Is muscle loss in GLP-1 receptor agonist-induced weight loss a real concern or much ado about nothing?

This was the topic of a lively debate held at the American Diabetes Association (ADA) 2026 Scientific Sessions.

The majority of weight loss with GLP-1s is fat mass, not fat-free mass, and there is no evidence that weight loss induced by GLP-1 drugs causes frailty or sarcopenia, argued Samuel Klein, MD, the William H. Danforth Professor of Medicine and Nutritional Science and director of the Weight Management Program at Washington University School of Medicine in St. Louis.

Supporting the other side was Eric Ravussin, PhD, the Douglas L. Gordon Chair in Diabetes and Metabolism and director of the Pennington-Louisiana Nutrition Obesity Research Center at Louisiana State University in Baton Rouge, who noted that while there is little evidence for harm due to loss of muscle mass in otherwise healthy individuals, there is concern about high-risk groups.

Moreover, Ravussin pointed out, few studies actually measure muscle mass directly, and the measures that are typically used, such as DEXA, don’t closely correlate with muscle mass.

Studies Don’t Support Damaging Muscle Loss

Klein began by explaining that the body is composed of fat and fat-free mass and that “lean body mass” is fat-free mass without bone, consisting of skeletal muscle, organs, and water. About 40% and 50% of fat-free mass is skeletal muscle in women and men, respectively.

Adipose tissue also contains fat-free mass, as about 20% of it is fluid and protein. “So when you lose adipose tissue mass, you also decrease your fat-free mass and lean body mass, which has to be considered in these estimates and evaluation of the reduction in lean body mass that occurs with weight loss,” said Klein.

Among all the studies of GLP-1 therapies in which participants have lost at least 15% of their body weight, the range of lean body mass as a contribution to total weight loss ranged from about 25% with tirzepatide to about 39% with semaglutide. Those represent a normal range for any type of weight loss, he noted.

Novo Nordisk’s STEP 1 trial of semaglutide in people with overweight or obesity caused concern because of the reported 39% loss of lean body mass; however, a subsequent study corrected the weight loss in the major GLP-1 trials by subtracting the “obligatory” fat-free mass that was lost from adipose tissue, and the 39% of fat-free mass lost in the semaglutide trial was reduced to just 30% (from 6.9 kg to 5.1 kg).

What’s more, in the appendix of that study, the subjective assessment of physical function and physical performance showed improvements in both despite the large percentage of lean body mass from total body mass lost, Klein said.

In a phase 3 trial of CagriSema (a combination of the amylin analogue cagrilintide with semaglutide), the proportion of total weight loss attributed to lean body mass lost was 33%. Nonetheless, the people who had the worst subjective physical function and were the frailest to begin with had the greatest improvements in physical function with the drug, Klein pointed out.

The evidence also doesn’t support a unique effect of GLP-1 drugs on body composition compared with other methods of weight loss. In a meta-analysis of studies of surgical weight loss in which people lost between 19% and 35% of their body weight, the percent weight loss from fat ranged from 56% to 88%, and percent weight loss from fat-free mass from 12% to 44%.

“There was a huge range. This means that you will never be able to show any therapy really has a unique effect on the composition of weight loss because the normal range is so large,” said Klein.

“There’s no evidence at all that GLP-1 therapy gives unique decreases in lean body mass compared to any other weight-loss therapy,” he added, noting that weight loss tends to have a significant and largely positive impact on muscle quality, defined in different ways including intermuscular adipose tissue, intramuscular triglyceride, skeletal muscle capillaries, and glucose rate of disposal during insulin infusion (a measure of muscle insulin sensitivity).

In another study of gastric bypass weight-loss surgery, relative muscle strength and physical function improved despite declines in lean mass and absolute grip strength.

And among 93 older adults with obesity, a combination of weight loss and exercise provided greater improvement in physical function than either intervention alone. The group randomly assigned to diet alone vs exercise along with diet had a 33% vs just 21% proportion of weight loss from lean body mass despite similar weight loss. “Exercise intervention is a critical component of the management of obesity,” Klein said.

At least three studies, including one from participants in the TV show The Biggest Loser, showed that when weight is regained, the composition is similar to that of the weight previously lost, with no preferential increase in fat mass compared to lean body mass.

Two other studies, including the 8-year Look AHEAD trial in type 2 diabetes (T2D), did show a preferential increase in fat mass when weight was regained after weight loss. However, Klein said, “I think that’s because [the participants were] getting older. As they’re getting older, they’re losing lean body mass, and there’s no difference in lean body mass between the two groups at the end of 8 years.”

Muscle Loss Maladaptive in High-Risk Individuals

Ravussin agreed that some loss of muscle with GLP-1-associated weight loss is adaptive, or a normal and acceptable physiologic response rather than a maladaptive, or harmful one. However, he added, “the problem is not the typical participant with obesity in phase 3 studies.”

“We must worry about at-risk populations,” including older patients, women in menopause, and those with sarcopenic obesity in general, said Ravussin. “Here, we have a problem if we create large weight loss.”

Loss of bone and muscle mass naturally accelerates in people past the age of 40 years, he explained. Past age 60, adipogenesis increases and bone resorption surpasses bone formation. “This is important if you start treating with GLP-1 at this point as you may have a problem with excessive loss of muscle.”

Movement, balance, posture, and strength “can all be altered if you have too much muscle loss,” Ravussin said. Indeed, loss of lean mass due to GLP-1 use could lead to osteoporosis, frailty, and fractures from falling.

Caution is also needed for other groups of individuals, including those whose weight is cycling, those with metabolic dysfunction-associated steatohepatitis, obstructive sleep apnea, cardiovascular disease, or a BMI < 30.

DEXA Scans Fall Short

Most studies that investigate body composition use DEXA scans, Ravussin pointed out.

“It’s important to realize that DEXA does not measure skeletal muscle mass” but fat-free mass, which is made up of bone and skeletal muscle, along with organs, water, and connective tissue, he said. “Some have attempted to use the appendicular lean muscle as an index of skeletal muscle mass. I think [that’s] not true either at this point.”

An emerging method to directly measure skeletal muscle mass is the D₃-creatine dilution, which does not correlate entirely with the DEXA fat-free mass values. Although MRI and CT scans do assess total and regional skeletal mass volume, only D₃Cr assesses total skeletal muscle mass. The cost of D₃Cr is lower than that of MRI and CT, and there is no exposure to ionizing radiation that occurs with CT scans. However, at this time, access to D₃Cr has limited clinical availability outside of research settings, Ravussin noted.

A large study of older men showed that when assessed by D₃Cr, reduced muscle mass was highly associated with decreased performance and increased risk for adverse outcomes, whereas DEXA appendicular lean mass was not.

And in another study using D₃Cr to directly assess muscle mass, lower muscle mass was correlated with higher mortality after multiple adjustments for confounders.

Low muscle mass is strongly related to the risk for disability, hip fracture, T2D, and mortality, and loss of muscle mass with age is associated with reduced strength and habitual walking speed at all ages. A recent review article described the dilemma faced in treating sarcopenic obesity — both overweight/obesity and weight loss leading to frailty are associated with diminished physical function.

“We have to realize the consequence of weight loss in these older people when we prescribe GLP-1s,” said Ravussin.

When prescribing GLP-1s to older adults, he advised first assessing physical function with questionnaires, such as the SF-36v2 or PROMIS; direct testing such as the Short Physical Performance Battery, gait speed, Timed Up and Go, or stair climb; and assessments of balance with tools such as the Berg Balance Scale or the Y-Balance. “Balance is very important for older people. There are some good tests of balance, and I think they should be implemented when you target older people with this kind of massive weight loss,” he said.

Among tests of muscular strength, he recommended the 6-minute walk, the handgrip strength test, the knee extensor strength, and the chair sit-to-stand test.

Weight cycling is another concern because each episode of weight regain can accelerate fat recovery and predispose the patient to sarcopenic obesity.

“In at-risk individuals, we need interventions to reduce the loss of muscle mass and function with GLP-1 treatment,” said Ravussin. Exercise training, particularly with resistance exercise, can help maintain muscle mass and function/strength in people prescribed GLP-1s, but only 20% of patients are prescribed exercise, and even when they are, adherence is poor.

Exercise should be emphasized more in clinical practice because it promotes fat oxidation and may increase short-term resting metabolic rate, Ravussin urged.

Ensuring sufficient dietary protein intake is also key, he said.

Pharmacologic approaches such as bimagrumab and enobosarm are in development to protect against the loss of fat-free mass with GLP-1 agonists.

Klein reported being on scientific advisory boards for AbbVie, Verdiva Bio, 89bio, and Merck. Ravussin reported consulting for Energesis Pharmaceuticals, Eli Lilly USA, Merck, Amway, Novo Nordisk, Altimmune, AbbVie, Amgen Inc., OrbiMed, and Boehringer Ingelheim.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and diaTribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.