Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

Abstract

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R 2 * (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three-and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019À004,557À92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21À58] mg/g and an eGFR of 73 (32) ml/min/1¢73m 2 . The mean changes in renal cortical R 2 * from baseline to six hours were for dapagliflozin -1¢1 (SD 0¢7) s À1 and for placebo +1¢3 (0¢7) s À1 , resulting in a difference between interventions of -2¢3 s À1 [95% CI -4¢0 to -0¢6]; p = 0¢012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R 2 * without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

Sodium-glucose cotransporter 2 (SGLT-2) inhibition and kidney protection: Does improvement in kidney hypoxia play a role?

“…Although the data presented by Laursen et al [5] fit perfectly with the hypoxia hypothesis, one should remain cautious with their interpretation. First, the authors investigated patients with type 1 diabetes and whether their results can be extrapolated to patients with type 2 diabetes remains to be demonstrated.…”

“…In an article published in EClinicalMedicine, Jens Christian Laursen and colleagues present the results of a randomized, double-blind, placebo-controlled crossover study assessing the acute effects of a high dose of dapagliflozin on kidney tissue oxygenation and perfusion in patients with diabetes [5]. In this study, 15 patients with type 1 diabetes and albuminuria and a mean estimated glomerular filtration of 73 ml/min/m 2 were enrolled and randomized to receive consecutively either a single dose of 50 mg dapagliflozin or a placebo with a two-week wash-out period between the two administrations.…”

The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists

“…There are also possibly complementary mechanisms. SGLT2 inhibitors improve tubular oxygenation and reduce tubular hypoxic stress 10 . MRAs reduce renal fibrosis and glomerulosclerosis by deactivating the mineralocorticoid receptor in fibroblasts.…”

Current Use and Complementary Value of Combining in Vivo Imaging Modalities to Understand the Renoprotective Effects of Sodium-Glucose Cotransporter-2 Inhibitors at a Tissue Level

“…Furthermore, cortical perfusion was consistently lower (28%-50%) in CKDand diabetic kidney disease (DKD) populations (Gillis et al, 2016;Li et al, 2017). ASL-MRI found no acute change in perfusion after a single dose of dapagliflozin in T1DM patients (Laursen et al, 2021). Also, in newly diagnosed T2DM patients, perfusion did not change after a 24-weeks treatment with 100 mg canagliflozin, despite a persistent eGFR-reduction (Zhou et al, 2021).…”

“…Although primarily used in cardiology (Gatehouse et al, 2005;Nayak et al, 2015), PC-MRI recently showed reduced RBF in CKD patients vs. healthy controls (Khatir et al, 2014;Khatir et al, 2015). In Type I diabetes (T1DM) patients, PC-MRI showed an acute RBF decrease following a single dose of 50 mg dapagliflozin, although not significantly different from the control group (Laursen et al, 2021).…”