Does pharmacologically induced weight loss improve cardiovascular outcome? Sibutramine pharmacology and the cardiovascular system
Department of Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada
* Corresponding author. E-mail address: sharma{at}ccc.mcmaster.ca
 |
Abstract |
|---|
 Top Abstract Sibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
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.
Key Words: Blood pressure • Obesity • Sibutramine • Sympathomimetic effects • Weight loss
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 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 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 |
|---|
|
TopAbstractSibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
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-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 sibutramine-treated 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=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=1898) or placebo (n=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 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 –0.8±9.2 (P=0.049). There was, however, no significant difference in the change in systolic BP (sibutramine –0.1±15.5 mmHg and placebo –0.2±15.2 mmHg; P=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. 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.
|
Sibutramine mode of action and its cardiovascular effects |
|---|
|
TopAbstractSibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
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 
-1, ß-1, and ß-2 receptors. However, there are also pre-synaptic -2 receptors; the role of this receptor is to inhibit noradrenaline release into the synapse. Agonists of the -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 -1 and ß-1 receptors resulting in
- increase in heart rate
- increase in BP
- increase in energy expenditure.
-2 receptors and result in:
- decrease in BP
- decrease in heart rate
- possible positive metabolic effects.
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 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 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 -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 |
|---|
|
TopAbstractSibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
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 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.
|
Key points |
|---|
|
TopAbstractSibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
- 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.
Conflict of interest: The author has consulted for Abbott and lectured at Abbott-sponsored symposia.
|
References |
|---|
|
TopAbstractSibutramine and cardiovascular...Sibutramine mode of action...ConclusionKey pointsReferences |
|---|
- Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med 1993;119:707–713.
[Abstract/Free Full Text] - Beales PL, Kopelman PG. Options for the management of obesity. Pharmacoeconomics 1994;5(Suppl. 1):18–32.
- Buckett WR, Thomas PC, Luscombe GP. The pharmacology of sibutramine hydrochloride (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation. Prog Neuropsychopharmacol Biol Psychiatry 1988;12:575–584.[CrossRef][Medline]
- Wong DT, Bymaster FP, Engleman EA. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci 1995;57:411–441.[CrossRef][ISI][Medline]
- Connolly HM, Crary JL, McGoon MD et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581–588.
[Abstract/Free Full Text] - Heal DJ, Aspley S, Prow MR et al. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from D-amphetamine and D-fenfluramine. Int J Obes Relat Metab Disord 1998;22(Suppl. 1):S18–S28.
- Hansen DL, Toubro S, Stock MJ et al. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obes Relat Metab Disord 1999;23:1016–1024.[CrossRef][ISI][Medline]
- Hansen DL, Toubro S, Stock MJ et al. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998;68:1180–1186.[Abstract]
- Walsh KM, Leen E, Lean ME. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes Relat Metab Disord 1999;23:1009–1015.[CrossRef][ISI][Medline]
- Sharma AM. Sibutramine in overweight/obese hypertensive patients. Int J Obes Relat Metab Disord 2001;24(Suppl. 4):S20–S23.
- Hazenberg BP. Randomized, double-blind, placebo-controlled, multicenter study of sibutramine in obese hypertensive patients. Cardiology 2000;94:152–158.[CrossRef][ISI][Medline]
- Fanghanel G, Cortinas L, Sanchez-Reyes L et al. Safety and efficacy of sibutramine in overweight Hispanic patients with hypertension. Adv Ther 2003;20:101–113.[ISI][Medline]
- Scholze J. Adipositasbehandlung mit Sibutramin unter Praxisbedingungen. Deutsche Medizinische Wochenschrift 2002;127:606–610.[CrossRef][Medline]
- Jordan J, Scholze J, Matiba B et al. Influence of sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes Relat Metab Disord 2005;29:1–8.[CrossRef][ISI][Medline]
- Birkenfeld AL, Schroeder C, Boschmann M et al. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation 2002;106:2459–2465.
[Abstract/Free Full Text] - Tank J, Schroeder C, Diedrich A et al. Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition. Circulation 2003;107:2949–2954.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  W. P. T. James The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients Eur. Heart J. Suppl., November 1, 2005; 7(suppl_L): L44 - L48. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||