Ann Intern Med
ACP 2026: Incretin-based weight loss often cuts into lean mass
Clinical Takeaway: When prescribing incretin-based obesity therapies, proactively address muscle preservation with resistance training, adequate protein intake, and follow-up assessment of body composition.
In two-thirds of incretin trials, muscle-related loss surpassed prespecified thresholds—raising concerns about long-term function and metabolic health.
In a systematic review published in Annals of Internal Medicine, investigators examined how incretin-based medications and nonpharmacologic approaches affect body composition—not just weight. The review included 36 randomized controlled trials of adults with overweight or obesity, with a median duration of 26 weeks and BMI ranging from about 28 to 42 kg/m2.
Across agents—liraglutide, semaglutide, tirzepatide, and dulaglutide—weight loss was consistently greater with incretin therapy than with placebo or lifestyle interventions. That loss was accompanied by clear reductions in total fat mass and visceral adiposity. But the “quality” of weight loss varied. Within incretin groups, the median proportion of total weight loss attributable to muscle-related indices was 34.9% (IQR, 19.0% to 48.2%), with 68% of studies exceeding the commonly cited 25% benchmark for fat-free mass loss. All studies using CT or MRI exceeded an even stricter 15% skeletal muscle benchmark.
Notably, about half of lifestyle or placebo comparator groups also exceeded muscle-loss benchmarks, suggesting that lean mass loss may be a feature of weight reduction itself rather than a drug-specific effect. No included trial assessed objective physical function, and heterogeneity in measurement methods precluded meta-analysis.
As the authors noted, “muscle-related losses were greater than anticipated in many treatment groups,” underscoring the need for future trials—and current clinical practice—to focus on muscle-preserving strategies alongside effective weight loss.
The findings were recently presented at a breaking news plenary session at the ACP Internal Medicine Meeting 2026.
Source: Bastis JA, et al. (2026, April 17). Ann Intern Med. Effect of Incretin-Based and Nonpharmacologic Weight Loss on Body Composition: A Systematic Review