Don’t Worry About Muscle Loss With GLP-1 Inhibitors, Viewpoint Asserts

Patients taking glucagon-like peptide-1 (GLP-1) receptor agonists—and the physicians who treat them—should not be worried about the muscle loss that occurs alongside what’s often rapid weight loss with these medications, according to experts who reviewed the existing data.

The popularity of GLP-1 drugs has grown exponentially, with patients reporting rapidly dropping up to 25% of their body weight amid known cardiovascular benefits.

Muscle loss always accounts for a certain proportion of weight loss, no matter the method, but senior author Samuel Klein, MD (Washington University School of Medicine in St. Louis, MO), told TCTMD that some clinicians have been concerned that patients might be harmed by losing too much muscle while attempting to get rid of body fat.

“Physical function and mobility are important aspects for quality of life, and so if you assume that losing weight by any kind of therapy would have adverse effects on your functional ability, that would be a major negative,” he said. Although some pharmaceutical companies have begun exploring new drugs to prevent this phenomenon, Klein argued that these attempts are “looking for a problem that doesn't seem to exist.”

In their viewpoint, published online last week in JAMA, Caterina Conte, MD, PhD (San Raffaele Roma Open University, Italy), Kevin D. Hall, PhD (National Institute of Diabetes and Digestive Kidney Diseases, Bethesda, MD), and Klein outline currently available data regarding the ratio of fat-free mass (FFM) to skeletal muscle mass (SMM) and how it is related to total weight loss in patients who lose weight quickly.

Even though these metrics are linked, they write, “the decrease in FFM/SMM in relation to baseline is usually small and the relative reduction in FFM/SMM is less than the relative reduction in fat mass, resulting in an improvement in physical function.”

Because of this, the authors argue, “the recent concern that marked weight loss induced by GLP-1–based anti-obesity medications can cause physical frailty or sarcopenia is not supported by data.”

‘Hypothetical’ Concerns

Michael Albert, MD (Accomplish Health and University of Oklahoma Health Sciences Center, Oklahoma City), who runs a telehealth obesity clinic, told TCTMD that concern over muscle loss with GLP-1 inhibitors “has always been more hypothetical,” given that the worry preceded any confirmatory data.

This JAMA viewpoint effectively frames that “the existing evidence does not suggest a concern that these medications make individuals more frail,” he said. “People become physically more functional. And while I think the data is early and we should study this directly, it doesn't suggest there is a major cause for concern.”

Weight loss is very therapeutic. Samuel Klein

Michael Blaha, MD (Johns Hopkins University, Baltimore, MD), agreed that fears over this issue have played out more on social media than in the clinic. “I do talk to [my patients] about muscle preservation, but they usually don't come to me with these concerns,” he told TCTMD. “They know they need to lose weight, and I will bring it up about preserving muscle mass and preserving fat free mass the best we can. But that's not usually a concern of theirs.”

Regardless, Blaha added, for his patients taking GLP-1 inhibitors, “I always try to frame it in the context of lifestyle and say that of course the medicine doesn't do all the work.” He encourages them to participate in strength training and increase their protein intake to better preserve their muscle mass, acknowledging that “you always lose muscle mass when you lose weight.”

Anecdotally, Blaha said he’s never had an issue with excess muscle loss in his patients on these drugs, and that if anything his patients have generally reported feeling like they have more energy and strength.

Room for Some Extra Caution

There are two cohorts of patients, however, for whom more caution is warranted when prescribing GLP-1 inhibitors, Albert said.

“For elderly patients, because they've already lost muscle and bone throughout their lives and are at risk of issues like sarcopenia, frailty, and osteoporosis, we absolutely are concerned and we want to make sure that they're being safe and we're not doing things like causing too much rapid weight loss that might jeopardize their health,” he explained.

Secondly, because there aren’t not enough outcomes data on those with weight loss greater than 25%, Albert said he takes extra steps—body composition scanning and blood work, for example—to guide treatment decisions. “How lean is too lean?” he asked. “And when do we start to potentially bring more cause and concern into the equation than actually benefiting them?”

Blaha agreed that he is more “tentative” of encouraging major weight loss in the elderly or others who would be at risk for fractures or who already can’t exercise for any reason. “I'm still getting accustomed to using the therapy in these patients, because I'm a little concerned about muscle mass [and bone density] loss,” he said.

For elderly patients, because they've already lost muscle and bone throughout their lives and are at risk of issues like sarcopenia, frailty, and osteoporosis, we absolutely are concerned and we want to make sure that they're being safe. Michael Albert

Ongoing research into activin type II receptor (ActRII) inhibitors may one day lead to drugs that can preserve muscle mass during weight loss. But Blaha said he is “skeptical,” adding that these medications potentially might be “abused or used in the wrong setting.”

“Any sort of experimental science is interesting to follow, but I just don't see a big need for it right now in my practice,” he said.

Ultimately, Klein said the data all point to the fact that “weight loss is very therapeutic.”

“There doesn't seem to be a harmful effect of losing too much muscle or fat-free mass when you lose weight by either diet therapy, bariatric surgery, or GLP-1 agonist therapy,” he concluded.