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

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 10; pp. 4253 - 4263
• Main Authors: Solini, Anna, Seghieri, Marta, Giannini, Livia, Biancalana, Edoardo, Parolini, Federico, Rossi, Chiara, Dardano, Angela, Taddei, Stefano, Ghiadoni, Lorenzo, Bruno, Rosa Maria
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.10.2019; Copyright Oxford University Press; Oxford University Press
• Subjects: Adult; Aged; Aldosterone; Analysis; Analysis of Variance; Antidiabetics; Benzhydryl Compounds - administration & dosage; Blood Glucose - drug effects; Blood pressure; Care and treatment; Catecholamines; Congestive heart failure; Dapagliflozin; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - drug therapy; Diabetes therapy; Diuresis; Epigenesis, Genetic - drug effects; Epigenetic inheritance; Epigenetics; Female; Glomerular filtration rate; Glomerular Filtration Rate - drug effects; Glucosides - administration & dosage; Hospitals, University; Humans; Hydrochlorothiazide; Hydrochlorothiazide - administration & dosage; Hypertension; Hypertension - complications; Hypertension - diagnosis; Hypertension - drug therapy; Italy; Magnesium; Male; MicroRNAs - drug effects; MicroRNAs - genetics; Middle Aged; Prognosis; Renal Circulation - drug effects; Renal function; Renin; Sodium-Glucose Transporter 2 Inhibitors - administration & dosage; Statistics, Nonparametric; Structure-function relationships; Treatment Outcome; Type 2 diabetes; Up-Regulation; Wave propagation; Italy
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2019-00706

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. Hemodynamic and systemic vascular effects of dapagliflozin undergo epigenetic regulation that favorably affects two miRs involved in heart failure.