A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese or overweight adults

Abstract

Background & aims: 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.

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 (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.

Results: 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).

Conclusions: Patient selection based on candidate genes may enhance response to multidimensional sibutramine and behavioral therapy for obesity.

Trial registration: ClinicalTrials.gov NCT00433641.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to disclose.

Figures

Figure 1. Conceptual diagram

shows the potential interaction between α2A adrenergic mechanisms, G protein translation and serotonin reuptake through SLC6A4 in mediating the effects of the norepinephrine and serotonin reuptake inhibitor, sibutramine.

Figure 2. Relationship between 12-Week Post-Treatment Body Weight and Sibutramine Dose Based on Single Genotypes

P-values indicate overall treatment effects for specific genotype. Least squares (adjusted for baseline weight and other covariates) means ± SE are plotted, unadjusted p-values from ITT analyses based on ANCOVA models. N refers to number of patients with complete data in each group. Upper panel identifies significant effects of sibutramine on post treatment weight in patients with the single genetic makeup indicated. Lower panel shows the corresponding treatment group values of post-treatment weight in patients with the alternative genetic variations for these single genes, and in which no significant treatment effects were detected.

Figure 3. Relationship between 12-Week Post-treatment Body Weight and Sibutramine Dose Based on Gene Combinations

P-values indicate overall treatment effects for specific genotype combination. Least squares (adjusted for baseline weight and other covariates) means ± SE are plotted, unadjusted p-values from ITT analyses based on ANCOVA models. N refers to number of patients with complete data in each group. There were significant effects of sibutramine on post treatment weight in patients with the specified genetic combination indicated.

Figure 4. Relationship between 12-Week Post-treatment Body Weight and Sibutramine Dose Based on Gene Combinations with GNβ3 Variations

P-values indicate overall treatment effects for specific genotype combination. Least squares (adjusted for baseline weight and other covariates) means ± SE are plotted, unadjusted p-values from ITT analyses based on ANCOVA models. N refers to number of patients with complete data in each group. Treatment effects were not detected in these combinations. The lack of effects of these gene combinations with GNβ3 CC genotype (data in Figure 4) should be contrasted the significant effects of 5HTTLPR LS/SS or α2A CC with GNβ3 TC/TT (data provided in Figure 3).

Figure 5. Estimates of treatment effect of sibutramine, 15 mg, vs. placebo (Y-axis) and sibutramine, 10 mg, vs. placebo (X-axis) in association with combined versus individual genotype variation

Note the differences in the responses to each dose of drug relative to placebo are not significantly greater for the different combinations of two genotype variations (means+SEM) relative to weight loss with individual genotype variations (mean data shown for clarity).