1. ^*Merck Research Laboratories, Rahway, New Jersey
2. ^†University of Melbourne, Department of Medicine, Austin Health, Melbourne, Australia
3. ^‡RVA University, Department of Human Nutrition, Frederiksberg, Denmark
4. ^§Helsinki University Central Hospital, Obesity Research Unit, Helsinki, Finland
5. ^¶Ullevål University Hospital, Department of Preventive Cardiology, Oslo, Norway
6. University of Iowa, Iowa City, Iowa

Correspondence: Ngozi Erondu Clinical Research, Metabolism, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, RY34A-Rahway, NJ 07065-0900. E-mail: Ngozi_Erondu@Merck.com

^*The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3 December 2006; Revised  0000; Accepted 24 January 2007.

Abstract

Objective: Central counter-regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK-0557 potentiates sibutramine and orlistat weight loss effects.

Research Methods and Procedures: Obese patients (497, BMI 30 to 43 kg/m²) were randomized to 1 of 5 treatment arms [ placebo, n = 101; sibutramine 10 mg/d, n = 100; MK-0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK-0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all-patients-treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline.

Results: The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK-0557 + sibutramine, 69% in orlistat alone, and 76% in MK-0557 + orlistat groups. Least squares (LS) mean difference [ 95% confidence interval (CI)] in weight change from baseline between MK-0557 + sibutramine and sibutramine alone was - 0.1 (- 1.6, 1.4) kg (p = 0.892) and between MK-0557 + orlistat and orlistat alone was - 0.9 (- 2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of - 5.9 (- 6.9, - 4.9) kg vs. - 4.6 (- 5.7, - 3.6) kg for orlistat (p = 0.097). There were no serious drug-related adverse events and MK-0557 was well tolerated.

Discussion: Blockade of the NPY5R with the potent antagonist MK-0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.