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

Autor:	Laursen JC; Steno Diabetes Center Copenhagen, Denmark.; University of Copenhagen, Denmark., Søndergaard-Heinrich N; Steno Diabetes Center Copenhagen, Denmark.; University of Copenhagen, Denmark., de Melo JML; Steno Diabetes Center Copenhagen, Denmark., Haddock B; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Denmark., Rasmussen IKB; Steno Diabetes Center Copenhagen, Denmark.; University of Copenhagen, Denmark., Safavimanesh F; Steno Diabetes Center Copenhagen, Denmark., Hansen CS; Steno Diabetes Center Copenhagen, Denmark., Størling J; Steno Diabetes Center Copenhagen, Denmark., Larsson HBW; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Denmark., Groop PH; Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia., Frimodt-Møller M; Steno Diabetes Center Copenhagen, Denmark., Andersen UB; Steno Diabetes Center Copenhagen, Denmark.; University of Copenhagen, Denmark.; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Denmark.; Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia., Rossing P; Steno Diabetes Center Copenhagen, Denmark.; University of Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	EClinicalMedicine [EClinicalMedicine] 2021 Jun 28; Vol. 37, pp. 100895. Date of Electronic Publication: 2021 Jun 28 (Print Publication: 2021).
DOI:	10.1016/j.eclinm.2021.100895
Abstrakt:	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 2019-004,557-92), 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 21-58] 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 -1 and for placebo +1·3 (0·7) s -1 , resulting in a difference between interventions of -2·3 s -1 [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. Competing Interests: P.R. has received honoraria to Steno Diabetes center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, Vifor, and research support from Astra Zeneca and Novo Nordisk. P-H.G. has received lecture honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc, and is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, Mundipharma, Novo Nordisk and Sanofi. N.S-H. reports having stock equity in Novo Nordisk A/S and Akcea Therapeutics Inc. C.S.H. has received lecture honoraria to Steno Diabetes center Copenhagen from Novo Nordisk. J.C.L., J.M.L.M., B.H., I.K.B.R., F.S., J.S., H.B.W.L., M.F-M., and U.B.A. declare no competing interests. (© 2021 The Author(s).)
Databáze:	MEDLINE
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