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Tirzepatide’s benefits expand: Lean mass up, serum lipids down
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
AT EASD 2022
Bariatric surgery prompts visceral fat reduction, cardiac changes
Weight loss after bariatric surgery was linked with visceral fat reduction as well as reduced blood pressure, fasting glucose, and left ventricular remodeling, based an imaging study in 213 patients.
“We found that ventricular function measured by strain imaging improved in both the left and right sides of the heart, but function measured in the traditional method using endocardial motion [in other words, ejection fraction] actually worsened,” senior investigator Barry A. Borlaug, MD, said in an interview.
Although previous studies have shown positive effects of weight loss on the heart after bariatric surgery, most have been short term and have not specifically examined the effects of visceral fat reduction, wrote the investigators.
“We are in the middle of an increasing epidemic of obesity worldwide, but particularly in the United States, where it is currently projected that one in two adults will be obese by 2030,” added Dr. Borlaug of Mayo Clinic, Rochester, Minn. “Heart failure with preserved ejection fraction (HFpEF) is growing in tandem, and numerous recent studies have shown that obesity is one of the strongest risk factors for developing HFpEF, and that the severity of HFpEF is intimately linked to excess body fat. This suggests that therapies to reduce body fat could improve the cardiac abnormalities that cause HFpEF, which was our focus in this study,” he explained.
In the study, published in the Journal of the American College of Cardiology, the researchers reviewed echocardiography data from 213 obese patients before and more than 180 days after bariatric surgery. They also measured abdominal visceral adipose tissue (VAT) of 52 patients via computed tomography. The average age of the patients was 54 years, the average body mass index was 45 kg/m2, and 67% were women. Comorbidities included hypertension, diabetes, dyslipidemia, and obstructive sleep apnea.
The primary outcome was changes in cardiac structure and function.
After a median follow-up of 5.3 years, patients overall averaged a 23% reduction in body weight and a 22% reduction in BMI. In the 52 patients with abdominal scans, the VAT area decreased by 30% overall. Changes in left ventricular mass were significantly correlated to changes in the VAT.
Epicardial adipose thickness decreased by 14% overall. Left and right ventricular longitudinal strains improved at follow-up, but left atrial strain deteriorated, the researchers noted.
Although the mechanism of action remains unclear, the results suggest that left ventricular remodeling was associated with visceral adiposity rather than subcutaneous fat, the researchers wrote.
They also found that right ventricular strain was negatively correlated with VAT, but not with body weight or BMI.
“These findings suggest that weight loss, particularly reduction in visceral adiposity, benefits [right ventricular] structure and function in a manner akin to that observed in the [left ventricle],” the researchers noted.
Some surprises and limitations
Dr. Borlaug said he found some, but not all, of the results surprising. “Earlier studies had shown evidence for benefit from weight loss on cardiac structure and function, but had been limited by smaller sample sizes, shorter durations of evaluation, and variable methods used,” he said in an interview.
The findings that strain imaging showed both left and right ventricular function improved while EF declined “shows some of the problems with using EF, as it is affected by chamber size and geometry. We have previously shown that patients with HFpEF display an increase in fat around the heart, and this affects cardiac function and interaction between the left and right sides of the heart, so we expected to see that this fat depot would be reduced, and this was indeed the case,” Dr. Borlaug added.
In the current study, “visceral fat was most strongly tied to the heart remodeling in obesity, and changes in visceral fat were most strongly tied to improvements in cardiac structure following weight loss,” Dr. Borlaug told this news organization. “This further supports this concept that excess visceral fat plays a key role in HFpEF, especially in the abdomen and around the heart,” he said.
However, “The biggest surprise was the discordant effects in the left atrium,” Dr. Borlaug said. “Left atrial remodeling and dysfunction play a crucial role in HFpEF as well, and we expected that this would improve following weight loss, but in fact we observed that left atrial function deteriorated, and other indicators of atrial myopathy worsened, including higher estimates of left atrial pressures and increased prevalence of atrial fibrillation,” he said.
This difference emphasizes that weight loss may not address all abnormalities that lead to HFpEF, although a key limitation of the current study was the lack of a control group of patients with the same degree of obesity and no weight-loss intervention, and the deterioration in left atrial function might have been even greater in the absence of weight loss, Dr. Borlaug added.
Larger numbers support effects
Previous research shows that structural heart changes associated with obesity can be reversed through weight loss, but the current study fills a gap by providing long-term data in a larger sample than previously studied, wrote Paul Heidenreich, MD, of Stanford (Calif.) University in an accompanying editorial).
“There has been uncertainty regarding the prolonged effect of weight loss on cardiac function; this study was larger than many prior studies and provided a longer follow-up,” Dr. Heidenreich said in an interview.
“One unusual finding was that, while weight loss led to left ventricle reverse remodeling (reduction in wall thickness), the same effect was not seen for the left atrium; the left atrial size continued to increase,” he said. “I would have expected the left atrial changes to mirror the changes in the left ventricle,” he noted.
The findings support the greater cardiac risk of visceral vs. subcutaneous adipose tissue, and although body mass index will retain prognostic value, measures of central obesity are more likely predictors of cardiac structural changes and events and should be reported in clinical studies, Dr. Heidenreich wrote.
However, “We need a better understanding of the factors that influence left atrial remodeling and reverse remodeling,” Dr. Heidenreich told this news organization. “While left ventricular compliance and pressure play a role, there are other factors that need to be elucidated,” he said.
Studies in progress may inform practice
The current data call for further study to test novel treatments to facilitate weight loss in patients with HFpEF and those at risk for HFpEF, and some of these studies with medicines are underway, Dr. Borlaug said in the interview.
“Until such studies are completed, we will not truly understand the effects of weight loss on the heart, but the present data certainly provide strong support that patients who have obesity and HFpEF or are at risk for HFpEF should try to lose weight through lifestyle interventions,” he said.
Whether the cardiac changes seen in the current study would be different with nonsurgical weight loss remains a key question because many obese patients are reluctant to undergo bariatric surgery, Dr. Borlaug said. “We cannot assess whether the effects would differ with nonsurgical weight loss, and this requires further study,” he added.
As for additional research, “Randomized, controlled trials of weight-loss interventions, with appropriate controls and comprehensive assessments of cardiac structure, function, and hemodynamics will be most informative,” said Dr. Borlaug. “Larger trials powered to evaluate cardiovascular outcomes such as heart failure hospitalization or cardiovascular death also are critically important to better understand the role of weight loss to treat and prevent HFpEF, the ultimate form of obesity-related heart disease,” he emphasized.
The study was supported in part by grants to lead author Dr. Hidemi Sorimachi of the Mayo Clinic from the Uehara Memorial Foundation, Japan, and to corresponding author Dr. Borlaug from the National Institutes of Health. Dr. Borlaug also disclosed previous grants from National Institutes of Health/National Heart, Lung, and Blood Institute, AstraZeneca, Corvia, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr. Heidenreich had no financial disclosures.
Weight loss after bariatric surgery was linked with visceral fat reduction as well as reduced blood pressure, fasting glucose, and left ventricular remodeling, based an imaging study in 213 patients.
“We found that ventricular function measured by strain imaging improved in both the left and right sides of the heart, but function measured in the traditional method using endocardial motion [in other words, ejection fraction] actually worsened,” senior investigator Barry A. Borlaug, MD, said in an interview.
Although previous studies have shown positive effects of weight loss on the heart after bariatric surgery, most have been short term and have not specifically examined the effects of visceral fat reduction, wrote the investigators.
“We are in the middle of an increasing epidemic of obesity worldwide, but particularly in the United States, where it is currently projected that one in two adults will be obese by 2030,” added Dr. Borlaug of Mayo Clinic, Rochester, Minn. “Heart failure with preserved ejection fraction (HFpEF) is growing in tandem, and numerous recent studies have shown that obesity is one of the strongest risk factors for developing HFpEF, and that the severity of HFpEF is intimately linked to excess body fat. This suggests that therapies to reduce body fat could improve the cardiac abnormalities that cause HFpEF, which was our focus in this study,” he explained.
In the study, published in the Journal of the American College of Cardiology, the researchers reviewed echocardiography data from 213 obese patients before and more than 180 days after bariatric surgery. They also measured abdominal visceral adipose tissue (VAT) of 52 patients via computed tomography. The average age of the patients was 54 years, the average body mass index was 45 kg/m2, and 67% were women. Comorbidities included hypertension, diabetes, dyslipidemia, and obstructive sleep apnea.
The primary outcome was changes in cardiac structure and function.
After a median follow-up of 5.3 years, patients overall averaged a 23% reduction in body weight and a 22% reduction in BMI. In the 52 patients with abdominal scans, the VAT area decreased by 30% overall. Changes in left ventricular mass were significantly correlated to changes in the VAT.
Epicardial adipose thickness decreased by 14% overall. Left and right ventricular longitudinal strains improved at follow-up, but left atrial strain deteriorated, the researchers noted.
Although the mechanism of action remains unclear, the results suggest that left ventricular remodeling was associated with visceral adiposity rather than subcutaneous fat, the researchers wrote.
They also found that right ventricular strain was negatively correlated with VAT, but not with body weight or BMI.
“These findings suggest that weight loss, particularly reduction in visceral adiposity, benefits [right ventricular] structure and function in a manner akin to that observed in the [left ventricle],” the researchers noted.
Some surprises and limitations
Dr. Borlaug said he found some, but not all, of the results surprising. “Earlier studies had shown evidence for benefit from weight loss on cardiac structure and function, but had been limited by smaller sample sizes, shorter durations of evaluation, and variable methods used,” he said in an interview.
The findings that strain imaging showed both left and right ventricular function improved while EF declined “shows some of the problems with using EF, as it is affected by chamber size and geometry. We have previously shown that patients with HFpEF display an increase in fat around the heart, and this affects cardiac function and interaction between the left and right sides of the heart, so we expected to see that this fat depot would be reduced, and this was indeed the case,” Dr. Borlaug added.
In the current study, “visceral fat was most strongly tied to the heart remodeling in obesity, and changes in visceral fat were most strongly tied to improvements in cardiac structure following weight loss,” Dr. Borlaug told this news organization. “This further supports this concept that excess visceral fat plays a key role in HFpEF, especially in the abdomen and around the heart,” he said.
However, “The biggest surprise was the discordant effects in the left atrium,” Dr. Borlaug said. “Left atrial remodeling and dysfunction play a crucial role in HFpEF as well, and we expected that this would improve following weight loss, but in fact we observed that left atrial function deteriorated, and other indicators of atrial myopathy worsened, including higher estimates of left atrial pressures and increased prevalence of atrial fibrillation,” he said.
This difference emphasizes that weight loss may not address all abnormalities that lead to HFpEF, although a key limitation of the current study was the lack of a control group of patients with the same degree of obesity and no weight-loss intervention, and the deterioration in left atrial function might have been even greater in the absence of weight loss, Dr. Borlaug added.
Larger numbers support effects
Previous research shows that structural heart changes associated with obesity can be reversed through weight loss, but the current study fills a gap by providing long-term data in a larger sample than previously studied, wrote Paul Heidenreich, MD, of Stanford (Calif.) University in an accompanying editorial).
“There has been uncertainty regarding the prolonged effect of weight loss on cardiac function; this study was larger than many prior studies and provided a longer follow-up,” Dr. Heidenreich said in an interview.
“One unusual finding was that, while weight loss led to left ventricle reverse remodeling (reduction in wall thickness), the same effect was not seen for the left atrium; the left atrial size continued to increase,” he said. “I would have expected the left atrial changes to mirror the changes in the left ventricle,” he noted.
The findings support the greater cardiac risk of visceral vs. subcutaneous adipose tissue, and although body mass index will retain prognostic value, measures of central obesity are more likely predictors of cardiac structural changes and events and should be reported in clinical studies, Dr. Heidenreich wrote.
However, “We need a better understanding of the factors that influence left atrial remodeling and reverse remodeling,” Dr. Heidenreich told this news organization. “While left ventricular compliance and pressure play a role, there are other factors that need to be elucidated,” he said.
Studies in progress may inform practice
The current data call for further study to test novel treatments to facilitate weight loss in patients with HFpEF and those at risk for HFpEF, and some of these studies with medicines are underway, Dr. Borlaug said in the interview.
“Until such studies are completed, we will not truly understand the effects of weight loss on the heart, but the present data certainly provide strong support that patients who have obesity and HFpEF or are at risk for HFpEF should try to lose weight through lifestyle interventions,” he said.
Whether the cardiac changes seen in the current study would be different with nonsurgical weight loss remains a key question because many obese patients are reluctant to undergo bariatric surgery, Dr. Borlaug said. “We cannot assess whether the effects would differ with nonsurgical weight loss, and this requires further study,” he added.
As for additional research, “Randomized, controlled trials of weight-loss interventions, with appropriate controls and comprehensive assessments of cardiac structure, function, and hemodynamics will be most informative,” said Dr. Borlaug. “Larger trials powered to evaluate cardiovascular outcomes such as heart failure hospitalization or cardiovascular death also are critically important to better understand the role of weight loss to treat and prevent HFpEF, the ultimate form of obesity-related heart disease,” he emphasized.
The study was supported in part by grants to lead author Dr. Hidemi Sorimachi of the Mayo Clinic from the Uehara Memorial Foundation, Japan, and to corresponding author Dr. Borlaug from the National Institutes of Health. Dr. Borlaug also disclosed previous grants from National Institutes of Health/National Heart, Lung, and Blood Institute, AstraZeneca, Corvia, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr. Heidenreich had no financial disclosures.
Weight loss after bariatric surgery was linked with visceral fat reduction as well as reduced blood pressure, fasting glucose, and left ventricular remodeling, based an imaging study in 213 patients.
“We found that ventricular function measured by strain imaging improved in both the left and right sides of the heart, but function measured in the traditional method using endocardial motion [in other words, ejection fraction] actually worsened,” senior investigator Barry A. Borlaug, MD, said in an interview.
Although previous studies have shown positive effects of weight loss on the heart after bariatric surgery, most have been short term and have not specifically examined the effects of visceral fat reduction, wrote the investigators.
“We are in the middle of an increasing epidemic of obesity worldwide, but particularly in the United States, where it is currently projected that one in two adults will be obese by 2030,” added Dr. Borlaug of Mayo Clinic, Rochester, Minn. “Heart failure with preserved ejection fraction (HFpEF) is growing in tandem, and numerous recent studies have shown that obesity is one of the strongest risk factors for developing HFpEF, and that the severity of HFpEF is intimately linked to excess body fat. This suggests that therapies to reduce body fat could improve the cardiac abnormalities that cause HFpEF, which was our focus in this study,” he explained.
In the study, published in the Journal of the American College of Cardiology, the researchers reviewed echocardiography data from 213 obese patients before and more than 180 days after bariatric surgery. They also measured abdominal visceral adipose tissue (VAT) of 52 patients via computed tomography. The average age of the patients was 54 years, the average body mass index was 45 kg/m2, and 67% were women. Comorbidities included hypertension, diabetes, dyslipidemia, and obstructive sleep apnea.
The primary outcome was changes in cardiac structure and function.
After a median follow-up of 5.3 years, patients overall averaged a 23% reduction in body weight and a 22% reduction in BMI. In the 52 patients with abdominal scans, the VAT area decreased by 30% overall. Changes in left ventricular mass were significantly correlated to changes in the VAT.
Epicardial adipose thickness decreased by 14% overall. Left and right ventricular longitudinal strains improved at follow-up, but left atrial strain deteriorated, the researchers noted.
Although the mechanism of action remains unclear, the results suggest that left ventricular remodeling was associated with visceral adiposity rather than subcutaneous fat, the researchers wrote.
They also found that right ventricular strain was negatively correlated with VAT, but not with body weight or BMI.
“These findings suggest that weight loss, particularly reduction in visceral adiposity, benefits [right ventricular] structure and function in a manner akin to that observed in the [left ventricle],” the researchers noted.
Some surprises and limitations
Dr. Borlaug said he found some, but not all, of the results surprising. “Earlier studies had shown evidence for benefit from weight loss on cardiac structure and function, but had been limited by smaller sample sizes, shorter durations of evaluation, and variable methods used,” he said in an interview.
The findings that strain imaging showed both left and right ventricular function improved while EF declined “shows some of the problems with using EF, as it is affected by chamber size and geometry. We have previously shown that patients with HFpEF display an increase in fat around the heart, and this affects cardiac function and interaction between the left and right sides of the heart, so we expected to see that this fat depot would be reduced, and this was indeed the case,” Dr. Borlaug added.
In the current study, “visceral fat was most strongly tied to the heart remodeling in obesity, and changes in visceral fat were most strongly tied to improvements in cardiac structure following weight loss,” Dr. Borlaug told this news organization. “This further supports this concept that excess visceral fat plays a key role in HFpEF, especially in the abdomen and around the heart,” he said.
However, “The biggest surprise was the discordant effects in the left atrium,” Dr. Borlaug said. “Left atrial remodeling and dysfunction play a crucial role in HFpEF as well, and we expected that this would improve following weight loss, but in fact we observed that left atrial function deteriorated, and other indicators of atrial myopathy worsened, including higher estimates of left atrial pressures and increased prevalence of atrial fibrillation,” he said.
This difference emphasizes that weight loss may not address all abnormalities that lead to HFpEF, although a key limitation of the current study was the lack of a control group of patients with the same degree of obesity and no weight-loss intervention, and the deterioration in left atrial function might have been even greater in the absence of weight loss, Dr. Borlaug added.
Larger numbers support effects
Previous research shows that structural heart changes associated with obesity can be reversed through weight loss, but the current study fills a gap by providing long-term data in a larger sample than previously studied, wrote Paul Heidenreich, MD, of Stanford (Calif.) University in an accompanying editorial).
“There has been uncertainty regarding the prolonged effect of weight loss on cardiac function; this study was larger than many prior studies and provided a longer follow-up,” Dr. Heidenreich said in an interview.
“One unusual finding was that, while weight loss led to left ventricle reverse remodeling (reduction in wall thickness), the same effect was not seen for the left atrium; the left atrial size continued to increase,” he said. “I would have expected the left atrial changes to mirror the changes in the left ventricle,” he noted.
The findings support the greater cardiac risk of visceral vs. subcutaneous adipose tissue, and although body mass index will retain prognostic value, measures of central obesity are more likely predictors of cardiac structural changes and events and should be reported in clinical studies, Dr. Heidenreich wrote.
However, “We need a better understanding of the factors that influence left atrial remodeling and reverse remodeling,” Dr. Heidenreich told this news organization. “While left ventricular compliance and pressure play a role, there are other factors that need to be elucidated,” he said.
Studies in progress may inform practice
The current data call for further study to test novel treatments to facilitate weight loss in patients with HFpEF and those at risk for HFpEF, and some of these studies with medicines are underway, Dr. Borlaug said in the interview.
“Until such studies are completed, we will not truly understand the effects of weight loss on the heart, but the present data certainly provide strong support that patients who have obesity and HFpEF or are at risk for HFpEF should try to lose weight through lifestyle interventions,” he said.
Whether the cardiac changes seen in the current study would be different with nonsurgical weight loss remains a key question because many obese patients are reluctant to undergo bariatric surgery, Dr. Borlaug said. “We cannot assess whether the effects would differ with nonsurgical weight loss, and this requires further study,” he added.
As for additional research, “Randomized, controlled trials of weight-loss interventions, with appropriate controls and comprehensive assessments of cardiac structure, function, and hemodynamics will be most informative,” said Dr. Borlaug. “Larger trials powered to evaluate cardiovascular outcomes such as heart failure hospitalization or cardiovascular death also are critically important to better understand the role of weight loss to treat and prevent HFpEF, the ultimate form of obesity-related heart disease,” he emphasized.
The study was supported in part by grants to lead author Dr. Hidemi Sorimachi of the Mayo Clinic from the Uehara Memorial Foundation, Japan, and to corresponding author Dr. Borlaug from the National Institutes of Health. Dr. Borlaug also disclosed previous grants from National Institutes of Health/National Heart, Lung, and Blood Institute, AstraZeneca, Corvia, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr. Heidenreich had no financial disclosures.
FROM JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Long-term antidepressant use tied to an increase in CVD, mortality risk
The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.
After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.
On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.
The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.
“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.
“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.
The study was published online in the British Journal of Psychiatry Open.
Monitoring of CVD risk ‘critical’
Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”
Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”
Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.
The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.
The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.
The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.
Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.
Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
Mechanism unclear
By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).
At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).
At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.
On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).
“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.
“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.
Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
Strengths, limitations
Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.
The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”
A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.
The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”
Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”
The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.
After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.
On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.
The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.
“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.
“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.
The study was published online in the British Journal of Psychiatry Open.
Monitoring of CVD risk ‘critical’
Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”
Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”
Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.
The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.
The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.
The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.
Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.
Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
Mechanism unclear
By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).
At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).
At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.
On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).
“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.
“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.
Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
Strengths, limitations
Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.
The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”
A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.
The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”
Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”
The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.
After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.
On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.
The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.
“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.
“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.
The study was published online in the British Journal of Psychiatry Open.
Monitoring of CVD risk ‘critical’
Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”
Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”
Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.
The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.
The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.
The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.
Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.
Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
Mechanism unclear
By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).
At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).
At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.
On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).
“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.
“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.
Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
Strengths, limitations
Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.
The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”
A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.
The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”
Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”
The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
FROM THE BRITISH JOURNAL OF PSYCHIATRY OPEN
Eating earlier offers health benefits, studies say
New research suggests there may be better times during the day for eating and fasting.
Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.
“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.
“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.
In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Combined, the changes may increase the risk for obesity, the study authors found.
In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.
The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.
In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.
“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.
The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.
The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.
The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.
“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”
The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.
In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease.
Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels.
The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.
During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.
A version of this article first appeared on WebMD.com.
New research suggests there may be better times during the day for eating and fasting.
Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.
“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.
“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.
In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Combined, the changes may increase the risk for obesity, the study authors found.
In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.
The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.
In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.
“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.
The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.
The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.
The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.
“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”
The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.
In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease.
Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels.
The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.
During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.
A version of this article first appeared on WebMD.com.
New research suggests there may be better times during the day for eating and fasting.
Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.
“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.
“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.
In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Combined, the changes may increase the risk for obesity, the study authors found.
In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.
The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.
In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.
“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.
The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.
The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.
The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.
“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”
The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.
In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease.
Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels.
The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.
During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.
A version of this article first appeared on WebMD.com.
FROM CELL METABOLISM
Newer drugs not cost effective for first-line diabetes therapy
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Food insecurity a growing problem for many with CVD
A growing number of Americans with cardiovascular disease (CVD) have limited or uncertain access to food, results of a new study suggest.
An analysis of data from the National Health and Nutrition Examination Survey (NHANES) representing more than 300 million American adults found that, overall, 38.1% of people with cardiovascular disease were food insecure in 2017-2019.
Twenty years earlier, that rate was 16.3%.
“What really stood out from our study is how frequent food insecurity is among people with cardiovascular disease, compared to those without cardiovascular disease,” lead author, Eric J. Brandt, MD, MHS, a cardiologist at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, said in an interview.
“We believe that the relationship between food insecurity and cardiovascular disease is bidirectional. Food insecurity puts people at risk for cardiovascular disease, which then makes them vulnerable to events like myocardial infarction or stroke, which in turn may make them less able to work, thereby worsening their financial situation and increasing their vulnerability to food insecurity,” Dr. Brandt said.
For the analysis, Dr. Brandt and his team used an analytic sample of 57,517 adults to represent 312 million non-institutionalized adults in the United States.
Overall, 6,770 individuals (11.8%) in the analytic sample reported food insecurity.
Food insecurity was more prevalent among Hispanic people (n = 1,938, 24.0%) and non-Hispanic Black people (n = 1,202, 18.2%), compared with non-Hispanic Asian people (n = 100, 8.0%), and non-Hispanic White people (n = 3,221, 8.5%).
The prevalence of cardiovascular disease in the sample was 7.9% (n = 4,527).
Hypertension was the most prevalent CVD risk factor, reported in 49.6% of the sample. This was followed by obesity in 33.2%, dyslipidemia in 30.8%, and diabetes in 11.2%.
The findings were published online in JAMA Cardiology.
“All cardiovascular disease and cardiometabolic diseases except coronary artery disease were more prevalent among those with food insecurity,” Dr. Brandt noted.
“The results of our study are especially timely, as the White House just hosted its first conference on Hunger, Nutrition, and Health in over 50 years. Food insecurity is a focus of that conference. In the last few years, especially in relation to the pandemic, there has been expansion of some of the federal programs to prevent food insecurity. I would like to see a continued effort to solve this,” he said.
Dr. Brandt added that he hopes clinicians will be more cognizant of the problem of food insecurity and other social determinants of health when they see their patients.
“If someone is not going to be able to afford the food on their table, they’re probably not going to pay for their medications. Recognizing these social determinants in the clinical setting and helping our patients access local resources may address the underlying factors contributing to heart disease,” he said.
Uphill battle
Johanna Contreras, MD, advanced heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, treats food insecure cardiovascular patients in her practice and tries to educate them about good nutrition. But it is an uphill battle.
“A lot of my patients live in the South Bronx. They have hypertension, hypercholesterolemia, and there are no grocery stores where they can buy fresh vegetables. I talk to them about eating healthy. They tell me it’s impossible. The stores only have pre-packaged foods. So even in the South Bronx, even though it is in New York, it is very hard to get fresh food. And when it is available, it is very expensive,” Dr. Contreras told this news organization.
“Fresh pineapples can cost $8. A fast-food burger costs $3. So that is what they buy: It’s what they can afford. Even the store managers don’t want to stock fresh produce because it can spoil. They open stores, like Whole Foods, but in the more affluent neighborhoods. They should open one in poor neighborhoods,” she said.
Dr. Contreras says she spends much of her time educating her patients about good nutrition. She asks them to keep a food diary and analyzes the results at each visit.
“I look at what they eat, and I try to see how I can use this information in a good way. I advise them to use frozen foods, and avoid canned, because it is a lot healthier. I am pragmatic, because I know that if I tell my patients to eat salmon, for example, they aren’t going to be able to afford it, if they can even access it.”
She also informs them about relatively healthy fast-food choices.
“I tell them to order 100% fruit juice, water, or milk when they go to McDonalds or other fast-food places. So I think this study is very important. Food insecurity is a very important component of cardiovascular disease, and unfortunately, minority communities are where this occurs.”
Dr. Brandt and Dr. Contreras report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A growing number of Americans with cardiovascular disease (CVD) have limited or uncertain access to food, results of a new study suggest.
An analysis of data from the National Health and Nutrition Examination Survey (NHANES) representing more than 300 million American adults found that, overall, 38.1% of people with cardiovascular disease were food insecure in 2017-2019.
Twenty years earlier, that rate was 16.3%.
“What really stood out from our study is how frequent food insecurity is among people with cardiovascular disease, compared to those without cardiovascular disease,” lead author, Eric J. Brandt, MD, MHS, a cardiologist at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, said in an interview.
“We believe that the relationship between food insecurity and cardiovascular disease is bidirectional. Food insecurity puts people at risk for cardiovascular disease, which then makes them vulnerable to events like myocardial infarction or stroke, which in turn may make them less able to work, thereby worsening their financial situation and increasing their vulnerability to food insecurity,” Dr. Brandt said.
For the analysis, Dr. Brandt and his team used an analytic sample of 57,517 adults to represent 312 million non-institutionalized adults in the United States.
Overall, 6,770 individuals (11.8%) in the analytic sample reported food insecurity.
Food insecurity was more prevalent among Hispanic people (n = 1,938, 24.0%) and non-Hispanic Black people (n = 1,202, 18.2%), compared with non-Hispanic Asian people (n = 100, 8.0%), and non-Hispanic White people (n = 3,221, 8.5%).
The prevalence of cardiovascular disease in the sample was 7.9% (n = 4,527).
Hypertension was the most prevalent CVD risk factor, reported in 49.6% of the sample. This was followed by obesity in 33.2%, dyslipidemia in 30.8%, and diabetes in 11.2%.
The findings were published online in JAMA Cardiology.
“All cardiovascular disease and cardiometabolic diseases except coronary artery disease were more prevalent among those with food insecurity,” Dr. Brandt noted.
“The results of our study are especially timely, as the White House just hosted its first conference on Hunger, Nutrition, and Health in over 50 years. Food insecurity is a focus of that conference. In the last few years, especially in relation to the pandemic, there has been expansion of some of the federal programs to prevent food insecurity. I would like to see a continued effort to solve this,” he said.
Dr. Brandt added that he hopes clinicians will be more cognizant of the problem of food insecurity and other social determinants of health when they see their patients.
“If someone is not going to be able to afford the food on their table, they’re probably not going to pay for their medications. Recognizing these social determinants in the clinical setting and helping our patients access local resources may address the underlying factors contributing to heart disease,” he said.
Uphill battle
Johanna Contreras, MD, advanced heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, treats food insecure cardiovascular patients in her practice and tries to educate them about good nutrition. But it is an uphill battle.
“A lot of my patients live in the South Bronx. They have hypertension, hypercholesterolemia, and there are no grocery stores where they can buy fresh vegetables. I talk to them about eating healthy. They tell me it’s impossible. The stores only have pre-packaged foods. So even in the South Bronx, even though it is in New York, it is very hard to get fresh food. And when it is available, it is very expensive,” Dr. Contreras told this news organization.
“Fresh pineapples can cost $8. A fast-food burger costs $3. So that is what they buy: It’s what they can afford. Even the store managers don’t want to stock fresh produce because it can spoil. They open stores, like Whole Foods, but in the more affluent neighborhoods. They should open one in poor neighborhoods,” she said.
Dr. Contreras says she spends much of her time educating her patients about good nutrition. She asks them to keep a food diary and analyzes the results at each visit.
“I look at what they eat, and I try to see how I can use this information in a good way. I advise them to use frozen foods, and avoid canned, because it is a lot healthier. I am pragmatic, because I know that if I tell my patients to eat salmon, for example, they aren’t going to be able to afford it, if they can even access it.”
She also informs them about relatively healthy fast-food choices.
“I tell them to order 100% fruit juice, water, or milk when they go to McDonalds or other fast-food places. So I think this study is very important. Food insecurity is a very important component of cardiovascular disease, and unfortunately, minority communities are where this occurs.”
Dr. Brandt and Dr. Contreras report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A growing number of Americans with cardiovascular disease (CVD) have limited or uncertain access to food, results of a new study suggest.
An analysis of data from the National Health and Nutrition Examination Survey (NHANES) representing more than 300 million American adults found that, overall, 38.1% of people with cardiovascular disease were food insecure in 2017-2019.
Twenty years earlier, that rate was 16.3%.
“What really stood out from our study is how frequent food insecurity is among people with cardiovascular disease, compared to those without cardiovascular disease,” lead author, Eric J. Brandt, MD, MHS, a cardiologist at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, said in an interview.
“We believe that the relationship between food insecurity and cardiovascular disease is bidirectional. Food insecurity puts people at risk for cardiovascular disease, which then makes them vulnerable to events like myocardial infarction or stroke, which in turn may make them less able to work, thereby worsening their financial situation and increasing their vulnerability to food insecurity,” Dr. Brandt said.
For the analysis, Dr. Brandt and his team used an analytic sample of 57,517 adults to represent 312 million non-institutionalized adults in the United States.
Overall, 6,770 individuals (11.8%) in the analytic sample reported food insecurity.
Food insecurity was more prevalent among Hispanic people (n = 1,938, 24.0%) and non-Hispanic Black people (n = 1,202, 18.2%), compared with non-Hispanic Asian people (n = 100, 8.0%), and non-Hispanic White people (n = 3,221, 8.5%).
The prevalence of cardiovascular disease in the sample was 7.9% (n = 4,527).
Hypertension was the most prevalent CVD risk factor, reported in 49.6% of the sample. This was followed by obesity in 33.2%, dyslipidemia in 30.8%, and diabetes in 11.2%.
The findings were published online in JAMA Cardiology.
“All cardiovascular disease and cardiometabolic diseases except coronary artery disease were more prevalent among those with food insecurity,” Dr. Brandt noted.
“The results of our study are especially timely, as the White House just hosted its first conference on Hunger, Nutrition, and Health in over 50 years. Food insecurity is a focus of that conference. In the last few years, especially in relation to the pandemic, there has been expansion of some of the federal programs to prevent food insecurity. I would like to see a continued effort to solve this,” he said.
Dr. Brandt added that he hopes clinicians will be more cognizant of the problem of food insecurity and other social determinants of health when they see their patients.
“If someone is not going to be able to afford the food on their table, they’re probably not going to pay for their medications. Recognizing these social determinants in the clinical setting and helping our patients access local resources may address the underlying factors contributing to heart disease,” he said.
Uphill battle
Johanna Contreras, MD, advanced heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, treats food insecure cardiovascular patients in her practice and tries to educate them about good nutrition. But it is an uphill battle.
“A lot of my patients live in the South Bronx. They have hypertension, hypercholesterolemia, and there are no grocery stores where they can buy fresh vegetables. I talk to them about eating healthy. They tell me it’s impossible. The stores only have pre-packaged foods. So even in the South Bronx, even though it is in New York, it is very hard to get fresh food. And when it is available, it is very expensive,” Dr. Contreras told this news organization.
“Fresh pineapples can cost $8. A fast-food burger costs $3. So that is what they buy: It’s what they can afford. Even the store managers don’t want to stock fresh produce because it can spoil. They open stores, like Whole Foods, but in the more affluent neighborhoods. They should open one in poor neighborhoods,” she said.
Dr. Contreras says she spends much of her time educating her patients about good nutrition. She asks them to keep a food diary and analyzes the results at each visit.
“I look at what they eat, and I try to see how I can use this information in a good way. I advise them to use frozen foods, and avoid canned, because it is a lot healthier. I am pragmatic, because I know that if I tell my patients to eat salmon, for example, they aren’t going to be able to afford it, if they can even access it.”
She also informs them about relatively healthy fast-food choices.
“I tell them to order 100% fruit juice, water, or milk when they go to McDonalds or other fast-food places. So I think this study is very important. Food insecurity is a very important component of cardiovascular disease, and unfortunately, minority communities are where this occurs.”
Dr. Brandt and Dr. Contreras report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Bariatric surgery may up risk for epilepsy
Analyzing health records, investigators compared almost 17,000 patients who had undergone bariatric surgery with more than 620,000 individuals with obesity who had not undergone the surgery.
During a minimum 3-year follow-up period, the surgery group had a 45% higher risk of developing epilepsy than the nonsurgery group. Moreover, patients who had a stroke after their bariatric surgery were 14 times more likely to develop epilepsy than those who did not have a stroke.
“When considering having bariatric surgery, people should talk to their doctors about the benefits and risks,” senior investigator Jorge Burneo, MD, professor of neurology, biostatistics, and epidemiology and endowed chair in epilepsy at Western University, London, told this news organization.
“While there are many health benefits of weight loss, our findings suggest that epilepsy is a long-term risk of bariatric surgery for weight loss,” Dr. Burneo said.
The findings were published online in Neurology.
Unrecognized risk factor?
Bariatric surgery has become more common as global rates of obesity have increased. The surgery has been shown to reduce the risk for serious obesity-related conditions, the researchers note.
However, “in addition to the positive outcomes of bariatric surgery, several long-term neurological complications have also been identified,” they write.
One previous study reported increased epilepsy risk following gastric bypass. Those findings “suggest that bariatric surgery may be an unrecognized epilepsy risk factor; however, this possible association has not been thoroughly explored,” write the investigators.
Dr. Burneo said he conducted the study because he has seen patients with epilepsy in his clinic who were “without risk factors, with normal MRIs, who shared the history of having bariatric surgery before the development of epilepsy.”
The researchers’ primary objective was to “assess whether epilepsy risk is elevated following bariatric surgery for weight loss relative to a nonsurgical cohort of patients who are obese,” he noted.
The study used linked administrative health databases in Ontario, Canada. Patients were accrued from July 1, 2010, to Dec. 31, 2016, and were followed until Dec. 31, 2019. The analysis included 639,472 participants, 2.7% of whom had undergone bariatric surgery.
The “exposed” cohort consisted of all Ontario residents aged 18 years or older who had undergone bariatric surgery during the 6-year period (n = 16,958; 65.1% women; mean age, 47.4 years), while the “unexposed” cohort consisted of patients hospitalized with a diagnosis of obesity who had not undergone bariatric surgery (n = 622,514; 62.8% women; mean age, 47.6 years).
Patients with a history of seizures, epilepsy, epilepsy risk factors, prior brain surgery, psychiatric disorders, or drug or alcohol abuse/dependence were excluded from the analysis.
The researchers collected data on patients’ sociodemographic characteristics at the index date, as well as Charlson Comorbidity Index scores during the 2 years prior to index, and data regarding several specific comorbidities, such as diabetes mellitus, hypertension, sleep apnea, depression/anxiety, and cardiovascular factors.
The exposed and unexposed cohorts were followed for a median period of 5.8 and 5.9 person-years, respectively.
‘Unclear’ mechanisms
Before weighting, 0.4% of participants in the exposed cohort (n = 73) developed epilepsy, versus 0.2% of participants in the unexposed cohort (n = 1,260) by the end of the follow-up period.
In the weighted cohorts, there were 50.1 epilepsy diagnoses per 100,000 person-years, versus 34.1 per 100,000 person-years (rate difference, 16 per 100,000 person-years).
The multivariable analysis of the weighted cohort showed the hazard ratio for epilepsy cases that were associated with bariatric surgery was 1.45 (95% confidence interval, 1.35-1.56), after adjusting for sleep apnea and including stroke as a time-varying covariate.
Having a stroke during the follow-up period increased epilepsy 14-fold in the exposed cohort (HR, 14.03; 95% CI, 4.25-46.25).
The investigators note that they were unable to measure obesity status or body mass index throughout the study and that some obesity-related comorbidities “may affect epilepsy risk.”
In addition, Dr. Burneo reported that the study did not investigate potential causes and mechanisms of the association between bariatric surgery and epilepsy risk.
Hypotheses “include potential nutritional deficiencies, receipt of general anesthesia, or other unclear causes,” he said.
“Future research should investigate epilepsy as a potential long-term complication of bariatric surgery, exploring the possible effects of this procedure,” Dr. Burneo added.
Risk-benefit discussion
In a comment, Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine, and director of NYU’s Epilepsy Study Consortium, said she was “not 100% surprised by the findings” because she has seen in her clinical practice “a number of patients who developed epilepsy after bariatric surgery or had a history of bariatric surgery at the time they developed epilepsy.”
On the other hand, she has also seen patients who did not have a history of bariatric surgery and who developed epilepsy.
“I’m unable to tell if there is an association, although I’ve had it at the back of my head as a thought and wondered about it,” said Dr. French, who is also the chief medical and innovation officer at the Epilepsy Foundation. She was not involved with the study.
She noted that possible mechanisms underlying the association are that gastric bypass surgery leads to a “significant alteration” in nutrient absorption. Moreover, “we now know that the microbiome is associated with epilepsy” and that changes occur in the gut microbiome after bariatric surgery, Dr. French said.
There are two take-home messages for practicing clinicians, she added.
“Although the risk [of developing epilepsy] is very low, it should be presented as part of the risks and benefits to patients considering bariatric surgery,” she said.
“It’s equally important to follow up on the potential differences in these patients who go on to develop epilepsy following bariatric surgery,” said Dr. French. “Is there a certain metabolic profile or some nutrient previously absorbed that now is not absorbed that might predispose people to risk?”
This would be “enormously important to know because it might not just pertain to these people but to a whole other cohort of people who develop epilepsy,” Dr. French concluded.
The study was funded by the Ontario Ministry of Health and Ministry of Long-Term Care and by the Jack Cowin Endowed Chair in Epilepsy Research at Western University. Dr. Burneo holds the Jack Cowin Endowed Chair in Epilepsy Research at Western University. The other investigators and Dr. French have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Analyzing health records, investigators compared almost 17,000 patients who had undergone bariatric surgery with more than 620,000 individuals with obesity who had not undergone the surgery.
During a minimum 3-year follow-up period, the surgery group had a 45% higher risk of developing epilepsy than the nonsurgery group. Moreover, patients who had a stroke after their bariatric surgery were 14 times more likely to develop epilepsy than those who did not have a stroke.
“When considering having bariatric surgery, people should talk to their doctors about the benefits and risks,” senior investigator Jorge Burneo, MD, professor of neurology, biostatistics, and epidemiology and endowed chair in epilepsy at Western University, London, told this news organization.
“While there are many health benefits of weight loss, our findings suggest that epilepsy is a long-term risk of bariatric surgery for weight loss,” Dr. Burneo said.
The findings were published online in Neurology.
Unrecognized risk factor?
Bariatric surgery has become more common as global rates of obesity have increased. The surgery has been shown to reduce the risk for serious obesity-related conditions, the researchers note.
However, “in addition to the positive outcomes of bariatric surgery, several long-term neurological complications have also been identified,” they write.
One previous study reported increased epilepsy risk following gastric bypass. Those findings “suggest that bariatric surgery may be an unrecognized epilepsy risk factor; however, this possible association has not been thoroughly explored,” write the investigators.
Dr. Burneo said he conducted the study because he has seen patients with epilepsy in his clinic who were “without risk factors, with normal MRIs, who shared the history of having bariatric surgery before the development of epilepsy.”
The researchers’ primary objective was to “assess whether epilepsy risk is elevated following bariatric surgery for weight loss relative to a nonsurgical cohort of patients who are obese,” he noted.
The study used linked administrative health databases in Ontario, Canada. Patients were accrued from July 1, 2010, to Dec. 31, 2016, and were followed until Dec. 31, 2019. The analysis included 639,472 participants, 2.7% of whom had undergone bariatric surgery.
The “exposed” cohort consisted of all Ontario residents aged 18 years or older who had undergone bariatric surgery during the 6-year period (n = 16,958; 65.1% women; mean age, 47.4 years), while the “unexposed” cohort consisted of patients hospitalized with a diagnosis of obesity who had not undergone bariatric surgery (n = 622,514; 62.8% women; mean age, 47.6 years).
Patients with a history of seizures, epilepsy, epilepsy risk factors, prior brain surgery, psychiatric disorders, or drug or alcohol abuse/dependence were excluded from the analysis.
The researchers collected data on patients’ sociodemographic characteristics at the index date, as well as Charlson Comorbidity Index scores during the 2 years prior to index, and data regarding several specific comorbidities, such as diabetes mellitus, hypertension, sleep apnea, depression/anxiety, and cardiovascular factors.
The exposed and unexposed cohorts were followed for a median period of 5.8 and 5.9 person-years, respectively.
‘Unclear’ mechanisms
Before weighting, 0.4% of participants in the exposed cohort (n = 73) developed epilepsy, versus 0.2% of participants in the unexposed cohort (n = 1,260) by the end of the follow-up period.
In the weighted cohorts, there were 50.1 epilepsy diagnoses per 100,000 person-years, versus 34.1 per 100,000 person-years (rate difference, 16 per 100,000 person-years).
The multivariable analysis of the weighted cohort showed the hazard ratio for epilepsy cases that were associated with bariatric surgery was 1.45 (95% confidence interval, 1.35-1.56), after adjusting for sleep apnea and including stroke as a time-varying covariate.
Having a stroke during the follow-up period increased epilepsy 14-fold in the exposed cohort (HR, 14.03; 95% CI, 4.25-46.25).
The investigators note that they were unable to measure obesity status or body mass index throughout the study and that some obesity-related comorbidities “may affect epilepsy risk.”
In addition, Dr. Burneo reported that the study did not investigate potential causes and mechanisms of the association between bariatric surgery and epilepsy risk.
Hypotheses “include potential nutritional deficiencies, receipt of general anesthesia, or other unclear causes,” he said.
“Future research should investigate epilepsy as a potential long-term complication of bariatric surgery, exploring the possible effects of this procedure,” Dr. Burneo added.
Risk-benefit discussion
In a comment, Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine, and director of NYU’s Epilepsy Study Consortium, said she was “not 100% surprised by the findings” because she has seen in her clinical practice “a number of patients who developed epilepsy after bariatric surgery or had a history of bariatric surgery at the time they developed epilepsy.”
On the other hand, she has also seen patients who did not have a history of bariatric surgery and who developed epilepsy.
“I’m unable to tell if there is an association, although I’ve had it at the back of my head as a thought and wondered about it,” said Dr. French, who is also the chief medical and innovation officer at the Epilepsy Foundation. She was not involved with the study.
She noted that possible mechanisms underlying the association are that gastric bypass surgery leads to a “significant alteration” in nutrient absorption. Moreover, “we now know that the microbiome is associated with epilepsy” and that changes occur in the gut microbiome after bariatric surgery, Dr. French said.
There are two take-home messages for practicing clinicians, she added.
“Although the risk [of developing epilepsy] is very low, it should be presented as part of the risks and benefits to patients considering bariatric surgery,” she said.
“It’s equally important to follow up on the potential differences in these patients who go on to develop epilepsy following bariatric surgery,” said Dr. French. “Is there a certain metabolic profile or some nutrient previously absorbed that now is not absorbed that might predispose people to risk?”
This would be “enormously important to know because it might not just pertain to these people but to a whole other cohort of people who develop epilepsy,” Dr. French concluded.
The study was funded by the Ontario Ministry of Health and Ministry of Long-Term Care and by the Jack Cowin Endowed Chair in Epilepsy Research at Western University. Dr. Burneo holds the Jack Cowin Endowed Chair in Epilepsy Research at Western University. The other investigators and Dr. French have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Analyzing health records, investigators compared almost 17,000 patients who had undergone bariatric surgery with more than 620,000 individuals with obesity who had not undergone the surgery.
During a minimum 3-year follow-up period, the surgery group had a 45% higher risk of developing epilepsy than the nonsurgery group. Moreover, patients who had a stroke after their bariatric surgery were 14 times more likely to develop epilepsy than those who did not have a stroke.
“When considering having bariatric surgery, people should talk to their doctors about the benefits and risks,” senior investigator Jorge Burneo, MD, professor of neurology, biostatistics, and epidemiology and endowed chair in epilepsy at Western University, London, told this news organization.
“While there are many health benefits of weight loss, our findings suggest that epilepsy is a long-term risk of bariatric surgery for weight loss,” Dr. Burneo said.
The findings were published online in Neurology.
Unrecognized risk factor?
Bariatric surgery has become more common as global rates of obesity have increased. The surgery has been shown to reduce the risk for serious obesity-related conditions, the researchers note.
However, “in addition to the positive outcomes of bariatric surgery, several long-term neurological complications have also been identified,” they write.
One previous study reported increased epilepsy risk following gastric bypass. Those findings “suggest that bariatric surgery may be an unrecognized epilepsy risk factor; however, this possible association has not been thoroughly explored,” write the investigators.
Dr. Burneo said he conducted the study because he has seen patients with epilepsy in his clinic who were “without risk factors, with normal MRIs, who shared the history of having bariatric surgery before the development of epilepsy.”
The researchers’ primary objective was to “assess whether epilepsy risk is elevated following bariatric surgery for weight loss relative to a nonsurgical cohort of patients who are obese,” he noted.
The study used linked administrative health databases in Ontario, Canada. Patients were accrued from July 1, 2010, to Dec. 31, 2016, and were followed until Dec. 31, 2019. The analysis included 639,472 participants, 2.7% of whom had undergone bariatric surgery.
The “exposed” cohort consisted of all Ontario residents aged 18 years or older who had undergone bariatric surgery during the 6-year period (n = 16,958; 65.1% women; mean age, 47.4 years), while the “unexposed” cohort consisted of patients hospitalized with a diagnosis of obesity who had not undergone bariatric surgery (n = 622,514; 62.8% women; mean age, 47.6 years).
Patients with a history of seizures, epilepsy, epilepsy risk factors, prior brain surgery, psychiatric disorders, or drug or alcohol abuse/dependence were excluded from the analysis.
The researchers collected data on patients’ sociodemographic characteristics at the index date, as well as Charlson Comorbidity Index scores during the 2 years prior to index, and data regarding several specific comorbidities, such as diabetes mellitus, hypertension, sleep apnea, depression/anxiety, and cardiovascular factors.
The exposed and unexposed cohorts were followed for a median period of 5.8 and 5.9 person-years, respectively.
‘Unclear’ mechanisms
Before weighting, 0.4% of participants in the exposed cohort (n = 73) developed epilepsy, versus 0.2% of participants in the unexposed cohort (n = 1,260) by the end of the follow-up period.
In the weighted cohorts, there were 50.1 epilepsy diagnoses per 100,000 person-years, versus 34.1 per 100,000 person-years (rate difference, 16 per 100,000 person-years).
The multivariable analysis of the weighted cohort showed the hazard ratio for epilepsy cases that were associated with bariatric surgery was 1.45 (95% confidence interval, 1.35-1.56), after adjusting for sleep apnea and including stroke as a time-varying covariate.
Having a stroke during the follow-up period increased epilepsy 14-fold in the exposed cohort (HR, 14.03; 95% CI, 4.25-46.25).
The investigators note that they were unable to measure obesity status or body mass index throughout the study and that some obesity-related comorbidities “may affect epilepsy risk.”
In addition, Dr. Burneo reported that the study did not investigate potential causes and mechanisms of the association between bariatric surgery and epilepsy risk.
Hypotheses “include potential nutritional deficiencies, receipt of general anesthesia, or other unclear causes,” he said.
“Future research should investigate epilepsy as a potential long-term complication of bariatric surgery, exploring the possible effects of this procedure,” Dr. Burneo added.
Risk-benefit discussion
In a comment, Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine, and director of NYU’s Epilepsy Study Consortium, said she was “not 100% surprised by the findings” because she has seen in her clinical practice “a number of patients who developed epilepsy after bariatric surgery or had a history of bariatric surgery at the time they developed epilepsy.”
On the other hand, she has also seen patients who did not have a history of bariatric surgery and who developed epilepsy.
“I’m unable to tell if there is an association, although I’ve had it at the back of my head as a thought and wondered about it,” said Dr. French, who is also the chief medical and innovation officer at the Epilepsy Foundation. She was not involved with the study.
She noted that possible mechanisms underlying the association are that gastric bypass surgery leads to a “significant alteration” in nutrient absorption. Moreover, “we now know that the microbiome is associated with epilepsy” and that changes occur in the gut microbiome after bariatric surgery, Dr. French said.
There are two take-home messages for practicing clinicians, she added.
“Although the risk [of developing epilepsy] is very low, it should be presented as part of the risks and benefits to patients considering bariatric surgery,” she said.
“It’s equally important to follow up on the potential differences in these patients who go on to develop epilepsy following bariatric surgery,” said Dr. French. “Is there a certain metabolic profile or some nutrient previously absorbed that now is not absorbed that might predispose people to risk?”
This would be “enormously important to know because it might not just pertain to these people but to a whole other cohort of people who develop epilepsy,” Dr. French concluded.
The study was funded by the Ontario Ministry of Health and Ministry of Long-Term Care and by the Jack Cowin Endowed Chair in Epilepsy Research at Western University. Dr. Burneo holds the Jack Cowin Endowed Chair in Epilepsy Research at Western University. The other investigators and Dr. French have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Balanced fat intake links with less type 2 diabetes
Researchers published the study covered in this summary on Preprints with The Lancet as a preprint that has not yet been peer reviewed.
Key takeaways
- Adults in China who consumed a “balanced,” moderate ratio (middle three quintiles) of animal-to-vegetable cooking oil had a lower rate of developing type 2 diabetes during a median follow-up of 8.6 years, compared with those who consumed the lowest ratio (first quintile), after multivariable adjustment using prospectively collected data.
- The results also indicate that increasing animal cooking oil (such as lard, tallow, or butter) and vegetable cooking oil (such as peanut or soybean oil) consumption were each positively associated with a higher rate of developing type 2 diabetes.
- Those who consumed the highest ratio (fifth quintile) of animal-to-vegetable cooking oil had a nonsignificant difference in their rate of developing type 2 diabetes, compared with those in the first quintile.
Why this matters
- The findings suggest that consuming a diet with a “balanced” moderate intake of animal and vegetable oil might lower the risk of type 2 diabetes, which would reduce disease burden and health care expenditures.
- The results imply that using a single source of cooking oil, either animal or vegetable, contributes to the incidence of type 2 diabetes.
- This is the first large epidemiological study showing a relationship between the ratio of animal- and vegetable-derived fats in people’s diets and their risk for incident type 2 diabetes.
Study design
- The researchers used data collected prospectively starting in 2010-2012 from 7,274 adult residents of Guizhou province, China, with follow-up assessment in 2020 after a median of 8.6 years.
- At baseline, participants underwent an oral glucose tolerance test and provided information on demographics, family medical history, and personal medical history, including whether they had been diagnosed with type 2 diabetes or were taking antihyperglycemic medications. The study did not include anyone with a history of diabetes.
- Data on intake of animal and vegetable cooking oil came from a dietary questionnaire.
- The authors calculated hazard ratios for development of type 2 diabetes after adjusting for multiple potential confounders.
Key results
- The study cohort averaged 44 years old, and 53% were women.
- During a median follow-up of 8.6 years, 747 people developed type 2 diabetes.
- Compared with those who had the lowest intake of animal cooking oil (first quintile), those with the highest intake (fifth quintile) had a significant 28% increased relative rate for developing type 2 diabetes after adjustment for several potential confounders.
- Compared with those with the lowest intake of vegetable cooking oil, those with the highest intake had a significant 56% increased rate of developing type 2 diabetes after adjustment.
- Compared with adults with the lowest animal-to-vegetable cooking oil ratio (first quintile), those in the second, third, and fourth quintiles for this ratio had significantly lower adjusted relative rates of developing type 2 diabetes, with adjusted hazard ratios of 0.79, 0.65, and 0.68, respectively. Those in the highest quintile (fifth quintile) did not have a significantly different risk, compared with the first quintile.
- The protective effect of a balanced ratio of animal-to-vegetable cooking oils was stronger in people who lived in rural districts and in those who had obesity.
Limitations
- The dietary information came from participants’ self-reports, which may have produced biased data.
- The study only included information about animal and vegetable cooking oil consumed at home.
- There may have been residual confounding from variables not included in the study.
- The time of diagnosis of type 2 diabetes may have been inaccurate because follow-up occurred only once.
- The study may have underestimated the incidence of type 2 diabetes because of a lack of information about hemoglobin A1c levels at follow-up.
Disclosures
- The study did not receive commercial funding.
- The authors reported no financial disclosures.
This is a summary of a preprint article “The consumption ratio of animal cooking oil to vegetable cooking oil and reduced risk of type 2 diabetes mellitus: A prospective cohort study in Southwest China” written by researchers primarily from Zunyi Medical University, China, on Preprints with The Lancet. This study has not yet been peer reviewed. The full text of the study can be found on papers.ssrn.com.
A version of this article first appeared on Medscape.com.
Researchers published the study covered in this summary on Preprints with The Lancet as a preprint that has not yet been peer reviewed.
Key takeaways
- Adults in China who consumed a “balanced,” moderate ratio (middle three quintiles) of animal-to-vegetable cooking oil had a lower rate of developing type 2 diabetes during a median follow-up of 8.6 years, compared with those who consumed the lowest ratio (first quintile), after multivariable adjustment using prospectively collected data.
- The results also indicate that increasing animal cooking oil (such as lard, tallow, or butter) and vegetable cooking oil (such as peanut or soybean oil) consumption were each positively associated with a higher rate of developing type 2 diabetes.
- Those who consumed the highest ratio (fifth quintile) of animal-to-vegetable cooking oil had a nonsignificant difference in their rate of developing type 2 diabetes, compared with those in the first quintile.
Why this matters
- The findings suggest that consuming a diet with a “balanced” moderate intake of animal and vegetable oil might lower the risk of type 2 diabetes, which would reduce disease burden and health care expenditures.
- The results imply that using a single source of cooking oil, either animal or vegetable, contributes to the incidence of type 2 diabetes.
- This is the first large epidemiological study showing a relationship between the ratio of animal- and vegetable-derived fats in people’s diets and their risk for incident type 2 diabetes.
Study design
- The researchers used data collected prospectively starting in 2010-2012 from 7,274 adult residents of Guizhou province, China, with follow-up assessment in 2020 after a median of 8.6 years.
- At baseline, participants underwent an oral glucose tolerance test and provided information on demographics, family medical history, and personal medical history, including whether they had been diagnosed with type 2 diabetes or were taking antihyperglycemic medications. The study did not include anyone with a history of diabetes.
- Data on intake of animal and vegetable cooking oil came from a dietary questionnaire.
- The authors calculated hazard ratios for development of type 2 diabetes after adjusting for multiple potential confounders.
Key results
- The study cohort averaged 44 years old, and 53% were women.
- During a median follow-up of 8.6 years, 747 people developed type 2 diabetes.
- Compared with those who had the lowest intake of animal cooking oil (first quintile), those with the highest intake (fifth quintile) had a significant 28% increased relative rate for developing type 2 diabetes after adjustment for several potential confounders.
- Compared with those with the lowest intake of vegetable cooking oil, those with the highest intake had a significant 56% increased rate of developing type 2 diabetes after adjustment.
- Compared with adults with the lowest animal-to-vegetable cooking oil ratio (first quintile), those in the second, third, and fourth quintiles for this ratio had significantly lower adjusted relative rates of developing type 2 diabetes, with adjusted hazard ratios of 0.79, 0.65, and 0.68, respectively. Those in the highest quintile (fifth quintile) did not have a significantly different risk, compared with the first quintile.
- The protective effect of a balanced ratio of animal-to-vegetable cooking oils was stronger in people who lived in rural districts and in those who had obesity.
Limitations
- The dietary information came from participants’ self-reports, which may have produced biased data.
- The study only included information about animal and vegetable cooking oil consumed at home.
- There may have been residual confounding from variables not included in the study.
- The time of diagnosis of type 2 diabetes may have been inaccurate because follow-up occurred only once.
- The study may have underestimated the incidence of type 2 diabetes because of a lack of information about hemoglobin A1c levels at follow-up.
Disclosures
- The study did not receive commercial funding.
- The authors reported no financial disclosures.
This is a summary of a preprint article “The consumption ratio of animal cooking oil to vegetable cooking oil and reduced risk of type 2 diabetes mellitus: A prospective cohort study in Southwest China” written by researchers primarily from Zunyi Medical University, China, on Preprints with The Lancet. This study has not yet been peer reviewed. The full text of the study can be found on papers.ssrn.com.
A version of this article first appeared on Medscape.com.
Researchers published the study covered in this summary on Preprints with The Lancet as a preprint that has not yet been peer reviewed.
Key takeaways
- Adults in China who consumed a “balanced,” moderate ratio (middle three quintiles) of animal-to-vegetable cooking oil had a lower rate of developing type 2 diabetes during a median follow-up of 8.6 years, compared with those who consumed the lowest ratio (first quintile), after multivariable adjustment using prospectively collected data.
- The results also indicate that increasing animal cooking oil (such as lard, tallow, or butter) and vegetable cooking oil (such as peanut or soybean oil) consumption were each positively associated with a higher rate of developing type 2 diabetes.
- Those who consumed the highest ratio (fifth quintile) of animal-to-vegetable cooking oil had a nonsignificant difference in their rate of developing type 2 diabetes, compared with those in the first quintile.
Why this matters
- The findings suggest that consuming a diet with a “balanced” moderate intake of animal and vegetable oil might lower the risk of type 2 diabetes, which would reduce disease burden and health care expenditures.
- The results imply that using a single source of cooking oil, either animal or vegetable, contributes to the incidence of type 2 diabetes.
- This is the first large epidemiological study showing a relationship between the ratio of animal- and vegetable-derived fats in people’s diets and their risk for incident type 2 diabetes.
Study design
- The researchers used data collected prospectively starting in 2010-2012 from 7,274 adult residents of Guizhou province, China, with follow-up assessment in 2020 after a median of 8.6 years.
- At baseline, participants underwent an oral glucose tolerance test and provided information on demographics, family medical history, and personal medical history, including whether they had been diagnosed with type 2 diabetes or were taking antihyperglycemic medications. The study did not include anyone with a history of diabetes.
- Data on intake of animal and vegetable cooking oil came from a dietary questionnaire.
- The authors calculated hazard ratios for development of type 2 diabetes after adjusting for multiple potential confounders.
Key results
- The study cohort averaged 44 years old, and 53% were women.
- During a median follow-up of 8.6 years, 747 people developed type 2 diabetes.
- Compared with those who had the lowest intake of animal cooking oil (first quintile), those with the highest intake (fifth quintile) had a significant 28% increased relative rate for developing type 2 diabetes after adjustment for several potential confounders.
- Compared with those with the lowest intake of vegetable cooking oil, those with the highest intake had a significant 56% increased rate of developing type 2 diabetes after adjustment.
- Compared with adults with the lowest animal-to-vegetable cooking oil ratio (first quintile), those in the second, third, and fourth quintiles for this ratio had significantly lower adjusted relative rates of developing type 2 diabetes, with adjusted hazard ratios of 0.79, 0.65, and 0.68, respectively. Those in the highest quintile (fifth quintile) did not have a significantly different risk, compared with the first quintile.
- The protective effect of a balanced ratio of animal-to-vegetable cooking oils was stronger in people who lived in rural districts and in those who had obesity.
Limitations
- The dietary information came from participants’ self-reports, which may have produced biased data.
- The study only included information about animal and vegetable cooking oil consumed at home.
- There may have been residual confounding from variables not included in the study.
- The time of diagnosis of type 2 diabetes may have been inaccurate because follow-up occurred only once.
- The study may have underestimated the incidence of type 2 diabetes because of a lack of information about hemoglobin A1c levels at follow-up.
Disclosures
- The study did not receive commercial funding.
- The authors reported no financial disclosures.
This is a summary of a preprint article “The consumption ratio of animal cooking oil to vegetable cooking oil and reduced risk of type 2 diabetes mellitus: A prospective cohort study in Southwest China” written by researchers primarily from Zunyi Medical University, China, on Preprints with The Lancet. This study has not yet been peer reviewed. The full text of the study can be found on papers.ssrn.com.
A version of this article first appeared on Medscape.com.
SMART-CHOICE 3-year results support dropping aspirin after PCI
Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.
“The current the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.
The 3-year results from the study were published online in JAMA Cardiology.
The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.
Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.
The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.
The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.
At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).
But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).
The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.
The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.
“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.
They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.
“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.
They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.
“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.
They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
P2Y12-inhibitor monotherapy ‘attractive concept’
In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.
Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.
The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.
They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.
“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.
“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.
The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.
A version of this article first appeared on Medscape.com.
Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.
“The current the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.
The 3-year results from the study were published online in JAMA Cardiology.
The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.
Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.
The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.
The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.
At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).
But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).
The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.
The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.
“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.
They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.
“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.
They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.
“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.
They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
P2Y12-inhibitor monotherapy ‘attractive concept’
In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.
Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.
The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.
They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.
“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.
“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.
The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.
A version of this article first appeared on Medscape.com.
Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.
“The current the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.
The 3-year results from the study were published online in JAMA Cardiology.
The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.
Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.
The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.
The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.
At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).
But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).
The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.
The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.
“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.
They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.
“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.
They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.
“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.
They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
P2Y12-inhibitor monotherapy ‘attractive concept’
In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.
Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.
The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.
They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.
“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.
“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.
The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.
A version of this article first appeared on Medscape.com.
FROM JAMA CARDIOLOGY
Ezetimibe-statin combo lowers liver fat in open-label trial
Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.
The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.
“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.
“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.
He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).
Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).
This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
Rationale for the ESSENTIAL study
Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.
“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.
“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.
Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”
Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
Addressing the Hawthorne effect
“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.
“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.
“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
A randomized, active-controlled, clinician-initiated trial
The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.
In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.
Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.
Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.
Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.
“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.
The results of the ESSENTIAL study have been published in BMC Medicine.
The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.
Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.
The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.
“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.
“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.
He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).
Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).
This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
Rationale for the ESSENTIAL study
Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.
“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.
“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.
Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”
Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
Addressing the Hawthorne effect
“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.
“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.
“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
A randomized, active-controlled, clinician-initiated trial
The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.
In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.
Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.
Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.
Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.
“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.
The results of the ESSENTIAL study have been published in BMC Medicine.
The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.
Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.
The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.
“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.
“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.
He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).
Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).
This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
Rationale for the ESSENTIAL study
Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.
“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.
“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.
Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”
Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
Addressing the Hawthorne effect
“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.
“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.
“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
A randomized, active-controlled, clinician-initiated trial
The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.
In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.
Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.
Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.
Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.
“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.
The results of the ESSENTIAL study have been published in BMC Medicine.
The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.
FROM EASD 2022