The Effects of Dapagliflozin on Systemic and Renal Vascular Function Display an Epigenetic Signature

Abstract

Context Mechanisms mediating the cardiovascular and renal protection exerted by SGLT2 inhibitors are still partially unknown. We investigated whether dapagliflozin modulates systemic and renal vascular function and structure, and induces epigenetic modifications. Subjects and Methods Forty hypertensive patients with type 2 diabetes were randomly assigned to 4-week treatment with dapagliflozin 10 mg or hydrochlorothiazide (HCT) 12.5 mg. Routine analyses; plasma renin activity; aldosterone, catecholamine, and 24-hour urinary electrolyte levels; flow-mediated dilation (FMD) of the brachial artery; carotid-femoral pulse-wave velocity (PWV); augmentation index; and resistive index and dynamic renal resistive index (DRIN) were measured at baseline and after treatment. Circulating miRNAs (miRs) related to heart failure (miR30e-5p, miR199a-3p), endothelial dysfunction (miR27b and miR200b), and renal function (miR130b-3p, miR21-5p) were assessed and related to the effects of treatments. Results Dapagliflozin and HCT marginally lowered blood pressure. Fasting glucose was lowered, whereas 24-hour diuresis, glycosuria, and osmolar clearance were increased by dapagliflozin (P < 0.001 for all), without affecting sodium excretion and glomerular filtration rate. Magnesium levels significantly increased after dapagliflozin treatment (P = 0.02). Neither dapagliflozin nor HCT modified FMD or PWV. DRIN did not vary in the dapagliflozin group, whereas it increased in the HCT group (P = 0.047 for time by treatment interaction). Both treatments induced variations in the expression of some miRs; dapagliflozin, but not HCT, significantly up-regulated miR30e-5p and downregulated miR199a-3p. Conclusion A putative epigenetic regulation of the protecting cardiovascular effect exerted by SGLT2 inhibitors was found. Dapagliflozin might exert nephroprotection by preserving renal vasodilating capacity.

Impact of Diabetes Mellitus on Bone Health

“…Despite these important advances, the mechanism of the cardiovascular and renal benefit of SGLT-2 inhibitors is still unknown. Furthermore, the epigenetic impact of these novel drugs on diabetes mellitus-induced bone fracture risk remains unexplored [222].…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…Despite the scarce information on DNA methylation and histone epigenetics, there is already some information on miRNAs. In an open label study in 40 diabetic patients comparing treatment with dapagliflozin or thiazides, circulating miR30e-5p was upregulated and miR199a-3p downregulated in dapagliflozin-treated patients [164]. This study suggests the indeed SGLT2 inhibitors may modulate epigenetic regulators.…”

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

“…Three previous studies in T2DM reported inconsistent dapagliflozin effects on FMD [22][23][24]. The first study showed improvement in FMD after two days of treatment [23]; however, the authors reported no effect after 4 weeks of treatment [25]. In a second trial, although FMD was not significantly changed in the intentionto-treat analysis, a post hoc analysis indicated that an improvement was detected in a subgroup of patients with HbA1c > 7.0% at baseline.…”