Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD)

Authors, Journal, Affiliations, Type, DOI

• Authors: Hiddo J.L. Heerspink, Bergur V. Stefánsson, Ricardo Correa-Rotter, Glenn M. Chertow, Tom Greene, Fan-Fan Hou, Johannes F.E. Mann, John J.V. McMurray, Magnus Lindberg, Peter Rossing, C. David Sjöström, Roberto D. Toto, Anna-Maria Langkilde, David C. Wheeler; for the DAPA-CKD Trial Committees and Investigators
• Journal: New England Journal of Medicine 2020;383:1436–46
• Affiliations: University of Groningen / UMCG (Netherlands); George Institute for Global Health (Sydney); AstraZeneca (Gothenburg); Stanford University; University of Utah; Nanfang Hospital/Southern Medical University (China); KfH Kidney Center/Erlangen (Germany); University of Glasgow; Steno Diabetes Center Copenhagen; UT Southwestern Medical Center (Dallas); University College London
• Type: Randomized, double-blind, placebo-controlled, multicenter clinical trial
• DOI: https://doi.org/10.1056/NEJMoa2024816
• Funding: AstraZeneca
• Trial registration: NCT03036150

Overview

The DAPA-CKD trial randomised 4,304 patients with CKD (eGFR 25–75; UACR 200–5000) — with or without type 2 diabetes — to dapagliflozin 10 mg once daily or placebo on a background of ACE inhibitor or ARB therapy. Conducted at 386 sites in 21 countries from February 2017 to June 2020, the trial was stopped early for clear efficacy after 408 primary events. Over a median of 2.4 years, dapagliflozin reduced the primary composite (≥50% sustained eGFR decline, ESKD, or death from renal/CV causes) by 39% (HR 0.61; NNT=19). Benefits extended to all-cause mortality (HR 0.69) and the CV composite (HR 0.71). Crucially, 32.5% of participants had no type 2 diabetes — this was the first large SGLT2 inhibitor trial to demonstrate renoprotection independent of diabetes status, expanding the indication beyond what was established in CREDENCE.

Keywords

Dapagliflozin; SGLT2 inhibitor; chronic kidney disease; DAPA-CKD; cardiorenal; eGFR; ESKD; albuminuria; non-diabetic CKD; tubuloglomerular feedback; intraglomerular pressure; end-stage kidney disease; cardiovascular death; heart failure

Key Takeaways

Trial Design and Population

• Randomized double-blind placebo-controlled multicenter RCT; 386 sites; 21 countries (February 2017–June 2020); median follow-up 2.4 years
• Inclusion: eGFR 25–75 mL/min/1.73m²; UACR 200–5000 mg/g; all required stable ACE-I or ARB ≥4 weeks (unless documented intolerance); T2DM or non-T2DM permitted; minimum 30% non-diabetes enrollment mandated
• Exclusion: type 1 diabetes, polycystic kidney disease, lupus nephritis, ANCA vasculitis, immunotherapy for kidney disease ≤6 months
• Key baseline characteristics: mean age 61.8±12.1 years; 33.1% female; mean eGFR 43.1±12.4 mL/min/1.73m²; median UACR 949 mg/g; 67.5% T2DM; 32.5% non-T2DM
• Stopped early per independent data monitoring committee recommendation based on 408 primary events

Primary Outcome

• Composite of ≥50% sustained eGFR decline, ESKD (dialysis ≥28 days, transplantation, or eGFR <15), or death from renal/CV causes
• 9.2% dapagliflozin vs 14.5% placebo; HR 0.61 (95% CI 0.51–0.72; P<0.001; NNT=19)
• Event rates for all individual components favoured dapagliflozin

Secondary Outcomes

• Renal-specific composite (≥50% eGFR decline, ESKD, or renal death): HR 0.56 (95% CI 0.45–0.68; P<0.001)
• CV composite (hospitalization for heart failure or CV death): HR 0.71 (95% CI 0.55–0.92; P=0.009)
• All-cause death: 4.7% vs 6.8%; HR 0.69 (95% CI 0.53–0.88; P=0.004)

Subgroup Analyses

• Effect was consistent across prespecified subgroups
• T2DM subgroup: HR 0.64 (95% CI 0.52–0.79)
• Non-T2DM subgroup: HR 0.50 (95% CI 0.35–0.72) — suggesting larger proportional benefit without diabetes
• No heterogeneity by baseline eGFR, UACR category, age, sex, or geographic region

eGFR Slope Analysis

• Acute phase (first 2 weeks): greater eGFR reduction with dapagliflozin than placebo (−3.97±0.15 vs −0.82±0.15 mL/min) — haemodynamic dip reflecting tubuloglomerular feedback activation
• Chronic phase (week 2 to end of treatment): dapagliflozin −1.67±0.11 vs placebo −3.59±0.11 mL/min/yr; between-group difference +1.92 mL/min/yr (95% CI 1.61–2.24)
• Total slope to 30 months: −2.86±0.11 vs −3.79±0.11; between-group difference +0.93 mL/min/yr (95% CI 0.61–1.25)
• The initial dip followed by slower chronic decline mirrors the eGFR pattern seen with other SGLT2 inhibitors (EMPA-KIDNEY, CREDENCE) and is the expected haemodynamic-then-structural benefit sequence

Safety and Adverse Events

• Overall incidences of adverse events and serious adverse events were similar between groups
• Diabetic ketoacidosis: 0 dapagliflozin vs 2 placebo; none in non-diabetic participants
• Severe hypoglycaemia: not observed in participants without T2DM
• Fournier's gangrene: 0 dapagliflozin vs 1 placebo
• Volume depletion, bone fractures, and amputations were collected but did not show clinically concerning imbalances
• Safety confirmed for eGFR as low as 25 mL/min/1.73m²

Limitations of the Document

• Trial stopped early for efficacy — may have reduced statistical power for some secondary outcomes (specifically mortality and CV composite were pre-planned secondary endpoints and were still significant)
• No post-treatment eGFR collection — reversibility of the initial acute eGFR dip could not be confirmed in this cohort (though observed in other dapagliflozin studies)
• Predominantly T2DM population (67.5%), though a minimum 30% non-DM was mandated; non-DM effect estimate has wider CI due to smaller subgroup
• Ethnicity imbalances: China enrollment delayed due to regulatory issues; 210 of 4,304 from China, added near trial close
• Population excludes polycystic kidney disease, lupus nephritis, ANCA vasculitis — generalizability to these CKD subtypes uncertain
• Funded by AstraZeneca; however, independent academic replication of analyses was performed (University Medical Center Groningen)

Key Concepts Mentioned

• concepts/SGLT2-Inhibitors-in-CKD — primary intervention; DAPA-CKD is foundational evidence for diabetes-independent renoprotection
• concepts/Cardiorenal-Syndrome — DAPA-CKD extends SGLT2i cardiorenal benefit across CKD spectrum, non-diabetic included

Key Entities Mentioned

• entities/Heart-Failure — CV composite (HF hospitalisation + CV death) reduced HR 0.71; placebo group enriched for CV risk
• entities/Type-2-Diabetes — trial enrolled both T2DM and non-T2DM patients; non-T2DM benefit establishes diabetes-independent mechanism
• entities/Hypertension — major CKD comorbidity; background RAAS inhibition required at entry

Wiki Pages Updated

• Created wiki/sources/dapagliflozin-dapackd-nejm-2020.md
• Updated wiki/concepts/SGLT2-Inhibitors-in-CKD.md — added DAPA-CKD trial section
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md