Diabetes

In his Guest Editorial “How to help patients become successful diabetes self-managers” (J Fam Pract. 2020;69:8-9), Dr. Unger makes several very good points. I especially liked his recommendation to ask patients why they are concerned about having diabetes; this question alone can kick-start the behavior modification process leading to improved diabetes control.

I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.”

However, I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.” Based on multiple case studies, clinical trials, results from lifestyle intervention programs, and my own experience as a family physician, it is clear that diabetes can be reversed with lifestyle changes designed to counteract the modifiable factors (eg, diet, lack of exercise) that usually cause this condition.

Rather than merely considering the diabetes measure of success to be blood glucose controlled by prescribed medication, it is important to offer a more collaborative approach to patients willing to make lifestyle changes. We can show many—if not most— that they can achieve the goal of blood glucose control without medication.

Allan Olson MD
Diplomate, American Board of Family Medicine and American Board of Lifestyle Medicine
Kewaunee, WI

In his Guest Editorial “How to help patients become successful diabetes self-managers” (J Fam Pract. 2020;69:8-9), Dr. Unger makes several very good points. I especially liked his recommendation to ask patients why they are concerned about having diabetes; this question alone can kick-start the behavior modification process leading to improved diabetes control.

I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.”

However, I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.” Based on multiple case studies, clinical trials, results from lifestyle intervention programs, and my own experience as a family physician, it is clear that diabetes can be reversed with lifestyle changes designed to counteract the modifiable factors (eg, diet, lack of exercise) that usually cause this condition.

Rather than merely considering the diabetes measure of success to be blood glucose controlled by prescribed medication, it is important to offer a more collaborative approach to patients willing to make lifestyle changes. We can show many—if not most— that they can achieve the goal of blood glucose control without medication.

Allan Olson MD
Diplomate, American Board of Family Medicine and American Board of Lifestyle Medicine
Kewaunee, WI

In his Guest Editorial “How to help patients become successful diabetes self-managers” (J Fam Pract. 2020;69:8-9), Dr. Unger makes several very good points. I especially liked his recommendation to ask patients why they are concerned about having diabetes; this question alone can kick-start the behavior modification process leading to improved diabetes control.

I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.”

However, I disagree with Dr. Unger’s assertion that “diabetes cannot be cured.” Based on multiple case studies, clinical trials, results from lifestyle intervention programs, and my own experience as a family physician, it is clear that diabetes can be reversed with lifestyle changes designed to counteract the modifiable factors (eg, diet, lack of exercise) that usually cause this condition.

Rather than merely considering the diabetes measure of success to be blood glucose controlled by prescribed medication, it is important to offer a more collaborative approach to patients willing to make lifestyle changes. We can show many—if not most— that they can achieve the goal of blood glucose control without medication.

Allan Olson MD
Diplomate, American Board of Family Medicine and American Board of Lifestyle Medicine
Kewaunee, WI

Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.

“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.

The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.

The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.

“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .

The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.

“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”

“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).

Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m².

“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.

Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.

The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.

Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”

Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.

[email protected]

Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.

“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.

The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.

The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.

“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .

The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.

“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”

“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).

Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m².

“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.

Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.

The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.

Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”

Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.

[email protected]

Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.

“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.

The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.

The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.

“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .

The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.

“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”

“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).

Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m².

“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.

Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.

The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.

Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”

Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.

[email protected]

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected].

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected].

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected].

Loss of meibomian glands in the eye, which contribute to producing tears, appears to be associated with high rates of dry eye in individuals with diabetes and may serve as a biomarker for suboptimal glycemic control, new research suggests.

Gloria Wu, MD, an ophthalmologist at the University of California, San Francisco, presented the findings from a small study using infrared imaging of the eyelids in 120 patients with dry eye during a virtual press briefing held March 30, originally scheduled for the ENDO 2020 meeting.

The meibomian glands are the vertical striations that line the margins of the lower eyelids. They produce the lipid that combines with aqueous fluid from the lacrimal gland to create the tear film. Absence of meibomian glands can lead to dry eyes, eye pain, discomfort, and blurred vision.

Dry eye affects about 7% of the U.S. population, compared with 57% of people with type 1 diabetes and 70% with type 2 diabetes. Two proposed mechanisms for the phenomenon in diabetes are microischemia and inflammation, Dr. Wu said.

In her study, loss of meibomian glands was far more common among the 60 participants with dry eye and diabetes than among the 60 participants with dry eye but without diabetes, and the amount of gland loss was directly linked to A_1c level.

The findings suggest that loss of meibomian glands could serve as a diabetes biomarker, particularly in underserved areas where A_1c testing might not be readily available.

Dr. Wu noted many newer smartphones, including the Samsung Galaxy 10S and iPhone 10, Xs, and 11, have infrared cameras that could help characterize dry eye in patients with diabetes.

“In the future, we hope patients can use [smartphones] and flip their own eyelids and take a picture. We hope that in rural health clinics and community health centers we can use this device that people have ... When people complain of dry eye and they have diabetes we can consider [closer diabetes monitoring],” said Dr. Wu.

Asked to comment, endocrinologist David C. Lieb, MD, said in an interview: “It’s important for providers who care for people with diabetes to know that diabetes is associated with a high incidence of meibomian gland dysfunction leading to dry eye. That’s another reason people with diabetes need to make sure they see their eye care specialist on a regular basis.

“When I ask patients if they’ve seen their eye specialist I may add dry eye to my list of questions rather than just asking them when was the last time they went,” added Dr. Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk.

“I may ask them if they have symptoms of dry eye, and if they do, it’s something they need to talk about with that individual.”
 

Gland disappearance correlated with glycemic control

Dr. Wu and colleagues retrospectively reviewed electronic health records for 120 patients diagnosed with dry eye: 60 patients with and 60 patients without type 2 diabetes.

Those with diabetes were a mean age of 65 years, and were split evenly between men and women. The controls were younger, averaging 54 years, and comprised 37 men and 23 women.

Researchers performed infrared imaging (820 nm) of the lid; percentage loss of meibomian glands was calculated for each eye, then averaged per patient.

They found that 51.5% of patients in the diabetes group had lost meibomian glands, compared with just 11.3% of controls, a highly significant difference (P = .0001).

When A_1c was also assessed, only 4 of 60 participants with A_1c ≤ 5.9% lost ≥ 25% of the glands, compared with 55 of 60 participants with A_1c ≥ 6.0%.

And specifically among those with diabetes, 35 of 37 with A_1c > 6.6% lost > 40% of the glands, compared with just 12 of 23 participants with A_1c < 6.5% (all P < .0001).

“In patients with dry eye and diabetes, loss of meibomian glands is associated with elevated A_1c ... [and] may suggest a need for ... further monitoring of the patient’s diabetic condition,” the researchers noted.

Asked whether the glands could re-grow with improved glycemic control, Dr. Wu said she has not looked at that in people with diabetes, but in some patients who receive intensive treatment for dry eye with artificial tears or cyclosporine, the glands do grow back after about 6 months.

Dr. Lieb said he found the smartphone diagnostic idea “fascinating, especially in an area where you might not be able to easily measure an A_1c. Most people have access to point-of-care A_1c testing but not everybody can make it to a doctor’s office.”

And, he added, “anything that’s noninvasive has some potential benefit.”

Dr. Wu and Dr. Lieb have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Loss of meibomian glands in the eye, which contribute to producing tears, appears to be associated with high rates of dry eye in individuals with diabetes and may serve as a biomarker for suboptimal glycemic control, new research suggests.

Gloria Wu, MD, an ophthalmologist at the University of California, San Francisco, presented the findings from a small study using infrared imaging of the eyelids in 120 patients with dry eye during a virtual press briefing held March 30, originally scheduled for the ENDO 2020 meeting.

The meibomian glands are the vertical striations that line the margins of the lower eyelids. They produce the lipid that combines with aqueous fluid from the lacrimal gland to create the tear film. Absence of meibomian glands can lead to dry eyes, eye pain, discomfort, and blurred vision.

Dry eye affects about 7% of the U.S. population, compared with 57% of people with type 1 diabetes and 70% with type 2 diabetes. Two proposed mechanisms for the phenomenon in diabetes are microischemia and inflammation, Dr. Wu said.

In her study, loss of meibomian glands was far more common among the 60 participants with dry eye and diabetes than among the 60 participants with dry eye but without diabetes, and the amount of gland loss was directly linked to A_1c level.

The findings suggest that loss of meibomian glands could serve as a diabetes biomarker, particularly in underserved areas where A_1c testing might not be readily available.

Dr. Wu noted many newer smartphones, including the Samsung Galaxy 10S and iPhone 10, Xs, and 11, have infrared cameras that could help characterize dry eye in patients with diabetes.

“In the future, we hope patients can use [smartphones] and flip their own eyelids and take a picture. We hope that in rural health clinics and community health centers we can use this device that people have ... When people complain of dry eye and they have diabetes we can consider [closer diabetes monitoring],” said Dr. Wu.

Asked to comment, endocrinologist David C. Lieb, MD, said in an interview: “It’s important for providers who care for people with diabetes to know that diabetes is associated with a high incidence of meibomian gland dysfunction leading to dry eye. That’s another reason people with diabetes need to make sure they see their eye care specialist on a regular basis.

“When I ask patients if they’ve seen their eye specialist I may add dry eye to my list of questions rather than just asking them when was the last time they went,” added Dr. Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk.

“I may ask them if they have symptoms of dry eye, and if they do, it’s something they need to talk about with that individual.”
 

Gland disappearance correlated with glycemic control

Dr. Wu and colleagues retrospectively reviewed electronic health records for 120 patients diagnosed with dry eye: 60 patients with and 60 patients without type 2 diabetes.

Those with diabetes were a mean age of 65 years, and were split evenly between men and women. The controls were younger, averaging 54 years, and comprised 37 men and 23 women.

Researchers performed infrared imaging (820 nm) of the lid; percentage loss of meibomian glands was calculated for each eye, then averaged per patient.

They found that 51.5% of patients in the diabetes group had lost meibomian glands, compared with just 11.3% of controls, a highly significant difference (P = .0001).

When A_1c was also assessed, only 4 of 60 participants with A_1c ≤ 5.9% lost ≥ 25% of the glands, compared with 55 of 60 participants with A_1c ≥ 6.0%.

And specifically among those with diabetes, 35 of 37 with A_1c > 6.6% lost > 40% of the glands, compared with just 12 of 23 participants with A_1c < 6.5% (all P < .0001).

“In patients with dry eye and diabetes, loss of meibomian glands is associated with elevated A_1c ... [and] may suggest a need for ... further monitoring of the patient’s diabetic condition,” the researchers noted.

Asked whether the glands could re-grow with improved glycemic control, Dr. Wu said she has not looked at that in people with diabetes, but in some patients who receive intensive treatment for dry eye with artificial tears or cyclosporine, the glands do grow back after about 6 months.

Dr. Lieb said he found the smartphone diagnostic idea “fascinating, especially in an area where you might not be able to easily measure an A_1c. Most people have access to point-of-care A_1c testing but not everybody can make it to a doctor’s office.”

And, he added, “anything that’s noninvasive has some potential benefit.”

Dr. Wu and Dr. Lieb have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Loss of meibomian glands in the eye, which contribute to producing tears, appears to be associated with high rates of dry eye in individuals with diabetes and may serve as a biomarker for suboptimal glycemic control, new research suggests.

Gloria Wu, MD, an ophthalmologist at the University of California, San Francisco, presented the findings from a small study using infrared imaging of the eyelids in 120 patients with dry eye during a virtual press briefing held March 30, originally scheduled for the ENDO 2020 meeting.

The meibomian glands are the vertical striations that line the margins of the lower eyelids. They produce the lipid that combines with aqueous fluid from the lacrimal gland to create the tear film. Absence of meibomian glands can lead to dry eyes, eye pain, discomfort, and blurred vision.

Dry eye affects about 7% of the U.S. population, compared with 57% of people with type 1 diabetes and 70% with type 2 diabetes. Two proposed mechanisms for the phenomenon in diabetes are microischemia and inflammation, Dr. Wu said.

In her study, loss of meibomian glands was far more common among the 60 participants with dry eye and diabetes than among the 60 participants with dry eye but without diabetes, and the amount of gland loss was directly linked to A_1c level.

The findings suggest that loss of meibomian glands could serve as a diabetes biomarker, particularly in underserved areas where A_1c testing might not be readily available.

Dr. Wu noted many newer smartphones, including the Samsung Galaxy 10S and iPhone 10, Xs, and 11, have infrared cameras that could help characterize dry eye in patients with diabetes.

“In the future, we hope patients can use [smartphones] and flip their own eyelids and take a picture. We hope that in rural health clinics and community health centers we can use this device that people have ... When people complain of dry eye and they have diabetes we can consider [closer diabetes monitoring],” said Dr. Wu.

Asked to comment, endocrinologist David C. Lieb, MD, said in an interview: “It’s important for providers who care for people with diabetes to know that diabetes is associated with a high incidence of meibomian gland dysfunction leading to dry eye. That’s another reason people with diabetes need to make sure they see their eye care specialist on a regular basis.

“When I ask patients if they’ve seen their eye specialist I may add dry eye to my list of questions rather than just asking them when was the last time they went,” added Dr. Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk.

“I may ask them if they have symptoms of dry eye, and if they do, it’s something they need to talk about with that individual.”
 

Gland disappearance correlated with glycemic control

Dr. Wu and colleagues retrospectively reviewed electronic health records for 120 patients diagnosed with dry eye: 60 patients with and 60 patients without type 2 diabetes.

Those with diabetes were a mean age of 65 years, and were split evenly between men and women. The controls were younger, averaging 54 years, and comprised 37 men and 23 women.

Researchers performed infrared imaging (820 nm) of the lid; percentage loss of meibomian glands was calculated for each eye, then averaged per patient.

They found that 51.5% of patients in the diabetes group had lost meibomian glands, compared with just 11.3% of controls, a highly significant difference (P = .0001).

When A_1c was also assessed, only 4 of 60 participants with A_1c ≤ 5.9% lost ≥ 25% of the glands, compared with 55 of 60 participants with A_1c ≥ 6.0%.

And specifically among those with diabetes, 35 of 37 with A_1c > 6.6% lost > 40% of the glands, compared with just 12 of 23 participants with A_1c < 6.5% (all P < .0001).

“In patients with dry eye and diabetes, loss of meibomian glands is associated with elevated A_1c ... [and] may suggest a need for ... further monitoring of the patient’s diabetic condition,” the researchers noted.

Asked whether the glands could re-grow with improved glycemic control, Dr. Wu said she has not looked at that in people with diabetes, but in some patients who receive intensive treatment for dry eye with artificial tears or cyclosporine, the glands do grow back after about 6 months.

Dr. Lieb said he found the smartphone diagnostic idea “fascinating, especially in an area where you might not be able to easily measure an A_1c. Most people have access to point-of-care A_1c testing but not everybody can make it to a doctor’s office.”

And, he added, “anything that’s noninvasive has some potential benefit.”

Dr. Wu and Dr. Lieb have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

PHOENIX, ARIZ. – Diabetes patients in China who were enrolled in a team-based care intervention with clinical decision support systems significantly reduced their hemoglobin A_1c, systolic blood pressure, and LDL cholesterol over 18 months, compared with those who received team-based care alone.

Doug Brunk/MDedge News

The finding comes from the Diabetes Complication Control in Community Clinics (D4C), a cluster randomized trial conducted in 38 community health centers in Xiamen, China.

“Diabetes has become a major public health challenge worldwide, especially in low- and middle-income countries where populations are large and growing and health care resources are limited,” Jiang He, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. He, chair and professor of epidemiology at Tulane School of Public Health and Tropical Medicine, New Orleans, the prevalence of diabetes has increased rapidly in recent decades in China, from 2.5% in 1994 to 11.6% in 2010. “It was estimated that 114 million Chinese adults had diabetes in 2010,” he said. “Hyperglycemia, high blood pressure, and elevated LDL cholesterol are major risk factors for cardiovascular disease and premature death. The majority of patients with diabetes have multiple uncontrolled CVD risk factors due to suboptimal care. Diabetes and its complications further strain an already overburdened and overwhelmed health care system, especially tertiary care facilities, in China. On the other hand, community health centers are underutilized.”

In D4C, Dr. He and colleagues set out to evaluate changes in CVD risk factors among patients with diabetes after implementing a team-based care model at community health centers in Xiamen, China. They compared the effectiveness of team-based care with clinical decision support systems versus team-based care alone on CVD risk factor control among patients with diabetes at these community health centers.

The study population consisted of 10,942 patients aged 50 years and older with uncontrolled diabetes and at least one of the following three additional CVD risk factors: systolic BP of at least 140 mm Hg and/or diastolic BP of at least 90 mm Hg; LDL cholesterol of at least 100 mg/dL, or clinical atherosclerotic cardiovascular disease (ASCVD). At the intervention clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The researchers trained the primary care physicians and nurses, and a clinical decision support system was integrated with guideline-based treatment algorithms for controlling glycemia, blood pressure, and lipids.

At the enhanced care control clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The city health commission trained the primary care physicians and nurses. The intervention lasted for 18 months in both groups.

Dr. He, the D4C study chair, reported findings from 10,942 patients: 5,394 in the intervention group and 5,548 in the enhanced care group. The mean baseline age was similar between the intervention group and the enhanced care group (a mean of 63 years), as was body mass index (a mean of 24.9 kg/m²), hemoglobin A_1c (a mean of 8.8 vs. 8.7%, respectively), LDL cholesterol (121.2 vs. 121.1 mg/dL), systolic blood pressure (136.6 vs. 136.9 mm Hg), and diastolic blood pressure (79.7 vs. 79.8 mm Hg).

The researchers found patients in both groups experienced significant reductions in HbA_1c, LDL cholesterol, and BP over the 18-month follow-up, but those in the intervention group fared better in all measures. Specifically, the mean change in HbA_1c from baseline was –.85% in the intervention group, compared with –.66% in the enhanced care group, while the change in LDL was –19 mg/dL, compared with –12.8 mg/dL, respectively; the change in systolic blood pressure was –8.9 mm Hg vs. –7.7 mm Hg, and the change in 10-year ASCVD risk was .57% vs. .28% (P < .0001 for all associations).

The researchers also observed that the proportions of controlled HbA_1c, LDL, and blood pressure at 18 months were higher in the intervention group, compared with the enhanced care group. Specifically, 38% of patients in the intervention group achieved glycemic control, compared with 35% of those in the enhanced care group (P =. 0006), while 48% vs. 39%, respectively, achieved control of LDL cholesterol (P < .0001), and 78% vs. 75% achieved control of blood pressure (P = .0009). In addition, 15% vs. 12% achieved control of all three risk factors at 18 months (P < .0001).

“Implementing team-based care with a clinical decision support system is an effective and sustainable strategy for diabetes control in primary care settings,” Dr. He said at the meeting, which was sponsored by the American Heart Association. “This implementation strategy could be scaled up within primary care settings in China and other low- to middle-income countries to improve CVD risk factor control in patients with diabetes.”

In an interview, session moderator Joshua J. Joseph, MD, of Ohio State University, Columbus, pointed out that since only 12%-15% of study participants achieved control of all three CVD risk factors, “that leaves a great opportunity for [figuring out] how to we get the other 88% or 85% of patients to target levels. That’s going to be important as we think about cardiovascular disease prevention in type 2 diabetes. The more we can use team-based care along with clinical decision support tools, the more we will continue to improve the lives of patients.”

The study was supported by the Xiamen City Health Commission. Dr. He reported having no financial disclosures.

[email protected]

SOURCE: He J et al. EPI/LIFESTYLE 2020, session 7A, abstract 17.

PHOENIX, ARIZ. – Diabetes patients in China who were enrolled in a team-based care intervention with clinical decision support systems significantly reduced their hemoglobin A_1c, systolic blood pressure, and LDL cholesterol over 18 months, compared with those who received team-based care alone.

Doug Brunk/MDedge News

The finding comes from the Diabetes Complication Control in Community Clinics (D4C), a cluster randomized trial conducted in 38 community health centers in Xiamen, China.

“Diabetes has become a major public health challenge worldwide, especially in low- and middle-income countries where populations are large and growing and health care resources are limited,” Jiang He, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. He, chair and professor of epidemiology at Tulane School of Public Health and Tropical Medicine, New Orleans, the prevalence of diabetes has increased rapidly in recent decades in China, from 2.5% in 1994 to 11.6% in 2010. “It was estimated that 114 million Chinese adults had diabetes in 2010,” he said. “Hyperglycemia, high blood pressure, and elevated LDL cholesterol are major risk factors for cardiovascular disease and premature death. The majority of patients with diabetes have multiple uncontrolled CVD risk factors due to suboptimal care. Diabetes and its complications further strain an already overburdened and overwhelmed health care system, especially tertiary care facilities, in China. On the other hand, community health centers are underutilized.”

In D4C, Dr. He and colleagues set out to evaluate changes in CVD risk factors among patients with diabetes after implementing a team-based care model at community health centers in Xiamen, China. They compared the effectiveness of team-based care with clinical decision support systems versus team-based care alone on CVD risk factor control among patients with diabetes at these community health centers.

The study population consisted of 10,942 patients aged 50 years and older with uncontrolled diabetes and at least one of the following three additional CVD risk factors: systolic BP of at least 140 mm Hg and/or diastolic BP of at least 90 mm Hg; LDL cholesterol of at least 100 mg/dL, or clinical atherosclerotic cardiovascular disease (ASCVD). At the intervention clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The researchers trained the primary care physicians and nurses, and a clinical decision support system was integrated with guideline-based treatment algorithms for controlling glycemia, blood pressure, and lipids.

At the enhanced care control clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The city health commission trained the primary care physicians and nurses. The intervention lasted for 18 months in both groups.

Dr. He, the D4C study chair, reported findings from 10,942 patients: 5,394 in the intervention group and 5,548 in the enhanced care group. The mean baseline age was similar between the intervention group and the enhanced care group (a mean of 63 years), as was body mass index (a mean of 24.9 kg/m²), hemoglobin A_1c (a mean of 8.8 vs. 8.7%, respectively), LDL cholesterol (121.2 vs. 121.1 mg/dL), systolic blood pressure (136.6 vs. 136.9 mm Hg), and diastolic blood pressure (79.7 vs. 79.8 mm Hg).

The researchers found patients in both groups experienced significant reductions in HbA_1c, LDL cholesterol, and BP over the 18-month follow-up, but those in the intervention group fared better in all measures. Specifically, the mean change in HbA_1c from baseline was –.85% in the intervention group, compared with –.66% in the enhanced care group, while the change in LDL was –19 mg/dL, compared with –12.8 mg/dL, respectively; the change in systolic blood pressure was –8.9 mm Hg vs. –7.7 mm Hg, and the change in 10-year ASCVD risk was .57% vs. .28% (P < .0001 for all associations).

The researchers also observed that the proportions of controlled HbA_1c, LDL, and blood pressure at 18 months were higher in the intervention group, compared with the enhanced care group. Specifically, 38% of patients in the intervention group achieved glycemic control, compared with 35% of those in the enhanced care group (P =. 0006), while 48% vs. 39%, respectively, achieved control of LDL cholesterol (P < .0001), and 78% vs. 75% achieved control of blood pressure (P = .0009). In addition, 15% vs. 12% achieved control of all three risk factors at 18 months (P < .0001).

“Implementing team-based care with a clinical decision support system is an effective and sustainable strategy for diabetes control in primary care settings,” Dr. He said at the meeting, which was sponsored by the American Heart Association. “This implementation strategy could be scaled up within primary care settings in China and other low- to middle-income countries to improve CVD risk factor control in patients with diabetes.”

In an interview, session moderator Joshua J. Joseph, MD, of Ohio State University, Columbus, pointed out that since only 12%-15% of study participants achieved control of all three CVD risk factors, “that leaves a great opportunity for [figuring out] how to we get the other 88% or 85% of patients to target levels. That’s going to be important as we think about cardiovascular disease prevention in type 2 diabetes. The more we can use team-based care along with clinical decision support tools, the more we will continue to improve the lives of patients.”

The study was supported by the Xiamen City Health Commission. Dr. He reported having no financial disclosures.

[email protected]

SOURCE: He J et al. EPI/LIFESTYLE 2020, session 7A, abstract 17.

PHOENIX, ARIZ. – Diabetes patients in China who were enrolled in a team-based care intervention with clinical decision support systems significantly reduced their hemoglobin A_1c, systolic blood pressure, and LDL cholesterol over 18 months, compared with those who received team-based care alone.

Doug Brunk/MDedge News

The finding comes from the Diabetes Complication Control in Community Clinics (D4C), a cluster randomized trial conducted in 38 community health centers in Xiamen, China.

“Diabetes has become a major public health challenge worldwide, especially in low- and middle-income countries where populations are large and growing and health care resources are limited,” Jiang He, MD, PhD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. He, chair and professor of epidemiology at Tulane School of Public Health and Tropical Medicine, New Orleans, the prevalence of diabetes has increased rapidly in recent decades in China, from 2.5% in 1994 to 11.6% in 2010. “It was estimated that 114 million Chinese adults had diabetes in 2010,” he said. “Hyperglycemia, high blood pressure, and elevated LDL cholesterol are major risk factors for cardiovascular disease and premature death. The majority of patients with diabetes have multiple uncontrolled CVD risk factors due to suboptimal care. Diabetes and its complications further strain an already overburdened and overwhelmed health care system, especially tertiary care facilities, in China. On the other hand, community health centers are underutilized.”

In D4C, Dr. He and colleagues set out to evaluate changes in CVD risk factors among patients with diabetes after implementing a team-based care model at community health centers in Xiamen, China. They compared the effectiveness of team-based care with clinical decision support systems versus team-based care alone on CVD risk factor control among patients with diabetes at these community health centers.

The study population consisted of 10,942 patients aged 50 years and older with uncontrolled diabetes and at least one of the following three additional CVD risk factors: systolic BP of at least 140 mm Hg and/or diastolic BP of at least 90 mm Hg; LDL cholesterol of at least 100 mg/dL, or clinical atherosclerotic cardiovascular disease (ASCVD). At the intervention clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The researchers trained the primary care physicians and nurses, and a clinical decision support system was integrated with guideline-based treatment algorithms for controlling glycemia, blood pressure, and lipids.

At the enhanced care control clinics, team-based care was delivered by a team of primary care physicians, nurses, and diabetes specialists. The city health commission trained the primary care physicians and nurses. The intervention lasted for 18 months in both groups.

Dr. He, the D4C study chair, reported findings from 10,942 patients: 5,394 in the intervention group and 5,548 in the enhanced care group. The mean baseline age was similar between the intervention group and the enhanced care group (a mean of 63 years), as was body mass index (a mean of 24.9 kg/m²), hemoglobin A_1c (a mean of 8.8 vs. 8.7%, respectively), LDL cholesterol (121.2 vs. 121.1 mg/dL), systolic blood pressure (136.6 vs. 136.9 mm Hg), and diastolic blood pressure (79.7 vs. 79.8 mm Hg).

The researchers found patients in both groups experienced significant reductions in HbA_1c, LDL cholesterol, and BP over the 18-month follow-up, but those in the intervention group fared better in all measures. Specifically, the mean change in HbA_1c from baseline was –.85% in the intervention group, compared with –.66% in the enhanced care group, while the change in LDL was –19 mg/dL, compared with –12.8 mg/dL, respectively; the change in systolic blood pressure was –8.9 mm Hg vs. –7.7 mm Hg, and the change in 10-year ASCVD risk was .57% vs. .28% (P < .0001 for all associations).

The researchers also observed that the proportions of controlled HbA_1c, LDL, and blood pressure at 18 months were higher in the intervention group, compared with the enhanced care group. Specifically, 38% of patients in the intervention group achieved glycemic control, compared with 35% of those in the enhanced care group (P =. 0006), while 48% vs. 39%, respectively, achieved control of LDL cholesterol (P < .0001), and 78% vs. 75% achieved control of blood pressure (P = .0009). In addition, 15% vs. 12% achieved control of all three risk factors at 18 months (P < .0001).

“Implementing team-based care with a clinical decision support system is an effective and sustainable strategy for diabetes control in primary care settings,” Dr. He said at the meeting, which was sponsored by the American Heart Association. “This implementation strategy could be scaled up within primary care settings in China and other low- to middle-income countries to improve CVD risk factor control in patients with diabetes.”

In an interview, session moderator Joshua J. Joseph, MD, of Ohio State University, Columbus, pointed out that since only 12%-15% of study participants achieved control of all three CVD risk factors, “that leaves a great opportunity for [figuring out] how to we get the other 88% or 85% of patients to target levels. That’s going to be important as we think about cardiovascular disease prevention in type 2 diabetes. The more we can use team-based care along with clinical decision support tools, the more we will continue to improve the lives of patients.”

The study was supported by the Xiamen City Health Commission. Dr. He reported having no financial disclosures.

[email protected]

SOURCE: He J et al. EPI/LIFESTYLE 2020, session 7A, abstract 17.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

People with diabetes may benefit less from bariatric surgery, compared with those without the disease, according to a retrospective review of patients receiving both sleeve gastrectomy and gastric bypass.

The difference was particularly pronounced and persistent for patients who had gastric bypass, Yingying Luo, MD, said during a virtual news conference held by the Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

“Our findings demonstrated that having bariatric surgery before developing diabetes may result in greater weight loss from the surgery, especially within the first 3 years after surgery and in patients undergoing gastric bypass surgery,” said Dr. Luo.

More than a third of U.S. adults have obesity, and more than half the population is overweight or has obesity, said Dr. Luo, citing data from the Centers for Disease Control and Prevention.

Bariatric surgery not only reduces body weight, but also “can lead to remission of many metabolic disorders, including diabetes, hypertension, and dyslipidemia,” said Dr. Luo, a visiting scholar at the University of Michigan’s division of metabolism, endocrinology, and diabetes. However, until now, it has not been known how diabetes interacts with bariatric surgery to affect weight loss outcomes.

To address that question, Dr. Luo and her colleagues looked at patients in the Michigan Bariatric Surgery Cohort who were at least 18 years old and had a body mass index (BMI) of more than 40 kg/m², or of more than 35 kg/m² with comorbidities.

The researchers followed 380 patients who received gastric bypass and 334 who received sleeve gastrectomy for at least 5 years. Over time, sleeve gastrectomy became the predominant type of surgery conducted, noted Dr. Luo.

At baseline, and yearly for 5 years thereafter, the researchers recorded participants’ BMI as well as their lipid levels and other laboratory values. Medication use was also tracked. Patients with a diagnosis of diabetes also had their hemoglobin A_1c levels recorded at each visit.

Overall, patients in the sleeve gastrectomy group were more overweight, and those in the gastric bypass group had higher HbA_1c and total cholesterol levels. The mean baseline weight for the sleeve gastrectomy recipients was 141.5 kg, compared with 133.5 kg for those receiving gastric bypass (BMI, 49.9 vs. 47.3 kg/m², respectively; P < .01 for both measures). Mean HbA_1c was 6.5% for the gastric bypass group, compared with 6.3% for the sleeve gastrectomy group (P = .03).

At baseline, 149 (39.2%) of the gastric bypass patients had diabetes, compared with 108 (32.3%) of the sleeve gastrectomy patients, but the difference was not statistically significant.

About two-thirds of the full cohort were tracked for at least 5 years, which is still considered “a good follow-up rate in a real-world study,” said Dr. Luo.

Total weight loss was defined as the difference between initial weight and postoperative weight at a given point in time. Excess weight was the difference between initial weight and an individual’s ideal weight, that is, what their weight would have been if they had a BMI of 25 kg/m².

“The probability of achieving a BMI of less than 30 kg/m² or excess weight loss of 50% or more was higher in patients who did not have diabetes diagnosis at baseline. We found that the presence of diabetes at baseline substantially impacted the probability of achieving both indicators,” said Dr. Luo. “Individuals without diabetes had a 1.5 times higher chance of achieving a BMI of under 30 kg/m², and … [they also] had a 1.6 times higher chance of achieving excess body weight loss of 50%, or more.” Both of those differences were statistically significant on univariate analysis (P = .0249 and .0021, respectively).

The researchers conducted further statistical analysis – adjusted for age, gender, surgery type, and baseline weight – to examine whether diabetes still predicted future weight loss after bariatric surgery. After those adjustments, they still found that “the presence of diabetes before surgery is an indicator of future weight loss outcomes,” said Dr. Luo.

The differences in outcomes for those with and without diabetes tended to diminish over time in looking at the cohort as a whole. However, greater BMI reduction for those without diabetes persisted for the full 5 years of follow-up for the gastric bypass recipients. Those trends held when the researchers looked at the proportion of patients whose BMI dropped to below 30 kg/m², and those who achieved excess weight loss of more than 50%.

Dr. Luo acknowledged that an ideal study would track patients for longer than 5 years and that studies involving more patients would also be useful. Still, she said, “our study opens the door for further research to understand why diabetes diminishes the weight loss effect of bariatric surgery.”

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

Dr. Luo reported no outside sources of funding and no conflicts of interest.
 

SOURCE: Luo Y et al. ENDO 2020, Abstract 590.

People with diabetes may benefit less from bariatric surgery, compared with those without the disease, according to a retrospective review of patients receiving both sleeve gastrectomy and gastric bypass.

The difference was particularly pronounced and persistent for patients who had gastric bypass, Yingying Luo, MD, said during a virtual news conference held by the Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

“Our findings demonstrated that having bariatric surgery before developing diabetes may result in greater weight loss from the surgery, especially within the first 3 years after surgery and in patients undergoing gastric bypass surgery,” said Dr. Luo.

More than a third of U.S. adults have obesity, and more than half the population is overweight or has obesity, said Dr. Luo, citing data from the Centers for Disease Control and Prevention.

Bariatric surgery not only reduces body weight, but also “can lead to remission of many metabolic disorders, including diabetes, hypertension, and dyslipidemia,” said Dr. Luo, a visiting scholar at the University of Michigan’s division of metabolism, endocrinology, and diabetes. However, until now, it has not been known how diabetes interacts with bariatric surgery to affect weight loss outcomes.

To address that question, Dr. Luo and her colleagues looked at patients in the Michigan Bariatric Surgery Cohort who were at least 18 years old and had a body mass index (BMI) of more than 40 kg/m², or of more than 35 kg/m² with comorbidities.

The researchers followed 380 patients who received gastric bypass and 334 who received sleeve gastrectomy for at least 5 years. Over time, sleeve gastrectomy became the predominant type of surgery conducted, noted Dr. Luo.

At baseline, and yearly for 5 years thereafter, the researchers recorded participants’ BMI as well as their lipid levels and other laboratory values. Medication use was also tracked. Patients with a diagnosis of diabetes also had their hemoglobin A_1c levels recorded at each visit.

Overall, patients in the sleeve gastrectomy group were more overweight, and those in the gastric bypass group had higher HbA_1c and total cholesterol levels. The mean baseline weight for the sleeve gastrectomy recipients was 141.5 kg, compared with 133.5 kg for those receiving gastric bypass (BMI, 49.9 vs. 47.3 kg/m², respectively; P < .01 for both measures). Mean HbA_1c was 6.5% for the gastric bypass group, compared with 6.3% for the sleeve gastrectomy group (P = .03).

At baseline, 149 (39.2%) of the gastric bypass patients had diabetes, compared with 108 (32.3%) of the sleeve gastrectomy patients, but the difference was not statistically significant.

About two-thirds of the full cohort were tracked for at least 5 years, which is still considered “a good follow-up rate in a real-world study,” said Dr. Luo.

Total weight loss was defined as the difference between initial weight and postoperative weight at a given point in time. Excess weight was the difference between initial weight and an individual’s ideal weight, that is, what their weight would have been if they had a BMI of 25 kg/m².

“The probability of achieving a BMI of less than 30 kg/m² or excess weight loss of 50% or more was higher in patients who did not have diabetes diagnosis at baseline. We found that the presence of diabetes at baseline substantially impacted the probability of achieving both indicators,” said Dr. Luo. “Individuals without diabetes had a 1.5 times higher chance of achieving a BMI of under 30 kg/m², and … [they also] had a 1.6 times higher chance of achieving excess body weight loss of 50%, or more.” Both of those differences were statistically significant on univariate analysis (P = .0249 and .0021, respectively).

The researchers conducted further statistical analysis – adjusted for age, gender, surgery type, and baseline weight – to examine whether diabetes still predicted future weight loss after bariatric surgery. After those adjustments, they still found that “the presence of diabetes before surgery is an indicator of future weight loss outcomes,” said Dr. Luo.

The differences in outcomes for those with and without diabetes tended to diminish over time in looking at the cohort as a whole. However, greater BMI reduction for those without diabetes persisted for the full 5 years of follow-up for the gastric bypass recipients. Those trends held when the researchers looked at the proportion of patients whose BMI dropped to below 30 kg/m², and those who achieved excess weight loss of more than 50%.

Dr. Luo acknowledged that an ideal study would track patients for longer than 5 years and that studies involving more patients would also be useful. Still, she said, “our study opens the door for further research to understand why diabetes diminishes the weight loss effect of bariatric surgery.”

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

Dr. Luo reported no outside sources of funding and no conflicts of interest.
 

SOURCE: Luo Y et al. ENDO 2020, Abstract 590.

People with diabetes may benefit less from bariatric surgery, compared with those without the disease, according to a retrospective review of patients receiving both sleeve gastrectomy and gastric bypass.

The difference was particularly pronounced and persistent for patients who had gastric bypass, Yingying Luo, MD, said during a virtual news conference held by the Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

“Our findings demonstrated that having bariatric surgery before developing diabetes may result in greater weight loss from the surgery, especially within the first 3 years after surgery and in patients undergoing gastric bypass surgery,” said Dr. Luo.

More than a third of U.S. adults have obesity, and more than half the population is overweight or has obesity, said Dr. Luo, citing data from the Centers for Disease Control and Prevention.

Bariatric surgery not only reduces body weight, but also “can lead to remission of many metabolic disorders, including diabetes, hypertension, and dyslipidemia,” said Dr. Luo, a visiting scholar at the University of Michigan’s division of metabolism, endocrinology, and diabetes. However, until now, it has not been known how diabetes interacts with bariatric surgery to affect weight loss outcomes.

To address that question, Dr. Luo and her colleagues looked at patients in the Michigan Bariatric Surgery Cohort who were at least 18 years old and had a body mass index (BMI) of more than 40 kg/m², or of more than 35 kg/m² with comorbidities.

The researchers followed 380 patients who received gastric bypass and 334 who received sleeve gastrectomy for at least 5 years. Over time, sleeve gastrectomy became the predominant type of surgery conducted, noted Dr. Luo.

At baseline, and yearly for 5 years thereafter, the researchers recorded participants’ BMI as well as their lipid levels and other laboratory values. Medication use was also tracked. Patients with a diagnosis of diabetes also had their hemoglobin A_1c levels recorded at each visit.

Overall, patients in the sleeve gastrectomy group were more overweight, and those in the gastric bypass group had higher HbA_1c and total cholesterol levels. The mean baseline weight for the sleeve gastrectomy recipients was 141.5 kg, compared with 133.5 kg for those receiving gastric bypass (BMI, 49.9 vs. 47.3 kg/m², respectively; P < .01 for both measures). Mean HbA_1c was 6.5% for the gastric bypass group, compared with 6.3% for the sleeve gastrectomy group (P = .03).

At baseline, 149 (39.2%) of the gastric bypass patients had diabetes, compared with 108 (32.3%) of the sleeve gastrectomy patients, but the difference was not statistically significant.

About two-thirds of the full cohort were tracked for at least 5 years, which is still considered “a good follow-up rate in a real-world study,” said Dr. Luo.

Total weight loss was defined as the difference between initial weight and postoperative weight at a given point in time. Excess weight was the difference between initial weight and an individual’s ideal weight, that is, what their weight would have been if they had a BMI of 25 kg/m².

“The probability of achieving a BMI of less than 30 kg/m² or excess weight loss of 50% or more was higher in patients who did not have diabetes diagnosis at baseline. We found that the presence of diabetes at baseline substantially impacted the probability of achieving both indicators,” said Dr. Luo. “Individuals without diabetes had a 1.5 times higher chance of achieving a BMI of under 30 kg/m², and … [they also] had a 1.6 times higher chance of achieving excess body weight loss of 50%, or more.” Both of those differences were statistically significant on univariate analysis (P = .0249 and .0021, respectively).

The researchers conducted further statistical analysis – adjusted for age, gender, surgery type, and baseline weight – to examine whether diabetes still predicted future weight loss after bariatric surgery. After those adjustments, they still found that “the presence of diabetes before surgery is an indicator of future weight loss outcomes,” said Dr. Luo.

The differences in outcomes for those with and without diabetes tended to diminish over time in looking at the cohort as a whole. However, greater BMI reduction for those without diabetes persisted for the full 5 years of follow-up for the gastric bypass recipients. Those trends held when the researchers looked at the proportion of patients whose BMI dropped to below 30 kg/m², and those who achieved excess weight loss of more than 50%.

Dr. Luo acknowledged that an ideal study would track patients for longer than 5 years and that studies involving more patients would also be useful. Still, she said, “our study opens the door for further research to understand why diabetes diminishes the weight loss effect of bariatric surgery.”

The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

Dr. Luo reported no outside sources of funding and no conflicts of interest.
 

SOURCE: Luo Y et al. ENDO 2020, Abstract 590.

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.