Clinical Endocrinology News

A new decision pathway for the management of hypertriglyceridemia, prompted by a large and growing body of evidence that elevated triglycerides to a targetable risk factor for atherosclerotic cardiovascular disease (ASCVD), has been issued by the American College of Cardiology.

According to the chairman of the writing committee, Salim S. Virani, MD, PhD, the recommendations amplify and update more than alter the hypertriglyceridemia treatment recommendations in the 2018 joint multisociety blood cholesterol guidelines issued in 2018.

This decision pathway, however, is focused on triglycerides alone.

“The previous guidelines included a section on strategies for addressing hypertriglyceridemia to reduce ASCVD risk, but this new decision pathway builds on the recommendations with more details and with additional information,” explained Dr. Virani, professor of medicine in the section of cardiovascular research, Baylor College of Medicine, Houston.

Within this newly published document, the definitions of hypertriglyceridemia and rationale for treatment are followed by detailed algorithms for four specific patient groups with varying triglyceride levels:

• Adults with ASCVD.
• Adults at least 40 years of age with diabetes but no ASCVD.
• Adults at least 20 years of age with no ASCVD or diabetes.
• Adults at least 20 years of age with severe hypertriglyceridemia.

“In the design of these algorithms, we made an active effort to make them suitable for use by primary care physicians as well as specialists,” said Dr. Virani. Despite “lots of boxes and arrows,” the flowcharts for each of these patient groups permit clinicians to follow the decision pathway without having to reread the text.

The common emphasis in all four algorithms is to begin by evaluating patients for secondary causes of hypertriglyceridemia, such as multifactorial chylomicronemia syndrome and other diseases associated with elevated triglycerides. The next steps, also common to all algorithms, are to optimize diet and lifestyle changes that lower triglycerides, optimize glycemic control, and optimize statin therapy.

“Although commonly recognized for their impact on LDL-C, statins also provide a 10%-30% dose-dependent reduction in triglycerides in patients with elevated levels,” the guidelines state. Statins are considered a fundamental step to secondary prevention of ASCVD regardless of triglyceride levels.

Once treatable causes or contributors to hypertriglyceridemia have been addressed, lifestyle interventions and statin therapy have been optimized, pharmacologic therapy directed specifically at control of hypertriglyceridemia “can be considered” in those at highest risk of ASCVD events, but Dr. Virani explained that this is never an early or first step in control of elevated triglycerides.

“The entire working group agreed that lifestyle interventions should be highlighted front and center before considering any other intervention,” Dr. Virani explained.

Pharmacologic therapy for hypertriglyceridemia is not ignored. Prescription omega-3 fatty acid products are preferred over nonprescription dietary supplements, which may vary in quality and purity. But these products, rather than a standalone solution, are best applied within the context of efforts to improve diet, lower body weight, and increase physical activity.

Several trials have associated ethyl ester and carboxylic acid preparations with meaningful reductions in triglycerides, but these drugs, including icosapent ethyl (IPE), are not without adverse events. In the pivotal REDUCE-IT trial, IPE was linked with an increased risk of atrial fibrillation relative to placebo.

IPE is “the best option” and the only therapy with an indication for reduction in ASCVD risk, according to Dr. Virani, but he explained that safety concerns led the authors of the new decision pathway to employ cautious language in regard to its use, suggesting that it be “considered” in high-risk patients after other methods of lowering triglycerides have been optimized.

In the algorithm for the four different risk groups, the decision pathways follow stratifications for different levels of hypertriglyceridemia (defined under fasting and nonfasting conditions) and also for specific levels of LDL cholesterol. ASCVD risk assessment is also a factor in determining the next steps along the decision pathway.

According to Michael Davidson, MD, director of the lipid clinic at the University of Chicago, the emphasis on lifestyle changes for hypertriglyceridemia and the prudent language in regard to pharmacologic therapy is appropriate.

“In light of the controversies regarding the REDUCE-IT trial, the writing committee has done a nice job with providing useful guidance regarding the utilization of icosapent ethyl in higher risk patients,” Dr. Davidson said.

Calling the ACC decision pathway “a welcome enhancement of the 2018 ACC/AHA cholesterol guidelines,” Dr. Davidson praised the way in which the limitations of the evidence regarding pharmacologic therapies were explained.

“Most importantly, this decision pathway helps clinicians appreciate that hypertriglyceridemia can be best managed with lifestyle changes and addressing potential secondary causes,” Dr. Davidson said.

Dr. Virani reports no potential conflicts of interest. Dr. Davidson reports financial relationships with multiple pharmaceutical companies including those making or pursuing therapies for control of hypertriglyceridemia.

A new decision pathway for the management of hypertriglyceridemia, prompted by a large and growing body of evidence that elevated triglycerides to a targetable risk factor for atherosclerotic cardiovascular disease (ASCVD), has been issued by the American College of Cardiology.

According to the chairman of the writing committee, Salim S. Virani, MD, PhD, the recommendations amplify and update more than alter the hypertriglyceridemia treatment recommendations in the 2018 joint multisociety blood cholesterol guidelines issued in 2018.

This decision pathway, however, is focused on triglycerides alone.

“The previous guidelines included a section on strategies for addressing hypertriglyceridemia to reduce ASCVD risk, but this new decision pathway builds on the recommendations with more details and with additional information,” explained Dr. Virani, professor of medicine in the section of cardiovascular research, Baylor College of Medicine, Houston.

Within this newly published document, the definitions of hypertriglyceridemia and rationale for treatment are followed by detailed algorithms for four specific patient groups with varying triglyceride levels:

• Adults with ASCVD.
• Adults at least 40 years of age with diabetes but no ASCVD.
• Adults at least 20 years of age with no ASCVD or diabetes.
• Adults at least 20 years of age with severe hypertriglyceridemia.

“In the design of these algorithms, we made an active effort to make them suitable for use by primary care physicians as well as specialists,” said Dr. Virani. Despite “lots of boxes and arrows,” the flowcharts for each of these patient groups permit clinicians to follow the decision pathway without having to reread the text.

The common emphasis in all four algorithms is to begin by evaluating patients for secondary causes of hypertriglyceridemia, such as multifactorial chylomicronemia syndrome and other diseases associated with elevated triglycerides. The next steps, also common to all algorithms, are to optimize diet and lifestyle changes that lower triglycerides, optimize glycemic control, and optimize statin therapy.

“Although commonly recognized for their impact on LDL-C, statins also provide a 10%-30% dose-dependent reduction in triglycerides in patients with elevated levels,” the guidelines state. Statins are considered a fundamental step to secondary prevention of ASCVD regardless of triglyceride levels.

Once treatable causes or contributors to hypertriglyceridemia have been addressed, lifestyle interventions and statin therapy have been optimized, pharmacologic therapy directed specifically at control of hypertriglyceridemia “can be considered” in those at highest risk of ASCVD events, but Dr. Virani explained that this is never an early or first step in control of elevated triglycerides.

“The entire working group agreed that lifestyle interventions should be highlighted front and center before considering any other intervention,” Dr. Virani explained.

Pharmacologic therapy for hypertriglyceridemia is not ignored. Prescription omega-3 fatty acid products are preferred over nonprescription dietary supplements, which may vary in quality and purity. But these products, rather than a standalone solution, are best applied within the context of efforts to improve diet, lower body weight, and increase physical activity.

Several trials have associated ethyl ester and carboxylic acid preparations with meaningful reductions in triglycerides, but these drugs, including icosapent ethyl (IPE), are not without adverse events. In the pivotal REDUCE-IT trial, IPE was linked with an increased risk of atrial fibrillation relative to placebo.

IPE is “the best option” and the only therapy with an indication for reduction in ASCVD risk, according to Dr. Virani, but he explained that safety concerns led the authors of the new decision pathway to employ cautious language in regard to its use, suggesting that it be “considered” in high-risk patients after other methods of lowering triglycerides have been optimized.

In the algorithm for the four different risk groups, the decision pathways follow stratifications for different levels of hypertriglyceridemia (defined under fasting and nonfasting conditions) and also for specific levels of LDL cholesterol. ASCVD risk assessment is also a factor in determining the next steps along the decision pathway.

According to Michael Davidson, MD, director of the lipid clinic at the University of Chicago, the emphasis on lifestyle changes for hypertriglyceridemia and the prudent language in regard to pharmacologic therapy is appropriate.

“In light of the controversies regarding the REDUCE-IT trial, the writing committee has done a nice job with providing useful guidance regarding the utilization of icosapent ethyl in higher risk patients,” Dr. Davidson said.

Calling the ACC decision pathway “a welcome enhancement of the 2018 ACC/AHA cholesterol guidelines,” Dr. Davidson praised the way in which the limitations of the evidence regarding pharmacologic therapies were explained.

“Most importantly, this decision pathway helps clinicians appreciate that hypertriglyceridemia can be best managed with lifestyle changes and addressing potential secondary causes,” Dr. Davidson said.

Dr. Virani reports no potential conflicts of interest. Dr. Davidson reports financial relationships with multiple pharmaceutical companies including those making or pursuing therapies for control of hypertriglyceridemia.

A new decision pathway for the management of hypertriglyceridemia, prompted by a large and growing body of evidence that elevated triglycerides to a targetable risk factor for atherosclerotic cardiovascular disease (ASCVD), has been issued by the American College of Cardiology.

According to the chairman of the writing committee, Salim S. Virani, MD, PhD, the recommendations amplify and update more than alter the hypertriglyceridemia treatment recommendations in the 2018 joint multisociety blood cholesterol guidelines issued in 2018.

This decision pathway, however, is focused on triglycerides alone.

“The previous guidelines included a section on strategies for addressing hypertriglyceridemia to reduce ASCVD risk, but this new decision pathway builds on the recommendations with more details and with additional information,” explained Dr. Virani, professor of medicine in the section of cardiovascular research, Baylor College of Medicine, Houston.

Within this newly published document, the definitions of hypertriglyceridemia and rationale for treatment are followed by detailed algorithms for four specific patient groups with varying triglyceride levels:

• Adults with ASCVD.
• Adults at least 40 years of age with diabetes but no ASCVD.
• Adults at least 20 years of age with no ASCVD or diabetes.
• Adults at least 20 years of age with severe hypertriglyceridemia.

“In the design of these algorithms, we made an active effort to make them suitable for use by primary care physicians as well as specialists,” said Dr. Virani. Despite “lots of boxes and arrows,” the flowcharts for each of these patient groups permit clinicians to follow the decision pathway without having to reread the text.

The common emphasis in all four algorithms is to begin by evaluating patients for secondary causes of hypertriglyceridemia, such as multifactorial chylomicronemia syndrome and other diseases associated with elevated triglycerides. The next steps, also common to all algorithms, are to optimize diet and lifestyle changes that lower triglycerides, optimize glycemic control, and optimize statin therapy.

“Although commonly recognized for their impact on LDL-C, statins also provide a 10%-30% dose-dependent reduction in triglycerides in patients with elevated levels,” the guidelines state. Statins are considered a fundamental step to secondary prevention of ASCVD regardless of triglyceride levels.

Once treatable causes or contributors to hypertriglyceridemia have been addressed, lifestyle interventions and statin therapy have been optimized, pharmacologic therapy directed specifically at control of hypertriglyceridemia “can be considered” in those at highest risk of ASCVD events, but Dr. Virani explained that this is never an early or first step in control of elevated triglycerides.

“The entire working group agreed that lifestyle interventions should be highlighted front and center before considering any other intervention,” Dr. Virani explained.

Pharmacologic therapy for hypertriglyceridemia is not ignored. Prescription omega-3 fatty acid products are preferred over nonprescription dietary supplements, which may vary in quality and purity. But these products, rather than a standalone solution, are best applied within the context of efforts to improve diet, lower body weight, and increase physical activity.

Several trials have associated ethyl ester and carboxylic acid preparations with meaningful reductions in triglycerides, but these drugs, including icosapent ethyl (IPE), are not without adverse events. In the pivotal REDUCE-IT trial, IPE was linked with an increased risk of atrial fibrillation relative to placebo.

IPE is “the best option” and the only therapy with an indication for reduction in ASCVD risk, according to Dr. Virani, but he explained that safety concerns led the authors of the new decision pathway to employ cautious language in regard to its use, suggesting that it be “considered” in high-risk patients after other methods of lowering triglycerides have been optimized.

In the algorithm for the four different risk groups, the decision pathways follow stratifications for different levels of hypertriglyceridemia (defined under fasting and nonfasting conditions) and also for specific levels of LDL cholesterol. ASCVD risk assessment is also a factor in determining the next steps along the decision pathway.

According to Michael Davidson, MD, director of the lipid clinic at the University of Chicago, the emphasis on lifestyle changes for hypertriglyceridemia and the prudent language in regard to pharmacologic therapy is appropriate.

“In light of the controversies regarding the REDUCE-IT trial, the writing committee has done a nice job with providing useful guidance regarding the utilization of icosapent ethyl in higher risk patients,” Dr. Davidson said.

Calling the ACC decision pathway “a welcome enhancement of the 2018 ACC/AHA cholesterol guidelines,” Dr. Davidson praised the way in which the limitations of the evidence regarding pharmacologic therapies were explained.

“Most importantly, this decision pathway helps clinicians appreciate that hypertriglyceridemia can be best managed with lifestyle changes and addressing potential secondary causes,” Dr. Davidson said.

Dr. Virani reports no potential conflicts of interest. Dr. Davidson reports financial relationships with multiple pharmaceutical companies including those making or pursuing therapies for control of hypertriglyceridemia.

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

The tragic loss of three medical residents in our beloved South Bronx hospital shook us to the core. They were our colleagues and friends – promising young physicians whose lives and contributions to our hospital family will never be forgotten. We miss them and we grieve them.

We have been keenly aware of the growing trend of physician suicides across the country. That’s one of the reasons why, years ago, we established the nationally recognized Helping Healers Heal program across our health system and more recently expanded other mental health counseling and support to our frontline clinicians.

Our focus is wellness and prevention, as well as helping address the sadness, anxiety, and depression that so many of us experience after a traumatic event. During the surge of the COVID pandemic, these programs proved to be essential, as we expanded these services to all staff, not just those on the frontlines of patient care.

We share Dr. Pamela Wible’s concerns about the physician suicide crisis in this country. However, she misrepresented our residency program and made numerous statements that are false and simply hurtful.

Out of respect for our colleagues and their families, we cannot share everything that we know about this tragic and irreparable loss. But we must set the record straight about a number of incorrect references made by Dr. Wible:

1. We lost two residents to suicide. Though no less horrific, the third death was investigated and declared an accident by the police department.

2. Resident work hours and workload are closely monitored to follow guidance set by the New York State Department of Health and by ACGME. In fact, at the peak of the COVID pandemic, when we were caring for nearly 130 intubated patients at a time, we adopted a strict residency program schedule with built-in breaks and reduced shifts and hours. Even at that tasking time, no one worked more than 80 hours. Although the maximum number of patients assigned to an intern allowed by ACGME is 10, we rarely have more than five or six patients assigned to each of our interns.

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

The tragic loss of three medical residents in our beloved South Bronx hospital shook us to the core. They were our colleagues and friends – promising young physicians whose lives and contributions to our hospital family will never be forgotten. We miss them and we grieve them.

We have been keenly aware of the growing trend of physician suicides across the country. That’s one of the reasons why, years ago, we established the nationally recognized Helping Healers Heal program across our health system and more recently expanded other mental health counseling and support to our frontline clinicians.

Our focus is wellness and prevention, as well as helping address the sadness, anxiety, and depression that so many of us experience after a traumatic event. During the surge of the COVID pandemic, these programs proved to be essential, as we expanded these services to all staff, not just those on the frontlines of patient care.

We share Dr. Pamela Wible’s concerns about the physician suicide crisis in this country. However, she misrepresented our residency program and made numerous statements that are false and simply hurtful.

Out of respect for our colleagues and their families, we cannot share everything that we know about this tragic and irreparable loss. But we must set the record straight about a number of incorrect references made by Dr. Wible:

1. We lost two residents to suicide. Though no less horrific, the third death was investigated and declared an accident by the police department.

2. Resident work hours and workload are closely monitored to follow guidance set by the New York State Department of Health and by ACGME. In fact, at the peak of the COVID pandemic, when we were caring for nearly 130 intubated patients at a time, we adopted a strict residency program schedule with built-in breaks and reduced shifts and hours. Even at that tasking time, no one worked more than 80 hours. Although the maximum number of patients assigned to an intern allowed by ACGME is 10, we rarely have more than five or six patients assigned to each of our interns.

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

The tragic loss of three medical residents in our beloved South Bronx hospital shook us to the core. They were our colleagues and friends – promising young physicians whose lives and contributions to our hospital family will never be forgotten. We miss them and we grieve them.

We have been keenly aware of the growing trend of physician suicides across the country. That’s one of the reasons why, years ago, we established the nationally recognized Helping Healers Heal program across our health system and more recently expanded other mental health counseling and support to our frontline clinicians.

Our focus is wellness and prevention, as well as helping address the sadness, anxiety, and depression that so many of us experience after a traumatic event. During the surge of the COVID pandemic, these programs proved to be essential, as we expanded these services to all staff, not just those on the frontlines of patient care.

We share Dr. Pamela Wible’s concerns about the physician suicide crisis in this country. However, she misrepresented our residency program and made numerous statements that are false and simply hurtful.

Out of respect for our colleagues and their families, we cannot share everything that we know about this tragic and irreparable loss. But we must set the record straight about a number of incorrect references made by Dr. Wible:

1. We lost two residents to suicide. Though no less horrific, the third death was investigated and declared an accident by the police department.

2. Resident work hours and workload are closely monitored to follow guidance set by the New York State Department of Health and by ACGME. In fact, at the peak of the COVID pandemic, when we were caring for nearly 130 intubated patients at a time, we adopted a strict residency program schedule with built-in breaks and reduced shifts and hours. Even at that tasking time, no one worked more than 80 hours. Although the maximum number of patients assigned to an intern allowed by ACGME is 10, we rarely have more than five or six patients assigned to each of our interns.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

The longer a person has diabetes, the greater their risk for also developing heart failure, according to an analysis of nearly 10,000 U.S. adults followed for a median of close to 23 years.

In a multivariable analysis the rate of incident heart failure increased steadily and significantly as diabetes duration increased. Among the 168 study subjects (2% of the total study group) who had diabetes for at least 15 years, the subsequent incidence of heart failure was nearly threefold higher than among the 4,802 subjects (49%) who never had diabetes or prediabetes, reported Justin B. Echouffo-Tcheugui, MD, PhD, and coauthors in an article published in JACC Heart Failure.

People with prediabetes (32% of the study population) had a significant but modest increased rate of incident heart failure that was 16% higher than in control subjects who never developed diabetes. People with diabetes for durations of 0-4.9 years, 5.0-9.9 years, or 10-14.9 years, had steadily increasing relative incident heart failure rates of 29%, 97%, and 210%, respectively, compared with controls, reported Dr. Echouffo-Tcheugui, an endocrinologist at Johns Hopkins Medicine in Baltimore.

Similar rates of HFrEF and HFpEF

Among all 1,841 people in the dataset with diabetes for any length of time each additional 5 years of the disorder linked with a significant, relative 17% increase in the rate of incident heart failure. Incidence of heart failure rose even more sharply with added duration among those with a hemoglobin A1c of 7% or greater, compared with those with better glycemic control. And the rate of incident heart failure with reduced ejection fraction (HFrEF) roughly matched the rate of incident heart failure with preserved ejection fraction (HFpEF).

The study dataset included 9,734 adults enrolled into the Atherosclerosis Risk in Communities (ARIC) study, and during a median follow-up of 22.5 years they had nearly 2,000 episodes of either hospitalization or death secondary to incident heart failure. This included 617 (31%) events involving HFpEF, 495 events (25%) involving HFrEF, and 876 unclassified heart failure events.

The cohort averaged 63 years of age; 58% were women, 23% were Black, and 77% were White (the study design excluded people with other racial and ethnic backgrounds). The study design also excluded people with a history of heart failure or coronary artery disease, as well as those diagnosed with diabetes prior to age 18 resulting in a study group that presumably mostly had type 2 diabetes when diabetes was present. The report provided no data on the specific numbers of patients with type 1 or type 2 diabetes.

“It’s not surprising that a longer duration of diabetes is associated with heart failure, but the etiology remains problematic,” commented Robert H. Eckel, MD, an endocrinologist at the University of Colorado at Denver, Aurora. “The impact of diabetes on incident heart failure is not well know, particularly duration of diabetes,” although disorders often found in patients with diabetes, such as hypertension and diabetic cardiomyopathy, likely have roles in causing heart failure, he said.
 

Diabetes duration may signal need for an SGLT2 inhibitor

“With emerging novel treatments like the SGLT2 [sodium-glucose cotransporter 2] inhibitors for preventing heart failure hospitalizations and deaths in patients with type 2 diabetes, this is a timely analysis,” Dr. Eckel said in an interview.

“There is no question that with increased duration of type 2 diabetes” the need for an agent from the SGLT2-inhibitor class increases. Although, because of the proven protection these drugs give against heart failure events and progression of chronic kidney disease, treatment with this drug class should start early in patients with type 2 diabetes, he added.

Dr. Echouffo-Tcheugui and his coauthors agreed, citing two important clinical take-aways from their findings:

First, interventions that delay the onset of diabetes may potentially reduce incident heart failure; second, patients with diabetes might benefit from cardioprotective treatments such as SGLT2 inhibitors, the report said.

“Our observations suggest the potential prognostic relevance of diabetes duration in assessing heart failure,” the authors wrote. Integrating diabetes duration into heart failure risk estimation in people with diabetes “could help refine the selection of high-risk individuals who may derive the greatest absolute benefit from aggressive cardioprotective therapies such as SGLT2 inhibitors.”

The analysis also identified several other demographic and clinical factors that influenced the relative effect of diabetes duration. Longer duration was linked with higher rates of incident heart failure in women compared with men, in Blacks compared with Whites, in people younger than 65 compared with older people, in people with an A1c of 7% or higher, and in those with a body mass index of 30 kg/m² or greater.

The ARIC study and the analyses run by Dr. Echouffo-Tcheugui and his coauthors received no commercial funding. Dr. Echouffo-Tcheugui and Dr. Eckel had no relevant disclosures.

mzoler@mdedge.com

The longer a person has diabetes, the greater their risk for also developing heart failure, according to an analysis of nearly 10,000 U.S. adults followed for a median of close to 23 years.

In a multivariable analysis the rate of incident heart failure increased steadily and significantly as diabetes duration increased. Among the 168 study subjects (2% of the total study group) who had diabetes for at least 15 years, the subsequent incidence of heart failure was nearly threefold higher than among the 4,802 subjects (49%) who never had diabetes or prediabetes, reported Justin B. Echouffo-Tcheugui, MD, PhD, and coauthors in an article published in JACC Heart Failure.

People with prediabetes (32% of the study population) had a significant but modest increased rate of incident heart failure that was 16% higher than in control subjects who never developed diabetes. People with diabetes for durations of 0-4.9 years, 5.0-9.9 years, or 10-14.9 years, had steadily increasing relative incident heart failure rates of 29%, 97%, and 210%, respectively, compared with controls, reported Dr. Echouffo-Tcheugui, an endocrinologist at Johns Hopkins Medicine in Baltimore.

Similar rates of HFrEF and HFpEF

Among all 1,841 people in the dataset with diabetes for any length of time each additional 5 years of the disorder linked with a significant, relative 17% increase in the rate of incident heart failure. Incidence of heart failure rose even more sharply with added duration among those with a hemoglobin A1c of 7% or greater, compared with those with better glycemic control. And the rate of incident heart failure with reduced ejection fraction (HFrEF) roughly matched the rate of incident heart failure with preserved ejection fraction (HFpEF).

The study dataset included 9,734 adults enrolled into the Atherosclerosis Risk in Communities (ARIC) study, and during a median follow-up of 22.5 years they had nearly 2,000 episodes of either hospitalization or death secondary to incident heart failure. This included 617 (31%) events involving HFpEF, 495 events (25%) involving HFrEF, and 876 unclassified heart failure events.

The cohort averaged 63 years of age; 58% were women, 23% were Black, and 77% were White (the study design excluded people with other racial and ethnic backgrounds). The study design also excluded people with a history of heart failure or coronary artery disease, as well as those diagnosed with diabetes prior to age 18 resulting in a study group that presumably mostly had type 2 diabetes when diabetes was present. The report provided no data on the specific numbers of patients with type 1 or type 2 diabetes.

“It’s not surprising that a longer duration of diabetes is associated with heart failure, but the etiology remains problematic,” commented Robert H. Eckel, MD, an endocrinologist at the University of Colorado at Denver, Aurora. “The impact of diabetes on incident heart failure is not well know, particularly duration of diabetes,” although disorders often found in patients with diabetes, such as hypertension and diabetic cardiomyopathy, likely have roles in causing heart failure, he said.
 

Diabetes duration may signal need for an SGLT2 inhibitor

“With emerging novel treatments like the SGLT2 [sodium-glucose cotransporter 2] inhibitors for preventing heart failure hospitalizations and deaths in patients with type 2 diabetes, this is a timely analysis,” Dr. Eckel said in an interview.

“There is no question that with increased duration of type 2 diabetes” the need for an agent from the SGLT2-inhibitor class increases. Although, because of the proven protection these drugs give against heart failure events and progression of chronic kidney disease, treatment with this drug class should start early in patients with type 2 diabetes, he added.

Dr. Echouffo-Tcheugui and his coauthors agreed, citing two important clinical take-aways from their findings:

First, interventions that delay the onset of diabetes may potentially reduce incident heart failure; second, patients with diabetes might benefit from cardioprotective treatments such as SGLT2 inhibitors, the report said.

“Our observations suggest the potential prognostic relevance of diabetes duration in assessing heart failure,” the authors wrote. Integrating diabetes duration into heart failure risk estimation in people with diabetes “could help refine the selection of high-risk individuals who may derive the greatest absolute benefit from aggressive cardioprotective therapies such as SGLT2 inhibitors.”

The analysis also identified several other demographic and clinical factors that influenced the relative effect of diabetes duration. Longer duration was linked with higher rates of incident heart failure in women compared with men, in Blacks compared with Whites, in people younger than 65 compared with older people, in people with an A1c of 7% or higher, and in those with a body mass index of 30 kg/m² or greater.

The ARIC study and the analyses run by Dr. Echouffo-Tcheugui and his coauthors received no commercial funding. Dr. Echouffo-Tcheugui and Dr. Eckel had no relevant disclosures.

mzoler@mdedge.com

The longer a person has diabetes, the greater their risk for also developing heart failure, according to an analysis of nearly 10,000 U.S. adults followed for a median of close to 23 years.

In a multivariable analysis the rate of incident heart failure increased steadily and significantly as diabetes duration increased. Among the 168 study subjects (2% of the total study group) who had diabetes for at least 15 years, the subsequent incidence of heart failure was nearly threefold higher than among the 4,802 subjects (49%) who never had diabetes or prediabetes, reported Justin B. Echouffo-Tcheugui, MD, PhD, and coauthors in an article published in JACC Heart Failure.

People with prediabetes (32% of the study population) had a significant but modest increased rate of incident heart failure that was 16% higher than in control subjects who never developed diabetes. People with diabetes for durations of 0-4.9 years, 5.0-9.9 years, or 10-14.9 years, had steadily increasing relative incident heart failure rates of 29%, 97%, and 210%, respectively, compared with controls, reported Dr. Echouffo-Tcheugui, an endocrinologist at Johns Hopkins Medicine in Baltimore.

Similar rates of HFrEF and HFpEF

Among all 1,841 people in the dataset with diabetes for any length of time each additional 5 years of the disorder linked with a significant, relative 17% increase in the rate of incident heart failure. Incidence of heart failure rose even more sharply with added duration among those with a hemoglobin A1c of 7% or greater, compared with those with better glycemic control. And the rate of incident heart failure with reduced ejection fraction (HFrEF) roughly matched the rate of incident heart failure with preserved ejection fraction (HFpEF).

The study dataset included 9,734 adults enrolled into the Atherosclerosis Risk in Communities (ARIC) study, and during a median follow-up of 22.5 years they had nearly 2,000 episodes of either hospitalization or death secondary to incident heart failure. This included 617 (31%) events involving HFpEF, 495 events (25%) involving HFrEF, and 876 unclassified heart failure events.

The cohort averaged 63 years of age; 58% were women, 23% were Black, and 77% were White (the study design excluded people with other racial and ethnic backgrounds). The study design also excluded people with a history of heart failure or coronary artery disease, as well as those diagnosed with diabetes prior to age 18 resulting in a study group that presumably mostly had type 2 diabetes when diabetes was present. The report provided no data on the specific numbers of patients with type 1 or type 2 diabetes.

“It’s not surprising that a longer duration of diabetes is associated with heart failure, but the etiology remains problematic,” commented Robert H. Eckel, MD, an endocrinologist at the University of Colorado at Denver, Aurora. “The impact of diabetes on incident heart failure is not well know, particularly duration of diabetes,” although disorders often found in patients with diabetes, such as hypertension and diabetic cardiomyopathy, likely have roles in causing heart failure, he said.
 

Diabetes duration may signal need for an SGLT2 inhibitor

“With emerging novel treatments like the SGLT2 [sodium-glucose cotransporter 2] inhibitors for preventing heart failure hospitalizations and deaths in patients with type 2 diabetes, this is a timely analysis,” Dr. Eckel said in an interview.

“There is no question that with increased duration of type 2 diabetes” the need for an agent from the SGLT2-inhibitor class increases. Although, because of the proven protection these drugs give against heart failure events and progression of chronic kidney disease, treatment with this drug class should start early in patients with type 2 diabetes, he added.

Dr. Echouffo-Tcheugui and his coauthors agreed, citing two important clinical take-aways from their findings:

First, interventions that delay the onset of diabetes may potentially reduce incident heart failure; second, patients with diabetes might benefit from cardioprotective treatments such as SGLT2 inhibitors, the report said.

“Our observations suggest the potential prognostic relevance of diabetes duration in assessing heart failure,” the authors wrote. Integrating diabetes duration into heart failure risk estimation in people with diabetes “could help refine the selection of high-risk individuals who may derive the greatest absolute benefit from aggressive cardioprotective therapies such as SGLT2 inhibitors.”

The analysis also identified several other demographic and clinical factors that influenced the relative effect of diabetes duration. Longer duration was linked with higher rates of incident heart failure in women compared with men, in Blacks compared with Whites, in people younger than 65 compared with older people, in people with an A1c of 7% or higher, and in those with a body mass index of 30 kg/m² or greater.

The ARIC study and the analyses run by Dr. Echouffo-Tcheugui and his coauthors received no commercial funding. Dr. Echouffo-Tcheugui and Dr. Eckel had no relevant disclosures.

mzoler@mdedge.com

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

mzoler@mdedge.com

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

mzoler@mdedge.com

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

mzoler@mdedge.com

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.