Obesity

Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

For the past 4 years, primary care clinicians have labored under a seemingly endless onslaught of bad news. A recent report estimated that there were over 1.3 million excess deaths in the United States from March 2020 to May 2023, including nearly half a million Americans younger than age 65. Social isolation and an ailing economy accelerated preexisting rises in drug overdoses and obesity, while teenage vaping threatened to hook a new generation on tobacco products even as adult smoking plummeted. Meanwhile, more than half of the nation’s physicians now report feelings of burnout, pay for family doctors appears to be stagnating, and our interactions with an increasing number of patients are fraught with suspicions about the value of vaccines— not just against COVID-19 but against flu and other viruses, too — and the medical system as a whole, doctors included. 

Now, for the good news.

A year and a half since the end of the pandemic emergency, we are seeing gains on several fronts, and physicians deserve much of the credit. Preliminary data from the Centers for Disease Control and Prevention show that 10,000 fewer people died from drug overdoses than in the previous year. Although multiple factors contributed to this change, the elimination of the X-waiver, which had previously been required for physicians to prescribe buprenorphine for opioid use disorder, in January 2023 has improved access to medications for addiction treatment. In addition, the expansion of state requirements to check prescription drug monitoring programs when opioids or benzodiazepines are prescribed, and to prescribe naloxone to patients taking more than a certain number of morphine milligram equivalents per day, has probably reduced the harms of hazardous drug use.

On the obesity front, recent data from the National Health and Nutrition Examination Survey found that the prevalence of obesity in adults fell for the first time in more than a decade, from 41.9% to 40.3%. To be sure, obesity remains far too common, and this finding could be the result of statistical chance rather than representing a true decline. But the widespread prescribing of GLP-1 receptor agonists by primary care physicians, in particular, could have played a role in the encouraging trend.

Although more research is needed to prove causality, one analysis suggests that these drugs could easily have lowered the body mass index (BMI) of more than enough patients to account for the observed decline. What’s more, the rise in prevalence of BMIs above 40 (from 7.7% to 9.7%) could be explained by the mortality benefit of the drugs: More people remained in this severe obesity category because they didn’t die from complications of their weight. Whether future studies support keeping people on GLP-1s for life or eventually “off-ramping” them to other weight control strategies, family physicians are well positioned to help.

Finally, with little fanfare, the youth smoking rate has fallen precipitously. In 2023, 1.9% of high school students and 1.1% of middle-schoolers reported smoking cigarettes in the past 30 days. And they didn’t simply swap one form of nicotine delivery device for another. The 30-day prevalence of vaping among high school students fell from 27.5% in 2019 to 7.8% this year. Changing social norms and stricter federal regulation of tobacco products are probably more responsible for this positive trend than medical care, though the US Preventive Services Task Force recommends education or brief counseling to prevent initiation of tobacco use among school-aged children and adolescents. Should tobacco use in youth remain at these historically low levels, millions of premature deaths from lung cancer and heart disease will have been prevented.

America’s doctors have earned the right to take a bow. We have much more work to do, but our efforts are making a meaningful difference in three seemingly intractable health problems.

Dr. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.

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

Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

For the past 4 years, primary care clinicians have labored under a seemingly endless onslaught of bad news. A recent report estimated that there were over 1.3 million excess deaths in the United States from March 2020 to May 2023, including nearly half a million Americans younger than age 65. Social isolation and an ailing economy accelerated preexisting rises in drug overdoses and obesity, while teenage vaping threatened to hook a new generation on tobacco products even as adult smoking plummeted. Meanwhile, more than half of the nation’s physicians now report feelings of burnout, pay for family doctors appears to be stagnating, and our interactions with an increasing number of patients are fraught with suspicions about the value of vaccines— not just against COVID-19 but against flu and other viruses, too — and the medical system as a whole, doctors included. 

Now, for the good news.

A year and a half since the end of the pandemic emergency, we are seeing gains on several fronts, and physicians deserve much of the credit. Preliminary data from the Centers for Disease Control and Prevention show that 10,000 fewer people died from drug overdoses than in the previous year. Although multiple factors contributed to this change, the elimination of the X-waiver, which had previously been required for physicians to prescribe buprenorphine for opioid use disorder, in January 2023 has improved access to medications for addiction treatment. In addition, the expansion of state requirements to check prescription drug monitoring programs when opioids or benzodiazepines are prescribed, and to prescribe naloxone to patients taking more than a certain number of morphine milligram equivalents per day, has probably reduced the harms of hazardous drug use.

On the obesity front, recent data from the National Health and Nutrition Examination Survey found that the prevalence of obesity in adults fell for the first time in more than a decade, from 41.9% to 40.3%. To be sure, obesity remains far too common, and this finding could be the result of statistical chance rather than representing a true decline. But the widespread prescribing of GLP-1 receptor agonists by primary care physicians, in particular, could have played a role in the encouraging trend.

Although more research is needed to prove causality, one analysis suggests that these drugs could easily have lowered the body mass index (BMI) of more than enough patients to account for the observed decline. What’s more, the rise in prevalence of BMIs above 40 (from 7.7% to 9.7%) could be explained by the mortality benefit of the drugs: More people remained in this severe obesity category because they didn’t die from complications of their weight. Whether future studies support keeping people on GLP-1s for life or eventually “off-ramping” them to other weight control strategies, family physicians are well positioned to help.

Finally, with little fanfare, the youth smoking rate has fallen precipitously. In 2023, 1.9% of high school students and 1.1% of middle-schoolers reported smoking cigarettes in the past 30 days. And they didn’t simply swap one form of nicotine delivery device for another. The 30-day prevalence of vaping among high school students fell from 27.5% in 2019 to 7.8% this year. Changing social norms and stricter federal regulation of tobacco products are probably more responsible for this positive trend than medical care, though the US Preventive Services Task Force recommends education or brief counseling to prevent initiation of tobacco use among school-aged children and adolescents. Should tobacco use in youth remain at these historically low levels, millions of premature deaths from lung cancer and heart disease will have been prevented.

America’s doctors have earned the right to take a bow. We have much more work to do, but our efforts are making a meaningful difference in three seemingly intractable health problems.

Dr. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.

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

Hi, everyone. I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

For the past 4 years, primary care clinicians have labored under a seemingly endless onslaught of bad news. A recent report estimated that there were over 1.3 million excess deaths in the United States from March 2020 to May 2023, including nearly half a million Americans younger than age 65. Social isolation and an ailing economy accelerated preexisting rises in drug overdoses and obesity, while teenage vaping threatened to hook a new generation on tobacco products even as adult smoking plummeted. Meanwhile, more than half of the nation’s physicians now report feelings of burnout, pay for family doctors appears to be stagnating, and our interactions with an increasing number of patients are fraught with suspicions about the value of vaccines— not just against COVID-19 but against flu and other viruses, too — and the medical system as a whole, doctors included. 

Now, for the good news.

A year and a half since the end of the pandemic emergency, we are seeing gains on several fronts, and physicians deserve much of the credit. Preliminary data from the Centers for Disease Control and Prevention show that 10,000 fewer people died from drug overdoses than in the previous year. Although multiple factors contributed to this change, the elimination of the X-waiver, which had previously been required for physicians to prescribe buprenorphine for opioid use disorder, in January 2023 has improved access to medications for addiction treatment. In addition, the expansion of state requirements to check prescription drug monitoring programs when opioids or benzodiazepines are prescribed, and to prescribe naloxone to patients taking more than a certain number of morphine milligram equivalents per day, has probably reduced the harms of hazardous drug use.

On the obesity front, recent data from the National Health and Nutrition Examination Survey found that the prevalence of obesity in adults fell for the first time in more than a decade, from 41.9% to 40.3%. To be sure, obesity remains far too common, and this finding could be the result of statistical chance rather than representing a true decline. But the widespread prescribing of GLP-1 receptor agonists by primary care physicians, in particular, could have played a role in the encouraging trend.

Although more research is needed to prove causality, one analysis suggests that these drugs could easily have lowered the body mass index (BMI) of more than enough patients to account for the observed decline. What’s more, the rise in prevalence of BMIs above 40 (from 7.7% to 9.7%) could be explained by the mortality benefit of the drugs: More people remained in this severe obesity category because they didn’t die from complications of their weight. Whether future studies support keeping people on GLP-1s for life or eventually “off-ramping” them to other weight control strategies, family physicians are well positioned to help.

Finally, with little fanfare, the youth smoking rate has fallen precipitously. In 2023, 1.9% of high school students and 1.1% of middle-schoolers reported smoking cigarettes in the past 30 days. And they didn’t simply swap one form of nicotine delivery device for another. The 30-day prevalence of vaping among high school students fell from 27.5% in 2019 to 7.8% this year. Changing social norms and stricter federal regulation of tobacco products are probably more responsible for this positive trend than medical care, though the US Preventive Services Task Force recommends education or brief counseling to prevent initiation of tobacco use among school-aged children and adolescents. Should tobacco use in youth remain at these historically low levels, millions of premature deaths from lung cancer and heart disease will have been prevented.

America’s doctors have earned the right to take a bow. We have much more work to do, but our efforts are making a meaningful difference in three seemingly intractable health problems.

Dr. Lin, Associate Director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania, has disclosed no relevant financial relationships.

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

TOPLINE:

Weight loss interventions using medication or behavioral changes can improve insulin resistance, hormonal markers, and menstrual frequency in women with polycystic ovary syndrome (PCOS), according to a new meta-analysis. Losing weight may not significantly reduce hirsutism or improve quality of life in women with the condition, however.

METHODOLOGY:

• Researchers systematically reviewed randomized controlled trials comparing weight loss interventions to usual care in women with PCOS.
• They focused on 12 studies with behavioral interventions (mainly diets with modest energy deficits), nine trials that used glucagon-like peptide 1 (GLP-1) receptor agonists, and eight studies using other weight loss medications.
• A total of 1529 participants were included in the analysis.
• The investigators synthesized the data using a random-effects meta-analysis with Knapp-Hartung adjustment to examine pooled mean differences.

TAKEAWAY:

• Menstrual frequency increased by 2.64 menses per year (95% CI, 0.65-4.63) with weight loss interventions.
• “To our knowledge, this is the first review to show a clinically significant association in improvement in menstrual frequency with weight loss interventions, an important indicator of subsequent fertility and an important outcome for women,” the researchers wrote.
• Glycemic control also improved, with a mean reduction in homeostatic model assessment of insulin resistance of 0.45 (95% CI, –0.75 to –0.15).
• Free androgen index decreased by an average of 2.03 (95% CI, –3.0 to –1.07).

IN PRACTICE:

“Clinicians may use these findings to counsel women with PCOS on the expected improvements in PCOS markers after weight loss and direct patients toward interventions,” the authors of the study wrote. “Because weight loss programs are cost-effective interventions to improve cardiometabolic risk, they may be particularly valuable for this population at elevated risk.”

SOURCE:

The study was led by Jadine Scragg, PhD, with the Nuffield Department of Primary Care Health Sciences at the University of Oxford in England. It was published online in Annals of Internal Medicine.

LIMITATIONS:

Interventions using GLP-1 agonists were dosed for glycemic control rather than weight management. The studies in the meta-analysis were relatively few and heterogeneous. Data were insufficient to assess ovulation and acne.

DISCLOSURES:

The meta-analysis was supported by grants from the National Institute for Health and Care Research School for Primary Care Research. Authors disclosed ties to Nestlé Health Science and Second Nature.

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 first appeared on Medscape.com.

TOPLINE:

Weight loss interventions using medication or behavioral changes can improve insulin resistance, hormonal markers, and menstrual frequency in women with polycystic ovary syndrome (PCOS), according to a new meta-analysis. Losing weight may not significantly reduce hirsutism or improve quality of life in women with the condition, however.

METHODOLOGY:

• Researchers systematically reviewed randomized controlled trials comparing weight loss interventions to usual care in women with PCOS.
• They focused on 12 studies with behavioral interventions (mainly diets with modest energy deficits), nine trials that used glucagon-like peptide 1 (GLP-1) receptor agonists, and eight studies using other weight loss medications.
• A total of 1529 participants were included in the analysis.
• The investigators synthesized the data using a random-effects meta-analysis with Knapp-Hartung adjustment to examine pooled mean differences.

TAKEAWAY:

• Menstrual frequency increased by 2.64 menses per year (95% CI, 0.65-4.63) with weight loss interventions.
• “To our knowledge, this is the first review to show a clinically significant association in improvement in menstrual frequency with weight loss interventions, an important indicator of subsequent fertility and an important outcome for women,” the researchers wrote.
• Glycemic control also improved, with a mean reduction in homeostatic model assessment of insulin resistance of 0.45 (95% CI, –0.75 to –0.15).
• Free androgen index decreased by an average of 2.03 (95% CI, –3.0 to –1.07).

IN PRACTICE:

“Clinicians may use these findings to counsel women with PCOS on the expected improvements in PCOS markers after weight loss and direct patients toward interventions,” the authors of the study wrote. “Because weight loss programs are cost-effective interventions to improve cardiometabolic risk, they may be particularly valuable for this population at elevated risk.”

SOURCE:

The study was led by Jadine Scragg, PhD, with the Nuffield Department of Primary Care Health Sciences at the University of Oxford in England. It was published online in Annals of Internal Medicine.

LIMITATIONS:

Interventions using GLP-1 agonists were dosed for glycemic control rather than weight management. The studies in the meta-analysis were relatively few and heterogeneous. Data were insufficient to assess ovulation and acne.

DISCLOSURES:

The meta-analysis was supported by grants from the National Institute for Health and Care Research School for Primary Care Research. Authors disclosed ties to Nestlé Health Science and Second Nature.

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 first appeared on Medscape.com.

TOPLINE:

Weight loss interventions using medication or behavioral changes can improve insulin resistance, hormonal markers, and menstrual frequency in women with polycystic ovary syndrome (PCOS), according to a new meta-analysis. Losing weight may not significantly reduce hirsutism or improve quality of life in women with the condition, however.

METHODOLOGY:

• Researchers systematically reviewed randomized controlled trials comparing weight loss interventions to usual care in women with PCOS.
• They focused on 12 studies with behavioral interventions (mainly diets with modest energy deficits), nine trials that used glucagon-like peptide 1 (GLP-1) receptor agonists, and eight studies using other weight loss medications.
• A total of 1529 participants were included in the analysis.
• The investigators synthesized the data using a random-effects meta-analysis with Knapp-Hartung adjustment to examine pooled mean differences.

TAKEAWAY:

• Menstrual frequency increased by 2.64 menses per year (95% CI, 0.65-4.63) with weight loss interventions.
• “To our knowledge, this is the first review to show a clinically significant association in improvement in menstrual frequency with weight loss interventions, an important indicator of subsequent fertility and an important outcome for women,” the researchers wrote.
• Glycemic control also improved, with a mean reduction in homeostatic model assessment of insulin resistance of 0.45 (95% CI, –0.75 to –0.15).
• Free androgen index decreased by an average of 2.03 (95% CI, –3.0 to –1.07).

IN PRACTICE:

“Clinicians may use these findings to counsel women with PCOS on the expected improvements in PCOS markers after weight loss and direct patients toward interventions,” the authors of the study wrote. “Because weight loss programs are cost-effective interventions to improve cardiometabolic risk, they may be particularly valuable for this population at elevated risk.”

SOURCE:

The study was led by Jadine Scragg, PhD, with the Nuffield Department of Primary Care Health Sciences at the University of Oxford in England. It was published online in Annals of Internal Medicine.

LIMITATIONS:

Interventions using GLP-1 agonists were dosed for glycemic control rather than weight management. The studies in the meta-analysis were relatively few and heterogeneous. Data were insufficient to assess ovulation and acne.

DISCLOSURES:

The meta-analysis was supported by grants from the National Institute for Health and Care Research School for Primary Care Research. Authors disclosed ties to Nestlé Health Science and Second Nature.

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 first appeared on Medscape.com.

TOPLINE:

In women with polycystic ovary syndrome (PCOS) and with obesity or overweight, the combination of topiramate and metformin along with a low-calorie diet can result in effective weight loss and improve androgen levels, lipid levels, and psychosocial scores, without any serious adverse events.

METHODOLOGY:

• Topiramate is often used off-label for weight loss and may be a promising option added to a metformin regimen to improve cardiometabolic and reproductive health in women with PCOS and obesity or overweight when lifestyle changes alone fall short.
• This double-blind trial conducted at Hospital de Clínicas de Porto Alegre in Porto Alegre, Brazil, evaluated the effects of adding topiramate to metformin in 61 women aged 14-40 years with PCOS and body mass index (BMI) ≥ 30 or BMI ≥ 27 with concurrent hypertension, type 2 diabetes, or dyslipidemia.
• All participants were prescribed a 20 kcal/kg diet, as well as desogestrel for contraception during the study, and either started on 850 mg metformin or continued with their existing metformin regimen.
• They were randomly assigned to receive either topiramate or placebo (25 mg for 15 days and then 50 mg at night) along with metformin, with dose adjustments based on weight loss at 3 months.
• The primary outcome was the percent change in body weight from baseline, and the secondary outcomes included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features at 3 and 6 months.

TAKEAWAY:

• Topiramate combined with metformin resulted in greater mean weight loss at 3 months (−3.4% vs −1.6%; P = .03) and 6 months (−4.5% vs −1.4%; P = .03) than placebo plus metformin.
• Both treatment groups showed improvements in androgen and lipid levels and psychosocial scores, while the levels of C-reactive protein decreased only in the topiramate plus metformin group.
• Women who experienced ≥ 3% weight loss at 6 months showed a significant improvement in hirsutism scores (change in modified Ferriman-Gallwey scores, 8.4-6.5), unlike those who experienced < 3% weight loss (change in modified Ferriman-Gallwey scores, 8.02-8.78).
• Paresthesia was more common in the topiramate plus metformin group than in the metformin plus placebo group (23.3% vs 3.2%), but no serious adverse events were reported.

IN PRACTICE:

“In the era of new effective drugs for treating obesity, topiramate with metformin can be an option for women with obesity and PCOS, considering its low cost, reports of long-term experience with this medication, and ease to use,” the authors wrote.

SOURCE:

The study was led by Lucas Bandeira Marchesan, Gynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre, and was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The small sample size and high attrition rates were major limitations of this study. Increasing the topiramate dose at 3 months in those with < 3% weight loss did not provide additional benefit, and this study did not test for a higher topiramate dose response from the beginning, which could have potentially provided a better response to the medication. The small sample size of the study also prevented the authors from conducting a subgroup analysis.

DISCLOSURES:

The study was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil. 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 first appeared on Medscape.com.

TOPLINE:

In women with polycystic ovary syndrome (PCOS) and with obesity or overweight, the combination of topiramate and metformin along with a low-calorie diet can result in effective weight loss and improve androgen levels, lipid levels, and psychosocial scores, without any serious adverse events.

METHODOLOGY:

• Topiramate is often used off-label for weight loss and may be a promising option added to a metformin regimen to improve cardiometabolic and reproductive health in women with PCOS and obesity or overweight when lifestyle changes alone fall short.
• This double-blind trial conducted at Hospital de Clínicas de Porto Alegre in Porto Alegre, Brazil, evaluated the effects of adding topiramate to metformin in 61 women aged 14-40 years with PCOS and body mass index (BMI) ≥ 30 or BMI ≥ 27 with concurrent hypertension, type 2 diabetes, or dyslipidemia.
• All participants were prescribed a 20 kcal/kg diet, as well as desogestrel for contraception during the study, and either started on 850 mg metformin or continued with their existing metformin regimen.
• They were randomly assigned to receive either topiramate or placebo (25 mg for 15 days and then 50 mg at night) along with metformin, with dose adjustments based on weight loss at 3 months.
• The primary outcome was the percent change in body weight from baseline, and the secondary outcomes included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features at 3 and 6 months.

TAKEAWAY:

• Topiramate combined with metformin resulted in greater mean weight loss at 3 months (−3.4% vs −1.6%; P = .03) and 6 months (−4.5% vs −1.4%; P = .03) than placebo plus metformin.
• Both treatment groups showed improvements in androgen and lipid levels and psychosocial scores, while the levels of C-reactive protein decreased only in the topiramate plus metformin group.
• Women who experienced ≥ 3% weight loss at 6 months showed a significant improvement in hirsutism scores (change in modified Ferriman-Gallwey scores, 8.4-6.5), unlike those who experienced < 3% weight loss (change in modified Ferriman-Gallwey scores, 8.02-8.78).
• Paresthesia was more common in the topiramate plus metformin group than in the metformin plus placebo group (23.3% vs 3.2%), but no serious adverse events were reported.

IN PRACTICE:

“In the era of new effective drugs for treating obesity, topiramate with metformin can be an option for women with obesity and PCOS, considering its low cost, reports of long-term experience with this medication, and ease to use,” the authors wrote.

SOURCE:

The study was led by Lucas Bandeira Marchesan, Gynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre, and was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The small sample size and high attrition rates were major limitations of this study. Increasing the topiramate dose at 3 months in those with < 3% weight loss did not provide additional benefit, and this study did not test for a higher topiramate dose response from the beginning, which could have potentially provided a better response to the medication. The small sample size of the study also prevented the authors from conducting a subgroup analysis.

DISCLOSURES:

The study was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil. 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 first appeared on Medscape.com.

TOPLINE:

In women with polycystic ovary syndrome (PCOS) and with obesity or overweight, the combination of topiramate and metformin along with a low-calorie diet can result in effective weight loss and improve androgen levels, lipid levels, and psychosocial scores, without any serious adverse events.

METHODOLOGY:

• Topiramate is often used off-label for weight loss and may be a promising option added to a metformin regimen to improve cardiometabolic and reproductive health in women with PCOS and obesity or overweight when lifestyle changes alone fall short.
• This double-blind trial conducted at Hospital de Clínicas de Porto Alegre in Porto Alegre, Brazil, evaluated the effects of adding topiramate to metformin in 61 women aged 14-40 years with PCOS and body mass index (BMI) ≥ 30 or BMI ≥ 27 with concurrent hypertension, type 2 diabetes, or dyslipidemia.
• All participants were prescribed a 20 kcal/kg diet, as well as desogestrel for contraception during the study, and either started on 850 mg metformin or continued with their existing metformin regimen.
• They were randomly assigned to receive either topiramate or placebo (25 mg for 15 days and then 50 mg at night) along with metformin, with dose adjustments based on weight loss at 3 months.
• The primary outcome was the percent change in body weight from baseline, and the secondary outcomes included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features at 3 and 6 months.

TAKEAWAY:

• Topiramate combined with metformin resulted in greater mean weight loss at 3 months (−3.4% vs −1.6%; P = .03) and 6 months (−4.5% vs −1.4%; P = .03) than placebo plus metformin.
• Both treatment groups showed improvements in androgen and lipid levels and psychosocial scores, while the levels of C-reactive protein decreased only in the topiramate plus metformin group.
• Women who experienced ≥ 3% weight loss at 6 months showed a significant improvement in hirsutism scores (change in modified Ferriman-Gallwey scores, 8.4-6.5), unlike those who experienced < 3% weight loss (change in modified Ferriman-Gallwey scores, 8.02-8.78).
• Paresthesia was more common in the topiramate plus metformin group than in the metformin plus placebo group (23.3% vs 3.2%), but no serious adverse events were reported.

IN PRACTICE:

“In the era of new effective drugs for treating obesity, topiramate with metformin can be an option for women with obesity and PCOS, considering its low cost, reports of long-term experience with this medication, and ease to use,” the authors wrote.

SOURCE:

The study was led by Lucas Bandeira Marchesan, Gynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre, and was published online in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

The small sample size and high attrition rates were major limitations of this study. Increasing the topiramate dose at 3 months in those with < 3% weight loss did not provide additional benefit, and this study did not test for a higher topiramate dose response from the beginning, which could have potentially provided a better response to the medication. The small sample size of the study also prevented the authors from conducting a subgroup analysis.

DISCLOSURES:

The study was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil. 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 first appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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

CHICAGO — Patients who are new users of glucagon-like peptide 1 (GLP-1) receptor agonists have a low absolute risk of thyroid cancer, according to a new study presented at the annual meeting of the American Thyroid Association (ATA).

The study, presented by Juan Brito Campana, MBBS, of the Mayo Clinic in Rochester, Minnesota, used Medicare records to perform a secondary analysis of 41,000 adults with type 2 diabetes and moderate cardiovascular risk who were new users of GLP-1 receptor agonists, compared to users of other diabetes medications. 

“We took the innovative approach of applying the methodological rigor of a randomized clinical trial to the very large dataset of observational studies,” said Brito Campana.

The results showed a low absolute risk of thyroid cancer, with only 0.17% of patients in the GLP-1 group developing the disease. However, the data also showed a potential relative increase in risk during the first year of GLP-1 receptor agonist use. 

“This is likely due to increased detection rather than true incidence, as the latency period for thyroid cancer development is typically longer,” Brito Campana said. 

“We also note the limitations of the observational study design, including the short follow-up period and lack of detailed histological data. However, we believe the benefits of GLP-1 receptor agonists likely outweigh the risk of thyroid cancer.”
 

Malignancy in Bethesda III and IV Thyroid Nodules

At the same ATA session, Sapir Nachum Goldberg, MD, of the University of Pennsylvania, Philadelphia, presented the results of a retrospective record review that examined the prevalence of malignancy in Bethesda III and IV thyroid nodules with negative Thyrogen Receptor Signaling (ThyroSeq) version 3 molecular testing results.

Goldberg reported that 87% of patients with ThyroSeq negative subtype results were managed nonoperatively. “Based on our data, the true prevalence of malignancy likely lies between our low and high estimates of 3% and 23%,” she said. “We believe that the prevalence of malignancy may be higher in real-world practice than validation studies.”

Additionally, nodules with “currently negative” or “negative but limited” ThyroSeq results had a higher prevalence of malignancy (7%), compared with those with a “negative” result (2%). Factors like immediate vs delayed surgery, nodule size, and ultrasound pattern did not significantly impact malignancy prevalence.

The study results also indicated that surveillance ultrasonography is not routinely performed in up to one-third of patients, Goldberg said.

She closed by suggesting that colleagues consider the negative subtype in clinical decision-making. For “negative but limited” nodules, repeat the fine needle aspiration and, for “negative” and “currently negative” nodules, consider ultrasound follow-up as per ATA guidelines for Bethesda II cytology, she said.
 

RET-Mutated Medullary Thyroid Cancer

For patients with RET-mutated medullary thyroid cancer, Julien Hadoux, MD, PhD, of Institut de Cancérologie Gustave Roussy, Villejuif, France, presented a combined analysis of the efficacy of the RET inhibitor selpercatinib from the phase 1/2 LIBRETTO-001 and phase 3 LIBRETTO-531 trials.

This post hoc analysis used a combined cohort of 509 patients with RET-mutated advanced or metastatic medullary thyroid cancer who had received selpercatinib in the two trials.

Hadoux reported that robust and durable responses were seen across all mutation groups, including M918T, extracellular cysteine, and an “other” group composed of various uncommon RET mutations. “The median [progression-free survival] PFS was not reached for either the M918T or extracellular groups and it was 51.4 months for the Other group,” he said. 

“Selpercatinib showed superior median PFS vs control, regardless of the RET mutation. This analysis constitutes the largest catalog of RET mutations in medullary thyroid cancers treated with RET-specific inhibitors.”
 

TRK-Fusion Differentiated Thyroid Cancer

Steven Waguespack, MD, of the University of Texas MD Anderson Cancer Center, Houston, shared updated efficacy and safety data from three phase 1/2 pooled clinical trials of the tropomyosin kinase receptor (TRK) inhibitor larotrectinib in thyroid cancer. These data updated results initially published in 2022.

“Larotrectinib continues to demonstrate rapid and durable responses, extended survival, and offers a favorable safety profile in patients with TRK fusion differentiated thyroid cancer, with limited activity in anaplastic thyroid cancer,” Waguespack said. 

“Additionally, in a subset of patients, we identified some acquired on-target NTRK mutations and off-target GNAS and TP53 mutations that may give further insight into mechanisms of resistance.”

The primary endpoint was the investigator-assessed objective response rate (ORR); at 48 months, the ORR was 79% by independent review. The median PFS in patients with TRK fusion differentiated thyroid cancer was 44 months, while the median duration of response was 41 months. The 4-year overall survival rate was 86%.

Waguespack closed with a cautionary note to colleagues: “While circulating tumor DNA next-generation sequencing (NGS) analysis can be used to test for NTRK gene fusions, negative results should be followed up with tissue-based NGS,” he said.

Brito Campana and Goldberg disclosed no relevant financial relationships. Hadoux reported receiving honoraria for speaker engagements, advisory roles, or funding for CME from Eli Lilly, AAA, IPSEN, Roche, Pharma Mar, and EISAI, and research grants from Novartis, Sanofi, and Eli Lilly.

A version of this article appeared on Medscape.com.

CHICAGO — Patients who are new users of glucagon-like peptide 1 (GLP-1) receptor agonists have a low absolute risk of thyroid cancer, according to a new study presented at the annual meeting of the American Thyroid Association (ATA).

The study, presented by Juan Brito Campana, MBBS, of the Mayo Clinic in Rochester, Minnesota, used Medicare records to perform a secondary analysis of 41,000 adults with type 2 diabetes and moderate cardiovascular risk who were new users of GLP-1 receptor agonists, compared to users of other diabetes medications. 

“We took the innovative approach of applying the methodological rigor of a randomized clinical trial to the very large dataset of observational studies,” said Brito Campana.

The results showed a low absolute risk of thyroid cancer, with only 0.17% of patients in the GLP-1 group developing the disease. However, the data also showed a potential relative increase in risk during the first year of GLP-1 receptor agonist use. 

“This is likely due to increased detection rather than true incidence, as the latency period for thyroid cancer development is typically longer,” Brito Campana said. 

“We also note the limitations of the observational study design, including the short follow-up period and lack of detailed histological data. However, we believe the benefits of GLP-1 receptor agonists likely outweigh the risk of thyroid cancer.”
 

Malignancy in Bethesda III and IV Thyroid Nodules

At the same ATA session, Sapir Nachum Goldberg, MD, of the University of Pennsylvania, Philadelphia, presented the results of a retrospective record review that examined the prevalence of malignancy in Bethesda III and IV thyroid nodules with negative Thyrogen Receptor Signaling (ThyroSeq) version 3 molecular testing results.

Goldberg reported that 87% of patients with ThyroSeq negative subtype results were managed nonoperatively. “Based on our data, the true prevalence of malignancy likely lies between our low and high estimates of 3% and 23%,” she said. “We believe that the prevalence of malignancy may be higher in real-world practice than validation studies.”

Additionally, nodules with “currently negative” or “negative but limited” ThyroSeq results had a higher prevalence of malignancy (7%), compared with those with a “negative” result (2%). Factors like immediate vs delayed surgery, nodule size, and ultrasound pattern did not significantly impact malignancy prevalence.

The study results also indicated that surveillance ultrasonography is not routinely performed in up to one-third of patients, Goldberg said.

She closed by suggesting that colleagues consider the negative subtype in clinical decision-making. For “negative but limited” nodules, repeat the fine needle aspiration and, for “negative” and “currently negative” nodules, consider ultrasound follow-up as per ATA guidelines for Bethesda II cytology, she said.
 

RET-Mutated Medullary Thyroid Cancer

For patients with RET-mutated medullary thyroid cancer, Julien Hadoux, MD, PhD, of Institut de Cancérologie Gustave Roussy, Villejuif, France, presented a combined analysis of the efficacy of the RET inhibitor selpercatinib from the phase 1/2 LIBRETTO-001 and phase 3 LIBRETTO-531 trials.

This post hoc analysis used a combined cohort of 509 patients with RET-mutated advanced or metastatic medullary thyroid cancer who had received selpercatinib in the two trials.

Hadoux reported that robust and durable responses were seen across all mutation groups, including M918T, extracellular cysteine, and an “other” group composed of various uncommon RET mutations. “The median [progression-free survival] PFS was not reached for either the M918T or extracellular groups and it was 51.4 months for the Other group,” he said. 

“Selpercatinib showed superior median PFS vs control, regardless of the RET mutation. This analysis constitutes the largest catalog of RET mutations in medullary thyroid cancers treated with RET-specific inhibitors.”
 

TRK-Fusion Differentiated Thyroid Cancer

Steven Waguespack, MD, of the University of Texas MD Anderson Cancer Center, Houston, shared updated efficacy and safety data from three phase 1/2 pooled clinical trials of the tropomyosin kinase receptor (TRK) inhibitor larotrectinib in thyroid cancer. These data updated results initially published in 2022.

“Larotrectinib continues to demonstrate rapid and durable responses, extended survival, and offers a favorable safety profile in patients with TRK fusion differentiated thyroid cancer, with limited activity in anaplastic thyroid cancer,” Waguespack said. 

“Additionally, in a subset of patients, we identified some acquired on-target NTRK mutations and off-target GNAS and TP53 mutations that may give further insight into mechanisms of resistance.”

The primary endpoint was the investigator-assessed objective response rate (ORR); at 48 months, the ORR was 79% by independent review. The median PFS in patients with TRK fusion differentiated thyroid cancer was 44 months, while the median duration of response was 41 months. The 4-year overall survival rate was 86%.

Waguespack closed with a cautionary note to colleagues: “While circulating tumor DNA next-generation sequencing (NGS) analysis can be used to test for NTRK gene fusions, negative results should be followed up with tissue-based NGS,” he said.

Brito Campana and Goldberg disclosed no relevant financial relationships. Hadoux reported receiving honoraria for speaker engagements, advisory roles, or funding for CME from Eli Lilly, AAA, IPSEN, Roche, Pharma Mar, and EISAI, and research grants from Novartis, Sanofi, and Eli Lilly.

A version of this article appeared on Medscape.com.

CHICAGO — Patients who are new users of glucagon-like peptide 1 (GLP-1) receptor agonists have a low absolute risk of thyroid cancer, according to a new study presented at the annual meeting of the American Thyroid Association (ATA).

The study, presented by Juan Brito Campana, MBBS, of the Mayo Clinic in Rochester, Minnesota, used Medicare records to perform a secondary analysis of 41,000 adults with type 2 diabetes and moderate cardiovascular risk who were new users of GLP-1 receptor agonists, compared to users of other diabetes medications. 

“We took the innovative approach of applying the methodological rigor of a randomized clinical trial to the very large dataset of observational studies,” said Brito Campana.

The results showed a low absolute risk of thyroid cancer, with only 0.17% of patients in the GLP-1 group developing the disease. However, the data also showed a potential relative increase in risk during the first year of GLP-1 receptor agonist use. 

“This is likely due to increased detection rather than true incidence, as the latency period for thyroid cancer development is typically longer,” Brito Campana said. 

“We also note the limitations of the observational study design, including the short follow-up period and lack of detailed histological data. However, we believe the benefits of GLP-1 receptor agonists likely outweigh the risk of thyroid cancer.”
 

Malignancy in Bethesda III and IV Thyroid Nodules

At the same ATA session, Sapir Nachum Goldberg, MD, of the University of Pennsylvania, Philadelphia, presented the results of a retrospective record review that examined the prevalence of malignancy in Bethesda III and IV thyroid nodules with negative Thyrogen Receptor Signaling (ThyroSeq) version 3 molecular testing results.

Goldberg reported that 87% of patients with ThyroSeq negative subtype results were managed nonoperatively. “Based on our data, the true prevalence of malignancy likely lies between our low and high estimates of 3% and 23%,” she said. “We believe that the prevalence of malignancy may be higher in real-world practice than validation studies.”

Additionally, nodules with “currently negative” or “negative but limited” ThyroSeq results had a higher prevalence of malignancy (7%), compared with those with a “negative” result (2%). Factors like immediate vs delayed surgery, nodule size, and ultrasound pattern did not significantly impact malignancy prevalence.

The study results also indicated that surveillance ultrasonography is not routinely performed in up to one-third of patients, Goldberg said.

She closed by suggesting that colleagues consider the negative subtype in clinical decision-making. For “negative but limited” nodules, repeat the fine needle aspiration and, for “negative” and “currently negative” nodules, consider ultrasound follow-up as per ATA guidelines for Bethesda II cytology, she said.
 

RET-Mutated Medullary Thyroid Cancer

For patients with RET-mutated medullary thyroid cancer, Julien Hadoux, MD, PhD, of Institut de Cancérologie Gustave Roussy, Villejuif, France, presented a combined analysis of the efficacy of the RET inhibitor selpercatinib from the phase 1/2 LIBRETTO-001 and phase 3 LIBRETTO-531 trials.

This post hoc analysis used a combined cohort of 509 patients with RET-mutated advanced or metastatic medullary thyroid cancer who had received selpercatinib in the two trials.

Hadoux reported that robust and durable responses were seen across all mutation groups, including M918T, extracellular cysteine, and an “other” group composed of various uncommon RET mutations. “The median [progression-free survival] PFS was not reached for either the M918T or extracellular groups and it was 51.4 months for the Other group,” he said. 

“Selpercatinib showed superior median PFS vs control, regardless of the RET mutation. This analysis constitutes the largest catalog of RET mutations in medullary thyroid cancers treated with RET-specific inhibitors.”
 

TRK-Fusion Differentiated Thyroid Cancer

Steven Waguespack, MD, of the University of Texas MD Anderson Cancer Center, Houston, shared updated efficacy and safety data from three phase 1/2 pooled clinical trials of the tropomyosin kinase receptor (TRK) inhibitor larotrectinib in thyroid cancer. These data updated results initially published in 2022.

“Larotrectinib continues to demonstrate rapid and durable responses, extended survival, and offers a favorable safety profile in patients with TRK fusion differentiated thyroid cancer, with limited activity in anaplastic thyroid cancer,” Waguespack said. 

“Additionally, in a subset of patients, we identified some acquired on-target NTRK mutations and off-target GNAS and TP53 mutations that may give further insight into mechanisms of resistance.”

The primary endpoint was the investigator-assessed objective response rate (ORR); at 48 months, the ORR was 79% by independent review. The median PFS in patients with TRK fusion differentiated thyroid cancer was 44 months, while the median duration of response was 41 months. The 4-year overall survival rate was 86%.

Waguespack closed with a cautionary note to colleagues: “While circulating tumor DNA next-generation sequencing (NGS) analysis can be used to test for NTRK gene fusions, negative results should be followed up with tissue-based NGS,” he said.

Brito Campana and Goldberg disclosed no relevant financial relationships. Hadoux reported receiving honoraria for speaker engagements, advisory roles, or funding for CME from Eli Lilly, AAA, IPSEN, Roche, Pharma Mar, and EISAI, and research grants from Novartis, Sanofi, and Eli Lilly.

A version of this article appeared on Medscape.com.

Our current healthcare system, which is a costly and unending cycle of merely managing chronic disease symptoms, is failing us. What we truly need is a patient-centered approach that restores health by addressing not just diagnoses but also the physical, emotional, and social needs of each individual. This is the essence of whole-person health, and transformation toward this model of care is already underway.

This shift underscores why clinicians like me support placing lifestyle medicine at the foundation of health and healthcare. Evidence-based lifestyle medicine — which applies interventions in nutrition, physical activity, restorative sleep, stress management, positive social connections, and avoidance of risky substances to prevent, treat, and when used intensively, even reverse lifestyle-related chronic disease — is a medical specialty equipped to successfully address patients’ whole-person health in an effective, high-value clinical care delivery model.

As this transformation continues, here are four key lifestyle medicine trends for 2025.
 

Lifestyle Medicine Becomes More Ingrained in Primary Care

The 2021 National Academies of Science, Engineering, and Medicine report, “Implementing High-Quality Primary Care” sounded the alarm about the state of primary care and outlined a comprehensive approach to transform it. Lifestyle medicine emerged as a solution as clinicians found innovative ways to integrate lifestyle behavior interventions into existing care models in a financially sustainable, scalable manner. Examples include Blue Zones Health, a new delivery model that aligns lifestyle medicine–certified clinicians with community and payers in California, and the University of Pittsburgh Medical Center lifestyle medicine program, where primary care patients are referred to virtual group coaching, a teaching kitchen, and classes on food as medicine, obesity, type 2 diabetes, and more.

Organizations dedicated to advancing primary care are paying close attention to the potential of lifestyle medicine. Currently, The Primary Care Collaborative has launched a new multi-year initiative on whole-person care and lifestyle medicine. This initiative aims to broaden the primary care community’s understanding of whole health and lifestyle medicine concepts and the evidence behind them, as well as lay the groundwork for future work to promote whole-person primary care and lifestyle medicine among an engaged and committed community of members. 
 

Digital Tools and AI Spark Lifestyle Medicine Innovations

American College of Lifestyle Medicine partner organizations are increasingly utilizing digital tools, such as health apps tailored to lifestyle behavior interventions, to expand access to care and support behavior change. One of the biggest challenges in lifestyle interventions is the limited time during patient encounters. But artificial intelligence (AI) tools can record (with patient permission) and summarize encounters, enabling clinicians to turn away from their keyboards and be more present to learn about the unique living, environmental, and societal factors that impact every individual’s lifestyle choices. AI tools can create individualized whole-food, plant-predominant meal plans or physical activity schedules for patients in just a few seconds. The potential for AI in lifestyle medicine is vast, and its applications were further explored at the American College of Lifestyle Medicine’s annual conference in October.

Behavior Change and Sustainability of the Food-as-Medicine Movement

Significant investments have been made in food as medicine to address diet-related chronic diseases. But merely providing medically tailored meals or produce prescriptions is not enough because once the prescriptions end, so will the health benefits. Clinicians certified in lifestyle medicine are prepared to coach patients into long-term behavior change, supporting them with education and information to shop for and prepare tasty, nutritious, and affordable food. The same applies to the use of glucagon-like peptide 1 drugs. Although the initial weight loss offers motivation, lifestyle changes are necessary to sustain long-term health benefits beyond medications.

Lifestyle Medicine Emerges as a Strategy to Achieve Health Equity 

Lifestyle behavior interventions have the unique ability to address health status and social drivers of health. For example, food as medicine affects an individual’s health while also addressing nutrition security. Certainly, no medication can both improve health status and feed someone. The addition of payment for the screening of social drivers of health to the 2024 Medicare Physician Fee Schedule is an important step toward connecting clinicians with community health–based organizations that can address factors that influence patients’ ability to adhere to lifestyle behavior care plans. Lifestyle medicine clinicians are poised to lead this effort because they are already having conversations with patients about their environment, living conditions, and access to nutritious food. 

The changes coming to our healthcare system are exciting and long overdue. Lifestyle medicine is positioned to be at the forefront of this transformation now and in the future.

Dr. Patel, president of the American College of Lifestyle Medicine in St. Louis, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Our current healthcare system, which is a costly and unending cycle of merely managing chronic disease symptoms, is failing us. What we truly need is a patient-centered approach that restores health by addressing not just diagnoses but also the physical, emotional, and social needs of each individual. This is the essence of whole-person health, and transformation toward this model of care is already underway.

This shift underscores why clinicians like me support placing lifestyle medicine at the foundation of health and healthcare. Evidence-based lifestyle medicine — which applies interventions in nutrition, physical activity, restorative sleep, stress management, positive social connections, and avoidance of risky substances to prevent, treat, and when used intensively, even reverse lifestyle-related chronic disease — is a medical specialty equipped to successfully address patients’ whole-person health in an effective, high-value clinical care delivery model.

As this transformation continues, here are four key lifestyle medicine trends for 2025.
 

Lifestyle Medicine Becomes More Ingrained in Primary Care

The 2021 National Academies of Science, Engineering, and Medicine report, “Implementing High-Quality Primary Care” sounded the alarm about the state of primary care and outlined a comprehensive approach to transform it. Lifestyle medicine emerged as a solution as clinicians found innovative ways to integrate lifestyle behavior interventions into existing care models in a financially sustainable, scalable manner. Examples include Blue Zones Health, a new delivery model that aligns lifestyle medicine–certified clinicians with community and payers in California, and the University of Pittsburgh Medical Center lifestyle medicine program, where primary care patients are referred to virtual group coaching, a teaching kitchen, and classes on food as medicine, obesity, type 2 diabetes, and more.

Organizations dedicated to advancing primary care are paying close attention to the potential of lifestyle medicine. Currently, The Primary Care Collaborative has launched a new multi-year initiative on whole-person care and lifestyle medicine. This initiative aims to broaden the primary care community’s understanding of whole health and lifestyle medicine concepts and the evidence behind them, as well as lay the groundwork for future work to promote whole-person primary care and lifestyle medicine among an engaged and committed community of members. 
 

Digital Tools and AI Spark Lifestyle Medicine Innovations

American College of Lifestyle Medicine partner organizations are increasingly utilizing digital tools, such as health apps tailored to lifestyle behavior interventions, to expand access to care and support behavior change. One of the biggest challenges in lifestyle interventions is the limited time during patient encounters. But artificial intelligence (AI) tools can record (with patient permission) and summarize encounters, enabling clinicians to turn away from their keyboards and be more present to learn about the unique living, environmental, and societal factors that impact every individual’s lifestyle choices. AI tools can create individualized whole-food, plant-predominant meal plans or physical activity schedules for patients in just a few seconds. The potential for AI in lifestyle medicine is vast, and its applications were further explored at the American College of Lifestyle Medicine’s annual conference in October.

Behavior Change and Sustainability of the Food-as-Medicine Movement

Significant investments have been made in food as medicine to address diet-related chronic diseases. But merely providing medically tailored meals or produce prescriptions is not enough because once the prescriptions end, so will the health benefits. Clinicians certified in lifestyle medicine are prepared to coach patients into long-term behavior change, supporting them with education and information to shop for and prepare tasty, nutritious, and affordable food. The same applies to the use of glucagon-like peptide 1 drugs. Although the initial weight loss offers motivation, lifestyle changes are necessary to sustain long-term health benefits beyond medications.

Lifestyle Medicine Emerges as a Strategy to Achieve Health Equity 

Lifestyle behavior interventions have the unique ability to address health status and social drivers of health. For example, food as medicine affects an individual’s health while also addressing nutrition security. Certainly, no medication can both improve health status and feed someone. The addition of payment for the screening of social drivers of health to the 2024 Medicare Physician Fee Schedule is an important step toward connecting clinicians with community health–based organizations that can address factors that influence patients’ ability to adhere to lifestyle behavior care plans. Lifestyle medicine clinicians are poised to lead this effort because they are already having conversations with patients about their environment, living conditions, and access to nutritious food. 

The changes coming to our healthcare system are exciting and long overdue. Lifestyle medicine is positioned to be at the forefront of this transformation now and in the future.

Dr. Patel, president of the American College of Lifestyle Medicine in St. Louis, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Our current healthcare system, which is a costly and unending cycle of merely managing chronic disease symptoms, is failing us. What we truly need is a patient-centered approach that restores health by addressing not just diagnoses but also the physical, emotional, and social needs of each individual. This is the essence of whole-person health, and transformation toward this model of care is already underway.

This shift underscores why clinicians like me support placing lifestyle medicine at the foundation of health and healthcare. Evidence-based lifestyle medicine — which applies interventions in nutrition, physical activity, restorative sleep, stress management, positive social connections, and avoidance of risky substances to prevent, treat, and when used intensively, even reverse lifestyle-related chronic disease — is a medical specialty equipped to successfully address patients’ whole-person health in an effective, high-value clinical care delivery model.

As this transformation continues, here are four key lifestyle medicine trends for 2025.
 

Lifestyle Medicine Becomes More Ingrained in Primary Care

The 2021 National Academies of Science, Engineering, and Medicine report, “Implementing High-Quality Primary Care” sounded the alarm about the state of primary care and outlined a comprehensive approach to transform it. Lifestyle medicine emerged as a solution as clinicians found innovative ways to integrate lifestyle behavior interventions into existing care models in a financially sustainable, scalable manner. Examples include Blue Zones Health, a new delivery model that aligns lifestyle medicine–certified clinicians with community and payers in California, and the University of Pittsburgh Medical Center lifestyle medicine program, where primary care patients are referred to virtual group coaching, a teaching kitchen, and classes on food as medicine, obesity, type 2 diabetes, and more.

Organizations dedicated to advancing primary care are paying close attention to the potential of lifestyle medicine. Currently, The Primary Care Collaborative has launched a new multi-year initiative on whole-person care and lifestyle medicine. This initiative aims to broaden the primary care community’s understanding of whole health and lifestyle medicine concepts and the evidence behind them, as well as lay the groundwork for future work to promote whole-person primary care and lifestyle medicine among an engaged and committed community of members. 
 

Digital Tools and AI Spark Lifestyle Medicine Innovations

American College of Lifestyle Medicine partner organizations are increasingly utilizing digital tools, such as health apps tailored to lifestyle behavior interventions, to expand access to care and support behavior change. One of the biggest challenges in lifestyle interventions is the limited time during patient encounters. But artificial intelligence (AI) tools can record (with patient permission) and summarize encounters, enabling clinicians to turn away from their keyboards and be more present to learn about the unique living, environmental, and societal factors that impact every individual’s lifestyle choices. AI tools can create individualized whole-food, plant-predominant meal plans or physical activity schedules for patients in just a few seconds. The potential for AI in lifestyle medicine is vast, and its applications were further explored at the American College of Lifestyle Medicine’s annual conference in October.

Behavior Change and Sustainability of the Food-as-Medicine Movement

Significant investments have been made in food as medicine to address diet-related chronic diseases. But merely providing medically tailored meals or produce prescriptions is not enough because once the prescriptions end, so will the health benefits. Clinicians certified in lifestyle medicine are prepared to coach patients into long-term behavior change, supporting them with education and information to shop for and prepare tasty, nutritious, and affordable food. The same applies to the use of glucagon-like peptide 1 drugs. Although the initial weight loss offers motivation, lifestyle changes are necessary to sustain long-term health benefits beyond medications.

Lifestyle Medicine Emerges as a Strategy to Achieve Health Equity 

Lifestyle behavior interventions have the unique ability to address health status and social drivers of health. For example, food as medicine affects an individual’s health while also addressing nutrition security. Certainly, no medication can both improve health status and feed someone. The addition of payment for the screening of social drivers of health to the 2024 Medicare Physician Fee Schedule is an important step toward connecting clinicians with community health–based organizations that can address factors that influence patients’ ability to adhere to lifestyle behavior care plans. Lifestyle medicine clinicians are poised to lead this effort because they are already having conversations with patients about their environment, living conditions, and access to nutritious food. 

The changes coming to our healthcare system are exciting and long overdue. Lifestyle medicine is positioned to be at the forefront of this transformation now and in the future.

Dr. Patel, president of the American College of Lifestyle Medicine in St. Louis, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

PHILADELPHIA — Roux-en-Y gastric bypass (RYGB) produces maximal weight loss in patients with obesity, compared with other surgical procedures and with weight loss drugs, according to a meta-analysis comparing the efficacy and safety of the different treatment options. 

However, tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP-1 RA), produces comparable weight loss and has a favorable safety profile, reported principal investigator Jena Velji-Ibrahim, MD, MSc, from Prisma Health–Upstate/University of South Carolina School of Medicine in Greenville. 

In addition, there was “no significant difference in percentage total body weight loss between tirzepatide when comparing it to one-anastomosis gastric bypass (OAGB), as well as laparoscopic sleeve gastrectomy,” she said. 

All 11 interventions studied exerted weight loss effects, and side-effect profiles were also deemed largely favorable, particularly for endoscopic interventions, she added. 

“When we compare bariatric surgery to bariatric endoscopy, endoscopic sleeve gastroplasty and transpyloric shuttle offer a minimally invasive alternative with good weight loss outcomes and fewer adverse events,” she said.

Velji-Ibrahim presented the findings at the annual meeting of the American College of Gastroenterology (ACG). 
 

Comparing Weight Loss Interventions

Many of the studies comparing weight loss interventions to date have been limited by relatively small sample sizes, observational designs, and inconsistent results. This prompted Velji-Ibrahim and her colleagues to conduct what they believe to be the first-of-its-kind meta-analysis on this topic. 

They began by conducting a systematic search of the literature to identify randomized controlled trials (RCTs) that compared the efficacy of Food and Drug Administration–approved bariatric surgeries, bariatric endoscopies, and medications — against each other or with placebo — in adults with a body mass index of 25-45, with or without concurrent type 2 diabetes. 

A network meta-analysis was then performed to assess the various interventions’ impact on percentage total weight loss and side-effect profiles. P-scores were calculated to rank the treatments and identify the preferred interventions. The duration of therapy was 52 weeks. 

In total, 34 eligible RCTs with 15,660 patients were included. Overall, the RCTs analyzed 11 weight loss treatments, including bariatric surgeries (four studies), bariatric endoscopies (three studies), and medications (four studies). 

Specifically, the bariatric surgeries included RYGB, laparoscopic sleeve gastrectomy, OAGB, and laparoscopic adjustable gastric banding; bariatric endoscopies included endoscopic sleeve gastroplasty, transpyloric shuttle, and intragastric balloon; and medications included tirzepatide, semaglutide, and liraglutide.

Although all interventions were associated with reductions in percentage total weight loss compared with placebo, RYGB led to the greatest reductions (19.29%) and was ranked as the first preferred treatment (97% probability). It was followed in the rankings by OAGB, tirzepatide 15 mg, laparoscopic sleeve gastrectomy, and semaglutide 2.4 mg. 

Tirzepatide 15 mg had a slightly lower percentage total weight loss (15.18%) but a favorable safety profile. There was no significant difference in percentage total weight loss between tirzepatide 15 mg and OAGB (mean difference, 2.97%) or laparoscopic sleeve gastrectomy (mean difference, 0.43%). 

There was also no significant difference in percentage total weight loss between semaglutide 2.4 mg, compared with endoscopic sleeve gastroplasty and transpyloric shuttle. 

Endoscopic sleeve, transpyloric shuttle, and intragastric balloon all resulted in weight loss > 5%. 

When compared with bariatric surgery, “endoscopic interventions had a better side-effect profile, with no increased odds of mortality and intensive care needs,” Velji-Ibrahim said. 

When it came to the medications, “the most common side effects were gastrointestinal in nature, which included nausea, vomiting, diarrhea, and constipation,” she said.
 

Combining, Rather Than Comparing, Therapies

Following the presentation, session co-moderator Shivangi T. Kothari, MD, assistant professor of medicine and associate director of endoscopy at the University of Rochester Medical Center in New York, shared her thoughts of what the future of obesity management research might look like. 

It’s not just going to be about percentage total weight loss, she said, but about how well the effect is sustained following the intervention. 

And we might move “away from comparing one modality to another” and instead study combination therapies, “which would be ideal,” said Kothari.

This was the focus of another meta-analysis presented at ACG 2024, in which Nihal Ijaz I. Khan, MD, and colleagues compared the efficacy of endoscopic bariatric treatment alone vs its combined use with GLP-1 RAs.

The researchers identified three retrospective studies with 266 patients, of whom 143 underwent endoscopic bariatric treatment alone (either endoscopic sleeve gastroplasty or intragastric balloon) and 123 had it combined with GLP-1 RAs, specifically liraglutide. 

They reported that superior absolute weight loss was achieved in the group of patients receiving GLP-1 RAs in combination with endoscopic bariatric treatment. The standardized mean difference in body weight loss at treatment follow-up was 0.61 (P <.01). 

“Further studies are required to evaluate the safety and adverse events comparing these two treatment modalities and to discover differences between comparing the two endoscopic options to various GLP-1 receptor agonists,” Khan noted. 

Neither study had specific funding. Velji-Ibrahim and Khan reported no relevant financial relationships. Kothari reported serving as a consultant for Boston Scientific and Olympus, as well as serving as an advisory committee/board member for Castle Biosciences.

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

PHILADELPHIA — Roux-en-Y gastric bypass (RYGB) produces maximal weight loss in patients with obesity, compared with other surgical procedures and with weight loss drugs, according to a meta-analysis comparing the efficacy and safety of the different treatment options. 

However, tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP-1 RA), produces comparable weight loss and has a favorable safety profile, reported principal investigator Jena Velji-Ibrahim, MD, MSc, from Prisma Health–Upstate/University of South Carolina School of Medicine in Greenville. 

In addition, there was “no significant difference in percentage total body weight loss between tirzepatide when comparing it to one-anastomosis gastric bypass (OAGB), as well as laparoscopic sleeve gastrectomy,” she said. 

All 11 interventions studied exerted weight loss effects, and side-effect profiles were also deemed largely favorable, particularly for endoscopic interventions, she added. 

“When we compare bariatric surgery to bariatric endoscopy, endoscopic sleeve gastroplasty and transpyloric shuttle offer a minimally invasive alternative with good weight loss outcomes and fewer adverse events,” she said.

Velji-Ibrahim presented the findings at the annual meeting of the American College of Gastroenterology (ACG). 
 

Comparing Weight Loss Interventions

Many of the studies comparing weight loss interventions to date have been limited by relatively small sample sizes, observational designs, and inconsistent results. This prompted Velji-Ibrahim and her colleagues to conduct what they believe to be the first-of-its-kind meta-analysis on this topic. 

They began by conducting a systematic search of the literature to identify randomized controlled trials (RCTs) that compared the efficacy of Food and Drug Administration–approved bariatric surgeries, bariatric endoscopies, and medications — against each other or with placebo — in adults with a body mass index of 25-45, with or without concurrent type 2 diabetes. 

A network meta-analysis was then performed to assess the various interventions’ impact on percentage total weight loss and side-effect profiles. P-scores were calculated to rank the treatments and identify the preferred interventions. The duration of therapy was 52 weeks. 

In total, 34 eligible RCTs with 15,660 patients were included. Overall, the RCTs analyzed 11 weight loss treatments, including bariatric surgeries (four studies), bariatric endoscopies (three studies), and medications (four studies). 

Specifically, the bariatric surgeries included RYGB, laparoscopic sleeve gastrectomy, OAGB, and laparoscopic adjustable gastric banding; bariatric endoscopies included endoscopic sleeve gastroplasty, transpyloric shuttle, and intragastric balloon; and medications included tirzepatide, semaglutide, and liraglutide.

Although all interventions were associated with reductions in percentage total weight loss compared with placebo, RYGB led to the greatest reductions (19.29%) and was ranked as the first preferred treatment (97% probability). It was followed in the rankings by OAGB, tirzepatide 15 mg, laparoscopic sleeve gastrectomy, and semaglutide 2.4 mg. 

Tirzepatide 15 mg had a slightly lower percentage total weight loss (15.18%) but a favorable safety profile. There was no significant difference in percentage total weight loss between tirzepatide 15 mg and OAGB (mean difference, 2.97%) or laparoscopic sleeve gastrectomy (mean difference, 0.43%). 

There was also no significant difference in percentage total weight loss between semaglutide 2.4 mg, compared with endoscopic sleeve gastroplasty and transpyloric shuttle. 

Endoscopic sleeve, transpyloric shuttle, and intragastric balloon all resulted in weight loss > 5%. 

When compared with bariatric surgery, “endoscopic interventions had a better side-effect profile, with no increased odds of mortality and intensive care needs,” Velji-Ibrahim said. 

When it came to the medications, “the most common side effects were gastrointestinal in nature, which included nausea, vomiting, diarrhea, and constipation,” she said.
 

Combining, Rather Than Comparing, Therapies

Following the presentation, session co-moderator Shivangi T. Kothari, MD, assistant professor of medicine and associate director of endoscopy at the University of Rochester Medical Center in New York, shared her thoughts of what the future of obesity management research might look like. 

It’s not just going to be about percentage total weight loss, she said, but about how well the effect is sustained following the intervention. 

And we might move “away from comparing one modality to another” and instead study combination therapies, “which would be ideal,” said Kothari.

This was the focus of another meta-analysis presented at ACG 2024, in which Nihal Ijaz I. Khan, MD, and colleagues compared the efficacy of endoscopic bariatric treatment alone vs its combined use with GLP-1 RAs.

The researchers identified three retrospective studies with 266 patients, of whom 143 underwent endoscopic bariatric treatment alone (either endoscopic sleeve gastroplasty or intragastric balloon) and 123 had it combined with GLP-1 RAs, specifically liraglutide. 

They reported that superior absolute weight loss was achieved in the group of patients receiving GLP-1 RAs in combination with endoscopic bariatric treatment. The standardized mean difference in body weight loss at treatment follow-up was 0.61 (P <.01). 

“Further studies are required to evaluate the safety and adverse events comparing these two treatment modalities and to discover differences between comparing the two endoscopic options to various GLP-1 receptor agonists,” Khan noted. 

Neither study had specific funding. Velji-Ibrahim and Khan reported no relevant financial relationships. Kothari reported serving as a consultant for Boston Scientific and Olympus, as well as serving as an advisory committee/board member for Castle Biosciences.

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

PHILADELPHIA — Roux-en-Y gastric bypass (RYGB) produces maximal weight loss in patients with obesity, compared with other surgical procedures and with weight loss drugs, according to a meta-analysis comparing the efficacy and safety of the different treatment options. 

However, tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP-1 RA), produces comparable weight loss and has a favorable safety profile, reported principal investigator Jena Velji-Ibrahim, MD, MSc, from Prisma Health–Upstate/University of South Carolina School of Medicine in Greenville. 

In addition, there was “no significant difference in percentage total body weight loss between tirzepatide when comparing it to one-anastomosis gastric bypass (OAGB), as well as laparoscopic sleeve gastrectomy,” she said. 

All 11 interventions studied exerted weight loss effects, and side-effect profiles were also deemed largely favorable, particularly for endoscopic interventions, she added. 

“When we compare bariatric surgery to bariatric endoscopy, endoscopic sleeve gastroplasty and transpyloric shuttle offer a minimally invasive alternative with good weight loss outcomes and fewer adverse events,” she said.

Velji-Ibrahim presented the findings at the annual meeting of the American College of Gastroenterology (ACG). 
 

Comparing Weight Loss Interventions

Many of the studies comparing weight loss interventions to date have been limited by relatively small sample sizes, observational designs, and inconsistent results. This prompted Velji-Ibrahim and her colleagues to conduct what they believe to be the first-of-its-kind meta-analysis on this topic. 

They began by conducting a systematic search of the literature to identify randomized controlled trials (RCTs) that compared the efficacy of Food and Drug Administration–approved bariatric surgeries, bariatric endoscopies, and medications — against each other or with placebo — in adults with a body mass index of 25-45, with or without concurrent type 2 diabetes. 

A network meta-analysis was then performed to assess the various interventions’ impact on percentage total weight loss and side-effect profiles. P-scores were calculated to rank the treatments and identify the preferred interventions. The duration of therapy was 52 weeks. 

In total, 34 eligible RCTs with 15,660 patients were included. Overall, the RCTs analyzed 11 weight loss treatments, including bariatric surgeries (four studies), bariatric endoscopies (three studies), and medications (four studies). 

Specifically, the bariatric surgeries included RYGB, laparoscopic sleeve gastrectomy, OAGB, and laparoscopic adjustable gastric banding; bariatric endoscopies included endoscopic sleeve gastroplasty, transpyloric shuttle, and intragastric balloon; and medications included tirzepatide, semaglutide, and liraglutide.

Although all interventions were associated with reductions in percentage total weight loss compared with placebo, RYGB led to the greatest reductions (19.29%) and was ranked as the first preferred treatment (97% probability). It was followed in the rankings by OAGB, tirzepatide 15 mg, laparoscopic sleeve gastrectomy, and semaglutide 2.4 mg. 

Tirzepatide 15 mg had a slightly lower percentage total weight loss (15.18%) but a favorable safety profile. There was no significant difference in percentage total weight loss between tirzepatide 15 mg and OAGB (mean difference, 2.97%) or laparoscopic sleeve gastrectomy (mean difference, 0.43%). 

There was also no significant difference in percentage total weight loss between semaglutide 2.4 mg, compared with endoscopic sleeve gastroplasty and transpyloric shuttle. 

Endoscopic sleeve, transpyloric shuttle, and intragastric balloon all resulted in weight loss > 5%. 

When compared with bariatric surgery, “endoscopic interventions had a better side-effect profile, with no increased odds of mortality and intensive care needs,” Velji-Ibrahim said. 

When it came to the medications, “the most common side effects were gastrointestinal in nature, which included nausea, vomiting, diarrhea, and constipation,” she said.
 

Combining, Rather Than Comparing, Therapies

Following the presentation, session co-moderator Shivangi T. Kothari, MD, assistant professor of medicine and associate director of endoscopy at the University of Rochester Medical Center in New York, shared her thoughts of what the future of obesity management research might look like. 

It’s not just going to be about percentage total weight loss, she said, but about how well the effect is sustained following the intervention. 

And we might move “away from comparing one modality to another” and instead study combination therapies, “which would be ideal,” said Kothari.

This was the focus of another meta-analysis presented at ACG 2024, in which Nihal Ijaz I. Khan, MD, and colleagues compared the efficacy of endoscopic bariatric treatment alone vs its combined use with GLP-1 RAs.

The researchers identified three retrospective studies with 266 patients, of whom 143 underwent endoscopic bariatric treatment alone (either endoscopic sleeve gastroplasty or intragastric balloon) and 123 had it combined with GLP-1 RAs, specifically liraglutide. 

They reported that superior absolute weight loss was achieved in the group of patients receiving GLP-1 RAs in combination with endoscopic bariatric treatment. The standardized mean difference in body weight loss at treatment follow-up was 0.61 (P <.01). 

“Further studies are required to evaluate the safety and adverse events comparing these two treatment modalities and to discover differences between comparing the two endoscopic options to various GLP-1 receptor agonists,” Khan noted. 

Neither study had specific funding. Velji-Ibrahim and Khan reported no relevant financial relationships. Kothari reported serving as a consultant for Boston Scientific and Olympus, as well as serving as an advisory committee/board member for Castle Biosciences.

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

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In daily practice, physicians need a quick and simple way to assess whether a patient’s weight presents a health risk. For decades, the body mass index (BMI) has been used for this purpose, with calculations based on height and weight. Despite its convenience, BMI has faced increasing criticism. Recent research suggests that another metric, the body roundness index (BRI), might better gauge the health risks associated with obesity.

According to experts, BRI may more accurately identify people with high levels of visceral fat than BMI. It’s well documented that abdominal fat is strongly linked to higher risks for obesity-related diseases.
 

Studies Support BRI

Several studies have suggested that BRI could be a valuable tool for assessing health risks. In June of this year, researchers from China reported a significant U-shaped association between BRI and overall mortality in a paper published in JAMA Network Open. People with very low or very high BRI had an increased risk for death, noted Xiaoqian Zhang, MD, from Beijing University of Chinese Medicine, Beijing, China, and his colleagues.

A study published in September in the Journal of the American Heart Association showed that elevated BRI over several years was associated with an increased risk for cardiovascular diseases. “The BRI can be included as a predictive factor for cardiovascular disease incidence,” stated the authors, led by Man Yang, MD, from Nanjing Medical University in Nanjing, China.
 

Why Replace BMI?

Why is a replacement for BMI necessary? When asked by this news organization, Manfred Müller, MD, senior professor at the Institute of Human Nutrition and Food Science at the University of Kiel, in Germany, explained: “BMI was designed to provide a simple value that was as independent of body size as possible, that could detect obesity and estimate related disease risks. But scientifically, BMI has always been a very crude measure to characterize disease risks.”

Müller was part of a research group led by US mathematician Diana Thomas, PhD, who, at the time, worked at Montclair State University, Montclair, New Jersey, and now holds a position at the US Military Academy at West Point, in New York. The group developed and published the BRI in 2013.
 

BMI Classifies Bodybuilders as Obese

The researchers justified their search for a “better” anthropometric measure with two aspects of BMI that still constitute the main points of criticism of the widely used index today:

BMI incorrectly classifies individuals with significant muscle mass, like bodybuilders, as obese, as it doesn’t distinguish between fat and muscle mass. 

BMI provides no information about fat distribution in the body — whether it’s concentrated in the hips or the abdomen, for example. 

In practice, this means that a person with a normal BMI could already have prediabetes, high blood pressure, and high cholesterol, which might go undetected if no further investigations are conducted based solely on their BMI.

The BRI aims to solve this problem. As the name suggests, this index seeks to capture a person’s “roundness.” The formula for calculating BRI includes waist circumference and height but excludes body weight:

BRI = 364.2 − 365.5 × √(1 − [Waist circumference in cm/2π]²/[0.5 × Height in cm]²)

In their 2013 article, Thomas, Müller, and colleagues wrote that it still needed to be proven whether their newly developed index correlated with mortality and the risk for cardiovascular and metabolic diseases — and whether it was sufficiently better than BMI to justify the more complex calculation.
 

Could BRI Replace BMI?

Opinions differ on whether the BRI should replace the BMI. Zhang’s team concluded that the BRI needs to be validated in additional independent cohorts. If it does, it could become a practical screening tool in patient care.

Yang’s research group is optimistic about the BRI’s future: “The longitudinal trajectory of the BRI could be used as a novel indicator of cardiovascular disease risk, which provides a new possibility for cardiovascular disease prevention,” they wrote.

However, even BRI Co-creator Thomas has concerns. “Our entire medical system has been built around the BMI,” she told JAMA, referring to factors such as children’s growth charts and dosage recommendations for medications. That cannot be changed overnight.

Any anthropometric measure intended to replace BMI would need to be rigorously validated across all age groups, genders, and ethnicities. The impact of interventions such as bariatric surgery, diet, and exercise on the new measure would also need to be demonstrated.
 

Anthropometric Measures Only for Clinical Use

Even if BRI proves to be a “better” metric than BMI for patient care, Müller believes it would be no more suitable for research than BMI. “Regardless of the anthropometric measure, these are practical tools for everyday use,” he stressed.

“A high BRI, like a high BMI, is a risk factor — similar to high blood pressure, high cholesterol levels, or smoking — but it is not a disease,” he added. “In practice, as a physician, I know that a patient with a high BMI or BRI has an increased risk. I need to pay attention to that patient.”

Problems arise when indices like BMI or BRI are used in research. “These ‘invented’ anthropometric measures have no biological basis, which can harm obesity research,” Müller emphasized.

He cited the example of genetic research into obesity, which seeks to identify associations between specific genetic patterns and BMI values. “Why should weight in kilograms divided by height in meters squared be genetically determined?” he asked. “These measures are human-made constructs that have nothing to do with biology.”

Müller believes that the use of BMI has created a “gray area in obesity research” that may account for many of the “unexplained” phenomena in this field.
 

The BMI Might Be Responsible for the ‘Healthy Obese’

One such phenomenon is the much-discussed “healthy obese,” referring to individuals with a BMI over 30 who do not have high blood sugar, high blood pressure, metabolic disorders, or elevated uric acid levels. “It’s speculated that it must be due to genetic factors, but in reality, the classification is simply wrong,” Müller said.

According to Müller, research should rely on other methods to determine obesity or relevant fat. For example, to assess diabetes risk, liver fat needs to be measured through enzyme tests, ultrasonography, CT, or MRI.

Visceral fat is also important in assessing cardiometabolic risk. “In the doctor’s office, it’s acceptable to estimate this by looking at waist circumference or even BRI. But for research, that’s inadequate,” noted Müller. Direct measurement of trunk fat with dual-energy x-ray absorptiometry or visceral fat with CT or MRI is needed.

“You always have to distinguish between research and patient care. In daily practice, measures like BRI or BMI are sufficient for assessing cardiometabolic risk. But in research, they are not,” Müller explained. To accurately study the disease risks associated with obesity, one must be aware that “with BMI, you cannot create scientifically valid patient or population groups because this value is far too imprecise.”
 

This story was translated from Medscape’s German edition 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.

In daily practice, physicians need a quick and simple way to assess whether a patient’s weight presents a health risk. For decades, the body mass index (BMI) has been used for this purpose, with calculations based on height and weight. Despite its convenience, BMI has faced increasing criticism. Recent research suggests that another metric, the body roundness index (BRI), might better gauge the health risks associated with obesity.

According to experts, BRI may more accurately identify people with high levels of visceral fat than BMI. It’s well documented that abdominal fat is strongly linked to higher risks for obesity-related diseases.
 

Studies Support BRI

Several studies have suggested that BRI could be a valuable tool for assessing health risks. In June of this year, researchers from China reported a significant U-shaped association between BRI and overall mortality in a paper published in JAMA Network Open. People with very low or very high BRI had an increased risk for death, noted Xiaoqian Zhang, MD, from Beijing University of Chinese Medicine, Beijing, China, and his colleagues.

A study published in September in the Journal of the American Heart Association showed that elevated BRI over several years was associated with an increased risk for cardiovascular diseases. “The BRI can be included as a predictive factor for cardiovascular disease incidence,” stated the authors, led by Man Yang, MD, from Nanjing Medical University in Nanjing, China.
 

Why Replace BMI?

Why is a replacement for BMI necessary? When asked by this news organization, Manfred Müller, MD, senior professor at the Institute of Human Nutrition and Food Science at the University of Kiel, in Germany, explained: “BMI was designed to provide a simple value that was as independent of body size as possible, that could detect obesity and estimate related disease risks. But scientifically, BMI has always been a very crude measure to characterize disease risks.”

Müller was part of a research group led by US mathematician Diana Thomas, PhD, who, at the time, worked at Montclair State University, Montclair, New Jersey, and now holds a position at the US Military Academy at West Point, in New York. The group developed and published the BRI in 2013.
 

BMI Classifies Bodybuilders as Obese

The researchers justified their search for a “better” anthropometric measure with two aspects of BMI that still constitute the main points of criticism of the widely used index today:

BMI incorrectly classifies individuals with significant muscle mass, like bodybuilders, as obese, as it doesn’t distinguish between fat and muscle mass. 

BMI provides no information about fat distribution in the body — whether it’s concentrated in the hips or the abdomen, for example. 

In practice, this means that a person with a normal BMI could already have prediabetes, high blood pressure, and high cholesterol, which might go undetected if no further investigations are conducted based solely on their BMI.

The BRI aims to solve this problem. As the name suggests, this index seeks to capture a person’s “roundness.” The formula for calculating BRI includes waist circumference and height but excludes body weight:

BRI = 364.2 − 365.5 × √(1 − [Waist circumference in cm/2π]²/[0.5 × Height in cm]²)

In their 2013 article, Thomas, Müller, and colleagues wrote that it still needed to be proven whether their newly developed index correlated with mortality and the risk for cardiovascular and metabolic diseases — and whether it was sufficiently better than BMI to justify the more complex calculation.
 

Could BRI Replace BMI?

Opinions differ on whether the BRI should replace the BMI. Zhang’s team concluded that the BRI needs to be validated in additional independent cohorts. If it does, it could become a practical screening tool in patient care.

Yang’s research group is optimistic about the BRI’s future: “The longitudinal trajectory of the BRI could be used as a novel indicator of cardiovascular disease risk, which provides a new possibility for cardiovascular disease prevention,” they wrote.

However, even BRI Co-creator Thomas has concerns. “Our entire medical system has been built around the BMI,” she told JAMA, referring to factors such as children’s growth charts and dosage recommendations for medications. That cannot be changed overnight.

Any anthropometric measure intended to replace BMI would need to be rigorously validated across all age groups, genders, and ethnicities. The impact of interventions such as bariatric surgery, diet, and exercise on the new measure would also need to be demonstrated.
 

Anthropometric Measures Only for Clinical Use

Even if BRI proves to be a “better” metric than BMI for patient care, Müller believes it would be no more suitable for research than BMI. “Regardless of the anthropometric measure, these are practical tools for everyday use,” he stressed.

“A high BRI, like a high BMI, is a risk factor — similar to high blood pressure, high cholesterol levels, or smoking — but it is not a disease,” he added. “In practice, as a physician, I know that a patient with a high BMI or BRI has an increased risk. I need to pay attention to that patient.”

Problems arise when indices like BMI or BRI are used in research. “These ‘invented’ anthropometric measures have no biological basis, which can harm obesity research,” Müller emphasized.

He cited the example of genetic research into obesity, which seeks to identify associations between specific genetic patterns and BMI values. “Why should weight in kilograms divided by height in meters squared be genetically determined?” he asked. “These measures are human-made constructs that have nothing to do with biology.”

Müller believes that the use of BMI has created a “gray area in obesity research” that may account for many of the “unexplained” phenomena in this field.
 

The BMI Might Be Responsible for the ‘Healthy Obese’

One such phenomenon is the much-discussed “healthy obese,” referring to individuals with a BMI over 30 who do not have high blood sugar, high blood pressure, metabolic disorders, or elevated uric acid levels. “It’s speculated that it must be due to genetic factors, but in reality, the classification is simply wrong,” Müller said.

According to Müller, research should rely on other methods to determine obesity or relevant fat. For example, to assess diabetes risk, liver fat needs to be measured through enzyme tests, ultrasonography, CT, or MRI.

Visceral fat is also important in assessing cardiometabolic risk. “In the doctor’s office, it’s acceptable to estimate this by looking at waist circumference or even BRI. But for research, that’s inadequate,” noted Müller. Direct measurement of trunk fat with dual-energy x-ray absorptiometry or visceral fat with CT or MRI is needed.

“You always have to distinguish between research and patient care. In daily practice, measures like BRI or BMI are sufficient for assessing cardiometabolic risk. But in research, they are not,” Müller explained. To accurately study the disease risks associated with obesity, one must be aware that “with BMI, you cannot create scientifically valid patient or population groups because this value is far too imprecise.”
 

This story was translated from Medscape’s German edition 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.

In daily practice, physicians need a quick and simple way to assess whether a patient’s weight presents a health risk. For decades, the body mass index (BMI) has been used for this purpose, with calculations based on height and weight. Despite its convenience, BMI has faced increasing criticism. Recent research suggests that another metric, the body roundness index (BRI), might better gauge the health risks associated with obesity.

According to experts, BRI may more accurately identify people with high levels of visceral fat than BMI. It’s well documented that abdominal fat is strongly linked to higher risks for obesity-related diseases.
 

Studies Support BRI

Several studies have suggested that BRI could be a valuable tool for assessing health risks. In June of this year, researchers from China reported a significant U-shaped association between BRI and overall mortality in a paper published in JAMA Network Open. People with very low or very high BRI had an increased risk for death, noted Xiaoqian Zhang, MD, from Beijing University of Chinese Medicine, Beijing, China, and his colleagues.

A study published in September in the Journal of the American Heart Association showed that elevated BRI over several years was associated with an increased risk for cardiovascular diseases. “The BRI can be included as a predictive factor for cardiovascular disease incidence,” stated the authors, led by Man Yang, MD, from Nanjing Medical University in Nanjing, China.
 

Why Replace BMI?

Why is a replacement for BMI necessary? When asked by this news organization, Manfred Müller, MD, senior professor at the Institute of Human Nutrition and Food Science at the University of Kiel, in Germany, explained: “BMI was designed to provide a simple value that was as independent of body size as possible, that could detect obesity and estimate related disease risks. But scientifically, BMI has always been a very crude measure to characterize disease risks.”

Müller was part of a research group led by US mathematician Diana Thomas, PhD, who, at the time, worked at Montclair State University, Montclair, New Jersey, and now holds a position at the US Military Academy at West Point, in New York. The group developed and published the BRI in 2013.
 

BMI Classifies Bodybuilders as Obese

The researchers justified their search for a “better” anthropometric measure with two aspects of BMI that still constitute the main points of criticism of the widely used index today:

BMI incorrectly classifies individuals with significant muscle mass, like bodybuilders, as obese, as it doesn’t distinguish between fat and muscle mass. 

BMI provides no information about fat distribution in the body — whether it’s concentrated in the hips or the abdomen, for example. 

In practice, this means that a person with a normal BMI could already have prediabetes, high blood pressure, and high cholesterol, which might go undetected if no further investigations are conducted based solely on their BMI.

The BRI aims to solve this problem. As the name suggests, this index seeks to capture a person’s “roundness.” The formula for calculating BRI includes waist circumference and height but excludes body weight:

BRI = 364.2 − 365.5 × √(1 − [Waist circumference in cm/2π]²/[0.5 × Height in cm]²)

In their 2013 article, Thomas, Müller, and colleagues wrote that it still needed to be proven whether their newly developed index correlated with mortality and the risk for cardiovascular and metabolic diseases — and whether it was sufficiently better than BMI to justify the more complex calculation.
 

Could BRI Replace BMI?

Opinions differ on whether the BRI should replace the BMI. Zhang’s team concluded that the BRI needs to be validated in additional independent cohorts. If it does, it could become a practical screening tool in patient care.

Yang’s research group is optimistic about the BRI’s future: “The longitudinal trajectory of the BRI could be used as a novel indicator of cardiovascular disease risk, which provides a new possibility for cardiovascular disease prevention,” they wrote.

However, even BRI Co-creator Thomas has concerns. “Our entire medical system has been built around the BMI,” she told JAMA, referring to factors such as children’s growth charts and dosage recommendations for medications. That cannot be changed overnight.

Any anthropometric measure intended to replace BMI would need to be rigorously validated across all age groups, genders, and ethnicities. The impact of interventions such as bariatric surgery, diet, and exercise on the new measure would also need to be demonstrated.
 

Anthropometric Measures Only for Clinical Use

Even if BRI proves to be a “better” metric than BMI for patient care, Müller believes it would be no more suitable for research than BMI. “Regardless of the anthropometric measure, these are practical tools for everyday use,” he stressed.

“A high BRI, like a high BMI, is a risk factor — similar to high blood pressure, high cholesterol levels, or smoking — but it is not a disease,” he added. “In practice, as a physician, I know that a patient with a high BMI or BRI has an increased risk. I need to pay attention to that patient.”

Problems arise when indices like BMI or BRI are used in research. “These ‘invented’ anthropometric measures have no biological basis, which can harm obesity research,” Müller emphasized.

He cited the example of genetic research into obesity, which seeks to identify associations between specific genetic patterns and BMI values. “Why should weight in kilograms divided by height in meters squared be genetically determined?” he asked. “These measures are human-made constructs that have nothing to do with biology.”

Müller believes that the use of BMI has created a “gray area in obesity research” that may account for many of the “unexplained” phenomena in this field.
 

The BMI Might Be Responsible for the ‘Healthy Obese’

One such phenomenon is the much-discussed “healthy obese,” referring to individuals with a BMI over 30 who do not have high blood sugar, high blood pressure, metabolic disorders, or elevated uric acid levels. “It’s speculated that it must be due to genetic factors, but in reality, the classification is simply wrong,” Müller said.

According to Müller, research should rely on other methods to determine obesity or relevant fat. For example, to assess diabetes risk, liver fat needs to be measured through enzyme tests, ultrasonography, CT, or MRI.

Visceral fat is also important in assessing cardiometabolic risk. “In the doctor’s office, it’s acceptable to estimate this by looking at waist circumference or even BRI. But for research, that’s inadequate,” noted Müller. Direct measurement of trunk fat with dual-energy x-ray absorptiometry or visceral fat with CT or MRI is needed.

“You always have to distinguish between research and patient care. In daily practice, measures like BRI or BMI are sufficient for assessing cardiometabolic risk. But in research, they are not,” Müller explained. To accurately study the disease risks associated with obesity, one must be aware that “with BMI, you cannot create scientifically valid patient or population groups because this value is far too imprecise.”
 

This story was translated from Medscape’s German edition 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.