Semaglutide and Bimagrumab Combination Shows Greater Weight Loss While Preserving Muscle Mass

Key Takeaways: 

• A phase 2 clinical trial found that combining semaglutide with the antibody bimagrumab produced greater overall weight loss while largely preserving lean body mass.
  
• Participants receiving the two-drug combination lost 22.1% of body weight on average, with over 90% of the reduction coming from fat mass.
  
• The findings highlight the importance of focusing on body composition rather than weight alone when evaluating treatments for people living with obesity.
  
  
  

Combining two mechanisms to improve obesity treatment

A recent clinical trial has found that combining the GLP-1 receptor agonist semaglutide with bimagrumab, an antibody that blocks activin signalling pathways, may produce greater weight loss while preserving lean body mass.

The findings were reported in the paper “Bimagrumab and semaglutide alone or in combination for the treatment of obesity: a phase 2 randomized clinical trial”, published in the journal Nature Medicine. The study describes the results of the BELIEVE trial, led by Dr Steven Heymsfield of the Pennington Biomedical Research Center.

GLP-1–based therapies have become highly effective tools for reducing body weight in people living with obesity. However, a recognised limitation of these therapies is that up to 40% of the weight lost may come from lean mass, which includes skeletal muscle and connective tissue.

The BELIEVE trial explored whether combining semaglutide with bimagrumab could address this issue by enhancing fat loss while protecting lean body mass.

Why lean mass preservation matters

Historically, obesity treatment has often focused on reductions in body weight as the primary outcome. However, researchers increasingly emphasise the importance of preserving muscle mass, which plays a vital role in both physical function and metabolic health.

Dr Heymsfield explained that maintaining lean mass could be particularly important for people living with obesity who may already be at risk of low muscle mass.

“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.

He also highlighted the complementary biological mechanisms of the two drugs.

“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.”

Design of the BELIEVE phase 2 trial

The BELIEVE study was designed as a double-blind, placebo-controlled clinical trial evaluating the effects of semaglutide and bimagrumab used either alone or in combination.

Participants were randomly assigned to several treatment groups:

• Bimagrumab only
  
• Semaglutide only
  
• Combination therapy
  

Each medication was also administered at two different dosing levels:

• Bimagrumab: 10 mg/kg or 30 mg/kg
  
• Semaglutide: 1.0 mg or 2.4 mg
  

Because of these dosing combinations, the trial ultimately included nine randomised groups.

Bimagrumab was administered every 12 weeks, while semaglutide was given once weekly. Participants were followed over a 72-week treatment period.

Weight loss and body composition outcomes

The results showed clear differences between the treatment groups in terms of both total weight loss and the composition of that weight loss.

Participants receiving bimagrumab alone experienced an average weight reduction of 10.8%. Notably, all of this reduction was attributable to fat mass, while lean mass increased by 2.5%.

Those treated with semaglutide alone lost an average of 15.7% of body weight, with 71.8% of the weight loss coming from fat mass.

The most striking results were seen in participants receiving the combination therapy. These individuals experienced an average weight loss of 22.1%, with 92.8% of the weight reduction attributable to fat mass, while lean mass was largely preserved.

These findings suggest that the combination therapy may offer a way to achieve substantial reductions in body weight while maintaining the muscle mass that supports metabolic health and physical function.

Improvements in metabolic and inflammatory markers

Beyond weight loss and body composition, the study also identified several favourable metabolic changes.

Participants experienced up to an 83% reduction in high-sensitivity C-reactive protein (hsCRP), an inflammatory marker that is associated with increased cardiovascular risk.

The study also reported a substantial increase in adiponectin, a hormone that plays an important role in:

• Improving insulin sensitivity
  
• Supporting fat metabolism
  
• Promoting anti-inflammatory processes
  

Among participants who had indicators of prediabetes at baseline, some of the groups receiving the two-drug combination experienced complete reversion to normoglycaemia, meaning all participants in those groups moved from a prediabetic state to normal blood glucose levels.

Safety and tolerability

Overall, the drug combination was generally well tolerated by participants. Reported side effects were broadly consistent with the known safety profiles of the individual drugs.

However, researchers noted that participants receiving bimagrumab experienced some common adverse events, including:

• Mild-to-moderate acne
  
• Muscle spasms
  

The study authors emphasised the need for continued clinical development and further investigation to better understand these effects.

Moving beyond the number on the scale

The BELIEVE trial also underscores a broader shift in how obesity treatments may be evaluated in the future.

Rather than focusing solely on weight or body mass index, researchers increasingly argue that body composition measures, such as the proportion of fat mass and lean mass, provide more meaningful insight into treatment effectiveness and overall health outcomes for people living with obesity.

Funding and study oversight

The study was funded by Eli Lilly and Company. The trial was originally designed by Versanis Bio, a wholly owned subsidiary of Eli Lilly.

Versanis Bio oversaw the clinical trial and provided partial funding before its acquisition by Lilly.

CCH insight:

The results for bimagrumab are very exciting. Although overall weight loss was less for bimagrumab than semaglutide, the amount of fat lost was very similar, but with retention or even increase of muscle mass. As muscle is an important metabolic tissue, you can argue that in this case the lesser weight loss is a better outcome than the higher weight loss, because the weight that is retained is muscle, not fat.