Sodium-glucose cotransporter-2 (SGLT2) inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption by inhibiting target SGLT2 receptors present in the renal tubule. |
All studies which have reported experimental effects of SGLT-2 inhibitors suggest that this class of drug may exert ‘off-target’ cardiovascular benefits by modulating vascular endothelial cell activation and improving endothelial cell dysfunction, a critical early step in atherogenesis. |
Chronic and acute treatment with dapagliflozin led to a significant endothelial-dependent vasorelaxation in the aorta of diabetic mice, which some studies suggest may be due to a direct effect on vascular cells. |
The ex vivo and in vitro studies reviewed here support a possible class effect of SGLT-2 inhibitors on the regulation of endothelial function. |
Anti-inflammatory effects of SGLT-2 inhibitors have been observed in diabetic nephropathy models, via a suppression of the advanced glycation endproducts (AGEs)-receptor pathway, as well as in in vitro studies, thereby implicating anti-inflammatory effects that are independent of glucose-lowering. |
Systemic administration of SGLT-2 inhibitors markedly reduced expression of pro-inflammatory adhesion markers and cytokines in diabetic rodent models. |
Arguably, the evidence from the experimental studies reported in this review points towards SGLT-2 inhibitors exerting additional benefits beyond their primary receptor targets in the renal tubule as well as acting independently of glucose control. |
Introduction
Methodology
Database Search
Study Selection and Data Extraction
Quality and Risk of Bias Assessment
Results
Search Findings
Study Characteristics
Animal species | Animal model | Glyemic condition | Drug (dose)/route | Major finding | References |
---|---|---|---|---|---|
ApoE−/− mice | T1D | Hyperglycemic | Empagliflozin (20 mg/kg/day)/12 weeks/P.O | ↓ MCP-1, VCAM-1, NADPH oxidase, NOX2, and p22phox mRNA expression in the atherosclerotic aorta ↓ MCP-1, VCAM-1 mRNA and macrophage accumulation expressions in atherosclerotic lesions in the aortic root ↓ MCP-1, VCAM-1, CD68, NOX2, and p22phox RNA expression in the abdominal aorta ↓ PGE2 and TXB2 plasma level ↓ MCP-1, ICAM-1, VCAM-1 mRNA, CD68, p47phox, and p22phox expression in the PVAT ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas in response of acetylcholine | [29] |
Dahl salt-sensitive rats | Hypertension | Euglycemic | Dapagliflozin (0.1 mg/kg/day)/6 weeks/P.O | ↓ VCAM-1, E-selectin and eNOS protein expression ↓ NF-κB, MCP1 and IL-6 protein expression | [54] |
ApoE−/− mice | Obesity | Euglycemic | Empagliflozin (10 mg/kg/day)/10 weeks/P.O | ↓ Vcam-1 and MCP-1 mRNA Marginally ↓ Timp-1 and Timp-2 expression level in the aortic root (locally in the atherosclerotic lesion) | [55] |
Rtas | Healthy aortic ring | Euglycemic | Canagliflozin (10 μM) | ↑ Endothelium-dependent vasodilation | [36] |
ApoE−/− mice | Obesity | Euglycemic | Canagliflozin (10 mg/kg/day)/5 weeks/P.O | ↓ Vcam-1 and MCP-1 mRNA levels in the aortic root | [56] |
db/db mice | T2D | Hyperglycemic | Canagliflozin (10 mg/kg/day)/5 weeks/P.O | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas | [32] |
C57Bl/6 J mice | – | Euglycemic | Dapagliflozin (1.0 μM) | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas | [26] |
ApoE−/− mice | Adult/obesity | Euglycemic | Dapagliflozin (1.0 mg/kg/day)/4 weeks/P.O | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas | [26] |
ApoE−/− mice | Aged/obesity | Euglycemic | Dapagliflozin (1.0 mg/kg/day)/4 weeks/P.O | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas ↓ NFκB activation ↓ P-IκBα protein expression ↓ ICAM-1 and F4/80 protein expression | [26] |
C57BLKS/J-leprdb/Leprdb mice | T2D | Hyperglycemic | Dapagliflozin (60 mg/kg diet; 0.006%)/8 weeks | ↓ Impairment of vascular endothelium- dependent relaxation in thoracic aortas ↓ MCP-1, IL-1β, IL-17, IL-10, CCL5 and IL-6 circulating markers | [27] |
White rabbits | Aortic smooth muscle | Euglycemic | Dapagliflozin 10, 30, 100, 300, and 1000 μM/30 min to 1 h | ↑ Vasodilation in a concentration-dependent manner Activation of Kv channels and PKG, and was independent of other K+ channels, Ca2+ channels, intracellular Ca2+, and the endothelium | [34] |
C57Bl/6J mice | T1D | Hyperglycemic | Empagliflozin (10 mg/kg/day)/ 20 weeks/P.O | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas ↓ ICAM1 and VCAM1 protein level upregulation | [30] |
ApoE−/− mice | Atherosclerosis | Euglycemic | Empagliflozin (3 mg/kg/day)/8 weeks/P.O | ↓ TNF-α, IL-6, MCP-1, and hsCRP circulating levels | [33] |
(ZDF)rats | T2D | Hyperglycemic | Empagliflozin (10 mg/kg/day, 30 mg/kg/day)/6 weeks/P.O | ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas ↓ vascular oxidative stress | [57] |
KK/Ay mice | T2D | Hyperglycemic | Ipragliflozin and dapagliflozin: (0.1–1 mg/kg/day) Tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin: (1–10 mg/kg/day)/4 weeks/P.O | Improved IL-1β, IL-6, MCP-1, and TNF-α, ICAM-1, VCAM-1, and E-selectin circulation level | [47] |
ApoE−/− mice | T1DM/obesity | Hyperglycemic | Dapagliflozin (1 mg/kg/day)/12 weeks/via intragastrical route | ↓ NLRP3, IL-1β, and IL-18 serum level attenuation of vascular ROS production ↓ ROS formation and NLRP3, IL-1β, and IL-18 protein expression in aortic tissue | [39] |
C57Bl/6 J mice | T1D | Hyperglycemic | Ipragliflozin (3 mg/kg/day)/3 weeks/P.O | ↓ ICAM-1, VCAM-1, and MCP-1 RNA and protein expression ↑ impaired Akt & eNOSSer1177phosphorylation ↓ 8-OHdG ↓ Impairment of vascular endothelium- dependent relaxation in thoracic aortas | [28] |
C57Bl/6J mice | T1D | Hyperglycemic | Canagliflozin, (30 mg/kg/day)/4 weeks/P.O | ↓ Impairment of coronary vasodilation in the diabetic group only | [35] |
C57Bl/6J mice | Pulmonary arteries and coronary arteries | Hyperglycemic | Canaglflozin 100 pmol-1 nmol/l | ↓ Vascular tone in pulmonary arteries only | [35] |
10 and 100 μmol/l | ↑ Coronary vasodilation (SNP-induced) | ||||
db/db mice | Diabetes/obesity | Hyperglycemic | 0.03% empagliflozin/diet/10 weeks | ↓ Impairment of vascular endothelium- dependent relaxation in thoracic aortas ↓ elevated aortic superoxide | [58] |
Wistar rats | T1D | Hyperglycemic | Empagliflozin (30 or 10 mg/kg/day)/8 weeks/P.O | ↓ Impairment of vascular endothelium- dependent relaxation in thoracic aortas | [31] |
Cell lines | Drug (dose) | Stimulant (dose) | Major finding | References |
---|---|---|---|---|
HCAECs | Empagliflozin and dapagliflozin (1 μM)/2 h | TNFα (10 ng/ml)/ 4–24 h | ↓ ROS level in TNFα-stimulated cells | [59] |
HUVECs | Empagliflozin and dapagliflozin (1 μM)/2 h | TNFα (10 ng/ml)/4–24 h | ↑ NO bioavailability in TNFα-stimulated cells | [59] |
Porcine coronary artery endothelial cells | Empagliflozin (1–100 nmol/l)/30 min | HG (25 mmol/l) or H2O2 (100 μmol/l)/24 h | ↓ SA‐β‐gal in HG‐treated cells ↓ p21 and p16 expression level in HG‐treated cells ↓ eNOS and VCAM‐1 mRNA and protein expression level in HG‐treated cells ↑ mRNA SGLT-1 and SGLT-2 expression in H2O2‐ and HG‐treated ECs | [37] |
HAAECs | Empagliflozin (50 μM)/24 h | Statically cultured or subjected to a steady wall shear stress of 10 dyne/cm | ↓ Roundness of the cells under static conditions ↓ TNFα-associated HAAEC-NB4 cell adhesion under static and flow conditions ↓ NB4-HAAEC adhesion under static and perfused conditions ↑ HS intensity level under static and flow culture conditions in heparinase III-treated cells | [60] |
HUVECs | Canagliflozin (0–50 μM), empagliflozin (0–50 μM), dapagliflozin (0–50 μM)/3 days | ↓ DNA synthesis in a dose-dependent manner by dapagliflozin ↓ Proliferation in a dose-dependent manner by three SGLT-2 inhibitors Canagliflozin disrupts cell cycle progression, ↓ cyclin A expression and the phosphorylation of retinoblastoma protein | [61] | |
Murine endothelial cells | Empagliflozin (25 nM-10 μM)/24 h | HG (25 mM)/24 h | ↓ Src-kinase, EGF receptor-kinase, protein kinase-C and Rho-kinase ↑ PAR2-mediated vasodilation in tissues cultured under hyperglycaemic conditions | [62] |
HUVECs | Canagliflozin (10 μM)/30 min | IL-1β (10 ng/ml) for 6 h | ↓ IL-6 and MCP-1 protein and MRNA expression | [45] |
HAECs | Canagliflozin (10 μM)/15 min | IL-1β (5 ng/ml) for 4 h | ↓ IL-6 and MCP-1 protein and mRNA expression | [45] |
HUVECs | Dapagliflozin (1.0–5.0 nM)/24 h Dapagliflozin (100 nM)/24 h | TNFα (10 ng/ml) or HG (10–30 mM) for 24 h | ↓ ICAM-1 & VCAM-1 protein levels ↑ PAI-1 protein ↓ ICAM-1, PAI-1 mRNA and protein expression in hyperglycemia-treated cells | [26] |
HUVECs | Empagliflozin (0.1–100 μM) | VEGF (10 ng/ml) for 1 h | Neutral effect of the drug on endothelial cell proliferation | [35] |
HUVECs | Empagliflozin (1 or 10 μM)/6 days | Ach (1 μM)/30 min after cultured under HG (30 mM) | ↑ viability of hyperglycemic endothelial cells | [57] |