MON-716 - Efficacy and Safety of Setmelanotide in Genetic Obesity Due to Leptin-Melanocortin Pathway Defects: A Meta Analysis

Background
Monogenic obesity due to defects in the melanocortin-4 receptor (MC4R) pathway is associated with severe, early-onset obesity and limited response to conventional weight-loss therapies. Setmelanotide, a selective MC4R agonist, is an approved targeted therapy for specific genetic obesity syndromes and has demonstrated clinically meaningful reductions in body weight and body mass index (BMI) in clinical studies. However, individual trials are small, include heterogeneous genetic subtypes, and report variable outcomes, limiting precise estimation of treatment effects. Although prior meta-analyses have evaluated setmelanotide efficacy, recently published studies warrant an updated meta-analysis to more precisely estimate treatment effects on weight and BMI and to evaluate between-study heterogeneity.

Methods
A systematic search of PubMed, Embase, and the Cochrane Library was conducted to identify studies evaluating patients treated with setmelanotide that reported at least one relevant outcome. Eleven studies met inclusion criteria. Data were pooled using an inverse-variance–weighted random-effects model implemented in RStudio (version 4.5.2). Pooled effect estimates, 95% confidence intervals, and heterogeneity were assessed, and results were visualized using forest plots.

Results
A total of 178 patients from 11 studies were included to evaluate the effect of setmelanotide on percent weight change and percent body mass index (BMI) change. The pooled analysis demonstrated a statistically significant reduction in percent body weight, with a mean difference of −10.84% (95% CI −21.64 to −0.03; p = 0.049). However, substantial heterogeneity was observed across studies (I² = 98.3%), indicating considerable between-study variability.
In contrast, percent BMI change showed a robust and statistically significant reduction, with a pooled mean difference of −11.50% (95% CI −13.92 to −9.08; p < 0.0001). Heterogeneity for BMI change was moderate (I² = 42.3%), suggesting more consistent treatment effects across studies.

Conclusions
In this updated meta-analysis, setmelanotide was associated with significant reductions in BMI and modest but clinically relevant weight loss in patients with rare genetic forms of obesity. While weight-related outcomes demonstrated substantial heterogeneity, the consistent direction and magnitude of BMI reduction support the therapeutic benefit of setmelanotide in real-world clinical populations. These findings reinforce the role of setmelanotide as a targeted treatment option in appropriately selected patients and emphasize the importance of individualized, genotype-informed clinical decision-making in managing rare monogenic obesity.

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