Glucose-lowering agents and risk of ventricular arrhythmias and sudden cardiac death: A comprehensive review ranging from sulphonylureas to SGLT2 inhibitors

Abstract

Type 2 diabetes is associated with a higher risk of cardiac arrhythmias, especially in presence of cardiovascular disease and/or heart failure. Even if atrial fibrillation/flutter episodes are the most frequent and well-studied, ventricular arrhythmias (VA: tachycardia/fibrillation) are more severe and can lead to sudden cardiac arrest/death (SCA/SCD). The effects of glucose-lowering agents on the risk of VA/SCD remain poorly understood. Findings may be derived from experimental animal studies, randomised controlled trials/cardiovascular outcome trials and observational retrospective studies. A higher risk was attributed to hypoglycaemia when induced by insulin or even more critically by sulphonylureas. Insulin-secreting agents seem to be associated with a higher risk of cardiac arrhythmias compared with insulin sensitizers (metformin, thiazolidinediones), yet the risk linked to sulphonylureas remains controverted. Incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) overall appear to be neutral regarding the risk of cardiac arrhythmias, despite some heterogeneous results. SGLT2 inhibitors appear to reduce the risk of SCA/SCD and possibly VA, yet only a non-significant trend was noticed in most reports. Overall, hazard ratios with SGLT2 inhibitors versus other therapies were lower for SCD (presumably of diverse causes) than for well demonstrated VA episodes. Underlying mechanisms remain uncertain and numerous pleiotropic effects may be involved. Prospective controlled trials and experimental studies specifically devoted to the effects of SGLT2 inhibitors on cardiac arrhythmias are needed to confirm their positive effects in diabetic patients and in individuals with heart failure irrespective of diabetes and, if possible, to carefully dissect the underlying protective mechanisms.