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Obesity is a significant healthcare problem worldwide and increases the risk of developing debilitating diseases including type 2 diabetes, cardiovascular disease, and cancer. Although the health benefits of weight reduction are well-recognized, weight loss by diet and exercise fail in most patients, and the current marketed drugs have had limited success. It is clear that there is a significant unmet medical need for safe and effective weight-reducing agents. In this review, the current status of potential weight loss approaches that are in development by the pharmaceutical and biotechnology industry are discussed. This should lead to novel treatments that can be used long-term to effectively treat this serious metabolic disorder.
Key Words: weight loss • antiobesity • pharmacotherapy • drug development • metabolic syndrome
We are in the throes of a global obesity crisis, which currently afflicts over 300 million adults in both industrialized and developing countries (1) . Excessive body weight increases the risk of developing serious and life-threatening diseases including type 2 diabetes, cardiovascular disease, and some forms of cancer (2) (3) (4) . Obesity is the direct cause of the epidemic of type 2 diabetes that is rapidly escalating at an alarming rate, and obesity is projected to overtake cigarette smoking as the leading cause of preventable death. There is clearly a significant unmet medical need for safe and effective weight-reducing therapies to prevent the debilitating metabolic diseases and mortality that are associated with increasing adiposity.
Numerous studies have demonstrated the health risks associated with weight gain and the benefits of intentional weight loss. A weight gain of 1 kg increases cardiovascular risk by 3.1% (5) and diabetes risk by 4.5% to 9% (6) (7) . Intentional weight loss of 11% of body weight is associated with a 25% reduction in cardiovascular disease and diabetes mortality (8) , and a weight loss of 4 kg in overweight subjects with impaired glucose tolerance reduced the risk of developing diabetes by 58% (9) .
A weight loss of 5% to 10% has a significant impact on improving cardiovascular risk factors and the progression to type 2 diabetes (8) (9) (10) (11) . However, even this modest degree of weight loss has been difficult to achieve in the obese population. Diet and exercise fail in the vast majority of patients, whereas the marketed drugs have had limited success. Thus, there is an important need to treat obesity to prevent the progression toward additional disease states such as diabetes and cardiovascular disease. This has led to an intense effort to identify new targets for pharmacological intervention. A number of agents that are being developed by the pharmaceutical industry are directed at inhibiting caloric intake and/or increasing energy expenditure by unique mechanisms. The current status of drugs that are in preclinical and clinical development are shown in Tables 123 . (The information was obtained from corporate press releases, web sites, publications, and patent searches.)
In the comprehensive review that appears in this issue, Dr. Harold Bays discusses the limitations of the drugs that are on the market, the current status of investigational antiobesity agents that are in development, and the novel targets that hold promise for the future. Although there are many challenges to developing novel pharmaceuticals to treat obesity, the extensive research that is ongoing within the academic and pharmaceutical community should yield safe and effective long-term treatments, which can be used, either alone or in combination, to treat this serious metabolic disease.
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