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Abstract
Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na+ entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.
Highlights
Numbers of diabetic patients are reported to be increasing across the world
We reported functional sodium glucose co-transporter 2 (SGLT2) expression in mesangial cells and retinal pericytes [28,29,30,31,32] and showed that SGLT2 acts as a physiological glucose sensor; pericytes and mesangial cells alter their tone via SGLT2 and Na+-Ca2+ exchangers according to glucose concentration [32]
The results of recent large trials of SGLT2 inhibitors [9,10,11,34,35] seem to indicate the effects of SGLT2 inhibitors on capillaries in the heart and kidney, since the dysfunction of SGLT2-expressing pericytes and mesangial cells is thought to be the cause of heart failure (HF) and diabetic nephropathy (DN), as mentioned above
Summary
Numbers of diabetic patients are reported to be increasing across the world. The International Diabetes Federation (IDF) estimated 451 million people had diabetes worldwide in 2017, and that the number will increase to 693 million by 2045, which leads to a large social, financial, and health system burden [1]. Among the recent studies of SGLT2 inhibitors in T2DM patients [9,10,11,12], some reported significant decreases in 3-point major adverse cardiovascular events (MACE), the occurrence of cardiovascular death [1,3] and hospitalization for HF (HHF) [9,10,11,12] in patients treated with SGLT2 inhibitors compared with the placebo-treated controls These trials differed only in the proportions of subjects with established atherosclerosis and with multiple risk factors: 99% and 1% in EMPA-REG OUTCOME (empagliflozin), 64% and 36% in the CANVAS Program (canagliflozin) and 40% and 60% in DECLARE-TIMI 58 (dapagliflozin), respectively. N.S.: not significantN.D.: not determined; HHF: hospitalization for heart failure; MI: myocardial infarction
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