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Table 2 Summary of the effects of SGLT-2 inhibitors on cardiac structure in animal models

From: Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

Animal species Model Drug/dose/route Major findings Interpretation References
Wistar rats Streptozotocin-induced diabetic cardiomyopathy Empagliflozin (30 or 10 mg/kg/days)/PO/8 weeks ↓ Disorganized cell arrays and focal necrosis in dose-dependent manner Empagliflozin improved structural changes in the myocardium of streptozotocin-induced diabetic cardiomyopathy rats [62]
SHR/NDmcr-cp(+/+) rats Prediabetes/metabolic syndrome 0.03% empagliflozin/diet/10 weeks ↓ LV weight and cardiomyocyte size
↓ Interstitial fibrosis
Empagliflozin improved cardiac hypertrophy and interstitial fibrosis in genetic prediabetic metabolic syndrome rats [57]
db/db mice Diabetes/obesity (diastolic dysfunction and LVH) Empagliflozin (10 mg/kg/days)/PO/5 weeks ↓ Cardiomyocyte cross sectional area
↓ Interstitial collagen I and III depositions
↓ SGK1 and ENaC expressions
Empagliflozin improved LVH and myocardial fibrosis in db/db mice [59]
db/db mice Diabetes/obesity (diastolic dysfunction and LVH) 0.03% empagliflozin/diet/10 weeks ↓ Cardiac interstitial and pericoronary arterial fibrosis
↓ Coronary arterial thickening
Empagliflozin attenuated cardiovascular remodeling in db/db mice [58]
ob/ob mice T2DM/obesity (LV diastolic dysfunctions) Empagliflozin (10 mg/kg/days)/PO/6 weeks ↔ LV mass, myocardial fibrosis
↓ Anf, β-Mhc mRNA levels
↓ p-ERKs, p-JNKs and p-P38 expressions
Empagliflozin attenuated markers of cardiac hypertrophy and remodeling, but not altered cardiac fibrosis in ob/ob mice [60]
BTBR ob/ob mice T2DM Dapagliflozin (1 mg/kg/days)/PO/8 weeks ↓ Collagen-1 and collagen-3 mRNA levels
↓ % fibrosis
Dapagliflozin attenuated cardiac fibrosis in BTBR ob/ob mice [63]
Rats High fat diet induced obese-insulin resistance for 4 weeks then I/R injury by LAD ligation Dapagliflozin (1 mg/kg/days)/PO/4 weeks ↓ Infarct size Dapagliflozin attenuated MI size in pre-diabetic rats with cardiac I/R injury [64]
Wistar rats MI by LAD ligation in rats Dapagliflozin (0.1 mg/kg/days)/PO/Start after 1-day infarction for 4 weeks ↔ Infarct size
↓ Myofibroblast infiltration and cardiac fibrosis
Dapagliflozin attenuated myofibroblast infiltration during post-infarction remodeling in rats [65]
cmlc2::GFP zebrafish embryos Aristolochic acid induced heart failure Empagliflozin (0.1, 10 μM)/media/3 days ↓ Morphologic changes in a concentration-dependent manner included unlooping defects, cardiac edema, and deformed cardiac chambers
↓ ANP, BNP signaling
Empagliflozin improved heart failure morphology and attenuated heart failure markers in zebrafish embryos [66]
  1. SGLT-2 sodium–glucose co-transporter 2, PO per oral, LV left ventricular, LVH left ventricular hypertrophy, SGK1 serum and glucocorticoid-inducible kinase 1, ENaC epithelial Na+ channel, T2DM type 2 diabetic mellitus, Anf atrial natriuretic peptide/factor, β-Mhc beta-myosin heavy chain, p-ERKs phosphorylated extracellular signal-regulated kinase, p-JNKs phosphorylated c-Jun NH2-terminal kinase, I/R ischemic/reperfusion, LAD left anterior descending artery, MI myocardial infarction