Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial
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Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories. Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25–75 ml min−1 [1.73 m]−2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200–5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories. Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories. Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity. Trial registration: ClinicalTrials.gov NCT03036150. Funding: The study was funded by AstraZeneca. Graphical abstract: [Figure not available: see fulltext.].
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetologia |
| Vol/bind | 65 |
| Udgave nummer | 7 |
| Sider (fra-til) | 1085-1097 |
| Antal sider | 13 |
| ISSN | 0012-186X |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
SWW, PV and NJ have no disclosures. DZIC has received consulting fees or speaking honoraria, or both, from Bristol Myers Squibb, Novo Nordisk, Mitsubishi Tanabe, MAZE, Janssen, Bayer, Boehringer Ingelheim/Eli Lilly, AstraZeneca, Merck & Co., Prometic and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim/Eli Lilly, Sanofi, AstraZeneca, Novo Nordisk and Merck & Co. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from NIDDK and Amgen; he is on the board of directors for Satellite Healthcare, has received fees for advisory boards for Baxter, Cricket, DiaMedica and Reata, holds stock options for Ardelyx, CloudCath, Durect, DxNow and Outset, has received fees from Akebia, Sanifit and Vertex for trial steering committees, and has received fees for data and safety monitoring board service from Angion, Bayer and ReCor. AML and BVS are employees and stockholders of AstraZeneca. JFEM reports receipt of speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bayer, Fresenius, Medice, Novo Nordisk, Relypsa and Roche, research support from the European Union, the Canadian Institutes Health Research, Boehringer Ingelheim, Celgene, Idorsia, Novo Nordisk, Roche and Sandoz, and consultation fees from AstraZeneca, Bayer, Celgene, Novo Nordisk and Vifor Pharma. OM has received grants and personal fees from AstraZeneca, Bristol Myers Squibb and Novo Nordisk, and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson and Novartis. JJVM reports payments to his employer, Glasgow University, for his work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardurion, Cytokinetics, GSK, Novartis, Pfizer and Theracos and personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals and Medsca. PR has received honoraria to Steno Diabetes Center Copenhagen for steering group membership and/or lectures and advice from AstraZeneca, Novo Nordisk, Bayer and Eli Lilly, for advisory board participation from Sanofi Aventis and Boehringer Ingelheim, and for steering group participation from Gilead. RC-R has received honoraria from AstraZeneca, GlaxoSmithKline, Medtronic and Boehringer Ingelheim, has lectured for Amgen, Janssen and Boehringer Ingelheim, and has received research support from GlaxoSmithKline, Novo Nordisk and AstraZeneca. RDT received funding from AstraZeneca for participating in the steering committee for the DAPA-CKD trial. He has received fees for consultancy from Boehringer Ingelheim, Reata Pharma and Chinook Pharma. He has received honoraria for lectures from Medscape and Medical Education Resources. He has participated in data and safety monitoring or advisory boards for Bayer, Viofor, Akebia and Otsuka. DCW provides ongoing consultancy services to AstraZeneca and has received honoraria and/or consultancy fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Merck Sharp and Dohme, Reata, Tricida and Vifor Fresenius. HJLH is a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe, Novo Nordisk and Retrophin. He received research support from Abbvie, AstraZeneca, Boehringer Ingelheim and Janssen.
Funding Information:
The authors thank all investigators, trial teams and patients for their participation in the trial. The authors would also like to acknowledge Marco Favretto and Nicola Truss, inScience Communications, London, UK, for assistance in preparation of figures and editing the manuscript. This support was funded by AstraZeneca. SWW, PV and NJ have no disclosures. DZIC has received consulting fees or speaking honoraria, or both, from Bristol Myers Squibb, Novo Nordisk, Mitsubishi Tanabe, MAZE, Janssen, Bayer, Boehringer Ingelheim/Eli Lilly, AstraZeneca, Merck & Co., Prometic and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim/Eli Lilly, Sanofi, AstraZeneca, Novo Nordisk and Merck & Co. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from NIDDK and Amgen; he is on the board of directors for Satellite Healthcare, has received fees for advisory boards for Baxter, Cricket, DiaMedica and Reata, holds stock options for Ardelyx, CloudCath, Durect, DxNow and Outset, has received fees from Akebia, Sanifit and Vertex for trial steering committees, and has received fees for data and safety monitoring board service from Angion, Bayer and ReCor. AML and BVS are employees and stockholders of AstraZeneca.
Publisher Copyright:
© 2022, The Author(s).
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