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
2019; Elsevier BV; Volume: 97; Issue: 1 Linguagem: Inglês
10.1016/j.kint.2019.09.013
ISSN1523-1755
AutoresErik J.M. van Bommel, Marcel H.A. Muskiet, Michaël J.B. van Baar, Lennart Tonneijck, Mark M. Smits, Anna L. Emanuel, Andrea Božović, A.H. Jan Danser, Frank Geurts, Ewout J. Hoorn, Daan J. Touw, Emil List Larsen, Henrik E. Poulsen, Mark H.H. Kramer, Max Nieuwdorp, Jaap A. Joles, Daniël H. van Raalte,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoSodium-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. 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. Do sodium-glucose cotransporter-2 inhibitors affect renal hemodynamics by different mechanisms in type 1 and type 2 diabetes?Kidney InternationalVol. 97Issue 1PreviewCardiovascular and renal outcome trials demonstrate nephroprotection with sodium-glucose cotransporter-2 inhibitors in people with type 2 diabetes. Attenuation of hyperfiltration is believed to be responsible for the nephroprotection, and studies in young adults with type 1 diabetes suggest that afferent arteriolar vasoconstriction induced by a tubuloglomerular feedback mechanism may be responsible for this effect. The study by van Bommel et al. suggests that this mechanism may not hold true in older adults with type 2 diabetes, who instead attenuate elevated glomerular filtration rate via post-glomerular vasodilation. Full-Text PDF Corrigendum to “van Bommel EJM, Muskiet MHA, van Baar MJB, et al. 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.” Kidney Int. 2020;97:202–212Kidney InternationalVol. 97Issue 5PreviewThe authors regret an error in Supplementary Figure S1. Of patients treated with dapagliflozin, 24 were analyzed; of those treated with gliclazide, 20 were analyzed. Full-Text PDF SGLT2i and postglomerular vasodilationKidney InternationalVol. 97Issue 4PreviewSodium-glucose cotransporter 2 inhibitors have emerged as nephroprotective agents.1,2 van Bommel et al.3 report that in type 2 diabetes mellitus, dapagliflozin reduced measured glomerular filtration rate (mGFR) and filtration fraction without increasing renal vascular resistance, while gliclazide did not consistently alter renal hemodynamic parameters. They conclude that dapagliflozin may promote postglomerular vasodilation rather than preglomerular vasoconstriction.3 However, compared with gliclazide, the only consistent impact of dapagliflozin was an increased hematocrit. Full-Text PDF The authors replyKidney InternationalVol. 97Issue 4PreviewWe thank Soler and colleagues for their interest in our work.1 However, we respectfully disagree with their comments.2 Our trial was a mechanistic physiology study detailing the renal hemodynamic actions of dapagliflozin and should be appreciated as such. The use of costly and burdensome state-of-the-art methodologies limits study size and power. We clearly show that dapagliflozin reduces measured glomerular filtration rate (mGFR) (highly significant for each treatment phase within-group), while mGFR is unaffected by gliclazide. Full-Text PDF Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney functionKidney InternationalVol. 97Issue 4PreviewSodium-glucose cotransporter 2 (SGLT2) inhibitors prevent coupled glucose and sodium reabsorption in the proximal tubule. This leads to glucosuria and lowering of plasma glucose concentrations in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). Additional beneficial effects of SGLT2 inhibitors include reductions in body weight, blood pressure, and plasma uric acid concentrations.1,2 In people with T2D with and without diabetic kidney disease, SGLT2 inhibition improves hard renal outcomes in large-scale clinical trials. Full-Text PDF
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