CANagliflozin In DIALysis Patients

Summary

Rationale: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of drugs originally developed for the treatment of diabetes. Cardiovascular outcome trials with these drugs showed also beneficial effects of these agents on heart failure, cardiovascular disease and kidney outcomes. Secondary analyses from these trials demonstrated that these benefits were consistent in patients with or without type 2 diabetes and with or without chronic kidney disease (CKD) with a lower eGFR threshold of 20 mL/min/1.73m2. However, it is not yet clear if these drugs can also be used in patients with severe kidney disease who require dialysis. This is in part explained because SGLT2 inhibitors bind to a transporter which is located in the luminal side of proximal tubes in the kidney. If kidney function is low, and these patients have no or limited filtering capacity, it is possible that the efficacy of these drugs decrease. Notwithstanding, several animal experiments and preliminary clinical data have suggested that these drugs do have kidney and cardiac protective effects in case of severely decreased kidney function. The investigators hypothesize that SGLT2 inhibitors are distributed to several tissues in the body on top of the kidney and therefore the investigators would like to investigate the specific tissue distribution of SGLT2 inhibitors in patients on dialysis with-and without residual diuresis.

Timeline

Start

2026-06-01

Primary completion

2027-01-30

Completion

2027-01-30

Publications

• Background Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
• Background Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
• Background The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4.
• Background Juni RP, Al-Shama R, Kuster DWD, van der Velden J, Hamer HM, Vervloet MG, Eringa EC, Koolwijk P, van Hinsbergh VWM. Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction. Kidney Int. 2021 May;99(5):1088-1101. doi: 10.1016/j.kint.2020.12.013. Epub 2020 Dec 23.
• Background Uthman L, Homayr A, Juni RP, Spin EL, Kerindongo R, Boomsma M, Hollmann MW, Preckel B, Koolwijk P, van Hinsbergh VWM, Zuurbier CJ, Albrecht M, Weber NC. Empagliflozin and Dapagliflozin Reduce ROS Generation and Restore NO Bioavailability in Tumor Necrosis Factor alpha-Stimulated Human Coronary Arterial Endothelial Cells. Cell Physiol Biochem. 2019;53(5):865-886. doi: 10.33594/000000178.
• Background Billing AM, Kim YC, Gullaksen S, Schrage B, Raabe J, Hutzfeldt A, Demir F, Kovalenko E, Lasse M, Dugourd A, Fallegger R, Klampe B, Jaegers J, Li Q, Kravtsova O, Crespo-Masip M, Palermo A, Fenton RA, Hoxha E, Blankenberg S, Kirchhof P, Huber TB, Laugesen E, Zeller T, Chrysopoulou M, Saez-Rodriguez J, Magnussen C, Eschenhagen T, Staruschenko A, Siuzdak G, Poulsen PL, Schwab C, Cuello F, Vallon V, Rinschen MM. Metabolic Communication by SGLT2 Inhibition. Circulation. 2024 Mar 12;149(11):860-884. doi: 10.1161/CIRCULATIONAHA.123.065517. Epub 2023 Dec 28.
• Background Bakker WM, Heerspink HJL, Berger SP, Wanner C, Badve SV, Arnott C, Abrahams AC, van den Born JC, van Faassen TC, Gaillard CAJM, Gelens MACJ, Gorris JL, Hemmelder MH, Jakulj L, van Kruijsdijk RCM, Kuypers DRJ, van der Meer P, van der Net JB, Nijmeijer HH, Vervloet MG, de Vries APJ, Walsh M, Wang AY, Gansevoort RT; Renal Lifecycle Trial Investigators. Rationale and design of the Renal Lifecycle trial assessing the effect of dapagliflozin on cardiorenal outcomes in severe chronic kidney disease. Nephrol Dial Transplant. 2025 Aug 29;40(9):1746-1755. doi: 10.1093/ndt/gfaf046.
• Background van der Hoek S, Willemsen ATM, Visser T, Heeres A, Mulder DJ, Bokkers RPH, Slart RHJA, Elsinga PH, Heerspink HJL, Stevens J. Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes. Clin Pharmacol Ther. 2023 Jun;113(6):1295-1303. doi: 10.1002/cpt.2886. Epub 2023 Mar 26.

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