Effect of NPY5R antagonist MK-0557 on weight regain after very-low-calorie diet-induced weight loss

Objective: To evaluate whether MK‐0557, a highly selective, orally administered neuropeptide Y Y5 receptor antagonist, could limit weight regain after very‐low‐calorie diet (VLCD)‐induced weight loss. Research Methods and Procedures: We enrolled 502 patients 18 to 65 years of age with a BMI of 30 to 43 kg/m². Patients were placed on a VLCD (800 kcal/d liquid diet) for 6 weeks. Patients who lost ≥6% of initial body weight (n = 359) were randomized to 52 weeks of 1 mg/d MK‐0557 or placebo and maintained on a hypocaloric diet (300 kcal below weight maintenance requirements). Results: In randomized patients, the VLCD was associated with an average weight loss of 9.1 kg. After 12 weeks of double‐blind treatment, weight began to gradually increase for both placebo‐ and MK‐0557‐treated patients. The mean weight change (95% confidence interval) from baseline at the end of the VLCD to Week 52 was +3.1 (2.1, 4.0) and +1.5 (0.5, 2.4) kg for patients treated with placebo and MK‐0557, respectively. The difference of 1.6 kg between the two groups was significant (p = 0.014). Secondary endpoints, such as blood pressure, lipid profile, insulin, and leptin, as well as waist circumference and quality‐of‐life measurements, did not show significant differences between MK‐0557 and placebo treatments. Discussion: Although the difference in weight regain between placebo‐ and MK‐0557‐treated patients was statistically significant, the magnitude of the effect was small and not clinically meaningful. Antagonism of the neuropeptide Y Y5 receptor is not an efficacious treatment strategy for reducing weight regain after VLCD.