GLP-1 Receptor Agonists and Sarcopenia

By: Yekta Dowlati, PhD

The therapeutic landscape for obesity and type 2 diabetes mellitus (T2DM) has been revolutionized by glucagon-like peptide-1 receptor agonists (GLP-1 RAs), with weight reductions approaching magnitudes once exclusive to bariatric surgery. Yet, alongside dramatic fat mass loss, emerging data underscore a concerning reality: a substantial fraction of weight shed on GLP-1 RAs is lean mass — up to 40% in some trials.^1,2 As muscle quantity and quality are integral to metabolic resilience, physical function, and overall longevity, understanding this duality is paramount.

Sarcopenia: More Than Age-Related Atrophy

Sarcopenia, traditionally defined as the progressive and generalized loss of skeletal muscle mass, strength, and function, has profound clinical ramifications including increased falls, frailty, insulin resistance, and mortality. While often viewed through the lens of aging, sarcopenia’s pathophysiology is multifactorial: chronic low-grade inflammation, anabolic resistance, hormonal shifts, mitochondrial dysfunction, and impaired muscle satellite cell dynamics all converge to erode muscle integrity.²

Recent discourse around sarcopenic obesity — the coexistence of excess adiposity and diminished muscle mass — highlights an insidious phenotype particularly vulnerable to cardiometabolic and functional decline.

GLP-1 RAs: Metabolic Miracle or Muscle Compromise?

While much of the enthusiasm surrounding GLP-1 RAs stems from their ability to induce profound weight loss and improve cardiovascular risk profiles,³ the story of how these agents influence muscle is more nuanced. Few clinical trials rigorously quantify actual muscle mass, typically opting for lean mass measured by dual-energy X-ray absorptiometry (DEXA) — a composite that encompasses not just muscle, but also organs, bones, body water, and fat-free elements of adipose tissue.

Recent systematic reviews underscore that 20% to 50% of total weight loss achieved through GLP-1 RAs (and similarly, SGLT2 inhibitors) is attributed to lean mass reductions, a range overlapping with that seen in lifestyle interventions and even bariatric surgery.⁴ For context, a meta-analysis showed dietary, behavioral, and pharmacologic weight loss interventions typically result in lean mass losses ranging from 5.9% to 26.1% of total weight lost, while surgical cohorts averaged about 19.2% to 23.6%.⁵

But GLP-1 RA registration trials reveal even starker figures:

• In the STEP 1 trial, patients treated with semaglutide lost on average 6.92 kg of lean mass (placebo-corrected 5.44 kg) alongside a 15.2 kg total weight reduction, translating to lean mass accounting for roughly 45.5% of total weight loss.⁶
• In SURMOUNT-1, tirzepatide recipients saw lean mass decline by 5.26 kg (placebo-corrected 3.43 kg) with a 15.3 kg overall weight reduction, meaning about 34.3% of weight lost was lean mass.⁷
• Meanwhile, the SUSTAIN 8 sub-study reported semaglutide-treated patients with T2DM lost 2.3 kg of lean mass out of 5.3 kg total, yielding a proportion of 43.4%, though interestingly the relative composition improved slightly, with lean mass as a share of total body mass increasing by 1.2%.⁸

Other studies comparing semaglutide or tirzepatide with placebo in T2DM patients found lean mass losses of approximately 15% or less of total weight loss,⁹ suggesting substantial variability. Indeed, some trials report no exaggerated lean mass decline at all. This heterogeneity likely stems from differences in molecular pharmacodynamics, dosing regimens, trial durations, patient populations (with or without diabetes), and the nature of concurrent lifestyle interventions.

Mechanistic Insights: Why Might GLP-1 RAs Influence Muscle?

Several hypotheses explain this paradoxical muscle trajectory:

• Nutritional Deficits: GLP-1 RAs reduce appetite and total energy intake, often disproportionately lowering protein intake. Inadequate protein exacerbates anabolic resistance, impairing muscle protein synthesis.¹
• Myostatin Upregulation & Inflammation: GLP-1 RAs could influence muscle-regulatory pathways, including increased myostatin, a negative regulator of muscle growth, or heightened pro-inflammatory signaling, redirecting amino acids away from myofibrillar synthesis.²
• Mitochondrial Remodeling: Preclinical studies demonstrate GLP-1 RAs can increase mitochondrial area and quality, potentially offsetting quantitative losses with qualitative gains, though this remains speculative in human cohorts.³

Navigating Clinical Practice: Preserving Muscle on GLP-1 Therapy

Given the dual imperatives of reducing adiposity while safeguarding muscle, HCPs must adopt a proactive, individualized strategy:

1. Optimized Protein Nutrition: Evidence supports protein intakes of ≥1.2–1.5 g/kg/day, ideally distributed across meals, to counteract anabolic resistance. Special emphasis on leucine-rich proteins may stimulate mTOR signaling critical for muscle protein synthesis.¹ While traditional animal proteins are well studied for this role, modern formulations combining complementary plant protein fractions can now deliver complete amino acid profiles with high digestibility and absorption — offering practical alternatives for patients with dairy sensitivities or specific dietary preferences.

For individuals struggling with reduced appetite or early satiety — common with GLP-1 RA therapy — nutrient-dense, lower-volume protein options, including concentrated powders or ready-to-mix blends, can provide an effective strategy to meet daily targets without overwhelming gastric capacity.

1. Resistance Exercise: More than aerobic activity alone, resistance training robustly enhances muscle protein turnover and functional capacity, mitigating sarcopenic risk.¹ Even modest “exercise snacks” — short bouts of band or bodyweight exercises — can produce meaningful hypertrophic signals.
2. Micronutrient & Supplement Adjuncts: Emerging data suggest vitamin D, omega-3s, and specialized pro-resolving mediators (SPMs) may dampen muscle inflammatory catabolism and support synthesis. Creatine and targeted essential amino acids, particularly high-leucine blends, are under investigation.¹
3. Microbiome Considerations: The gut-muscle axis remains an underexplored avenue. Manipulating microbiota through probiotics (e.g., Lactobacillus) has demonstrated promise in preliminary studies to enhance muscle mass and function — offering intriguing potential synergy with GLP-1 therapy.¹ 

Looking Forward: Reframing “Lean Mass Loss”

Is lean mass loss inherently detrimental? Not necessarily. Contemporary paradigms stress muscle quality — insulin sensitivity, mitochondrial density, and reduced lipid infiltration — over sheer volume.² Nonetheless, in older adults or those with pre-existing sarcopenia, even proportionate losses can tip the balance toward frailty.²

Conclusion: A Call for Nuance

GLP-1 RAs embody one of the most powerful tools in metabolic medicine, capable of transforming trajectories of diabetes, cardiovascular disease, and obesity. Yet as with all potent interventions, vigilance is warranted. Protecting skeletal muscle — the largest reservoir of insulin-sensitive tissue and a critical determinant of vitality — must become a cornerstone of any pharmacologically assisted weight loss regimen.

This calls for a nuanced, integrative approach. Ensuring optimal protein intake — whether through traditional sources or modern formulations that combine complementary plant proteins to deliver complete amino acid profiles — alongside resistance training, judicious use of supportive micronutrients, and attention to gut-muscle dynamics, all serve to safeguard skeletal muscle even as fat mass declines.

For healthcare professionals and thought leaders, the message is clear: in this new era of potent pharmacotherapy, we must champion strategies that pair targeted fat loss with deliberate muscle preservation. By doing so, we not only extend lifespan but enhance health span — enabling patients not merely to weigh less, but to live stronger, more vital lives.

References:

1. Linge J et al. Circulation. 2024;150(16):1288-1298.
2. Memel Z et al. Curr Nutr Rep. 2025;14(1):63.
3. Old VJ et al. J Cachexia Sarcopenia Muscle. 2025;16(1):e13677.
4. Sargeant JA et al. Endocrinol Metab (Seoul). 2019;34(3):247-262.
5. Chaston TB et al. Int J Obes (Lond). 2007;31(5):743-750.
6. Wilding JPH et al. N Engl J Med. 2021;384(11):989–1002.
7. Jastreboff AM et al. N Engl J Med. 2022;387(3):205-216.
8. McCrimmon RJ et al. Diabetologia. 2020;63(3):473-485.
9. Heise T et al. Diabetes Care. 2023;46(5):998-1004.