https://doi.org/10.1007/s00392-025-02625-4
1Friedrich-Alexander-Universität Erlangen-Nürnberg Medizinische Klinik 2 - Kardiologie und Angiologie Erlangen, Deutschland; 2Universitätsklinikum Erlangen Medizinische Klinik 4 Erlangen, Deutschland
Background:
Recently, we demonstrated that a combination therapy with empagliflozin and linagliptin in patients with type 2 diabetes mellitus (T2DM) induce changes in renal hemodynamics. The purpose of this study was to analyse the influence of basal nitric oxide (NO) activity of the renal vasculature on the described changes of the renal hemodynamic profile.
Methods:
In this study patients with T2DM were randomized to receive either empagliflozin and linagliptin (E+L, n=50) or metformin and insulin glargine (M+I, n=46), for 3 months. Renal hemodynamics were assessed with 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. Due to withdrawal of inulin from the market during the study, GFR was measured only in a sub-group of patients (E+L: n=34; M+I: n=31). Intraglomerular hemodynamics were calculated according the model established by Gomez. The basal NO activity in the renal circulation has been assessed by analysing change in RPF in response to intravenously administrated NG-monomethyl-l-arginine (NO inhibitor).
Results:
After 3 months of treatment, we did not observe any change in renal basal NO activity compared to baseline in either of the groups. In patients with E+L treatment, we found a correlation between basal 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 (r=0.459, p<0.001) and efferent postglomerular (RE) arterioles (r=0.513, p=0.02) have been found. No such relationships with renal basal NO activity were found in the M+I group after 3 months of treatment.
Conclusion:
Renal NO activity emerged as a determinant of the renal hemodynamic response in the combination therapy of empagliflozin and linagliptin, but not in the combination therapy of insulin and metformin. Our study provides evidence that the treatment effect of SGLT-2 inhibitors may be contributed at least partly by the renal NO activity in patients with T2D.