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Triple Therapy May Be Effective in Drug-Naive T2D
TOPLINE:
A triple combination therapy (TCT) of metformin, dapagliflozin, and saxagliptin is an effective and safe treatment option for drug-naive patients with type 2 diabetes (T2D) compared with stepwise add-on therapy.
METHODOLOGY:
- Current guidelines recommend early combination therapy to extend the time to treatment failure, reduce the risk for diabetic complications, and prevent clinical inertia in patients with T2D.
- This randomized controlled open-label trial conducted at nine sites in South Korea included 105 drug-naive patients with T2D (mean age, 49.5 years; 32.4% women) who either received triple therapy (metformin, dapagliflozin, and saxagliptin) or stepwise add-on therapy (initiated with metformin, followed by glimepiride and sitagliptin for those with baseline hemoglobin A1c levels < 9.0% or with initial dual metformin and glimepiride in those with A1c levels ≥ 9.0% followed by sitagliptin).
- The primary outcome was the proportion of patients who achieved A1c levels < 6.5% without hypoglycemia, weight gain ≥ 5%, or discontinuation of drugs because of adverse events at week 104.
- The secondary outcomes were the proportion of patients whose A1c levels dropped to < 7.0% at weeks 56 and 104 and dropped to < 6.5% at week 56, all without hypoglycemia, weight gain, nor discontinuation due to adverse events.
TAKEAWAY:
- At week 104, a higher proportion of patients in the triple therapy group achieved the primary outcome than those in the stepwise add-on therapy group (39.0% vs 17.1%; P = .027).
- In both groups, a similar proportion of patients (46.3%) achieved A1c levels < 6.5% at week 104, but the proportion of patients without hypoglycemia, weight gain, or discontinuation because of adverse events was higher in the triple therapy group than those in the stepwise add-on therapy group (83.3% vs 38.0%; P < .001).
IN PRACTICE:
The authors wrote: “Although the glycemic efficacy of each drug in the TCT was modest, the combination of these drugs resulted in a 2-year durable glycemic efficacy, with greater than a 2.5% reduction in A1c levels from baseline. The overall results of this study suggest a novel strategy for initial combination therapy in newly diagnosed T2D patients.”
SOURCE:
The study was led by Nam Hoon Kim, MD, of the Department of Internal Medicine, Korea University College of Medicine, Seoul. It was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study had a relatively small sample size as compared with previous clinical trials. More people in the standard therapy group had A1c levels ≥ 9.0%, which resulted in more than double the number of people receiving dual combination therapy over monotherapy in that group. The trial duration was insufficient to evaluate the cardiovascular outcomes.
DISCLOSURES:
The study was funded by AstraZeneca. Some authors reported financial ties with AstraZeneca and other pharmaceutical and medical device companies as members of advisory boards or recipients of grants, consulting fees, honoraria, or lecture fees.
A version of this article appeared on Medscape.com.
TOPLINE:
A triple combination therapy (TCT) of metformin, dapagliflozin, and saxagliptin is an effective and safe treatment option for drug-naive patients with type 2 diabetes (T2D) compared with stepwise add-on therapy.
METHODOLOGY:
- Current guidelines recommend early combination therapy to extend the time to treatment failure, reduce the risk for diabetic complications, and prevent clinical inertia in patients with T2D.
- This randomized controlled open-label trial conducted at nine sites in South Korea included 105 drug-naive patients with T2D (mean age, 49.5 years; 32.4% women) who either received triple therapy (metformin, dapagliflozin, and saxagliptin) or stepwise add-on therapy (initiated with metformin, followed by glimepiride and sitagliptin for those with baseline hemoglobin A1c levels < 9.0% or with initial dual metformin and glimepiride in those with A1c levels ≥ 9.0% followed by sitagliptin).
- The primary outcome was the proportion of patients who achieved A1c levels < 6.5% without hypoglycemia, weight gain ≥ 5%, or discontinuation of drugs because of adverse events at week 104.
- The secondary outcomes were the proportion of patients whose A1c levels dropped to < 7.0% at weeks 56 and 104 and dropped to < 6.5% at week 56, all without hypoglycemia, weight gain, nor discontinuation due to adverse events.
TAKEAWAY:
- At week 104, a higher proportion of patients in the triple therapy group achieved the primary outcome than those in the stepwise add-on therapy group (39.0% vs 17.1%; P = .027).
- In both groups, a similar proportion of patients (46.3%) achieved A1c levels < 6.5% at week 104, but the proportion of patients without hypoglycemia, weight gain, or discontinuation because of adverse events was higher in the triple therapy group than those in the stepwise add-on therapy group (83.3% vs 38.0%; P < .001).
IN PRACTICE:
The authors wrote: “Although the glycemic efficacy of each drug in the TCT was modest, the combination of these drugs resulted in a 2-year durable glycemic efficacy, with greater than a 2.5% reduction in A1c levels from baseline. The overall results of this study suggest a novel strategy for initial combination therapy in newly diagnosed T2D patients.”
SOURCE:
The study was led by Nam Hoon Kim, MD, of the Department of Internal Medicine, Korea University College of Medicine, Seoul. It was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study had a relatively small sample size as compared with previous clinical trials. More people in the standard therapy group had A1c levels ≥ 9.0%, which resulted in more than double the number of people receiving dual combination therapy over monotherapy in that group. The trial duration was insufficient to evaluate the cardiovascular outcomes.
DISCLOSURES:
The study was funded by AstraZeneca. Some authors reported financial ties with AstraZeneca and other pharmaceutical and medical device companies as members of advisory boards or recipients of grants, consulting fees, honoraria, or lecture fees.
A version of this article appeared on Medscape.com.
TOPLINE:
A triple combination therapy (TCT) of metformin, dapagliflozin, and saxagliptin is an effective and safe treatment option for drug-naive patients with type 2 diabetes (T2D) compared with stepwise add-on therapy.
METHODOLOGY:
- Current guidelines recommend early combination therapy to extend the time to treatment failure, reduce the risk for diabetic complications, and prevent clinical inertia in patients with T2D.
- This randomized controlled open-label trial conducted at nine sites in South Korea included 105 drug-naive patients with T2D (mean age, 49.5 years; 32.4% women) who either received triple therapy (metformin, dapagliflozin, and saxagliptin) or stepwise add-on therapy (initiated with metformin, followed by glimepiride and sitagliptin for those with baseline hemoglobin A1c levels < 9.0% or with initial dual metformin and glimepiride in those with A1c levels ≥ 9.0% followed by sitagliptin).
- The primary outcome was the proportion of patients who achieved A1c levels < 6.5% without hypoglycemia, weight gain ≥ 5%, or discontinuation of drugs because of adverse events at week 104.
- The secondary outcomes were the proportion of patients whose A1c levels dropped to < 7.0% at weeks 56 and 104 and dropped to < 6.5% at week 56, all without hypoglycemia, weight gain, nor discontinuation due to adverse events.
TAKEAWAY:
- At week 104, a higher proportion of patients in the triple therapy group achieved the primary outcome than those in the stepwise add-on therapy group (39.0% vs 17.1%; P = .027).
- In both groups, a similar proportion of patients (46.3%) achieved A1c levels < 6.5% at week 104, but the proportion of patients without hypoglycemia, weight gain, or discontinuation because of adverse events was higher in the triple therapy group than those in the stepwise add-on therapy group (83.3% vs 38.0%; P < .001).
IN PRACTICE:
The authors wrote: “Although the glycemic efficacy of each drug in the TCT was modest, the combination of these drugs resulted in a 2-year durable glycemic efficacy, with greater than a 2.5% reduction in A1c levels from baseline. The overall results of this study suggest a novel strategy for initial combination therapy in newly diagnosed T2D patients.”
SOURCE:
The study was led by Nam Hoon Kim, MD, of the Department of Internal Medicine, Korea University College of Medicine, Seoul. It was published online in Diabetes, Obesity and Metabolism.
LIMITATIONS:
The study had a relatively small sample size as compared with previous clinical trials. More people in the standard therapy group had A1c levels ≥ 9.0%, which resulted in more than double the number of people receiving dual combination therapy over monotherapy in that group. The trial duration was insufficient to evaluate the cardiovascular outcomes.
DISCLOSURES:
The study was funded by AstraZeneca. Some authors reported financial ties with AstraZeneca and other pharmaceutical and medical device companies as members of advisory boards or recipients of grants, consulting fees, honoraria, or lecture fees.
A version of this article appeared on Medscape.com.
Exercise Plus GLP-1 RAs Upped Weight Loss, Bone Retention
TOPLINE:
People with obesity who exercise while taking glucagon-like peptide 1 receptor agonists (GLP-1 RAs; liraglutide) showed increased weight loss and preserved bone health, according to a study published in JAMA Network Open.
METHODOLOGY:
- Patients were placed on an initial diet that consisted of no more than 800 calories per day for 8 weeks. Those who lost at least 5% of their starting weight were then placed into a 1-year program.
- Participants included 195 adults aged between 18 and 65 years with obesity and no diabetes, 64% of whom were women.
- They were split into four groups of interventions: Exercise only (48 patients), liraglutide only (49 patients), a combination of both (49 participants), and placebo (49 participants), for a 1-year period.
- Patients received liraglutide or volume-matched placebo as daily injections starting at 0.6 mg/d with a weekly increase until 3 mg/d was reached; exercise entailed 30-minute sessions for 4 days a week.
- Researchers studied bone health at each patient’s hip, spine, and forearm after they lost weight, by measuring bone mineral density (BMD).
TAKEAWAY:
- The overall average change in weight loss over the course of 52 weeks was 7.03 kg in the placebo group, 11.19 kg in the exercise group, 13.74 kg in the liraglutide group, and 16.88 kg in the combination group.
- BMD did not change in the combination group in comparison to the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) or spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20).
- BMD of the spine in the liraglutide group decreased in comparison to the exercise group (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04) and the placebo group, in addition to decreases in the hip.
IN PRACTICE:
“Our results show that the combination of exercise and GLP-1 RA was the most effective weight loss strategy while preserving bone health,” study authors wrote.
SOURCE:
The study was led by Simon Birk Kjær Jensen, PhD, of the Department of Biomedical Sciences and Faculty of Health and Medical Sciences at the University of Copenhagen in Denmark, and published on June 25 in JAMA Network Open.
LIMITATIONS:
The study only included adults aged between 18 and 65 years without other chronic diseases and may not apply to patients who are older or have diabetes. The study sample was diverse but was conducted in Denmark, with a population of generally similar ancestry.
DISCLOSURES:
One study author reported serving on advisory boards for AstraZeneca, Boehringer Ingelheim, Bayer, and Amgen, among others. Other authors reported various financial interests, including grants, personal fees, and salaries, from Amgen, Novo Nordisk, and Abbott Lab, among others.
A version of this article first appeared on Medscape.com.
TOPLINE:
People with obesity who exercise while taking glucagon-like peptide 1 receptor agonists (GLP-1 RAs; liraglutide) showed increased weight loss and preserved bone health, according to a study published in JAMA Network Open.
METHODOLOGY:
- Patients were placed on an initial diet that consisted of no more than 800 calories per day for 8 weeks. Those who lost at least 5% of their starting weight were then placed into a 1-year program.
- Participants included 195 adults aged between 18 and 65 years with obesity and no diabetes, 64% of whom were women.
- They were split into four groups of interventions: Exercise only (48 patients), liraglutide only (49 patients), a combination of both (49 participants), and placebo (49 participants), for a 1-year period.
- Patients received liraglutide or volume-matched placebo as daily injections starting at 0.6 mg/d with a weekly increase until 3 mg/d was reached; exercise entailed 30-minute sessions for 4 days a week.
- Researchers studied bone health at each patient’s hip, spine, and forearm after they lost weight, by measuring bone mineral density (BMD).
TAKEAWAY:
- The overall average change in weight loss over the course of 52 weeks was 7.03 kg in the placebo group, 11.19 kg in the exercise group, 13.74 kg in the liraglutide group, and 16.88 kg in the combination group.
- BMD did not change in the combination group in comparison to the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) or spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20).
- BMD of the spine in the liraglutide group decreased in comparison to the exercise group (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04) and the placebo group, in addition to decreases in the hip.
IN PRACTICE:
“Our results show that the combination of exercise and GLP-1 RA was the most effective weight loss strategy while preserving bone health,” study authors wrote.
SOURCE:
The study was led by Simon Birk Kjær Jensen, PhD, of the Department of Biomedical Sciences and Faculty of Health and Medical Sciences at the University of Copenhagen in Denmark, and published on June 25 in JAMA Network Open.
LIMITATIONS:
The study only included adults aged between 18 and 65 years without other chronic diseases and may not apply to patients who are older or have diabetes. The study sample was diverse but was conducted in Denmark, with a population of generally similar ancestry.
DISCLOSURES:
One study author reported serving on advisory boards for AstraZeneca, Boehringer Ingelheim, Bayer, and Amgen, among others. Other authors reported various financial interests, including grants, personal fees, and salaries, from Amgen, Novo Nordisk, and Abbott Lab, among others.
A version of this article first appeared on Medscape.com.
TOPLINE:
People with obesity who exercise while taking glucagon-like peptide 1 receptor agonists (GLP-1 RAs; liraglutide) showed increased weight loss and preserved bone health, according to a study published in JAMA Network Open.
METHODOLOGY:
- Patients were placed on an initial diet that consisted of no more than 800 calories per day for 8 weeks. Those who lost at least 5% of their starting weight were then placed into a 1-year program.
- Participants included 195 adults aged between 18 and 65 years with obesity and no diabetes, 64% of whom were women.
- They were split into four groups of interventions: Exercise only (48 patients), liraglutide only (49 patients), a combination of both (49 participants), and placebo (49 participants), for a 1-year period.
- Patients received liraglutide or volume-matched placebo as daily injections starting at 0.6 mg/d with a weekly increase until 3 mg/d was reached; exercise entailed 30-minute sessions for 4 days a week.
- Researchers studied bone health at each patient’s hip, spine, and forearm after they lost weight, by measuring bone mineral density (BMD).
TAKEAWAY:
- The overall average change in weight loss over the course of 52 weeks was 7.03 kg in the placebo group, 11.19 kg in the exercise group, 13.74 kg in the liraglutide group, and 16.88 kg in the combination group.
- BMD did not change in the combination group in comparison to the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) or spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20).
- BMD of the spine in the liraglutide group decreased in comparison to the exercise group (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04) and the placebo group, in addition to decreases in the hip.
IN PRACTICE:
“Our results show that the combination of exercise and GLP-1 RA was the most effective weight loss strategy while preserving bone health,” study authors wrote.
SOURCE:
The study was led by Simon Birk Kjær Jensen, PhD, of the Department of Biomedical Sciences and Faculty of Health and Medical Sciences at the University of Copenhagen in Denmark, and published on June 25 in JAMA Network Open.
LIMITATIONS:
The study only included adults aged between 18 and 65 years without other chronic diseases and may not apply to patients who are older or have diabetes. The study sample was diverse but was conducted in Denmark, with a population of generally similar ancestry.
DISCLOSURES:
One study author reported serving on advisory boards for AstraZeneca, Boehringer Ingelheim, Bayer, and Amgen, among others. Other authors reported various financial interests, including grants, personal fees, and salaries, from Amgen, Novo Nordisk, and Abbott Lab, among others.
A version of this article first appeared on Medscape.com.
Does Semaglutide Reduce Inflammation?
LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.
The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.
“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”
The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.
In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.
But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.
Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
Reducing Cardiovascular Events
The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”
“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.
Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”
Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”
Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”
However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
A version of this article appeared on Medscape.com.
LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.
The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.
“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”
The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.
In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.
But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.
Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
Reducing Cardiovascular Events
The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”
“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.
Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”
Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”
Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”
However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
A version of this article appeared on Medscape.com.
LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.
The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.
“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”
The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.
In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.
But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.
Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
Reducing Cardiovascular Events
The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”
“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.
Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”
Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”
Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”
However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
A version of this article appeared on Medscape.com.
Pancreatic Gene Therapy: A ‘One-and-Done’ GLP-1 Treatment?
TOPLINE:
An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.
METHODOLOGY:
- With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
- The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
- The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
- At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.
TAKEAWAY:
- At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
- The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
- At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
- Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
- While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
- No indications of pancreatic inflammation or injury were observed in any of the groups.
IN PRACTICE:
The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.
The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
SOURCE:
The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).
LIMITATIONS:
The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.
Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”
Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
DISCLOSURES:
The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.
A version of this article first appeared on Medscape.com.
TOPLINE:
An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.
METHODOLOGY:
- With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
- The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
- The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
- At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.
TAKEAWAY:
- At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
- The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
- At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
- Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
- While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
- No indications of pancreatic inflammation or injury were observed in any of the groups.
IN PRACTICE:
The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.
The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
SOURCE:
The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).
LIMITATIONS:
The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.
Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”
Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
DISCLOSURES:
The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.
A version of this article first appeared on Medscape.com.
TOPLINE:
An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.
METHODOLOGY:
- With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
- The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
- The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
- At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.
TAKEAWAY:
- At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
- The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
- At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
- Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
- While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
- No indications of pancreatic inflammation or injury were observed in any of the groups.
IN PRACTICE:
The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.
The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
SOURCE:
The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).
LIMITATIONS:
The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.
Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”
Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
DISCLOSURES:
The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.
A version of this article first appeared on Medscape.com.
Compounded Semaglutide: How to Better Ensure Its Safety
Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.
Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.
Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
Potential Issues With Compounded Semaglutide
Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.
In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
Compound Pharmacies: A Closer Look
Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade.
Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.
Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA.
The FDA’s Latest Update on This Issue
This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products.
The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.
In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events.
How to Help Patients Receive Safe Compounded Semaglutide
For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing.
Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.
Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.
Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.
Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.
Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
Potential Issues With Compounded Semaglutide
Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.
In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
Compound Pharmacies: A Closer Look
Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade.
Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.
Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA.
The FDA’s Latest Update on This Issue
This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products.
The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.
In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events.
How to Help Patients Receive Safe Compounded Semaglutide
For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing.
Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.
Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.
Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.
Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.
Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
Potential Issues With Compounded Semaglutide
Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.
In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
Compound Pharmacies: A Closer Look
Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade.
Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.
Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA.
The FDA’s Latest Update on This Issue
This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products.
The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.
In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events.
How to Help Patients Receive Safe Compounded Semaglutide
For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing.
Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.
Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.
Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Diabetic Foot Infections: A Peptide’s Potential Promise
At the recent American Diabetes Association (ADA) Scientific Sessions, researchers unveiled promising data on a novel antimicrobial peptide PL-5 spray. This innovative treatment shows significant promise for managing mild to moderate infected diabetic foot ulcers.
Of the 1.6 million people with diabetes in the United States and the tens of millions of similar people worldwide, 50% will require antimicrobials at some time during their life cycle. Diabetic foot infections are difficult to treat because of their resistance to conventional therapies, often leading to severe complications, including amputations.
To address this issue, the antimicrobial peptide PL-5 spray was developed with a novel mechanism of action to potentially improve treatment outcomes. The study aimed to assess the clinical efficacy and safety of the PL-5 spray combined with standard debridement procedures in treating mild to moderate diabetic foot ulcers.
This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in four hospitals across China. Participants with mild to moderate diabetic foot ulcers were randomly assigned in a 2:1 ratio to either the PL-5 group or the placebo group, both receiving standard debridement. The primary endpoint was clinical efficacy at day 1 after the end of treatment (EOT1). Secondary endpoints included clinical efficacy at day 7 (EOT7), microbiological efficacy, drug-resistant bacteria clearance rate, wound healing rate, and safety outcomes evaluated at both EOT1 and EOT7.
The study included 47 participants, with 32 in the PL-5 group and 15 in the placebo group. Both groups had statistically comparable demographic and clinical characteristics. The primary endpoint showed a higher clinical efficacy (cure/improvement ratio) in the PL-5 group, compared with the control group (1.33 vs 0.55; P =.0764), suggesting a positive trend but not reaching statistical significance in this population.
Among the secondary endpoints, clinical efficacy at EOT7 was significantly higher in the PL-5 group than in the control group (1.6 vs 0.86). Microbial eradication rates were notably better in the PL-5 group at both EOT1 (57.89% vs 33.33%) and EOT7 (64.71% vs 40.00%). The clearance rates of drug-resistant bacteria were also higher in the PL-5 group at EOT1 (71.43% vs 50%).
Of importance, safety parameters showed no significant differences between the two groups (24.24% vs 33.33%), highlighting the favorable safety profile of PL-5 spray.
The study presented at the ADA Scientific Sessions provides a glint of promising evidence supporting the potential efficacy and safety of PL-5 spray in treating mild to moderate diabetic foot infections. Despite the limited sample size, the results suggest that PL-5 spray may enhance the recovery speed of diabetic foot wounds, particularly in clearing drug-resistant bacterial infections. These findings justify further investigation with larger sample sizes to confirm or refute the efficacy and potentially establish PL-5 spray as a standard treatment option in diabetic foot care.
The novel antimicrobial peptide PL-5 spray shows potential in addressing the challenging issue of diabetic foot infections. This recent ADA presentation sparked significant interest and discussions about the future of diabetic foot ulcer treatments, emphasizing the importance of innovative approaches in managing complex diabetic complications.
Dr. Armstrong is a professor of surgery and director of limb preservation at the University of Southern California, Los Angeles. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
At the recent American Diabetes Association (ADA) Scientific Sessions, researchers unveiled promising data on a novel antimicrobial peptide PL-5 spray. This innovative treatment shows significant promise for managing mild to moderate infected diabetic foot ulcers.
Of the 1.6 million people with diabetes in the United States and the tens of millions of similar people worldwide, 50% will require antimicrobials at some time during their life cycle. Diabetic foot infections are difficult to treat because of their resistance to conventional therapies, often leading to severe complications, including amputations.
To address this issue, the antimicrobial peptide PL-5 spray was developed with a novel mechanism of action to potentially improve treatment outcomes. The study aimed to assess the clinical efficacy and safety of the PL-5 spray combined with standard debridement procedures in treating mild to moderate diabetic foot ulcers.
This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in four hospitals across China. Participants with mild to moderate diabetic foot ulcers were randomly assigned in a 2:1 ratio to either the PL-5 group or the placebo group, both receiving standard debridement. The primary endpoint was clinical efficacy at day 1 after the end of treatment (EOT1). Secondary endpoints included clinical efficacy at day 7 (EOT7), microbiological efficacy, drug-resistant bacteria clearance rate, wound healing rate, and safety outcomes evaluated at both EOT1 and EOT7.
The study included 47 participants, with 32 in the PL-5 group and 15 in the placebo group. Both groups had statistically comparable demographic and clinical characteristics. The primary endpoint showed a higher clinical efficacy (cure/improvement ratio) in the PL-5 group, compared with the control group (1.33 vs 0.55; P =.0764), suggesting a positive trend but not reaching statistical significance in this population.
Among the secondary endpoints, clinical efficacy at EOT7 was significantly higher in the PL-5 group than in the control group (1.6 vs 0.86). Microbial eradication rates were notably better in the PL-5 group at both EOT1 (57.89% vs 33.33%) and EOT7 (64.71% vs 40.00%). The clearance rates of drug-resistant bacteria were also higher in the PL-5 group at EOT1 (71.43% vs 50%).
Of importance, safety parameters showed no significant differences between the two groups (24.24% vs 33.33%), highlighting the favorable safety profile of PL-5 spray.
The study presented at the ADA Scientific Sessions provides a glint of promising evidence supporting the potential efficacy and safety of PL-5 spray in treating mild to moderate diabetic foot infections. Despite the limited sample size, the results suggest that PL-5 spray may enhance the recovery speed of diabetic foot wounds, particularly in clearing drug-resistant bacterial infections. These findings justify further investigation with larger sample sizes to confirm or refute the efficacy and potentially establish PL-5 spray as a standard treatment option in diabetic foot care.
The novel antimicrobial peptide PL-5 spray shows potential in addressing the challenging issue of diabetic foot infections. This recent ADA presentation sparked significant interest and discussions about the future of diabetic foot ulcer treatments, emphasizing the importance of innovative approaches in managing complex diabetic complications.
Dr. Armstrong is a professor of surgery and director of limb preservation at the University of Southern California, Los Angeles. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
At the recent American Diabetes Association (ADA) Scientific Sessions, researchers unveiled promising data on a novel antimicrobial peptide PL-5 spray. This innovative treatment shows significant promise for managing mild to moderate infected diabetic foot ulcers.
Of the 1.6 million people with diabetes in the United States and the tens of millions of similar people worldwide, 50% will require antimicrobials at some time during their life cycle. Diabetic foot infections are difficult to treat because of their resistance to conventional therapies, often leading to severe complications, including amputations.
To address this issue, the antimicrobial peptide PL-5 spray was developed with a novel mechanism of action to potentially improve treatment outcomes. The study aimed to assess the clinical efficacy and safety of the PL-5 spray combined with standard debridement procedures in treating mild to moderate diabetic foot ulcers.
This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in four hospitals across China. Participants with mild to moderate diabetic foot ulcers were randomly assigned in a 2:1 ratio to either the PL-5 group or the placebo group, both receiving standard debridement. The primary endpoint was clinical efficacy at day 1 after the end of treatment (EOT1). Secondary endpoints included clinical efficacy at day 7 (EOT7), microbiological efficacy, drug-resistant bacteria clearance rate, wound healing rate, and safety outcomes evaluated at both EOT1 and EOT7.
The study included 47 participants, with 32 in the PL-5 group and 15 in the placebo group. Both groups had statistically comparable demographic and clinical characteristics. The primary endpoint showed a higher clinical efficacy (cure/improvement ratio) in the PL-5 group, compared with the control group (1.33 vs 0.55; P =.0764), suggesting a positive trend but not reaching statistical significance in this population.
Among the secondary endpoints, clinical efficacy at EOT7 was significantly higher in the PL-5 group than in the control group (1.6 vs 0.86). Microbial eradication rates were notably better in the PL-5 group at both EOT1 (57.89% vs 33.33%) and EOT7 (64.71% vs 40.00%). The clearance rates of drug-resistant bacteria were also higher in the PL-5 group at EOT1 (71.43% vs 50%).
Of importance, safety parameters showed no significant differences between the two groups (24.24% vs 33.33%), highlighting the favorable safety profile of PL-5 spray.
The study presented at the ADA Scientific Sessions provides a glint of promising evidence supporting the potential efficacy and safety of PL-5 spray in treating mild to moderate diabetic foot infections. Despite the limited sample size, the results suggest that PL-5 spray may enhance the recovery speed of diabetic foot wounds, particularly in clearing drug-resistant bacterial infections. These findings justify further investigation with larger sample sizes to confirm or refute the efficacy and potentially establish PL-5 spray as a standard treatment option in diabetic foot care.
The novel antimicrobial peptide PL-5 spray shows potential in addressing the challenging issue of diabetic foot infections. This recent ADA presentation sparked significant interest and discussions about the future of diabetic foot ulcer treatments, emphasizing the importance of innovative approaches in managing complex diabetic complications.
Dr. Armstrong is a professor of surgery and director of limb preservation at the University of Southern California, Los Angeles. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Ghrelin Paradox: Unlocking New Avenues in Obesity Management
Despite their best efforts, 80% of people who lose weight regain it and many end up heavier within 5 years. Why? Our bodies fight back, revving up hunger while slowing metabolism after weight loss. In ongoing obesity discussions, ghrelin is in the spotlight as the “hunger hormone” playing a crucial role in driving appetite and facilitating weight gain.
Weight loss interventions, such as diet or gastric bypass surgery, may trigger an increase in ghrelin levels, potentially fueling long-term weight gain. Consequently, ghrelin remains a focal point of research into innovative antiobesity treatments.
Ghrelin, a hormone produced in the stomach, is often called the “hunger hormone.” Ghrelin is a circulating orexigenic gut hormone with growth hormone–releasing activity.
Since the discovery of ghrelin, in 1999, research in mice and people has focused on its effect on regulating appetite and implications for long-term weight control. When hunger strikes, ghrelin levels surge, sending signals to the brain that ramp up the appetite. Following a meal, ghrelin decreases, indicating fullness.
Studies have found that people who were injected with subcutaneous ghrelin experienced a 46% increase in hunger and ate 28% more at their next meal than those who didn’t receive a ghrelin injection.
We might expect high levels of ghrelin in individuals with obesity, but this is not the case. In fact, ghrelin levels are typically lower in individuals with obesity than in leaner individuals. This finding might seem to contradict the idea that obesity is due to high levels of the hunger hormone.
Excess weight could increase sensitivity to ghrelin, where more receptors lead to higher hunger stimulation with less ghrelin. Beyond hunger, ghrelin can also lead us to eat for comfort, as when stressed or anxious. Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by activating receptors in the arcuate nucleus of the hypothalamus (Müller et al.; Bany Bakar et al.). There, it also activates the brain’s reward pathways, making us crave food even when we are not hungry. This connection between ghrelin and emotional eating can contribute to stress-induced obesity.
In my clinical practice, I have seen individuals gain maximum weight when they are under more stress and are sleep-deprived. This is because ghrelin levels increased in these scenarios. This elevation of ghrelin in high-stress, low-sleep situations affects weight gain in women during the postpartum period and menopause.
Evidence also suggests that certain foods affect ghrelin levels. After a person eats carbohydrates, their ghrelin levels initially decrease quickly, but this is followed by a rise in ghrelin, leading them to become hungry again. In contrast, protein intake helps suppress ghrelin levels for longer. Hence, we advise patients to increase protein intake while reducing their carb intake, or to always eat protein along with carbs.
It makes sense that when individuals with obesity lose weight by fasting or caloric restriction and try to maintain that weight loss, their bodies tend to produce more ghrelin. This effect might explain why people who lose weight often find it hard to keep it off: Rising ghrelin levels after weight loss might drive them to eat more and regain weight.
Two prominent weight loss surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), have opposite effects on ghrelin levels, reflecting their distinct mechanisms for weight loss. SG involves removal of the gastric fundus, where ghrelin is produced, resulting in a significant decrease in ghrelin levels; RYGB operates through malabsorption without directly affecting ghrelin production. Despite these differing approaches, both techniques demonstrate remarkable weight loss efficacy. Research comparing the two procedures reveals that SG leads to decreased fasting plasma ghrelin levels, whereas RYGB prompts an increase, highlighting the additional appetite-reducing mechanism of SG through ghrelin suppression. This contrast underscores the intricate role of ghrelin in appetite regulation and suggests that its manipulation can significantly influence weight loss outcomes.
With the effect of ghrelin in stimulating appetite being established, other studies have explored the relationship between ghrelin and insulin resistance. A meta-analysis by researchers at Qingdao University, Qingdao, China, found that circulating ghrelin levels were negatively correlated with insulin resistance in individuals with obesity and normal fasting glucose levels. The findings suggest that the role of ghrelin in obesity might extend beyond appetite regulation to influence metabolic pathways and that ghrelin may be a marker for predicting obesity.
Researchers are exploring potential therapeutic targets focusing on ghrelin modulation. Although selective neutralization of ghrelin has not yielded consistent results in rodent models, the interplay between ghrelin and LEAP2— a hormone that attaches to the same brain receptors — could be an area of interest for future obesity treatments.
Could ghrelin be the key to tackling obesity? Blocking ghrelin pharmacologically might be a strategy to keep weight off after weight loss, and it could help prevent the typical rebound effect seen with diets and withdrawal of medications. Considering the high rates of weight regain after diet-induced weight loss and withdrawal of weight loss medications, targeting ghrelin might be the missing link in long-term obesity treatment. It could be a valuable approach to improving long-term outcomes for obesity. However, these blockers might have significant side effects, given that ghrelin affects not only hunger but also the brain’s reward and pleasure centers. Therefore, caution will be needed in developing such medications owing to their potential impact on mood and mental health.
With ghrelin playing roles in hunger, reward pathways, and energy regulation, understanding this hormone is crucial in the fight against obesity. Stay tuned for future research that could shed light on the underlying mechanisms at play and hopefully results in clinical action steps.
Dimpi Desai, MD, is a professor in the Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University, Stanford, California, and has disclosed no relevant financial relationships. Ashni Dharia, MD, is a resident in the Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
A version of this article appeared on Medscape.com.
Despite their best efforts, 80% of people who lose weight regain it and many end up heavier within 5 years. Why? Our bodies fight back, revving up hunger while slowing metabolism after weight loss. In ongoing obesity discussions, ghrelin is in the spotlight as the “hunger hormone” playing a crucial role in driving appetite and facilitating weight gain.
Weight loss interventions, such as diet or gastric bypass surgery, may trigger an increase in ghrelin levels, potentially fueling long-term weight gain. Consequently, ghrelin remains a focal point of research into innovative antiobesity treatments.
Ghrelin, a hormone produced in the stomach, is often called the “hunger hormone.” Ghrelin is a circulating orexigenic gut hormone with growth hormone–releasing activity.
Since the discovery of ghrelin, in 1999, research in mice and people has focused on its effect on regulating appetite and implications for long-term weight control. When hunger strikes, ghrelin levels surge, sending signals to the brain that ramp up the appetite. Following a meal, ghrelin decreases, indicating fullness.
Studies have found that people who were injected with subcutaneous ghrelin experienced a 46% increase in hunger and ate 28% more at their next meal than those who didn’t receive a ghrelin injection.
We might expect high levels of ghrelin in individuals with obesity, but this is not the case. In fact, ghrelin levels are typically lower in individuals with obesity than in leaner individuals. This finding might seem to contradict the idea that obesity is due to high levels of the hunger hormone.
Excess weight could increase sensitivity to ghrelin, where more receptors lead to higher hunger stimulation with less ghrelin. Beyond hunger, ghrelin can also lead us to eat for comfort, as when stressed or anxious. Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by activating receptors in the arcuate nucleus of the hypothalamus (Müller et al.; Bany Bakar et al.). There, it also activates the brain’s reward pathways, making us crave food even when we are not hungry. This connection between ghrelin and emotional eating can contribute to stress-induced obesity.
In my clinical practice, I have seen individuals gain maximum weight when they are under more stress and are sleep-deprived. This is because ghrelin levels increased in these scenarios. This elevation of ghrelin in high-stress, low-sleep situations affects weight gain in women during the postpartum period and menopause.
Evidence also suggests that certain foods affect ghrelin levels. After a person eats carbohydrates, their ghrelin levels initially decrease quickly, but this is followed by a rise in ghrelin, leading them to become hungry again. In contrast, protein intake helps suppress ghrelin levels for longer. Hence, we advise patients to increase protein intake while reducing their carb intake, or to always eat protein along with carbs.
It makes sense that when individuals with obesity lose weight by fasting or caloric restriction and try to maintain that weight loss, their bodies tend to produce more ghrelin. This effect might explain why people who lose weight often find it hard to keep it off: Rising ghrelin levels after weight loss might drive them to eat more and regain weight.
Two prominent weight loss surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), have opposite effects on ghrelin levels, reflecting their distinct mechanisms for weight loss. SG involves removal of the gastric fundus, where ghrelin is produced, resulting in a significant decrease in ghrelin levels; RYGB operates through malabsorption without directly affecting ghrelin production. Despite these differing approaches, both techniques demonstrate remarkable weight loss efficacy. Research comparing the two procedures reveals that SG leads to decreased fasting plasma ghrelin levels, whereas RYGB prompts an increase, highlighting the additional appetite-reducing mechanism of SG through ghrelin suppression. This contrast underscores the intricate role of ghrelin in appetite regulation and suggests that its manipulation can significantly influence weight loss outcomes.
With the effect of ghrelin in stimulating appetite being established, other studies have explored the relationship between ghrelin and insulin resistance. A meta-analysis by researchers at Qingdao University, Qingdao, China, found that circulating ghrelin levels were negatively correlated with insulin resistance in individuals with obesity and normal fasting glucose levels. The findings suggest that the role of ghrelin in obesity might extend beyond appetite regulation to influence metabolic pathways and that ghrelin may be a marker for predicting obesity.
Researchers are exploring potential therapeutic targets focusing on ghrelin modulation. Although selective neutralization of ghrelin has not yielded consistent results in rodent models, the interplay between ghrelin and LEAP2— a hormone that attaches to the same brain receptors — could be an area of interest for future obesity treatments.
Could ghrelin be the key to tackling obesity? Blocking ghrelin pharmacologically might be a strategy to keep weight off after weight loss, and it could help prevent the typical rebound effect seen with diets and withdrawal of medications. Considering the high rates of weight regain after diet-induced weight loss and withdrawal of weight loss medications, targeting ghrelin might be the missing link in long-term obesity treatment. It could be a valuable approach to improving long-term outcomes for obesity. However, these blockers might have significant side effects, given that ghrelin affects not only hunger but also the brain’s reward and pleasure centers. Therefore, caution will be needed in developing such medications owing to their potential impact on mood and mental health.
With ghrelin playing roles in hunger, reward pathways, and energy regulation, understanding this hormone is crucial in the fight against obesity. Stay tuned for future research that could shed light on the underlying mechanisms at play and hopefully results in clinical action steps.
Dimpi Desai, MD, is a professor in the Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University, Stanford, California, and has disclosed no relevant financial relationships. Ashni Dharia, MD, is a resident in the Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
A version of this article appeared on Medscape.com.
Despite their best efforts, 80% of people who lose weight regain it and many end up heavier within 5 years. Why? Our bodies fight back, revving up hunger while slowing metabolism after weight loss. In ongoing obesity discussions, ghrelin is in the spotlight as the “hunger hormone” playing a crucial role in driving appetite and facilitating weight gain.
Weight loss interventions, such as diet or gastric bypass surgery, may trigger an increase in ghrelin levels, potentially fueling long-term weight gain. Consequently, ghrelin remains a focal point of research into innovative antiobesity treatments.
Ghrelin, a hormone produced in the stomach, is often called the “hunger hormone.” Ghrelin is a circulating orexigenic gut hormone with growth hormone–releasing activity.
Since the discovery of ghrelin, in 1999, research in mice and people has focused on its effect on regulating appetite and implications for long-term weight control. When hunger strikes, ghrelin levels surge, sending signals to the brain that ramp up the appetite. Following a meal, ghrelin decreases, indicating fullness.
Studies have found that people who were injected with subcutaneous ghrelin experienced a 46% increase in hunger and ate 28% more at their next meal than those who didn’t receive a ghrelin injection.
We might expect high levels of ghrelin in individuals with obesity, but this is not the case. In fact, ghrelin levels are typically lower in individuals with obesity than in leaner individuals. This finding might seem to contradict the idea that obesity is due to high levels of the hunger hormone.
Excess weight could increase sensitivity to ghrelin, where more receptors lead to higher hunger stimulation with less ghrelin. Beyond hunger, ghrelin can also lead us to eat for comfort, as when stressed or anxious. Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by activating receptors in the arcuate nucleus of the hypothalamus (Müller et al.; Bany Bakar et al.). There, it also activates the brain’s reward pathways, making us crave food even when we are not hungry. This connection between ghrelin and emotional eating can contribute to stress-induced obesity.
In my clinical practice, I have seen individuals gain maximum weight when they are under more stress and are sleep-deprived. This is because ghrelin levels increased in these scenarios. This elevation of ghrelin in high-stress, low-sleep situations affects weight gain in women during the postpartum period and menopause.
Evidence also suggests that certain foods affect ghrelin levels. After a person eats carbohydrates, their ghrelin levels initially decrease quickly, but this is followed by a rise in ghrelin, leading them to become hungry again. In contrast, protein intake helps suppress ghrelin levels for longer. Hence, we advise patients to increase protein intake while reducing their carb intake, or to always eat protein along with carbs.
It makes sense that when individuals with obesity lose weight by fasting or caloric restriction and try to maintain that weight loss, their bodies tend to produce more ghrelin. This effect might explain why people who lose weight often find it hard to keep it off: Rising ghrelin levels after weight loss might drive them to eat more and regain weight.
Two prominent weight loss surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), have opposite effects on ghrelin levels, reflecting their distinct mechanisms for weight loss. SG involves removal of the gastric fundus, where ghrelin is produced, resulting in a significant decrease in ghrelin levels; RYGB operates through malabsorption without directly affecting ghrelin production. Despite these differing approaches, both techniques demonstrate remarkable weight loss efficacy. Research comparing the two procedures reveals that SG leads to decreased fasting plasma ghrelin levels, whereas RYGB prompts an increase, highlighting the additional appetite-reducing mechanism of SG through ghrelin suppression. This contrast underscores the intricate role of ghrelin in appetite regulation and suggests that its manipulation can significantly influence weight loss outcomes.
With the effect of ghrelin in stimulating appetite being established, other studies have explored the relationship between ghrelin and insulin resistance. A meta-analysis by researchers at Qingdao University, Qingdao, China, found that circulating ghrelin levels were negatively correlated with insulin resistance in individuals with obesity and normal fasting glucose levels. The findings suggest that the role of ghrelin in obesity might extend beyond appetite regulation to influence metabolic pathways and that ghrelin may be a marker for predicting obesity.
Researchers are exploring potential therapeutic targets focusing on ghrelin modulation. Although selective neutralization of ghrelin has not yielded consistent results in rodent models, the interplay between ghrelin and LEAP2— a hormone that attaches to the same brain receptors — could be an area of interest for future obesity treatments.
Could ghrelin be the key to tackling obesity? Blocking ghrelin pharmacologically might be a strategy to keep weight off after weight loss, and it could help prevent the typical rebound effect seen with diets and withdrawal of medications. Considering the high rates of weight regain after diet-induced weight loss and withdrawal of weight loss medications, targeting ghrelin might be the missing link in long-term obesity treatment. It could be a valuable approach to improving long-term outcomes for obesity. However, these blockers might have significant side effects, given that ghrelin affects not only hunger but also the brain’s reward and pleasure centers. Therefore, caution will be needed in developing such medications owing to their potential impact on mood and mental health.
With ghrelin playing roles in hunger, reward pathways, and energy regulation, understanding this hormone is crucial in the fight against obesity. Stay tuned for future research that could shed light on the underlying mechanisms at play and hopefully results in clinical action steps.
Dimpi Desai, MD, is a professor in the Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University, Stanford, California, and has disclosed no relevant financial relationships. Ashni Dharia, MD, is a resident in the Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
A version of this article appeared on Medscape.com.
Tirzepatide Reduces Sleep Interruptions, Halting Almost Half of CPAP Use
ORLANDO, FLA. — The diabetes and weight loss drug tirzepatide (Mounjaro for type 2 diabetes; Zepbound for obesity) was so effective at reducing sleep disruptions in patients with obesity and obstructive sleep apnea (OSA) that 40%-50% no longer needed to use a continuous positive airway pressure (CPAP) device, according to two new studies.
Tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 (GLP-1) receptor agonist, also lowered C-reactive protein levels and systolic blood pressure. And patients taking the medication lost 18%-20% of their body weight.
said lead author Atul Malhotra, MD, professor of medicine at the University of California, San Diego, and director of sleep medicine at UC San Diego Health.
The two double-blind, randomized, controlled trials in patients with obesity and moderate to severe OSA were conducted at 60 sites in nine countries. The results were presented at the American Diabetes Association (ADA) 84th Scientific Sessions and simultaneously published online in the New England Journal of Medicine.
OSA affects 1 billion people worldwide and 30 million American adults, many of whom are undiagnosed. Obesity is a common risk factor. According to the ADA, 40% of those with obesity have OSA and 70% of those with OSA have obesity.
CPAP is an effective and the most-used intervention for OSA, but many patients refuse to use the device, stop using it, or cannot use it. Should tirzepatide eventually gain Food and Drug Administration approval for OSA, it would be the first drug approved for the condition.
“This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies,” said Dr. Malhotra.
Huge Reduction in Episodes, Severity
For the two studies, patients were enrolled who had moderate to severe OSA, defined as more than 15 events per hour (using the apnea-hypopnea index [AHI]) and a body mass index of 30 kg/m2 or greater. Those not using a CPAP device were enrolled in study 1, and those using a CPAP device were enrolled in study 2.
Participants received either the maximum tolerated dose of tirzepatide (10 or 15 mg by once-weekly injection) or placebo for 1 year. In study 1, 114 individuals received tirzepatide and 120 received placebo. For study 2, 119 patients received tirzepatide and 114 received placebo. All participants received regular lifestyle counseling sessions about nutrition and were instructed to reduce food intake by 500 kcal/day and to engage in at least 150 min/week of physical activity.
Enrollment was limited to 70% men to ensure adequate representation of women.
At baseline, 65%-70% of participants had severe OSA, with more than 30 events/hour on the AHI scale and a mean of 51.5 events/hour.
By 1 year, patients taking tirzepatide had 27-30 fewer events/hour, compared with 4-6 fewer events/hour for those taking placebo.
Up to half of those who received tirzepatide in both trials had less than 5 events/hour or 5-14 AHI events/hour and an Epworth Sleepiness Scale score of 10 or less. Those thresholds “represent a level at which CPAP therapy may not be recommended,” wrote the authors.
Patients in the tirzepatide group also had a decrease in systolic blood pressure from baseline of 9.7 mm Hg in study 1 and 7.6 mm Hg in study 2 at week 48.
The most common adverse events were diarrhea, nausea, and vomiting, which occurred in approximately a quarter of patients taking tirzepatide. There were two adjudicated-confirmed cases of acute pancreatitis in those taking tirzepatide in study 2.
Patients who received tirzepatide also reported fewer daytime and nighttime disturbances, as measured using the Patient-Reported Outcomes Measurement Information System Short Form scale for Sleep-Related Impairment and Sleep Disturbance.
Tirzepatide Plus CPAP Are Best
Writing in an accompanying editorial, Sanjay R. Patel, MD, noted that, although clinical guidelines have recommended that weight loss strategies be incorporated as part of OSA treatment, “the integration of obesity management into the approaches to care for obstructive sleep apnea has lagged.”
As many as half of patients abandon CPAP therapy within 3 years, wrote Dr. Patel, who is professor of medicine and epidemiology at the University of Pittsburgh, Pittsburgh, Pennsylvania, and medical director of the UPMC Comprehensive Sleep Disorders program. “An effective medication to treat obesity is thus an obvious avenue to pursue.”
Dr. Patel noted the large reductions in the number of events on the AHI scale. He wrote that the improvement in systolic blood pressure “was substantially larger than effects seen with CPAP therapy alone and indicate that tirzepatide may be an attractive option for those patients who seek to reduce their cardiovascular risk.”
Dr. Patel raised concerns about whether patients outside of a trial would stick with therapy, noting studies have shown high rates of discontinuation of GLP-1 receptor agonists.
And, he wrote, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”
Commenting on the study during the presentation of the results, Louis Aronne, MD, said he believes the trials demonstrate “the treatment of obesity with tirzepatide plus CPAP is really the optimal treatment for obstructive sleep apnea and obesity-related cardiometabolic risks.” Dr. Aronne is the Sanford I. Weill professor of metabolic research at Weill Cornell Medical College, New York City.
Dr. Aronne added there is still much to learn. It is still not clear whether tirzepatide had an independent effect in the OSA trial — as has been seen in other studies where the drug clearly reduced cardiovascular risk — or whether the positive results were primarily caused by weight loss.
“I believe that over time we’ll see that this particular effect in sleep apnea is related to weight,” he said.
The study was supported by Eli Lilly. Dr. Malhotra has reported being a paid consultant for Lilly and ZOLL Medical and a cofounder of Healcisio.
A version of this article appeared on Medscape.com.
ORLANDO, FLA. — The diabetes and weight loss drug tirzepatide (Mounjaro for type 2 diabetes; Zepbound for obesity) was so effective at reducing sleep disruptions in patients with obesity and obstructive sleep apnea (OSA) that 40%-50% no longer needed to use a continuous positive airway pressure (CPAP) device, according to two new studies.
Tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 (GLP-1) receptor agonist, also lowered C-reactive protein levels and systolic blood pressure. And patients taking the medication lost 18%-20% of their body weight.
said lead author Atul Malhotra, MD, professor of medicine at the University of California, San Diego, and director of sleep medicine at UC San Diego Health.
The two double-blind, randomized, controlled trials in patients with obesity and moderate to severe OSA were conducted at 60 sites in nine countries. The results were presented at the American Diabetes Association (ADA) 84th Scientific Sessions and simultaneously published online in the New England Journal of Medicine.
OSA affects 1 billion people worldwide and 30 million American adults, many of whom are undiagnosed. Obesity is a common risk factor. According to the ADA, 40% of those with obesity have OSA and 70% of those with OSA have obesity.
CPAP is an effective and the most-used intervention for OSA, but many patients refuse to use the device, stop using it, or cannot use it. Should tirzepatide eventually gain Food and Drug Administration approval for OSA, it would be the first drug approved for the condition.
“This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies,” said Dr. Malhotra.
Huge Reduction in Episodes, Severity
For the two studies, patients were enrolled who had moderate to severe OSA, defined as more than 15 events per hour (using the apnea-hypopnea index [AHI]) and a body mass index of 30 kg/m2 or greater. Those not using a CPAP device were enrolled in study 1, and those using a CPAP device were enrolled in study 2.
Participants received either the maximum tolerated dose of tirzepatide (10 or 15 mg by once-weekly injection) or placebo for 1 year. In study 1, 114 individuals received tirzepatide and 120 received placebo. For study 2, 119 patients received tirzepatide and 114 received placebo. All participants received regular lifestyle counseling sessions about nutrition and were instructed to reduce food intake by 500 kcal/day and to engage in at least 150 min/week of physical activity.
Enrollment was limited to 70% men to ensure adequate representation of women.
At baseline, 65%-70% of participants had severe OSA, with more than 30 events/hour on the AHI scale and a mean of 51.5 events/hour.
By 1 year, patients taking tirzepatide had 27-30 fewer events/hour, compared with 4-6 fewer events/hour for those taking placebo.
Up to half of those who received tirzepatide in both trials had less than 5 events/hour or 5-14 AHI events/hour and an Epworth Sleepiness Scale score of 10 or less. Those thresholds “represent a level at which CPAP therapy may not be recommended,” wrote the authors.
Patients in the tirzepatide group also had a decrease in systolic blood pressure from baseline of 9.7 mm Hg in study 1 and 7.6 mm Hg in study 2 at week 48.
The most common adverse events were diarrhea, nausea, and vomiting, which occurred in approximately a quarter of patients taking tirzepatide. There were two adjudicated-confirmed cases of acute pancreatitis in those taking tirzepatide in study 2.
Patients who received tirzepatide also reported fewer daytime and nighttime disturbances, as measured using the Patient-Reported Outcomes Measurement Information System Short Form scale for Sleep-Related Impairment and Sleep Disturbance.
Tirzepatide Plus CPAP Are Best
Writing in an accompanying editorial, Sanjay R. Patel, MD, noted that, although clinical guidelines have recommended that weight loss strategies be incorporated as part of OSA treatment, “the integration of obesity management into the approaches to care for obstructive sleep apnea has lagged.”
As many as half of patients abandon CPAP therapy within 3 years, wrote Dr. Patel, who is professor of medicine and epidemiology at the University of Pittsburgh, Pittsburgh, Pennsylvania, and medical director of the UPMC Comprehensive Sleep Disorders program. “An effective medication to treat obesity is thus an obvious avenue to pursue.”
Dr. Patel noted the large reductions in the number of events on the AHI scale. He wrote that the improvement in systolic blood pressure “was substantially larger than effects seen with CPAP therapy alone and indicate that tirzepatide may be an attractive option for those patients who seek to reduce their cardiovascular risk.”
Dr. Patel raised concerns about whether patients outside of a trial would stick with therapy, noting studies have shown high rates of discontinuation of GLP-1 receptor agonists.
And, he wrote, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”
Commenting on the study during the presentation of the results, Louis Aronne, MD, said he believes the trials demonstrate “the treatment of obesity with tirzepatide plus CPAP is really the optimal treatment for obstructive sleep apnea and obesity-related cardiometabolic risks.” Dr. Aronne is the Sanford I. Weill professor of metabolic research at Weill Cornell Medical College, New York City.
Dr. Aronne added there is still much to learn. It is still not clear whether tirzepatide had an independent effect in the OSA trial — as has been seen in other studies where the drug clearly reduced cardiovascular risk — or whether the positive results were primarily caused by weight loss.
“I believe that over time we’ll see that this particular effect in sleep apnea is related to weight,” he said.
The study was supported by Eli Lilly. Dr. Malhotra has reported being a paid consultant for Lilly and ZOLL Medical and a cofounder of Healcisio.
A version of this article appeared on Medscape.com.
ORLANDO, FLA. — The diabetes and weight loss drug tirzepatide (Mounjaro for type 2 diabetes; Zepbound for obesity) was so effective at reducing sleep disruptions in patients with obesity and obstructive sleep apnea (OSA) that 40%-50% no longer needed to use a continuous positive airway pressure (CPAP) device, according to two new studies.
Tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 (GLP-1) receptor agonist, also lowered C-reactive protein levels and systolic blood pressure. And patients taking the medication lost 18%-20% of their body weight.
said lead author Atul Malhotra, MD, professor of medicine at the University of California, San Diego, and director of sleep medicine at UC San Diego Health.
The two double-blind, randomized, controlled trials in patients with obesity and moderate to severe OSA were conducted at 60 sites in nine countries. The results were presented at the American Diabetes Association (ADA) 84th Scientific Sessions and simultaneously published online in the New England Journal of Medicine.
OSA affects 1 billion people worldwide and 30 million American adults, many of whom are undiagnosed. Obesity is a common risk factor. According to the ADA, 40% of those with obesity have OSA and 70% of those with OSA have obesity.
CPAP is an effective and the most-used intervention for OSA, but many patients refuse to use the device, stop using it, or cannot use it. Should tirzepatide eventually gain Food and Drug Administration approval for OSA, it would be the first drug approved for the condition.
“This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies,” said Dr. Malhotra.
Huge Reduction in Episodes, Severity
For the two studies, patients were enrolled who had moderate to severe OSA, defined as more than 15 events per hour (using the apnea-hypopnea index [AHI]) and a body mass index of 30 kg/m2 or greater. Those not using a CPAP device were enrolled in study 1, and those using a CPAP device were enrolled in study 2.
Participants received either the maximum tolerated dose of tirzepatide (10 or 15 mg by once-weekly injection) or placebo for 1 year. In study 1, 114 individuals received tirzepatide and 120 received placebo. For study 2, 119 patients received tirzepatide and 114 received placebo. All participants received regular lifestyle counseling sessions about nutrition and were instructed to reduce food intake by 500 kcal/day and to engage in at least 150 min/week of physical activity.
Enrollment was limited to 70% men to ensure adequate representation of women.
At baseline, 65%-70% of participants had severe OSA, with more than 30 events/hour on the AHI scale and a mean of 51.5 events/hour.
By 1 year, patients taking tirzepatide had 27-30 fewer events/hour, compared with 4-6 fewer events/hour for those taking placebo.
Up to half of those who received tirzepatide in both trials had less than 5 events/hour or 5-14 AHI events/hour and an Epworth Sleepiness Scale score of 10 or less. Those thresholds “represent a level at which CPAP therapy may not be recommended,” wrote the authors.
Patients in the tirzepatide group also had a decrease in systolic blood pressure from baseline of 9.7 mm Hg in study 1 and 7.6 mm Hg in study 2 at week 48.
The most common adverse events were diarrhea, nausea, and vomiting, which occurred in approximately a quarter of patients taking tirzepatide. There were two adjudicated-confirmed cases of acute pancreatitis in those taking tirzepatide in study 2.
Patients who received tirzepatide also reported fewer daytime and nighttime disturbances, as measured using the Patient-Reported Outcomes Measurement Information System Short Form scale for Sleep-Related Impairment and Sleep Disturbance.
Tirzepatide Plus CPAP Are Best
Writing in an accompanying editorial, Sanjay R. Patel, MD, noted that, although clinical guidelines have recommended that weight loss strategies be incorporated as part of OSA treatment, “the integration of obesity management into the approaches to care for obstructive sleep apnea has lagged.”
As many as half of patients abandon CPAP therapy within 3 years, wrote Dr. Patel, who is professor of medicine and epidemiology at the University of Pittsburgh, Pittsburgh, Pennsylvania, and medical director of the UPMC Comprehensive Sleep Disorders program. “An effective medication to treat obesity is thus an obvious avenue to pursue.”
Dr. Patel noted the large reductions in the number of events on the AHI scale. He wrote that the improvement in systolic blood pressure “was substantially larger than effects seen with CPAP therapy alone and indicate that tirzepatide may be an attractive option for those patients who seek to reduce their cardiovascular risk.”
Dr. Patel raised concerns about whether patients outside of a trial would stick with therapy, noting studies have shown high rates of discontinuation of GLP-1 receptor agonists.
And, he wrote, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”
Commenting on the study during the presentation of the results, Louis Aronne, MD, said he believes the trials demonstrate “the treatment of obesity with tirzepatide plus CPAP is really the optimal treatment for obstructive sleep apnea and obesity-related cardiometabolic risks.” Dr. Aronne is the Sanford I. Weill professor of metabolic research at Weill Cornell Medical College, New York City.
Dr. Aronne added there is still much to learn. It is still not clear whether tirzepatide had an independent effect in the OSA trial — as has been seen in other studies where the drug clearly reduced cardiovascular risk — or whether the positive results were primarily caused by weight loss.
“I believe that over time we’ll see that this particular effect in sleep apnea is related to weight,” he said.
The study was supported by Eli Lilly. Dr. Malhotra has reported being a paid consultant for Lilly and ZOLL Medical and a cofounder of Healcisio.
A version of this article appeared on Medscape.com.
FROM ADA 2024
Intermittent Fasting Tops Calorie Restriction for Gut Health
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
Metformin Gets a Reproductive Reprieve — For Diabetic Moms and Dads Alike
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.