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


METHODS
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.


CONCLUSIONS
Blockade of the NPY5R with the potent antagonist MK-0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.
Erondu
Ngozi
N
Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, RY34A-Rahway, NJ 07065-0900, USA. Ngozi_Erondu@Merck.com
Addy
Carol
C
Lu
Kaifeng
K
Mallick
Madhuja
M
Musser
Bret
B
Gantz
Ira
I
Proietto
Joseph
J
Astrup
Arne
A
Toubro
Søren
S
Rissannen
Aila M
AM
Tonstad
Serena
S
Haynes
William G
WG
Gottesdiener
Keith M
KM
Kaufman
Keith D
KD
Amatruda
John M
JM
Heymsfield
Steven B
SB
D000293:Adolescent; D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003503:Cyclobutanes / Q000009:adverse effects / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D000077403:Orlistat; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects
D019440:Anti-Obesity Agents; D003503:Cyclobutanes; D003510:Cyclohexanes; D007783:Lactones; D011720:Pyrazoles; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; C100568:neuropeptide Y5 receptor; D000077403:Orlistat; C515547:spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-; C058254:sibutramine