Combination Treatment Reduces Weight While Keeping Muscle

Medscape

24-06-2025

CHICAGO — Combined use of semaglutide with an investigational monoclonal antibody called bimagrumab produced significant fat mass loss while preserving lean mass, results from the phase 2b BELIEVE study found.
Loss of muscle mass is an emerging concern with increasing use of GLP-1 agonists for weight loss as lean body mass is estimated to account for up to 15%-40% of total weight loss from GLP-1 drugs.
One potential solution is bimagrumab, which blocks the activin pathways that inhibit growth in skeletal muscle and increases lipid storage in adipose tissue, leading to both increased muscle mass and decreased fat mass.
'We're presenting an entirely new mechanism for managing obesity. We've heard a lot about GLP-1s and their combinations. This is going to be a unique one with bimagrumab, a drug that has completely different mechanism of action,' study investigator Steven B. Heymsfield, MD, professor and director of the Body Composition-Metabolism Laboratory at the Pennington Biomedical Research Center of the Louisiana State University System, Baton Rouge, told Medscape Medical News .
Results from the study comparing bimagrumab and semaglutide alone and in combination for treating obesity were presented on June 23, 2025, here at the American Diabetes Association 85th Scientific Sessions.
Bimagrumab's effects are complementary to those of GLP-1 drugs and other appetite suppressants, explained co-investigator Louis J. Aronne, MD, professor of metabolic research and director of the Comprehensive Weight Control Center at Weill-Cornell Medical College, New York, at a press briefing.
As such, he added, the drug's potential uses include being an adjunct to GLP-1 agonists for obesity induction therapy as an alternative to incretins for people who can't tolerate them or who don't respond adequately, and as a potential preferred maintenance therap.
Fat Mass vs Muscle Mass
The BELIEVE study was a randomized, double-blind, placebo-controlled, multicenter study in 507 adults with obesity or overweight.
Participants were randomized into a total of nine groups: placebo; bimagrumab alone at doses of 10 mg/kg and 30 mg/kg; semaglutide 1.0 mg or 2.4 mg plus placebo; and one of four groups of combined bimagrumab and semaglutide — bimagrumab 10 mg/kg plus semaglutide 1 mg; bimagrumab 30 mg/kg plus semaglutide 1 mg; bimagrumab 10 mg/kg plus semaglutide 2.4 mg; or bimagrumab 30 mg/kg plus semaglutide 2.4 mg.
Bimagrumab was given intravenously at weeks 4, 16, 28, and 40; subcutaneous semaglutide was given weekly.
The primary treatment period was 48 weeks, followed by an open-label extension to 72 weeks with both the placebo and bimagrumab 10 mg/kg groups switching to bimagrumab 30 mg/kg. Body composition was assessed with DEXA.
At week 72, body weight was reduced by 22.1% from baseline in the combined bimagrumab 30 mg/kg plus semaglutide 2.4 mg group (highest of both doses), compared with reductions of 15.7% with semaglutide 2.4 mg alone and 10.8% with bimagrumab 30 mg/kg alone.
Loss of fat mass was 45.7% with the high-dose combination vs 27.8% with semaglutide 2.4 mg and 28.5% with bimagrumab 30 mg/kg alone.
Lean mass loss was 2.9% with the high-dose combination, compared with a loss of 7.4% with semaglutide 2.4 mg and a gain of 2.5% with bimagrumab 30 mg/kg alone.
The percentage of weight loss that was due to fat mass at week 48 was 92.9% for the high-dose combination, 71.5% for semaglutide alone, and 100% for bimagrumab alone.
The proportions of participants achieving weight loss of 20% or more were 69.8% with the combination versus 25.0% with semaglutide, and 10.9% with bimagrumab. And, the proportions achieving 30% or greater fat mass reduction were 94.0%, 36.4%, and 50.0%, respectively, Heymsfield reported.
Visceral adipose tissue decreased more with bimagrumab alone or in combination compared with semaglutide alone, with parallel changes from baseline in waist circumference. High-sensitivity C-reactive protein, a key inflammatory biomarker, decreased by 83% in the high-dose combination group by week 48, Aronne said.
Adiponectin also increased more with bimagrumab alone or in combination compared with semaglutide alone.
Both total and LDL cholesterol rose in the bimagrumab groups and then returned to baseline in the combination groups containing semaglutide 2.4 mg by week 72. Baseline LDL was 114.3 mg/dL, rising by about 15%-30% in the bimagrumab groups by 12-24 weeks. The combination groups returned to baseline by 72 weeks, whereas the bimagrumab-only group dropped, but not back to baseline.
When asked about that, Aronne said 'We believe that the route of administration might be a reason for that observation. I think we need more research to figure this out.'
Increased LDL Cholesterol: Is It a Concern?
Asked to comment, Simeon Taylor, MD, PhD, professor of medicine and director of the Institutional Research Training Program in Diabetes & Obesity at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News that the efficacy data were 'amazing,' and that the combination 'delivered unprecedented efficacy as judged by biomarkers, specifically the combination of loss of fat mass plus the increase in lean mass. These changes were accompanied by clinically meaningful improvements in blood pressure and glycemic indices. It will be critical to understand the impact on 'hard' clinical endpoints such as cardiovascular outcomes.'
However, Taylor added that the trial raised some safety concerns, particularly an increase in LDL cholesterol that the investigators said was transient, but they didn't present data about what measures might have been used by the individual clinicians in the study to mitigate that rise.
'It will be important for the investigators to clarify how statin doses were managed. If the adverse effects of bimagrumab were transient, that could be a favorable scenario. If the LDL cholesterol returned toward baseline because statin doses were increased, that would have different implications,' he said.
Obesity expert Amy E. Rothberg, MD, clinical professor of internal medicine and of nutritional sciences at the University of Michigan, Ann Arbor, agreed, and also cited other missing information, such as muscle quality. 'There were no biopsies done. They were doing DEXA. That tells us about distribution and volume, but it doesn't tell us anything about quality.'
Rothberg also noted that the only objective functional measure was hand grip, while the rest were self-administered survey instruments. 'There are a lot of unknowns, but impressive data just the same.'
Hard to Predict Safety Concerns
Common adverse events with bimagrumab-containing groups included muscle spasms (ranging from 46.4% with 10 mg to 63.6% with the high-dose combination), diarrhea, and acne, while semaglutide was associated with the typical nausea, diarrhea, constipation, and fatigue.
Similar events occurred in the four combination groups, in which 9% of those treated discontinued due to adverse events over 72 weeks. There were no deaths.
The bimagrumab-containing groups showed early and transient increases in alanine aminotransferase and lipase, while semaglutide-containing groups had sustained increases in lipase.
'The biology of activin receptors is extremely complex. It is hard to predict all of the possible safety concerns. Phase 3 studies and pharmacovigilance will provide better understanding,' Taylor told Medscape Medical News .
'Some potential safety issues only become apparent when large numbers of people have taken the drug for long periods of time, he said, adding that 'obesity drugs are understandably required to have a very 'clean' safety profile.'
The BELIEVE phase 2 study was essentially proof-of-concept, said Heymsfield.
Semaglutide is a product of Lilly competitor Novo Nordisk. This unusual situation came about because the study was initiated in 2023 by Versanis Bio, which Lilly later acquired.
Lilly is now conducting phase 2 trials of bimagrumab with its own GLP-1-based drug tirzepatide, this time co-formulated with bimagrumab in a subcutaneous injection.
Heymsfield has a contract with Lilly for clinical trials (institutional support). He has received honoraria for serving on medical advisory boards of Tanita Corporation, Novo Nordisk, Lilly, Regeneron, Abbott, and Medifast. He is on the Data Safety Monitoring Committee for Novo Nordisk.
Aronne receives consulting fees from/and serving on advisory boards for Altimmune, Atria, Eli Lilly, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Juvena Therapeutics, Kallyope, Novartis, Novo Nordisk, Pfizer, Prosciento, Senda Biosciences, Versanis, Veru Pharmaceuticals, and Zealand Pharmaceuticals; receives research funding from AstraZeneca, United Kingdom, Eli Lilly, Janssen Pharmaceuticals, Belgium, and Novo Nordisk, Denmark; having equity interests in ERX Pharmaceuticals, Intellihealth, Jamieson Wellness, Kallyope, Myos Corp, and Veru Pharmaceuticals; and serves on a board of directors for ERX Pharmaceuticals, Intellihealth, and Jamieson Wellness.
Taylor has reported receiving payments from the National Institute of Diabetes and Digestive and Kidney Diseases for an inventor's share of a patent covering metreleptin as a treatment for generalized lipodystrophy. He was employed by Eli Lilly in 2000-2002 and Bristol Myers Squibb in 2002-2013.