Background The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial assessed dapagliflozin versus placebo, in addition to standard therapy, in patients with chronic kidney disease (CKD) and albuminuria, and was terminated prematurely due to overwhelming efficacy. The study objective was to model the long-term clinical outcomes of DAPA-CKD beyond the trial follow-up. Methods A Markov model extrapolated event incidence per 1000 patients and CKD progression rates for patients receiving dapagliflozin or placebo over a 10-year time horizon. We derived treatment-specific CKD stage transition matrices using DAPA-CKD trial data. We extrapolated relevant efficacy endpoints using parametric survival equations for all-cause mortality and generalized estimating equations for recurrent events. Results When extrapolated over a 10-year period, patients randomized to dapagliflozin spent more time in CKD stages 1-3 and less in stages 4-5 than placebo [0.65 (95% CrI 0.41, 0.90) and -0.23 (95% CrI -0.45, 0.00) years per patient, respectively]. Dapagliflozin prevented an estimated 83 deaths and 51 patients initiating kidney replacement therapy per 1000 patients over 10 years. Predicted rates of hospitalized heart failure and abrupt declines in kidney function were reduced (19 and 39 estimated events per 1000 patients, respectively). Conclusions Adding dapagliflozin to standard therapeutic management of CKD is expected to have long-term cardiorenal benefit beyond what has been demonstrated in the DAPA-CKD trial, with patients predicted to live longer with fewer complications.

Introduction: Mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of kidney failure in chronic kidney disease (CKD). We performed an analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial by baseline conventional MRA (spironolactone and eplerenone) prescription. Methods: Participants with CKD (estimated glomerular filtration rate [eG FR] 25-75 ml/min per 1.73 m(2); urinary a lbumin-to-creatinine ratio 200-500 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. The primary outcome was a composite of sustained >= 50% eG FR decline, end-stage kidney disease, or kidney or cardiovascular (CV) death. A prespecified kidney-specific secondary outcome was as the primary outcome but without CV death. Hyperkalemia (serum potassium >= 6.0 mmol/l) was an exploratory end point. Time-to-event analyses (proportional hazards [Cox] regression) assessed dapagliflozin versus placebo in patient subgroups defined by baseline conventional MRA use. Results: A total of 229 of 4304 DAPA-CKD participants (5.3%) were receiving conventional MRAs at baseline (dapagliflozin n = 109, placebo n = 120). The effect of dapagliflozin on the primary outcome was consistent in participants prescribed (hazard ratio [HR] 0.76, 95% CI 0.40-1.47) and not prescribed (HR 0.60, 95% CI 0.50-0.72, P-interaction = 0.59) MRAs. This consistency was maintained for the kidney-specific outcome. The effect of dapagliflozin on hyperkalemia (HR 0.87, 95% CI 0.70-1.09) was consistent among those prescribed (HR 0.94, 95% CI 0.41-2.20) and not prescribed (HR 0.87, 95% CI 0.69-1.10, P-interaction = 0.96) MRAs. Adverse events (AEs) leading to discontinuation and serious AEs were similar between treatment groups, regardless of baseline MRA prescription. Conclusion: Dapagliflozin was similarly safe and efficacious in reducing major adverse kidney outcomes in participants with CKD who were or were not prescribed MRAs at baseline.

Background Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. Methods This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. Findings 4003 participants (1398 [34·9%] from the DAPA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of −0·01% [95% CI −0·03 to 0·01], −0·1 mmol/mol [95% CI −0·3 to 0·1] at 12 months). Interpretation Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. Funding AstraZeneca.

Background Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its associations with efficacy and safety outcomes are unknown. Methods The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflo-zin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (> 10% or > 0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter. Results A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFR > 10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFR > 10% experienced a long-term eGFR decline of-1.58 ml/min per 1.73 m(2) per year compared with-2.44 and-2.48 ml/min per 1.73 m(2) per year among those experiencing a less pronounced reduction or increase in eGFR, respectively (P-interaction=0.05). In the placebo group, long-term eGFR decline was-3.27,-3.84, and-3.77 ml/min per 1.73 m(2) per year for acute eGFR reduction subgroups of > 10%, > 0%-10%, or increase in eGFR (P-interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change. Conclusions Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression.

OBJECTIVES:To evaluate the association between diuretic use by class with chronic kidney disease (CKD) progression and onset of end-stage renal disease (ESRD). DESIGN:Retrospective cohort study. SETTING:Large integrated healthcare delivery system in Northern California. PARTICIPANTS:Adults with an estimated glomerular filtration rate (eGFR) 15-59 min/1.73 m2 by the CKD-Epidemiology Collaboration equation with no prior diuretic use. MAIN OUTCOME MEASURES:ESRD and a renal composite outcome including eGFR <15 mL/min/1.73 m2, 50% reduction in eGFR and/or ESRD. RESULTS:Among 47 666 eligible adults with eGFR 15-59 min/1.73 m2 and no previous receipt of loop or thiazide diuretics, mean age was 71 years, 49% were women and 26% were persons of colour. Overall, the rate (per 100 person-years) of the renal composite outcome was 1.35 (95% CI: 1.30 to 1.41) and 0.42 (95% CI: 0.39 to 0.45) for ESRD. Crude rates (per 100 person-years) of the composite renal outcome were higher in patients who initiated loop diuretics (12.85 (95% CI: 11.81 to 13.98) vs 1.06 (95% CI: 1.02 to 1.12)) and thiazide diuretics (2.68 (95% CI: 2.33 to 3.08) vs 1.29 (95% CI: 1.24 to 1.35)) compared with those who did not. Crude rates (per 100-person years) of ESRD where higher in patients who initiated loop diuretics (4.92 (95% CI: 4.34 to 5.59) vs 0.30 (95% CI: 0.28 to 0.33)), but not in those who initiated thiazide diuretics (0.30 (95% CI: 0.20 to 0.46) vs 0.43 (95% CI: 0.40 to 0.46)). However, neither initiation of diuretics or type of diuretic were significantly associated with CKD progression or ESRD after accounting for receipt of other medications and time-dependent confounders using causal inference methods. CONCLUSIONS:The use of thiazide and loop diuretics was not independently associated with an increased risk of CKD progression and/or ESRD in adults with stage 3/4 CKD.

Introduction: This study aimed to examine the efficacy and safety of dapagliflozin in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (NCT03036150) by geographic region. Methods: Adults with chronic kidney disease (CKD) with or without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25 to 75 ml/min per 1.73 m(2) and urinary albumin-to-creatinine ratio (UACR) 200 to 5000 mg/g were randomized to dapagliflozin (10 mg once daily) or placebo. The primary end point was a composite of a sustained decline in eGFR of $50%, end-stage kidney disease or death from kidney or cardiovascular causes. We categorized recruiting countries into 4 broad global regions: Asia, Europe, Latin America, and North America. Of 4304 randomized patients, 1346 (31.3%) were from Asia, 1233 (28.6%) from Europe, 912 (21.2%) from Latin America, and 813 (18.9%) from North America. Results: The relative risk of the primary composite end point was lower in patients randomized to dapagliflozin (relative to placebo) in all regions, with hazard ratios (95% CI) of 0.70 (0.48-1.00), 0.60 (0.43-0.85), 0.61 (0.43-0.86), and 0.51 (0.34-0.76) among patients from Asia, Europe, Latin America, and North America, respectively. There was no effect modification by region (interaction P = 0.77). Occurrence of serious adverse events (SAEs) was lower among patients randomized to dapagliflozin versus placebo (21.9% vs. 26.8%, 34.1% vs. 38.6%, 29.8% vs. 31.5%, and 34.9% vs. 41.0% in Asia, Europe, Latin America, and North America, respectively). Conclusion: Dapagliflozin reduced kidney and cardiovascular events and prolonged survival in patients with CKD, with and without type 2 diabetes, with no apparent effect modification by geographic region.

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

Aim To assess the effects of dapagliflozin in patients with chronic kidney disease (CKD) and albuminuria, with and without type 2 diabetes, stratified by the Quetelet (body mass) index (BMI). Methods We randomized 4304 adult patients with an estimated glomerular filtration rate (eGFR) of 25-75 ml/min/1.73m(2) and urinary albumin-to-creatinine ratio of 200-5000 mg/g to dapagliflozin 10 mg/day or placebo. The primary outcome was a composite of sustained decline in eGFR of 50% or more, kidney failure, or death from kidney or cardiovascular causes. Secondary outcomes included kidney composite endpoint (primary composite endpoint without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure/ cardiovascular death), and all-cause mortality. We categorized participants according to World Health Organization BMI criteria: lean/ideal (<25 kg/m(2)), overweight (25-< 30 kg/m(2)), grade 1 obesity (30-<35 kg/m(2)), and grade 2/3 obesity (>= 35 kg/m(2)). Results Of 4296 (99.8%) randomized participants, 888 (20.7%), 1491 (34.7%), 1136 (26.4%), and 781 (18.2%) were categorized as lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity, respectively. Median follow-up was 2.4 years. Benefits of dapagliflozin were observed independent of baseline BMI for primary and secondary endpoints. Hazard ratios (95% CI) for dapagliflozin versus placebo for the primary composite endpoint were 0.60 (0.43, 0.85), 0.55 (0.40, 0.75), 0.71 (0.49, 1.04), and 0.57 (0.37, 0.87) among participants in the lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity groups (interaction P = .72). Conclusion Among participants with CKD and albuminuria, with or without type 2 diabetes, kidney and cardiovascular benefits of dapagliflozin were evident and consistent across the BMI spectrum.

Abstract BACKGROUND AND AIMS Treatment guidelines for patients with chronic kidney disease (CKD) recommend renin–angiotensin system inhibition (RASi) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) to reduce the risk of kidney failure. However, patients with more advanced CKD do not always tolerate RASi. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of kidney failure in patients with CKD in the DAPA-CKD trial. We performed a post hoc analysis of this trial to assess the efficacy of dapagliflozin by baseline dose level of ACEi or ARB. METHOD Participants with CKD [estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. Participants were to be treated with the recommended target dose, or a stable tolerated dose of ACEi or ARB, unless medically contraindicated, for ≥4 weeks prior to inclusion. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease or death from a kidney or cardiovascular cause. A prespecified kidney-specific secondary outcome was the same as the primary endpoint, but without cardiovascular death. A composite cardiovascular outcome (heart failure hospitalization or cardiovascular death), and all-cause mortality were other secondary endpoints. Time-to-event analyses were performed to assess the effects of dapagliflozin versus placebo according to baseline prescription and dose of ACEi or ARB treatment. RESULTS Of 4296 (99.9%) participants with available data on ACEi/ARB doses, 1231 (28.7%) were using the target dose, 1867 (43.5%) a dose ≥50% to <100% of target, 1068 (24.9%) a dose 0 to <50% of target and 130 (3.0%) were not using an ACEi/ARB. In the placebo group, the event rate for the primary outcome was highest among participants not using ACEi/ARBs compared to the other subgroups (figure 1). The benefit of dapagliflozin on the primary composite outcome was consistent regardless of use or non-use of the target dose of ACEi/ARBs. This consistency was maintained for the secondary outcomes (Figure 1). Dapagliflozin compared to placebo reduced the rate of eGFR decline over the study by –0.93 [95% confidence interval (95% CI) 0.61–1.25] mL/min/1.73 m2. This effect was present regardless of the use or non-use of target doses of ACEi/ARBs (P for interaction 0.877). CONCLUSION Dapagliflozin was similarly efficacious in reducing major adverse kidney and cardiovascular outcomes in participants with CKD regardless of the use or dose of ACEi/ARB.

Abstract Background and Aims Reductions in albuminuria are consistently associated with a subsequent lower risk of kidney failure. The sodium glucose co-transporter 2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes. Whether this effect persist in patients with chronic kidney disease (CKD) with and without diabetes is unknown. We therefore assessed and compared the effects of dapagliflozin on albuminuria in patients with CKD with and without type 2 diabetes from the DAPA-CKD trial. Method We randomized 4304 patients with CKD and an eGFR of 25-75 ml/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g to dapagliflozin (10 mg once daily) or placebo. Change in albuminuria was a pre-specified exploratory outcome. We used regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to micro- or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from non-nephrotic (<3000 mg/g) to nephrotic range albuminuria (≥3000 mg/g), as additional endpoints. Subgroup analyses were performed according to baseline type 2 diabetes status. Results Median (25th to 75th Percentile) UACR was 949 (477-1885) mg/g. In patients with and without type 2 diabetes baseline median UACR was 1017 mg/g and 861 mg/g, respectively. Dapagliflozin, compared to placebo, reduced UACR by 29.3% (95% confidence interval [CI] 25.2, 33.1; p<0.001), with a 35.1% (95%CI 30.6, 39.4) reduction in patients with type 2 diabetes and 14.8% (95%CI 5.9, 22.9) reduction in patients without type 2 diabetes (p for interaction <0.001). Among 3860 patients with UACR ≥300 mg/g at baseline, dapagliflozin significantly increased the likelihood of regression in UACR stage (hazard ratio [HR] 1.81; 95%CI 1.60, 2.05). The corresponding HRs for patients with and without type 2 diabetes were 2.06 (95%CI 1.78, 2.39) and 1.33 (95%CI 1.07, 1.66), respectively (p for interaction 0.001). Among 3820 patients with UACR <3000 mg/g at baseline, dapagliflozin significantly decreased the risk of nephrotic range albuminuria (HR 0.41; 95%CI 0.32, 0.52). The corresponding HRs for patients with and without type 2 diabetes were 0.39 (95%CI 0.29, 0.51) and 0.50 (95%CI 0.30, 0.82), respectively (p for interaction 0.401). Conclusion In patients with CKD with and without type 2 diabetes dapagliflozin significantly reduced albuminuria, with a larger reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR suggest that part of dapagliflozin’s protective effect in patients without diabetes is mediated through pathways unrelated to UACR reduction.

Source Citation Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9:22-31. 33338413

Significance Statement Relatively little is known about the relative safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with advanced (stage 4) CKD. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial enrolled patients with CKD with or without type 2 diabetes (mean eGFR 43 ± 12 ml/min per 1.73m2), finding that patients receiving the drug had lower risks of major kidney and cardiovascular events and an attenuation of progressive eGFR loss compared with patients receiving placebo. In this analysis within a subgroup of patients with stage 4 CKD and albuminuria, the authors found that the benefits of the SGLT2 inhibitor dapagliflozin in patients with baseline eGFR<30 ml/min per 1.73m2 were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks. Background In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes. Methods Adults with eGFR of 25–75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio of 200–5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin’s effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m2) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death. Results A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: −2 to 47%) reduction in the primary composite endpoint, and 29% (−2 to 51%), 17% (−53 to 55%), and 32% (−21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m2 per year in the dapagliflozin and placebo groups, respectively (P=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest. Conclusions Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.

BACKGROUND:Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. METHODS:DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS:Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056). INTERPRETATION:In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. FUNDING:AstraZeneca.

Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m(2) and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m(2); and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m(2)/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.

OBJECTIVES:The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF). BACKGROUND:Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline. METHODS:A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified. RESULTS:HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF. CONCLUSIONS:Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).