Table 2.
In Vivo Studies Demonstrating the Cardioprotective Effects of SGLT2 Inhibitors Against Cancer Treatment–Related Cardiotoxicity
| First Author (Year) | Species/Strain | Anticancer Treatment | SGLT2 Inhibitor Treatment | Key Findings | Proposed Mechanisms |
|---|---|---|---|---|---|
| Oh et al (2019)39 | Male C57BL/6J mice | DOX (15 mg/kg, single dose, i.p.) | EMPA (0.03% in NCD) | ↑ FS ↓ Hypertrophic pathologic changes Preserved LV mass ↓ Perivascular and interstitial fibrosis |
↑ βOHB levels |
| DOX (2.5 mg/kg every other day for 12 d, i.p.) | |||||
| Yang et al (2019)40 | Male Sprague-Dawley rats with subtotal nephrectomy | DOX, CRS (7 mg/kg, once every 5 d for 20 d, i.p.) | EMPA (20 mg/kg/d, i.p., from day 24 after CRS induction) | ↑ EF ↓ LV remodeling ↓ BNP |
↓ NOX-1, NOX-2, and oxidized protein ↓ TNF-α, NF-κB, IL-1β, and MMP-9 ↓ Mitochondrial-Bax, cleaved caspase-3, and cleaved PARP ↓ TGF-β and Smad3 ↓ γ-H2AX, cytosolic cytochrome c ↑ Mitochondrial cytochrome c |
| Wang et al (2020)41 | Male C57BL/6 mice | DOX (5 mg/kg, once per week for 4 wk, i.v. and i.p.) | EMPA (50 mg/kg/d in NCD for 5 wk, 1 wk before DOX) | ↑ FS ↓ cTnT ↓ BNP ↑ Contractility, ↓ DNA damage ↓ Cardiac fibrosis |
↑ Autophagic flux with ↑ in autophagosomes ↓ Accumulation of autolysosomes ↑ Beclin 1 in the heart ↑ TLR9 and SIRT3 in the heart ↑ Formation of beclin 1–TLR9–SIRT3 complex |
| Sabatino et al (2020)17 | Male C57BL/6 mice | DOX (5 mg/kg per week for 5 wk, i.p.) | EMPA (10 mg/kg, daily for 5 wk, oral gavage) | Improved SBP and DBP ↑ FS, EF ↓ Myocardial fibrosis and remodeling ↓ cTnT |
↓ ERK activity |
| Baris et al (2021)42 | Male Sprague-Dawley rats | DOX (2.5 mg/kg every other day for 14 d, i.p.) | EMPA (10 mg/kg daily for 14 d, oral gavage) | ↓ Prolongation of QT and QTc intervals ↑ EF, FS Preserved LVEDD and LVESD ↓ Myofibril loss |
↑ Mitochondrial biogenesis probably by PGC-1α up-regulation |
| Quagliariello et al (2021)43 | Female C57BL/6 mice | DOX (2.17 mg/kg/d for 7 d, i.p.) | EMPA (10 mg/kg/d, 3 d before DOX, oral gavage) | ↑ EF, FS ↓ Cardiac fibrosis |
↓ Ferroptosis and MDA content in the heart ↓ XO ↓ IL-1β, IL-6, and IL-8 cardiac expression ↓ MyD88 and NLRP3 ↓ Cardiac procollagen 1α1, MMP-9 ↓ Apoptosis |
| Chen (2023)49 | Male Sprague-Dawley rats | DOX (2.5 mg/kg twice a week for 4 wk, i.p.) | EMPA (30 mg/kg/d for 4 wk, intragastric) | ↓ LVEDD and LVESD, ↑ EF and FS ↓ CK-MB and NT-proBNP |
↓ Oxidative stress (↑ SOD and CAT) ↑ Energy metabolism (↑ serum ATP/ADP) ↑ AMPK/SIRT1/PGC-1α pathway |
| Chang et al (2021)44 | Male Sprague-Dawley diabetic rats | DOX (5 mg/kg/wk for 4 wk, i.p.) | DAPA (10 mg/kg/d for 6 wk, oral) followed by DOX | ↑ EF, FS ↑ Survival ↓ Hemodynamic declines (+dP/dt) and (−dP/dt) ↓ Fibrosis |
↓ ER stress (GRP78, PERK, eIF-2α, ATF-4, and CHOP) ↓ Apoptosis (Bax and cleaved caspase-3, ↑ Bcl-2) |
| Chang et al (2022)46 | Male Sprague-Dawley rats | DOX (5 mg/kg/wk for 4 wk i.p.) | DAPA (10 mg/kg/d for 6 wk oral) | ↑ Survival, ↑ EF, FS, ↓ myocardial fibrosis ↓ Hemodynamic changes (Ves, Ved ESPVR, +dP/dt, −dP/dt, and tau) |
↓ Apoptosis (mechanisms in vitro) |
| Hsieh et al (2022)47 | Male Sprague-Dawley rats | DOX (3 mg/kg for 4 wk, i.p.) | DAPA (0.1 mg/kg/d for 5 d for 4 wk, oral gavage) | ↑ EF, FS | ↓ Smad3, BNP, α-SMA, and phosphorylated p38 (mechanisms in vitro) |
| Belen et al (2022)45 | Male Sprague-Dawley albino rats | DOX (2.5 mg/kg/d every other day, 6 doses, i.p.) | DAPA (1 mg/kg/d, oral gavage) | ↓ cTnT, pro-BNP, TNF-α, FGF-21 levels | |
| Kim et al (2022)48 | C57BL/6J mice | DOX (15 mg/kg single dose, i.p.) | DAPA (1 mg/kg/d, oral) + high ARNI (sacubitril/valsartan 68 mg/kg/d) or low ARNI (34 mg/kg/d) 1 d after DOX | DAPA + low ARNI was the best regarding improved survival rate, cardiac function, hemodynamic change, and kidney function ↑ EF, FS ↑ β-MHC and MyBPC3 ↓ NT-proANP ↓ ANP and BNP |
Improved metabolic flexibility in DOX-injected heart through PPAR signaling pathway ↑ Genes related to fatty acid transport, fatty acid oxidation, ketogenesis, and gluconeogenesis-modulating metabolic pathway, including glucose, ketone bodies, and fatty acids |
| DOX (2.5 mg/kg every 4 d for 24 d, cumulative dose, 15 mg/kg, i.p.) | |||||
| Hu et al (2023)50 | Male C57BL/6 mice | DOX (5 mg/kg, once a week for 4 wk, i.p.) | DAPA (1.5 mg/kg/d for 4 wk, oral gavage) | ↓ LVIDd and LVIDs, ↑ EF and FS ↓ Remodeling |
↓ NLRP3 inflammasome ↓ Inflammatory markers (IL-6, IL-1β, and IL-18) |
| Satyam et al (2023)51 | Female Wistar rats | DOX (20 mg/kg, single dose, i.p.) | DAPA (0.9 mg/kg/d for 8 d, oral gavage) | Reversed DOX ECG changes ↓ CK-MB, AST |
|
| Quagliariello et al (2023)52 | Female C57BL/6 mice | DOX (2.17 mg/kg for 10 d, i.p.) | DAPA (12 mg/kg/d, oral gavage) | ↑ EF | ↓ Cardiac NLRP3, MyD88, DAMPs, and NF-κB ↓ Inflammatory markers (IL-1β, IL-6, TNF-α, G-CSF, and GM-CSF) ↑ Phosphorylated AMPK ↓ Calgranulin S100 and galectine-3 ↓ Myocardial and renal NF-κB |
| Ulusan et al (2023)53 | Male Wistar albino rats | DOX (2.15 mg/kg, every 3 d for 21 d, i.p.) | DAPA (10 mg/kg/d, oral gavage) | ↑ EF ↓ Prolongation of QRS, QT |
|
| Ren et al (2021)20 | Male C57BL/6J | Sunitinib (40 mg/kg/d for 28 consecutive days, oral gavage) | EMPA (10 mg/kg/d for 28 consecutive days, oral gavage) | ↓ HTN ↑ EF, FS Reversed left ventricular systolic and diastolic dysfunction ↑ CFR |
↓ cTnT, pro-BNP levels Autophagy restoration ↑ AMPK-mTOR signaling pathway |
| Min et al (2023)21 | Male C57BL/6J mice | Trastuzumab (10 mg/kg, once a week for 6 wk, i.p.) | EMPA (10 mg/kg twice per week for 6 wk, i.p.) | ↑ EF, FS, ↓ LVESD Improved cardiomyocyte mechanical and intracellular dysfunction Preserved mitochondrial integrity and function |
↓ Apoptosis, ferroptosis, DNA damage ↓ Oxidative stress ↓ Intracellular Ca2+ decay rate ↑ Mitochondrial biogenesis (PGC-1α) |
| Ali et al (2023)19 | Wistar albino rats | Cisplatin (7 mg/kg, single dose, i.p.) | CANA (10 mg/kg/d, oral) | ↓ AST, ALP, CK-MB, LDH | ↑ Nrf2 ↓ NO, MPO ↓ iNOS, NF-κB, TNF-a, IL-1β ↑ PI3K/AKT pathway ↓ Bax, Bcl-2, cytochrome c |
AKT = protein kinase B; ALP = alkaline phosphatase; α-SMA = α-smooth muscle actin; AMPK = adenosine monophosphate–activated protein kinase; ANP = atrial natriuretic peptide; ARN = angiotensin receptor neprilysin inhibitor; AST = aspartate aminotransferase; ATF-4 = activating transcription factor 4; Bax = Bcl-2-associated X protein; β-MHC = β-myosin heavy chain; βOHB = β-hydroxy butyrate; BNP = B-type natriuretic peptide; CAT = catalase; CFR = coronary flow reserve; CK-MB = creatine kinase MB; CRS = cardiorenal syndrome; cTnT = cardiac troponin T; DAMP = damage-associated molecular pattern; DOX = doxorubicin; ECG = electrocardiographic; EF = ejection fraction; eIF-2α = eukaryotic initiation factor 2α; ER = endoplasmic reticulum; ERK = extracellular signal-regulated kinase; FGF = fibroblast growth factor; FS = fractional shortening; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GRP78 = glucose-regulated protein 78; HTN = hypertension; i.p. = intraperitoneally; IL = interleukin; IL = interleukin; IL = interleukin; iNOS = inducible nitric oxide synthase; LDH = lactate dehydrogenase; LV = left ventricle; LVEDD = left ventricular end-diastolic diameter; LVESD = left ventricular end-systolic diameter; LVIDd = left ventricular internal diameter at end-diastole; LVIDs = left ventricular internal diameter at end-systole; MDA = malondialdehyde; MMP = matrix metallopeptidase; MPO = myeloperoxidase; mTOR = mammalian target of rapamycin; MyBPC3 = myosin-binding protein C3; MyD88 = myeloid differentiation primary response 88; NCD = normal chow diet; NF-κB = nuclear factor kappa-B; NLRP3 = nod-like receptor protein 3; NO = nitric oxide; NOX-1 = NADPH oxidase 1; NOX-2 = NADPH oxidase 2; Nrf2 = nuclear factor erythroid 2–related factor 2; NT-proANP = N-terminal pro–atrial natriuretic peptide; NT-proBNP = N-terminal pro–B-type natriuretic peptide; p38 = p38 mitogen-activated protein kinase; PARP = poly(adenosine diphosphate–ribose) polymerase; PERK = protein kinase R-like endoplasmic reticulum kinase; PGC = peroxisome proliferator–activated receptor-γ coactivator; PI3K = phosphoinositide 3-kinase; PPAR = peroxisome proliferator–activated receptor; QTc = corrected QT; SIRT1 = sirtuin 1; SIRT3 = sirtuin 3; Smad3 = mothers against decapentaplegic homolog 3; SOD = superoxide dismutase; TGF = transforming growth factor; TLR9 = Toll-like receptor 9; TNF = tumor necrosis factor; XO = xanthine oxidase; other abbreviations as in Table 1.