Sodium-glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia-reperfusion injury: a meta-analysis.

AIMS/HYPOTHESIS: Large cardiovascular outcome trials demonstrated that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors might reach beyond glucose-lowering action. In this meta-analysis, we sought to evaluate the potential infarct size-modulating effect of SGLT2 inhibitors in preclinical studies. METHODS: In this preregistered meta-analysis (PROSPERO: CRD42020189124), we included placebo-controlled, interventional studies of small and large animal models of myocardial ischaemia-reperfusion injury, testing the effect of SGLT2 inhibitor treatment on myocardial infarct size (percentage of area at risk or total area). Standardised mean differences (SMDs) were calculated and pooled using random-effects method. We evaluated heterogeneity by computing Τ2 and I2 values. Meta-regression was performed to explore prespecified subgroup differences according to experimental protocols and their contribution to heterogeneity was assessed (pseudo-R2 values). RESULTS: We identified ten eligible publications, reporting 16 independent controlled comparisons on a total of 224 animals. Treatment with SGLT2 inhibitor significantly reduced myocardial infarct size compared with placebo (SMD = -1.30 [95% CI -1.79, -0.81], p < 0.00001), referring to a 33% [95% CI 20%, 47%] difference. Heterogeneity was moderate (Τ2 = 0.58, I2 = 60%). SGLT2 inhibitors were only effective when administered to the intact organ system, but not to isolated hearts (p interaction <0.001, adjusted pseudo-R2 = 47%). While acute administration significantly reduced infarct size, chronic treatment was superior (p interaction <0.001, adjusted pseudo-R2 = 85%). The medications significantly reduced infarct size in both diabetic and non-diabetic animals, favouring the former (p interaction = 0.030, adjusted pseudo-R2 = 12%). Treatment was equally effective in rats and mice, as well as in a porcine model. Individual study quality scores were not related to effect estimates (p = 0.33). The overall effect estimate remained large even after adjusting for severe forms of publication bias. CONCLUSIONS/INTERPRETATION: The glucose-lowering SGLT2 inhibitors reduce myocardial infarct size in animal models independent of diabetes. Future in vivo studies should focus on clinical translation by exploring whether SGLT2 inhibitors limit infarct size in animals with relevant comorbidities, on top of loading doses of antiplatelet agents. Mechanistic studies should elucidate the potential relationship between the infarct size-lowering effect of SGLT2 inhibitors and the intact organ system.