CURRENT AND FUTURE DRUG TREATMENT OF OBESITY

Richard L. Atkinson , M.D. (About the Speaker)
United States

Abstract:

Obesity is a chronic disease, and like other chronic diseases, will require long term treatment. Single treatments, whether they be lifestyle changes or drugs generally have quite modest effects over the long term. Virtually all other chronic diseases are treated with more than one intervention and clearly obesity will require combination treatment as well. The combination of diet, exercise, and behavior modification ("lifestyle change") is viewed as "standard treatment", but has a poor long term success rate. Diet, exercise, and behavior modification combined with obesity drugs is somewhat more positive. The rigid structure of a dietary supplement as a meal replacement helps some people. However, the future of the treatment of obesity likely will reside with drugs and particularly with combinations of obesity drugs. Drugs change the biochemistry of the body and it is clear that obese people have a different biochemistry than do non-obese people. Food intake, energy expenditure, and storage of calories as fat have been so essential to survival of all organisms on Earth that it is not surprising that there are multiple redundant systems to stabilize them. Single drug treatments usually affect only one biochemical pathway or physiologic system. Single drugs currently used for the treatment of obesity all show modest weight loss. The current drugs used singly are adrenergic agonists (eg phentermine); orlistat, a lipase inhibitor; and locaserin, a 5-HT2c serotonin re-uptake inhibitor. Phentermine may produce a 10% or more wt loss, but orlistat and locaserin produce only about a 5% wt loss. Until recently, there have been few combinations of obesity drugs studied or approved. The best known was the combination of phentermine and fenfluramine or dexfenfluramine. Phen-fen produced wt loss of ~16%, the largest wt loss of any obesity treatment except obesity surgery. The removal of fenfluramine and dexfenfluramine from the market relegated obesity treatment to single drugs again since the combinations of orlistat and either sibutramine or phentermine are reported to be ineffective. The combination of phentermine and fluoxetine attempted to reproduce the success of the combination of an adrenergic agent and a serotonergic agent. Phen-flu was not quite as effective as phen-fen, but since both drugs are available on the market, this combination may be used with caution for obese people by physicians willing to run the risk of displeasure of the governmental authorities. Recently the combination of phentermine and topiramate has been approved. Studies show a wt loss of 10%-13% at one year. The combination of bupropion and naltrexone is currently under consideration by the FDA and clinical trials show a weight loss of about 6%-8%. Locaserin is approved only as a single drug, but the combination with phentermine has a similar biochemical profile as phen-fen. It remains to be seen if this combination will give similar results as phen-fen. Potential future agents for obesity may fall into several categories, including CNS active agents, thermogenic agents, and nutrient partitioning agents. A particularly interesting possibility for combination drug therapy are gut hormones or analogues of gut hormones since it appears that the excellent clinical results seen with obesity surgery are due mainly to alterations of gut hormones. Gastric bypass and similar surgical procedures work by altering the biochemistry of the body and not by mechanical mechanisms. It is possible we eventually may be be able to reproduce these effects with drugs. In this category, liraglutide, a GLP-1 agonist has been shown to be quite effective for diabetes and is in clinical trials as an obesity drug. Initial reports suggest it alone causes an 8% wt loss. We are in our infancy of understanding obesity, its causes and its treatments. The belated interest of the drug companies and the more favorable attitude of the FDA for obesity drugs predict a bright future.