SGLT2 inhibitors and GLP-1R agonists show no increased ventricular arrhythmia risk; empagliflozin reduces VA in T2DM.
Background
Patients with Type 2 diabetes mellitus (T2DM) and/or heart failure (HF) face a heightened risk of adverse cardiovascular events, including potentially life-threatening ventricular arrhythmias (VAs). While sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) have demonstrated significant benefits in reducing major adverse cardiovascular and kidney events, their specific impact on VA incidence has remained uncertain. This knowledge gap creates a challenge for clinicians in optimizing therapeutic strategies for comprehensive cardiovascular protection in these vulnerable populations.
Study Design
Researchers conducted a disease-stratified network meta-analysis, systematically searching four major databases through May 2026 to identify randomised controlled trials (RCTs) investigating SGLT2 inhibitors and GLP-1 receptor agonists. The comprehensive analysis included 37 publications, corresponding to 32 independent RCTs and encompassing 140,156 participants. Nine distinct cardiovascular and safety outcomes were evaluated, including ventricular arrhythmias (VAs), cardiovascular mortality, all-cause mortality, and hospitalization for heart failure (HHF), with comparisons stratified for T2DM and HF patient networks.
Results
The extensive meta-analysis of 140,156 participants revealed that the majority of SGLT2 inhibitors and GLP-1 receptor agonists did not significantly increase ventricular arrhythmia (VA) risk. Notably, an exploratory signal indicated that: > Empagliflozin was associated with a statistically significant lower VA risk in the T2DM network (OR 0.31, 95% CI 0.11-0.86). Beyond VAs, dapagliflozin in the HF network, and both empagliflozin and liraglutide in the T2DM network, were linked to reduced cardiovascular mortality and all-cause mortality. SGLT2 inhibitors consistently lowered hospitalization for heart failure (HHF) across both T2DM and HF networks. Regarding safety, dapagliflozin was associated with lower AKI risk, while albiglutide and liraglutide showed reduced hypoglycemia risk. No statistically significant increase in diabetic ketoacidosis risk was detected for empagliflozin, and the semaglutide fracture signal was advised to be interpreted cautiously.
Key Findings
- Most SGLT2 inhibitors and GLP-1 receptor agonists did not significantly increase ventricular arrhythmia risk.
- Empagliflozin showed an exploratory signal for lower VA risk in T2DM (OR 0.31, 95% CI 0.11-0.86).
- Dapagliflozin, empagliflozin, and liraglutide were associated with lower cardiovascular and all-cause mortality.
- SGLT2 inhibitors consistently reduced hospitalization for heart failure across both T2DM and HF networks.
- Dapagliflozin reduced AKI risk; albiglutide and liraglutide reduced hypoglycemia risk.
Why It Matters
This network meta-analysis provides crucial reassurance that SGLT2 inhibitors and GLP-1 receptor agonists are generally safe concerning ventricular arrhythmias, a significant concern in cardiometabolic patients. For clinicians and individuals managing T2DM or HF, these findings reinforce the broad cardiovascular protective profile of these drug classes, particularly highlighting empagliflozin's potential to reduce VA risk in T2DM. The consistent reduction in hospitalization for heart failure by SGLT2 inhibitors further solidifies their role. While specific drug selection should be individualized, this evidence supports the continued and potentially expanded use of these agents for comprehensive cardiovascular risk reduction, without undue concern for VA exacerbation.