Targeting ActRII and GLP-1 Receptor Agonists: A New Era of High-Quality Weight Loss with Muscle Preservation

Overview

Obesity is a global chronic disease, but its primary threat is the long-term metabolic and cardiovascular damage from excess adiposity. Traditional weight loss therapies, including diet, lifestyle, and pharmacotherapies, reduce weight at an inevitable physiological cost, as twenty-five to forty percent of lost mass is lean tissue, such as skeletal muscle. This muscle loss impairs physical function and lowers metabolic rate, limiting overall clinical benefits. Therefore, maximizing fat reduction while preserving or promoting muscle growth is a critical unmet medical need.

To address this challenge, the phase 2 BELIEVE trial (ClinicalTrials.gov identifier: NCT05616013), published in Nature Medicine, evaluated bimagrumab, a fully human monoclonal antibody targeting activin type II receptors (ActRII), and semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, alone or in combination in adults with obesity. Conducted by Versanis Bio, a subsidiary of Eli Lilly and Company, this randomized, double-blind, placebo-controlled study offers key insights into high-quality weight management.

Highlights

• Dual-Action Mechanistic Synergy: Semaglutide acts on the central nervous system to suppress appetite and reduce energy intake, whereas bimagrumab acts peripherally by blocking the ActRII pathway to inhibit myostatin and activin A signaling. This peripheral blockade stimulates protein synthesis in skeletal muscle while promoting lipolysis and lipid mobilization in adipose tissue, creating a highly complementary therapeutic profile.
• Nine-Arm Full Factorial Design: The study randomized 507 participants with obesity in a 1:1:1:1:1:1:1:1:1 ratio to receive placebo, bimagrumab monotherapy (low or high dose), semaglutide monotherapy (low or high dose), or various dose-matched combinations, systematically mapping the dose-response relationship of the co-therapy.
• Precision Body Composition Tracking: Rather than relying solely on gross body weight measurements, the study utilized serial dual-energy X-ray absorptiometry (DXA) scans to continuously monitor changes in total body fat, lean mass, and abdominal fat.
• Extended Observation for Tolerability: Featuring a 48-week double-blind primary treatment period followed by an open-label extension to 72 weeks, the trial provided a robust dataset to evaluate the durability and safety of long-term tissue remodeling.

Key Findings

A total of 730 candidates were screened, and 507 participants were randomized. The cohort presented a mean age of 47.5 years, body weight of 107.5 kg, body mass index (BMI) of 37.3 kg/m², waist circumference of 118.1 cm, total body fat mass of 45.8 kg, and total body lean mass of 58.3 kg.

• Breakthroughs in Weight Loss and Efficacy Thresholds

At week 48, absolute weight loss was strongly dose-dependent under the treatment regimen estimand. The high-dose combination (bimagrumab 30 mg/kg plus semaglutide 2.4 mg) achieved a statistically superior weight loss of -17.8 kg compared to semaglutide monotherapy (-14.2 kg) and bimagrumab monotherapy (-9.3 kg) (P < 0.05 versus semaglutide; P < 0.001 versus placebo at -3.3 kg).

By week 72, the high-dose combination achieved an absolute weight loss of -24.2 kg (-22.1%), significantly outpacing semaglutide (-16.5 kg) and bimagrumab (-12.0 kg). In this group, 84.9 percent of participants achieved a weight loss of 15% or more, compared to 51.8 percent with semaglutide and 21.8 percent with bimagrumab.

Fig.1 Combined bimagrumab and semaglutide treatment produced greater metabolic and fat reduction benefits than placebo. (Heymsfield, et al., 2026)

• Gold-Standard Body Composition Optimization via DXA

Serial DXA scans proved that the combination therapy optimized the structural quality of weight loss:

• Profound Adiposity and Visceral Fat Elimination: The high-dose combination reduced total body fat mass by 33.7% at week 48 and 45.7% at week 72 (significantly exceeding semaglutide at 27.8%, P < 0.05). Additionally, 94.0 percent of combination-group participants achieved a total fat loss of 30% or more by week 72. Visceral adipose tissue (VAT) decreased by 54.8% at week 48 and 58.2% at week 72 in the combination group, driving a waist circumference reduction of -21.7 cm.
• Robust Muscle Preservation: While semaglutide monotherapy lost 6.9% of total lean mass at week 48, bimagrumab monotherapy increased lean mass by 1.1%. The high-dose combination successfully buffered muscle loss, limiting lean mass reductions to 2.3% at week 48 and 2.9% at week 72. Consequently, the fat loss index (proportion of weight loss from fat) reached 92.3% in the high-dose combination group and 100% in the bimagrumab monotherapy group, compared to only 71.1% in the semaglutide monotherapy group.

Fig.2 Long-term combination therapy maintained improvements in body composition and inflammatory markers through week 72. (Heymsfield, et al., 2026)

• Comprehensive Improvements in Metabolic and Cardiovascular Risk Profiles

• Glycemia and Inflammation Control: Among participants with prediabetes at baseline, 100 percent in the combination groups reverted to normoglycemia by week 72. Systemic inflammation, measured via high-sensitivity C-reactive protein (hsCRP), decreased by 84.0% in the high-dose combination group compared to 59.3% in the semaglutide group.
• Cardiovascular and Lipid Biomarkers: At week 48, the high-dose combination group demonstrated a superior diastolic blood pressure reduction compared to placebo (-6.7 mmHg versus -2.8 mmHg, P < 0.05). The transient elevation in low-density lipoprotein (LDL) cholesterol observed with bimagrumab monotherapy was completely mitigated when combined with high-dose semaglutide, returning to baseline (0.1%) by week 72, while triglycerides fell by 25.3%.

Fig.3 Serum lipid levels showed sustained improvement during extended treatment through week 72. (Heymsfield, et al., 2026)

• Safety, Tolerability, and Adverse Events

Overall safety aligned with the known profiles of both agents. Bimagrumab was primarily linked to muscle spasms, diarrhea, and acne, while semaglutide was associated with gastrointestinal symptoms. Notably, co-therapy improved tolerability, as no participants in the combination groups discontinued treatment due to muscle spasms, compared to five in the bimagrumab monotherapy groups. Early liver enzyme elevations (AST, ALT, ALP) in bimagrumab-containing cohorts stabilized during the trial. Total body and spinal bone density remained stable, with only a minor 2% decrease in total hip BMD.

Fig.4 Liver enzyme and lipase levels were monitored to evaluate treatment safety at week 48. (Heymsfield, et al., 2026)

Interpretation & Translational Value

The clinical findings of this trial break the long-standing metabolic dogma that significant weight loss must inevitably trigger muscle degradation, proving that combining a peripheral receptor antagonist with a central energy regulator can achieve highly efficient fat loss while preserving essential skeletal muscle. By directly blocking the activin pathway via ActRII, this combination therapy achieves deep clearance of visceral fat and systemic inflammation without sacrificing physical and metabolic function, mirroring the fat-loss efficacy of invasive bariatric surgery. This shifts the clinical goals of obesity therapeutics away from simply reducing the number on a scale and toward a modern, high-quality reconstruction of body composition, providing a safer and more precise therapeutic option for elderly patients or individuals with existing metabolic comorbidities who are highly vulnerable to sarcopenia.

Research Support

For research teams interested in exploring body composition optimization, skeletal muscle regulation, or novel metabolic compound screening, Protheragen provides comprehensive preclinical and translational research services. Utilizing our advanced metabolic phenotyping platforms, high-precision body composition technologies, and customized animal disease models, we can assist you throughout the entire scientific process, from experimental design and biomarker analysis to translational data exploration, accelerating your therapeutic discoveries in metabolic disease.

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