Efficacy and Safety of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Ventricular Arrhythmias and Cardiovascular Events: A Disease-Stratified Network Meta-Analysis.

BACKGROUND

The effects of individual sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) on ventricular arrhythmias (VAs) remain uncertain. This study aimed to comprehensively compare their effects on VAs and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and/or heart failure (HF).

METHODS

Four databases were systematically searched from inception through May 16, 2026, to identify randomised controlled trials. Nine outcomes were evaluated, including VAs, cardiovascular mortality, all-cause mortality and hospitalization for heart failure (HHF).

RESULTS

Thirty-seven publications, corresponding to 32 independent RCTs and 140 156 participants, were included. Most SGLT2 inhibitors and GLP-1 receptor agonists did not significantly increase VA risk; empagliflozin showed a statistically significant but exploratory signal for lower VA risk in the T2DM network (OR 0.31, 95% CI 0.11-0.86). Dapagliflozin in the HF network and empagliflozin and liraglutide in the T2DM network, were associated with lower cardiovascular and all-cause mortality. SGLT2 inhibitors consistently reduced HHF across both networks. Dapagliflozin was associated with lower AKI risk, while albiglutide and liraglutide were associated with lower hypoglycemia risk; however, these safety findings should be interpreted cautiously because adverse-event reporting was not uniform across trials. Several safety outcomes were based on sparse events and non-uniform adverse-event reporting; no statistically significant increase in diabetic ketoacidosis risk was detected for empagliflozin and the semaglutide fracture signal should be interpreted cautiously. Because the evidence networks were largely placebo-centered and lacked closed loops, treatment rankings and between-drug comparisons depend heavily on the transitivity assumption. These rankings, including P-score rankings, should be regarded as exploratory and should not be interpreted as head-to-head comparative evidence.

CONCLUSIONS

SGLT2 inhibitors consistently reduced HHF risk across the HF and T2DM networks and selected agents showed mortality benefits in clinically relevant populations. Empagliflozin showed an exploratory signal for lower VA risk in the T2DM network; however, this finding requires confirmation in trials with prespecified and adjudicated arrhythmia endpoints. Safety signals, including DKA and fracture, should be interpreted cautiously because adverse-event ascertainment was not uniform across trials.