Effects of Combination Treatment on Renal Endothelial Function in Type 2 Diabetes Mellitus

Recently, we demonstrated that a combination therapy with empagliflozin and linagliptin (E+L) in patients with type 2 diabetes mellitus (T2DM) induce changes in renal hemodynamics. The purpose of the present study was to analyze the influence of nitric oxide (NO) activity of the renal vasculature on the described changes of the renal hemodynamic profile.

Patients with T2DM were randomized to receive either E+L: (n = 34) or metformin and insulin glargine (M+I: n = 31), for 3 months. Renal hemodynamics were assessed using the constant-infusion input-clearance technique with p-aminohippuric acid for renal plasma flow (RPF) and inulin for glomerular filtration rate (GFR) at baseline and after treatment. Intraglomerular hemodynamics were calculated according to the model established by Gomez. The NO activity in the renal circulation was assessed by analyzing change in RPF in response to i.v. administrated NG-monomethyl-l-arginine (L-NMMA), an NO inhibitor.

After 3 months of treatment, changes in renal hemodynamic parameters were compared with baseline in both groups without any change in renal NO activity. In patients with E+L treatment, we observed a correlation between change in NO activity of the renal vasculature and change in RPF (r = -0.665, P < 0.001) after 3 months of treatment. Similar correlations with change in renal vascular resistance (RVR) (r = 0.439, P = 0.003) and resistance of the efferent postglomerular (R_E) arterioles (r = 0.513, P = 0.002) were observed. No such relationships with change in renal NO activity were observed in the M+I group after 3 months of treatment.

Renal NO activity emerged as a determinant of the renal hemodynamic response in the combination therapy of E+L, but not in the combination therapy of M+I. Our study provides evidence that the treatment effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors may be contributed at least partly by the renal NO activity in patients with T2DM.