Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) Reduce Hospitalization for Heart Failure Only and Have No Effect on Atherosclerotic Cardiovascular Events: A Meta-Analysis

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.

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.

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).

The predominant impact of SGLT-2i is on “hHF or CV mortality” composite driven predominantly by reduction in hHF and not atherosclerotic CV disease.