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Drugs for the treatment of obesity
New understanding of the molecular causes and medical consequences of obesity are inverting old models of pharmacologic treatment of obesity and many related conditions, said two physicians speaking in late January in San Antonio at the annual Nutrition Week sponsored by the American Society for Parenteral & Enteral Nutrition (ASPEN).
"In the past, clinicians treating hypertension, dyslipidemia, impaired glucose tolerance, and diabetes paid too little attention to obesity's causal influences in those conditions, but that is changing," noted Louis J. Aronne, M.D., clinical associate professor of medicine at Cornell University.
With obesity increasingly recognized as a causal factor in those and many other serious health conditions, more effort is being made to reduce excess weight to lower risk of those diseases, said Aronne. Caloric restriction and increased physical activity are safe and effective, but only 20% of overweight Americans use those methods, he said, even though almost two-thirds of the U.S. population now is overweight or obese.
Early use of weight-loss drugs as short-term adjuncts to behavioral treatment proved ineffective, and the popular combination of fenfluramine and phentermine ("fen-phen") had to be discontinued when fenfluramine was linked to heart valve disease, noted Aronne. And some early weight-loss drugs were abused.
Fortunately, improved understanding of molecular mechanisms involved in overeating, fat accumulation, and related phenomena has produced two new drugs effective against those mechanismsorlistat (Xenical, Roche) and sibutramine (Meridia, Abbott Laboratories)and neither is a drug of abuse, he said. Orlistat can cause oily stool, and sibutramine can increase blood pressure and heart rate, but careful patient selection and monitoring for side effects are solutions there, he maintained.
The recently completed XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study showed Xenical plus diet and lifestyle changes produce more weight loss and prevent progression of impaired glucose tolerance to diabetes better than the combination of diet and lifestyle alone, Aronne told the audience. In that trial, a 4% weight loss for four years reduced risk of diabetes by 58%, he noted.
"For a long time people would ask whether it could be proved that if someone loses weight, that clearly benefits his or her health," Aronne said. "Well, what greater benefit could there be for someone who is obese than that he doesn't develop diabetes?" he asked. Those results are helping swing more momentum to the new paradigm of treating obesity before it produces more problems, he noted.
But problems with the first generation of obesity drugs left some clinicians and patients reluctant to try pharmacologic treatment of obesity, and Aronne said some still have what he calls a "double standard" where obesity is concerned. "If a kid is not doing well in school, we give him amphetamines, and that's OK. But if he weighs 400 pounds, we don't want to prescribe antiobesity drugs because they can have side effects," he explained. "That needs to change."
Neither new drug is best for everyone, Aronne stressed, and likelihood of efficacy is increased when pharmacists and physicians help patients understand how the drugs work and counsel them against acting in ways that defeat the drugs' mechanisms of action, he said.
Sibutramine induces feelings of satiety by inhibiting uptake of norepinephrine and serotonin, so it isn't effective taken at bedtime or after meals, Aronne said. Orlistat inhibits fat absorption and won't work well if taken with low-fat meals, he added.
Following Aronne's presentation, David J. Goldstein, M.D., Ph.D., of PRN Consulting, told Nutrition Week participants why drug developers are excited about what is happening now. "Increased understanding of mechanisms involved in behavior influencing obesity leads us to a large number of molecular targets, and the Food & Drug Administration has shown with approval of orlistat and sibutramine its recognition of what is possible with this approach," he said.
Some new drug candidates block receptors for substances that could end up as stored fat, noted Goldstein, while others increase thermogenesis through effects on insulin, leptin, neurotensin, and other hormones, or decrease thermogenesis through effects on neuropeptide Y (NPY), glucocorticoids, or similar compounds.
The potential targets are many and their interactions complex, said Goldstein. But the pattern is clear and encouraging: Antiobesity medications can work when well targeted to specific mechanisms causal to weight gain or weight homeostasis.
"There is reason to believe that some, if not all, of the new targeted therapies will work, and that clinicians and patients who have found medications necessary to control obesity may soon have increased numbers of effective pharmacologic tools available to them," concluded Goldstein.
Dale Chenoweth. Better antiobesity drugs changing thinking, treatments.
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