Lipid Disorders

Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research. 

However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.

The study was published online Oct. 6 in the journal Circulation.

It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.

“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.

The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
 

Pooled data

After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.

The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year. 

Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.

The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.

Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).

In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).

In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
 

Risk-benefit balance

“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.

“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.

They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.

The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.

The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.

The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.

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

Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research. 

However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.

The study was published online Oct. 6 in the journal Circulation.

It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.

“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.

The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
 

Pooled data

After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.

The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year. 

Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.

The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.

Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).

In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).

In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
 

Risk-benefit balance

“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.

“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.

They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.

The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.

The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.

The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.

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

Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research. 

However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.

The study was published online Oct. 6 in the journal Circulation.

It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.

“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.

The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
 

Pooled data

After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.

The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year. 

Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.

The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.

Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).

In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).

In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
 

Risk-benefit balance

“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.

“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.

They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.

The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.

The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.

The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

Statin use is associated with increased likelihood of diabetes progression, according to a new matched cohort analysis of data from the Department of Veteran Affairs.

Patients with diabetes who were on statins were more likely to begin taking insulin, become hyperglycemic, and to develop acute glycemic complications, and they were also more likely to be prescribed medications from more glucose-lowering drug classes.

Although previous observational and randomized, controlled trials suggested a link between statin use and diabetes progression, they typically relied on measures like insulin resistance, hemoglobin A1c, or fasting blood glucose levels. The new work, however, outlines changes in glycemic control.

The differences between fasting glucose levels and A1c levels were generally smaller than the differences in insulin sensitivity. But A1c and fasting glucose may underestimate a potential effect of statins, since physicians may escalate antidiabetes therapy in response to changes.

Insulin sensitivity is also rarely measured in real-world settings. “This study translated findings reported on academic studies of increased insulin resistance associated with statin use in research papers into everyday language of patient care. That is, patients on statins may need to escalate their antidiabetes therapy and there may have higher occurrences of uncontrolled diabetes events,” lead author Ishak Mansi, MD, said in an interview.

The study was published online in JAMA Internal Medicine.

Dr. Mansi, who is staff internist at the VA North Texas Health System and a professor of medicine and data and population science at the University of Texas, both in Dallas, cautioned about overinterpretation of the findings. “This is an observational study; therefore, it can establish association, but not causation.”
 

No reason to turn down statins

Dr. Mansi noted that it’s important to distinguish between those being prescribed statins as a primary preventive measurement against cardiovascular disease, and those starting statins with preexisting cardiovascular disease for secondary prevention. Statins are a key therapeutic class for secondary prevention. “Their benefits are tremendous, and we should emphasize that no patient should stop taking their statins based on our study – rather, they should talk to their doctors,” said Dr. Mansi.

The study is one of few to look at statin use and diabetes progression in patients who already have diabetes, and the first with a propensity-matched design, according to Om Ganda, MD, who was asked for comment. The results should not deter physicians from prescribing and patients from accepting statins. “Statins should not be withheld in people with high risk of cardiovascular disease, even for primary prevention, as the risk of progression of glucose levels is relatively much smaller and manageable, rather than risking cardiovascular events by stopping or not initiating when indicated by current guidelines,” said Dr. Ganda, who is the medical director of the Lipid Clinic at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, both in Boston.

It’s possible that statins could increase risk of diabetes progression through promoting insulin resistance, and they may also reduce beta-cell function, which could in turn reduce insulin secretion, according to Dr. Ganda.

The study group included 83,022 pairs of statin users and matched controls, of whom 95% were men; 68.2% were White; 22% were Black; 2.1% were Native American, Pacific Islander, or Alaska Native; and 0.8% were Asian. The mean age was 60 years.

Some 56% of statin users experienced diabetes progression, compared with 48% of control patients (odds ratio, 1.37; P < .001). Progression was defined as intensification of diabetes therapy through new use of insulin or increase in the number of medication classes, new onset chronic hyperglycemia, or acute complications from hyperglycemia.

The association was seen in the component measures, including an increased number of glucose-lowering medication classes (OR, 1.41; P < .001), the frequency of new insulin use (OR, 1.16; P < .001), persistent glycemia (OR, 1.13; P < .001), and a new diagnosis of ketoacidosis or uncontrolled diabetes (OR, 1.24; P < .001).

There was also a dose-response relationship between the intensity of LDL cholesterol–lowering medication and diabetes progression.
 

More research needed

The findings don’t necessarily have a strong clinical impact, but the researchers hope it pushes toward greater personalization of statin treatment. The benefits of statins have been well studied, but their potential harms have not received the same attention. Dr. Mansi hopes to learn more about which populations stand to gain the most for primary cardiovascular disease prevention, such as older versus younger populations, healthier or sicker patients, and those with well-controlled versus uncontrolled diabetes. “Answering these questions [would] impact hundreds of millions of patients and cannot be postponed,” said Dr. Mansi. He also called for dedicated funding for research into the adverse events of frequently used medications.

Dr. Mansi and Dr. Ganda have no relevant financial disclosures.

Statin use is associated with increased likelihood of diabetes progression, according to a new matched cohort analysis of data from the Department of Veteran Affairs.

Patients with diabetes who were on statins were more likely to begin taking insulin, become hyperglycemic, and to develop acute glycemic complications, and they were also more likely to be prescribed medications from more glucose-lowering drug classes.

Although previous observational and randomized, controlled trials suggested a link between statin use and diabetes progression, they typically relied on measures like insulin resistance, hemoglobin A1c, or fasting blood glucose levels. The new work, however, outlines changes in glycemic control.

The differences between fasting glucose levels and A1c levels were generally smaller than the differences in insulin sensitivity. But A1c and fasting glucose may underestimate a potential effect of statins, since physicians may escalate antidiabetes therapy in response to changes.

Insulin sensitivity is also rarely measured in real-world settings. “This study translated findings reported on academic studies of increased insulin resistance associated with statin use in research papers into everyday language of patient care. That is, patients on statins may need to escalate their antidiabetes therapy and there may have higher occurrences of uncontrolled diabetes events,” lead author Ishak Mansi, MD, said in an interview.

The study was published online in JAMA Internal Medicine.

Dr. Mansi, who is staff internist at the VA North Texas Health System and a professor of medicine and data and population science at the University of Texas, both in Dallas, cautioned about overinterpretation of the findings. “This is an observational study; therefore, it can establish association, but not causation.”
 

No reason to turn down statins

Dr. Mansi noted that it’s important to distinguish between those being prescribed statins as a primary preventive measurement against cardiovascular disease, and those starting statins with preexisting cardiovascular disease for secondary prevention. Statins are a key therapeutic class for secondary prevention. “Their benefits are tremendous, and we should emphasize that no patient should stop taking their statins based on our study – rather, they should talk to their doctors,” said Dr. Mansi.

The study is one of few to look at statin use and diabetes progression in patients who already have diabetes, and the first with a propensity-matched design, according to Om Ganda, MD, who was asked for comment. The results should not deter physicians from prescribing and patients from accepting statins. “Statins should not be withheld in people with high risk of cardiovascular disease, even for primary prevention, as the risk of progression of glucose levels is relatively much smaller and manageable, rather than risking cardiovascular events by stopping or not initiating when indicated by current guidelines,” said Dr. Ganda, who is the medical director of the Lipid Clinic at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, both in Boston.

It’s possible that statins could increase risk of diabetes progression through promoting insulin resistance, and they may also reduce beta-cell function, which could in turn reduce insulin secretion, according to Dr. Ganda.

The study group included 83,022 pairs of statin users and matched controls, of whom 95% were men; 68.2% were White; 22% were Black; 2.1% were Native American, Pacific Islander, or Alaska Native; and 0.8% were Asian. The mean age was 60 years.

Some 56% of statin users experienced diabetes progression, compared with 48% of control patients (odds ratio, 1.37; P < .001). Progression was defined as intensification of diabetes therapy through new use of insulin or increase in the number of medication classes, new onset chronic hyperglycemia, or acute complications from hyperglycemia.

The association was seen in the component measures, including an increased number of glucose-lowering medication classes (OR, 1.41; P < .001), the frequency of new insulin use (OR, 1.16; P < .001), persistent glycemia (OR, 1.13; P < .001), and a new diagnosis of ketoacidosis or uncontrolled diabetes (OR, 1.24; P < .001).

There was also a dose-response relationship between the intensity of LDL cholesterol–lowering medication and diabetes progression.
 

More research needed

The findings don’t necessarily have a strong clinical impact, but the researchers hope it pushes toward greater personalization of statin treatment. The benefits of statins have been well studied, but their potential harms have not received the same attention. Dr. Mansi hopes to learn more about which populations stand to gain the most for primary cardiovascular disease prevention, such as older versus younger populations, healthier or sicker patients, and those with well-controlled versus uncontrolled diabetes. “Answering these questions [would] impact hundreds of millions of patients and cannot be postponed,” said Dr. Mansi. He also called for dedicated funding for research into the adverse events of frequently used medications.

Dr. Mansi and Dr. Ganda have no relevant financial disclosures.

Statin use is associated with increased likelihood of diabetes progression, according to a new matched cohort analysis of data from the Department of Veteran Affairs.

Patients with diabetes who were on statins were more likely to begin taking insulin, become hyperglycemic, and to develop acute glycemic complications, and they were also more likely to be prescribed medications from more glucose-lowering drug classes.

Although previous observational and randomized, controlled trials suggested a link between statin use and diabetes progression, they typically relied on measures like insulin resistance, hemoglobin A1c, or fasting blood glucose levels. The new work, however, outlines changes in glycemic control.

The differences between fasting glucose levels and A1c levels were generally smaller than the differences in insulin sensitivity. But A1c and fasting glucose may underestimate a potential effect of statins, since physicians may escalate antidiabetes therapy in response to changes.

Insulin sensitivity is also rarely measured in real-world settings. “This study translated findings reported on academic studies of increased insulin resistance associated with statin use in research papers into everyday language of patient care. That is, patients on statins may need to escalate their antidiabetes therapy and there may have higher occurrences of uncontrolled diabetes events,” lead author Ishak Mansi, MD, said in an interview.

The study was published online in JAMA Internal Medicine.

Dr. Mansi, who is staff internist at the VA North Texas Health System and a professor of medicine and data and population science at the University of Texas, both in Dallas, cautioned about overinterpretation of the findings. “This is an observational study; therefore, it can establish association, but not causation.”
 

No reason to turn down statins

Dr. Mansi noted that it’s important to distinguish between those being prescribed statins as a primary preventive measurement against cardiovascular disease, and those starting statins with preexisting cardiovascular disease for secondary prevention. Statins are a key therapeutic class for secondary prevention. “Their benefits are tremendous, and we should emphasize that no patient should stop taking their statins based on our study – rather, they should talk to their doctors,” said Dr. Mansi.

The study is one of few to look at statin use and diabetes progression in patients who already have diabetes, and the first with a propensity-matched design, according to Om Ganda, MD, who was asked for comment. The results should not deter physicians from prescribing and patients from accepting statins. “Statins should not be withheld in people with high risk of cardiovascular disease, even for primary prevention, as the risk of progression of glucose levels is relatively much smaller and manageable, rather than risking cardiovascular events by stopping or not initiating when indicated by current guidelines,” said Dr. Ganda, who is the medical director of the Lipid Clinic at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, both in Boston.

It’s possible that statins could increase risk of diabetes progression through promoting insulin resistance, and they may also reduce beta-cell function, which could in turn reduce insulin secretion, according to Dr. Ganda.

The study group included 83,022 pairs of statin users and matched controls, of whom 95% were men; 68.2% were White; 22% were Black; 2.1% were Native American, Pacific Islander, or Alaska Native; and 0.8% were Asian. The mean age was 60 years.

Some 56% of statin users experienced diabetes progression, compared with 48% of control patients (odds ratio, 1.37; P < .001). Progression was defined as intensification of diabetes therapy through new use of insulin or increase in the number of medication classes, new onset chronic hyperglycemia, or acute complications from hyperglycemia.

The association was seen in the component measures, including an increased number of glucose-lowering medication classes (OR, 1.41; P < .001), the frequency of new insulin use (OR, 1.16; P < .001), persistent glycemia (OR, 1.13; P < .001), and a new diagnosis of ketoacidosis or uncontrolled diabetes (OR, 1.24; P < .001).

There was also a dose-response relationship between the intensity of LDL cholesterol–lowering medication and diabetes progression.
 

More research needed

The findings don’t necessarily have a strong clinical impact, but the researchers hope it pushes toward greater personalization of statin treatment. The benefits of statins have been well studied, but their potential harms have not received the same attention. Dr. Mansi hopes to learn more about which populations stand to gain the most for primary cardiovascular disease prevention, such as older versus younger populations, healthier or sicker patients, and those with well-controlled versus uncontrolled diabetes. “Answering these questions [would] impact hundreds of millions of patients and cannot be postponed,” said Dr. Mansi. He also called for dedicated funding for research into the adverse events of frequently used medications.

Dr. Mansi and Dr. Ganda have no relevant financial disclosures.

Weight loss of at least 15% of body weight should become the “initial principal treatment goal” for many patients with type 2 diabetes, according to a new review and proposal published by an international quartet of diabetologists.

Although this proposition currently has formal backing from just the four authors of the article published in the Lancet, their recommendation to elevate substantial weight loss to the front line of management for many patients with type 2 diabetes drew quick support from leaders of several diabetes organizations, albeit with some caveats.

“Our main message is that treatment of obesity should be the future of diabetes treatment,” summed up Ildiko Lingvay, MD, lead author of the new review and proposal, at the annual meeting of the European Association for the Study of Diabetes.

“Right now, a relatively small percentage of clinicians [who treat patients with type 2 diabetes] address obesity and know how to treat it. That has to change. Every clinician who treats diabetes needs to know how to treat obesity,” said Dr. Lingvay, a professor in the division of endocrinology at the University of Texas Southwestern Medical Center, Dallas.

This requires a sea change in the way clinicians approach treating patients with type 2 diabetes, which until now has generally involved “exclusive focus on glycemic control,” the authors wrote. “Practice management should refocus to effectively incorporate weight management to treat patients with type 2 diabetes.”

Successfully implementing their new, proposed change in focus “will take fundamental change,” noted Dr. Lingvay, who expressed hope that international guidelines will soon endorse this approach, an action that would be “a huge step in the right direction.”
 

Target weight-loss drugs to the right patients.

Initial reactions from representatives of several diabetes and obesity groups suggested that official endorsements of this management strategy for at least a subset of patients with type 2 diabetes may be forthcoming.

“The American Diabetes Association’s standards of care is aligned with this approach in focusing on obesity as a target of management in people with type 2 diabetes,” commented Nuha A. El Sayed, MD, vice president for health care improvement for the ADA. An “area of discussion” is the specific weight-loss target of at least 15%, because patients benefit from more modest weight losses of 5%-7%, and a target loss of 15% may not be achievable for some patients, she noted in a statement.

The ADA’s leadership and its professional practice committee will “carefully consider” the new, published proposal, added Dr. El Sayed, a diabetologist at the Joslin Diabetes Center in Boston.

Similar caution over generalizability of the 15% loss target came from Stefano Del Prato, MD, president of the European Society for the Study of Diabetes.

“Not everyone responds to the same extent” to the newest pharmaceuticals for facilitating weight loss, such as the glucagonlike peptide-1 receptor agonists, so the ideal would be to try to “identify patients who respond better to weight loss and can lose at least 15% of their weight. We need to improve our ability to identify patients who respond better,” said Dr. Del Prato, a professor of endocrinology and metabolism at the University of Pisa (Italy).

Despite this, he agreed in an interview that “a significant reduction in body weight should be seen as a target for treatment of type 2 diabetes,”

“Appropriate training for obesity management is essential for those working on type 2 diabetes prevention or management,” commented Jason C.G. Halford, PhD, a professor of biological psychology at the University Of Leeds (England), and president of the European Association for the Study of Obesity.

For some patients with type 2 diabetes “losing 10%-15% of body weight can mean their diabetes goes into remission,” and “losing even a small amount of weight can be life changing, it can help people better manage their blood sugars and blood pressure, and reduce their risk for developing diabetes complications like heart disease and sight loss,” commented Lucy Chambers, PhD, head of research communications for Diabetes UK.

15% loss is a ‘reachable’ goal

Dr. Lingvay and coauthors acknowledged that weight loss of less than 15% can benefit many patients with type 2 diabetes, but they felt that a loss of at least 15% gives patients a realistic and potentially potent goal to strive for.

At least 15% loss “is a goal that is beneficial and reachable for many patients. Not everyone will get there, but the closer that patients get to this, or beyond, the bigger their benefit,” she explained. “There is no magic number” for exactly how much weight a patient needs to lose to improve their health. Dr. Lingvay also highlighted that weight loss is a better target for patients than remission of their diabetes because remission may no longer be possible in patients with longstanding type 2 diabetes.

The review divides patients with type 2 diabetes into three subgroups: those with adiposity-related disease, which includes about 40%-70% of patients with type 2 diabetes; patients with cardiovascular disease as their most prominent comorbidity, a subgroup that includes about a third of patients with type 2 diabetes; and the remaining patients with primarily beta-cell dysfunction with a principle morbidity of hyperglycemia, comprising about 10%-20% of patients with type 2 diabetes. Patients in the adiposity-related diabetes subgroup form the primary target group for interventions focused on weight loss.

Incretin-based weight-loss agents propel change.

The review also links the timing of the new recommendations to recent evidence that treatment with relatively new medications from classes such as the GLP-1 receptor agonists can produce weight loss of at least 15% in most patients with type 2 diabetes, especially those with the adiposity-related form of the disease.

“The number of patients who can achieve and maintain weight loss with lifestyle alone is limited, and while bariatric surgery is very effective [for producing substantial weight loss], only a minority of patients have access to it,” and the necessary scalability of surgery is doubtful, said Priya Sumithran, MBBS, PhD, an endocrinologist and leader of the obesity research group at the University of Melbourne, and a coauthor on the new review. Compelling evidence now exists that the gap between lifestyle interventions and bariatric surgery can now be filled by a new generation of incretin-based agents that can safely produce substantial weight loss.

New agents that work as GLP-1 receptor agonists and on related incretin pathways “have changed how we think about treating type 2 diabetes,” Dr. Lingvay declared.

Dr. Lingvay and Dr. Del Prato have each been consultants to numerous drug companies. Dr. Sumithran has been an adviser to and speaker on behalf of Novo Nordisk. Dr. El Sayed, Dr. Halford, and Dr. Chambers had no relevant disclosures.

[email protected]

Weight loss of at least 15% of body weight should become the “initial principal treatment goal” for many patients with type 2 diabetes, according to a new review and proposal published by an international quartet of diabetologists.

Although this proposition currently has formal backing from just the four authors of the article published in the Lancet, their recommendation to elevate substantial weight loss to the front line of management for many patients with type 2 diabetes drew quick support from leaders of several diabetes organizations, albeit with some caveats.

“Our main message is that treatment of obesity should be the future of diabetes treatment,” summed up Ildiko Lingvay, MD, lead author of the new review and proposal, at the annual meeting of the European Association for the Study of Diabetes.

“Right now, a relatively small percentage of clinicians [who treat patients with type 2 diabetes] address obesity and know how to treat it. That has to change. Every clinician who treats diabetes needs to know how to treat obesity,” said Dr. Lingvay, a professor in the division of endocrinology at the University of Texas Southwestern Medical Center, Dallas.

This requires a sea change in the way clinicians approach treating patients with type 2 diabetes, which until now has generally involved “exclusive focus on glycemic control,” the authors wrote. “Practice management should refocus to effectively incorporate weight management to treat patients with type 2 diabetes.”

Successfully implementing their new, proposed change in focus “will take fundamental change,” noted Dr. Lingvay, who expressed hope that international guidelines will soon endorse this approach, an action that would be “a huge step in the right direction.”
 

Target weight-loss drugs to the right patients.

Initial reactions from representatives of several diabetes and obesity groups suggested that official endorsements of this management strategy for at least a subset of patients with type 2 diabetes may be forthcoming.

“The American Diabetes Association’s standards of care is aligned with this approach in focusing on obesity as a target of management in people with type 2 diabetes,” commented Nuha A. El Sayed, MD, vice president for health care improvement for the ADA. An “area of discussion” is the specific weight-loss target of at least 15%, because patients benefit from more modest weight losses of 5%-7%, and a target loss of 15% may not be achievable for some patients, she noted in a statement.

The ADA’s leadership and its professional practice committee will “carefully consider” the new, published proposal, added Dr. El Sayed, a diabetologist at the Joslin Diabetes Center in Boston.

Similar caution over generalizability of the 15% loss target came from Stefano Del Prato, MD, president of the European Society for the Study of Diabetes.

“Not everyone responds to the same extent” to the newest pharmaceuticals for facilitating weight loss, such as the glucagonlike peptide-1 receptor agonists, so the ideal would be to try to “identify patients who respond better to weight loss and can lose at least 15% of their weight. We need to improve our ability to identify patients who respond better,” said Dr. Del Prato, a professor of endocrinology and metabolism at the University of Pisa (Italy).

Despite this, he agreed in an interview that “a significant reduction in body weight should be seen as a target for treatment of type 2 diabetes,”

“Appropriate training for obesity management is essential for those working on type 2 diabetes prevention or management,” commented Jason C.G. Halford, PhD, a professor of biological psychology at the University Of Leeds (England), and president of the European Association for the Study of Obesity.

For some patients with type 2 diabetes “losing 10%-15% of body weight can mean their diabetes goes into remission,” and “losing even a small amount of weight can be life changing, it can help people better manage their blood sugars and blood pressure, and reduce their risk for developing diabetes complications like heart disease and sight loss,” commented Lucy Chambers, PhD, head of research communications for Diabetes UK.

15% loss is a ‘reachable’ goal

Dr. Lingvay and coauthors acknowledged that weight loss of less than 15% can benefit many patients with type 2 diabetes, but they felt that a loss of at least 15% gives patients a realistic and potentially potent goal to strive for.

At least 15% loss “is a goal that is beneficial and reachable for many patients. Not everyone will get there, but the closer that patients get to this, or beyond, the bigger their benefit,” she explained. “There is no magic number” for exactly how much weight a patient needs to lose to improve their health. Dr. Lingvay also highlighted that weight loss is a better target for patients than remission of their diabetes because remission may no longer be possible in patients with longstanding type 2 diabetes.

The review divides patients with type 2 diabetes into three subgroups: those with adiposity-related disease, which includes about 40%-70% of patients with type 2 diabetes; patients with cardiovascular disease as their most prominent comorbidity, a subgroup that includes about a third of patients with type 2 diabetes; and the remaining patients with primarily beta-cell dysfunction with a principle morbidity of hyperglycemia, comprising about 10%-20% of patients with type 2 diabetes. Patients in the adiposity-related diabetes subgroup form the primary target group for interventions focused on weight loss.

Incretin-based weight-loss agents propel change.

The review also links the timing of the new recommendations to recent evidence that treatment with relatively new medications from classes such as the GLP-1 receptor agonists can produce weight loss of at least 15% in most patients with type 2 diabetes, especially those with the adiposity-related form of the disease.

“The number of patients who can achieve and maintain weight loss with lifestyle alone is limited, and while bariatric surgery is very effective [for producing substantial weight loss], only a minority of patients have access to it,” and the necessary scalability of surgery is doubtful, said Priya Sumithran, MBBS, PhD, an endocrinologist and leader of the obesity research group at the University of Melbourne, and a coauthor on the new review. Compelling evidence now exists that the gap between lifestyle interventions and bariatric surgery can now be filled by a new generation of incretin-based agents that can safely produce substantial weight loss.

New agents that work as GLP-1 receptor agonists and on related incretin pathways “have changed how we think about treating type 2 diabetes,” Dr. Lingvay declared.

Dr. Lingvay and Dr. Del Prato have each been consultants to numerous drug companies. Dr. Sumithran has been an adviser to and speaker on behalf of Novo Nordisk. Dr. El Sayed, Dr. Halford, and Dr. Chambers had no relevant disclosures.

[email protected]

Weight loss of at least 15% of body weight should become the “initial principal treatment goal” for many patients with type 2 diabetes, according to a new review and proposal published by an international quartet of diabetologists.

Although this proposition currently has formal backing from just the four authors of the article published in the Lancet, their recommendation to elevate substantial weight loss to the front line of management for many patients with type 2 diabetes drew quick support from leaders of several diabetes organizations, albeit with some caveats.

“Our main message is that treatment of obesity should be the future of diabetes treatment,” summed up Ildiko Lingvay, MD, lead author of the new review and proposal, at the annual meeting of the European Association for the Study of Diabetes.

“Right now, a relatively small percentage of clinicians [who treat patients with type 2 diabetes] address obesity and know how to treat it. That has to change. Every clinician who treats diabetes needs to know how to treat obesity,” said Dr. Lingvay, a professor in the division of endocrinology at the University of Texas Southwestern Medical Center, Dallas.

This requires a sea change in the way clinicians approach treating patients with type 2 diabetes, which until now has generally involved “exclusive focus on glycemic control,” the authors wrote. “Practice management should refocus to effectively incorporate weight management to treat patients with type 2 diabetes.”

Successfully implementing their new, proposed change in focus “will take fundamental change,” noted Dr. Lingvay, who expressed hope that international guidelines will soon endorse this approach, an action that would be “a huge step in the right direction.”
 

Target weight-loss drugs to the right patients.

Initial reactions from representatives of several diabetes and obesity groups suggested that official endorsements of this management strategy for at least a subset of patients with type 2 diabetes may be forthcoming.

“The American Diabetes Association’s standards of care is aligned with this approach in focusing on obesity as a target of management in people with type 2 diabetes,” commented Nuha A. El Sayed, MD, vice president for health care improvement for the ADA. An “area of discussion” is the specific weight-loss target of at least 15%, because patients benefit from more modest weight losses of 5%-7%, and a target loss of 15% may not be achievable for some patients, she noted in a statement.

The ADA’s leadership and its professional practice committee will “carefully consider” the new, published proposal, added Dr. El Sayed, a diabetologist at the Joslin Diabetes Center in Boston.

Similar caution over generalizability of the 15% loss target came from Stefano Del Prato, MD, president of the European Society for the Study of Diabetes.

“Not everyone responds to the same extent” to the newest pharmaceuticals for facilitating weight loss, such as the glucagonlike peptide-1 receptor agonists, so the ideal would be to try to “identify patients who respond better to weight loss and can lose at least 15% of their weight. We need to improve our ability to identify patients who respond better,” said Dr. Del Prato, a professor of endocrinology and metabolism at the University of Pisa (Italy).

Despite this, he agreed in an interview that “a significant reduction in body weight should be seen as a target for treatment of type 2 diabetes,”

“Appropriate training for obesity management is essential for those working on type 2 diabetes prevention or management,” commented Jason C.G. Halford, PhD, a professor of biological psychology at the University Of Leeds (England), and president of the European Association for the Study of Obesity.

For some patients with type 2 diabetes “losing 10%-15% of body weight can mean their diabetes goes into remission,” and “losing even a small amount of weight can be life changing, it can help people better manage their blood sugars and blood pressure, and reduce their risk for developing diabetes complications like heart disease and sight loss,” commented Lucy Chambers, PhD, head of research communications for Diabetes UK.

15% loss is a ‘reachable’ goal

Dr. Lingvay and coauthors acknowledged that weight loss of less than 15% can benefit many patients with type 2 diabetes, but they felt that a loss of at least 15% gives patients a realistic and potentially potent goal to strive for.

At least 15% loss “is a goal that is beneficial and reachable for many patients. Not everyone will get there, but the closer that patients get to this, or beyond, the bigger their benefit,” she explained. “There is no magic number” for exactly how much weight a patient needs to lose to improve their health. Dr. Lingvay also highlighted that weight loss is a better target for patients than remission of their diabetes because remission may no longer be possible in patients with longstanding type 2 diabetes.

The review divides patients with type 2 diabetes into three subgroups: those with adiposity-related disease, which includes about 40%-70% of patients with type 2 diabetes; patients with cardiovascular disease as their most prominent comorbidity, a subgroup that includes about a third of patients with type 2 diabetes; and the remaining patients with primarily beta-cell dysfunction with a principle morbidity of hyperglycemia, comprising about 10%-20% of patients with type 2 diabetes. Patients in the adiposity-related diabetes subgroup form the primary target group for interventions focused on weight loss.

Incretin-based weight-loss agents propel change.

The review also links the timing of the new recommendations to recent evidence that treatment with relatively new medications from classes such as the GLP-1 receptor agonists can produce weight loss of at least 15% in most patients with type 2 diabetes, especially those with the adiposity-related form of the disease.

“The number of patients who can achieve and maintain weight loss with lifestyle alone is limited, and while bariatric surgery is very effective [for producing substantial weight loss], only a minority of patients have access to it,” and the necessary scalability of surgery is doubtful, said Priya Sumithran, MBBS, PhD, an endocrinologist and leader of the obesity research group at the University of Melbourne, and a coauthor on the new review. Compelling evidence now exists that the gap between lifestyle interventions and bariatric surgery can now be filled by a new generation of incretin-based agents that can safely produce substantial weight loss.

New agents that work as GLP-1 receptor agonists and on related incretin pathways “have changed how we think about treating type 2 diabetes,” Dr. Lingvay declared.

Dr. Lingvay and Dr. Del Prato have each been consultants to numerous drug companies. Dr. Sumithran has been an adviser to and speaker on behalf of Novo Nordisk. Dr. El Sayed, Dr. Halford, and Dr. Chambers had no relevant disclosures.

[email protected]

Women with a history of polycystic ovary syndrome (PCOS) are more likely to experience somatic and urogenital symptoms post menopause, but they were no more likely to experience severe hot flashes than were other women with similar characteristics, according to research presented Sept. 24 at the hybrid annual meeting of the North American Menopause Society.

PCOS and vasomotor symptoms are each risk factors for cardiovascular disease, so researchers wanted to find out whether they were linked to one another, which might indicate that they are markers for the same underlying mechanisms that increase heart disease risk. The lack of an association, however, raises questions about how much each of these conditions might independently increase cardiovascular risk.

“Should we take a little more time to truly risk-assess these patients not just with their ASCVD risk score, but take into account that they have PCOS and they’re going through menopause, and how severe their hot flashes are?” asked Angie S. Lobo, MD, an internal medicine specialist at Mayo Clinic in Rochester, Minn., when she discussed her findings in an interview.

The association between PCOS and urogenital symptoms was surprising, Dr. Lobo said, but she said she suspects the reason for the finding may be the self-reported nature of the study.

“If you ask the question, you get the answer,” Dr. Lobo said. ”Are we just not asking the right questions to our patients? And should we be doing this more often? This is an exciting finding because there’s so much room to improve the clinical care of our patients.”

The researchers analyzed data from 3,308 women, ages 45-60, in a cross-sectional study from the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The study occurred at Mayo Clinic locations between May 2015 and December 2019 in Rochester, Minn., in Scottsdale, Ariz., and in Jacksonville, Fla.

The women were an average 53 years old and were primarily White, educated, and postmenopausal. Among the 4.6% of women with a self-reported history of PCOS, 56% of them reported depression symptoms, compared to 42% of women without PCOS. Those with PCOS also had nearly twice the prevalence of obesity – 42% versus 22.5% among women without PCOS – and had a higher average overall score on the Menopause Rating Scale (17.7 vs. 14.7; P < .001).

Although women with PCOS initially had a greater burden of psychological symptoms on the same scale, that association disappeared after adjustment for menopause status, body mass index, depression, anxiety, and current use of hormone therapy. Even after adjustment, however, women with PCOS had higher average scores for somatic symptoms (6.7 vs. 5.6) and urogenital symptoms (5.2 vs. 4.3) than those of women without PCOS (P < .001).

Severe or very severe hot flashes were no more likely in women with a history of PCOS than in the other women in the study.

”The mechanisms underlying the correlation between PCOS and menopause symptoms in the psychological and urogenital symptom domains requires further study, although the well-known association between PCOS and mood disorders may explain the high psychological symptom burden in these women during the menopause transition,” the authors concluded.

Rachael B. Smith, DO, clinical assistant professor of ob.gyn. at the University of Arizona in Phoenix, said she was not surprised to see an association between PCOS and menopause symptoms overall, but she was surprised that PCOS did not correlate with severity of vasomotor symptoms. But Dr. Smith pointed out that the sample size of women with PCOS is fairly small (n = 151).

“Given that PCOS prevalence is about 6%-10%, I feel this association should be further studied to improve our counseling and treatment for this PCOS population,” Dr. Smith, who was not involved in the research, said in an interview. “The take-home message for physicians is improved patient-tailored counseling that takes into account patients’ prior medical history of PCOS.”

Although it will require more research to find out, Dr. Smith said she suspects that PCOS and vasomotor symptoms are additive risk factors for cardiovascular disease. She also noted that the study is limited by the homogeneity of the study population.

The research was funded by the National Institutes of Health. Dr. Lobo and Dr. Smith had no disclosures.

Women with a history of polycystic ovary syndrome (PCOS) are more likely to experience somatic and urogenital symptoms post menopause, but they were no more likely to experience severe hot flashes than were other women with similar characteristics, according to research presented Sept. 24 at the hybrid annual meeting of the North American Menopause Society.

PCOS and vasomotor symptoms are each risk factors for cardiovascular disease, so researchers wanted to find out whether they were linked to one another, which might indicate that they are markers for the same underlying mechanisms that increase heart disease risk. The lack of an association, however, raises questions about how much each of these conditions might independently increase cardiovascular risk.

“Should we take a little more time to truly risk-assess these patients not just with their ASCVD risk score, but take into account that they have PCOS and they’re going through menopause, and how severe their hot flashes are?” asked Angie S. Lobo, MD, an internal medicine specialist at Mayo Clinic in Rochester, Minn., when she discussed her findings in an interview.

The association between PCOS and urogenital symptoms was surprising, Dr. Lobo said, but she said she suspects the reason for the finding may be the self-reported nature of the study.

“If you ask the question, you get the answer,” Dr. Lobo said. ”Are we just not asking the right questions to our patients? And should we be doing this more often? This is an exciting finding because there’s so much room to improve the clinical care of our patients.”

The researchers analyzed data from 3,308 women, ages 45-60, in a cross-sectional study from the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The study occurred at Mayo Clinic locations between May 2015 and December 2019 in Rochester, Minn., in Scottsdale, Ariz., and in Jacksonville, Fla.

The women were an average 53 years old and were primarily White, educated, and postmenopausal. Among the 4.6% of women with a self-reported history of PCOS, 56% of them reported depression symptoms, compared to 42% of women without PCOS. Those with PCOS also had nearly twice the prevalence of obesity – 42% versus 22.5% among women without PCOS – and had a higher average overall score on the Menopause Rating Scale (17.7 vs. 14.7; P < .001).

Although women with PCOS initially had a greater burden of psychological symptoms on the same scale, that association disappeared after adjustment for menopause status, body mass index, depression, anxiety, and current use of hormone therapy. Even after adjustment, however, women with PCOS had higher average scores for somatic symptoms (6.7 vs. 5.6) and urogenital symptoms (5.2 vs. 4.3) than those of women without PCOS (P < .001).

Severe or very severe hot flashes were no more likely in women with a history of PCOS than in the other women in the study.

”The mechanisms underlying the correlation between PCOS and menopause symptoms in the psychological and urogenital symptom domains requires further study, although the well-known association between PCOS and mood disorders may explain the high psychological symptom burden in these women during the menopause transition,” the authors concluded.

Rachael B. Smith, DO, clinical assistant professor of ob.gyn. at the University of Arizona in Phoenix, said she was not surprised to see an association between PCOS and menopause symptoms overall, but she was surprised that PCOS did not correlate with severity of vasomotor symptoms. But Dr. Smith pointed out that the sample size of women with PCOS is fairly small (n = 151).

“Given that PCOS prevalence is about 6%-10%, I feel this association should be further studied to improve our counseling and treatment for this PCOS population,” Dr. Smith, who was not involved in the research, said in an interview. “The take-home message for physicians is improved patient-tailored counseling that takes into account patients’ prior medical history of PCOS.”

Although it will require more research to find out, Dr. Smith said she suspects that PCOS and vasomotor symptoms are additive risk factors for cardiovascular disease. She also noted that the study is limited by the homogeneity of the study population.

The research was funded by the National Institutes of Health. Dr. Lobo and Dr. Smith had no disclosures.

Women with a history of polycystic ovary syndrome (PCOS) are more likely to experience somatic and urogenital symptoms post menopause, but they were no more likely to experience severe hot flashes than were other women with similar characteristics, according to research presented Sept. 24 at the hybrid annual meeting of the North American Menopause Society.

PCOS and vasomotor symptoms are each risk factors for cardiovascular disease, so researchers wanted to find out whether they were linked to one another, which might indicate that they are markers for the same underlying mechanisms that increase heart disease risk. The lack of an association, however, raises questions about how much each of these conditions might independently increase cardiovascular risk.

“Should we take a little more time to truly risk-assess these patients not just with their ASCVD risk score, but take into account that they have PCOS and they’re going through menopause, and how severe their hot flashes are?” asked Angie S. Lobo, MD, an internal medicine specialist at Mayo Clinic in Rochester, Minn., when she discussed her findings in an interview.

The association between PCOS and urogenital symptoms was surprising, Dr. Lobo said, but she said she suspects the reason for the finding may be the self-reported nature of the study.

“If you ask the question, you get the answer,” Dr. Lobo said. ”Are we just not asking the right questions to our patients? And should we be doing this more often? This is an exciting finding because there’s so much room to improve the clinical care of our patients.”

The researchers analyzed data from 3,308 women, ages 45-60, in a cross-sectional study from the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The study occurred at Mayo Clinic locations between May 2015 and December 2019 in Rochester, Minn., in Scottsdale, Ariz., and in Jacksonville, Fla.

The women were an average 53 years old and were primarily White, educated, and postmenopausal. Among the 4.6% of women with a self-reported history of PCOS, 56% of them reported depression symptoms, compared to 42% of women without PCOS. Those with PCOS also had nearly twice the prevalence of obesity – 42% versus 22.5% among women without PCOS – and had a higher average overall score on the Menopause Rating Scale (17.7 vs. 14.7; P < .001).

Although women with PCOS initially had a greater burden of psychological symptoms on the same scale, that association disappeared after adjustment for menopause status, body mass index, depression, anxiety, and current use of hormone therapy. Even after adjustment, however, women with PCOS had higher average scores for somatic symptoms (6.7 vs. 5.6) and urogenital symptoms (5.2 vs. 4.3) than those of women without PCOS (P < .001).

Severe or very severe hot flashes were no more likely in women with a history of PCOS than in the other women in the study.

”The mechanisms underlying the correlation between PCOS and menopause symptoms in the psychological and urogenital symptom domains requires further study, although the well-known association between PCOS and mood disorders may explain the high psychological symptom burden in these women during the menopause transition,” the authors concluded.

Rachael B. Smith, DO, clinical assistant professor of ob.gyn. at the University of Arizona in Phoenix, said she was not surprised to see an association between PCOS and menopause symptoms overall, but she was surprised that PCOS did not correlate with severity of vasomotor symptoms. But Dr. Smith pointed out that the sample size of women with PCOS is fairly small (n = 151).

“Given that PCOS prevalence is about 6%-10%, I feel this association should be further studied to improve our counseling and treatment for this PCOS population,” Dr. Smith, who was not involved in the research, said in an interview. “The take-home message for physicians is improved patient-tailored counseling that takes into account patients’ prior medical history of PCOS.”

Although it will require more research to find out, Dr. Smith said she suspects that PCOS and vasomotor symptoms are additive risk factors for cardiovascular disease. She also noted that the study is limited by the homogeneity of the study population.

The research was funded by the National Institutes of Health. Dr. Lobo and Dr. Smith had no disclosures.

Patients with type 2 diabetes who underwent bariatric surgery commonly experienced remission, but there was little increase in rates of remission above a threshold of 20% total weight loss (TWL), according to a retrospective analysis of 5,928 patients with diabetes in an integrated health care system in Southern California.

The findings should reassure physicians and patients that surgery will be beneficial, according to lead author Karen Coleman, PhD, professor of health systems science at Kaiser Permanente Southern California.

Dr. Coleman has heard from many physicians saying they recommend against bariatric surgery because of concerns that patients gain weight back and therefore won’t get a long-term benefit, but this is not supported by the literature. “Hundreds of articles at this point show that this simply is not true. In addition, providers seem to think about bariatric surgery as an ‘all or none’ treatment. Gaining any weight back means that patients ‘fail.’ Weight regain is a normal part of massive weight loss; however, maintaining a certain amount of weight loss still provides benefits for patients, especially those with cardiovascular conditions like diabetes,” said Dr. Coleman.

Most patients lose 20%-30% of their body weight after bariatric surgery, but they don’t have to lose that much to see an improvement in type 2 diabetes (T2D). In addition, if patients lose that much or more, and then gain some weight back, it doesn’t eliminate benefit. “Although we did not measure weight regain, a corollary statement is that patients can regain some of the weight they lose, but if they stay around 20% of their total weight lost, then their diabetes still remits,” said Dr. Coleman.

In the past, some standards to treat severe weight loss and metabolic disease called for 50% or more TWL. More recent standards target a 30% threshold. “We want physicians to understand that they need to have more reasonable expectations of weight loss with surgery and that these reasonable expectations still result in profound improvements in cardiovascular risk, death, and quality of life. A 20% TWL threshold is easier for these patients to get to, and like other patients, they still get the benefit. So even if these patients may not have as much weight loss they can still benefit from the surgery for their diabetes,” Dr. Coleman added.

Physicians have long assumed that the effect of bariatric surgery on T2D remission is tied to weight loss, but this has been tested only recently. Previous studies found a link and suggested that 25% TWL may be the needed threshold, but more data are needed, especially for sleeve gastrectomy.

In the current study, published in Diabetes Care, 73% of patients were female. Mean age was 49.8 years, and mean body mass index was 43.8 kg/m². Fifty-seven percent underwent Roux-en-Y gastric bypass (RYGB). Follow-up averaged 5.9 years. Overall, 71% of patients had an initial remission of their diabetes (72% RYGB, 70% sleeve). The average time to remission was 1.0 years. The researchers categorized participants by percentage TWL. Compared with the 0%-5% group, each 5% increase in TWL was linked with a greater likelihood of achieving remission: 5%-10%, hazard ratio 1.22 (P = .23); 10%-15%, HR 1.97 (95% confidence interval, 1.47-2.64); 15%-20%, HR 2.33 (95% CI, 1.74-3.11); 20%-25%, HR 2.81 (95% CI, 2.11-3.75); 25%-30%, HR 2.88 (95% CI, 2.16-3.83); >30%, HR, 2.92 (95% CI, 2.19-3.88). Categories above 25% TWL had remission rates similar to those of the 20%-25% group. Those in the over 20% TWL group who were taking insulin at the time of surgery had better odds of T2D remission than did those in the 0%-5% TWL group who were not taking insulin (HR, 2.18; 95% CI, 1.64-2.88).

The study is a useful addition to the literature on the topic, according to W. Timothy Garvey, MD, director of the diabetes research center at the University of Alabama at Birmingham. “This tends to quantify it a little bit more than people might have had before,” he said.

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Dr. Garvey noted that there were wide error bars in the outcomes grouped by TWL, and suggested that individual results of surgery may vary widely. “There are plenty of individuals in each of those bins that will require more weight loss for remission or less weight loss. That’s just the average of people in that weight loss category. So if a clinician is going to use this information, they need to take it with a grain of salt and realize that, just because they reach that 20% weight loss threshold, it doesn’t mean that their patient is going to go into remission. As a loose guide, as something to shoot for, I think this is valuable,” he added.

Dr. Coleman recommended that physicians not wait too long to suggest bariatric surgery, since patients are likely to have better outcomes if they are healthier going in. “Bariatric surgery is by far the most effective long-term treatment we have for severe obesity and we should be treating it as a secondary prevention strategy, not a last resort to save people’s lives. Bariatric surgery cannot regrow the cells in the pancreas that make insulin. So if we wait until patients with type 2 diabetes are insulin dependent to offer bariatric surgery, we are compromising the great effect surgery can have for them,” said Dr. Coleman.

Patients with type 2 diabetes who underwent bariatric surgery commonly experienced remission, but there was little increase in rates of remission above a threshold of 20% total weight loss (TWL), according to a retrospective analysis of 5,928 patients with diabetes in an integrated health care system in Southern California.

The findings should reassure physicians and patients that surgery will be beneficial, according to lead author Karen Coleman, PhD, professor of health systems science at Kaiser Permanente Southern California.

Dr. Coleman has heard from many physicians saying they recommend against bariatric surgery because of concerns that patients gain weight back and therefore won’t get a long-term benefit, but this is not supported by the literature. “Hundreds of articles at this point show that this simply is not true. In addition, providers seem to think about bariatric surgery as an ‘all or none’ treatment. Gaining any weight back means that patients ‘fail.’ Weight regain is a normal part of massive weight loss; however, maintaining a certain amount of weight loss still provides benefits for patients, especially those with cardiovascular conditions like diabetes,” said Dr. Coleman.

Most patients lose 20%-30% of their body weight after bariatric surgery, but they don’t have to lose that much to see an improvement in type 2 diabetes (T2D). In addition, if patients lose that much or more, and then gain some weight back, it doesn’t eliminate benefit. “Although we did not measure weight regain, a corollary statement is that patients can regain some of the weight they lose, but if they stay around 20% of their total weight lost, then their diabetes still remits,” said Dr. Coleman.

In the past, some standards to treat severe weight loss and metabolic disease called for 50% or more TWL. More recent standards target a 30% threshold. “We want physicians to understand that they need to have more reasonable expectations of weight loss with surgery and that these reasonable expectations still result in profound improvements in cardiovascular risk, death, and quality of life. A 20% TWL threshold is easier for these patients to get to, and like other patients, they still get the benefit. So even if these patients may not have as much weight loss they can still benefit from the surgery for their diabetes,” Dr. Coleman added.

Physicians have long assumed that the effect of bariatric surgery on T2D remission is tied to weight loss, but this has been tested only recently. Previous studies found a link and suggested that 25% TWL may be the needed threshold, but more data are needed, especially for sleeve gastrectomy.

In the current study, published in Diabetes Care, 73% of patients were female. Mean age was 49.8 years, and mean body mass index was 43.8 kg/m². Fifty-seven percent underwent Roux-en-Y gastric bypass (RYGB). Follow-up averaged 5.9 years. Overall, 71% of patients had an initial remission of their diabetes (72% RYGB, 70% sleeve). The average time to remission was 1.0 years. The researchers categorized participants by percentage TWL. Compared with the 0%-5% group, each 5% increase in TWL was linked with a greater likelihood of achieving remission: 5%-10%, hazard ratio 1.22 (P = .23); 10%-15%, HR 1.97 (95% confidence interval, 1.47-2.64); 15%-20%, HR 2.33 (95% CI, 1.74-3.11); 20%-25%, HR 2.81 (95% CI, 2.11-3.75); 25%-30%, HR 2.88 (95% CI, 2.16-3.83); >30%, HR, 2.92 (95% CI, 2.19-3.88). Categories above 25% TWL had remission rates similar to those of the 20%-25% group. Those in the over 20% TWL group who were taking insulin at the time of surgery had better odds of T2D remission than did those in the 0%-5% TWL group who were not taking insulin (HR, 2.18; 95% CI, 1.64-2.88).

The study is a useful addition to the literature on the topic, according to W. Timothy Garvey, MD, director of the diabetes research center at the University of Alabama at Birmingham. “This tends to quantify it a little bit more than people might have had before,” he said.

MDedge News

Dr. Garvey noted that there were wide error bars in the outcomes grouped by TWL, and suggested that individual results of surgery may vary widely. “There are plenty of individuals in each of those bins that will require more weight loss for remission or less weight loss. That’s just the average of people in that weight loss category. So if a clinician is going to use this information, they need to take it with a grain of salt and realize that, just because they reach that 20% weight loss threshold, it doesn’t mean that their patient is going to go into remission. As a loose guide, as something to shoot for, I think this is valuable,” he added.

Dr. Coleman recommended that physicians not wait too long to suggest bariatric surgery, since patients are likely to have better outcomes if they are healthier going in. “Bariatric surgery is by far the most effective long-term treatment we have for severe obesity and we should be treating it as a secondary prevention strategy, not a last resort to save people’s lives. Bariatric surgery cannot regrow the cells in the pancreas that make insulin. So if we wait until patients with type 2 diabetes are insulin dependent to offer bariatric surgery, we are compromising the great effect surgery can have for them,” said Dr. Coleman.

Patients with type 2 diabetes who underwent bariatric surgery commonly experienced remission, but there was little increase in rates of remission above a threshold of 20% total weight loss (TWL), according to a retrospective analysis of 5,928 patients with diabetes in an integrated health care system in Southern California.

The findings should reassure physicians and patients that surgery will be beneficial, according to lead author Karen Coleman, PhD, professor of health systems science at Kaiser Permanente Southern California.

Dr. Coleman has heard from many physicians saying they recommend against bariatric surgery because of concerns that patients gain weight back and therefore won’t get a long-term benefit, but this is not supported by the literature. “Hundreds of articles at this point show that this simply is not true. In addition, providers seem to think about bariatric surgery as an ‘all or none’ treatment. Gaining any weight back means that patients ‘fail.’ Weight regain is a normal part of massive weight loss; however, maintaining a certain amount of weight loss still provides benefits for patients, especially those with cardiovascular conditions like diabetes,” said Dr. Coleman.

Most patients lose 20%-30% of their body weight after bariatric surgery, but they don’t have to lose that much to see an improvement in type 2 diabetes (T2D). In addition, if patients lose that much or more, and then gain some weight back, it doesn’t eliminate benefit. “Although we did not measure weight regain, a corollary statement is that patients can regain some of the weight they lose, but if they stay around 20% of their total weight lost, then their diabetes still remits,” said Dr. Coleman.

In the past, some standards to treat severe weight loss and metabolic disease called for 50% or more TWL. More recent standards target a 30% threshold. “We want physicians to understand that they need to have more reasonable expectations of weight loss with surgery and that these reasonable expectations still result in profound improvements in cardiovascular risk, death, and quality of life. A 20% TWL threshold is easier for these patients to get to, and like other patients, they still get the benefit. So even if these patients may not have as much weight loss they can still benefit from the surgery for their diabetes,” Dr. Coleman added.

Physicians have long assumed that the effect of bariatric surgery on T2D remission is tied to weight loss, but this has been tested only recently. Previous studies found a link and suggested that 25% TWL may be the needed threshold, but more data are needed, especially for sleeve gastrectomy.

In the current study, published in Diabetes Care, 73% of patients were female. Mean age was 49.8 years, and mean body mass index was 43.8 kg/m². Fifty-seven percent underwent Roux-en-Y gastric bypass (RYGB). Follow-up averaged 5.9 years. Overall, 71% of patients had an initial remission of their diabetes (72% RYGB, 70% sleeve). The average time to remission was 1.0 years. The researchers categorized participants by percentage TWL. Compared with the 0%-5% group, each 5% increase in TWL was linked with a greater likelihood of achieving remission: 5%-10%, hazard ratio 1.22 (P = .23); 10%-15%, HR 1.97 (95% confidence interval, 1.47-2.64); 15%-20%, HR 2.33 (95% CI, 1.74-3.11); 20%-25%, HR 2.81 (95% CI, 2.11-3.75); 25%-30%, HR 2.88 (95% CI, 2.16-3.83); >30%, HR, 2.92 (95% CI, 2.19-3.88). Categories above 25% TWL had remission rates similar to those of the 20%-25% group. Those in the over 20% TWL group who were taking insulin at the time of surgery had better odds of T2D remission than did those in the 0%-5% TWL group who were not taking insulin (HR, 2.18; 95% CI, 1.64-2.88).

The study is a useful addition to the literature on the topic, according to W. Timothy Garvey, MD, director of the diabetes research center at the University of Alabama at Birmingham. “This tends to quantify it a little bit more than people might have had before,” he said.

MDedge News

Dr. Garvey noted that there were wide error bars in the outcomes grouped by TWL, and suggested that individual results of surgery may vary widely. “There are plenty of individuals in each of those bins that will require more weight loss for remission or less weight loss. That’s just the average of people in that weight loss category. So if a clinician is going to use this information, they need to take it with a grain of salt and realize that, just because they reach that 20% weight loss threshold, it doesn’t mean that their patient is going to go into remission. As a loose guide, as something to shoot for, I think this is valuable,” he added.

Dr. Coleman recommended that physicians not wait too long to suggest bariatric surgery, since patients are likely to have better outcomes if they are healthier going in. “Bariatric surgery is by far the most effective long-term treatment we have for severe obesity and we should be treating it as a secondary prevention strategy, not a last resort to save people’s lives. Bariatric surgery cannot regrow the cells in the pancreas that make insulin. So if we wait until patients with type 2 diabetes are insulin dependent to offer bariatric surgery, we are compromising the great effect surgery can have for them,” said Dr. Coleman.

Premature menopause is well known to be linked to cardiovascular disease in women, but it may not carry as much weight as more traditional cardiovascular risk factors in determining a patient’s 10-year risk of having a heart attack or stroke in this population, a cohort study that evaluated the veracity of premature menopause found.

Premature menopause can serve as a “marker or warning sign” that cardiologists should pay closer attention to traditional atherosclerotic cardiovascular disease (ASCVD) risk factors, lead study author Sadiya S. Khan, MD, MS, said in an interview. “When we looked at the addition of premature menopause into the risk-prediction equation, we did not see that it meaningfully improved the ability of the risk predictions of pooled cohort equations [PCEs] to identify who developed cardiovascular disease,” said Dr. Khan, a cardiologist at Northwestern University, Chicago.

The cohort study included 5,466 Black women and 10,584 White women from seven U.S. population-based cohorts, including the Women’s Health Initiative, of whom 951 and 1,039, respectively, self-reported early menopause. The cohort study researchers noted that the 2019 American College of Cardiology/American Heart Association guideline for prevention of CVD acknowledged premature menopause as risk-enhancing factor in the CVD assessment in women younger than 40.

The cohort study found that Black women had almost twice the rate of premature menopause than White women, 17.4% and 9.8%, respectively. And it found that premature menopause was significantly linked with ASCVD in both populations independent of traditional risk factors – a 24% greater risk for Black women and 28% greater risk for White women.
 

‘Surprising’ finding

However, when premature menopause was added to the pooled cohort equations per the 2013 ACC/AHA guideline, the researchers found no incremental benefit, a finding Dr. Khan called “really surprising to us.”

She added, “If we look at the differences in the characteristics of women who have premature menopause, compared with those who didn’t, there were slight differences in terms of higher blood pressure, higher body mass index, and slightly higher glucose. So maybe what we’re seeing – and this is more speculative – is that risk factors are developing after early menopause, and the focus should be earlier in the patient’s life course to try to prevent hypertension, diabetes, and obesity.”

Dr. Khan emphasized that the findings don’t obviate the value of premature menopause in assessing ASCVD risk in women. “We still know that this is an important marker for women and their risk for heart disease, and it should be a warning sign to pay close attention to those other risk factors and what other preventive measures can be taken,” she said.

Christie Ballantyne, MD, said it’s important to note that the study did not dismiss the relevance of premature menopause in shared decision-making for postmenopausal women. “It certainly doesn’t mean that premature menopause is not a risk,” Dr. Ballantyne said in an interview. “Premature menopause may cause a worsening of traditional CVD risk factors, so that’s one possible explanation for it. The other possible explanation is that women with worse ASCVD risk factors – who are more overweight, have higher blood pressure, and have more diabetes and insulin resistance – are more likely to have earlier menopause.” Dr. Ballantyne is chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston.

“You should still look very carefully at the patient’s risk factors, calculate the pooled cohort equations, and make sure you get a recommendation,” he said. “If their risks are up, give recommendations on how to improve diet and exercise. Consider if you need to treat lipids or treat blood pressure with more than diet and exercise because there’s nothing magical about 7.5%”, the threshold for lipid-lowering therapy in the ASCVD risk calculator.

Dr. Khan and coauthors disclosed receiving grants from the National Institutes of Health and the American Heart Association. One coauthor reported a financial relationship with HGM Biopharmaceuticals. Dr. Ballantyne is a lead investigator of the Atherosclerosis Risk in Communities study, one of the population-based cohorts used in the cohort study. He has no other relevant relationships to disclose.

Premature menopause is well known to be linked to cardiovascular disease in women, but it may not carry as much weight as more traditional cardiovascular risk factors in determining a patient’s 10-year risk of having a heart attack or stroke in this population, a cohort study that evaluated the veracity of premature menopause found.

Premature menopause can serve as a “marker or warning sign” that cardiologists should pay closer attention to traditional atherosclerotic cardiovascular disease (ASCVD) risk factors, lead study author Sadiya S. Khan, MD, MS, said in an interview. “When we looked at the addition of premature menopause into the risk-prediction equation, we did not see that it meaningfully improved the ability of the risk predictions of pooled cohort equations [PCEs] to identify who developed cardiovascular disease,” said Dr. Khan, a cardiologist at Northwestern University, Chicago.

The cohort study included 5,466 Black women and 10,584 White women from seven U.S. population-based cohorts, including the Women’s Health Initiative, of whom 951 and 1,039, respectively, self-reported early menopause. The cohort study researchers noted that the 2019 American College of Cardiology/American Heart Association guideline for prevention of CVD acknowledged premature menopause as risk-enhancing factor in the CVD assessment in women younger than 40.

The cohort study found that Black women had almost twice the rate of premature menopause than White women, 17.4% and 9.8%, respectively. And it found that premature menopause was significantly linked with ASCVD in both populations independent of traditional risk factors – a 24% greater risk for Black women and 28% greater risk for White women.
 

‘Surprising’ finding

However, when premature menopause was added to the pooled cohort equations per the 2013 ACC/AHA guideline, the researchers found no incremental benefit, a finding Dr. Khan called “really surprising to us.”

She added, “If we look at the differences in the characteristics of women who have premature menopause, compared with those who didn’t, there were slight differences in terms of higher blood pressure, higher body mass index, and slightly higher glucose. So maybe what we’re seeing – and this is more speculative – is that risk factors are developing after early menopause, and the focus should be earlier in the patient’s life course to try to prevent hypertension, diabetes, and obesity.”

Dr. Khan emphasized that the findings don’t obviate the value of premature menopause in assessing ASCVD risk in women. “We still know that this is an important marker for women and their risk for heart disease, and it should be a warning sign to pay close attention to those other risk factors and what other preventive measures can be taken,” she said.

Christie Ballantyne, MD, said it’s important to note that the study did not dismiss the relevance of premature menopause in shared decision-making for postmenopausal women. “It certainly doesn’t mean that premature menopause is not a risk,” Dr. Ballantyne said in an interview. “Premature menopause may cause a worsening of traditional CVD risk factors, so that’s one possible explanation for it. The other possible explanation is that women with worse ASCVD risk factors – who are more overweight, have higher blood pressure, and have more diabetes and insulin resistance – are more likely to have earlier menopause.” Dr. Ballantyne is chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston.

“You should still look very carefully at the patient’s risk factors, calculate the pooled cohort equations, and make sure you get a recommendation,” he said. “If their risks are up, give recommendations on how to improve diet and exercise. Consider if you need to treat lipids or treat blood pressure with more than diet and exercise because there’s nothing magical about 7.5%”, the threshold for lipid-lowering therapy in the ASCVD risk calculator.

Dr. Khan and coauthors disclosed receiving grants from the National Institutes of Health and the American Heart Association. One coauthor reported a financial relationship with HGM Biopharmaceuticals. Dr. Ballantyne is a lead investigator of the Atherosclerosis Risk in Communities study, one of the population-based cohorts used in the cohort study. He has no other relevant relationships to disclose.

Premature menopause is well known to be linked to cardiovascular disease in women, but it may not carry as much weight as more traditional cardiovascular risk factors in determining a patient’s 10-year risk of having a heart attack or stroke in this population, a cohort study that evaluated the veracity of premature menopause found.

Premature menopause can serve as a “marker or warning sign” that cardiologists should pay closer attention to traditional atherosclerotic cardiovascular disease (ASCVD) risk factors, lead study author Sadiya S. Khan, MD, MS, said in an interview. “When we looked at the addition of premature menopause into the risk-prediction equation, we did not see that it meaningfully improved the ability of the risk predictions of pooled cohort equations [PCEs] to identify who developed cardiovascular disease,” said Dr. Khan, a cardiologist at Northwestern University, Chicago.

The cohort study included 5,466 Black women and 10,584 White women from seven U.S. population-based cohorts, including the Women’s Health Initiative, of whom 951 and 1,039, respectively, self-reported early menopause. The cohort study researchers noted that the 2019 American College of Cardiology/American Heart Association guideline for prevention of CVD acknowledged premature menopause as risk-enhancing factor in the CVD assessment in women younger than 40.

The cohort study found that Black women had almost twice the rate of premature menopause than White women, 17.4% and 9.8%, respectively. And it found that premature menopause was significantly linked with ASCVD in both populations independent of traditional risk factors – a 24% greater risk for Black women and 28% greater risk for White women.
 

‘Surprising’ finding

However, when premature menopause was added to the pooled cohort equations per the 2013 ACC/AHA guideline, the researchers found no incremental benefit, a finding Dr. Khan called “really surprising to us.”

She added, “If we look at the differences in the characteristics of women who have premature menopause, compared with those who didn’t, there were slight differences in terms of higher blood pressure, higher body mass index, and slightly higher glucose. So maybe what we’re seeing – and this is more speculative – is that risk factors are developing after early menopause, and the focus should be earlier in the patient’s life course to try to prevent hypertension, diabetes, and obesity.”

Dr. Khan emphasized that the findings don’t obviate the value of premature menopause in assessing ASCVD risk in women. “We still know that this is an important marker for women and their risk for heart disease, and it should be a warning sign to pay close attention to those other risk factors and what other preventive measures can be taken,” she said.

Christie Ballantyne, MD, said it’s important to note that the study did not dismiss the relevance of premature menopause in shared decision-making for postmenopausal women. “It certainly doesn’t mean that premature menopause is not a risk,” Dr. Ballantyne said in an interview. “Premature menopause may cause a worsening of traditional CVD risk factors, so that’s one possible explanation for it. The other possible explanation is that women with worse ASCVD risk factors – who are more overweight, have higher blood pressure, and have more diabetes and insulin resistance – are more likely to have earlier menopause.” Dr. Ballantyne is chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center, both in Houston.

“You should still look very carefully at the patient’s risk factors, calculate the pooled cohort equations, and make sure you get a recommendation,” he said. “If their risks are up, give recommendations on how to improve diet and exercise. Consider if you need to treat lipids or treat blood pressure with more than diet and exercise because there’s nothing magical about 7.5%”, the threshold for lipid-lowering therapy in the ASCVD risk calculator.

Dr. Khan and coauthors disclosed receiving grants from the National Institutes of Health and the American Heart Association. One coauthor reported a financial relationship with HGM Biopharmaceuticals. Dr. Ballantyne is a lead investigator of the Atherosclerosis Risk in Communities study, one of the population-based cohorts used in the cohort study. He has no other relevant relationships to disclose.

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

MDedge News

PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

MDedge News

PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]

The SGLT2 inhibitor dapagliflozin scored a clear win in a randomized, controlled trial with more than 300 U.S. patients with heart failure with preserved ejection fraction (HFpEF), showing a significant and clinically meaningful benefit for the primary endpoint, a KCCQ measure of symptoms and physical limitations, after 12 weeks of treatment.

These results in the PRESERVED-HF study follow closely on the heals of the initial report from the EMPEROR-Preserved trial that showed a benefit from a different sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance) in nearly 6,000 randomized patients for the primary endpoint of preventing cardiovascular death or hospitalizations for heart failure.

In PRESERVED-HF, patients with HFpEF who received a standard, once-daily dose of dapagliflozin (Farxiga) had an average 5.8-point improvement in their condition as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS), the study’s primary endpoint.

This is “the first study to demonstrate that an SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF,” Mikhail N. Kosiborod, MD, reported at the annual scientific meeting of the Heart Failure Society of America. The secondary endpoint of 6-minute walking distance “has been very difficult to improve in many previous studies of other treatments” tested in patients with HFpEF, noted Dr. Kosiborod, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute.

The results are “highly complementary” to the findings from large outcome trials, such as the findings from EMPEROR-Preserved, he said, and collectively the recent findings from these studies of SGLT2 inhibitors in patients with HFpEF identify drugs in this class as a “new treatment option” for patients with a disorder that until now had no treatment with unequivocally proven efficacy and safety.
 

‘Impressive and unprecedented’ findings

The findings are “really impressive and unprecedented,” said Milton Packer, MD, a cardiologist at Baylor University Medical Center in Dallas who was not involved in the study. “This is the largest KCCQ benefit ever seen in either patients with HFpEF or in patients with heart failure with reduced ejection fraction,” said Dr. Packer, one of the investigators who led the EMPEROR-Preserved trial.

MDedge News

PRESERVED-HF randomized 324 patients diagnosed with heart failure and with a left ventricular ejection fraction of 45% or higher at any of 26 U.S. centers, with 304 patients completing the planned final analysis after 12 weeks on treatment. Patients could be in New York Heart Association (NYHA) functional class II-IV, they had to have a baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) level of at least 225 pg/mL (or higher if they also had atrial fibrillation), and they required at least one of three markers of established heart failure: recent hospitalization for heart failure or an urgent outpatient visit that required treatment with an IV diuretic, elevated filling pressure measured by left or right catheterization, or structural heart disease detected by echocardiography.

The average age of the enrolled patients was 70 years, and they had been diagnosed with heart failure for about 3 years; 57% were women, 30% were African American, and their median body mass index was 35 kg/m². Roughly 42% had NYHA class III or IV disease, 56% had type 2 diabetes, their median estimated glomerular filtration rate was about 55 mL/min per 1.73m², their median KCCQ-CS score at baseline was about 62, and their average 6-minute walk distance was 244 m.

These and other features of the enrolled population define a distinctly U.S. patient population, stressed Dr. Kosiborod, professor of medicine at the University of Missouri–Kansas City.

“The patients we enrolled are the patients we see in U.S. clinical practice,” he said in an interview. Importantly, the patient profile of a median BMI of 35 kg/m², a median KCCQ-CS score of 62 – “quite low,” noted Dr. Kosiborod – and having more than 40% of patients in NYHA functional class III defines a study population with a substantially greater burden of obesity, symptoms, and functional impairment compared with those enrolled in prior trials involving patients with HFpEF such as EMPEROR-Preserved.
 

Results complement findings from larger trials

PRESERVED-HF was an investigator-initiated study designed to inform clinical practice, not as a pivotal trial like EMPEROR-Preserved, which aims to gather evidence to support a new indication for regulatory approval. (On Sept. 9, 2021, the Food and Drug Administration granted empagliflozin “breakthrough therapy” status for treating HFpEF based on the EMPEROR-Preserved results, which will fast-track the agency’s decision on this indication.)

Dr. Kosiborod noted that he and his associates designed PRESERVED-HF with adequate patient numbers to power a statistically valid assessment of effect on KCCQ-CS score. While the new findings will not by themselves lead to a new indication for dapagliflozin to treat patients with HFpEF, they will potentially complement the pending results of another trial, DELIVER, by showing efficacy and safety in a uniquely U.S. patient population. DELIVER is a pivotal, global trial of dapagliflozin in more than 6,000 patients with HFpEF that’s on track to report findings in 2022.

Dr. Kosiborod also stressed that dapagliflozin has U.S.-approved indications for treating patients with type 2 diabetes, and for patients with chronic kidney disease, and that a majority of patients enrolled in PRESERVED-HF had one or both of these conditions. That makes the new findings especially compelling for patients with either type 2 diabetes or chronic kidney disease and HFpEF who are not already receiving an SGLT2 inhibitor.

Other findings that he reported showed a range of benefits consistent with the primary endpoint, including the KCCQ overall summary score, which also showed a significant 4.5-point average increase over placebo after 12 weeks. Analysis by the percentage of patients achieving at least a 5-point improvement in the KCCQ clinical summary score (the threshold for a clinically meaningful improvement) showed that about 45% of patients treated with dapagliflozin reached this mark compared with roughly 35% of patients in the placebo arm, indicating a number needed to treat of nine to have one additional patient achieve this threshold after 12 weeks. Average improvement in 6-minute walk distance was about 20 m with dapagliflozin compared with placebo.

No heterogeneity of effect by baseline ejection fraction.

Subgroup analyses showed no heterogeneity of response across 12 different ways of subdividing the study population, including age, sex, race, diabetes status, and BMI. The median left ventricular ejection fraction among enrolled patients was 60%, and the findings showed identical KCCQ improvements among patients with ejection fractions less than the median and those with an ejection fraction above the median.

This last finding was especially relevant because the EMPEROR-Preserved results showed a possible signal of heterogeneity by ejection fraction and an attenuated effect among patients with HFpEF and an ejection fraction above the 60%-65% range, although the certainty of this finding is currently controversial.

The impact of empagliflozin on KCCQ clinical summary score in EMPEROR-Preserved showed an average incremental improvement of 1.32 points compared with placebo, a significant difference, but more modest than the increment from dapagliflozin treatment seen in PRESERVED-HF. Dr. Kosiborod hypothesized that this difference might be mostly because of the different patient populations enrolled in the two studies.

Dr. Kosiborod noted that a report on the PRESERVED-HF results will soon appear in Nature Medicine.

PRESERVED-HF was funded by AstraZeneca, which markets dapagliflozin (Farxiga), but the trials’ design and conduct were independent of this funding source. Dr. Kosiborod has been a consultant to AstraZeneca and numerous other companies, and he has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Packer has had financial relationships with AstraZeneca and numerous other companies.

[email protected]