A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy
Authors: David C. Wheeler, Robert D. Toto, Bergur V. Stefánsson, Niels Jongs, Glenn M. Chertow, Tom Greene, Fan Fan Hou, John J.V. McMurray, Roberto Pecoits-Filho, Ricardo Correa-Rotter, Peter Rossing, C. David Sjöström, Kausik Umanath, Anna Maria Langkilde, Hiddo J.L. Heerspink
Journal: Kidney International (2021)

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/1.73m2 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/1.73m2; 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/1.73m2/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. 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/1.73m2 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/1.73m2; 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/1.73m2/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. IgA nephropathy is the most common primary glomerular disease worldwide.1Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (705) Google Scholar Despite advances in our understanding of its pathogenesis, treatment strategies have changed little over the last 2 or 3 decades.2Floege J. Barbour S.J. Cattran D.C. et al.Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney Int. 2019; 95: 268-280Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Over a period of 4 to 15 years (mean, 6.1 years), approximately 30% of patients with IgA nephropathy progress to kidney failure, and risk factors for deterioration of kidney function include decreased estimated glomerular filtration rate (eGFR), persistent proteinuria, and hypertension.3Lv J. Zhang H. Zhou Y. et al.Natural history of immunoglobulin A nephropathy and predictive factors of prognosis: a long-term follow up of 204 cases in China.Nephrology. 2008; 13: 242-246Crossref PubMed Scopus (87) Google Scholar There are no commercially available disease-specific therapies for IgA nephropathy,4Selvaskandan H. Cheung C.K. Muto M. et al.New strategies and perspectives on managing IgA nephropathy.Clin Exp Nephrol. 2019; 23: 577-588Crossref PubMed Scopus (33) Google Scholar in part because no large-scale, randomized clinical trials have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapeutic intervention. The established treatment approach for most patients with IgA nephropathy is to apply supportive measures that include the use of renin-angiotensin-aldosterone system blockade,5Cheng J. Zhang W. Zhang X.H. et al.ACEI/ARB therapy for IgA nephropathy: a meta analysis of randomised controlled trials.Int J Clin Pract. 2009; 63: 880-888Crossref PubMed Scopus (45) Google Scholar which is recommended for patients with at least moderate proteinuria (>1 g/d) in global clinical practice guidelines.6Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Abstract Full Text Full Text PDF Scopus (749) Google Scholar Fish oil is also a treatment option suggested for IgA nephropathy based on mixed data from largely underpowered clinical trials and a favorable safety profile.7Chou H.H. Chiou Y.Y. Hung P.H. et al.Omega-3 fatty acids ameliorate proteinuria but not renal function in IgA nephropathy: a meta-analysis of randomized controlled trials.Nephron Clin Pract. 2012; 121: c30-c35Crossref PubMed Scopus (20) Google Scholar Although IgA nephropathy is an immune-mediated disease, with mucosal-derived IgA forming circulating immune complexes that deposit in the mesangium,1Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (705) Google Scholar the role of immunosuppressive therapy remains controversial and is usually reserved for patients who do not respond to supportive measures. Many patients are offered corticosteroid therapy, or other immunosuppressive agents, such as azathioprine, mycophenolate mofetil, cyclophosphamide, or rituximab, despite a lack of consensus on whether the benefits of these therapies outweigh the risks.2Floege J. Barbour S.J. Cattran D.C. et al.Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney Int. 2019; 95: 268-280Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar,4Selvaskandan H. Cheung C.K. Muto M. et al.New strategies and perspectives on managing IgA nephropathy.Clin Exp Nephrol. 2019; 23: 577-588Crossref PubMed Scopus (33) Google Scholar Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that reduces glucose reabsorption in the proximal convoluted tubule of the kidney, thereby enhancing urinary glucose excretion.8Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.Annu Rev Med. 2015; 66: 255-270Crossref PubMed Scopus (184) Google Scholar Because they improve glycemic control, SGLT2 inhibitors were initially developed for the treatment of type 2 diabetes. Subsequently, in large cardiovascular outcome trials involving participants with type 2 diabetes, empagliflozin, canagliflozin, and dapagliflozin slowed the rate of decline of eGFR and reduced albuminuria, with a similar eGFR trend observed for ertugliflozin.9Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (1868) Google Scholar, 10Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (1947) Google Scholar, 11Mosenzon O. Wiviott S.D. Cahn A. et al.Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.Lancet Diabetes Endocrinol. 2019; 7: 606-617Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 12Cannon C.P. Pratley R. Dagogo-Jack S. et al.Cardiovascular outcomes with ertugliflozin in type 2 diabetes.N Engl J Med. 2020; 383: 1425-1435Crossref PubMed Scopus (466) Google Scholar In type 1 and type 2 diabetes, clinical studies have shown that early and reversible reductions in eGFR occurred on initiation of SGLT2 inhibitor therapy, including in those participants with good glycemic control,13Sridhar V.S. Rahman H.U. Cherney D.Z.I. What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?.Diabetes Obes Metab. 2020; 22: 55-68Crossref PubMed Scopus (12) Google Scholar, 14Cherney D.Z. Perkins B.A. Soleymanlou N. et al.Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597Crossref PubMed Scopus (854) Google Scholar, 15Heerspink H.J. Perkins B.A. Fitchett D.H. et al.Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Scopus (671) Google Scholar suggesting that SGLT2 inhibitors reduce intraglomerular pressure, which may preserve long-term kidney function. This same effect was also observed in patients with proteinuric chronic kidney disease (CKD) without diabetes,16Cherney D.Z.I. Dekkers C.C.J. Barbour S.J. et al.Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial.Lancet Diabetes Endocrinol. 2020; 8: 582-593Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar providing a rationale for the use of these agents as renoprotective therapies in patients with CKD due to causes other than diabetes. The Dapagliflozin and Prevention of Adverse Outcomes in CKD Trial (DAPA-CKD) tested the hypothesis that dapagliflozin was superior to placebo in reducing the risk of major adverse kidney and cardiovascular events as well as prolonging overall survival in a broad group of individuals with proteinuric CKD.17Heerspink H.J.L. Stefansson B.V. Chertow G.M. et al.Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.Nephrol Dial Transplant. 2020; 35: 274-282Crossref PubMed Scopus (110) Google Scholar The primary results showed that in patients with CKD, regardless of the presence or absence of type 2 diabetes and regardless of CKD etiology, dapagliflozin significantly reduced the risk of the primary composite outcome and the secondary outcomes, including all-cause mortality, compared with placebo.18Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (995) Google Scholar As previously reported, the DAPA-CKD study included 270 participants with a diagnosis of IgA nephropathy.19Wheeler D.C. Stefansson B.V. Batiushin M. et al.The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics.Nephrol Dial Transplant. 2020; 35: 1700-1711Crossref PubMed Scopus (58) Google Scholar In this prespecified analysis, we investigated the effects of dapagliflozin on progression of CKD and other major adverse kidney and cardiovascular events in patients with IgA nephropathy. DAPA-CKD was a multicenter, double-blind, placebo-controlled, randomized trial conducted at 386 study sites in 21 countries. The trial was designed to assess the effects of dapagliflozin on kidney and cardiovascular outcomes in patients with CKD, with or without type 2 diabetes, and was registered with ClinicalTrials.gov as NCT03036150. The trial was approved by Ethics Committees at each participating center. All participants provided written informed consent before commencement of any study-specific procedure. An independent Data Monitoring Committee provided oversight. The study protocol, statistical analysis plan, and patient eligibility criteria have been previously published, as have articles describing trial design, baseline characteristics, primary results, and results stratified by diabetes status and history of cardiovascular disease.17Heerspink H.J.L. Stefansson B.V. Chertow G.M. et al.Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.Nephrol Dial Transplant. 2020; 35: 274-282Crossref PubMed Scopus (110) Google Scholar, 18Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (995) Google Scholar, 19Wheeler D.C. Stefansson B.V. Batiushin M. et al.The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics.Nephrol Dial Transplant. 2020; 35: 1700-1711Crossref PubMed Scopus (58) Google Scholar, 20Wheeler D.C. Stefánsson B.V. 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: 22-31Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 21McMurray J.J.V. Wheeler D.C. Stefánsson B.V. et al.Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease.Circulation. 2020; 143: 438-448Crossref PubMed Scopus (38) Google Scholar Briefly, eligible participants had an eGFR between 25 and 75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio (UACR) between 200 and ≤5000 mg/g (22.6–≤565.6 mg/mmol) and were receiving a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 4 weeks before enrollment into the trial, unless contraindicated. Exclusion criteria included patients receiving immunotherapy for primary or secondary kidney disease within the previous 6 months before trial enrollment.17Heerspink H.J.L. Stefansson B.V. Chertow G.M. et al.Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.Nephrol Dial Transplant. 2020; 35: 274-282Crossref PubMed Scopus (110) Google Scholar,18Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (995) Google Scholar At the screening visit, investigators recorded the diagnosis of kidney disease and were asked to indicate whether this diagnosis was based on information obtained from a prior kidney biopsy. IgA nephropathy was included as a prespecified category among participants with glomerulonephritis. As described previously,17Heerspink H.J.L. Stefansson B.V. Chertow G.M. et al.Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.Nephrol Dial Transplant. 2020; 35: 274-282Crossref PubMed Scopus (110) Google Scholar,18Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (995) Google Scholar participants were randomly assigned to dapagliflozin, 10 mg once daily, or matching placebo, in accordance with the sequestered, fixed randomization schedule, using balanced blocks to ensure an approximate 1:1 ratio of the 2 regimens. Randomization was conducted using an interactive voice- or web-based system and stratified on the diagnosis of type 2 diabetes and UACR (≤1000 or >1000 mg/g). Study personnel (except the Independent Data Monitoring Committee) and participants were blinded to the treatment allocation. Drug and placebo were identically packaged, with uniform tablet appearance, labeling, and administration schedule. After randomization, study visits occurred at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter. At each visit, blood and urine samples were collected for laboratory assessment, vital signs were recorded, and information was gathered on potential study endpoints, adverse events, concomitant therapies, and study drug adherence. The study was stopped early because of clear efficacy following a recommendation by the Independent Data Monitoring Committee. Safety analyses included all the participants who had undergone randomization and received at least one dose of study drug. Selected adverse event data were collected during the trial. These included serious adverse events, adverse events leading to discontinuation of study drug, and adverse events of interest, including major hypoglycemia and potential diabetic ketoacidosis. Major hypoglycemia was defined by the following criteria, confirmed by the investigator: symptoms of severe impairment in consciousness or behaviour, need for external assistance, intervention to treat hypoglycemia, and prompt recovery from acute symptoms after the intervention. The primary outcome of the trial was a composite endpoint of sustained ≥50% decline in eGFR (confirmed by a second serum creatinine after at least 28 days), onset of end-stage kidney disease (ESKD; defined as maintenance dialysis for at least 28 days, kidney transplantation, or eGFR <15 ml/min per 1.73 m2 confirmed by a second measurement after at least 28 days), or death from a kidney disease–related or cardiovascular cause. The secondary outcomes, in hierarchical order, were a kidney-specific outcome, similar to the primary outcome but excluding cardiovascular death; a composite endpoint of cardiovascular death or hospitalization for heart failure; and all-cause mortality. An independent event adjudication committee assessed all clinical endpoints using these prespecified endpoint definitions. We prespecified analyses of the effects of dapagliflozin on the primary and secondary efficacy endpoints in participants according to the etiology of kidney disease, with the glomerulonephritis category further subcategorized by underlying cause, including IgA nephropathy. We included data from all randomized patients according to the intention-to-treat principle. Study data in tables and text are presented as mean ± SD (or mean ± SE for slope data), or as median with 25th and 75th percentile range. We fitted a series of Cox proportional hazards regression models, stratified by type 2 diabetes and UACR and adjusted for baseline eGFR to estimate the hazard ratio (HR) and 95% confidence intervals (CIs; dapagliflozin versus placebo) for the primary composite endpoint, secondary endpoints, and prespecified exploratory endpoints. We also assessed the effects of dapagliflozin versus placebo in subgroups by baseline eGFR and UACR. Testing for heterogeneity was done by adding interaction terms between eGFR or UACR, fitted as continuous variables, and randomizing treatment assignment to the relevant Cox model. Sensitivity analysis was restricted to participants with biopsy-proven IgA nephropathy. The effects of dapagliflozin on the mean on-treatment eGFR slope were analyzed by fitting a 2-slope mixed effects linear spline model (with a knot at week 2) to eGFR values, with random intercept and random slopes for treatment. The variance-covariance matrix was assumed to be unstructured (i.e., purely data dependent). The mean total slope was computed as a weighted combination of the short- and long-term slopes to reflect the mean rate of eGFR change to last on-treatment visit. We also visually presented the pattern of change in mean eGFR using a restricted maximum likelihood repeated measures approach. This analysis included the fixed, categoric effects of treatment, visit, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline eGFR and baseline eGFR-by-visit interaction. The same repeated measures approach was used to fit the change in systolic blood pressure and UACR over time. All analyses were performed using SAS version 9.4 (SAS Institute) or R version 4.0.2 (R-Foundation). The sponsor of the study was involved in the study design, analysis, interpretation of data, writing of the report, and the decision to submit the article for publication.