Obesity

A systematic review of 26 randomized controlled trials (RCTs) finds that, among glucagon-like peptide 1 (GLP-1) receptor agonists and co-agonists on the market or still being investigated, the experimental drug retatrutide (Eli Lilly) produces the greatest weight loss.

The review, conducted by researchers at McGill University, Montreal, Quebec, Canada, examined three commercially available medications in the class and nine that have not yet received regulatory approval.

In healthy adults with overweight or obesity who did not have diabetes, the highest mean reductions in relative and absolute body weight were achieved with once-weekly triple glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 and glucagon receptor agonist retatrutide, followed by the dual GIP/GLP-1 agonist tirzepatide (Eli Lilly) and lastly by the GLP-1 agonist semaglutide (Novo Nordisk), according to the authors.

The use of all the GLP-1s or co-agonist medications “led to decreased body mass index (BMI), waist circumference, SBP (systolic blood pressure), and DBP (diastolic blood pressure),” wrote the authors in Annals of Internal Medicine. All the medications had a similar safety profile.

The researchers did not find any head-to-head studies, so instead examined the results from 26 RCTs that enrolled more than 15,000 patients. Only trials with a treatment duration of at least 16 weeks were included, to ensure that patients had at least a month of a fixed dose.

Not surprisingly, the review found that, except for semaglutide, trials with “dual and triple agonists generally reported numerically greater mean weight losses than single GLP-1 agonists.”

They caution, however, against drawing conclusions about comparative efficacy, as the populations, control groups, and contexts of the various studies might not be directly comparable. All the trial enrollees also received lifestyle modification along with drug therapy or placebo, but the interventions and protocols varied across the studies.

The authors found that individuals on retatrutide (12-mg once-weekly injection) lost 22% of body weight from baseline after 48 weeks. Tirzepatide (15 mg once-weekly injection) recipients lost almost 18% of body weight after 72 weeks, while those on semaglutide (2.4-mg once-weekly injection) lost about 14% after 68 weeks. Both tirzepatide and semaglutide are commercially available.

Patients taking liraglutide (3-mg once-daily injection), also on the market, lost up to 6% of body weight after 26 weeks.

The authors also examined studies of investigational agents and reported that the greatest loss, aside from retatrutide, was with the dual glucagon/GLP-1 agonists survodutide (Boehringer Ingelheim; 6%-15%) and mazdutide (Innovent Biologics; 7%-11%).

Orforglipron (Eli Lilly), a once-daily pill, produced weight loss of 9%-15%, depending on the dose.

The study found that four investigational drugs did not produce as much weight loss: Beinaglutide (0.2-mg injection three times daily, 6%), efpeglenatide (4- to 8-mg injection once weekly, about 7%), exenatide (10-mcg injection twice daily, 5-kg change in weight), and noiiglutide (once-daily injection, 9%).

The most common adverse events for all GLP-1s were gastrointestinal (GI), such as nausea, diarrhea, constipation, and vomiting. Across all agents, 60%-80% of patients taking the medications experienced a GI adverse event, although most were transient, according to the authors. A total of 6%-26% of patients discontinued treatment as a result of a side effect.

The authors said that no serious GI disorders, such as bowel obstruction or gastroparesis, were reported in any of the 26 trials.

The review also shows that it is likely that GLP-1s would have to be used chronically to have the greatest effect, said the authors. They noted that they found that trials “with longer treatment durations demonstrate similar weight loss results to those with shorter follow-up, reinforcing the idea that continuous treatment may be required.”

One coauthor reported receiving payments or honoraria from Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, and Novo Nordisk. The study was carried out independently without any grant or other funding.

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

A systematic review of 26 randomized controlled trials (RCTs) finds that, among glucagon-like peptide 1 (GLP-1) receptor agonists and co-agonists on the market or still being investigated, the experimental drug retatrutide (Eli Lilly) produces the greatest weight loss.

The review, conducted by researchers at McGill University, Montreal, Quebec, Canada, examined three commercially available medications in the class and nine that have not yet received regulatory approval.

In healthy adults with overweight or obesity who did not have diabetes, the highest mean reductions in relative and absolute body weight were achieved with once-weekly triple glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 and glucagon receptor agonist retatrutide, followed by the dual GIP/GLP-1 agonist tirzepatide (Eli Lilly) and lastly by the GLP-1 agonist semaglutide (Novo Nordisk), according to the authors.

The use of all the GLP-1s or co-agonist medications “led to decreased body mass index (BMI), waist circumference, SBP (systolic blood pressure), and DBP (diastolic blood pressure),” wrote the authors in Annals of Internal Medicine. All the medications had a similar safety profile.

The researchers did not find any head-to-head studies, so instead examined the results from 26 RCTs that enrolled more than 15,000 patients. Only trials with a treatment duration of at least 16 weeks were included, to ensure that patients had at least a month of a fixed dose.

Not surprisingly, the review found that, except for semaglutide, trials with “dual and triple agonists generally reported numerically greater mean weight losses than single GLP-1 agonists.”

They caution, however, against drawing conclusions about comparative efficacy, as the populations, control groups, and contexts of the various studies might not be directly comparable. All the trial enrollees also received lifestyle modification along with drug therapy or placebo, but the interventions and protocols varied across the studies.

The authors found that individuals on retatrutide (12-mg once-weekly injection) lost 22% of body weight from baseline after 48 weeks. Tirzepatide (15 mg once-weekly injection) recipients lost almost 18% of body weight after 72 weeks, while those on semaglutide (2.4-mg once-weekly injection) lost about 14% after 68 weeks. Both tirzepatide and semaglutide are commercially available.

Patients taking liraglutide (3-mg once-daily injection), also on the market, lost up to 6% of body weight after 26 weeks.

The authors also examined studies of investigational agents and reported that the greatest loss, aside from retatrutide, was with the dual glucagon/GLP-1 agonists survodutide (Boehringer Ingelheim; 6%-15%) and mazdutide (Innovent Biologics; 7%-11%).

Orforglipron (Eli Lilly), a once-daily pill, produced weight loss of 9%-15%, depending on the dose.

The study found that four investigational drugs did not produce as much weight loss: Beinaglutide (0.2-mg injection three times daily, 6%), efpeglenatide (4- to 8-mg injection once weekly, about 7%), exenatide (10-mcg injection twice daily, 5-kg change in weight), and noiiglutide (once-daily injection, 9%).

The most common adverse events for all GLP-1s were gastrointestinal (GI), such as nausea, diarrhea, constipation, and vomiting. Across all agents, 60%-80% of patients taking the medications experienced a GI adverse event, although most were transient, according to the authors. A total of 6%-26% of patients discontinued treatment as a result of a side effect.

The authors said that no serious GI disorders, such as bowel obstruction or gastroparesis, were reported in any of the 26 trials.

The review also shows that it is likely that GLP-1s would have to be used chronically to have the greatest effect, said the authors. They noted that they found that trials “with longer treatment durations demonstrate similar weight loss results to those with shorter follow-up, reinforcing the idea that continuous treatment may be required.”

One coauthor reported receiving payments or honoraria from Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, and Novo Nordisk. The study was carried out independently without any grant or other funding.

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

A systematic review of 26 randomized controlled trials (RCTs) finds that, among glucagon-like peptide 1 (GLP-1) receptor agonists and co-agonists on the market or still being investigated, the experimental drug retatrutide (Eli Lilly) produces the greatest weight loss.

The review, conducted by researchers at McGill University, Montreal, Quebec, Canada, examined three commercially available medications in the class and nine that have not yet received regulatory approval.

In healthy adults with overweight or obesity who did not have diabetes, the highest mean reductions in relative and absolute body weight were achieved with once-weekly triple glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 and glucagon receptor agonist retatrutide, followed by the dual GIP/GLP-1 agonist tirzepatide (Eli Lilly) and lastly by the GLP-1 agonist semaglutide (Novo Nordisk), according to the authors.

The use of all the GLP-1s or co-agonist medications “led to decreased body mass index (BMI), waist circumference, SBP (systolic blood pressure), and DBP (diastolic blood pressure),” wrote the authors in Annals of Internal Medicine. All the medications had a similar safety profile.

The researchers did not find any head-to-head studies, so instead examined the results from 26 RCTs that enrolled more than 15,000 patients. Only trials with a treatment duration of at least 16 weeks were included, to ensure that patients had at least a month of a fixed dose.

Not surprisingly, the review found that, except for semaglutide, trials with “dual and triple agonists generally reported numerically greater mean weight losses than single GLP-1 agonists.”

They caution, however, against drawing conclusions about comparative efficacy, as the populations, control groups, and contexts of the various studies might not be directly comparable. All the trial enrollees also received lifestyle modification along with drug therapy or placebo, but the interventions and protocols varied across the studies.

The authors found that individuals on retatrutide (12-mg once-weekly injection) lost 22% of body weight from baseline after 48 weeks. Tirzepatide (15 mg once-weekly injection) recipients lost almost 18% of body weight after 72 weeks, while those on semaglutide (2.4-mg once-weekly injection) lost about 14% after 68 weeks. Both tirzepatide and semaglutide are commercially available.

Patients taking liraglutide (3-mg once-daily injection), also on the market, lost up to 6% of body weight after 26 weeks.

The authors also examined studies of investigational agents and reported that the greatest loss, aside from retatrutide, was with the dual glucagon/GLP-1 agonists survodutide (Boehringer Ingelheim; 6%-15%) and mazdutide (Innovent Biologics; 7%-11%).

Orforglipron (Eli Lilly), a once-daily pill, produced weight loss of 9%-15%, depending on the dose.

The study found that four investigational drugs did not produce as much weight loss: Beinaglutide (0.2-mg injection three times daily, 6%), efpeglenatide (4- to 8-mg injection once weekly, about 7%), exenatide (10-mcg injection twice daily, 5-kg change in weight), and noiiglutide (once-daily injection, 9%).

The most common adverse events for all GLP-1s were gastrointestinal (GI), such as nausea, diarrhea, constipation, and vomiting. Across all agents, 60%-80% of patients taking the medications experienced a GI adverse event, although most were transient, according to the authors. A total of 6%-26% of patients discontinued treatment as a result of a side effect.

The authors said that no serious GI disorders, such as bowel obstruction or gastroparesis, were reported in any of the 26 trials.

The review also shows that it is likely that GLP-1s would have to be used chronically to have the greatest effect, said the authors. They noted that they found that trials “with longer treatment durations demonstrate similar weight loss results to those with shorter follow-up, reinforcing the idea that continuous treatment may be required.”

One coauthor reported receiving payments or honoraria from Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, and Novo Nordisk. The study was carried out independently without any grant or other funding.

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

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

TOPLINE:

Aerobic exercise shows a linear relationship with weight loss, with 30 minutes of weekly exercise linked to reduced body weight, waist circumference, and body fat in adults who were overweight or had obesity.

METHODOLOGY:

• Researchers conducted a meta-analysis of randomized clinical trials to investigate the association of varying intensities and durations of aerobic exercise with adiposity measures in adults with obesity or who were overweight.
• Overall, 116 randomized clinical trials that spanned across North America, Asia, Europe, Australia, South America, and Africa and involved 6880 adults (mean age, 46 years; 61% women) were included.
• The trials were required to have intervention durations of at least 8 weeks; all trials used supervised aerobic exercise, such as walking or running, while the control groups remained sedentary or continued usual activities.
• The intensity of exercise was defined as: Light (40%-55% maximum heart rate), moderate (55%-70% maximum heart rate), and vigorous (70%-90% maximum heart rate).
• The primary outcomes were body weight changes and adverse events; the secondary outcomes included changes in waist circumference, quality-of-life scores, and reduction in medications like antihypertensives.

TAKEAWAY:

• Every 30 minutes of aerobic exercise per week was associated with a 1.14 lb reduction in body weight (certainty of evidence, moderate).
• Every 30 minutes of aerobic exercise per week was also associated with lower waist circumference (mean difference, −0.56 cm; 95% CI, –0.67 to –0.45), body fat percentage (mean difference, –0.37%; 95% CI, –0.43 to –0.31), and body fat mass (mean difference, –0.20 kg; 95% CI, –0.32 to –0.08), along with reduced visceral and subcutaneous adipose tissue.
• A dose-response meta-analysis revealed that body fat percentage improved most significantly with 150 minutes of aerobic exercise per week, while body weight and waist circumference decreased linearly with increasing duration of aerobic exercise at 300 min/wk at different intensities.
• Adverse events with aerobic exercise were mostly mild or moderate musculoskeletal symptoms.

IN PRACTICE:

“Point-specific estimates for different aerobic exercise duration and intensity can help patients and healthcare professionals select the optimal aerobic exercise duration and intensity according to their weight loss goals,” the authors wrote.

 

SOURCE:

The study was led by Ahmad Jayedi, PhD, of the Department of Epidemiology and Biostatistics in the School of Public Health at the Imperial College London in England. It was published online on December 26, 2024, in JAMA Network Open.

 

LIMITATIONS:

High heterogeneity was present in the data. Only one trial included measures of health-related quality of life, and two studies included measures of medication use. Dietary habits and smoking status of participants were not included in studies, so any potential effects were not risk adjusted for.

 

DISCLOSURES:

No funding sources were reported. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Aerobic exercise shows a linear relationship with weight loss, with 30 minutes of weekly exercise linked to reduced body weight, waist circumference, and body fat in adults who were overweight or had obesity.

METHODOLOGY:

• Researchers conducted a meta-analysis of randomized clinical trials to investigate the association of varying intensities and durations of aerobic exercise with adiposity measures in adults with obesity or who were overweight.
• Overall, 116 randomized clinical trials that spanned across North America, Asia, Europe, Australia, South America, and Africa and involved 6880 adults (mean age, 46 years; 61% women) were included.
• The trials were required to have intervention durations of at least 8 weeks; all trials used supervised aerobic exercise, such as walking or running, while the control groups remained sedentary or continued usual activities.
• The intensity of exercise was defined as: Light (40%-55% maximum heart rate), moderate (55%-70% maximum heart rate), and vigorous (70%-90% maximum heart rate).
• The primary outcomes were body weight changes and adverse events; the secondary outcomes included changes in waist circumference, quality-of-life scores, and reduction in medications like antihypertensives.

TAKEAWAY:

• Every 30 minutes of aerobic exercise per week was associated with a 1.14 lb reduction in body weight (certainty of evidence, moderate).
• Every 30 minutes of aerobic exercise per week was also associated with lower waist circumference (mean difference, −0.56 cm; 95% CI, –0.67 to –0.45), body fat percentage (mean difference, –0.37%; 95% CI, –0.43 to –0.31), and body fat mass (mean difference, –0.20 kg; 95% CI, –0.32 to –0.08), along with reduced visceral and subcutaneous adipose tissue.
• A dose-response meta-analysis revealed that body fat percentage improved most significantly with 150 minutes of aerobic exercise per week, while body weight and waist circumference decreased linearly with increasing duration of aerobic exercise at 300 min/wk at different intensities.
• Adverse events with aerobic exercise were mostly mild or moderate musculoskeletal symptoms.

IN PRACTICE:

“Point-specific estimates for different aerobic exercise duration and intensity can help patients and healthcare professionals select the optimal aerobic exercise duration and intensity according to their weight loss goals,” the authors wrote.

 

SOURCE:

The study was led by Ahmad Jayedi, PhD, of the Department of Epidemiology and Biostatistics in the School of Public Health at the Imperial College London in England. It was published online on December 26, 2024, in JAMA Network Open.

 

LIMITATIONS:

High heterogeneity was present in the data. Only one trial included measures of health-related quality of life, and two studies included measures of medication use. Dietary habits and smoking status of participants were not included in studies, so any potential effects were not risk adjusted for.

 

DISCLOSURES:

No funding sources were reported. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Aerobic exercise shows a linear relationship with weight loss, with 30 minutes of weekly exercise linked to reduced body weight, waist circumference, and body fat in adults who were overweight or had obesity.

METHODOLOGY:

• Researchers conducted a meta-analysis of randomized clinical trials to investigate the association of varying intensities and durations of aerobic exercise with adiposity measures in adults with obesity or who were overweight.
• Overall, 116 randomized clinical trials that spanned across North America, Asia, Europe, Australia, South America, and Africa and involved 6880 adults (mean age, 46 years; 61% women) were included.
• The trials were required to have intervention durations of at least 8 weeks; all trials used supervised aerobic exercise, such as walking or running, while the control groups remained sedentary or continued usual activities.
• The intensity of exercise was defined as: Light (40%-55% maximum heart rate), moderate (55%-70% maximum heart rate), and vigorous (70%-90% maximum heart rate).
• The primary outcomes were body weight changes and adverse events; the secondary outcomes included changes in waist circumference, quality-of-life scores, and reduction in medications like antihypertensives.

TAKEAWAY:

• Every 30 minutes of aerobic exercise per week was associated with a 1.14 lb reduction in body weight (certainty of evidence, moderate).
• Every 30 minutes of aerobic exercise per week was also associated with lower waist circumference (mean difference, −0.56 cm; 95% CI, –0.67 to –0.45), body fat percentage (mean difference, –0.37%; 95% CI, –0.43 to –0.31), and body fat mass (mean difference, –0.20 kg; 95% CI, –0.32 to –0.08), along with reduced visceral and subcutaneous adipose tissue.
• A dose-response meta-analysis revealed that body fat percentage improved most significantly with 150 minutes of aerobic exercise per week, while body weight and waist circumference decreased linearly with increasing duration of aerobic exercise at 300 min/wk at different intensities.
• Adverse events with aerobic exercise were mostly mild or moderate musculoskeletal symptoms.

IN PRACTICE:

“Point-specific estimates for different aerobic exercise duration and intensity can help patients and healthcare professionals select the optimal aerobic exercise duration and intensity according to their weight loss goals,” the authors wrote.

 

SOURCE:

The study was led by Ahmad Jayedi, PhD, of the Department of Epidemiology and Biostatistics in the School of Public Health at the Imperial College London in England. It was published online on December 26, 2024, in JAMA Network Open.

 

LIMITATIONS:

High heterogeneity was present in the data. Only one trial included measures of health-related quality of life, and two studies included measures of medication use. Dietary habits and smoking status of participants were not included in studies, so any potential effects were not risk adjusted for.

 

DISCLOSURES:

No funding sources were reported. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Combined exposure to dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) is significantly associated with an increased risk for obesity in adults, with 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) showing the greatest contribution.

METHODOLOGY:

• Recent evidence has shown that environmental contaminants, particularly dioxins and dioxin-like polychlorinated biphenyls, may be linked to an increased risk for obesity as endocrine-disrupting chemicals.
• Researchers evaluated the relationship between mixed exposure to nine types of dioxins and DL-PCBs and obesity or obesity indices in 852 adults using data from the National Health and Nutrition Examination Survey from 2003 to 2004.
• They chose nine chemicals for analysis: 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD); 3,3’,4,4’,5-pentachlorodibenzofuran (PnCB); PCB28; PCB66; PCB74; PCB105; PCB118; and PCB156.
• General and abdominal obesity were present in 34% and 53.9% of participants, respectively.
• Multiple statistical approaches were employed to evaluate the association of exposures to dioxins and DL-PCBs with obesity. Mediation analysis was performed to assess the potential role of A1c in this association.

TAKEAWAY:

• Multivariable logistic regression analysis found that a single exposure to higher concentrations of 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-OCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 was associated with an increased risk for general and abdominal obesity (P for trend < .001 for all). A stratified analysis by sex found that except for PCB28, PCB66, PCB74, and PCB156, all chemicals were linked to increased general and abdominal obesity risk in both men and women.
• Combined exposure to dioxins and DL-PCBs was positively associated with the risk for obesity, with 1,2,3,4,6,7,8-HpCDD showing the greatest contribution.
• When considering obesity indices, 1,2,3,4,6,7,8,9-OCDD; 1,2,3,4,6,7,8-HpCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 were significantly associated with body mass index and waist circumference.
• A1c levels significantly mediated the association between mixed exposure to dioxins and DL-PCBs and obesity (P < .05), with mediation proportions of 6.94% for general obesity and 5.21% for abdominal obesity.

IN PRACTICE:

“Our findings suggested that dioxins and DL-PCBs may be independent risk factors for obesity,” the authors wrote. “The hazards of dioxins on obesity should be emphasized, and additional studies are desirable to elucidate the potential mechanisms for dioxins on obesity in adults.”

SOURCE:

This study, led by Zhao-Xing Gao, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University and Center for Big Data and Population Health of IHM, both in Hefei, China, was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The cross-sectional nature of this study prevented the establishment of causal relationships between dioxins or DL-PCBs and obesity. This study relied on a small sample. Replacing chemical concentrations below the limit of detection with fixed values may have introduced bias.

DISCLOSURES:

This study was funded by grants from the National Natural Science Foundation of China, Research Fund of Anhui Institute of Translational Medicine, and Research Fund of Center for Big Data and Population Health of IHM. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Combined exposure to dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) is significantly associated with an increased risk for obesity in adults, with 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) showing the greatest contribution.

METHODOLOGY:

• Recent evidence has shown that environmental contaminants, particularly dioxins and dioxin-like polychlorinated biphenyls, may be linked to an increased risk for obesity as endocrine-disrupting chemicals.
• Researchers evaluated the relationship between mixed exposure to nine types of dioxins and DL-PCBs and obesity or obesity indices in 852 adults using data from the National Health and Nutrition Examination Survey from 2003 to 2004.
• They chose nine chemicals for analysis: 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD); 3,3’,4,4’,5-pentachlorodibenzofuran (PnCB); PCB28; PCB66; PCB74; PCB105; PCB118; and PCB156.
• General and abdominal obesity were present in 34% and 53.9% of participants, respectively.
• Multiple statistical approaches were employed to evaluate the association of exposures to dioxins and DL-PCBs with obesity. Mediation analysis was performed to assess the potential role of A1c in this association.

TAKEAWAY:

• Multivariable logistic regression analysis found that a single exposure to higher concentrations of 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-OCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 was associated with an increased risk for general and abdominal obesity (P for trend < .001 for all). A stratified analysis by sex found that except for PCB28, PCB66, PCB74, and PCB156, all chemicals were linked to increased general and abdominal obesity risk in both men and women.
• Combined exposure to dioxins and DL-PCBs was positively associated with the risk for obesity, with 1,2,3,4,6,7,8-HpCDD showing the greatest contribution.
• When considering obesity indices, 1,2,3,4,6,7,8,9-OCDD; 1,2,3,4,6,7,8-HpCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 were significantly associated with body mass index and waist circumference.
• A1c levels significantly mediated the association between mixed exposure to dioxins and DL-PCBs and obesity (P < .05), with mediation proportions of 6.94% for general obesity and 5.21% for abdominal obesity.

IN PRACTICE:

“Our findings suggested that dioxins and DL-PCBs may be independent risk factors for obesity,” the authors wrote. “The hazards of dioxins on obesity should be emphasized, and additional studies are desirable to elucidate the potential mechanisms for dioxins on obesity in adults.”

SOURCE:

This study, led by Zhao-Xing Gao, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University and Center for Big Data and Population Health of IHM, both in Hefei, China, was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The cross-sectional nature of this study prevented the establishment of causal relationships between dioxins or DL-PCBs and obesity. This study relied on a small sample. Replacing chemical concentrations below the limit of detection with fixed values may have introduced bias.

DISCLOSURES:

This study was funded by grants from the National Natural Science Foundation of China, Research Fund of Anhui Institute of Translational Medicine, and Research Fund of Center for Big Data and Population Health of IHM. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Combined exposure to dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) is significantly associated with an increased risk for obesity in adults, with 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) showing the greatest contribution.

METHODOLOGY:

• Recent evidence has shown that environmental contaminants, particularly dioxins and dioxin-like polychlorinated biphenyls, may be linked to an increased risk for obesity as endocrine-disrupting chemicals.
• Researchers evaluated the relationship between mixed exposure to nine types of dioxins and DL-PCBs and obesity or obesity indices in 852 adults using data from the National Health and Nutrition Examination Survey from 2003 to 2004.
• They chose nine chemicals for analysis: 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD); 3,3’,4,4’,5-pentachlorodibenzofuran (PnCB); PCB28; PCB66; PCB74; PCB105; PCB118; and PCB156.
• General and abdominal obesity were present in 34% and 53.9% of participants, respectively.
• Multiple statistical approaches were employed to evaluate the association of exposures to dioxins and DL-PCBs with obesity. Mediation analysis was performed to assess the potential role of A1c in this association.

TAKEAWAY:

• Multivariable logistic regression analysis found that a single exposure to higher concentrations of 1,2,3,4,6,7,8-HpCDD; 1,2,3,4,6,7,8,9-OCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 was associated with an increased risk for general and abdominal obesity (P for trend < .001 for all). A stratified analysis by sex found that except for PCB28, PCB66, PCB74, and PCB156, all chemicals were linked to increased general and abdominal obesity risk in both men and women.
• Combined exposure to dioxins and DL-PCBs was positively associated with the risk for obesity, with 1,2,3,4,6,7,8-HpCDD showing the greatest contribution.
• When considering obesity indices, 1,2,3,4,6,7,8,9-OCDD; 1,2,3,4,6,7,8-HpCDD; 3,3’,4,4’,5-PnCB; PCB74; PCB105; and PCB118 were significantly associated with body mass index and waist circumference.
• A1c levels significantly mediated the association between mixed exposure to dioxins and DL-PCBs and obesity (P < .05), with mediation proportions of 6.94% for general obesity and 5.21% for abdominal obesity.

IN PRACTICE:

“Our findings suggested that dioxins and DL-PCBs may be independent risk factors for obesity,” the authors wrote. “The hazards of dioxins on obesity should be emphasized, and additional studies are desirable to elucidate the potential mechanisms for dioxins on obesity in adults.”

SOURCE:

This study, led by Zhao-Xing Gao, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University and Center for Big Data and Population Health of IHM, both in Hefei, China, was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The cross-sectional nature of this study prevented the establishment of causal relationships between dioxins or DL-PCBs and obesity. This study relied on a small sample. Replacing chemical concentrations below the limit of detection with fixed values may have introduced bias.

DISCLOSURES:

This study was funded by grants from the National Natural Science Foundation of China, Research Fund of Anhui Institute of Translational Medicine, and Research Fund of Center for Big Data and Population Health of IHM. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

December 31, 2024

This transcript has been edited for clarity. 

I’m Tamaan K. Osbourne-Roberts, family medicine physician and lifestyle medicine physician, here to discuss GLP-1 receptor agonist (RA) contraindications — the skinny on when not to prescribe. 

It can be hard not to think of GLP-1 RAs like Ozempic and Mounjaro as silver bullets, long-awaited miracle drugs that we should probably be putting in the water. And it’s true they have the potential to help a lot of people. 

However, there are definitely groups of patients who should not take these drugs or should take them with caution. They include the following: 

Patients with a family history of certain cancers. Given that GLP-1 RAs can increase the risk for thyroid cancer, patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 should not take these drugs.

Gut motility issues. Since one of the primary mechanisms of action for these drugs is to slow down the gut, patients with gastroparesis — diabetic or otherwise — or other gut motility issues should avoid these drugs. Patients with inflammatory bowel disease also should not use GLP-1 RAs. 

Pancreatitis. These medications can increase the risk for serious pancreatitis on their own, so use in patients who have had pancreatitis already is not recommended.

Renal impairment. An eGFR [estimated glomerular filtrationrate] below threshold, typically around 30 mL/min per 1.73 m², excludes GLP-1 RAs for some patients. Be certain to check the threshold for individual medications before prescribing. 

And finally, pregnancy. These drugs generally should not be used in pregnancy, and people of childbearing age with the ability to become pregnant should use contraception while taking these medications.

GLP-1 RAs are great medications and have the potential to revolutionize obesity medicine, but like all drugs, it’s important to use them safely. Knowing when not to prescribe them is an important step in ensuring patient safety and will help ensure they are available for those who need them.

Tamaan K. Osbourne-Roberts, MD, MBA, Denver, Colorado, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

December 31, 2024

This transcript has been edited for clarity. 

I’m Tamaan K. Osbourne-Roberts, family medicine physician and lifestyle medicine physician, here to discuss GLP-1 receptor agonist (RA) contraindications — the skinny on when not to prescribe. 

It can be hard not to think of GLP-1 RAs like Ozempic and Mounjaro as silver bullets, long-awaited miracle drugs that we should probably be putting in the water. And it’s true they have the potential to help a lot of people. 

However, there are definitely groups of patients who should not take these drugs or should take them with caution. They include the following: 

Patients with a family history of certain cancers. Given that GLP-1 RAs can increase the risk for thyroid cancer, patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 should not take these drugs.

Gut motility issues. Since one of the primary mechanisms of action for these drugs is to slow down the gut, patients with gastroparesis — diabetic or otherwise — or other gut motility issues should avoid these drugs. Patients with inflammatory bowel disease also should not use GLP-1 RAs. 

Pancreatitis. These medications can increase the risk for serious pancreatitis on their own, so use in patients who have had pancreatitis already is not recommended.

Renal impairment. An eGFR [estimated glomerular filtrationrate] below threshold, typically around 30 mL/min per 1.73 m², excludes GLP-1 RAs for some patients. Be certain to check the threshold for individual medications before prescribing. 

And finally, pregnancy. These drugs generally should not be used in pregnancy, and people of childbearing age with the ability to become pregnant should use contraception while taking these medications.

GLP-1 RAs are great medications and have the potential to revolutionize obesity medicine, but like all drugs, it’s important to use them safely. Knowing when not to prescribe them is an important step in ensuring patient safety and will help ensure they are available for those who need them.

Tamaan K. Osbourne-Roberts, MD, MBA, Denver, Colorado, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

December 31, 2024

This transcript has been edited for clarity. 

I’m Tamaan K. Osbourne-Roberts, family medicine physician and lifestyle medicine physician, here to discuss GLP-1 receptor agonist (RA) contraindications — the skinny on when not to prescribe. 

It can be hard not to think of GLP-1 RAs like Ozempic and Mounjaro as silver bullets, long-awaited miracle drugs that we should probably be putting in the water. And it’s true they have the potential to help a lot of people. 

However, there are definitely groups of patients who should not take these drugs or should take them with caution. They include the following: 

Patients with a family history of certain cancers. Given that GLP-1 RAs can increase the risk for thyroid cancer, patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 should not take these drugs.

Gut motility issues. Since one of the primary mechanisms of action for these drugs is to slow down the gut, patients with gastroparesis — diabetic or otherwise — or other gut motility issues should avoid these drugs. Patients with inflammatory bowel disease also should not use GLP-1 RAs. 

Pancreatitis. These medications can increase the risk for serious pancreatitis on their own, so use in patients who have had pancreatitis already is not recommended.

Renal impairment. An eGFR [estimated glomerular filtrationrate] below threshold, typically around 30 mL/min per 1.73 m², excludes GLP-1 RAs for some patients. Be certain to check the threshold for individual medications before prescribing. 

And finally, pregnancy. These drugs generally should not be used in pregnancy, and people of childbearing age with the ability to become pregnant should use contraception while taking these medications.

GLP-1 RAs are great medications and have the potential to revolutionize obesity medicine, but like all drugs, it’s important to use them safely. Knowing when not to prescribe them is an important step in ensuring patient safety and will help ensure they are available for those who need them.

Tamaan K. Osbourne-Roberts, MD, MBA, Denver, Colorado, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “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.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “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.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “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.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

Clinicians frequently reach out to Catherine Varney, DO, asking if it’s safe to prescribe glucagon-like peptide 1 receptor agonists (GLP-1 RAs) to patients with thyroid disorders, such as hypothyroidism, goiter, hyperthyroidism, and nodules.

The concerns often stem from prior animal studies that revealed a link between the medications and abnormal alterations in thyroid C cells.

“What physicians need to understand is that the increased risk of thyroid cancers is specifically in those with a personal or family history of multiple endocrine neoplasia 2 (MEN2) syndrome or medullary thyroid carcinoma [MTC],” said Varney, an assistant professor of family medicine at the University of Virginia (UVA) and obesity medicine director for UVA Health, both in Charlottesville.

MTC is a common manifestation of the MEN2 syndrome, a genetic disorder that affects the endocrine glands and can cause tumors in the thyroid gland. However, MTC is very rare, making up only 3%-5% of all thyroid cancers, Varney said.

More common types of thyroid cancers, such as papillary thyroid cancer, are not contraindications to GLP-1 RAs, said Laura Davisson, MD, MPH, a professor of medicine and director of Medical Weight Management at West Virginia University, Morgantown. Papillary thyroid cancer makes up about 80% of all thyroid cancers.

If physicians are thinking about prescribing GLP-1 RAs, it’s important to learn the specific types of thyroid disorders in a patient or in their family history, Davisson said. A history of thyroid conditions, such as Graves disease, Hashimoto thyroiditis, or disorders requiring a patient to take thyroid medicine, such as levothyroxine, does not preclude a person from taking GLP-1 RAs.

If a patient does not know their family history, then a discussion about whether GLP-1 RAs are right for them should take place, Davisson said.

“They should take into consideration the risks and benefits of the medicine, and the fact that medullary thyroid cancer and MEN2 syndrome are rare, making the chances of them running in their family low,” she said. “If the patient understands the risks, they may decide the potential benefits may outweigh the risks.”

Keep in mind that the elevated risk for medullary thyroid carcinoma has not been clearly demonstrated in humans during clinical trials, only in rodents, Varney added. Rodents are more likely to develop thyroid cancer after exposure to a GLP-1 RA because rodents have higher numbers of GLP-1 receptors in their thyroid cells.

The risk for thyroid cancer is also dose dependent, and the amount of GLP-1 RA that induced thyroid tumors in the rodents was 8-60 times higher than that given to humans, Varney said.

“Nonetheless, there have been case reports of MTC in humans after taking GLP-1 RA,” she said.

 

What About GLP-1 RAs and Pancreatitis?

Pancreatitis is another condition that requires consideration when it comes to prescribing GLP-1 RAs.

While some studies show that GLP-1 RA analogs can increase the risk for pancreatitis, it’s important to know the reason behind pancreatitis before making a prescription decision, said Anila Chadha, MD, a family physician and obesity medicine physician at Dignity Health in Bakersfield, California.

If the pancreatitis is caused by alcohol or is medication induced, GLP-1 RAs are not recommended, Chadha said. If gallbladder stones are behind the pancreatitis, that’s different.

“If a patient has a well-documented history of gallstone-induced pancreatitis and the patient has had a cholecystectomy, it would be OK to prescribe GLP-1 [medications] after shared decision-making with the patient,” she said.

Some patients worry about taking GLP-1 RAs if they have other types of pancreatic disease beyond pancreatitis, said Davisson, but guidelines do not identify conditions such as pancreatic cysts or a family history of pancreatic cancer as contraindications to GLP-1 RAs.

However, be mindful that GLP-1 RA medications can increase gallbladder disease, Chadha said. A 2022 analysis in JAMA Internal Medicine, for example, found that the use of GLP-1 RAs was associated with an increased risk for gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

If a history of gallstones is present, physicians should tell patients that GLP-1 RA analogs can increase biliary colic, chances of cholecystitis, or even cholecystitis, Chadha said.

Gallbladder disease itself is not a contraindication, she said, but these patients can experience more disease complications when taking GLP-1 RAs.

Varney recently treated a middle-aged female patient who experienced biliary colic after taking a GLP-1 RA medication. The patient had a starting body mass index (BMI) of about 45 and lost 24% of her starting weight over 12 months using a combination of strengthening and cardiovascular training; a reduced-calorie, high-protein diet; and semaglutide for weight loss, Varney said.

The patient began developing upper gastrointestinal symptoms, including mild biliary colic, without concerning lab findings. An ultrasound revealed that she had new gallstones, compared with an ultrasound a few years prior. Varney started the patient on ursodeoxycholic acid, and over the course of 6 weeks, the patient’s symptoms gradually improved and eventually resolved.

“In a situation like this, many physicians might have discontinued the obesity medication, potentially deciding not to restart it due to the symptoms she was experiencing,” Varney said. “However, I believe it’s important to recognize that these medications offer far more than just weight loss benefits. The positive effects extend to cardiovascular, metabolic, and mental health, which are often overlooked when the focus is solely on the number on the scale or BMI.”

Other medical conditions that GLP-1 RAs may exacerbate include gastroparesis and diabetic retinopathy, Chadha noted. GLP-1 RA drugs can worsen these conditions and are not recommended for patients with such a history.

Nor are GLP-1 RA medications a good idea for patients struggling with severe constipation.

“It is very difficult to tolerate these medications because it can make constipation worse,” Chadha said. “In addition, if a patient struggles with severe heartburn, it can make the tolerability of these medications difficult.”

 

What Patients Should Know Before Using GLP-1 RAs

Not every overweight patient is a good candidate for GLP-1 RAs, and it’s important that doctors explain why the medications may not be right for them, Davisson said.

“If a patient only has a few pounds to lose (15-20 lb) and does not accept that these medications are intended to be a long-term treatment for the chronic diseases of diabetes or obesity, then they might not be a good candidate for the medication,” Davisson said.

Also essential is making sure patients are willing to follow appropriate healthy eating guidelines when on the medications, including getting enough protein and produce to maintain lean body mass and the necessary fiber to keep bowel habits regular.

Varney often hears concerns from physicians about the long-term effects of GLP-1 RAs. She said this class of medications has been used for nearly 20 years to treat type 2 diabetes, and the data over the past two decades have shown that the benefits of GLP-1 RAs far outweigh the risks for most patients.

Recent studies have also highlighted significant long-term benefits, including a marked reduction in cardiovascular events, heart failure, and kidney disease, she said.

“These outcomes underscore the effectiveness and safety of GLP-1 RAs not just for obesity treatment but for improving overall health, particularly in high-risk populations,” she said. “As physicians, it’s crucial to consider this extensive body of evidence when evaluating the use of these medications for patients, especially when the potential health benefits extend well beyond weight loss alone.”

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

Clinicians frequently reach out to Catherine Varney, DO, asking if it’s safe to prescribe glucagon-like peptide 1 receptor agonists (GLP-1 RAs) to patients with thyroid disorders, such as hypothyroidism, goiter, hyperthyroidism, and nodules.

The concerns often stem from prior animal studies that revealed a link between the medications and abnormal alterations in thyroid C cells.

“What physicians need to understand is that the increased risk of thyroid cancers is specifically in those with a personal or family history of multiple endocrine neoplasia 2 (MEN2) syndrome or medullary thyroid carcinoma [MTC],” said Varney, an assistant professor of family medicine at the University of Virginia (UVA) and obesity medicine director for UVA Health, both in Charlottesville.

MTC is a common manifestation of the MEN2 syndrome, a genetic disorder that affects the endocrine glands and can cause tumors in the thyroid gland. However, MTC is very rare, making up only 3%-5% of all thyroid cancers, Varney said.

More common types of thyroid cancers, such as papillary thyroid cancer, are not contraindications to GLP-1 RAs, said Laura Davisson, MD, MPH, a professor of medicine and director of Medical Weight Management at West Virginia University, Morgantown. Papillary thyroid cancer makes up about 80% of all thyroid cancers.

If physicians are thinking about prescribing GLP-1 RAs, it’s important to learn the specific types of thyroid disorders in a patient or in their family history, Davisson said. A history of thyroid conditions, such as Graves disease, Hashimoto thyroiditis, or disorders requiring a patient to take thyroid medicine, such as levothyroxine, does not preclude a person from taking GLP-1 RAs.

If a patient does not know their family history, then a discussion about whether GLP-1 RAs are right for them should take place, Davisson said.

“They should take into consideration the risks and benefits of the medicine, and the fact that medullary thyroid cancer and MEN2 syndrome are rare, making the chances of them running in their family low,” she said. “If the patient understands the risks, they may decide the potential benefits may outweigh the risks.”

Keep in mind that the elevated risk for medullary thyroid carcinoma has not been clearly demonstrated in humans during clinical trials, only in rodents, Varney added. Rodents are more likely to develop thyroid cancer after exposure to a GLP-1 RA because rodents have higher numbers of GLP-1 receptors in their thyroid cells.

The risk for thyroid cancer is also dose dependent, and the amount of GLP-1 RA that induced thyroid tumors in the rodents was 8-60 times higher than that given to humans, Varney said.

“Nonetheless, there have been case reports of MTC in humans after taking GLP-1 RA,” she said.

 

What About GLP-1 RAs and Pancreatitis?

Pancreatitis is another condition that requires consideration when it comes to prescribing GLP-1 RAs.

While some studies show that GLP-1 RA analogs can increase the risk for pancreatitis, it’s important to know the reason behind pancreatitis before making a prescription decision, said Anila Chadha, MD, a family physician and obesity medicine physician at Dignity Health in Bakersfield, California.

If the pancreatitis is caused by alcohol or is medication induced, GLP-1 RAs are not recommended, Chadha said. If gallbladder stones are behind the pancreatitis, that’s different.

“If a patient has a well-documented history of gallstone-induced pancreatitis and the patient has had a cholecystectomy, it would be OK to prescribe GLP-1 [medications] after shared decision-making with the patient,” she said.

Some patients worry about taking GLP-1 RAs if they have other types of pancreatic disease beyond pancreatitis, said Davisson, but guidelines do not identify conditions such as pancreatic cysts or a family history of pancreatic cancer as contraindications to GLP-1 RAs.

However, be mindful that GLP-1 RA medications can increase gallbladder disease, Chadha said. A 2022 analysis in JAMA Internal Medicine, for example, found that the use of GLP-1 RAs was associated with an increased risk for gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

If a history of gallstones is present, physicians should tell patients that GLP-1 RA analogs can increase biliary colic, chances of cholecystitis, or even cholecystitis, Chadha said.

Gallbladder disease itself is not a contraindication, she said, but these patients can experience more disease complications when taking GLP-1 RAs.

Varney recently treated a middle-aged female patient who experienced biliary colic after taking a GLP-1 RA medication. The patient had a starting body mass index (BMI) of about 45 and lost 24% of her starting weight over 12 months using a combination of strengthening and cardiovascular training; a reduced-calorie, high-protein diet; and semaglutide for weight loss, Varney said.

The patient began developing upper gastrointestinal symptoms, including mild biliary colic, without concerning lab findings. An ultrasound revealed that she had new gallstones, compared with an ultrasound a few years prior. Varney started the patient on ursodeoxycholic acid, and over the course of 6 weeks, the patient’s symptoms gradually improved and eventually resolved.

“In a situation like this, many physicians might have discontinued the obesity medication, potentially deciding not to restart it due to the symptoms she was experiencing,” Varney said. “However, I believe it’s important to recognize that these medications offer far more than just weight loss benefits. The positive effects extend to cardiovascular, metabolic, and mental health, which are often overlooked when the focus is solely on the number on the scale or BMI.”

Other medical conditions that GLP-1 RAs may exacerbate include gastroparesis and diabetic retinopathy, Chadha noted. GLP-1 RA drugs can worsen these conditions and are not recommended for patients with such a history.

Nor are GLP-1 RA medications a good idea for patients struggling with severe constipation.

“It is very difficult to tolerate these medications because it can make constipation worse,” Chadha said. “In addition, if a patient struggles with severe heartburn, it can make the tolerability of these medications difficult.”

 

What Patients Should Know Before Using GLP-1 RAs

Not every overweight patient is a good candidate for GLP-1 RAs, and it’s important that doctors explain why the medications may not be right for them, Davisson said.

“If a patient only has a few pounds to lose (15-20 lb) and does not accept that these medications are intended to be a long-term treatment for the chronic diseases of diabetes or obesity, then they might not be a good candidate for the medication,” Davisson said.

Also essential is making sure patients are willing to follow appropriate healthy eating guidelines when on the medications, including getting enough protein and produce to maintain lean body mass and the necessary fiber to keep bowel habits regular.

Varney often hears concerns from physicians about the long-term effects of GLP-1 RAs. She said this class of medications has been used for nearly 20 years to treat type 2 diabetes, and the data over the past two decades have shown that the benefits of GLP-1 RAs far outweigh the risks for most patients.

Recent studies have also highlighted significant long-term benefits, including a marked reduction in cardiovascular events, heart failure, and kidney disease, she said.

“These outcomes underscore the effectiveness and safety of GLP-1 RAs not just for obesity treatment but for improving overall health, particularly in high-risk populations,” she said. “As physicians, it’s crucial to consider this extensive body of evidence when evaluating the use of these medications for patients, especially when the potential health benefits extend well beyond weight loss alone.”

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

Clinicians frequently reach out to Catherine Varney, DO, asking if it’s safe to prescribe glucagon-like peptide 1 receptor agonists (GLP-1 RAs) to patients with thyroid disorders, such as hypothyroidism, goiter, hyperthyroidism, and nodules.

The concerns often stem from prior animal studies that revealed a link between the medications and abnormal alterations in thyroid C cells.

“What physicians need to understand is that the increased risk of thyroid cancers is specifically in those with a personal or family history of multiple endocrine neoplasia 2 (MEN2) syndrome or medullary thyroid carcinoma [MTC],” said Varney, an assistant professor of family medicine at the University of Virginia (UVA) and obesity medicine director for UVA Health, both in Charlottesville.

MTC is a common manifestation of the MEN2 syndrome, a genetic disorder that affects the endocrine glands and can cause tumors in the thyroid gland. However, MTC is very rare, making up only 3%-5% of all thyroid cancers, Varney said.

More common types of thyroid cancers, such as papillary thyroid cancer, are not contraindications to GLP-1 RAs, said Laura Davisson, MD, MPH, a professor of medicine and director of Medical Weight Management at West Virginia University, Morgantown. Papillary thyroid cancer makes up about 80% of all thyroid cancers.

If physicians are thinking about prescribing GLP-1 RAs, it’s important to learn the specific types of thyroid disorders in a patient or in their family history, Davisson said. A history of thyroid conditions, such as Graves disease, Hashimoto thyroiditis, or disorders requiring a patient to take thyroid medicine, such as levothyroxine, does not preclude a person from taking GLP-1 RAs.

If a patient does not know their family history, then a discussion about whether GLP-1 RAs are right for them should take place, Davisson said.

“They should take into consideration the risks and benefits of the medicine, and the fact that medullary thyroid cancer and MEN2 syndrome are rare, making the chances of them running in their family low,” she said. “If the patient understands the risks, they may decide the potential benefits may outweigh the risks.”

Keep in mind that the elevated risk for medullary thyroid carcinoma has not been clearly demonstrated in humans during clinical trials, only in rodents, Varney added. Rodents are more likely to develop thyroid cancer after exposure to a GLP-1 RA because rodents have higher numbers of GLP-1 receptors in their thyroid cells.

The risk for thyroid cancer is also dose dependent, and the amount of GLP-1 RA that induced thyroid tumors in the rodents was 8-60 times higher than that given to humans, Varney said.

“Nonetheless, there have been case reports of MTC in humans after taking GLP-1 RA,” she said.

 

What About GLP-1 RAs and Pancreatitis?

Pancreatitis is another condition that requires consideration when it comes to prescribing GLP-1 RAs.

While some studies show that GLP-1 RA analogs can increase the risk for pancreatitis, it’s important to know the reason behind pancreatitis before making a prescription decision, said Anila Chadha, MD, a family physician and obesity medicine physician at Dignity Health in Bakersfield, California.

If the pancreatitis is caused by alcohol or is medication induced, GLP-1 RAs are not recommended, Chadha said. If gallbladder stones are behind the pancreatitis, that’s different.

“If a patient has a well-documented history of gallstone-induced pancreatitis and the patient has had a cholecystectomy, it would be OK to prescribe GLP-1 [medications] after shared decision-making with the patient,” she said.

Some patients worry about taking GLP-1 RAs if they have other types of pancreatic disease beyond pancreatitis, said Davisson, but guidelines do not identify conditions such as pancreatic cysts or a family history of pancreatic cancer as contraindications to GLP-1 RAs.

However, be mindful that GLP-1 RA medications can increase gallbladder disease, Chadha said. A 2022 analysis in JAMA Internal Medicine, for example, found that the use of GLP-1 RAs was associated with an increased risk for gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

If a history of gallstones is present, physicians should tell patients that GLP-1 RA analogs can increase biliary colic, chances of cholecystitis, or even cholecystitis, Chadha said.

Gallbladder disease itself is not a contraindication, she said, but these patients can experience more disease complications when taking GLP-1 RAs.

Varney recently treated a middle-aged female patient who experienced biliary colic after taking a GLP-1 RA medication. The patient had a starting body mass index (BMI) of about 45 and lost 24% of her starting weight over 12 months using a combination of strengthening and cardiovascular training; a reduced-calorie, high-protein diet; and semaglutide for weight loss, Varney said.

The patient began developing upper gastrointestinal symptoms, including mild biliary colic, without concerning lab findings. An ultrasound revealed that she had new gallstones, compared with an ultrasound a few years prior. Varney started the patient on ursodeoxycholic acid, and over the course of 6 weeks, the patient’s symptoms gradually improved and eventually resolved.

“In a situation like this, many physicians might have discontinued the obesity medication, potentially deciding not to restart it due to the symptoms she was experiencing,” Varney said. “However, I believe it’s important to recognize that these medications offer far more than just weight loss benefits. The positive effects extend to cardiovascular, metabolic, and mental health, which are often overlooked when the focus is solely on the number on the scale or BMI.”

Other medical conditions that GLP-1 RAs may exacerbate include gastroparesis and diabetic retinopathy, Chadha noted. GLP-1 RA drugs can worsen these conditions and are not recommended for patients with such a history.

Nor are GLP-1 RA medications a good idea for patients struggling with severe constipation.

“It is very difficult to tolerate these medications because it can make constipation worse,” Chadha said. “In addition, if a patient struggles with severe heartburn, it can make the tolerability of these medications difficult.”

 

What Patients Should Know Before Using GLP-1 RAs

Not every overweight patient is a good candidate for GLP-1 RAs, and it’s important that doctors explain why the medications may not be right for them, Davisson said.

“If a patient only has a few pounds to lose (15-20 lb) and does not accept that these medications are intended to be a long-term treatment for the chronic diseases of diabetes or obesity, then they might not be a good candidate for the medication,” Davisson said.

Also essential is making sure patients are willing to follow appropriate healthy eating guidelines when on the medications, including getting enough protein and produce to maintain lean body mass and the necessary fiber to keep bowel habits regular.

Varney often hears concerns from physicians about the long-term effects of GLP-1 RAs. She said this class of medications has been used for nearly 20 years to treat type 2 diabetes, and the data over the past two decades have shown that the benefits of GLP-1 RAs far outweigh the risks for most patients.

Recent studies have also highlighted significant long-term benefits, including a marked reduction in cardiovascular events, heart failure, and kidney disease, she said.

“These outcomes underscore the effectiveness and safety of GLP-1 RAs not just for obesity treatment but for improving overall health, particularly in high-risk populations,” she said. “As physicians, it’s crucial to consider this extensive body of evidence when evaluating the use of these medications for patients, especially when the potential health benefits extend well beyond weight loss alone.”

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