Combo therapy enhances fat loss while preserving lean mass

Bimagrumab, when combined with semaglutide, enhances weight loss while preserving lean mass better than either treatment alone in the phase IIb BELIEVE study presented at ADA 2025.

Bimagrumab is a monoclonal antibody that targets activin type II receptors, whereas semaglutide is a GRP-1 receptor agonist.

Patients who received an intravenous infusion of bimagrumab 30 mg/kg along with a once-weekly subcutaneous injection of semaglutide 2.4 mg experienced an average 22.1 percent reduction in body weight by week 72. In comparison, those who received the GLP-1 RA therapy alone had a 15.7 percent weight reduction, and individuals taking the monoclonal antibody by itself achieved a 10.8 percent weight loss. [Heymsfield SB, et al, ADA 2025]

Notably, a higher percentage of weight loss was attributed to fat mass reduction in the combination group (92.8 percent) compared to the semaglutide-only group (71.8 percent).

Although both groups experienced some muscle loss, the combination group lost less lean mass than the semaglutide-only group (2.9 percent loss vs 7.4 percent loss). Conversely, the bimagrumab group gained 2.5 percent.

BELIEVE population

Researchers investigated the effects of combining bimagrumab with semaglutide in people with obesity who do not have diabetes. A total of 507 participants were randomly assigned to receive semaglutide and/or bimagrumab at weeks 4, 16, 28, and 40.

The primary treatment period lasted 48 weeks, followed by a 24-week extension during which all patients remained on their original regimens except for the placebo and bimagrumab 10 mg/kg groups, which were switched to bimagrumab 30 mg/kg.

The primary endpoint of the trial was the change in body weight from baseline, with secondary endpoints including changes in waist circumference, total body fat mass, visceral adipose tissue, and lean mass.

“The combination regimen also resulted in a 21.7 cm reduction in waist circumference. To my knowledge, this is the best result we’ve seen. To put it into perspective, that’s equivalent to 8½ holes on your belt,” said Dr Louis Aronne from the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine in New York, US during a press conference.

At 48 weeks, adiponectin levels, which are known to be protective against diabetes and heart disease, increased to 29 µg/mL in the bimagrumab 30 mg/kg group, 7.2 µg/mL in the semaglutide 2.4 mg group, and 37.9 µg/mL in the bimagrumab 30 mg/kg/semaglutide 2.4 mg group.

“This study represents another major step forward in the evolution of obesity treatment, building on the significant weight loss benefits of semaglutide and combining it with bimagrumab to improve patient outcomes,” said study author Dr Steven Heymsfield, professor in the department of metabolism and body composition at Pennington Biomedical Research Center at Louisiana State University in Louisiana, US. “These insights demonstrate that it is not only possible to achieve substantial fat loss but also to preserve—or even enhance—lean mass during the process.”

Muscle mass matters

“As we enter a new era of obesity treatments, it’s vital to focus not just on the amount of weight lost but also on preserving muscle mass and gaining the health benefits that result from treating obesity,” said Dr Samar Hafida, vice president of Obesity Association, a division of the ADA, in a news release. “We are championing research to ensure that people living with obesity have access to effective treatments to reduce adiposity while maintaining muscle mass, which is critical to their well-being and supports durable, long-term outcomes.”