Advances in the Long-Term Treatment of Obesity


  • Samuel Klein MD

    Corresponding author
      Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St. Louis, MO 63110. E-mail:
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  • On December 1, 2004, Johnson & Johnson Pharmaceutical Research & Development announced discontinuation of the current clinical development program for its controlled-release formulation of topiramate in obesity and type 2 diabetes.

Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St. Louis, MO 63110. E-mail:

Obesity is a major health problem in the United States and many other countries in the world because of its increasing prevalence, causal relationship with serious clinical abnormalities, and financial costs associated with providing medical care for obesity and obesity-induced diseases. According to a national survey conducted during 1999 to 2000, ∼64% of adults (20 to 74 years old) and 15% of children and adolescents (6 to 19 years old) were obese or overweight, defined by a BMI of 25 kg/m2 or more in adults and by an age- and sex-specific BMI ≥ 95th percentile based on the National Center for Health Statistics growth charts in children and adolescents (1). Obesity has serious clinical consequences and is associated with dyslipidemia, high blood pressure, type 2 diabetes, coronary heart disease, liver disease, osteoarthritis, sleep apnea, various cancers, and other health problems. A specific constellation of metabolic abnormalities [i.e., increased waist circumference, insulin-resistant glucose metabolism (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes), dyslipidemia (high serum triglyceride and low serum high-density lipoprotein-cholesterol concentrations), and increased blood pressure] is known as the metabolic syndrome and is associated with an increased risk of coronary heart disease and stroke. Obese persons are also more likely to have low self-esteem and impaired quality of life and to experience discrimination than lean persons (2). The medical care costs for overweight and obese persons accounted for 9.1% of total U.S. medical expenditures in 1998 and $92.6 billion in 2002 (3).

Weight loss is an important therapeutic goal for obese persons because it improves or completely resolves obesity-related medical complications and can prevent the development of new obesity-related diseases. For example, even moderate weight loss (5% of body weight) and increased physical activity can improve insulin action, decrease fasting blood glucose concentrations, reduce the need for hypoglycemic medications in patients who have type 2 diabetes (4), and prevent the onset of diabetes in high-risk persons (5, 6). Although many obese persons can achieve moderate weight loss, long-term weight management success is difficult, and people who are able to lose weight often regain their lost weight over time. Recent clinical and basic scientific advances have increased our understanding of the pathogenesis, pathophysiology, and therapy of obesity. This supplement, based on a symposium that was held in October 2003 at the annual meeting of the North American Association for the Study of Obesity, reviews the key issues and advances in the long-term, nonsurgical management of obese persons.

In the first article, Dr. Thomas Wadden reviews the nonpharmacological approach to obesity management, with a focus on examining how behavioral methods can be used to improve long-term weight control. Maintaining patient motivation is critical for successful weight management and requires long-term contact with the health care team.

In the second article, Dr. Samuel Klein reviews the safety and efficacy of long-term pharmacotherapy for obesity. The article focuses on sibutramine and orlistat, which are the only two agents approved by the Food and Drug Administration (FDA) for long-term weight loss.

The third article, by Dr. Arne Astrup, discusses current knowledge of the safety and efficacy of topiramate for treating obesity. Topiramate, which is approved by the FDA to treat specific seizure disorders, is currently undergoing clinical investigation for the treatment of obesity.*Dr. Astrup reviews three large clinical trials that evaluated the use of topiramate: a 6-month dose-ranging study, a 1-year weight loss study, and a 44-week weight loss maintenance study.

In the final article, Dr. Pi-Sunyer describes the pathophysiology and potential therapy of the metabolic syndrome. Successful management of metabolic syndrome requires early recognition and reduction of insulin resistance by implementing lifestyle interventions and appropriate obesity pharmacotherapy when necessary and by treating specific metabolic syndrome abnormalities.