Does retatrutide have less muscle loss compared to other treatments?

Retatrutide and Muscle Loss: Current Evidence

Based on the most recent evidence, retatrutide does not cause a greater proportion of lean muscle mass loss compared to other weight loss treatments, despite producing more significant overall weight reduction.

Body Composition Effects of Retatrutide

• Retatrutide, a novel triple agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors, has demonstrated substantial weight reduction capabilities in clinical trials 1
• In a 2025 phase 2 substudy specifically examining body composition, retatrutide showed significant reductions in total body fat mass compared to both placebo and dulaglutide 2
• The proportion of lean mass loss to total weight loss with retatrutide was similar to other obesity treatments, providing reassurance that a greater proportion of lean muscle is not lost despite the overall increased weight loss 2

Dose-Dependent Effects on Body Composition

• Retatrutide demonstrated dose-dependent effects on body composition with percent reduction from baseline in total fat mass of:
  • 4.9% with retatrutide 0.5 mg
  • 15.2% with retatrutide 4 mg
  • 26.1% with retatrutide 8 mg
  • 23.2% with retatrutide 12 mg 2
• These reductions were significantly greater than those seen with dulaglutide (2.6%) and placebo (4.5%) 2

Importance of Muscle Preservation During Weight Loss

• Maintaining muscle mass during weight loss is crucial for several reasons:
  • Muscle mass increases resting energy expenditure (approximately 21 kcal/d per kg of muscle) 3
  • Preserving muscle mass helps prevent age-associated fat gains 3
  • Muscle preservation contributes to reduction of visceral adipose tissue, which is associated with metabolic syndrome 3

Strategies to Optimize Muscle Preservation During Weight Loss

• Resistance training (RT) should be incorporated alongside pharmacological weight loss treatments to maintain muscle mass 3
• RT has been shown to:
  • Increase muscle mass and strength 3
  • Improve insulin sensitivity in skeletal muscle 3
  • Reduce visceral adipose tissue 3
  • Enhance physical function, particularly in older adults 3

Clinical Implications and Recommendations

• When prescribing retatrutide for weight loss, clinicians should:
  • Recommend concurrent resistance training to optimize muscle preservation 3
  • Monitor body composition changes when possible, not just total weight loss 2
  • Consider that the proportion of lean mass loss with retatrutide appears comparable to other weight loss treatments, despite greater overall weight reduction 2

Potential Pitfalls and Caveats

• While retatrutide does not appear to cause disproportionate muscle loss, all weight loss interventions result in some degree of lean mass loss 2
• The long-term effects of retatrutide on muscle mass beyond 36 weeks have not yet been fully characterized 2
• As with other GLP-1 receptor agonists, retatrutide may increase heart rate (up to 6.7 beats/min), which could potentially offset some benefits of weight loss 4
• Most common adverse events with retatrutide are gastrointestinal (nausea, diarrhea, vomiting), which are dose-related but mostly mild to moderate in severity 1