Anti-obesity drugs: a critical review of current therapies and future opportunities

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Abstract

The last 25 years have seen a great increase in the incidence of obesity, both in the Western world and in developing third world countries. Despite the seeming inexorable progression of this disease, there have been limited advances in the pharmacotherapy of this condition. Of the newest introductions to the obesity drug portfolio, orlistat, which acts to prevent dietary fat absorption, and sibutramine, which seems to affect both arms of the energy balance equation, were the first new chemical entities to be introduced for the treatment of obesity in 30 years. In this article, we review these and other agents available in various countries for the treatment of obesity. Perhaps more importantly, we have focussed on areas of potential productivity in the future. The huge recent increase in our knowledge in this area has largely stemmed from discovery research at the genomics level. Over the last 5 or so years, this impetus in obesity research has provided us with exciting new drug targets involved in the regulation of feeding behaviour and cellular mechanisms involved in energy expenditure. Compared with the last 25 years, the future offers more hope.

Introduction

It is clear to people living in the Western world that obesity is increasing, probably as a consequence of easily available, fat-rich food and an increasingly sedentary lifestyle. Interacting with the cultural changes is the influence of genetic predisposition, which is most easily demonstrated in populations that have evolved in situations where food supply was variable, for example, the North American Pima Indians. However, the genetic liability for the vast majority of the population does not reside in a single gene: obesity is a multigenic disorder. What is not apparently clear to people living in the Western world is the major health burden of obesity, not just in terms of the increased risk of Type 2 diabetes, cardiovascular morbidity, and cancer, but also in the economic costs to healthcare providers (McIntyre, 1998).

The obvious recourse to diet and exercise in the treatment of obesity is successful in just a small minority. When all else fails, many morbidly obese patients resort to surgical intervention, which, although effective, is not without risk in itself; risk exacerbated by gross overweight. There is a clear need for effective pharmaceutical intervention, but this appears to be an area in medicine with a very limited armamentarium, even today. The most effective drug treatment, a combination of fenfluramine with phentermine, could, in combination with diet, produce up to 30% reductions in body weight, but was withdrawn in 1997 when fenfluramine was found to cause valvular heart disease. The drug treatments on offer today are limited in their efficacy: in combination with diet, 10–15% reduction of body weight, of which at best 5% is attributable to the drug. Doubts have been raised on the long-term sustainability of this weight loss (Kolanowski, 1999). However, the health benefits of modest reductions in body weight have been recognised since the early 1990s Goldstein, 1992, Van Gaal et al., 1997.

In this article, we review existing drug therapies, but we also focus on areas of potential productivity in the future. Over the last 5 years, there has been an explosion in our knowledge of the mechanisms involved in regulating feeding behaviour and cellular mechanisms involved in energy expenditure. A rich harvest of potential new drug targets have arisen from this research, which may offer hope of safe and effective treatments for obesity. An indication of the potential impact of this research on new anti-obesity drugs is illustrated in Table 1, which lists drugs at Phase II of clinical trials or beyond. This review is broadly divided into drugs and drug targets influencing energy intake and factors affecting energy expenditure, although it must be recognised that many centrally acting “anorectic” drugs may also stimulate energy expenditure Arch, 1981, Picard et al., 1999.

Section snippets

Biogenic amines

Until recently, the only widely approved agents for the treatment of obesity were centrally acting appetite suppressants or anorectic agents. Even now, drug therapy options for obesity remain very limited, in spite of the epidemic scale of the disease. Public and practitioner perception of drug treatment of obesity has also been severely affected by the withdrawal of fenfluramine and dexfenfluramine in September 1997 as a result of mounting reports of heart valve defects. The centrally acting

Ephedrine/caffeine

Ephedrine (Fig. 10) is not new to medicine. It was first isolated over 100 years ago from the Asian plant ma huang, one of 40 species of the plant genus Ephedra, which itself has been used as a herbal remedy in Chinese medicine for over 2000 years. Today, ephedrine is widely available in over-the-counter remedies for nasal congestion and hay fever. Another well-established property of ephedrine is its anorectic activity and, hence, its use as an obesity treatment.

Following its introduction as

Future perspectives

The last 25 years have seen great increases in the incidence of obesity, but limited progress in the development of new anti-obesity drugs. The older agents have come under increasing pressure from regulatory agencies, and fenfluramine and dexfenfluramine have been withdrawn. To offset this bleak picture, orlistat and, in the United States, sibutramine recently have been approved, but sibutramine owes its discovery to its investigation in humans as an anti-depressant, its effect on body weight

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