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207-OR: Myostatin Inhibition Synergizes with GLP-1R Agonism to Accelerate Weight Loss in Male, Obese Nonhuman Primates
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become standard-of-care for the pharmacological treatment of obesity by inducing clinically meaningful weight loss through a reduction in appetite. While these agents potently reduce fat mass, the caloric restriction also reduces skeletal muscle mass. Strategies to preserve skeletal muscle in the presence of caloric restriction are needed to improve weight loss quality in obese patents. Trevogrumab (∝-MSTN) and garetosmab (∝-ActA) are fully human monoclonal antibodies that potently inhibit two mediators of skeletal muscle atrophy: myostatin (MSTN) and activin A (ActA). We first tested the effects of ∝-MSTN, ∝-ActA and GLP-1RA (Semaglutide [Sema]) on body composition of diet-induced obese mice either alone or in combination. Sema (-29.8%) and ∝-MSTN/∝-ActA (-23.4%) produced significant reduction in fat mass after 4 weeks of treatment vs baseline. Adding MTSN and ActA blockade to Sema produced an additive effect on fat mass (-54.2%). This combination also increased lean mass by 9.8% vs a 1.9% loss with Sema alone. To test this in primates, we performed a 20-week study with the combined administration of either Sema + ∝-MSTN or Sema + ∝-MSTN and ∝-ActA in obese male cynomolgus monkeys. The combination of ∝-MSTN + Sema was sufficient to cause an additive effect on fat mass -43.9% vs -25.1% for Sema alone. The addition of ∝-ActA to the combination produced a similar reduction in fat (-49.6%). The Sema control group also los…
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In primates with obesity, semaglutide combined with trevogrumab and garetosmab showed a large fat mass loss with an increase of lean mass.
“Further, a study of semaglutide combined with trevogrumab (anti-myostatin) and garetosmab (anti-activin A) in primates with obesity showed a large fat mass loss with an increase of lean mass.93”
From Changes in lean body mass with glucagon‐like peptide ‐1‐based therapies and mitigation strategies (2024) · cites this paper as [93]
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Metadata
- Authors
- MASTAITIS, J., GOMEZ, D., LE ROUZIC, V., STEC, M., KHAN, N., NA, E., MCWILLIAMS, T., MIN, S., & SLEEMAN, M.
- Affiliations
- Tarrytown, NY
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2023-06-20
- Volume
- 72
- Issue
- Supplement_1
- ISSN
- 0012-1797 (ISSN-L)
- OpenAlex
- W4381378300
- Cited by
- 11
- References
- 0
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- myostatin inhibition, GLP-1 receptor agonists, semaglutide, obesity, weight loss, fat mass, lean body mass, combination therapy, Macaca fascicularis, non-human primates, body composition, appetite suppression, caloric restriction, anti-obesity drugs
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