The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

• Authors: Erik J M van Bommel, Marcel H A Muskiet, Michaël J B van Baar, Lennart Tonneijck, Mark M Smits, Anna L Emanuel, Andrea Bozovic, A H Jan Danser, Frank Geurts, Ewout J Hoorn, Daan J Touw, Emil L Larsen, Henrik E Poulsen, Mark H H Kramer, Max Nieuwdorp, Jaap A Joles, Daniël H van Raalte
• Journal: Kidney international (Kidney Int) Vol. 97 Issue 1 Pg. 202-212 (01 2020) ISSN: 1523-1755 [Electronic] United States
• PMID: 31791665 (Publication Type: Clinical Trial, Phase IV, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. All rights reserved.

Chemical References

• Benzhydryl Compounds
• Glucosides
• Glycated Hemoglobin A
• Sodium-Glucose Transporter 2 Inhibitors
• hemoglobin A1c protein, human
• dapagliflozin
• Metformin
• Gliclazide

Topics

• Aged
• Benzhydryl Compounds (pharmacology, therapeutic use)
• Diabetes Mellitus, Type 2 (blood, complications, diagnosis, drug therapy)
• Diabetic Nephropathies (blood, etiology, pathology, prevention & control)
• Double-Blind Method
• Female
• Gliclazide (pharmacology, therapeutic use)
• Glomerular Filtration Rate (drug effects)
• Glucosides (pharmacology, therapeutic use)
• Glycated Hemoglobin (analysis)
• Humans
• Kidney (blood supply, drug effects, pathology)
• Male
• Metformin (pharmacology, therapeutic use)
• Middle Aged
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)
• Treatment Outcome
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)