Study Overview
Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.
Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.
Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m2 of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.
Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.
Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).
Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m2, the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.
The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.