Lose muscle with RA GLP-1? There may be a cure for this

NEW ORLEANS Developmental drugs would preserve muscle mass and increase fat loss when used in combination with glucagon-like peptide 1 (GLP-1) receptor agonists taken for weight loss.

As medications such as semaglutide (Wegovy) and the glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 dual agonist tirzepatide (Zepbound) are producing unprecedented rates of weight loss in increasing numbers of people, concern has been raised about the percentage of lost. weight, approximately 30%-50%, which is beneficial for lean body mass versus fat mass. While some loss of muscle mass is expected with any rapid overall weight loss, it is not clear what long-term effect it may have on physical function, bone density, and life expectancy, particularly in older adults with sarcopenic obesity, who are at risk for muscle atrophy. and weakness.

Several drugs in various stages of development are intended to preserve or build muscle mass and increase fat loss when used in combination with one of these weight loss medications. Trials now underway will need to show improved function, not just muscle growth, and also establish safety, experts said. Medscape Medical News.

One such agent is Veru Inc.’s selective oral androgen receptor modulator (SARM) enobosarm, currently in a phase 2b clinical trial for use with semaglutide in people who are at risk for muscle atrophy and weakness.

Also in a phase 2b trial for use with semaglutide is the intravenous antimyostatin agent bimagrumab. In July 2023, Eli Lilly bought Versanis, the company that was developing that drug. Earlier phase 2 data on bimagrumab alone versus placebo in people with obesity and type 2 diabetes showed improvement in muscle mass with greater fat loss, but also produced a signal for pancreatitis that warrants further evaluation.

Scholar Rock’s intravenous antimyostatin apitegromab is also now in a phase 2 trial, and Biohaven Pharmaceuticals is expected to start a phase 2 trial of the subcutaneous antimyostatin taldefgrobep alfa later this year.

Most of these and other similar agents have also been under investigation for use in one or more other muscle-wasting conditions, including spinal muscular atrophy, sarcopenia, and cancer.

“Wouldn’t it be great if there was a drug that created muscle mass?”

Data presented in two delayed posters at the annual meeting of the American Society of Clinical Endocrinology held May 9-11, 2024, laid the groundwork for subsequent phase 2 studies of enobosarm in combination with a GLP-1 RA. One showed increases in total lean mass and decreases in total fat mass with 3 mg enobosarm for 14 days compared with placebo in both healthy young and older men (60 years), with the greatest benefit observed in men older women who had lower lean mass. and higher fat mass at the base.

The other was a post hoc analysis of a phase 3 clinical trial of oral enobosarm 3 mg/d for the treatment of muscle wasting in advanced lung cancer. Here, a subgroup of participants who were 60 years old and obese also showed reductions in fat mass and maintenance of lean body mass with the drug compared to placebo, leading to “high-quality weight loss.”

Endocrinologist Adrian Dobs, MD, professor of medicine and oncology at Johns Hopkins University School of Medicine, Baltimore, an investigator in both Veru-sponsored studies, said Medscape Medical News, “The wishful thinking about these drugs has been around for a long time, especially in the cancer population or a lean population. The hope was, wouldn’t it be great if there was a drug that created muscle mass? Of course, we we know going to the gym does that, but the research on some drugs was the point that this class of drugs was thought to have a muscle building effect, an anabolic effect without an androgenic effect that causes masculinization.

The problem with those studies in terms of regulatory approval, Dobs said, was defining endpoints. “To [US Food and Drug Administration] is very interested in functional status. You can tell that there is an increase in muscle mass. But to take that step and show that a person can walk up, carry groceries and be more functionally capable is hard to prove.”

And she noted that bringing frail elderly people into clinical trials is not easy. But now, “this is an interesting new avenue of scientific research, looking at this particular population that is losing weight because of GLP-1 [agonists]. Now we’re dealing with a large number of patients who are easy to identify because they’re taking those medications.”

“We must also focus on ‘first, do no harm'”

Asked for comment, Angela Fitch, MD, associate director of the Weight Center at Massachusetts General Hospital, Boston, expressed caution. “We have to remember that it’s not all about muscle mass. Maintaining muscle mass with weight loss is obviously important, but even today, with 30% of weight loss coming from lean mass, that’s not the same with muscle, there are major benefits to fat loss, including reduced cardiovascular and cancer risk, increased longevity, and remission of diabetes.”

Additionally, Fitch pointed out, SARMs have been linked to increased cardiovascular events and blood clots.

“So we also have to focus on ‘first, do no harm.’ A lot of these muscle-boosting drugs have been associated with increased risk of other things. So it’s going to take a lot of time and testing to do sure they are safe While I am supportive of research to weigh these risks versus benefits, we need to be aware of the risks and recognize that in most cases of weight loss in people with obesity the loss of lean mass is acceptable and their benefits. Losing fat outweighs the risks of losing fat, especially if people do resistance exercise and maintain strength.”

“Wherever GLP-1s go, we go”

In an investor call held on May 8, 2024, Veru Chairman, CEO and President Mitchell Steiner, MD, said that the current phase 2b study of enobosarm with semaglutide is only looking at people age 60 to maximize the functional outcome benefit. But Phase 3, he predicts, will be “all comers, for sure. And then we’ll put in special populations.” The thinking, he said, is “Wherever GLP-1s go, we go.”

Fitch has served on advisory boards for Jenny Craig, Novo Nordisk, Eli Lily, Sidekick Health, and Vivus. Dobs had no discovery beyond doing research on Veru.

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She’s in X @MiriamETucker.

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Image Source : www.medscape.com

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