Pharmacological treatment of obesity: therapeutic strategies.

Abstract

Obesity is now a common disorder in the industrialized world.1 Much has been reported during the past several years in the popular press about the increasing incidence of obesity and the comorbidity of associated conditions. In addition, there have recently been fundamental advances in our understanding of factors which mediate hunger and satiety and those involved with energy utilization and storage. In this Perspective, we summarize the present state of research in the field of therapeutics targeted for obesity, including promising new approaches for the future. Obesity is a chronic condition characterized by an overabundance of adipose tissue and can be measured in a variety of different ways.2 Excess energy is stored in the form of triglycerides in adipose tissue, and increased adipose tissue mass can occur through increases in cell size, cell number, or both. Increased adipose cell size alone results in hypertrophic obesity which is relatively mild. Increased fat cell number, however, causes hyperplastic obesity characteristic of a more severe condition. While the volume of lipid an individual adipocyte can accumulate is finite, the capacity of adipose tissue to expand is virtually limitless. The most common obesity measure is the body mass index or BMI, defined as weight in kilograms divided by (height in meters)2. BMI values are easy to calculate and correlate well with rankings obtained from more sophisticated techniques and the cormorbidities associated with obesity. It is difficult to set a definitive BMI level threshold to define obesity, particularly for women in which excess weight is often found in the pelvis and not in the abdomen. For example, the BMI scale does not take the distribution of body fat or lean muscle mass into account. Nevertheless, obesity is defined by the World Health Organization as a BMI of 30.0 kg/m2 and above, with a BMI of 25.0-29.9 kg/m2 classified as overweight or preobese.3 A large body of epidemiological data correlates increased body weight with risks such as high blood pressure, coronary heart disease, diabetes, altered steroid metabolism, gallstones, and certain forms of cancer.4 In one study, involving a cohort of >115 000 female nurses over a period of 14-16 years, increased risks of cardiovascular disease and cancer were observed with increasing BMI. Excluding smokers from all groups, there was a 100% greater risk of death from all causes for a BMI of >29.0 kg/m2 relative to the risk of death for slender women (BMI of <19.0 kg/m2) during the course of the study.5 On the basis of an increasing awareness of the public health risks associated with excess weight, the American Heart Association has recently reclassified obesity as a “major, modifiable risk factor for coronary heart disease”.6 Second only to smoking, obesity is a major threat to the public health with ca. 300 000 deaths attributed annually in the United States.1,7 Our understanding of the prevalence of obesity in the U.S. population has come largely from the four cycles of the National Health and Nutrition Examination Surveys, conducted by the National Center for Health Statistics.8 In 1994, 55% of the population was considered overweight and 22.5% were obese. These alarmingly high levels represent a marked increase from previous years and are accompanied by a worldwide * Address correspondence to either author. A. B. Reitz: tel, 215628-5615; fax, 215-628-4985; e-mail, areitz@prius.jnj.com. C. P. Kordik: tel, 215-628-7986; fax, 215-628-4985; e-mail, ckordik@prius.jnj.com. © Copyright 1999 by the American Chemical Society