Pharmacotherapy for Obesity

A Field in Crisis?

Wiebke Fenske; Jennifer Parker; Stephen R Bloom

Disclosures

Expert Rev Endocrinol Metab. 2011;6(4):563-577. 

In This Article

Abstract and Introduction

Abstract

Despite the requirement for effective and safe pharmacotherapies to tackle the obesity epidemic, there is currently only one drug, orlistat, licensed for this purpose, but the effectiveness of this drug falls far short of the medical needs. Recent advances in the understanding of energy balance control have highlighted a number of new biological targets for the treatment of obesity. Some pharmacological approaches for bodyweight loss have yielded promising results in clinical trials. However, finding the correct balance between efficacy and safety has proven challenging. Given the high unmet need and our growing understanding of the complexity of bodyweight homeostasis, novel, more efficacious and better tolerated treatments for obesity are clearly required. In this article, we provide an overview of currently available anti-obesity agents, the reasons for the failure of a number of recent drug candidates and discuss future strategies for pharmacological interventions to treat obesity.

Introduction

Obesity is associated with a wide range of metabolic and cardiovascular conditions that substantially increase the risk of stroke, coronary heart disease and myocardial infarction.[1] The combination of widespread consumption of the energy-dense Western diet with an increasingly sedentary lifestyle has increased the global prevalence of obesity and the associated causes of mortality and morbidity. The WHO reported that in 2008, 500 million adults were obese globally, which is expected to rise to 700 million by 2015.[201] Approximately two-thirds of US adults are overweight or obese[2] and the obesity rate in English men increased from 13.2% in 1993 to 23.1% in 2005 and in English women from 16.4 to 24.8% during the same period.[202] Diet and exercise remain the most commonly prescribed strategies for weight loss, but have proved unsuccessful for many affected individuals.[3] Therefore, industrial interest in the development of effective pharmacological therapies has been sustained.

The approval criteria demanded of novel anti-obesity drugs as set out by the US FDA were revised in 2007,[203] necessitating a 5% or more mean placebo-subtracted weight loss after 1 year of therapy or a minimum of 35% of participants achieving more than 5% weight loss. The European Medicines Agency (EMA) guidelines similarly require a 10% or more weight loss over 1 year, which should be more than 5% above that achieved by placebo.[4] As an important secondary end point, the EMA also stipulate prevention of weight gain after cessation of therapy. Of note, both agencies also call for evidence of improvements in metabolic comorbidities as these are known to affect the cardiovascular risk more than weight loss alone. Treatments that induce weight reduction without specifically reducing cardiovascular risk are considered of primarily cosmetic benefit and would be less likely to gain approval for clinical use.

Despite these high demands for new drug approval, the market for a safe and efficacious drug is still potentially huge. However, the value of currently approved therapies that have effects on weight do not reflect this potential, which is evidence of their limited efficacy and/or unacceptable side-effect profiles. Persistent efficacy and safety, however, is of particular important in the management of obesity, which, as a chronic condition, requires ongoing therapy over decades to achieve and maintain weight loss.

This article provides an overview of the efficacy and safety of weight-loss therapies and addresses the therapeutic targets of past and current pharmacotherapies, as well those in advanced clinical development.

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