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Potent and Selective Agonism of the Melanocortin Receptor 4 With MK‐0493 Does Not Induce Weight Loss in Obese Human Subjects: Energy Intake Predicts Lack of Weight Loss Efficacy
Author(s) -
Krishna R,
Gumbiner B,
Stevens C,
Musser B,
Mallick M,
Suryawanshi S,
Maganti L,
Zhu H,
Han T H,
Scherer L,
Simpson B,
Cosgrove D,
Gottesdiener K,
Amatruda J,
Rolls B J,
Blundell J,
Bray G A,
Fujioka K,
Heymsfield S B,
Wagner J A,
Herman G A
Publication year - 2009
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2009.167
Subject(s) - sibutramine , placebo , weight loss , agonist , melanocortin 4 receptor , antagonist , pharmacology , medicine , dosing , partial agonist , endocrinology , obesity , crossover study , confidence interval , receptor , melanocortin , alternative medicine , pathology
MK‐0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best‐validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy‐intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK‐0493 showed a small and marginally significant effect on 24‐h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24‐h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK‐0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed‐dose study and also after 18 weeks of stepped‐titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics. Clinical Pharmacology & Therapeutics (2009) 86 6, 659–666. doi: 10.1038/clpt.2009.167 TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov on 6/1/2007 (NCT00482196).