The effect of melanocortin-4 receptor agonist drugs on obesity and metabolic risk factors: a systematic review and meta-analysis

The melanocortin-4 receptor (MC4R) agonists have emerged as potential treatments for obesity, particularly in patients with rare genetic syndromes. However, their overall effects on obesity and cardiometabolic risk factors remain uncertain. To systematically evaluate the efficacy of MC4R agonists on weight-related outcomes and cardiometabolic risk factors. We conducted this study following PRISMA 2020 guidelines. Eligible studies included clinical trials ((RCTs and single-arm trials) of the effects of MC4R agonist drugs on anthropometric factors and cardiovascular risk factors. Random model effects meta-analyses were performed for this meta-analysis, with heterogeneity and small-study effects explored through sensitivity and publication bias analyses. A total of 12 studies were included. Treatment with MC4R agonists significantly reduced body weight compared with placebo in RCTs (WMD − 5.07 kg; 95% CI − 8.13 to − 2.02), with even larger reductions in single-arm studies (–11.23%; 95% CI − 15.43 to − 7.04). MC4R agonists also lowered BMI by − 13.67% (95% CI − 17.21 to − 10.12), waist circumference by − 11.75 cm, BMI Z-score by − 0.98, and hunger scores by − 3.38. These agents reduced triglyceride levels by − 35.53 mg/dL and LDL-C levels by − 9.14 mg/dL, while HDL-C levels showed a nonsignificant increase of + 2.37 mg/dL. Systolic blood pressure declined by − 4.38 mmHg, while diastolic pressure showed no meaningful change. MC4R agonists produce clinically meaningful weight reduction and improvements in several cardiometabolic risk factors. These findings support MC4R agonists as a promising therapy for genetic forms of obesity, while their role in nonspecific obesity requires confirmation in large, long-term randomized trials.