Addressing muscle loss associated with GLP-1 medication use

April 02, 2024 - Glucagon-like peptide-1 (GLP-1) receptor agonists — also known as GLP-1 drugs — have gained a significant amount of attention in recent years because of their utility in managing type 2 diabetes (T2D) and, even more so, in weight management for overweight or obese adults. Despite the scientifically proven benefits of these drugs, there are many challenges posed by their use.

Among these challenges is muscle loss. For example, a study on semaglutide in the New England Journal of Medicine showed a decline in lean mass in patients taking a weekly subcutaneous injection of the drug.

“Anywhere between 20% and 40% of the total weight [loss can] come from losing muscle mass,” Jay Backstrom, MD, MPH, President and CEO of Scholar Rock, explained in an interview with PharmaNewsIntelligence. “Inherently, that is problematic, [considering] the role that muscle plays.”

Retaining muscle mass is beneficial for multiple reasons. It improves bone health and metabolic function, among other factors. According to the National Institute of Arthritis and Musculoskeletal and Skin Disease, a part of the NIH, muscle is critical for multiple bodily functions. Beyond strengthening the body and providing more effortless movement, skeletal muscle helps with posture and balance. Smooth muscle in the body plays an essential role in the digestive system, and cardiac muscle helps ensure adequate and proper blood flow.

Although losing muscle mass is a natural byproduct of aging, for certain patients, the risk of losing muscle mass is enough of a concern that it contraindicates the use of weight-loss drugs. For example, patients 65 and older who are already at risk of muscle loss may hesitate to begin GLP-1 medications because of the risk of muscle loss.

Myostatin

“Scholar rock was really founded on our ability to understand how to selectively and safely target a family of growth factors, one of which is myostatin, which is the key regulator of muscle,” noted Backstrom.

He said that myostatin is considered the master regulator of muscle mass, inhibiting its growth. In pre-clinical and clinical studies, blocking myostatin helps increase muscle mass and function. In other contexts, aside from weight loss, such as spinal muscular atrophy, researchers have proven the utility of blocking myostatin to increase muscle mass. Multiple studies, including a 2021 mouse study published in Nutrients, have demonstrated that blocking myostatin is beneficial for building muscle mass.

Understanding this connection, Scholar Rock is exploring how myostatin inhibitors that enhance muscle can work alongside weight loss drugs, such as GLP-1 drugs, that can cause muscle loss.

Enhancing the Impact of GLP-1 Drugs

“When we look at the models that everyone uses to understand the effect on weight, we're seeing that we have the potential to actually enhance the effects of the GLP-1 receptor agonists nicely, not just preserving and maintaining that muscle mass, but because muscle plays such a role in metabolism,” Backstrom continued. “We believe that we can enhance the profile of the GLP-1 receptor agonist by bringing those good effective outcomes from targeting the muscle, enhancing muscle, and its effect on metabolism.”

Muscle impacts how glucose is metabolized and increases insulin sensitivity, prompting an additive effect when combined with GLP-1 medications. Backstrom explained that muscle matters in healthy, sustainable weight loss management.

“If we restore and maintain that muscle, it'll do its job. It'll uptake glucose; it'll protect against insulin resistance. And because muscle is the major energy consumer, basal metabolic rate will be enhanced,” he said. “It's all about energy metabolism or energy balance that also might be able to reduce the amount of GLP-1 receptor agonist that [a patient] needs.”

GLP-1 drugs are a relatively new class of medications, which means there is limited understanding of their long-term effects; however, the short-term effects include gastrointestinal upset, which is dose-dependent. Higher doses correlate with an increased probability of experiencing side effects, but by optimizing weight loss with a myostatin inhibitor, patients may be able to take lower GLP-1 doses.

Proof-of-Concept Study

Scholar Rock is launching a proof-of-concept study to test this theory. Backstrom explained that the proof-of-concept study on the drug is rooted in the company’s previous work on spinal muscular atrophy (SMA). However, this study is focused on whether they can enhance or preserve muscle for patients on a GLP-1 drug, which has been known to reduce muscle mass. Data from the clinical trial are expected in 2025 and will be used to inform further clinical development of SRK-439, a novel investigational myostatin inhibitor for the treatment of obesity. 

Apitegromab targets and selectively inhibits myostatin, allowing patients to build muscle, as the company has proven in its SMA studies. These analyses have also deemed the medication as tolerable.

With previous studies that evaluated the drug in other disease areas, the company launched the proof-of-concept study to assess its impact on obesity for patients using GLP-1 drugs.

“We're applying apitegromab map into a proof-of-concept study in obesity in combination with the GLP-1 receptor agonist. For five years, we've been deeply trying to understand the role, and we've shown, again in our nonclinical work, that sets the stage for the clinical studies, that when we combine [apitegromab] with semaglutide in these clinical models, we preserve lean muscle and enhance glucose metabolism.”

“Our key question for this proof of concept is, does our very selective and specific strategy do that?” Backstrom continued. “The way to show that, the gold standard, is something called DEXA scans. It was introduced to measure bone mineral density.”

Using DEXA scans in the proof-of-concept study will help Scholar Rock quantify the amount of fat loss and muscle loss, which will be one of the study’s primary endpoints.

The other insight the company hopes to gain from this study is an understanding of the benefit–risk of this drug.

“We’ve had highly effective weight loss therapies over the years. The problem is that the risks of those effective therapies outweighed the benefits,” noted Backstrom. For example, amphetamines also aid in weight loss, but they come with intense risks.

While they hypothesize that their myostatin targeting is selective and will not bring about additional toxicities, Scholar Rock hopes the study supports that.

“Safety will be important in our proof of concept because it'll be a randomized study, and we'll be able to look at the profile for the GL-1s. Then we'll be able to show our program side by side, and it's our view from our current data that we will not bring any additional problematic issues,” Backstrom added. “Tolerability will be just what you'd expect. And if anything, if we [expect] an additive effect.”

As the study progresses, the company will continue to monitor how apitegromab works alongside GLP-1 drugs to maintain muscle mass during weight loss.

Editor's Note: This article has been edited to clarify the study's role in SRK-439 research.