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

Abstract

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. Graphical abstract

The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

“…Furthermore, two recent clinical trials (EMPEROR-Reduced [10] and DAPA-HF [11]) support the use of SGLT2 inhibitors for the treatment of patients with heart failure and a reduced ejection fraction, regardless of the presence or absence of diabetes. Additionally, it has been shown that short-or long-term administration of CANA attenuates myocardial IRI in diabetic and nondiabetic rats [12][13][14]. These findings support the hypothesis that CANA might also protect against vascular IRI, irrespective of diabetic status and raise the possibility of repurposing the SGLT-2 inhibitor as a novel cardioprotective intervention in high-risk nondiabetic patients with significant pre-existing cardiovascular disease.…”

The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus

“…Evidence supports significant reduction in cardiovascular and kidney outcomes with both SGLT2is and GLP-1 RAs as well as potential benefit from their combination. Although evidence from preclinical studies suggests that SGLT2is reduce infarct size [ 18 ], the reduction in incidence of nonfatal and fatal MI in patients with type 2 diabetes on this treatment is modest, approximately 11% [ 3 ]. Rather than a direct effect on platelet activation, thrombus formation, or atherosclerotic plaque stability, this benefit is postulated to result from a reduction in preload with a resultant reduction in myocardial wall tension, myocardial oxygen demands, and a consequential reduction in myocardial ischemia [ 8 ].…”

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

“…Recent clinical studies demonstrated favorable cardiovascular effects of the antidiabetic drugs from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, including a reduction of cardiovascular death, non-fatal myocardial infarction (MI), heart failure, and non-fatal stroke, as well as all-cause mortality [ 1 , 2 , 3 , 4 , 5 , 6 ]. In experimental models, cardiac contractility was improved in heart failure with preserved and reduced ejection fractions [ 7 , 8 , 9 , 10 , 11 ], in ischemia/reperfusion [ 12 ], MI models [ 13 , 14 , 15 , 16 , 17 ], and diabetic cardiomyopathy [ 18 ]. Recently, the antiarrhythmic properties of SGLT2 inhibitors were shown in the ischemia-reperfusion model [ 19 ] and atrial fibrillation [ 20 ].…”