When humans lose weight with any currently available treatment (from lifestyle changes to obesity medications to bariatric surgery), about 1/3 of the weight is lost as muscle, and about 2/3 as fat. As blogged previously, there is an increased risk of developing a state of low muscle mass, called sarcopenia, with weight loss treatment. Not only that, people with obesity and people with type 2 diabetes are at increased risk of having low muscle mass, called sarcopenia, even before weight loss.

There is much interest to develop medications that build muscle while preferentially shedding fat, thus improving the quality of weight loss. As blogged previously, a phase 2 study in 2021 suggested that bimagrumab could do just that. Bimagrumab is a human monoclonal antibody that binds to the activin type II receptor, preventing the action of natural ligands that negatively regulate skeletal muscle growth, and possibly having an effect on brown adipose tissue (BAT) differentiation and activity.

However, bimagrumab doesn’t do anything on the appetite/cravings side of the equation, and we know by now that reducing appetite, food noise, and cravings are central to successful obesity management (this is how the GLP1 medications work). So, a study was undertaken to combine bimagrumab with the GLP1 medication semaglutide 1mg (Ozempic) or 2.4mg (Wegovy).

The phase 2 BELIEVE study included 507 adults with obesity (without diabetes) and randomized them to nine groups, each receiving various combinations of intravenous (IV) bimagrumab (either low dose 10mg/kg, or high dose 30mg/kg) every 12 weeks, subcutaneous (under the skin) semaglutide 1mg weekly, semaglutide 2.4mg weekly, or placebo for 48 weeks, with an extension phase to 72 weeks. BMI at the start of the study was 37.3 kg/m2, and 57% were female.

At 48 weeks:

  • Weight loss with bimagrumab was up to 8.6%, all of the weight lost was fat, and there was perhaps a small increase in lean mass (about 1%).
  • Weight loss with semaglutide was up to 13.5%, 71% of the weight lost was fat with the 2.4mg dose, and lean mass decreased by up to 6.9%.
  • Weight loss with bimagrumab + semaglutide was up to 16.4%, 92% of the weight lost was fat with the high dose combination, and lean mass decreased a little bit (up to 2.3%).
  • Weight loss with placebo was 3.5%.

Regarding metabolic health, A1c (diabetes report card) improved by 0.2% with the highest dose of bimagrumab, 0.4% with semaglutide 2.4mg, and 0.6% with the high dose combination (remembering that participants did not have diabetes, so we would not expect big changes in A1c). At 72 weeks, bad cholesterol (LDL) had increased by 17.6% in the high dose bimagrumab group, decreased by 8.9% with semaglutide 2.4mg, and no difference with the high dose combination. hsCRP (a marker of inflammation) decreased by 72% with high dose bimagrumab, 59.3% with semaglutide 2.4mg, and 84% with the high dose combination.

Physical function (asssessed with SF-36 survey) was similar across treatment groups at 48 weeks. Grip strength was increased vs placebo only in the high dose bimagrumab + semaglutide 1mg group. Combination medication groups showed greater improvent in quality of life (measured with IWQOL-Lite-CT survey) than placebo. There was a significant decrease vs placebo in hip bone density in the semaglutide 2.4mg group and most of the combination groups, but not in either of the bimagrumab alone group. (This could be because there was less weight loss with bimagrumab alone, but it is also enticing to consider whether preserved muscle helped to keep bones strong as well).

Side effects with bimagrumab included muscles spasms (45-74%), diarrhea (41-55%), and acne (34-55%), though few stopped treatment because of these side effects. Side effects with semaglutide were in keeping with what we already know (mostly gastrointestinal).

BOTTOM LINE: Bimagrumab (given intravenously) facilitated loss of fat while preserving muscle mass, though without much improvement in physical function, and with half or more of people experiencing each of muscle spasms, diarrhea, and acne. Combining bimagrumab with semaglutide further increased weight loss, with 92% of the weight lost as fat. While some aspects of metabolic health improved with bimagrumab, bad cholesterol (LDL) increased. The ongoing 32-week followup of people in this study (after treatment) will be important to see if weight can be maintained after stopping bimagrumab treatment, whether or not bad cholesterol goes back down, and what happens to body composition if there is weight regain. Study authors postulate whether side effects may be reduced by giving bimagrumab subcutaneously (under the skin) instead of intravenously, currently under evaulation in a study as monotherapy and combined with tirzepatide (Zepbound/Mounjaro).

Disclaimer: I am/have been an investigator in clinical trials of semaglutide and tirzepatide. I receive honoraria as a continuing medical education speaker and consultant from the makers of bimagrumab and tirzepatide (Eli Lilly) and semaglutide (Novo Nordisk).

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