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Pharmacogenomics: Genotype specific response to a weight loss drug

Pharmacogenomics: Genotype specific response to a weight loss drug. Paper by Hauner et al. Pharmacogenetics 2003; 13(8): 453-459 Presented by: Payal Sipahimalani. The drug: Sibutramine. Chemical name: Sibutramine hydrochloride monohydrate Used for management of obesity (BMI ≥ 30kg/m 2 )

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Pharmacogenomics: Genotype specific response to a weight loss drug

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  1. Pharmacogenomics: Genotype specific response to a weight loss drug Paper by Hauner et al. Pharmacogenetics 2003; 13(8): 453-459 Presented by: Payal Sipahimalani

  2. The drug: Sibutramine • Chemical name: Sibutramine hydrochloride monohydrate • Used for management of obesity (BMI≥30kg/m2) • Mode of action: Inhibits uptake of serotonin, dopamine and norepinephrine • Side effects may include headache, dry mouth, anorexia, constipation, insomnia, dizziness, nausea, nervousness, dyspepsia, increase in blood pressure and heart rate.

  3. Sibutramine • Variability in response • Reasons unknown • Ideally: want to be able to identify responders

  4. This study • G-protein b3 subunit gene (GNB3) • C825T polymorphism • Alternative splicing • Truncated, but functional protein variant • Increased signal transduction • Associated with obesity • Association between C825T status and treatment outcome?

  5. Study design Previous study: • 348 subjects (BMI: 30 - 40) • 174 = sibutramine group • 174 = placebo group • Weight loss after 54 weeks This study: • Genotyped the C825T polymorphism – pyrosequencing • 111 individuals

  6. Genotype distribution • 825T frequency = 35.1% in entire group • Higher than in non-obese subjects

  7. Sibutramine vs. placebo • Mean weight loss: • Sibutramine • 10.3 + 1.0 kg • Placebo • 5.0 + 1.5 kg • Therefore, significantly greater weight loss with sibutramine. Figure 1: Weight loss after 54 weeks

  8. Placebo group Weight loss in: TT = 7.8kg TC = 6.9kg CC = 2.7kg • Genotype specific difference in weight loss • T allele carriers: 4.3 + 2.0 kg greater than CC

  9. 6.9 7.8 7.8 15.6 10.2 2.7 7.1 9.6 Figure 3: Genotype specific weight loss with sibutramine treatment vs. placebo. Sibutramine group • TT and TC – no additional effect with drug • CC – strong effect (P=0.003)

  10. Sibutramine vs. Placebo Odds Ratios (95% Confidence Intervals)

  11. Long term effects Two years after study termination: • No overall advantage of sibutramine over placebo • ≥ 5% weight loss • Placebo group: greater in T carriers • Sibutramine group: greater in CC individuals.

  12. Summary and Conclusions • Polymorphism  drug response? • 825T allele of GNB3 • associated with obesity • Increased weight loss without drug • Sibutramine • increased overall weight loss • Genotype specific weight loss (C>T)

  13. Mechanism of action • 825T allele = intracellular signalling = response to drugs • Not here!!! • set-point for body weight– easily shifted up or down • Handle stress better? • CC individuals defend body weight set point.

  14. Future directions • Side effects  genotype? • Are psychological mechanisms of weight control allele specific? • Other polymorphic genes involved in body weight regulation? • Predict outcome of non-pharmacological and pharmacological programmes of weight loss.

  15. Critique • Ethnicity • variation in frequency of polymorphism • other effects? • Sample size • Graphs and tables

  16. Discussion • Side effects and the lawsuit • Long term effect?

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