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D RUG N OTES
Sibutramine
H Venkataraman, G McKay*
Introduction
Sustained weight loss of 5–10% in the
obese individual confers health
benefits. Current strategies in the
management of obesity include
lifestyle interventions and pharmacotherapy. At present, two drugs have
been approved for the medical
management of obesity: sibutramine
and orlistat. Sibutramine (Meridia,
Reductil) belongs to a group of drugs
called seratonin norepinephrine
re-uptake inhibitors (SNRIs) which
includes other drugs such as the antidepressant venlafaxine. Sibutramine
was initially investigated for its antidepressant properties but a serendipitous discovery in 1995 showed that this
novel antidepressant had effects on
weight loss, leading to its development
as an anti-obesity drug.
Pharmacology
Figure 1 outlines the pharmacological
action of sibutramine. Sibutramine
hydrochloride monohydrate is a
centrally acting SNRI. It inhibits
neuronal re-uptake of the neurotransmitters 5HT (5-hydroxytryptamine,
serotonin), norepinephrine and
dopamine. Its action on weight loss is
mainly through inhibition of 5HT and
norepinephrine re-uptake in the
hypothalamus which controls hunger
and satiety. It increases 5HT and
norepinephrine levels in the synaptic
cleft without stimulating an increased
release from neurons, so avoiding
neuronal depletion of these neurotransmitters.
It is well absorbed from the
gastrointestinal tract and undergoes
extensive first pass metabolism into
two active amine metabolites M1 and
M2 which are about 100 times more
potent and longer acting, allowing
for once-daily dosing. About 85% is
excreted in the urine and faeces. The
Dr Hema Venkataraman, MRCP,
Specialty Trainee (ST3), Endocrinology and
Diabetes, Doncaster Royal Infirmary,
Doncaster, UK
Dr Gerry McKay, BSc(Hons), FRCP,
Figure 1. The pharmacological action of sibutramine
Sibutramine blocks
Re-uptake
5HT
Norepinephrine
Satiety
Synapse
NOTES. Sibutramine inhibits neuronal re-uptake of the neurotransmitters 5HT
(5-hydroxytryptamine, serotonin), norepinephrine and dopamine. Its action on weight
loss is mainly through inhibition of 5HT and norepinephrine re-uptake in the
hypothalamus which controls hunger and satiety.
side effects of sibutramine include
dry mouth, anorexia, insomnia, and
increases in the pulse rate and blood
pressure (BP), in part due to the
peripheral sympathomimetic action.
Trials of safety and efficacy
Several randomised controlled trials
have demonstrated the efficacy of
sibutramine in combination with
lifestyle measures over placebo. The
LOSE Weight study recruited 588
obese patients who were undergoing
a weight management programme.1
Patients were randomly assigned to
participate in the programme alone,
or to take part in the programme and
receive sibutramine for 12 months.
The mean weight loss was greater
in the sibutramine treated group,
being -6.8kg (95% CI -7.4 to -6.1kg)
vs -3.1kg (95% CI -3.8 to -2.4kg);
p<0.001. There were significantly
greater decreases in the percentage
weight loss, BMI, percentage body fat
and waist circumference. Significantly
more people showed >5% weight loss
Consultant Physician, Medical Directorate,
Glasgow Royal Infirmary, Glasgow UK
in the drug group (47.3% vs 19.1%)
at 12 months. In this study there were
no significant changes in BP but there
was a significant increase in heart rate
(1.7bpm [95% CI 0.5–2.9bpm] vs
-0.4bpm [95% CI -1.5 to 0.8bpm];
p<0.004) in the sibutramine group.
The STORM study was a doubleblind, randomised controlled trial
that investigated maintaining weight
loss after an initial six months
of treatment with sibutramine
10mg/day in conjunction with a low
calorie diet in 605 obese patients
(BMI 30–45).2 Of the 499 patients
entering the trial, 467 (77%) showed
>5% weight loss after the initial six
months of treatment. Patients with
>5% weight loss were randomised to
receive either sibutramine or placebo
for 18 months. Forty-three percent of
sibutramine treated patients maintained >80% of their weight loss
compared to 16% in the placebo
group (odds ratio 4.64, p<0.001);
69% of the sibutramine treated
group maintained at least 5% weight
Glasgow Royal Infirmary, Castle Street,
Glasgow G4 0SF, UK; e-mail:
[email protected]
*Correspondence to: Dr Gerry McKay,
Consultant Physician, Wards 29 & 30,
Pract Diab Int November/December 2009 Vol. 26 No. 9
Copyright © 2009 John Wiley & Sons
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Sibutramine
loss and 46% maintained a 10%
weight loss. Therefore the STORM
study showed that sibutramine was
efficacious in maintaining weight loss
for up to two years after the start of
therapy. Twenty (3%) patients were
withdrawn because of increases in
BP; in the sibutramine group, systolic
BP (SBP) rose from baseline to two
years by 0.1mmHg (SD 12.9), diastolic BP (DBP) by 2.3mmHg (9.4),
and pulse rate by 4.1bpm (11.9).
The ongoing SCOUT trial is a
large-scale, randomised, doubleblind comparison of sibutramine vs
placebo to specifically assess the
cardiovascular risks in obese subjects
who are at increased risk of cardiovascular disease, including patients with
diabetes.3 The trial recruited 10 742
patients with cardiovascular risks –
including hypertension, diabetes,
coronary artery disease and strokes.
In the six-week lead in period
normotensive patients with little
weight loss had moderate increases
in both SBP and DBP, while in those
who had most weight loss and who
were hypertensive the SBP and DBP
decreased. The mean increase in
heart rate was 4–7bpm.
rate increased significantly more with
sibutramine, being ≥10bpm higher
in 42% of treated patients vs 17%
with placebo (p<0.01).
A 24-week double-blind, multicentre trial of 175 obese, poorly
controlled patients with type 2
diabetes
showed
significantly
greater weight loss (p<0.01) in those
randomised to sibutramine.5 Weight
loss (>5% and >10%) was achieved
in 33% and 8% of patients on
sibutramine but not in placebo
patients. Improvement in glycaemic
control correlated with weight loss
(p<0.001). In 5% and 10% weight-loss
responders the HbA1c differences
were -0.53% and -1.65% respectively
(p≤0.05). Sibutramine also showed
favourable differences in HDL,
triglycerides, insulin and fasting
blood glucose. Sibutramine treatment was associated with small mean
increases in BP and pulse, although
an increase in BP was not seen in
sibutramine treated patients who lost
≥5% of their weight. In the SCOUT
trial,3 BP reductions were greater
for those with diabetes who were
hypertensive and/or lost the most
weight (>5%).
Specific evidence for use
in diabetes
A randomised, prospective, placebocontrolled, double-blind study was
conducted over 12 months in 195
obese patients with type 2 diabetes on
metformin.4 Sibutramine was shown
to produce significant weight loss
(p<0.01). More than 10% weight loss
was seen in 14% and 27% of those
receiving 15 and 20mg respectively,
but none in the placebo group.
Glycaemic control paralleled the
decrease in weight loss. Patients with
>10% weight loss had a significant
decrease in HbA1c (-1.2±0.4%,
p<0.0001) and fasting plasma glucose
(-1.8mmol/L). HDL increased and
plasma triglycerides decreased,
especially in patients with >10%
weight loss (p<0.01). Treatment was
generally well tolerated. Sibutramine
treatment raised sitting DBP by
≥5mmHg in a higher proportion of
patients than did placebo (43% with
15mg/day vs 25% with placebo,
p<0.05), but this effect was less
evident in subjects who had a
weight loss of ≥10% weight. Pulse
Discussion
Sibutramine has been shown to produce statistically significant weight
loss, maintain long-term weight loss
and produce favourable metabolic
changes in obese patients with type 2
diabetes. Although sibutramine has
been shown to promote weight loss,
concerns over cardiovascular adverse
effects have limited its market
penetration. Notably, the Italian
regulatory authority temporarily
suspended marketing authorisation
of sibutramine in 2002, citing 50
adverse reactions, including two
cardiovascular-related deaths. The
European Committee for Proprietary
Medicinal Products and the Health
Sciences Authority (UK) subsequently conducted independent
reviews of sibutramine and concluded that the risk–benefit profile
remains positive. NICE recommends
sibutramine in those with a BMI >27
with cardiovascular risk factors, and
in those with a BMI >30 without
cardiovascular risk factors. Pulse and
BP should be monitored regularly.
Sibutramine should be continued for
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Pract Diab Int November/December 2009 Vol. 26 No. 9
Key points
• Sibutramine is a drug that can be
used to facilitate weight loss in
obese patients, including those
with type 2 diabetes mellitus
• The response to treatment should
be reviewed on a regular basis
and the drug discontinued if no
efficacy is demonstrated
• Although side effects of increased
pulse and blood pressure are to
be anticipated, this is not a major
issue as long as the patients are
carefully selected and monitored
appropriately
more than three months only if there
is a weight loss >5%. Currently, it is
not licensed for use for longer than
12 months.
Conflict of interest statement
There are no conflicts of interest.
References
1. Porter JA, Raebel MA, Conner DA, et
al. The Long-Term Outcomes of
Sibutramine Effectiveness on Weight
(LOSE Weight) study: evaluating the
role of drug therapy within a weight
management program in a groupmodel health maintenance organization. Am J Manag Care 2004; 10:
369–376.
2. James WP, Astrup A, Finer N, et al.
Effect of sibutramine on weight
maintenance after weight loss: a
randomised trial. STORM Study
Group. Sibutramine Trial of Obesity
Reduction and Maintenance. Lancet
2000; 356: 2119–2125.
3. Van Gaal LF, Caterson ID, Coutinho W,
et al., on behalf of the SCOUT
Investigators. Weight and blood pressure response to weight management
and sibutramine in diabetic and nondiabetic high-risk patients: an analysis
from the 6-week lead-in period of the
sibutramine cardiovascular outcomes
(SCOUT) trial. Diabetes Obes Metab 2009
Sep 16. [Epub ahead of print.]
4. McNulty SJ, Ur E, Williams G;
Multicenter Sibutramine Study Group.
A randomized trial of sibutramine in the
management of obese Type 2 diabetic
patients treated with metformin. Diabetes
Care 2003; 26: 125–131.
5. Fujioka K, Seaton TB, Rowe E, et al.
Weight loss with sibutramine improves
glycaemic control and other metabolic
parameters in obese patients with type
2 diabetes mellitus. Diabetes Obes Metab
2000; 2: 175–187.
Copyright © 2009 John Wiley & Sons