetes with additional atherosclerotic CV disease risk factors, a less strong recommendation is to consider using moderate-intensity or high-intensity statins. For patients older than 75 years with diabetes without additional atherosclerotic CV disease risk factors, consider using moderate-intensity statin therapy; high-intensity statin therapy may be considered in older adults with risk factors for atherosclerotic cardiovascular disease.

Both women and men who are at least 50 years old and have diabetes with at least one additional cardiovascular risk factor should consider taking daily aspirin therapy (75-162 mg/day) if they do not have any risk for excessive bleeding.

In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic CV disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

Microvascular disease and foot care

Large prospective studies have demonstrated that optimized glucose control can reduce the onset and progression of diabetic microvascular complications. Diabetic kidney disease occurs in about 20%-40% of persons with diabetes. Annual screening includes estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio. Treatment includes ACE inhibitors or ARBs in addition to a target blood pressure of under 140/90 mm Hg.

Diabetic retinopathy screening includes a dilated eye exam by an eye care professional. Treatment includes laser photocoagulation therapy for high risk nonproliferative retinopathy or proliferative retinopathy, or intravitreal injections of antivascular endothelial growth factor agents for central-involved diabetic macular edema.

Diabetic peripheral neuropathy screening includes annual 10-g monofilament and 128-HZ tuning fork vibration sensation. Medications for painful diabetic neuropathy may include gabapentin, pregabalin, duloxetine, and other agents.

Neuropathy and vascular disease are contributors to diabetic foot ulcers and amputation. A comprehensive foot examination along with appropriate risk factor oriented history to include neuropathic and vascular components (pulses, claudication) should be performed annually, while all patients with diabetes should have their feet checked at every visit.
 

Older adults

Prioritizing treatment goals in older adults is important in this heterogeneous population. Cardiovascular risk factor treatment is likely to be beneficial.

In setting HbA_1c goals, functional status, and comorbid conditions should be considered. Metformin can still be a first-line agent for many older adults with type 2 diabetes, with consideration to renal status (creatinine clearance above 30 mL/min per 1.73 m²) and heart failure. DPP-4s have few side effects and low risk of hypoglycemia. GLP-1 receptor agonists have a low risk of hypoglycemia but may be associated with GI side effects and weight loss. SGLT-2 inhibitors have a low risk of hypoglycemia, and attention should be paid to renal thresholds for use. Thiazolidinediones should be used cautiously in those with heart failure or at elevated fracture risk. Sulfonylureas should be used cautiously because of their elevated risk of hypoglycemia. When used, a short-acting sulfonylurea – such as glipizide – is preferred, as long-acting sulfonylureas are contraindicated because of even greater hypoglycemic risk. Single-injection basal insulin may be appropriate for many with ease of use and efficacy.
 

The bottom line

Diabetes is a rapidly changing field and each year the American Diabetes Association updates the Standards of Medical Care document to be consistent with the latest evidence. Highlights of the standards include emphasis on diabetes self-management education, individualized glycemic goal setting, obesity management, setting blood pressure targets to less than 140/90 mm Hg, as well as statins and daily aspirin for most people with diabetes. In addition, ADA now recommends the use of specific antihyperglycemic medications to reduce cardiovascular and all-cause mortality in patients with diabetes and established cardiovascular disease.

Reference

American Diabetes Association Standards of Medical Care in Diabetes – 2017. Diabetes Care 2017; 40 (sup 1):S1-S138

Dr. Skolnik is professor of family and community medicine, Temple University School of Medicine, Philadelphia, and associate director, Family Medicine Residency Program, Abington-Jefferson Health, Abington, Pa. Dr. Johnson is associate professor at the University of North Dakota School of Medicine and Health Sciences, and practices at the Altru Diabetes Center, Grand Forks. Ms. Neuman practices at St. Mark’s Hospital, Salt Lake City.