Table 1.

Cardiac outcomes of treatments with SGLT-2i in pre-clinical models of HFrEF.

Preclinical Models (species)	Drug Dosage Duration	Cardiac Function	Cardiac Remodeling	Inflammation, ROS, ED
Hypertensive HF model (rat)	Empagliflozin 20 mg/kg/day 12 weeks [70]	Normalized end diastolic, end systolic volume. LVEF not significantly improved [70]	Reduced cardiac fibrosis [70]
Genetic HFrEF model (rat)	Empagliflozin 10 mg/kg/day 4 weeks	Increased cardiac function and LVEF [80]		Decreased infiltration by macrophages [80]
Post-MI HFrEF model (rat; mouse, pig)	Empagliflozin 10mg orally 2 months [61]	Increased LV systolic volume [61]	Attenuated remodeling post-MI (lower LV, dilation, sphericity) [61]
	20 mg/kg/day 6 weeks [75]	Improved contractility, stroke work, end-systolic blood pressure diastolic function [75]	No improvement in interstitial fibrosis or cardiomyocyte hypertrophy [75]
	30 mg/kg/day 2 weeks [72]	Improved LVEF [72]	Attenuated cardiomyocyte hypertrophy, fibrosis [72]	Decreased inflammation alleviated oxidative stress [72,83, 84, 85];
	10 mg/day 2 months [78]	Improved diastolic function [78]	Ameliorated diastolic dysfunction [78]	Reduced extracellular volume [78] Increased eNOS activity and NO production and bioavailability associated with cGMP-PKG axis [78]
	10 mg/kg/day 2 weeks [81]		Improved cardiac remodeling [81]
	Dapagliflozin 1 mg/kg/day 28 days [72, 74]	Improved LVEF [72, 74]
	1.5 mg/kg/day 4 weeks [77]	Systolic function [77]	Inhibited cardiac apoptosis and reduced LV mass, cardiac collagen 1/3, ANP/BNP, TGF-β1 transcripts, cardiac fibrosis [77]	Lowered levels of inflammatory cytokines [77]
	Canagliflozin 3 µg/kg 5 mins [76, 82]	Alleviated LV systolic and diastolic dysfunction [76, 82]
Ang II-induced cardiomyopathy (mouse)	Dapagliflozin 1.5 mg/kg/day 30 days [79]	Increased LV fractional shortening [79]		Decreased inflammation and ROS production [79]
DOX-induced cardiomyopathy (mouse)	Empagliflozin (not provided) [81]	Ameliorated LV function [81]	Lowered myocardial fibrosis [81]
LPS-induced cardiomyopathy (mouse)	Empagliflozin 5 mg/kg [86]	Preserved cardiac function [86]		Reduced cardiac iNOS, plasma TNFα and creatine kinase MB [86]
TAC-induced HFrEF (mouse)	Empagliflozin 10 mg/kg/day 2 weeks post-surgery [73, 82]	Attenuated the decline in cardiac function [73, 82]	Attenuated LV remodeling [82]	Decreased expression of markers of cardiac inflammation [73]

Heart failure (HF); Left ventricular ejection fraction (LVEF); Heart failure with reduced ejection fraction (HFrEF); Left ventricular (LV); Angiotensin II (Ang II); Reactive oxygen species (ROS); Endothelial dysfunction (ED); Doxorubicin (DOX); lipopolysaccharides (LPS); Inducible nitric oxide synthase (iNOS); Tumor necrosis factor alpha (TNFα); Transverse aortic constriction (TAC).