Pharmacological Treatment of Obesity: Present Status
Total Page：16
File Type：pdf, Size：1020Kb
International Journal of Obesity (1999) 23, Suppl 1, 47±53 ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00 http://www.stockton-press.co.uk/ijo Pharmacological treatment of obesity: present status AJ Scheen1* and PJ LefeÂbvre1 1Division of Diabetes, Nutrition and Metabolic Diseases, Department of Medicine, CHU Sart Tilman, B-4000 LieÁge 1, Belgium OBJECTIVE: Obesity poses a serious health hazard and its treatment is often disappointing. This review describes the present status of pharmacological treatment of obesity in man. DESIGN: Obesity treatment may include drugs that reduce food intake, drugs that increase energy expenditure and drugs that affect nutrient partitioning or metabolism. The mode of action, ef®cacy and safety of each approach will be brie¯y discussed. RESULTS: All of the pharmacological possibilities have potential activities, but also serious limitations. While current anti-obesity pharmacotherapy essentially uses centrally-acting anorectic drugs, severe side-effects (more particularly pulmonary hypertension and valvular heart disease) have been reported, leading to the withdrawal of licensed fen¯uramine and d-fen¯uramine. New approaches have been recently proposed, such as sibutramine, an amine reuptake inhibitor which decreases food intake, and orlistat, an intestinal lipase inhibitor which decreases fat absorption. Obesity is a chronic disease and should be treated as such with reasonable expectations. Large-scale one-year placebo-controlled studies demonstrated that d-fen¯uramine, sibutramine and orlistat signi®cantly increased body weight loss by an average of 2 ± 4 kg when compared to placebo and, more interestingly, multiplied by 2 ± 3 the number of patients who succeeded in obtaining and maintaining a reduction of more than 10% of initial body weight. Interestingly, some of these compounds may also exert favourable effects on other vascular risk factors, indepen- dently of weight loss. CONCLUSIONS: Even if all anti-obesity pharmacological approaches can be helpful, they also have important limitations so that other strategies including either combined therapies or new drugs (peptides) are currently under investigation. Keywords: anorectic drugs; appetite; energy expenditure; nutrient partitioning; weight loss; risk factors Introduction Considering the controlled system regulating body weight, three different mechanisms may be used to classify pharmacological treatments of obesity: (1) Obesity prevention and management should be given drugs that reduce food intake; (2) drugs that increase as much priority and skill by all professionals as it energy expenditure; and (3) drugs that affect metabo- would be given to any other common chronic disease lism or nutrient partitioning.1,4,5±7 Although the phar- with such serious consequences.1,2 The basis of obe- macological approach for the last decades was mainly sity management is very simple but the expectations based on the use of centrally-acting appetite-suppres- are usually unrealistic3 and the treatment using con- sing agents,9 various drugs are under development servative methods (low-calorie diet and regular phy- which open new perspectives for the treatment of sical exercise) remains a largely unachieved goal.1 obesity. Several pharmacological approaches have been pro- posed to promote weight loss and=or minimize weight regain (review in refs.4±7) and the need for and logic of anti-obesity drug treatment have been recognized.8 Drugs that reduce food intake While the pharmacological market of anti-obesity drugs remained almost unchanged for several decades, the last year has been characterized by two major By diminishing appetite, anorectic drugs result in a events: ®rst, the withdrawal, because of reported reduction of food intake which over time leads to a serious side effects, of two drugs widely used in loss in body weight and fat mass. Anorectic drugs can Europe and in the US (fen¯uramine and dexfen¯ur- play a useful role in an overall weight reduction programme, and should only be prescribed as part of amine); and second, the ®nal clinical development of 9 two promising new compounds with different modes such a programme. of action (sibutramine and orlistat). Noradrenergic drugs Correspondence: Prof AJ Scheen, Division of Diabetes, CHU Sart All of the currently available appetite-suppressing Tilman (B35), B-4000 LieÁ ge 1 Belgium. drugs, except mazindol, are derivatives of phenylethyl- Anti-obesity drugs AJ Scheen and PJ LefeÂbvre 48 amine (amphetamine, phenmetrazine, amfepramone Fluoxetine. Fluoxetine is a well-known antidepres- or diethylpropion, phentermine, phenylpropanol- sant drug which acts by inhibiting the reuptake of amine). Noradrenergic drugs release norepinephrine serotonin into presynaptic neurons and which also or block its reuptake into neurons of the hypothala- exerts anorectic activity.14 It is worth of noting that, mus. The only exception is phenylpropanolamine in contrast to fen¯uramine, ¯uoxetine does not stimu- which acts as an alpha-1 adrenergic agonist.4 ± 7,9 late serotonin release. This characteristic may explain Among the catecholaminergic anorectics, ampheta- why no cases of pulmonary hypertension or of cardiac mine and phenmetrazine are no longer recommended valvular abnormalities have been described with this because of their strong stimulatory properties and compound despite a very wide utilization as an anti- addictive potential. Amfepramone (diethylpropion), depressant drug. That ¯uoxetine is an effective anor- phentermine, phenylpropanolamine, and mazindol ectic agent promoting weight loss has been con®rmed have reduced stimulant action but preserved anorectic in the obese subject, even in the absence of depres- effects. Side effects of a sympathomimetic nature may sion.15 However, the dose effective to reduce body occur in some subjects. These drugs should be used weight is higher (60 mg=d) than that generally used in with care because of the danger of psychological the role of anti-depressant drug (20 mg=d) and the dependence and drug abuse, although most obese effect may be transient as a signi®cant weight regain people do not experience this dif®culty. Recently, has been reported between 6 and 12 months after more serious side effects such as pulmonary hyperten- starting chronic treatment.15 sion10 and valve heart disease11 have been described, but most cases were observed when these noradrener- gic drugs (essentially phentermine) were prescribed Drugs affecting both norepinephrine and serotonin together with fen¯uramine (see below). Interestingly, intermittent treatment is as good and cheaper than Drug combinations. As both norepinephrine and continuous treatment with such catecholamine- 9 serotonin affect food behaviour, and as drugs acting mediated drugs. on either norepinephrine or serotonin are available, the temptation was high to combine such compounds Serotoninergic drugs (especially phentermine fen¯uramine in the US and amfepramone fen¯uramine in some European coun- tries such as Belgium) in order to improve the ef®cacy Fen¯uramine and dexfen¯uramine. Fen¯uramine on weight loss or to minimize side effects by reducing and dexfen¯uramine are metabolized in the liver to the dosage of each anorectic agent.16 The combination d-norfen¯uramine which enhances serotonin release of phentermine and fen¯uramine has attracted con- from the neurons and acts as an agonist for 5-HT2C siderable medical and media attention in the US since receptors. In addition, d-fen¯uramine acts to block the publication of a long-term trial which suggested reuptake of serotonin into the neurons. These pro- 17 4 ± 7,9 the ef®cacy and safety of such a combination, and cesses concur in decreasing food intake. The these results were con®rmed in another large study.16 clinical ef®cacy of fen¯uramine (60 mg=d) and dex- However, the recent publication pointing out the risk fen¯uramine (2 Â 15 mg=d) has been demonstrated in of severe valvular cardiac abnormalities with the trials of short and long duration conducted over the combination phentermine ± fen¯uramine,11 associated past 30 years and was almost similar to that reported 10 12,13 with the potential risk of pulmonary hypertension, with noradrenergic agents. In contrast to catecho- has recently thrown discredit on such a combined laminergic drugs, serotoninergic compounds should therapy. be used continuously and do not exert stimulant or sympathomimetic activities nor induce tolerance. However, although it was generally considered that Sibutramine. Sibutramine is a beta-phenethylamine, these compounds have a wide margin of safety, initially developed as antidepressant agent, with an several reports of pulmonary hypertension10 and, interesting pharmacological pro®le. It inhibits the more recently, of cardiac valvular abnormalities,11 reuptake of both norepinephrine and serotonin at have been published. Despite the fact that only very nerve endings, making it functionally similar to a few cases of valvular heart disease have been combination of a noradrenergic drug and a serotoni- described with the use of these serotoninergic drugs nergic drug.18,19 Devoid of anti-depressant activity, it alone, these dramatic observations led the Servier decreases food intake through b1 and 5HT2A=2C company to withdraw, by caution, both fen¯uramine receptor agonist activity. In contrast to the association and dexfen¯uramine from the world market. It still fen¯uramine ± phentermine, sibutramine does not sti- remains unclear, however, whether treatment with mulate norepinephrine