Some Doubts About the Mantra on the Deleterious Cardiovascular Effects of Sulfonylureas

Patients with type 2 diabetes are at increased mortality risk, mainly because of cardiovascular disease (1). On the basis of the evidence that a pharmacological approach against hypertension, dyslipidemia, and hyperglycemia is needed to tackle this devastating clinical outcome (2), such patients are usually aggressively treated. In the U.S., prescribed retail pharmaceutical spending accounted for approximately half of the annual diabetes cost, which approximated $100 billion in 2013 (3). How long will we be able to cope with such a burden, especially considering it is likely to increase over the next decades (4)? Under this scenario, it is both ethical and smart to pay attention to the costs.In treating hyperglycemia we are facing a tendency, partly driven by pressure from pharmaceutical companies, to abandon the old, well-known, and cheap sulfonylureas in favor of new and costly glucose-lowering molecules. One of the reasons given is that there is a deleterious effect of sulfonylureas on cardiovascular disease suggested by various observational studies but never proven by randomized clinical trials (5–7), the gold standard approach for addressing similar issues. Unfortunately, as sulfonylureas entered the market long before the U.S. Food and Drug Administration request of cardiovascular risk assessment for novel antidiabetes drugs to be approved (8), an adequately powered cardiovascular trial on sulfonylurea therapy is not available. One should, therefore, wonder if the mantra of cardiovascular deleterious effects of this class of drugs is destined to last forever.Recently, genetic studies have been appropriately designed to get deeper insights on on-target drug pleiotropic effects, such as that of GLP-1 agonists on cardiovascular outcomes (9) or that of statins on the risk of type 2 diabetes …