The fruits of pharmacological research and innovation are producing a rapidly growing number of new products in new categories for the treatment of hyperglycemia in patients with diabetes, especially type 2 diabetes. We now have at least four discreet, separable, and unique pharmacological categories of anti-diabetic oral agents. These compounds have greatly improved our ability to control hyperglycemia given only modest compliance on the part of patients.

In contrast, the promised revolution in pharmacologically assisted weight-loss programs has collapsed into a debacle of potentially severe toxicity of unknown proportions. The scope of the cardiovascular toxicity produced by fenfluramine, phentermine, or a combination of both popularly known as "phen-fen," is presently unknown. Dex- fenfluramine (sold as Redux in the United States), is also associated with cardiovascular problems of a somewhat different nature, most specifically primary pulmonary hypertension.

Cardiac events and cardiac death have been attributed to each of these dietary adjuncts alone or in combination. This is remarkable considering their relatively short life span in the American market. One might have expected cardiac valvular toxicity to appear years after initiation of a pharmacological agent. Similarly, the striking and rapid development of primary pulmonary hypertension soon after the initiation of therapy (within a matter of one to several months) produces concern regarding the actual incidence of such toxicity after prolonged periods of therapy.

Initially, practitioner enthusiasm for pharmacologically assisted weight loss was based on the idea that such agents would be used for a relatively short time period, as a means of helping patients begin on a path toward attaining and maintaining a normal body weight. This approach appears to be less and less common. Instead, the concept of pharmacologically assisted weight loss is slowly being replaced by the concept of pharmacologically dependent weight loss.

Without continued administration of such agents, the failure of most previously obese patients to maintain weight loss seems quite probable. Generally, rates of return are no different with pharmacology than with other forms of weight reduction, and are perhaps not even as satisfactory as behavioral modification. We now recognize that obesity is a lifelong chronic illness requiring continuing lifelong attention and commitment of a rather substantial degree to reverse obesity and maintain reasonably normal body weight.

Physicians are, in many ways, no better than their patients. The frustrations of multiple failed weight-loss attempts are as difficult for physicians to bear as they are for patients. Both have a clear need for long-term therapies that make weight reduction easier than it is with currently available techniques.

Clearly, the era of "easy" is over now, even before it truly began. Long-term use of anorectic agents seems out of the question in light of recent revelations regarding their toxicity. The status of lipase inhibitors such as Xenical (orlistat) is presently unclear. The application for Food and Drug Administration (FDA) approval of orlistat was withdrawn due to adverse effects. Because of inadequate safety data and the high rate of reported adverse reactions, this agent may never be made available for widespread clinical use.

Not one of these agents, nor any of those currently in development, has been subjected to the same long-term scrutiny and risk/benefit analysis as have agents in other fields, especially the cholesterol-lowering compounds. In retrospect, it is clear that most long-term, chronic therapies must be subjected to long-term safety studies and calculations of risk/benefit ratios in order to assess whether the merits of long-term exposure to these compounds outweigh the potential hazards they create. Reductase inhibitors for hypercholesterolemia have passed such rigorous scrutiny. In other areas, particularly that of weight-loss agents, scrutiny of that level has never been applied. If obesity is a lifelong disease and if weight loss is to become an event dependent upon continuous pharmacological treatment, then long-term safety and toxicity studies must be made available before pharmacological agents can be employed in a chronic fashion.

In the interim, what are we to make of the current status of anorectic agents, particularly for patients with type 2 diabetes? The data suggest that short-term pharmacological use for assisted weight reduction may be acceptable. In the case of patients with serious chronic illnesses such as diabetes, the need for pharmacological compounds sustaining persistent weight loss seems obvious. Short-term therapies alone will not produce the kind of long-term diabetes control necessary to avert the chronic complications of the illness. For these reasons, even short-term initiation of pharmacologically assisted weight-reduction programs seems ill-advised at best, not only because of the increased risk of cardiovascular and pulmonary problems resultant from these exposures, but also because the diabetic state is a lifelong condition. However few adverse reactions of any agent there may be, the likelihood of long-term benefit to patients is smaller still.

Unless and until long-term safety and risk/benefit data become available regarding any proposed pharmacological intervention for weight loss in patients with chronic illnesses such as diabetes, reliance on such easily prescribed agents as part of the disease management program simply shifts attention attention away from far safer but less readily accepted weight-reduction treatments such as exercise and diet, perhaps with behavioral modification techniques.

Thus, I think it clear that the era of easily achieved weight loss is over, however brief its life span. We are not likely to see such an era again in the foreseeable future. For some, this means that the old ways, although inefficient, may still be the safest. For others, it means delay and a continuing search for other fast and easy treatments hopefully to become available with adequate safety documentation in the not-too-distant future.