Introduction: Although the positive effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on hospitalization for heart failure in type 2 diabetes (T2D) seem definite, some doubt exists about their effects on atherosclerotic cardiovascular disease (ASCVD). This study aims to shed light on this debatable issue.
Methods: An electronic database search (Cochrane Library, PubMed and Embase) was performed using two groups of terms ["sodium glucose cotransporter2 inhibitor", "dapagliflozin", "canagliflozin", "empagliflozin", "ertugliflozin"] AND ["major adverse cardiac events", "MACE", "cardiovascular death or hospitalization for heart failure", non-fatal myocardial infarction", "non-fatal stroke", "cardiovascular death", "hospitalization for heart failure"] and the cardiovascular outcome trials (CVOT) and pre-approval studies in phase 3 of all the SGLT2i analysed using comprehensive meta-analysis (CMA) software, version 3, Biostat Inc., Englewood, NJ, USA.
Results: Analysis of the CVOT revealed that the hazard ratio of the pooled effect size for MACE was statistically significant (HR 0.89, 95% CI 0.83-0.96, P = 0.002). There was a significant reduction in non-fatal myocardial infarction (MI) (HR 0.87, 95% CI 0.78-0.97, P = 0.01), but no improvement was seen for non-fatal stroke (HR 1.01, 95% CI 0.89-1.16, P = 0.83). The pooled analysis of this end point showed statistically significant reduction of the composite of CV death or hospitalization for heart failure (hHF) (HR 0.76, 95% CI 0.67-0.87, P < 0.001) and hHF (HR 0.69, 95% CI 0.61-0.79, P < 0.001), but not for CV death alone (HR 0.82, 95% CI 0.64-1.05, P = 0.11). The meta-analysis of the events in the pooled analysis of the phase 3 trials reveals that the hazard ratio for MACE was statistically nonsignificant (HR 0.83, 95% CI 0.66-1.03, P = 0.10). There was a 34% statistically significant reduction in MI (95% CI 0.48-0.91, P = 0.01), a 36% statistically significant reduction in CV death (95% CI 0.41-0.97, P = 0.04) and a 64% statistically significant reduction in hHF (95% CI 0.18-0.69, P < 0.01). In contrast, there was a 17% statistically nonsignificant increased risk of stroke (95% CI 0.80-1.70, P = 0.40).
Conclusion: The predominant impact of SGLT-2i is on "hHF or CV mortality" composite driven predominantly by reduction in hHF and not atherosclerotic CV disease.
Keywords: Cardiovascular death; Hospitalization for heart failure; Major cardiovascular events; Meta-analysis; Sodium glucose cotransporter 2 inhibitor; Type 2 diabetes.