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

Associations between Oral Glucose-Lowering Agents and Increased Risk for Life-Threatening Arrhythmias in Patients with Type 2 Diabetes Mellitus—A Literature Review

“…By contrary, less information on their potential association with VA and/or SCA are available [1,[38][39][40]. However, there are several studies (19 of them analyzed in this review), and even some meta-analyses [15,16,20,41,42], most of them focusing on SGLT2, written in the last five years. Thus, the reported data are frequently contradictory.…”

“…The comprehensive reviews of Scheen and Savarese et al [16,41], published in 2022, summarize extensive information on the interaction between the most important classes of GLA and VA, specifically SCA, as well as the current guidelines recommendations for the administration of each class [1,43,44].…”

“…In the last decades, efforts have been made to develop new glucose-lowering agents (GLA) that not only offer a good control of blood glucose values (BGV) over a 24-h interval, but also have a favorable impact on cardiovascular (CV) morbidity and mortality, as well as protecting renal function [14][15][16]. Numerous scientific articles, reviews, and meta-analyses of the existing medical literature, as well as the results of clinical trials, have been published in the last decade.…”

“…Numerous scientific articles, reviews, and meta-analyses of the existing medical literature, as well as the results of clinical trials, have been published in the last decade. Most of them debate the beneficial cardiac effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i), but also of other classes of medication such as thiazolidinedione, metformin versus sulfonylureas, glucagon-like peptide-1 receptor agonists (GLP1a), and dipeptidyl-peptidase 4 inhibitors (DPP4i) [3,[16][17][18][19]. While there is an agreement that drugs for the last classes have little if any effect on VA or/and SCA, excepting perhaps metformin, which also lowers inflammation and oxidative stress, there are controversial opinions on SGLT2i agents [3,15,20,21].…”

“…This class of drugs is considered to have direct beneficial effects on the myocardium by improving the cardiac energetic metabolism, reducing oxidative stress, inflammation, fibrosis, and adverse ventricular remodeling, but also impacting cardiac ion channels and mediators that modulate cardiac electrophysiology, effects that could favor an antiarrhythmic effect, additionally ameliorating the renal function. While in the medical literature there is a consensus on the effectiveness of SGLT2i on CV morbidity, mortality, and hospitalization duration for HF regardless of the presence or absence of T2DM, the effects on VA and SCA are still a matter of dispute [15,16,22,23]. Considering that rigorous randomized clinical trials specifically on the effects of various GLA on malignant arrhythmias are missing, the available data mostly represent incidental observations, and that actual information relays mainly on observational studies (many of them retrospective) conducted on diabetic populations inhomogeneous from the point of view of ethnicity, age, risk factors and associated pathology, and the severity and extent of diabetes, the conclusions of these studies are heterogeneous and biased, although it seems that SGLT2i may exert a protective effect for SCA [16].…”