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European Heart Journal Supplements (2005) 7 (Supplement L), L39–L43
doi:10.1093/eurheartj/sui085
Does pharmacologically induced weight loss improve
cardiovascular outcome? Sibutramine pharmacology
and the cardiovascular system
Arya M. Sharma*
Department of Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada
KEYWORDS
The serotonin and noradrenaline re-uptake inhibitor, sibutramine, is a widely used
anti-obesity drug that promotes weight loss by increasing satiety, although a mild
increase in energy expenditure may also contribute. Noradrenaline re-uptake inhibition with sibutramine in peripheral tissues could theoretically exacerbate arterial
hypertension through an increase in synaptic noradrenaline concentrations. This has
led to a widespread perception that sibutramine contributes to hypertension and
should not be used in patients at high risk of cardiovascular disease. However,
neither published trials nor post hoc re-analysis of randomized trial data support
this notion; the incidence of sustained blood pressure (BP) increase with sibutramine
is not significantly different from control. Indeed, post-marketing surveillance data
suggest a significant decrease in BP with sibutramine in obese hypertensives. The biological basis of this effect is underpinned by detailed consideration of adrenergic
receptor pharmacology and confirmed by mechanistic studies.
Sibutramine belongs to a new class of weight loss drugs
that act by inhibiting the re-uptake of both serotonin
(5-hydroxytryptamine) and noradrenaline released from
neurones in the hypothalamus. These actions distinguish
sibutramine from the older weight loss agents, dexamphetamine and phentermine, which were noradrenaline
and dopamine-releasing agents, and fenfluramine and
dexfenfluramine, which were serotonin-releasing agents
(Table 1). The direct releasing effect is thought to have
contributed to the unwanted side effects associated
with these older drugs, particularly with the combination
of fenfluramine and phentermine, which resulted in the
carcinoid type of valvular heart disease.5
Rather than releasing neurotransmitters, sibutramine
inhibits the re-uptake of both serotonin and noradrenaline, thereby increasing the neural transmission of
neurones that rely on these two neurotransmitters. This
important distinction can be measured in animals by
intracerebral microdialysis techniques. Measurement of
* Corresponding author.
E-mail address: [email protected]
hypothalamic levels of serotonin in freely moving rats
given sibutramine 10 mg/kg were similar to those seen
in rats given the same dose of fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), but were markedly
lower than those seen in rats given the same dose of
dexfenfluramine.6 The very high levels of serotonin
induced by dexfenfluramine have been implicated in
the development of valvular problems. Fluoxetine and
other SSRIs have been widely used in the treatment of
depression for many years, with no indication that
these agents lead to valvular disease or to pulmonary
hypertension. Therefore, it is not surprising that so far
none of these effects have been seen with sibutramine.
Sibutramine has a dual mode of action in terms of
weight control.7–9 It increases satiety and the feeling
of fullness such that patients taking sibutramine may be
able to reduce their portion sizes and thus be more in
control of the amount of food they eat. There is also
thought to be, at higher doses, an effect on energy
expenditure. Indeed, part of the weight loss effect of
sibutramine, particularly perhaps when it comes to
weight maintenance, is attributed to the fact that it
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Blood pressure;
Obesity;
Sibutramine;
Sympathomimetic effects;
Weight loss
L40
A.M. Sharma
Table 1 Pharmacology of centrally acting agents known to produce weight loss
Agent
Releasing agent
Serotonin
Dexamphetamine1
Phentermine1
Fenfluramine2
Dexfenfluramine2
Sibutramine3
Fluoxetine4
Reuptake inhibitor
Noradrenaline
Dopamine
p
p
p
p
Serotonin
Noradrenaline
p
p
p
Dopamine
p
p
prevents the decline in energy expenditure that accompanies weight loss. This is thought to be a peripheral
effect rather than a central effect of sibutramine.
Sibutramine and cardiovascular risk
Figure 1 Dose-related effects of sibutramine on systolic BP (Abbott
Laboratories, data on file).
term clinical trials comparing sibutramine and placebo
shows no significant difference in terms of hypertension,
palpitations, or vasodilatation. The incidence of hypertension is not only extremely low, it is also not significantly different between placebo and sibutramine
(Table 2). The only significant difference in terms of
cardiovascular parameters is a slight increase in the incidence of withdrawal for tachycardia among sibutraminetreated patients, which can be a sustained effect of this
drug in some individuals.10
Analysis of the effects of sibutramine on BP in small
studies conducted in obese patients with controlled
hypertension shows that in both patients on sibutramine
and placebo there is a decrease in BP in the majority of
patients.11,12
So the reality concerning the effect of sibutramine on
BP certainly differs from the perception that this is a
drug that contributes to hypertension and that should
not be used in patients who are at high risk. This perception is also not supported by a new post hoc analysis of
21 randomized, double-blind, placebo-controlled trials
using sibutramine, all of which lasted for a minimum of
12 weeks.
This analysis involves a large population of overweight
and obese patients (n ¼ 3419), all of whom had normal
or controlled BP at baseline. The treatment used in
these studies was the licensed sibutramine dosage of
10–15 mg (n ¼ 1898) or placebo (n ¼ 1521), in addition
to a reduced calorie diet.
Analysis shows that there is a high variability in BP in
these patients, as is commonly observed in office-based
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There has been concern that noradrenaline re-uptake
inhibition with sibutramine could exacerbate arterial
hypertension and increase patients’ cardiovascular risk.
This concern is understandable given the previous
history of weight loss drugs. However, due to a combination of both central and peripheral effects, the cardiovascular response to sibutramine is more complex than is
apparent at first glance.
On the basis of data submitted at the time of registration,
the European datasheet for sibutramine states that: ‘In
placebo-controlled, clinical trials (dose range 1–30 mg), a
mean increase in resting systolic and diastolic blood
pressures (BP) of 2–3 mmHg, and a mean increase in
heart rate of 3–7 b.p.m. have been observed.’
This statement was based largely on combined analysis
of dose-finding studies including doses of 20 and 30 mg
conducted in normotensive individuals. Analysis of
those studies shows that there is a modest dose-related
increase in BP. However, at the doses currently used in
clinical practice, 10 and 15 mg daily, the increase in BP
was of the order of 1 mmHg systolic (Figure 1).
Cardiovascular studies show that even an increase of
1 mmHg in systolic BP can translate into negative outcomes. Therefore, this raises the question of how frequently in clinical trials there is a significant increase in
BP in patients taking sibutramine.
Placebo-controlled studies involving 5300 patients
have consistently shown an absolute increase in heart
rate (of 4–5 b.p.m. relative to placebo) and on average
an absolute increase of 1 mmHg but an increase in systolic BP of 2–3 mmHg relative to the normal reduced levels
on placebo. However, analysis of the clinical trials and of
the post-marketing surveillance data, now available,
does not show evidence for an increased risk of cardiovascular or cerebrovascular events; nor is there
any evidence of pulmonary hypertension or valvular
dysfunction, in line with the notion that this would not
be expected given the mode of action of the drug.
Analysis of the adverse effects leading to discontinuation of study drug among patients enrolled in long-
Sibutramine pharmacology and the cardiovascular system
Table 2 Patient withdrawals from long-term clinical studies
show no differences between placebo and sibutramine in the
incidence of cardiovascular events. (Adapted from Sharma.10)
COSTART
preferred term
Hypertension
Palpitations
Tachycardia
Vasodilatation
Long-term studies
Placebo
(n ¼ 770) (%)
Sibutramine
(n ¼ 1741) (%)
0.6
0.0
0.0
0.0
1.1
0.2
0.6
0.1
L41
Overall, there was no indication that patients with hypertension are more likely to get an increase in BP; in fact
the reverse seems to be true.
P,
Sibutramine mode of action and its
cardiovascular effects
0.21
0.22
0.048
0.48
.
.
.
increase in heart rate
increase in BP
increase in energy expenditure.
With central stimulation of the sympathetic nervous
system, effects are mediated by pre-synaptic a-2 receptors and result in:
.
.
.
decrease in BP
decrease in heart rate
possible positive metabolic effects.
Thus, systemic application of sibutramine is thought to
have both central and peripheral effects on the sympathetic nervous system, resulting in complex and opposing
cardiovascular effects.15
Sympathetic activity can only be blocked in subjects with a high sympathetic activity. If sympathetic
activity is elevated, as in the case of obese hypertensive
subjects, then sibutramine has a clonidine-like effect on
BP and hence the significant decrease in BP with sibutramine in obese hypertensives.13 However, in normotensive
patients and those with controlled hypertension, in
whom sympathetic activity is normal, sibutramine is
likely to have primarily peripheral effects, as noted
in the product label. In normotensive individuals with
low sympathetic activity, stimulatory tests like the cold
pressor test or hand grip exercise may be required to
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measurements of BP; some placebo patients experienced
increases in BP of 25, 35, or even 40 mmHg. It is well
known that BP can randomly fluctuate up or down in
any given patient on a given day; clinicians expect to
see this spontaneous change in BP. With sibutramine,
there was no statistically significant difference from
placebo; patients were as likely to experience an
increase of 30 mmHg on sibutramine as on placebo,
clearly showing that the risk of hypertension was not
different for sibutramine vs. placebo.
Analysis of BP in post-marketing surveillance studies
confirms the safety of sibutramine. One such study has
been published.13 This German study included 3259
patients who received sibutramine for 3 months. As
Figure 2 demonstrates, for normotensive individuals
there does appear to be a slight increase in both systolic
and diastolic BP of 1–2 mmHg. However, among patients
who have stage 1 hypertension, this increase in BP is
not seen; in fact, there is a decrease in BP that is most
pronounced for diastolic BP. Among patients with stage
2 hypertension, this fall in BP is even more prominent.
Thus, although there does appear to be a modest effect
of sibutramine on BP, this is more likely to occur in
normotensive individuals. In hypertensive individuals, it
appears that sibutramine may in fact lower BP.
In order to determine whether a similar pattern is seen
in clinical trials, we recently conducted a meta-analysis
of two placebo-controlled clinical trials in 1336 obese
patients who were normotensive or had different
degrees of hypertension [isolated systolic hypertension
(ISH) or grades 1 and 2 hypertension] at baseline.14
Mean diastolic BP change with sibutramine was
0.3 + 9.5 mmHg, which was significantly different from
the placebo change of 20.8 + 9.2 (P ¼ 0.049). There
was, however, no significant difference in the change in
systolic BP (sibutramine 20.1 + 15.5 mmHg and
placebo 20.2 + 15.2 mmHg; P ¼ 0.9). The BP change
in patients with grade 1 or grade 2 hypertension or in
patients with ISH was not different from the change
observed in normotensive patients.
As in the German post-marketing surveillance study,
analysis of normotensive individuals showed a slight
increase in BP. In contrast, BP fell among patients with
grade 1 hypertension, with a more pronounced decline
in those with grade 2 hypertension. Similarly, it fell
among patients with ISH treated with sibutramine.
How do these observations fit in with what is known about
the mode of action of sibutramine? While it is generally
assumed that increasing the levels of noradrenaline in
the synaptic cleft would result in an increase in sympathetic activity, this is, in fact, not how the sympathetic
nervous system works.
Typical sympathomimetic effects are mediated by
post-synaptic a-1, b-1, and b-2 receptors. However,
there are also pre-synaptic a-2 receptors; the role of
this receptor is to inhibit noradrenaline release into the
synapse. Agonists of the a-2 receptor are widely used
for the treatment of hypertension, the most common
example being clonidine.
Although sibutramine has always been considered a
centrally acting inhibitor of noradrenaline and serotonin
re-uptake, in considering its potential effects on the
sympathetic nervous system, it is important to remember
that there are also adrenergic synapses in the peripheral
nervous system. In addition, the effect of sibutramine
appears to vary depending on the balance between
pre-synaptic and post-synaptic adrenergic receptors,
which differs in the peripheral nervous system from
that in the central nervous system.
In the peripheral nervous system the effects of
adrenergic stimulation are mediated by post-synaptic
a-1 and b-1 receptors resulting in
L42
A.M. Sharma
Figure 2 BP changes in sibutramine-treated patients in a German post-marketing surveillance study (n ¼ 3259) stratified by baseline hypertension
classification. (Adapted from Scholze.13)
normotensive subjects is likely a consequence of the peripheral effects of sibutramine, whereas in hypertensive
patients, the observed fall in BP is likely due to central
effects, which appear to be mediated by a clonidine-like
stimulation of the pre-synaptic a-2 receptors.
So the general belief among clinicians that sibutramine
is a drug that increases BP because it is a sympathomimetic agent is overly simplistic if not incorrect. There
are, in fact, no data showing that sibutramine increases
central sympathetic activity; all the studies conducted
so far confirm that blocking noradrenaline re-uptake
switches off central sympathetic activity. Clinical data collected from hypertensive individuals support the notion
that in a hypertensive individual who has elevated sympathetic activity, sibutramine will most likely reduce BP.
Conclusion
The incidence of sustained BP increases with sibutramine
is not significantly different from control. However, sibutramine causes a significantly greater weight loss than
control, preventing weight regain and fostering weight
maintenance. As patients taking placebo are more
likely to experience an increase in body weight, they
are, therefore, more likely to have an increase in BP
than patients who are treated with sibutramine.
The peripheral effects of sibutramine explain the slight
increase in heart rate and BP that are sometimes seen in
clinical practice in normotensive individuals. In contrast,
in individuals with increased sympathetic activity, such as
obese-hypertensive patients, the central ‘clonidine-like’
sympatholytic effects of sibutramine may predominate.
Clinicians should, therefore, feel confident that in
patients with hypertension, they are more likely to see
a fall rather than an increase in BP on treatment with
sibutramine. There is, however, no doubt that BP and
heart rate should be monitored carefully during
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unmask the inhibitory effect of sibutramine on sympathetic activity.
Indeed, placebo-controlled studies in which human
subjects are given sibutramine and are then subjected
to sympathomimetic tests have confirmed that sibutramine actually lowers sympathetic activity. One such
study used the hand-grip test to stimulate the sympathetic nervous system.15 Subjects in the placebo group
showed a marked increase in BP, but with sibutramine
there was a statistically significant smaller increase
in BP. If sibutramine was a sympathomimetic drug, the
expected response would be an increase in BP; this
study suggests that sibutramine blocks central sympathetic activity and is not simply a sympathomimetic drug.
A similar result is seen with the cold pressor test,
although direct measurements confirm that sibutramine
results in a significant decrease in plasma noradrenaline
concentrations rather than an increase.15
All of these data suggest that sibutramine blocks rather
than stimulates the central sympathetic nervous system,
and that the sympathomimetic effects seen in normotensive individuals are largely peripheral effects. Further
evaluation of sympathetic activity can be conducted by
direct measurement of muscle sympathetic nerve
activity (MSNA). When compared with normal weight,
normotensive individuals, overweight subjects show
markedly increased sympathetic nerve activity. In this
model, the effect of noradrenaline re-uptake inhibition
was demonstrated using the selective noradrenaline
re-uptake inhibitor, reboxetine, which does not have
the serotonergic effects of sibutramine. This agent,
which leads to an even stronger blockade of
noradrenaline re-uptake than sibutramine clearly blocks
sympathetic activity.16
Therefore, when considering sibutramine it is important to differentiate between peripheral and central
cardiovascular effects of the drug. The fact that there
is an increase in heart rate and an increase in BP in
Sibutramine pharmacology and the cardiovascular system
sibutramine treatment, and that in patients who experience a clinically significant and sustained increase in BP,
the drug should be discontinued, in line with product
label recommendations.
L43
4.
5.
Key points
.
.
.
.
The incidence of sustained blood pressure increases
with sibutramine is not significantly different from
control.
Neither published trials nor post hoc re-analysis of
randomized trial data support the notion that sibutramine contributes to hypertension and should
not be used in patients at high risk.
More untreated obese patients gain weight than
those treated with sibutramine, and are, therefore,
more likely to experience a rise in blood pressure.
In addition to peripheral sympathomimetic effects,
sibutramine may have ‘clonidine-like’ sympatholytic
effects. This may be responsible for the significant
decrease in blood pressure noted in obese hypertensive patients treated with sibutramine.
6.
7.
8.
9.
10.
11.
12.
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Conflict of interest: The author has consulted for Abbott and
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