New approaches to the pharmacological treatment of obesity: Can they break through the efficacy barrier?

Abstract

In this review we assess the range of centrally active anorectics that are either in human clinical trials, or are likely to be so in the near future. We describe their weight loss efficacy, mode of action at both pharmacological and behavioural levels, where understood, together with the range of side effects that might be expected in clinical use. We have however evaluated these compounds against the considerably more rigorous criteria that are now being used by the Federal Drugs Agency and European Medicines Agency to decide approvals and market withdrawals. Several trends are evident. Recent advances in the understanding of energy balance control have resulted in the exploitation of a number of new targets, some of which have yielded promising data in clinical trials for weight loss. A second major trend is derived from the hypothesis that improved weight loss efficacy over current therapy is most likely to emerge from treatments targeting multiple mechanisms of energy balance control. This reasoning has led to the development of a number of new treatments for obesity where multiple mechanisms are targeted, either by a single molecule, such as tesofensine, or through drug combinations such as qnexa, contrave, empatic, and pramlintide + metreleptin. Many of these approaches also utilise advances in formulation technology to widen safety margins. Finally, the practicality of peptide therapies for obesity has become better validated in recent studies and this may allow more rapid exploitation of novel targets, rather than awaiting the development of orally available small molecules. We conclude that novel, more efficacious and better tolerated treatments for obesity may become available in the near future.

Introduction

Obesity is a chronic state associated with a wide range of metabolic and cardiovascular conditions such as dyslipidaemia, atherosclerosis, hypertension and type 2 diabetes which also substantially increase the risk of stroke, angina and myocardial infarction. Obesity also predisposes to colon, breast, kidney and digestive tract cancers. In addition, non-life threatening disease states associated with obesity include arthritis, sleep apnea, gallstones and gout as well as low self esteem and affective disorder (Heal et al., 2009). There is also growing evidence that obesity and type II diabetes may predispose towards Alzheimer's disease (Luchsinger and Gustafson, 2009). Unfortunately, the increasing adoption of Western diet and sedentary lifestyle throughout the world is causing a global increase in obesity and, unless checked, is expected to become an indirect but leading cause of mortality and morbidity (Heal et al., 2009). Diet and exercise are the most obvious remedies for obesity but have proved ineffective for most individuals (e.g. Wu et al., 2009). Pharmaceutical companies have therefore sought to discover novel therapies that could serve as adjunctive treatments in support of diet, exercise and lifestyle modification regimes (Table 1).

To this end, a number of treatments have been introduced for the treatment of obesity. The most widely used at present are phentermine, sibutramine and orlistat. All three are associated with between 3 and 5% body weight loss over 6–12 months (see Table 2) in addition to that achieved by placebo controls (Li et al., 2005). Efficacy of this magnitude seems undeniably modest, but is only just below the criterion of 5–10% weight loss that is associated with clinically meaningful reductions in the risk of obesity co-morbidities (Goldstein, 1992, Knowler et al., 2002). One of the principal reasons that all three of these most commonly prescribed agents fail to exert greater efficacy is the need to limit dosage to avoid significant tolerability issues. Indeed, the most efficacious of the three, sibutramine, can no longer be prescribed in Europe due to concerns of increased risk of heart attacks and strokes (See Section 7.9). The use of phentermine is also limited by the risk of cardiovascular effects and abuse potential (See Section 7.7) and it is not available for use in Europe. In contrast to both sibutramine and phentermine, orlistat, a gut lipase inhibitor, is not associated with major safety concerns. Indeed, the drug is itself not absorbed from the gut. However, by preventing the breakdown of ingested fats in the gut and thereby preventing their absorption, orlistat causes socially undesirable side effects such as oily stools, faecal spotting and faecal urgency, diarrhoea, flatulence, dyspepsia and gastric pain (Li et al., 2005, Filippatos et al., 2008). Orlistat also interferes with the absorption of many drugs and fat soluble vitamins, the latter giving concerns over the effects of long term use (Filippatos et al., 2008).

For these reasons, new treatments for obesity that are better tolerated and more efficacious are urgently needed.