New approach to safer weight-loss drug therapy
A recent study from the University of Alberta suggests that a simple ketone-based supplement could help protect lean muscle while patients shed fat on popular weight-loss drugs like semaglutide. The research, described as a way to “fine-tune” the therapy, indicates that ketones may preserve skeletal and cardiac muscle without compromising fat loss.
What the study set out to discover
The team led by Jason Dyck, a pediatrics professor in the Faculty of Medicine & Dentistry, began by confirming the concern that semaglutide-based treatments could cause a notable loss of skeletal muscle. Earlier work had documented that up to roughly 40 percent of total weight loss could be from muscle rather than fat, a worrisome finding for long-term health. More troubling, the researchers found that the heart itself could shrink in response to the therapy, beyond what is expected from weight reduction alone.
“The question is, if you have a healthy heart, what are the long-term effects of it shrinking more than it should?” Dyck noted. The implications of heart muscle loss prompted the team to search for protective strategies that could be implemented alongside the drug treatment.
Why ketones? A natural energy source
Ketones are molecules the liver produces when carbohydrate intake is low or during fasting. They provide an alternative energy source for muscles and other tissues. Prior work in metabolism and muscle biology has shown that ketones can help preserve skeletal muscle mass, prompting researchers to test whether supplementing with ketones could counteract the muscle loss seen with semaglutide therapy.
The researchers turned to a drinkable ketone ester, which raises blood ketone levels and mimics the metabolic state achieved during fasting or a ketogenic diet. The aim was to see whether this exogenous ketone boost could safeguard muscle while allowing the fat loss trend to continue.
Promising results in animal models
In obese mice treated with semaglutide alone, the team observed significant losses in both skeletal muscle and cardiac mass. When the ketone ester was added to the treatment, the results were striking. Mice did not exhibit the same degree of muscle loss, and cardiac muscle loss was substantially reduced as well. Interestingly, the total body weight loss was similar in those receiving semaglutide with or without the ketone supplement, but the composition of that loss shifted toward fat while preserving lean tissue.
“It turns out it does a fantastic job in protecting from muscle loss — skeletal muscle loss and loss of cardiac mass,” Dyck said. “It really just fine-tunes, potentially, this therapy.”
How the mechanism might work
The team’s interpretation centers on mitochondria, the cell’s energy factories. Semaglutide appears to impair mitochondrial function in muscle, contributing to muscle breakdown for fuel. By supplying ketones, the mitochondria may stay healthier and more active, reducing muscle wasting even when overall energy balance would otherwise favor catabolism.
“When you give animal models ketones, it protects the mitochondria from being impaired,” Dyck explained. “We think the ketones are making the mitochondria more active, healthier.”
From animal data to potential human trials
With millions using semaglutide, improving safety and tolerability is a priority. The Alberta team has secured a Transformational Medical Research Grant to begin human trials, a step that could bring ketone supplementation into clinical practice alongside weight-loss drugs in the future.
Dyck emphasized the broader significance: while some may focus on reducing drug-related risks, the real win could be achieving the same fat loss while protecting muscle mass, a critical factor for metabolic health, immunity, and recovery after weight changes.
Funding and collaboration
The study was supported by the Canadian Institutes of Health Research, Stollery Children’s Hospital Foundation, and Alberta Women’s Health Foundation through the Women and Children’s Health Research Institute and the Alberta Diabetes Institute. The research team’s work is guided by an aim to translate laboratory discoveries into practical options for patients on weight-loss regimens.
As researchers move toward human trials, the potential for a simple, effective adjunct to weight-loss therapy offers new hope for safer, more sustainable outcomes for millions who seek healthier bodies through semaglutide-based treatments.
