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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 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?
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
Genotype distribution
Overall
Sibutramine
Placebo
TT
15
8
7
TC
48
19
29
CC
48
25
23
• 825T frequency = 35.1% in entire group
• Higher than in non-obese subjects
Sibutramine vs. placebo
Mean weight loss:
• Sibutramine
10.3 + 1.0 kg
• Placebo
5.0 + 1.5 kg
Figure 1: Weight loss after 54 weeks
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
6.9
7.8
7.8
15.6
10.2
7.1
9.6
2.7
Figure 3: Genotype specific weight loss with sibutramine
treatment vs. placebo.
• TT and TC
– no
additional
effect with
drug
• CC –
strong
effect
(P=0.003)
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?