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 (10). Along this line, the study by Emdin et al. (11) in this issue of Diabetes adds important, and somehow reassuring, evidence on the cardiovascular effect of sulfonylureas. The common p.A1369S nonsynonymous polymorphism in ABCC8 (the gene encoding for SUR1, a component of the sulfonylurea receptor) was used as a naturally occurring model of SUR1 activation to test for an association with coronary heart disease (CHD) in 120,286 participants from the UK Biobank and in summary data from several previous genome-wide association studies. In addition, the authors investigated the association with type 2 diabetes and various cardiometabolic traits. Data obtained by this intelligent study design clearly show that the p.A1369S amino acid change, previously known 1) to mimic in vitro the pharmacological effects of sulfonylureas by promoting closure of the ATP-sensitive potassium channel (12), 2) to increase in vivo insulin secretion (13), and 3) to protect from type 2 diabetes (13,14), was in fact associated with a reduced risk of CHD and a composite cardiovascular end point, including stroke, heart failure, and peripheral vascular disease (per allele reduction equal to 2% and 3%, respectively). Each copy of the p.A1369S variant was also associated with a 7% lower risk of type 2 diabetes, thus replicating previous findings (13). This makes it possible to calculate that per 10% reduction in type 2 diabetes risk the ABCC8 p.A1369S variant exerts a 4% reduction on CHD risk. Such a relationship is very similar to that reported for a missense variant in GLP1R, encoding the GLP-1 receptor, the specific target of GLP-1 agonists, which—notably, in our specific context—have been recently reported to be cardioprotective (15,16). Although association studies cannot provide definite mechanistic evidences, one cannot avoid asking how ABCC8 p.A1369S exerts such positive effect on cardiovascular outcomes. Considering that SUR1 is mostly expressed in brain, pancreatic (a, b, and d), and other neuroendocrine cells (17), it is unlikely that ABCC8 p.A1369S acts directly on the vasculature and heart. By referring to previous studies addressing the role of genetic predisposition of diabetes on the risk of CHD (18), Emdin et al. (11) suggest that the cardioprotective effect of p.A1369S variant is based on more than just diabetes risk reduction. Although this is an intriguing possibility, it remains truly impossible to determine whether and to what