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Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD)

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Author Block: John J V McMurray, Inst of Cardiovascular and Medical Sciences, Glasgow, United Kingdom; David C Wheeler, Univ Coll London, London, United Kingdom; Bergur V Stefansson, AstraZeneca, Gothenburg, Sweden; Ricardo Correa Rotter, Natl Medical Science and Nutrition Inst Salvador Zubirán, Mexico City, Mexico; Glenn M Chertow, Stanford Univ Sch of Med, Stanford, CA; Tom Greene, Univ of Utah Health Sciences, Salt Lake City, UT; Fan Fan Hou, Nanfang Hosp & Southern Medical Univ, Guangzhou, China; Magnus B Lindberg, AstraZeneca, Gothenburg, Sweden; Peter Rossing, Steno Diabetes Ctr & Univ of Copenhagen, Copenhagen, Denmark; David Sjostrom, AstraZeneca, Gothenburg, Sweden; Robert D Toto, UT Southwestern Medical Ctr, Dallas, TX; Anna Maria Langkilde, AstraZeneca, Gothenburg, Sweden; Hiddo Jl Lambers Heerspink, Univ of Groningen, Groningen, Netherlands; on behalf of the DAPA-CKD Committees and Investigators
Disclosure Block: J.J. McMurray: Other; Modest; Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, Abbvie, Dalcor, Pfizer, Merck. Other; Significant; Novartis, Glaxo Smith Kline (GSK). Other; Modest; Bristol Myers Squibb (BMS), Vifor-Fresenius, Kidney Research UK (KRUK). Other; Significant; Novartis, AstraZeneca. D.C. Wheeler: Other; Significant; Amgen, AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mitsubishi, Mundipharma, Napp, Ono Pharma, Tricida, Vifor Fresenius. Speaker/Speaker's Bureau; Modest; Amgen, Astellas, Boehringer Ingelhiem, Astellas, Napp, Merck Sharpe and Dohme, Mundipharma,. B.V. Stefansson: Employment; Significant; AstraZeneca. R. Correa Rotter: Other Research Support; Modest; AstraZeneca. Research Grant; Modest; Abbvie, GSK, NovoNordisk. Other Research Support; Modest; Boheringer Ingelheim. Speaker/Speaker's Bureau; Modest; Medtronic, Amgen, Takeda. G.M. Chertow: Other; Modest; Akebia, Amgen. Stock Shareholder; Modest; Ardelyx. Other; Modest; AstraZeneca, Baxter, Cricket Health, Durect, Gilead. Stock Shareholder; Modest; Outset. Other; Modest; Reata, Sanfit, Vertex. T. Greene: Other; Modest; Janssen, Durect, Astrazeneca, CSL, Boehringer-Ingleheim and Pfizer. F. Hou: Other; Significant; AstraZeneca, AbbVie. M.B. Lindberg: None. P. Rossing: Other; Modest; Bayer, Astellas, Astra Zeneca, Boehringer ingelheim, Novo Nordisk, Gilead, Mundipharma, Merck, Vifor, Sanofi. D. Sjostrom: Employment; Significant; AstraZeneca. Stock Shareholder; Modest; AstraZeneca. R.D. Toto: Other; Modest; Amgen, Boehringer-Ingelheim, Bayer, Astra-Zeneca, Quest Diagnostics, Reata, Relypsa, Otsuka, Medscape. A. Langkilde: Employment; Significant; AstraZeneca. Stock Shareholder; Modest; AstraZeneca. H.J. Lambers Heerspink: Research Grant; Significant; AstraZeneca. Research Grant; Modest; Abbvie, Boehringer Ingelheim, Janssen. Other; Modest; Gilead, merck, Mitsubishi Tanabe, MundiPharma, Chinook, CSL Pharma, Bayer, Retrophin, Novo Nordisk.
Background: Patients with chronic kidney disease (CKD) are at high risk of adverse renal and cardiovascular (CV) outcomes. We investigated the effects of dapagliflozin in patients with CKD, with and without type 2 diabetes (T2D). DAPA-CKD is the first trial to test the effects of a SGLT2 inhibitor on renal and CV outcomes in CKD patients without T2D and included patients with a lower eGFR than in prior trials. Methods: We enrolled CKD patients with and without T2D with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and UACR 200-5000 mg/g, randomized (1:1) to dapagliflozin (10 mg once-daily) or placebo. Patients were maintained on a stable dose of ACE inhibitor or ARB for ≥4 weeks before screening, if not contraindicated. The primary composite endpoint was worsening of kidney function (≥50% decline in eGFR, occurrence of end-stage kidney disease [ESKD]), or renal or CV death. Secondary endpoints were (1) renal composite (primary endpoint without CV death); (2) composite of CV death or hospitalization for heart failure (hHF); and (3) death from any cause. The trial was stopped early following routine review by the data monitoring committee, because of overwhelming evidence of efficacy. Results: Overall, 4304 patients were randomized at 386 centers in 21 countries; 2152 to dapagliflozin, 2152 to placebo. The mean age was 62 years and 67% were male. Mean eGFR was 43.1 mL/min/1.73m2 and median UACR was 949 mg/g. At baseline, 2906 (67.5%) patients had T2D, 96% had a history of hypertension, 37% other CV disease, and 11% heart failure. 4174 (97%) were receiving an ACEi/ARB or another renin-angiotensin system blocker. Baseline characteristics were balanced between treatment groups. The median follow-up was 2.4 years. There were 197 primary endpoint events with dapagliflozin and 312 with placebo; the HR for the primary endpoint was 0.61 (95% CI, 0.51-0.72; P=0.000000028). The HR for secondary endpoints were: (1) renal composite, 0.56 (95% CI, 0.45-0.68; P<0.0001); (2) CV death/hHF, 0.71 (95% CI, 0.55-0.92; P=0.0089); and (3) death from any cause, 0.69 (95% CI 0.53-0.88; P=0.0035). The benefit of dapagliflozin on the primary endpoint was consistent in patients with and without T2D. Safety was generally consistent with the known safety profile of dapagliflozin. Conclusions: Dapagliflozin significantly reduced the risk of CKD progression, including progression to ESKD, reduced incidence of CV death/hHF, and prolonged survival in patients with CKD, with and without T2D. The aim of this submission is to provide the first public presentation of the cardiovascular outcomes in DAPA-CKD according to 1) baseline diabetes status, with a focus on the effects of dapagliflozin in patients without diabetes at baseline and 2) baseline CV disease status (comparing patients with and without CV disease at baseline i.e. primary vs. secondary prevention). (Funded by AstraZeneca; NCT03036150)