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

ABSTRACT 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 ( R 2 = 0.87, SEE = 0.635 kg/m 2 ) 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.