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Out with the new, in with the old
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In 2011, there was a continuation of trends from the past few years toward increasing emphasis on drug safety by the FDA. Unfortunately, the wrong aspects are being emphasized.
We are seeing an expansion of the tendency to emphasize rare untoward events while overlooking the potential for much more frequent untoward events of the agents under review — or of comparable agents already approved — or of the disease state itself. This obsession with the rare and the new began with the controversy regarding excess coronary heart disease risk with rosiglitazone (Avandia, GlaxoSmithKline) and has spread inexorably into most clinical issues touching the diabetes and endocrinology arena.
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Indeed, whereas the FDA does not regard prediabetes as an approvable disease entity and considers obesity an entity even more remotely related to diabetes, there seems to have developed a tendency to include CHD assessments into the profile of anti-obesity agents. Thus, the three recently submitted and reviewed anti-obesity agents considered at advisory boards were heavily scrutinized for potential excess CHD risk, and overall approval was granted to none of these agents by their respective advisory boards.
Although the agency has yet to act to produce final decisions regarding the approval or approvability of these drugs, it is clear that there is tremendous reluctance to clear them as long as there is a scintilla of skepticism regarding the existence of any adverse consequence of these agents. Of course, the rampant near-epidemic spread of obesity worldwide seems not to have affected these discussions in any measured manner. This indicates a clear imbalance between the occurrence of rare adverse effects of agents compared with the demonstration of widespread benefits with respect to the specific diseases for which they seek approval. In this instance, the rare trumps the widespread.
In the case of antidiabetic drugs, 2011 saw an FDA advisory board become obsessed with an imbalance of nine excess cases of breast cancer and nine excess cases of bladder cancer in the database of the first of a new class of oral antidiabetic agents — the SGLT2 inhibitors. Although this imbalance was not statistically significant, it became almost the principal focus of the advisory board’s discussions and crowded out needed discussions in other areas, such as potential adverse effects on bone and kidney function.
Moreover, this agent had clear and evident benefits with respect not only to glucose control, but also an absence of hypoglycemia and some weight loss rather than the more usual weight gain. Thus, there is much to recommend this agent as an addition to the existing antidiabetic armamentarium.
The absence of hypoglycemia is often given short shrift in the evaluation of medications for type 2 diabetes because many believe that hypoglycemic episodes are rare with type 2 patients and are limited to patients taking insulin, especially intensive, complex basal-bolus regimens. Nothing could be further from the truth. In the ADOPT study, patients taking glyburide had a 39% total rate of hypoglycemia during the study. This was dismissed as the fault of glyburide, which is widely thought to have a high rate of hypoglycemia, unlike the other sulfonylureas.
More recently, we saw in the ADVANCE study that a mild sulfonylurea, gliclazide — thought to have a very low rate of hypoglycemia — produced an overall rate of 52% hypoglycemia, and severe hypoglycemia was associated with a tripling of mortality and of major adverse coronary events. This, too, seems to have been minimized in the minds of many, and the use of sulfonylureas continues undeterred.
Late in 2011 came the stunning report by Budnitz and colleagues in The New England Journal of Medicine showing that antidiabetic drugs are the second most frequent class of agents producing ED visits for adverse drug effects.
Because this study was performed using the Medicare population, it is unlikely that there were many type 1 diabetic patients and that the use of sulfonylureas was likely to be substantial. We may, therefore, conclude that the weight of evidence suggests that hypoglycemia in type 2 patients is not only undesirable, but is also lethal and expensive to deal with in the ED.
This nullifies any advantage of lower drug costs with generic sulfonylureas; makes the approval of therapies free of hypoglycemia almost mandatory; and suggests that the FDA consider the adverse effects of competing existing therapies when evaluating new therapies for complex and highly prevalent disease states such as diabetes.
We can only hope that 2012 will bring these changes.
Alan J. Garber, MD, PhD, is the Chief Medical Editor of Endocrine Today.