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 Function

Sodium-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 van Bommel E.J. Muskiet M.H. Tonneijck L. et al. SGLT2 inhibition in the diabetic kidney—from mechanisms to clinical outcome. Clin J Am Soc Nephrol. 2017; 12: 700-710 Crossref PubMed Scopus (137) Google Scholar ,2 McCrimmon R.J. Henry R.R. SGLT inhibitor adjunct therapy in type 1 diabetes. Diabetologia. 2018; 61: 2126-2133 Crossref PubMed Scopus (59) Google Scholar In people with T2D with and without diabetic kidney disease, SGLT2 inhibition improves hard renal outcomes in large-scale clinical trials. 3 Zinman B. Wanner C. Lachin J.M. et al. for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128 Crossref PubMed Scopus (7932) Google Scholar , 4 Wiviott S.D. Raz I. Bonaca M.P. et al. for the DECLARE-TIMI 58 InvestigatorsDapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380: 347-357 Crossref PubMed Scopus (3553) Google Scholar , 5 Neal B. Perkovic V. Mahaffey K.W. et al. for the CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377: 644-657 Crossref PubMed Scopus (2519) Google Scholar , 6 Perkovic V. Jardine M.J. Neal B. et al. for the CREDENCE Trial InvestigatorsCanagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380: 2295-2306 Crossref PubMed Scopus (3224) Google Scholar Despite these salutary clinical effects, the mechanisms responsible remain incompletely understood, as they are not fully explained by the improvement of aforementioned renal risk factors. However, the fact that estimated glomerular filtration rate (eGFR) changes over time in the trials may provide important insights. After the initiation of treatment, SGLT2 inhibitors induce an initial eGFR dip of 2 to 5 ml/min per 1.73 m2, while renal function loss over time (eGFR slope) is subsequently attenuated. This effect, together with the observation that eGFR tends to return back to or above baseline after cessation of treatment, leads to the prevailing hypothesis that renoprotection is at least partly achieved through direct renal hemodynamic effects resulting in a lowering of intraglomerular pressure, resembling the effect of blockers of the renin-angiotensin system (RAS). 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 trialKidney InternationalVol. 97Issue 1PreviewSodium-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). Full-Text PDF