A Review of the Metabolic Effects of Sibutramine

T. D. Filippatos; D. N. Kiortsis; E. N. Liberopoulos; D. P. Mikhailidis; M. S. Elisaf

Disclosures

Curr Med Res Opin. 2005;21(3):457-468. 

In This Article

Abstract and Introduction

Background: Obesity is associated with an Obesity is associated with an increased incidence of diabetes, hypertension, increased incidence of diabetes, hypertension, dyslipidaemia and coronary artery disease. Current dyslipidaemia and coronary artery disease. Current management strategies of obesity include lifestyle management strategies of obesity include lifestyle interventions and pharmaco therapy. Sibutramine interventions and pharmaco therapy. Sibutramine is a drug with established efficacy in weight reduction and maintenance of weight loss. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss.
Objective: To review the metabolic effects associated with sibutramine use.
Methods: Relevant articles were identified through a Medline search (up to December 2004).
Results: Weight loss with sibutramine treatment is associated with improved insulin sensitivity and a fall in glycosylated haemoglobin levels in type 2 diabetic patients. In most trials sibutramine exerted favourable effects on lipids, especially on high density lipoprotein (HDL) cholesterol and triglycerides, as well as on the total:HDL cholesterol ratio. Sibutramine also lowers serum uric acid concentrations. Furthermore, this drug seems to favourably influence adipocytokines; it reduces serum leptin and resistin levels and increases adiponectin levels. Sibutramine also exerts a beneficial effect on hyper androgenaemia in obese women with polycystic ovary syndrome. Preliminary findings also suggest that weight loss following treatment with sibutramine is useful in patients with non-alcoholic fatty liver disease (NAFLD).
Conclusion: Weight loss following sibutramine administration is associated with several favourable metabolic effects.

Obesity is a multifactorial chronic disorder which has reached epidemic proportions.[1] Obesity is associated with increased incidence of diabetes, hypertension, dyslipid aemia, coronary artery disease and some cancers.[2] On the other hand, a sustained weight loss of 5%-10% in the obese confers marked health benefits.[3] Current strategies for the management of obesity include lifestyle interven tions and pharmacotherapy.[4,5] At present, two drugs are approved for the medical management of obesity: orlistat and sibutramine.[6]

Sibutramine is a selective inhibitor of the reuptake of monoamines, primarily serotonin and noradrenaline and, to a lesser extent, dopamine.[7,8,9] The drug is rapidly metabolized to two active metabolites, which are 100-fold more potent than the parent compound.[10] The half-life of the two active metabolites is 14 h-16 h, with the peak concentration at 3 h-4 h and a plateau from 3 h to 7 h.[11] This pharmacological profile allows for once-aday dosing, which is an advantage when appetite control is the aim. Sibutramine and its metabolites are not serotonin-, adrenaline- nor dopamine-releasing agents[12] and have low affinity for monoamine receptors.[13] The dose range of sibutramine is 5 mg-15 mg once daily.[14]

Sibutramine has a dual mode of action. It reduces food intake and attenuates the fall in metabolic rate which occurs during weight loss.[15] In a study in normalweight adult men, sibutramine significantly decreased the amount of food and the energy content of food that the subjects chose to consume, resulting in an average reduction of 312 kcal during the day ( p < 0.01 vs. placebo).[16] In non-dieting obese women, the administration of sibutramine 10 mg/day for 14 days was associated with a significant reduction in food intake ( p < 0.05 vs. placebo) along with a reduction in total energy intake of 356 kcal per day.[17] Weight loss with sibutramine has been reported to be attributable to enhanced satiety, as well as to decreased hunger and food consumption.[8,17] In a study of the acute effects of sibutramine in energy expenditure, a single 30 mg dose of sibutramine in 11 non-obese men signif icantly increased basal energy expenditure compared with placebo ( p < 0.02).[18] Walsh et al .[19] studied the thermogenic effects of sibutramine (15 mg/day) for 12 weeks in obese women receiving a low-calorie diet. The expected decline in resting energy expenditure usually observed with weight loss and documented in the placebotreated patients was blunted in the sibutramine-treated patients. In the same study, the sibutramine effect was equivalent to 100 kcal/day. According to the authors, this effect could promote weight-loss maintenance over the long term.[19]

The most common adverse events in placebo-controlled studies involving 2068 patients on sibutramine treatment and 884 receiving placebo were dry mouth, anorexia, insomnia, constipation and headache.[20] Withdrawal rates due to adverse events were slightly higher with sibutramine (9%) than with placebo (7%).[20] Sibutramine has not shown significant euphoric or stimulant effects and has very low abuse potential.[21] The effect of the drug on blood pressure (BP) can be viewed as a balance between a predictable fall as a result of weight loss and an increase due to noradrenaline re-uptake inhibition. Alternatively, this effect can be viewed as the drug preventing the expected beneficial effect of weight reduction on BP. Therefore, in some studies, increases in BP were reported in patients with[22,23] or without preexisting hypertension,[23,24] while in other studies, weight reduction may have overcome any BP increase.[25,26] A meta-analysis of 21 trials (over 4500 patients) showed that sibutramine use is associated with slight increases in both systolic (1.6 mmHg) and diastolic BP (1.8 mmHg).[27] Therefore, sibutramine should be used cautiously in patients with borderline or high BP. The addition of low-dose metoprolol (25 mg/day) to sibutramine therapy (10 mg/day) increased patient compliance and decreased the frequency and severity of side effects, including hypertension and palpitations without decreasing sibutramine efficacy or causing significant deleterious changes in metabolic parameters.[28] Furthermore, in obese hypertensive patients whose BP is well controlled at the outset with an angiotensinconverting enzyme inhibitor (with or without a thiazide diuretic) sibutramine safely and effectively achieves weight loss without compromising good BP control.[29] There may be other ways to obviate the effect of sibutramine on BP and heart rate. In a small study ( n = 8)[30] that included a diet and exercise program together with the use of sibutramine there was greater weight loss than expected, a fall in resting heart rate and a decrease in diastolic BP. In another study ( n = 57)[31] involving hypertensive Hispanic patients that had their BP well controlled before starting on sibutramine, the BP changed from 128/82 mmHg to 125/82 mmHg in the sibutramine group and from 129/81 mmHg to 123/80 mmHg in the placebo group. The authors concluded that sibutramine is safe and effective in overweight Hispanic patients with hypertension, but monitoring of BP and titration of antihypertensive medication are necessary.[31]

Sibutramine has not been associated with pulmonary hypertension.[32] Moreover, in a double-blind study[33] involving 210 patients receiving sibutramine or placebo for 7.6 months, the prevalence of left-sided cardiac valve dysfunction (assessed by transthoracic echocardiographic imaging and colour Doppler) was similar in both groups (2.3% and 2.6% respectively). Sibutramine slightly increases the heart rate and it should be used cautiously in patients with pre-existing heart disease.[34,35] The overall benefit-risk profile of sibutramine remains positive.[36] In this review we discuss the metabolic effects of sibutramine ( Table 1 ).

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