Pro- and Antiarrhythmic Actions of Sulfonylureas: Mechanistic and Clinical Evidence

Abstract

Sulfonylureas are the most commonly-used second line drug class for treating type 2 diabetes mellitus. While the cardiovascular safety of sulfonylureas has been examined in a number of trials and non-randomized studies, little is known of their specific effects on sudden cardiac arrest and related serious arrhythmic outcomes. This knowledge gap is striking, as persons with diabetes mellitus are at increased risk of sudden cardiac arrest. This review explores sulfonylureas’ influence on the risk of serious arrhythmias, with specific foci on ischemic preconditioning, cardiac excitability, and serious hypoglycemia as putative mechanisms. Elucidating the relationship between individual sulfonylureas and serious arrhythmias is critical, especially as the diabetes epidemic intensifies and sudden cardiac arrest incidence increases in persons with diabetes.

Comparative cardiovascular and hypoglycaemic safety of glimepiride in type 2 diabetes: A population‐based cohort study

“…SU, sulphonylureas myocardium could preserve or even elicit ischaemic preconditioning, a self-protective mechanism of the heart, while also preventing ventricular arrhythmias. [22][23][24] Thus, our results showing a lower incidence of allcause mortality and possibly of cardiovascular death associated with glimepiride compared with other second-generation sulphonylureas are in line with these preclinical observations.…”

“…Indeed, pancreas‐non‐specific sulphonylureas, such as glimepiride, bind also to cardiac muscle and vascular smooth muscle cells, and over the years, concerns have been raised about whether binding to extrapancreatic tissues could increase cardiovascular risk . However, such concerns have been alleviated, at least for glimepiride, with animal studies suggesting that binding of this sulphonylurea to the myocardium could preserve or even elicit ischaemic preconditioning, a self‐protective mechanism of the heart, while also preventing ventricular arrhythmias . Thus, our results showing a lower incidence of all‐cause mortality and possibly of cardiovascular death associated with glimepiride compared with other second‐generation sulphonylureas are in line with these preclinical observations.…”

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety

“…This post-market comparative safety study using realworld healthcare data is the first to estimate effects of thiazolidinediones on SCA/VA as a stand-alone endpoint. The crude incidence rate of SCA/VA among thiazolidinedione users (2.86 per 1000 p-y) reported herein is less than we previously found among sulfonylurea users (3.57 per 1000 p-y); [58] this may be partly driven by different rates of serious hypoglycemia between these pharmacologic classes [59,60]. Our overall finding of no difference in SCA/VA between new users of rosiglitazone vs. pioglitazone (adjusted marginal HR = 0.91) was robust across numerous secondary analyses and conceptually replicated in an independent dataset (adjusted marginal HR = 0.88).…”

Comparative Safety of Sulfonylureas and the Risk of Sudden Cardiac Arrest and Ventricular Arrhythmia

“…In the setting of DM, incidence rates of SCA are 3.2 and 13.8 per 1,000 personyears (p-y) in persons without and persons with clinically recognized heart disease (9)dindicative that DM confers a twoto fourfold risk of SCA (4). This may be due to a combination of atherosclerotic, thrombotic, neural, and other factors (10,11). The relative importance of these determinants is unknown, although recent opinion has emphasized the roles of coronary artery disease, myocardial dysfunction, and electrical abnormalities (9) while downplaying the role of cardiac autonomic dysfunction (12).…”