Drug combination shows greater weight loss while preserving muscle mass

A recent research study found that a combination of the GLP-1 receptor agonist semaglutide and bimagrumab, an antibody that blocks activin signaling pathways, results in greater weight loss while also preserving lean mass, such as skeletal muscle and connective tissue. In the paper "Bimagrumab and semaglutide alone or in combination for the treatment of obesity: a phase 2 randomized clinical trial," published Monday in the journal Nature Medicine, Dr. Steven Heymsfield of Pennington Biomedical Research Center describes the results of the BELIEVE study, which showed that the therapy combination addressed lean mass loss associated with GLP-1-based therapies.

GLP-1-based therapies have been highly successful in reducing weight, but up to 40% of weight lost may come from lean mass. However, the study described in the paper indicates that the combination of semaglutide with bimagrumab delivered substantial weight loss over 72 weeks with lean mass preserved.

"Obesity treatment has traditionally focused on the number on a scale. Patients with obesity who are at risk for low muscle mass, affecting both physical and metabolic function, may benefit from treatments that maximize fat mass reduction while preserving skeletal muscle," said Heymsfield, who is an LSU Boyd Professor and director of the Metabolism and Body Composition Laboratory. "Bimagrumab and semaglutide work through distinct biological pathways, and when combined, we observed not only a preservation of lean mass but also an additive reduction in fat mass that exceeded what either therapy achieved alone."

Study participants were divided into groups, with some receiving bimagrumab only, some receiving semaglutide only, and others receiving the combination. Participants receiving only bimagrumab saw an average weight loss of 10.8%, with all weight loss attributable to fat mass and lean mass increasing by 2.5%. Those receiving only semaglutide lost an average of 15.7% of body weight, with 71.8% of the loss from fat mass. Participants receiving the drug combination lost an average of 22.1% of body weight, with 92.8% of the weight loss composed of fat mass while lean mass was largely preserved.

The double-blind, placebo-controlled study administered the drugs at two dosing levels for each – 10 or 30 mg/kg of bimagrumab and 1.0 or 2.4 mg of semaglutide – used alone or in combination. These various combinations and doses resulted in nine randomized groups. Bimagrumab doses were administered every 12 weeks while semaglutide doses were administered weekly.

In addition to weight loss, participants demonstrated up to an 83% decrease in high-sensitivity C-reactive protein (hsCRP), a key marker of inflammation linked to cardiovascular risk, and a substantial increase in adiponectin, a protein hormone that supports insulin sensitivity, fat metabolism and anti-inflammatory processes. In a subgroup of participants with indicators of prediabetes, some of the two-drug combination therapy groups had 100% reversion to normoglycemia among participants with prediabetes at baseline, essentially moving them to a nonprediabetes status.

The drug combination was generally well tolerated, with side effects consistent with the known profiles of the individual drugs. The trial demonstrated positive results in terms of both lean mass retention and weight loss, but researchers recommend continued clinical development and refinement of the drug combination to better understand the common adverse events observed in the bimagrumab groups, such as mild-to-moderate acne and muscle spasms. The study also points to a need for researchers to shift focus from weight and body mass index to other measurements such as body composition as more informative indicators of optimal obesity management.

Eli Lilly and Company funded the study, which was designed by Versanis Bio, a wholly owned subsidiary of Eli Lilly and Company. Versanis Bio oversaw the clinical trial and partially funded the study before its acquisition by Lilly.