Journal of Cachexia, Sarcopenia and Muscle · Jul 15, 2026

Defining Healthy Weight Loss and Target Weight in the Era of Highly Effective Treatment of Patients With Obesity

By Bosy-Westphal A, Enderle J, Norman K et al.

BACKGROUND: Highly effective anti-obesity medications (AOMs) induce substantial weight loss and have renewed debate on appropriate treatment targets. Weight loss comprises reductions in fat mass (FM) and fat-free mass (FFM), with skeletal muscle (SM) as the major component of FFM. Clinical trials report that 20%-40% of total weight loss is attributable to FFM, raising concerns about excessive SM loss and sarcopenia risk. METHODS: This narrative review integrates physiological principles and quantitative data from clinical trials to derive a rationale for redefining healthy weight loss targets based on body composition. Determinants of energy partitioning (baseline adiposity, age, diet and physical activity) are combined with predictive and reference-based approaches. Skeletal muscle index (SMI) was estimated from FFM, body weight, sex and age (R² = 0.87, SEE = 0.635 kg/m²) and evaluated using SMI standard deviation scores (SDS). RESULTS: SM accounts for 92%-97% of FFM loss during weight reduction. In incretin-based trials, FM decreased by -18.7% to -33.9% and FFM by -6.8% to -10.9%, corresponding to 33%-38% of total weight loss. Model-based estimates predict lower FFM reductions (~6.8%-6.9%), indicating that observed FFM losses exceed physiological expectations under conditions of large energy deficits. Across studies, diet- or AOM-induced weight loss without structured exercise is associated with higher proportions of FFM loss than expected, whereas interventions including exercise show more favourable partitioning. An SMI-SDS threshold of -0.67 (25th percentile) identifies clinically relevant SM depletion. CONCLUSIONS: Disproportionate SM loss is common with considerable weight reduction and may exceed physiologically expected levels. An SMI-based framework enables definition of individualized, safe treatment targets and may help prevent sarcopenia during obesity treatment.

doi.org/10.1002/jcsm.70334Open accessPubMed 42455525Interventions