As use of the popular anti-diabetic and weight-loss drug Ozempic skyrockets, so have concerns about the medication's side effects. One such side effect is loss of "lean mass"-body weight that isn't fat-raising concerns that Ozempic could be reducing muscle mass and strength.

New research in mice suggests that muscle mass changes less than expected, but muscles may still get weaker, pointing out an urgent need for clinical studies to pin down the full effects of the popular medications.

"If we want to really help the individuals who may be losing muscle mass, then we need to know that they're actually losing muscle mass," says Katsu Funai, PhD, associate professor of nutrition and integrative physiology in the University of Utah College of Health and the senior author on the study. "We have data in mice that suggest that things are not as straightforward as they might seem."

The results are published in Cell Metabolism.

A weighty concern

Researchers found that Ozempic-induced weight loss did decrease lean mass by about 10%. Most of this lost weight wasn't from skeletal muscles but instead from other tissues like the liver, which shrunk by nearly half. The researchers emphasize that more research is needed to determine whether similar changes to organ size occur in humans-and whether those changes come with any risks.

"Loss of mass in metabolically active organs, such as the liver, is expected as part of healthy weight loss," says Ran Hee Choi, PhD, research instructor in nutrition and integrative physiology at U of U Health and co-first author on the study. In both mice and humans, weight gain and loss can affect the size of organs like the liver without affecting their function.

It's unlikely that the observed lean mass loss represents a serious adverse effect."

Takuya Karasawa, PhD, postdoctoral researcher in the U of U Molecular Medicine Program and co-first author on the study

Some skeletal muscles did shrink as the mice lost weight-on average, by about 6%, not enough to explain the overall loss in lean mass. Other muscles stayed the same size.

Some of this loss in muscle mass is a return to baseline, the researchers say. Gains in fat also tend to lead to gains in skeletal muscle, since the body must do more work to move around. So loss of fat can lead to loss of muscle without affecting overall quality of life.

Size isn't strength

Interestingly, when the researchers tested the amount of force the mice's muscles could exert, they found that, for some muscles, strength decreased as the mice lost weight, even when the size of the muscle stayed roughly the same. For other muscles, strength was unchanged. It's unknown how weight loss drugs affect this balance in people, the researchers say.

A potential loss of strength when taking Ozempic may be of particular concern for adults over the age of 60, who are at higher baseline risk for muscle loss and reduced mobility. "The loss of physical function is a strong predictor of not just quality of life but longevity," Funai adds.

Clinical trials are needed

The researchers caution against extrapolating their results directly into humans, because mice and humans gain and lose weight in different ways. In people, obesity is associated with lower physical activity, but mice don't tend to become less active when they gain weight. And the mice in this study became overweight because they ate a high-fat diet, whereas people become overweight for a wide variety of reasons that include genetics, diet, sleeping patterns, and age.

Instead of drawing a one-to-one parallel with humans, the researchers say their results emphasize the need for more clinical studies. "There remains a significant need for validation in humans, especially concerning muscle strength," Karasawa says.

Funai adds that clinical trials should check for changes in muscle strength not just for Ozempic but also future weight-loss drugs. "There are many additional weight loss drugs that are in clinical trials and coming out in the next three to five years," Funai says. "But with all those clinical trials, if they're interested in measuring lean mass loss, they need to consider physical function."

"Our findings are really interesting, but this is a preclinical model," he adds. "We need these data in people."

The results are published in Cell Metabolism as "Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice."

This study was supported by the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers DK107397 and DK127979), the National Institute of General Medical Sciences (grant number GM144613), the National Institute on Aging (grant numbers AG074535, AG065993, AG076075, and AG086328), and the National Cancer Institute (grant number CA286584), as well as by the Grant-in-aid for Japan Society for Promotion of Science Fellows (grant number 24KJ2039). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.