A Controlled Pharmacogenetic Trial of Sibutramine on Weight Loss and Body Composition in Obese or Overweight Adults

Abstract

Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate alpha2A adrenoreceptor, 5-HT transporter, and GNbeta3 genes and weight loss with sibutramine. We conducted a randomized, double-blind, pharmacogenetic study of behavioral therapy and sibutramine (10 or 15 mg daily) or placebo for 12 weeks in 181 overweight or obese participants. We measured body weight, body mass index, body composition, gastric emptying, and genetic variation (alpha2A C1291G, 5-HTTLPR, and GNbeta3 C825T genotypes). Analysis of covariance was used to assess treatment effects on and associations of the specific markers of candidate genes with weight loss and body composition. Sibutramine, 10 and 15 mg, caused weight loss (P = .009); there was a statistically significant gene by dose interaction for GNbeta3 genotype. For each candidate gene, significant treatment effects at 12 weeks were observed (P < .017) for all specific genotype variants (Delta weight loss in the 2 sibutramine doses vs placebo): alpha2A CC (Delta, approximately 5 kg), GNbeta3 TC/TT (Delta, approximately 6 kg), and 5-HTTLPR LS/SS (Delta, approximately 4.5 kg). Gene pairs resulted in significantly greater sibutramine treatment effects on weight (both P < .002): in participants with 5-HTTLPR LS/SS with GNbeta3 TC/TT; Delta, approximately 6 kg and those with alpha2A CC with GNbeta3 TC/TT; Delta, approximately 8 kg; however, effects were not synergistic. Treatment with sibutramine also resulted in significantly greater reduction of body fat for specific alpha2A CC and GNbeta3 TC/TT genotype variants individually (both P < .02). Patient selection based on candidate genes may enhance response to multidimensional sibutramine and behavioral therapy for obesity.