New findings suggest a simple supplement could safeguard lean mass during weight-loss drug therapy
A University of Alberta study points to a promising way to mitigate a tricky consequence of popular weight-loss medications: the loss of lean muscle and even heart muscle when using semaglutide-based treatments such as Ozempic, Wegovy, and Rybelsus. Researchers explored whether a ketone ester supplement could “fine-tune” the therapy to shed fat while protecting muscle tissue.
Why muscle loss matters in weight-loss therapies
Semaglutide, the active ingredient behind many modern obesity drugs, is effective at reducing body weight largely by suppressing appetite and altering metabolism. But early animal studies revealed a concerning pattern: skeletal muscle mass declines during treatment, and the heart also showed signs of muscle loss. While some muscle loss is expected with weight reduction, the team worried that disproportionate loss could have long-term health implications beyond the immediate weight change.
“The question is, if you have a healthy heart, what are the long-term effects of it shrinking more than it should?” said Jason Dyck, a pediatrics professor and Canada Research Chair in Molecular Medicine. The team sought strategies to preserve lean mass without compromising fat loss.
The ketone strategy: how it works
Ketones are a natural energy source produced by the liver when carbohydrate intake is low. They are known to help preserve skeletal muscle during metabolic stress and are now being tested as a protective measure for patients on semaglutide. In the follow-up study, researchers paired semaglutide with a ketone ester—an easily metabolized drinkable supplement that raises blood ketone levels, mirroring the body’s response during fasting or a ketogenic diet.
Robust results in animal models
In obese mice, the semaglutide-plus-ketone ester combination produced striking results. Not only did the group avoid more severe total body weight loss, but deeper analysis showed that the fat lost with treatment was the same as with semaglutide alone—only now the ketones shielded the muscles from wasting. In other words, the body could shed fat while retaining skeletal muscle and crucial heart tissue.
Mechanism: mitochondria as the key
The team’s insight centers on mitochondria, the cellular powerhouses responsible for energy production in muscles. Semaglutide appears to dampen mitochondrial function, which can drive the body to break down muscle for fuel. Ketones, by contrast, seem to support mitochondrial health and activity, helping muscles keep their energy supply intact during drug-induced weight loss.
“When you give animal models ketones, it protects the mitochondria from being impaired,” Dyck explains. This healthier mitochondrial state helps preserve both skeletal muscle and cardiac muscle during fat loss.
From animals to humans: next steps
The encouraging animal data have spurred plans for human trials. The University of Alberta team secured a Transformational Medical Research Grant, funded by The River Philip Foundation, to evaluate the ketone approach in people using semaglutide. If successful, this strategy could become a practical way to maximize fat loss while minimizing muscle-related side effects.
experts say that maintaining lean mass is crucial for immunity, wound healing, and overall metabolic health. By protecting muscle during weight reduction, patients may experience safer, more sustainable outcomes without sacrificing the benefits of semaglutide-based therapies.
Implications for patients and clinicians
As millions now use semaglutide products, adding a ketone ester supplement could become a simple, accessible adjunct to treatment. Clinical trials will determine dosing, safety, and efficacy, but the current findings offer a hopeful path toward safer, more effective obesity care.
Support and ongoing research
The work was supported by the Canadian Institutes of Health Research and Alberta-based health foundations, with ongoing collaboration across several research institutes. If human studies confirm benefits, this approach could become a common component of weight-loss regimens, aligning fat loss with preserved muscle health.
