NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine.

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.

• Authors: Ngozi Erondu, Carol Addy, Kaifeng Lu, Madhuja Mallick, Bret Musser, Ira Gantz, Joseph Proietto, Arne Astrup, Søren Toubro, Aila M Rissannen, Serena Tonstad, William G Haynes, Keith M Gottesdiener, Keith D Kaufman, John M Amatruda, Steven B Heymsfield
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 15 Issue 8 Pg. 2027-42 (Aug 2007) ISSN: 1930-7381 [Print] United States
• PMID: 17712121 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Cyclobutanes
• Cyclohexanes
• Lactones
• Pyrazoles
• Receptors, Neuropeptide Y
• Spiro Compounds
• neuropeptide Y5 receptor
• Orlistat
• spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-
• sibutramine

Topics

• Adolescent
• Adult
• Aged
• Anti-Obesity Agents (adverse effects, therapeutic use)
• Cyclobutanes (adverse effects, therapeutic use)
• Cyclohexanes (adverse effects, therapeutic use)
• Double-Blind Method
• Drug Synergism
• Drug Therapy, Combination
• Female
• Humans
• Lactones (adverse effects, therapeutic use)
• Male
• Middle Aged
• Obesity (drug therapy)
• Orlistat
• Pyrazoles (adverse effects, therapeutic use)
• Receptors, Neuropeptide Y (antagonists & inhibitors)
• Spiro Compounds (adverse effects, therapeutic use)
• Weight Loss (drug effects)