GLP-1 Muscle Loss: How Much Lean Mass Do Users Actually Lose?

What the Registration Trials Actually Measured

The question "Do GLP-1s cause muscle loss?" doesn't have a simple yes/no answer. A more precise question: How much of the weight lost is lean mass versus fat mass, and how does this compare to other weight loss methods?

Both the STEP trials (semaglutide) and SURMOUNT trials (tirzepatide) included DXA body composition substudies. Here's what they found:

STEP 1 DXA Substudy (Semaglutide 2.4mg)

The STEP 1 body composition analysis by Wilding et al. examined 140 participants over 68 weeks:

In the STEP 1 substudy, lean mass accounted for approximately 39-45% of total weight lost. This is on the higher end of what's been reported.

SURMOUNT-1 DXA Substudy (Tirzepatide)

The SURMOUNT-1 body composition analysis published in 2025 examined 160 participants over 72 weeks:

The SURMOUNT-1 data is notable because this ratio held constant across subgroups by age, sex, and total weight loss amount—suggesting the body composition effects are relatively predictable.

How Does This Compare to Other Weight Loss Methods?

A 2024 review in Diabetes, Obesity and Metabolism by Neeland et al. examined the relationship between total weight loss and lean mass loss across multiple interventions. Their conclusion: the proportion of lean mass reduction per pound of body weight lost is highly variable but broadly similar across diet, GLP-1 therapy, and surgical interventions.

A December 2024 network meta-analysis of 22 randomized controlled trials (2,258 participants) found GLP-1s reduced lean mass by an average of 0.86 kg, comprising approximately 25% of total weight loss.

The Muscle Quality Story: SURPASS-3 MRI Data

DXA measures total lean mass but can't distinguish between muscle quality changes. The SURPASS-3 MRI substudy published in The Lancet Diabetes & Endocrinology (April 2025) used advanced imaging to examine muscle composition in people with type 2 diabetes.

Lead author Professor Naveed Sattar from University of Glasgow commented: "The amount of muscle volume changes with tirzepatide appears to be in line with muscle volume changes seen in the population for similar differences in weight. More importantly, these data suggest a clear reduction in the amount of fat in muscles, changes that may in fact improve muscle efficiency."

This is significant because fatty infiltration of muscle (myosteatosis) is associated with poorer physical function and metabolic outcomes. Less fat within muscle tissue may improve contractile function even if total muscle volume decreases.

What About Physical Function?

If people are losing lean mass, are they getting weaker? Not necessarily.

The SURMOUNT-1 trial measured physical function using the SF-36v2 questionnaire. Despite decreases in lean mass, tirzepatide-treated participants reported significantly improved physical function scores compared to placebo—suggesting the weight loss benefits outweigh any detriment from reduced lean mass in most patients.

A 12-month real-world study (SEMALEAN) measured handgrip strength in patients taking semaglutide. Despite losing appendicular skeletal muscle mass, handgrip strength increased by approximately 4 kg from baseline—evidence that muscle function can improve even as total mass decreases.

Mitigation Strategies: What Actually Works

Can you minimize lean mass loss while on GLP-1 medications? The evidence says yes—with the right interventions.

Resistance Training

A 2025 case series published in Obesity Science & Practice documented three patients who prioritized lean mass preservation during GLP-1 therapy. Their results:

All three patients engaged in resistance training 3-5 days per week and maintained protein intake of 1.6-2.3 g/kg of fat-free mass per day.

One patient actually gained 2.5% lean mass while losing 26.8% of body weight—demonstrating that aggressive muscle preservation strategies can completely flip the typical ratio.

Protein Intake Recommendations

A 2025 joint advisory from the American College of Lifestyle Medicine, American Society for Nutrition, Obesity Medicine Association, and The Obesity Society provides consensus recommendations:

The advisory emphasizes: "Increased protein intake alone is likely inadequate to support the preservation of muscle mass in the absence of structured resistance/strength training."

Exercise Protocols

Based on the evidence review by Mechanick et al. in Obesity (2024):

• Resistance training: 2-3 sessions per week targeting all major muscle groups
• Aerobic activity: 150+ minutes per week of moderate-to-vigorous activity
• Combined approach: Mixed resistance + aerobic programs preserve more lean mass than either alone
• Compound movements: Squats, deadlifts, rows, and presses are most efficient

Retrospective studies suggest that more intensive programs (360 minutes/week with emphasis on strength exercises) may be needed to fully preserve fat-free mass during rapid weight reduction.

Who's at Higher Risk?

Certain populations warrant extra attention to lean mass preservation:

• Older adults (65+): Already experiencing age-related muscle loss; less reserve capacity
• Sarcopenic obesity: Patients with pre-existing low muscle mass and high fat mass
• Sedentary individuals: Less mechanical stimulus to maintain muscle
• Low protein intake: Inadequate building blocks for muscle maintenance
• Rapid weight loss: Faster reduction correlates with higher lean mass proportion lost

For these populations, the 2025 review in Current Opinion in Clinical Nutrition notes that emerging pharmacological approaches (such as myostatin inhibitors) are being studied as potential adjuncts to preserve muscle during GLP-1 therapy.

The Developing Pipeline

Pharmaceutical companies are actively developing combination approaches:

• BioAge Labs: Combining BGE-105 with tirzepatide in Phase 1 study
• Regeneron: Testing antibody drugs with semaglutide for muscle preservation
• Veru: Phase 2b trial of enobosarm with GLP-1s in sarcopenic obese patients
• Bimagrumab: Monoclonal antibody targeting ActRII receptor showing promise in preserving muscle

These approaches target pathways like myostatin/activin, apelin, and mTOR to drive fat loss while maintaining or building lean tissue.

Key Takeaways