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/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.

Sibutramine

• Variability in response

• Reasons unknown

• Ideally: want to be able to identify responders

This study• G-protein 3 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?

Study designPrevious 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

Genotype distribution

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

Overall Sibutramine Placebo

TT 15 8 7

TC 48 19 29

CC 48 25 23

Sibutramine vs. placebo

Figure 1: Weight loss after 54 weeks

Mean weight loss:

• Sibutramine

10.3 + 1.0 kg

• Placebo

5.0 + 1.5 kg

Therefore, significantly greater weight loss with sibutramine.

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

Sibutramine group

• TT and TC – no additional effect with drug

• CC – strong effect (P=0.003)

Figure 3: Genotype specific weight loss with sibutramine treatment vs. placebo.

15.6

7.8 7.86.9

10.2 7.1 9.62.7

Sibutramine vs. Placebo

Odds Ratios (95% Confidence Intervals)

Overall CC

5% weight loss 3.5 (1.6-8.1) 6.8 (1.8-25.6)

10% weight loss 2.9 (1.2-6.8) 9.6 (1.7-53.8)

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.

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)

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.

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.

Critique

• Ethnicity– variation in frequency of polymorphism– other effects?

• Sample size

• Graphs and tables

Discussion

• Side effects and the lawsuit

• Long term effect?