Background & Aims: Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate α2A adrenoreceptor, 5-HT transporter, and GNβ3 genes and weight loss with sibutramine. Methods: 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 (α2A C1291G, 5-HTTLPR, and GNβ3 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. Results: Sibutramine, 10 and 15 mg, caused weight loss (P = .009); there was a statistically significant gene by dose interaction for GNβ3 genotype. For each candidate gene, significant treatment effects at 12 weeks were observed (P < .017) for all specific genotype variants (Δ weight loss in the 2 sibutramine doses vs placebo): α2A CC (Δ, ∼5 kg), GNβ3 TC/TT (Δ, ∼6 kg), and 5-HTTLPR LS/SS (Δ, ∼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 GNβ3 TC/TT; Δ, ∼6 kg and those with α2A CC with GNβ3 TC/TT; Δ, ∼8 kg; however, effects were not synergistic. Treatment with sibutramine also resulted in significantly greater reduction of body fat for specific α2A CC and GNβ3 TC/TT genotype variants individually (both P < .02). Conclusions: Patient selection based on candidate genes may enhance response to multidimensional sibutramine and behavioral therapy for obesity.
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