Efficacy and Safety of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Ventricular Arrhythmias and Cardiovascular Events: A Disease-Stratified Network Meta-Analysis.
Empagliflozin showed a potential lower risk for ventricular arrhythmias, but this finding needs confirmation in future trials. SGLT2 inhibitors consistently reduced hospitalization for heart failure across both networks.
Where it sits
this study against the rest of the albiglutide corpusSummary and findings
This study compared the effects of SGLT2 inhibitors and GLP-1 receptor agonists on ventricular arrhythmias and cardiovascular outcomes in patients with type 2 diabetes mellitus and/or heart failure. A total of 140,156 participants were included across 32 independent RCTs. The findings indicated that most agents did not significantly increase ventricular arrhythmia risk, with some showing potential mortality benefits.
Abstract
<h4>Background</h4>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).<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusions</h4>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.
Background
The study addresses the uncertain effects of SGLT2 inhibitors and GLP-1 receptor agonists on ventricular arrhythmias and cardiovascular outcomes in patients with type 2 diabetes mellitus and heart failure. Prior research has indicated potential benefits of these agents, but comprehensive comparisons remain limited. This study aims to fill that gap by evaluating multiple outcomes across a large participant pool.
Methods
The study conducted a systematic search of four databases for randomized controlled trials up to May 16, 2026. A total of 32 independent RCTs involving 140,156 participants were included. Nine outcomes were evaluated, including ventricular arrhythmias, cardiovascular mortality, all-cause mortality, and hospitalization for heart failure.
Results
The primary endpoint showed that empagliflozin had an OR of 0.31 (95% CI 0.11-0.86) for lower ventricular arrhythmia risk in the T2DM network. Most agents did not significantly increase the risk of ventricular arrhythmias. Dapagliflozin and empagliflozin were associated with lower cardiovascular and all-cause mortality.
Interpretation
These findings suggest that while some SGLT2 inhibitors and GLP-1 receptor agonists may offer benefits regarding mortality and hospitalization, the effect sizes are not uniformly large or clinically significant. The exploratory nature of some findings, such as the lower VA risk with empagliflozin, requires further investigation. Limitations such as small sample sizes for certain outcomes and non-uniform adverse-event reporting may confound the conclusions.
Key findings
- OR 0.31, 95% CI 0.11-0.86 for lower VA risk with empagliflozin in the T2DM network.
- Dapagliflozin and empagliflozin were associated with lower cardiovascular mortality.
- SGLT2 inhibitors consistently reduced HHF across both networks.
- Albiglutide and liraglutide were associated with lower hypoglycemia risk.
- No statistically significant increase in diabetic ketoacidosis risk was detected for empagliflozin.
Limitations
- Several safety outcomes based on sparse events.
- Non-uniform adverse-event reporting across trials.
- Evidence networks largely placebo-centered.
- Lacked closed loops, limiting treatment ranking reliability.