Muscle loss with Ozempic® and similar drugs

What’s the risk to people with muscular dystrophy?

by Rich Holmes, Sandwich, Massachusetts

Heard about Ozempic, Mounjaro®, and related drugs and wonder if one might help you lose weight?

That’s a decision you should make with your doctor, but be aware of three points:

• Weight loss typically includes both fat and some muscle.
• How much muscle a person with FSHD might lose when taking one of these drugs isn’t known.
• The severity of your FSHD, your age, and your general health should be considered.

The weight-loss drugs known as GLP-1 agonists include Ozempic and Wegovy® (both semaglutide), and Mounjaro (tirzepatide). They work like a hormone in your body named GLP-1 (glucagon-like peptide 1), one of a group of gut peptides called incretins that are secreted when you eat. GLP-1 agonists (drugs that stimulate GLP-1) cause the pancreas to make insulin and slow stomach emptying, as well as increasing muscle uptake of glucose and reducing liver creation of glucose, according to a January 2023 article in the National Library of Medicine. They’ve been used to treat type 2 diabetes and obesity, and are being eyed for other uses.

For a typical overweight or obese person who loses weight by dieting, about 20% to 30% of the loss may be lean tissue, according to a May 2017 article in Advances in Nutrition. But what about weight loss via one of these GLP-1 agonists?

“I think as of now data are really limited regarding the GLP-1 agonists and effects on muscle wasting in muscular dystrophy or FSHD,” wrote Jeffrey Statland, MD, in a recent email. Dr. Statland is a professor of neurology and co-director of MDA clinics at the University of Kansas Medical Center in Lawrence. “There are articles suggesting some portion of the weight loss is lean muscle mass, likely due to the rapid weight loss, which may be exaggerated in people who already have a low lean muscle mass (e.g., aging or muscular dystrophy).”

Clinical trials have shown that these drugs can cause muscle loss:

• A 68-week-long trial of semaglutide involving 140 par-ticipants found each had an average loss of 23 pounds of fat and 15 pounds of lean muscle, according to a September 2023 Fortune Well article.
• A clinical trial involving Eli Lilly, the maker of Mounjaro (tirzepatide), reported in October 2023 that MRIs of 296 participants with type 2 diabetes not well controlled with metformin found that those given tirzepatide had more fat-free muscle loss but less fat infiltration of muscles than those given insulin.

Eli Lilly has pursued limiting muscle loss from these drugs by studying a drug called bimagrumab, an antibody that promotes muscle growth. Last August, the pharmaceutical giant announced it had completed acquisition of Versanis Bio, the company that makes bimagrumab. According to Eli Lilly’s statement, the drug was being tested alone and with semaglutide in overweight and obese people, and bimagrumab and related drugs were being considered for use in combination with tirzepatide and other gut hormones.

Fellow drug makers are taking similar steps, according to a March article in Nature Biotechnology. Regeneron is studying employing two of its antibodies with Ozempic, made by Novo Nordisk. Clinical trials start this year on drugs to target myostatin, a substance in our bodies that restricts muscle growth and other biological pathways, and to increase muscle stem cells. Drug developers hope to cash in on potentially treating both obesity and age-related muscle loss, known as sarcopenia.

Interestingly, a drug targeting myostatin is currently in a Phase 1/2 clinical trial for FSHD. It is intended to help slow or reverse muscle loss in the disease. (See trial update.)

GLP-1 agonists and age-related muscle loss

While we may not understand how these drugs affect people with FSHD, some research has been done on GLP-1 agonists and age-related muscle loss. This condition raises the likelihood of developing type 2 diabetes, as muscle uses most of the body’s glucose (sugar), and significant muscle loss increases the risk of insulin resistance, according to a review of research on diabetes drugs and sarcopenia published in November 2021 in World Journal of Clinical Cases. Obese older people with type 2 diabetes experience more sarcopenia than those without diabetes.

The review found mixed results for GLP-1 agonists. On the positive side, it found two drugs countered muscle atrophy in mice. One, dulaglutide, restored muscle mass and function in mice used as a model for Duchenne muscular dystrophy, a finding originally reported in an August 2019 article in Journal of Cachexia, Sarcopenia and Muscle.

A second drug, exendin-4, increased muscle mass and function in mice with muscle atrophy induced by dexamethasone, a glucocorticoid. The review also found that in a very small study, nine obese diabetic patients treated for 24 weeks with liraglutide, another GLP-1 agonist, lost fat while their skeletal muscle mass apparently stabilized.

On the negative side, the review found a six-month treatment of dulaglutide with insulin in diabetics receiving dialysis shrank both fat and muscle mass. The review concluded it is uncertain whether GLP-1 drugs are beneficial or not regarding muscle mass and strength.

A November 2023 article in Drug Discovery & Development reported some well-designed studies have shown that the weight loss from these drugs includes a substantial amount of lean tissue – ranging from 20% to 50% of the total number of pounds shed. According to the article, these results are similar to those from weight loss through dieting or bariatric surgery. It noted that a review of research indicates these drugs may improve body composition and possibly offer some protection against muscle wasting.

Comments from FSHD experts

Physicians familiar with FSHD who were contacted for this story haven’t yet seen many patients taking one of these drugs. Some said exercise might help limit drug-related muscle loss. While cautious about the risk, they recognized the considerable benefits weight loss could bring.

“The subject has come up in regard to other patients with muscular dystrophy. There is not much evidence that these meds lead to increased weakness. No good, large study has been done, of course (e.g., a randomized controlled trial of GLP-1 vs. no such treatment in patients with dystrophy). So now it is anecdotal. But from my limited experience, I have not seen any significant trend to worsening weakness,” wrote Anthony A. Amato, MD, neurology department vice chair and distinguished chair in neurology at Brigham and Women’s Hospital’s Neurosciences Center in Boston.

“I follow a couple of patients taking these; one feels the weight loss has contributed significantly to improved mobility. But I agree that muscle loss in those more severely affected could be a big concern,” wrote Lawrence J. Hayward, MD PhD, professor of neurology and director of the Neuromuscular Division and FSHD Clinic at the UMass Chan Medical School in Worcester, Massachusetts. Dr. Hayward suggested that, in light of the lack of research specific to people with FSHD, those who take these drugs should be closely followed by their doctors. “Balancing weight loss with increasing activity as tolerated may be helpful to maintain muscle mass,” he added.

“Looks like GLP-1 agonists are very effective in lowering insulin levels and reducing fat. There is potential concern the drug can cause loss of bone density and loss of muscle mass (sarcopenia). However, studies in mice suggest that GLP-1 agonists may actually increase muscle mass,” wrote Rabi N. Tawil, MD, co-director (until his recent retirement) of the MDA Neuromuscular Disease Clinic at the University of Rochester. According to Dr. Tawil, a clinic patient who reported taking a GLP-1 agonist for six months experienced significant weight loss and improved motor function. “Whether the improved function is due to loss of weight or stronger muscles remains to be seen,” he added.

Dr. Statland urged patients to discuss the pros and cons with their physician, “weighing the risk of rapid weight loss and loss of lean mass against the functional improvement people may experience with weight loss and increased mobility. “I agree certainly a protein-rich diet and aerobic exercise likely will help to some degree mitigate this – although there have not been studies verifying this,” he continued.

“My recommendation is if weight loss is a goal and someone has had difficulty with weight loss using diet and exercise – they could try the drugs. But they should develop a plan to monitor with their physician or neurologist: A physical regimen with an activity they can monitor while taking the drug, maintain a high-protein diet, and if they feel they notice muscle wasting, let their doctor know.

“In the meantime, on the medical side, we are trying to collect the experience of our patients taking this class of medication and follow their outcomes,” Dr. Statland wrote. “Hopefully we will have more detailed guidance in the not-too-distant future.”