Diabetes

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.

The move also paves the way for the review and authorization of similar devices in the future.

The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.

The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that, with limited user intervention outside of mealtimes, the controller coordinated the components of such systems to determine and command safe and effective insulin delivery.

However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.

This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”

More information can be found in the full release, available on the FDA website.

[email protected]

The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.

The move also paves the way for the review and authorization of similar devices in the future.

The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.

The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that, with limited user intervention outside of mealtimes, the controller coordinated the components of such systems to determine and command safe and effective insulin delivery.

However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.

This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”

More information can be found in the full release, available on the FDA website.

[email protected]

The Food and Drug Administration has authorized marketing of the Tandem Diabetes Care Control-IQ Technology, an interoperable automated glycemic controller, for use in a customizable glucose control system, according to a release from the agency.

The move also paves the way for the review and authorization of similar devices in the future.

The Control-IQ Technology controller coordinates with an alternate controller-enabled insulin pump and an integrated continuous glucose monitor, which can be made by other manufacturers as long they are compatible with this modular technology.

The agency reviewed data from a clinical study of 168 patients with type 1 diabetes who were randomized to use either the Control-IQ Technology controller installed on a Tandem t:slim X2 insulin pump, or a continuous glucose monitor and insulin pump without the Control-IQ controller. The findings showed that, with limited user intervention outside of mealtimes, the controller coordinated the components of such systems to determine and command safe and effective insulin delivery.

However, the agency noted that, although the system has been assessed for reliability, delays in insulin delivery remain possible and care should be taken when using it.

This authorization comes along with establishment of criteria and regulatory requirements that create a new regulatory classification for this type of device, whereby future devices of the same type and with the same purpose can go through the FDA’s 510(k) premarket process. Such a process would mean that, going forward, similar devices can “obtain marketing authorization by demonstrating substantial equivalence to a predicate device.”

More information can be found in the full release, available on the FDA website.

[email protected]

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

LOS ANGELES – Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits’ end watching the beta-cell function of their patients decline on metformin treatment.

Doug Brunk/MDedge News

“The kids were not doing well. It was like they were being treated with water,” Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med. 2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. “The worst arm was the metformin arm,” said Dr. Caprio, who was involved with the study. “Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes.”

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018 Aug; 41[8]:1717-25).

“The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs,” said Dr. Caprio, who was one of the study investigators. “The beta cell is unresponsive to metformin and other treatments. The question is, why?”

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A_1c (HbA_1c) level of less than 8.5%. “I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications,” she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m², their mean fasting glucose was 8.4 mmol/L, and their mean HbA_1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

“There was also a significant drop in BMI z score in patients treated with liraglutide, which is important,” Dr. Caprio said. “This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study.”

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

“I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults.”

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. “That’s a big problem we face with children,” Dr. Caprio said. “Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group.”

“Finally, we have something else to help children and teenagers to delay the complications we are seeing,” Dr. Caprio said. “To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don’t think the weight loss [concerns are] going to go away without medication, unfortunately.”

Dr. Caprio reported having no financial disclosures.

BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.

Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.

Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.

He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.

But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.

Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
 

Yes: Diabetes eliminates female CVD protection

Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.

In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.

The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.

In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.

In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.

And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.

Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).

Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.

“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
 

Are disparities because of differences in cvd risk factor management?

The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.

A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.

And some studies suggest medication adherence is lower in women than men.

In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.

He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.

Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.

The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.

“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.

“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.

“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.

He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.

“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
 

No: Confusion about relative risk within each sex and absolute risk

Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.

And that risk, he stressed, is actually higher in men.

“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.

And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).

In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.

Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.

And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.

The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”

But, Dr. Davis emphasized, rates were not higher in females.

So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?

“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
 

ADA Standards of Medical Care 2019 don’t mention gender

Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.

“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.

But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.

“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.

Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.

“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.

And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.

Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.

What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”

“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.

A version of this story originally appeared on medscape.com.

BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.

Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.

Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.

He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.

But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.

Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
 

Yes: Diabetes eliminates female CVD protection

Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.

In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.

The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.

In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.

In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.

And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.

Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).

Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.

“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
 

Are disparities because of differences in cvd risk factor management?

The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.

A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.

And some studies suggest medication adherence is lower in women than men.

In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.

He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.

Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.

The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.

“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.

“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.

“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.

He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.

“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
 

No: Confusion about relative risk within each sex and absolute risk

Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.

And that risk, he stressed, is actually higher in men.

“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.

And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).

In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.

Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.

And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.

The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”

But, Dr. Davis emphasized, rates were not higher in females.

So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?

“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
 

ADA Standards of Medical Care 2019 don’t mention gender

Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.

“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.

But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.

“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.

Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.

“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.

And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.

Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.

What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”

“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.

A version of this story originally appeared on medscape.com.

BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.

Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.

Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.

He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.

But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.

Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
 

Yes: Diabetes eliminates female CVD protection

Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.

In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.

The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.

In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.

In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.

And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.

Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).

Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.

“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
 

Are disparities because of differences in cvd risk factor management?

The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.

A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.

And some studies suggest medication adherence is lower in women than men.

In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.

He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.

Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.

The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.

“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.

“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.

“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.

He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.

“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
 

No: Confusion about relative risk within each sex and absolute risk

Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.

And that risk, he stressed, is actually higher in men.

“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.

And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).

In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.

Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.

And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.

The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”

But, Dr. Davis emphasized, rates were not higher in females.

So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?

“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
 

ADA Standards of Medical Care 2019 don’t mention gender

Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.

“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.

But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.

“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.

Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.

“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.

And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.

Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.

What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”

“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.

A version of this story originally appeared on medscape.com.

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

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

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

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

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

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