Does glycine supplementation help prevent muscle loss in patients taking semaglutide (glucagon-like peptide-1 receptor agonist)?

Glycine Does Not Prevent Muscle Loss with Semaglutide—Focus on Resistance Training Instead

There is no evidence that glycine supplementation prevents muscle loss in patients taking semaglutide. The available guidelines and research do not mention glycine as a protective strategy against GLP-1 receptor agonist-induced muscle loss. Instead, the evidence consistently points to resistance training and physical activity as the primary interventions to preserve lean body mass during semaglutide therapy.

Understanding Muscle Loss with Semaglutide

Magnitude of Muscle Loss

• Semaglutide causes significant reductions in both fat mass and lean mass, with psoas muscle volume decreasing by 9.3% over 24 weeks in people with HIV receiving semaglutide for metabolic dysfunction-associated steatotic liver disease 1
• A network meta-analysis demonstrated that semaglutide causes a significant decrease in fat-free mass (FFM) compared to placebo (mean difference: -1.68 kg, 95% CI: -2.84 to -0.52), which was more pronounced than with SGLT2 inhibitors 2
• Despite substantial muscle volume loss, physical function may be maintained, as evidenced by nonsignificant improvements in chair rise time and gait speed, with the prevalence of slow gait speed decreasing from 63% to 46% 1

Muscle Quality vs. Quantity

• Oral semaglutide induces loss of body fat mass (from 28.3 kg to 25.5 kg over 24 weeks) without significantly affecting whole-body lean mass or appendicular skeletal muscle index in Japanese patients with type 2 diabetes 3
• Semaglutide improves skeletal muscle mitochondrial efficiency, increasing ATP production per oxygen consumed (P/O ratio), which may partially compensate for reduced muscle volume 4
• GLP-1 receptor agonists like liraglutide and semaglutide protect against obesity-induced muscle atrophy via the SIRT1 pathway, reducing muscle atrophy markers and improving myogenic differentiation 5

Evidence-Based Strategies to Preserve Muscle Mass

Primary Recommendation: Resistance Training

• Physical activity, specifically resistance training, should be part of the recommended approach to preserve lean body mass alongside GLP-1 receptor agonists 6
• Combining GLP-1 receptor agonists with lifestyle modifications, including diet, physical activity, and behavioral interventions, is recommended for patients with BMI ≥30 or BMI ≥27 with weight-related complications 6
• The Academy of Nutrition and Dietetics recommends combining GLP-1 receptor agonists with reduced-calorie diet and increased physical activity, including resistance training, for optimal results and to preserve lean body mass 7

Clinical Concerns About Muscle Loss

• Loss of muscle mass is a particular concern in older people at risk for sarcopenia when using glucagon-like peptide-1 receptor agonist therapy 8
• Potential for lean body mass loss when GLP-1 receptor agonists are used without concurrent physical activity is a significant consideration 6
• In patients with polycystic ovary syndrome (PCOS), liraglutide may result in lean body mass loss when used without lifestyle co-interventions 6

Why Glycine Is Not the Answer

The medical literature on semaglutide and muscle preservation does not identify glycine as an intervention. The mechanisms by which semaglutide affects muscle are related to:

• SIRT1 pathway activation, which protects against obesity-induced muscle atrophy 5
• Improved mitochondrial efficiency in skeletal muscle, with changes in complex III assembly proteins 4
• Glucose-dependent mechanisms that improve insulin sensitivity and glucose uptake in muscle tissue 5

None of these mechanisms would be directly influenced by glycine supplementation based on current evidence.

Practical Clinical Algorithm

For All Patients Starting Semaglutide:

1. Initiate resistance training before or concurrent with semaglutide to maximize muscle preservation 6, 7
2. Ensure adequate protein intake as part of the reduced-calorie diet to support muscle maintenance 7
3. Monitor body composition every 3 months, not just body weight, to assess changes in lean mass versus fat mass 6
4. Adjust exercise intensity as weight loss progresses to maintain muscle-building stimulus 6

For High-Risk Populations:

• Older adults (>65 years): Emphasize resistance training even more strongly due to baseline sarcopenia risk 8
• Patients with baseline low muscle mass: Consider delaying semaglutide until resistance training program is established 6
• Patients unable to exercise: Weigh risks and benefits more carefully, as muscle loss may be more pronounced without physical activity 6

Common Pitfalls to Avoid

• Relying on unproven supplements like glycine instead of evidence-based interventions like resistance training
• Focusing solely on weight loss without monitoring body composition changes 6
• Failing to counsel patients that lifestyle modifications, particularly resistance training, are essential components of treatment, not optional 7
• Discontinuing semaglutide due to muscle loss concerns without first optimizing exercise interventions, as functional capacity may be preserved despite volume loss 1