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Randomized Controlled Trial
. 2024 Nov 27;39(12):2040-2047.
doi: 10.1093/ndt/gfae106.

The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis

Phil McEwan  1 , Peter D Gabb  1 , Jason A Davis  1 , Juan Jose Garcia Sanchez  2 , C David Sjöström  3 , Salvatore Barone  4 , Pavlos Kashioulis  3 , Mario Ouwens  5 , Syd Cassimaty  6 , Ricardo Correa-Rotter  7 , Peter Rossing  8   9 , David C Wheeler  10 , Hiddo J L Heerspink  11   12
Affiliations
Randomized Controlled Trial

The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis

Phil McEwan et al. Nephrol Dial Transplant. .

Abstract

Background: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial demonstrated that patients with or without type 2 diabetes who were treated with dapagliflozin experienced slower progression of CKD versus those receiving placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data.

Methods: Patient-level data from the DAPA-CKD trial were used to parameterize a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function and hospitalization for heart failure). Data were pooled with a subpopulation of the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population.

Results: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function and hospitalization for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years [dapagliflozin: 25.2, 95% confidence interval (CI) 19.0-31.5; standard therapy: 18.5, 95% CI 14.7-23.4] in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95% CI 31.9-38.3; standard therapy: 29.6, 95% CI 25.5-34.7).

Conclusion: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Keywords: SGLT2 inhibitor; chronic kidney disease; chronic renal failure; diabetic kidney disease; mortality.

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Conflict of interest statement

P.M., P.D.G and J.A.D. are employees of Health Economics and Outcomes Research Ltd, Cardiff, UK, who received fees from AstraZeneca in relation to this study. C.D.S., S.B., P.K., M.O., S.C. and J.J.G.S. are employees of AstraZeneca. R.C.-R. has received honoraria as consultant from AstraZeneca, Boehringer Ingelheim, Janssen, Bayer, Chinook, AbbVie and Novo Nordisk, and research support from AstraZeneca, Boehringer Ingelheim, Roche and Novo Nordisk. P.R. has received honoraria to Steno Diabetes Center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi and Vifor, and research support from AstraZeneca, Bayer and Novo Nordisk. D.C.W. has provided ongoing consultancy services to AstraZeneca in the last 2 years and has received honoraria and/or consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, Eledon, Galderma, GSK, George Clinical, Janssen, Merck Sharp and Dohme, ProKidney, Takeda, Vifor and Zydus. He also reports speaking fees from Astellas, AstraZeneca and Vifor, and support for travel/meeting attendance from Astellas, AstraZeneca and Pro. He has served on DSMBs for Eledon, Galderma, Merck, ProKidney and Pathalys. He is a member of the International Society of Nephrology and National Institute of Health Research, UK. H.J.L.H. is a consultant for AstraZeneca, AbbVie, Boehringer Ingelheim, CSL Behring, Bayer, Chinook, Dimerix, Gilead, Goldfinch, Merck, Novo Nordisk, Janssen and Travere Pharmaceuticals. He received research support from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Patient baseline disease characteristics, stratified by T2D status, and eGFR/UACR bands as defined by KDIGO guidelines [14]. Bars represent proportions while superimposed numbers correspond to patient counts in each category. T2DM, type 2 diabetes mellitus.
Figure 2:
Figure 2:
Extrapolated mean time-to-event for ESKD, ≥40% sustained decline in eGFR, hospitalization for heart failure, all-cause mortality for patients treated with dapagliflozin plus standard therapy (blue) vs standard therapy alone. Outcomes are provided per 1000 patients treated with dapagliflozin in addition to standard therapy (blue) versus standard therapy alone (grey). Values indicate the mean time-to-event, conditional on a patient's experiencing an event during the observation period, taken as the predicted lifespan (defined as the first time for survival to reach numerically less than one individual out of the cohort of 1000). ACM: all-cause mortality; ESKD: end-stage kidney disease; HHF: hospitalization for heart failure.
See this image and copyright information in PMC

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