MK-0364, a Novel Cannabinoid-1 Receptor Inverse Agonist, Increases Energy Expenditure in Overweight and Moderately Obese Subjects

Addy, Carol; Heymsfield, Steven; Cilissen, Caroline; Gendrano III, Isaias Noel; De Smet, Marina; De Decker, Marijke; Yuan, Jinyu; Larson, Pat; Dunbar, Stephanie; Stoch, Aubrey; Wagner, John
June 2007
Diabetes;Jun2007 Supplement 1, Vol. 56, pA461
Academic Journal
Cannabinoid-1 receptor (CB-1R) inverse agonists are associated with weight loss efficacy in clinical trials. Whether this is due to reduction in food intake, an increase in energy expenditure, or a combination of the two remains to be determined. This study was designed to evaluate the effect of single doses of MK-0364, a novel CB-1R inverse agonist, compared to placebo on resting energy expenditure (REE) in overweight and moderately obese male volunteers. This was a double-blind, double-dummy, active comparator- and placebo-controlled, 4-period crossover study in which 16 overweight and moderately obese male subjects were randomized to receive 1 of 4 single-dose treatments (placebo, MK-0364 4 mg, MK-0364 12 mg, and sibutramine 30 mg as a positive control). REE was assessed using indirect calorimetry over a 5-hour post-dose period and at 24 hours postdose. Peak REE was obtained as the maximum of the average of 2 consecutive 30-minute measurements within 2-5 hours postdose. The initial ANOVA model contained the factors: subject, period, treatment, and first order carryover effect. The model did not detect a significant carryover or period effect. However, baseline REE was detected as a significant covariate and was included in the final ANOVA model. The REE geometric mean ratio (GMR) and 90% confidence interval (CI) for MK-0364 12 mg, MK-0364 4 mg, and sibutramine 30 mg versus placebo was 1.06 (1.02, 1.09), 1.02 (0.98, 1.05), and 1.03 (0.99, 1.07), respectively. Single doses of MK-0364 and sibutramine were generally well tolerated. This is the first clinical study to demonstrate that a CB-1R inverse agonist is associated with increases in REE, which may, in part, explain the basis for weight loss efficacy with this mechanism. MK-0364 was generally well tolerated and may show promise as a medication to induce weight loss in overweight and obese patients.


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