What is the effect of Glucagon-like peptides (GLPs) on muscle mass in patients, particularly those with type 2 diabetes or obesity?

GLP-1 Receptor Agonists and Muscle Mass: An Adaptive Response to Weight Loss

GLP-1 receptor agonists cause a reduction in lean body mass that accounts for less than 20% of total weight loss, but this appears to be an adaptive physiological response rather than pathological muscle wasting, with improvements in muscle quality offsetting concerns about quantity.

Magnitude of Muscle Mass Changes

In Patients with Type 2 Diabetes

• GLP-1 receptor agonists induce a non-significant mean reduction in muscle mass measures of -0.74 kg (95% CI: -1.61,0.14, p = 0.10), despite significantly reducing fat mass by -3.18 kg 1
• The reduction in muscle mass measures accounts for less than 20% of total weight reduction in this population 1
• When compared with controls, lean body mass reductions are -1.02 kg (95% CI: -1.46 to -0.57 kg), while lean mass percentage remains comparable between GLP-1 users and non-users 2

In Non-Diabetic Patients with Obesity

• A significant mean reduction in muscle mass measures of -1.41 kg (95% CI: -2.12, -0.71, p = 0.0001) occurs, which is significantly less than the reduction in fat mass of -6.02 kg 1
• This muscle mass reduction still accounts for less than 20% of total weight loss 1
• Clinical trials show heterogeneity, with some studies reporting lean mass reductions between 40-60% of total weight lost, while others show approximately 15% or less 3

Why This Represents an Adaptive Response

Muscle Quality Improvements

• Skeletal muscle changes with GLP-1 receptor agonist treatments appear to be adaptive: reductions in muscle volume are commensurate with what is expected given aging, disease status, and weight loss achieved 3, 4
• The improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function 3, 4
• Changes in muscle volume z-score indicate a change in muscle volume that is commensurate with expected changes given aging, disease status, and weight loss 4

Important Distinction: Lean Mass vs. Muscle Mass

• Changes in lean mass may not always reflect changes in muscle mass, as lean mass includes not only muscle but also organs, bone, fluids, and water in fat tissue 3
• This distinction is critical when interpreting study results, as reductions in "lean body mass" overestimate actual skeletal muscle loss 3

Body Composition Changes

Fat Mass Reduction

• GLP-1 receptor-based agonists produce substantial reductions in fat body mass of -2.25 kg (95% CI -3.40 to -1.10 kg) compared with controls 2
• Subcutaneous fat area decreases by -38.35 cm² (95% CI, -54.75 to -21.95 cm²) 2
• Visceral fat area decreases by -14.61 cm² (95% CI, -23.77 to -5.44 cm²), demonstrating body shaping effects 2

Lean Mass Percentage Preservation

• Despite absolute reductions in lean body mass, the changes in lean mass percentage are comparable between GLP-1 receptor-based agonist users and non-users 2
• This indicates that muscle loss is proportional to overall weight loss, not excessive 2

Risk Factors for Maladaptive Muscle Loss

High-Risk Populations

• Older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia 3
• Factors such as older age and prefrailty may influence appropriate candidate selection because of sarcopenia risk 4
• Diabetes is an independent risk factor for muscle mass loss, with possible mechanisms including impaired insulin signaling and chronic inflammation 2

Mitigation Strategies to Preserve Muscle Mass

Lifestyle Interventions

• Resistance training and adequate protein intake can mitigate muscle loss, though evidence for their efficacy in the context of GLP-1 receptor agonist therapy is mixed 5
• Resistance training should be part of the recommended approach to preserve lean body mass alongside GLP-1 receptor agonists 6
• Physical activity, specifically resistance training, is recommended to preserve lean body mass 6

Nutritional Supplementation

• If resistance training and protein intake are insufficient to prevent and maintain muscle mass, the use of some nutrients may be beneficial 5
• Specific nutrients that may help include: branched chain amino acids, creatine, leucine, omega-3 fatty acids, and vitamin D 5

Pharmacological Approaches Under Development

• Several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development 3, 4
• Bimagrumab, a human monoclonal antibody that acts by binding to the activin type II receptor II (ActRII), and other activin or myostatin inhibitors show promise in preserving muscle mass while promoting fat loss 5

Clinical Implications and Monitoring

Patient Selection Considerations

• GLP-1 receptor agonist therapy for obesity should include resistance training, optimal protein intake and, if needed, specific nutrients and possibly pharmacological interventions to preserve muscle mass 5
• In patients with polycystic ovary syndrome (PCOS), liraglutide shows benefits for anthropometric outcomes but may result in lean body mass loss when used without lifestyle co-interventions 6

Future Research Needs

• Future research on GLP-1-based therapies should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength 3
• The introduction of more objective and comprehensive ways of assessing muscle health (including accurate assessments of muscle quantity, composition, function, mobility, and strength) is important 4
• More high-quality, multicenter studies of newer agents like semaglutide in special populations are urgently needed 6

Common Pitfalls to Avoid

• Do not equate lean body mass loss with skeletal muscle loss, as lean mass includes multiple non-muscle components 3
• Do not withhold GLP-1 receptor agonists solely due to concerns about muscle loss in appropriate candidates, as the benefits typically outweigh risks and muscle changes appear adaptive 3, 4
• Do not prescribe GLP-1 receptor agonists without concurrent resistance training and protein optimization, as this increases the risk of disproportionate muscle loss 5, 6
• Do not ignore sarcopenia risk in older adults or those with prefrailty, as these populations require more careful monitoring 3, 4