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

AbstractOBJECTIVE:
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.
AuthorsNgozi 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
JournalObesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 15 Issue 8 Pg. 2027-42 (Aug 2007) ISSN: 1930-7381 [Print] United States
PMID17712121 (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
  • spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-
  • orlistat
  • 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)
  • Pyrazoles (adverse effects, therapeutic use)
  • Receptors, Neuropeptide Y (antagonists & inhibitors)
  • Spiro Compounds (adverse effects, therapeutic use)
  • Weight Loss (drug effects)

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