The BELIEVE Trial: Rethinking What "Successful" Weight Loss Looks Like

For decades, obesity treatment has focused heavily on how much weight someone loses. But a new frontier in obesity medicine is shifting that focus—toward the quality of weight loss. At this year’s American Diabetes Association Scientific Sessions (ADA SciSessions), the BELIEVE study made a compelling case for this evolution, showcasing a combination therapy that significantly reduces fat mass while preserving muscle mass.

The Problem with Current Weight Loss Therapies: Mixed Tissue Loss

GLP-1 receptor agonists like semaglutide and tirzepatide have changed the game in obesity management, helping patients lose significant amounts of weight. But while the total weight loss is substantial, it's important to recognize what that weight consists of.

Studies show that:

• Semaglutide 2.4 mg over 52 weeks yields about 60% fat mass loss and 40% lean soft tissue loss

• Tirzepatide over 72 weeks shows 74% fat mass loss and 25% lean soft tissue loss.

While these medications work primarily through appetite suppression and energy intake reduction, the consequence is often loss of lean mass—especially skeletal muscle—which is critical for mobility, metabolic health, and long-term weight maintenance.

In short, even with powerful medications, patients may lose muscle right alongside fat—and that’s not ideal.

Enter: Bimagrumab—A Different Kind of Molecule

The BELIEVE trial explores a new approach: combining the proven effects of semaglutide with a different kind of drug, bimagrumab—a monoclonal antibody that inhibits the activin type II receptor (ActRII), impacting GDF-8/myostatin and GDF-11 signaling pathways.

Unlike GLP-1s, bimagrumab doesn’t work through the brain or appetite suppression. Instead, it promotes muscle growth and enhances fat metabolism directly in tissues, including muscle, fat, and liver. This mechanism has previously been shown to:

• Stimulate muscle hypertrophy

• Reduce visceral and liver fat

• Increase resting energy expenditure (REE)

It’s an exciting candidate to address the “mixed tissue loss” problem we see with incretin therapies.

Inside the BELIEVE Trial

The BELIEVE trial was a randomized, double-blind, placebo-controlled Phase 2 study evaluating the effects of semaglutide, bimagrumab, and their combination over 48 weeks, with a 24-week open-label extension.

At baseline, participants had:

• Mean weight: 236.5 lbs (107.5 kg)

• BMI: 37.3

• Waist circumference: 46.5 in (118.1 cm)

• Fat mass: 101 lbs (45.8 kg)

• Lean mass: 128 lbs (58.3 kg)

Results That Redefine "Success"

At 72 weeks, participants receiving the high-dose semaglutide + bimagrumab combination experienced:

• 22.1% total body weight loss (52 lbs)

• 46 lbs of fat mass lost (46% reduction)

• Only 3.7 lbs of lean mass lost (2.9%)

• 93% of weight lost was fat mass

That’s a huge shift compared to the 60/40 or 75/25 ratios we see with GLP-1 monotherapy. Preserving muscle during weight loss has the potential to mitigate drops in metabolic rate and reduce weight regain—a common challenge in obesity care.

Additional findings included:

• 58.2% reduction in visceral adipose tissue (from 3.3 lbs to 1.4 lbs)

• 8.6-inch (22 cm) reduction in waist circumference

• 83% reduction in C-reactive protein (CRP)

• Significant drops in leptin and increases in adiponectin—markers that point to improvements in inflammation and insulin sensitivity

What This Means for Obesity Care

The BELIEVE trial signals a pivotal moment in how we evaluate and define success in obesity treatment.

It’s not just about the number on the scale. It’s about preserving what matters—muscle, function, metabolism—while targeting the tissue that poses the most risk: excess adipose tissue, especially visceral fat.

This combination therapy could potentially:

• Support better physical function and strength

• Maintain higher REE during and after weight loss

• Improve metabolic and inflammatory profiles

• Help patients sustain weight loss long term

The Road Ahead

As the field evolves, we must continue pushing for approaches that honor the complexity of body composition—not just weight. This means better measurement tools (like DEXA and BIA), more nuanced outcome goals, and therapies that protect lean mass.

We BELIEVE this is just the beginning.