Necessity of New Antidiabetics
Despite the epidemic of T2D, leading medical authorities have recently questioned the need for new drugs to treat the disease. In 2006, the ADA and the European Association for the Study of Diabetes (EASD) published a consensus statement on optimal ways to treat T2D using current oral antidiabetics and insulin. These recommendations emphasized using the older, more inexpensive drugs: insulin, metformin, and sulfonyureas (of which the latter two are available as generics), as well as the more expensive, branded thaizolidinediones (TZDs), pioglitazone (Lilly’s Actos), and rosiglitazone (GlaxoSmithKline’s Avandia).
The consensus statement de-emphasized the use of the more recently approved agents: exenatide (Amylin/Lilly’s Byetta) and pramlintide (Amylin/Lilly’s Symlin). The latter two drugs were rejected because of their expense, their lesser efficacy in lowering plasma glycosylated hemoglobin (HbA1c, a measure of long-term glycemic control) than the older drugs, and the lack of experience in using the newer drugs in the medical community.
In early 2007, the head of the panel that developed the consensus statement, David M. Nathan, M.D., at Massachusetts General Hospital and Harvard Medical School, published a Perspective in the New England Journal of Medicine that questioned whether the novel drugs launched in the last two years including exenatide and pramlintide as well as sitagliptin (Merck’s Januvia), which the FDA approved after the publication of the ADA/EASD consensus statement, are necessary to treat type 2 diabetes or even whether at least some of them should have been approved at all.
As in the ADA/EASD consensus statement, the reason for this conclusion was that the efficacy of the newer drugs in lowering HbA1c is less than that of established drugs, there is little experience in using them in humans (especially in the case of Januvia, which was approved after a few clinical trials), they may have new side effects that may emerge during the postmarketing period, and they are expensive.
Since the publication of Dr. Nathan’s Perspective, the safety of the TZD Avandia has been questioned. This is the result of the publication of a meta-analysis by cardiologist Steven Nissen, M.D., that concluded that Avandia increased the risk of myocardial infarction (MI) in diabetics by approximately 40%.
A later meta-analysis by Dr. Nissen concluded that the other marketed TZD, Actos, in contrast to Avandia, reduced the risk of MI in diabetics. The results of these meta-analyses are controversial. However, both TZDs are known to increase the risk of heart failure in diabetics. In August 2007, the FDA mandated a new black box label warning on the risk of heart failure for both TZDs.
In his Perspective, Dr. Nathan stated that, in his opinion, type 2 diabetes is already treatable with fairly safe and effective established drugs and that the biggest issue is to implement currently available therapeutic regimens aggressively, not to develop and market new classes of drugs.
The result of the new safety concerns with TZDs, as well as their expense, would seem to mandate focusing on treatment with the three older classes of antidiabetic drugs following the logic of the ADA/EASD consensus statement and Dr. Nathan’s Perspective. To the extent that this approach is valid, it would put a damper not only on the use of the newer classes of marketed drugs but also on the development of agents now in corporate pipelines and on further diabetes R&D.