Sibutramine

Abstract

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54 505) and secondary (M1; BTS 54 354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake. In clinical trials, once-daily sibutramine was administered at dosages of ≤30mg for ≤24 weeks and 10 or 15mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages ≥10 mg/day. Weight loss of >1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of ≤24 weeks’ duration; data from longer trials are unavailable. Up to 15% of patients in ≤6-month studies did not respond to treatment irrespective of dose. Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear.. Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks’ treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo. Concerns over potential pressor effects with sibutramine are reflected in the manufacturer’s dosage and administration recommendations. Although long term tolerability data are scarce, pooled data from 2952 patients in placebo-controlled trials (≤1 year) revealed that the drug was generally well tolerated. The most commonly reported adverse events were headache, dry mouth, anorexia, insomnia and constipation. Echocardiographs indicated that sibutramine therapy (⁈8 months) did not adversely affect cardiac valve function in obese patients. Conclusion: Currently, there are few options for the long term management of obesity. Evidence, although limited, suggests that in selected obese patients, sibutramine may be considered a useful adjunct to traditional nonpharmacological therapy, to effect a sustained moderate weight loss during treatment which is greater than that with placebo. Concerns over potential pressor effects of sibutramine may be allayed by careful patient selection and subsequent monitoring. A number of factors may contribute to the development of obesity, including genetic predisposition, endocrine factors, psychological make-up and level of physical activity. However, the most important factor remains that when energy intake exceeds energy output, bodyweight gain is inevitable. The determination of a genetic association with obesity confirms that it should be classified as a disease. As a life-long disease, ideally, obesity requires long term management which should begin with nonpharmacological intervention such as diet, exercise and behavioural modifications. Obesity is quite distinct from being overweight. It may be classified using several methods. For example, the phenotype may be recognised by the distribution of excess body fat and the severity by the individual’s body mass index (BMI) value; the latter method is endorsed by the WHO. According to US-developed obesity management guidelines, a BMI of >25 kg/m² is considered the point at which pharmacological intervention may be considered. Drugs developed for the loss and maintenance of weight aim to cause appetite suppression, satiety enhancement, nutrient partitioning and/or alteration of thermogenic activity. Sibutramine is an orally administered agent that primarily acts to promote a sense of satiety; this is the result of serotonin (5 hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake inhibition effected by the drug. Sibutramine also has a moderate effect on energy expenditure by attenuating the decrease in energy output during rest. Increased satiety (i.e. decreased energy intake) combined with increased physical activity (i.e. increased energy output), which is encouraged during therapy, should lead to an overall decrease in bodyweight. Sibutramine is a centrally acting agent that dose-dependently inhibits serotonin and noradrenaline reuptake. The effect of sibutramine is largely attributable to its active primary (M2; BTS 54 505) and secondary (Ml; BTS 54 354) amine metabolites. The pharmacological activity of sibutramine does not appear to be a result of increased serotonin release; this differentiates it from the actions of dexfenfluramine, which predominantly releases serotonin, and dexamfetamine, which predominantly releases dopamine and noradrenaline. In in vitro studies as well as trials conducted in animals and humans, sibutramine and its metabolites also showed no significant potential for inducing dopamine release, unlike dexamfetamine. This may account for the lack of abuse potential with sibutramine as shown in rats and in healthy volunteers with histories of substance abuse. The binding affinity and number of dopamine D¹ or D² receptors were not affected by sibutramine; additionally, sibutramine and its metabolites were stated to have low in vitro activity at central and peripheral muscarinic cholinoceptors, which suggests a lack of potential for sedative effects. Monoamine oxidase activity was unaffected by sibutramine or...