Antidiabetic agents and risk of atrial fibrillation/flutter: A comparative critical analysis with a focus on differences between SGLT2 inhibitors and GLP-1 receptor agonists

Atrial fibrillation/flutter (AF/AFL) is a common cardiac arrhythmia in patients with diabetes and is associated with an increased risk of morbidity, including ischaemic stroke and heart failure, and mortality. Different classes of glucose-lowering agents have shown distinct effects on the risk of stroke and heart failure. Their effects on cardiac arrhythmias such as AF/AFL have not been carefully investigated yet and even less their possible relationship with classical complications such as stroke and heart failure. The present comprehensive review aims at analysing the effects of each pharmacological class on the risk of new-onset AF/AFL episodes in patients with type 2 diabetes mellitus (T2DM) and in patients with heart failure (with or without diabetes). Relevant findings were collected both in post-hoc analyses of placebo-controlled trials and in real-life retrospective observational studies, which both led to the publication of several meta-analyses. Of note, no randomised controlled trials evaluated the effects on AF/AFL as a pre-specified endpoint and none included head-to-head active drug comparisons, so that caution is required in the conclusion. Overall, sodium-glucose cotransporter 2 inhibitors, besides their remarkable effects on heart failure issues, were associated with the most pronounced and consistent reduction in incident AF/AFL, an effect surprisingly not accompanied by a significant reduction in stroke. In contrast, glucagon-like peptide-1 receptor agonists, which have proven their ability to reduce stroke, apparently failed to demonstrate a significant reduction in new-onset AF/AFL in most reports. A better understanding of both reasons for these discrepancies and underlying mechanisms supporting the drug antiarrhythmic effect requires further careful dedicated studies.