Results Show Bimagrumab With Semaglutide Achieve Substantial Weight Reduction

Results from the phase 2 BELIEVE (NCT05616013) trial, published in Nature Medicine, demonstrate that combining the investigational activin receptor antagonist bimagrumab with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide can achieve substantial weight reduction while specifically preserving skeletal muscle. This approach addresses a significant clinical hurdle, showing roughly 25% to 40% of weight lost through caloric restriction and traditional incretin-based therapies is often lean tissue rather than fat.^1,2

“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,” Steven Heymsfield, MD, Boyd professor at Louisiana State University and director of the Metabolism and Body Composition Laboratory at Pennington Biomedical Research Center, said in a news release.²

The BELIEVE study, a multicenter, randomized, double-blind, placebo-controlled trial, randomized 507 adults with obesity to 9 different treatment arms for a 48-week primary period, followed by an open-label extension to week 72. Participants received various combinations of intravenous bimagrumab and subcutaneous semaglutide.^1-3

For pharmacists monitoring these developments, the distinct mechanisms of action are key to the trial's success. Although semaglutide reduces body weight by targeting central mechanisms to decrease appetite and food intake, bimagrumab is a human monoclonal antibody that targets activin type II receptors such as ActRIIA and ActRIIB. By inhibiting myostatin and activin A signaling, bimagrumab induces anabolic effects in skeletal muscle while simultaneously promoting lipid mobilization and fat mass reduction in adipose tissue.^1,4

The efficacy results were particularly striking in the high-dose combination group, which received 30 mg/kg of bimagrumab every 12 weeks alongside 2.4 mg of weekly semaglutide. This cohort achieved a least squares mean weight loss of 22.1% at week 72 compared with 15.7% for semaglutide monotherapy and 10.8% for bimagrumab monotherapy.¹

More importantly, the combination therapy significantly altered the composition of that weight loss. In the high-dose combination group, approximately 92.2% of the total weight reduction was attributable to fat mass loss, effectively shielding participants from the significant muscle depletion typically seen in high-magnitude weight loss. Bimagrumab monotherapy even resulted in a 2.5% increase in total body lean mass above baseline.^1,2

“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,” Heymsfield said.²

Beyond weight, the trial highlighted profound metabolic improvements. Participants in the combination groups showed a significant decrease in the inflammatory marker high-sensitivity C-reactive protein (hsCRP) of up to 84% by week 72. Furthermore, in a subgroup of participants who entered the trial with prediabetes, 100% of those in the combination groups reverted to normoglycemia by the end of the study period.¹

These findings align with an earlier 2021 study published in JAMA Network Open, which found that bimagrumab monotherapy in adults with type 2 diabetes led to a 20.5% reduction in total body fat mass and a 0.76 percentage point decrease in hemoglobin A_1c.⁴

From a safety and dispensing perspective, pharmacists should note that the adverse effect (AEs) profiles of the 2 drugs remained distinct and consistent with previous observations. Common AEs associated with semaglutide included nausea, constipation, and fatigue, while bimagrumab was uniquely linked to muscle spasms—often reported as cramps—and acne. Treatment discontinuations due to AEs were higher in bimagrumab groups, ranging from 14.0% to 21.4%, compared with much lower rates in the semaglutide and combination groups. Laboratory monitoring in the bimagrumab groups showed transient increases in alkaline phosphatase, creatine kinase, and liver transaminases (ALT and AST), as well as a transient increase in serum lipase.^1,4

Researchers involved in the trial suggest that these findings support a shift in obesity management toward more sophisticated measures like body composition and waist circumference rather than relying solely on body mass index. By uncoupling fat loss from lean mass loss, the combination of bimagrumab and semaglutide offers a potential solution for patients at high risk for physical or metabolic dysfunction due to low muscle mass.^1,2

Although intravenous administration was used in this trial, future studies are exploring subcutaneous dosing for bimagrumab to potentially attenuate early laboratory abnormalities and improve patient convenience. Additional ongoing research, including a phase 2 trial combining bimagrumab with tirzepatide, will further define the role of activin receptor blockade in the evolving landscape of metabolic health.^1,4

READ MORE: Diabetes Resource Center

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REFERENCES

1. Heymsfield SB, Aronne LJ, Montgomery P, et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial. Nat Med. Published online March 2, 2026. doi:10.1038/s41591-026-04204-0

2. Combination GLP-1 therapy shows fat mass loss while preserving lean mass in adults with obesity. News release. Pennington Biomedical Research Center. March 5, 2026. Accessed March 6, 2026. https://www.eurekalert.org/news-releases/1118938

3. Safety and efficacy of bimagrumab and semaglutide in adults who are overweight or obese. ClinicalTrials.gov identification: NCT05616013. July 18, 2025. Accessed March 6, 2026. https://clinicaltrials.gov/study/NCT05616013

4. Heymsfield SB, Coleman LA, Miller R, et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021;4(1):e2033457. Published 2021 Jan 4. doi:10.1001/jamanetworkopen.2020.33457