Table 3.

Effects in heart failure with reduced ejection fraction: animal and human studies

Author, year	Study characteristics	Main findings
Animal studies
Ideishi et al. 2021 [42]	Streptozotocin-induced diabetic mice were divided into control, empagliflozin, linagliptin, and combination groups and treated for 7 days	Combination therapy with linagliptin and empagliflozin preserved cardiac systolic function
Connelly et al. 2020 [43]	Non-diabetic rats with induced MI of the LV randomized to vehicle or empagliflozin	Empagliflozin improved cardiac function independent of loading conditions
	Non-diabetic rats with induced MI randomized to empagliflozin or control chow for 2 weeks	Empagliflozin improved cardiac function, remodeling, cardiac metabolism
Daud et al. 2021 [45]	Non-diabetic rats with induced MI randomized to empagliflozin or control for 4 weeks	Empagliflozin reduced myocardial fibrosis and inhibited the TGF-beta1/Smad3 fibrotic pathway
Baker et al. 2019 [46]	Lean swine received canagliflozin or placebo 24 h before temporary occlusion of the circumflex coronary artery	Canagliflozin preserved cardiac contractile function and efficiency and provided ischemia protection
Goerg et al. 2021 [47]	Studied effects of empagliflozin on cardiac function in normoglycemic rats for 7 days followed by experimental MI	Empagliflozin increased cardiac output, stroke volume, and fractional shortening and after MI improved global longitudinal strain
Ren et al. 2021 [48]	Male randomized into control, empagliflozin, sunitinib, or sunitinib + empagliflozin for 28 days	Mice treated with suninitib showed decreased LVEF compared to controls that was attenuated with empagliflozin
Gong et al. 2021 [49]	Rat cardiac cells exposed to hypoxia/reoxygenation to simulate an ischemia/reperfusion (I/R) injury	Co-administration of rosuvastatin and dapagliflozin significantly enhanced cell viability and upregulated expression of p-PI3K, p-Akt, p-mTOR, and Bcl-2.
Lin et al. 2021 [50]	Rats with mitral regurgitation induced left heart dilatation and functional decline	Dapagliflozin partially restored LVEF and significantly diminished cardiac fibrosis and apoptosis
Shi et al. 2019 [51]	Transverse aortic constriction induced cardiac remodeling in mice then treated with dapagliflozin	Dapagliflozin improved cardiac systolic function, and inhibited myocardial fibrosis and cardiomyocyte apoptosis
Yerra et al. 2022 [52]	Transverse aortic constriction induced cardiac remodeling in mice then treated with empagliflozin	Empagliflozin attenuated LV enlargement in mice
Chen et al. [53]	Model of diabetes using male BTBR ob/ob mice; dapagliflozin, ticagrelor, or both administered for 12 weeks	Both agents improved left ventricular end-systolic and end-diastolic volumes as well as LVEF
Byrne et al. 2020 [54]	Rodent model of HF administered empagliflozin	Empagliflozin associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a Ca(2+)-dependent manner
Santos-Gallego et al. 2019 [55]	Heart failure induced in nondiabetic pigs that were randomized to empagliflozin or placebo for 2 months	Empagliflozin ameliorated adverse cardiac remodeling and HF and improved myocardial energetics
Li et al., 2021 [56]	Mice subjected to sham surgery or transverse aortic constriction and after 2 weeks given empagliflozin or vehicle was for 4 weeks.	Empagliflozin increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis
Human studies
Thirunavukarasu et al. [57]	Patients with T2D underwent cardiac magnetic resonance and (31)P-MRS scans before and after 12 weeks of empagliflozin	Improvements seen in LVEF, global longitudinal strain, and mean myocardial cell volume
Chan et al. [58]	Compare changes in echocardiographic parameters in patients with T2D receiving SGLT2i with a different baseline LV ejection fraction (LVEF).	SGLT2i associated with an improvement in LV systolic function in patients with T2DM with reduced and moderately reduced LVEF
Lee et al. 2021 [59]	Randomized patients with T2D/prediabetes and HFrEF to empagliflozin or placebo for 36 weeks	Empagliflozin reduced LV volumes
Ilyas et al. 2021 [60]	Investigated the effects of 2 weeks of therapy with dapagliflozin in patients with T2D and HFrEF	No functional effects on cardiac function were observed
Santos-Gallego et al. 2021 [61].	Randomized HFrEF patients without diabetes to empagliflozin or placebo for 6 months	Empagliflozin significantly improved LV volumes, LV mass, LV systolic function, and functional capacity
Omar et al. 2021 [62]	Post hoc analysis of the randomized Empire HF trial in patients with HFrEF treated with empagliflozin or placebo for 12 weeks	Empagliflozin associated with modest reductions in LV and left atrial volumes with no association with ejection fraction
Hwang et al. 2020 [63]	Evaluated patients with diabetic patients with HF by echocardiography before, and 6 to 24 months after the initiation of SGLT2i	SGLT2i improved cardiac function, regardless of the presence of HF, but the improvements were more prominent in HF patients, especially in those with HFrEF
Maragkoudakis et al. 2021 [64]	Prospective cohort study of symptomatic HF patients with EF < 35% who had dapagliflozin added to therapy	Dapagliflozin improved both systolic and diastolic function
Omar et al. 2020 [65]	Randomized patients with HFrEF to empagliflozin or placebo once daily for 12 weeks	Empagliflozin significantly reduced pulmonary capillary wedge pressure
Mullens et al. 2020 [66]	Investigated effects of dapagliflozin after 7 days in consecutive HFrEF with elevated pulmonary artery pressure	Dapagliflozin reduced pulmonary artery pressure
Requena-Ibanez et al. [67].	Patients without diabetes and HFrEF underwent cardiac magnetic resonance at baseline and after 6 months of empagliflozin	Empagliflozin improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers

HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle; LVEF, left ventricular ejection fraction; MI, myocardial infarction; T2D, type 2 diabetes