A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function
Authors: Hiddo J.L. Heerspink, David Cherney, Douwe Postmus, Bergur V. Stefánsson, Glenn M. Chertow, Jamie P. Dwyer, Tom Greene, Mikhail Kosiborod, Anna Maria Langkilde, John J.V. McMurray, Ricardo Correa-Rotter, Peter Rossing, C. David Sjöström, Robert D. Toto, David C. Wheeler, Hiddo J.L. Heerspink, David C. Wheeler, Glenn Chertow, Ricardo Correa-Rotter, Tom Greene, Fan Fan Hou, John McMurray, Peter Rossing, Robert Toto, Bergur Stefansson, Anna Maria Langkilde, L.E. Maffei, P. Raffaele, S.E. Solis, C.A. Arias, D. Aizenberg, C. Luquez, C. Zaidman, N. Cluigt, M. Mayer, A. Alvarisqueta, A. Wassermann, R. Maldonado, J. Bittar, M. Maurich, L.E. Gaite, N. Garcia, L. Sivak, P.O. Ramallo, J.C. Santos, R. Garcia Duran, J.A. Oddino, A. Maranon, L.N. Maia, D.D. Avila, E.J.G. Barros, M.H. Vidotti, D. Panarotto, I.D.L. Noronha, L.A.A. Turatti, L. Deboni, M.E. Canziani, M.C. Riella, M.R. Bacci, R.P. Paschoalin, R.J. Franco, J.C. Goldani, E. St-Amour, A.W. Steele, R. Goldenberg, S. Pandeya, H. Bajaj, D. Cherney, S.M. Kaiser, J.R. Conway, S.S. Chow, G. Bailey, J. Lafrance, J. Winterstein, S. Cournoyer, D. Gaudet, F. Madore, R.L. Houlden, A. Dowell, M. Langlois, N. Muirhead, H. Khandwala, A. Levin, F. Hou, Y. Xue, L. Zuo, C. Hao, Z. Ni, C. Xing, N. Chen, Y. Dong, R. Zhou, X. Xiao, Y. Zou, C. Wang, B. Liu, Q. Chen, M. Lin, Q. Luo, D. Zhang, J. Wang, M. Chen, X. Wang, A. Zhong, J. Dong, C. Zhu, T. Yan, P. Luo, Y. Ren, P. Pai, D. Li, R. Zhang, J. Zhang, M. Xu, Y. Zhuang, Y. Kong, X. Yao, X. Peng, F.I. Persson, T.K. Hansen, R. Borg, U. Pedersen Bjergaard, D. Hansen, M. Hornum, H. Haller, G. Klausmann, D. Tschope, T. Kruger, P. Gross, C. Hugo, N. Obermuller, L. Rose, P. Mertens, H. Zeller-Stefan, A. Fritsche, L. Renders, J. Muller, K. Budde, B. Schroppel, I. Wittmann, P. Voros, M. Dudas, G.A. Tabak, R. Kirschner, A. Letoha, I. Balku, Z. Hermanyi, G. Zakar, I. Mezei, G.G. Nagy, J. Lippai, A. Nemeth, D. Khullar, P.K. Gowdaiah, E. Fernando Mervin, V.A. Rao, D. Dewan, K. Goplani, V.S.K. Maddi, M.S. Vyawahare, R.K. Pulichikkat, R. Pandey, S.K. Sonkar, V.K. Gupta, S. Agarwal, A.J. Asirvatham, A. Ignatius, S. Chaubey, S. Melemadathil, H. Alva, Y. Kadam, H. Shimizu, A. Sueyoshi, H. Takeoka, Y. Abe, T. Imai, Y. Onishi, Y. Fujita, Y. Tokita, M. Oura, Y. Makita, A. Idogaki, R. Koyama, H. Kikuchi, N. Kashihara, T. Hayashi, Y. Ando, T. Tanaka, M. Shimizu, S. Hidaka, T. Gohda, K. Tamura, M. Abe, Y. Kamijo, T. Imasawa, Y. Takahashi, M. Nakayama, M. Tomita, F. Hirano, M. Nakayama, Y. Fukushima, A. Kiyosue, S. Kurioka, E. Imai, K. Kitagawa, M. Waki, J. Wada, K. Uehara, H. Iwatani, K. Ota, S. Shibazaki, K. Tamura, K. Katayama, I. Narita, M. Iinuma, S. Matsueda, S. Sasaki, A. Yokochi, T. Tsukamoto, T. Yoshimura, S. Kang, S. Lee, C.S. Lim, H. Chin, K.W. Joo, S.Y. Han, T.I. Chang, S. Park, H. Park, C.W. Park, B.G. Han, D.R. Cha, S.A. Yoon, W. Kim, S.W. Kim, D. Ryu, R. Correa Rotter, S.S. Irizar Santana, G. Hernandez Llamas, R. Valdez Ortiz, N.C. Secchi Nicolas, G. Gonzalez Galvez, J.R. Lazcano Soto, T. Bochicchio Riccardelli, E.A. Bayram Llamas, D.R. Ramos Ibarra, M.G.S. Melo, J.G. Gonzalez Gonzalez, J.H. Sanchez Mijangos, M. Madero Robalo, A. Garcia Castillo, H.A. Manrique, J.C. Farfan, R. Vargas, A. Valdivia, A. Dextre, E. Escudero, J.R. Calderon Ticona, L. Gonzales, J. Villena, L. Leon, G. Molina, A. Saavedra, E. Garrido, H. Arbanil, S. Vargas Marquez, J. Rodriguez, R. Isidto, A.J. Villaflor, M.A. Gumba, L. Tirador, R.S. Comia, R.A. Sy, M.L.V.V. Guanzon, G. Aquitania, N.C. De Asis, A.A. Silva, C.M. Romero, M.E. Lim, R.A. Danguilan, M. Nowicki, H. Rudzki, K. Landa, I. Kucharczyk-Bauman, B. Gogola-Migdal, M. Golski, A. Olech-Cudzik, T. Stompor, T. Szczepanik, B. Miklaszewicz, R. Sciborski, M. Kuzniewski, K. Ciechanowski, D. Wronska, W. Klatko, S. Mazur, G. Popenda, M. Myslicki, L.Z. Bolieva, S. Berns, A. Galyavich, T. Abissova, I. Karpova, D. Platonov, N. Koziolova, L. Kvitkova, R. Nilk, T. Medina, A. Rebrov, M. Rossovskaya, I. Sinitsina, E. Vishneva, N. Zagidullin, T. Novikova, N. Krasnopeeva, O. Magnitskaya, N. Antropenko, M. Batiushin, V. Escudero Quesada, C. Barrios Barrea, E. Espinel Garauz, J.M. Cruzado Garrit, C. Morales Portillo, J.L. Gorriz Teruel, S. Cigarran Guldris, M. Praga Terente, N.R. Robles Perez-Monteoliva, F.J. Tinahones Madueno, A. Soto Gonzalez, C. Diaz Rodriguez, H. Furuland, A. Saeed, K. Dreja, J. Spaak, A. Bruchfeld, M. Kolesnyk, O. Levchenko, N. Pyvovarova, V. Stus, V. Doretskyy, N. Korobova, O. Horoshko, I. Katerenchuk, Y.M. Mostovoy, M. Orynchak, O. Legun, I. Dudar, O. Bilchenko, S. Andreychyn, A. Levchenko, L. Zub, N. Tereshchenko, I. Topchii, T. Ostapenko, S. Bezuglova, M. Kopytsya, O. Turenko, P. Mark, J. Barratt, S. Bhandari, D. Fraser, P. Kalra, S.P. Kon, K. Mccafferty, A. Mikhail, S.P. Kon, O.P. Alvarado, R. Anderson, N.S. Andrawis, A. Arif, S.A. Benjamin, G. Bueso, R.S. Busch, K.W. Carr, P. Crawford, N. Daboul, G.M. De La Calle, B. Delgado, J. Earl, M.A. El-Shahawy, R.J. Graf, G. Greenwood, A. Guevara, E.M. Wendland, R.K. Mayfield, M. Montero, D.J. Morin, P. Narayan, V. Numrungroad, A.C. Reddy, R. Reddy, M.B. Samson, R. Trejo, M.B. Butcher, J.K. Wise, L.R. Zemel, M. Raikhel, D. Weinstein, P. Hernandez, A. Wynne, B.V. Khan, G.A. Sterba, A. Jamal, D. Ross, S.F. Rovner, A. Tan, F. Ovalle, R.J. Patel, J. Talano, D.R. Patel, A. Burgner, N. Aslam, M. Elliott, S. Goral, A. Jovanovich, J.A. Manley, K. Umanath, D. Waguespack, D. Weiner, M. Yu, L. Schneider, D. Jalal, T. Le, N. Nguyen, H. Nguyen, D. Nguyen, V. Nguyen, T. Do, P. Chu, D. Ta, N. Tran, D. Nguyen, B. Pham, Marc A. Pfeffer, Stuart Pocock, Karl Swedberg, Jean L. Rouleau, Nishi Chaturvedi, Peter Ivanovich, Andrew S. Levey, Heidi Christ-Schmidt, Claes Held, Christina Christersson, Johannes Mann, Christoph Varenhorst
Journal: Kidney International (2021)

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200–5000 mg/g and estimated glomerular filtration rate 25–75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury–related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury–related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function. This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200–5000 mg/g and estimated glomerular filtration rate 25–75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury–related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury–related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function. see commentary on page 20 see commentary on page 20 Acute kidney injury (AKI) occurs in approximately 13 million individuals globally per year, mainly in hospitalized patients.1Susantitaphong P. Cruz D.N. Cerda J. et al.World incidence of AKI: a meta-analysis.Clin J Am Soc Nephrol. 2013; 8: 1482-1493Crossref PubMed Scopus (720) Google Scholar Although more severe chronic kidney disease (CKD) is known to be associated with elevated AKI risk, emerging data from large epidemiologic studies have demonstrated that episodes of AKI also increase the risk of CKD progression.2Coca S.G. Singanamala S. Parikh C.R. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.Kidney Int. 2012; 81: 442-448Abstract Full Text Full Text PDF PubMed Scopus (1263) Google Scholar, 3Thakar C.V. Christianson A. Himmelfarb J. Leonard A.C. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.Clin J Am Soc Nephrol. 2011; 6: 2567-2572Crossref PubMed Scopus (316) Google Scholar, 4James M.T. Grams M.E. Woodward M. et al.A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury.Am J Kidney Dis. 2015; 66: 602-612Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Moreover, AKI is associated with adverse clinical outcomes, including dialysis, cardiovascular disease, and mortality, especially in patients with diabetes and those with significant albuminuria.4James M.T. Grams M.E. Woodward M. et al.A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury.Am J Kidney Dis. 2015; 66: 602-612Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar,5Vallon V. Do tubular changes in the diabetic kidney affect the susceptibility to acute kidney injury?.Nephron Clin Pract. 2014; 127: 133-138Crossref PubMed Scopus (19) Google Scholar Large randomized controlled trials in patients with type 2 diabetes have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow progression of the decline in kidney function and reduce the risk of kidney failure. During the early stages of development of SGLT2 inhibitors, concerns were raised that these agents could increase the risk of AKI resulting from hypovolemia, treatment-induced acute reduction in glomerular filtration rate (GFR), and the potential to trigger kidney medullary hypoxic injury. These concerns were supported by early case reports suggesting that risk of AKI is higher among patients with type 2 diabetes mellitus and preserved kidney function who initiated SGLT2 inhibitors.6Perlman A. Heyman S.N. Matok I. et al.Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: analysis of the FDA adverse event report system database.Nutr Metab Cardiovasc Dis. 2017; 27: 1108-1113Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar However, large cardiovascular and kidney outcome trials demonstrated that SGLT2 inhibitors could in fact reduce the risk of AKI. The consistency of this finding across multiple trials suggests that this is a class effect and not limited to a specific SGLT2 inhibitor. Moreover, subsequent work has identified biologically plausible mechanisms by which SGLT2 inhibition could reduce AKI risk.7van Raalte D.H. Cherney D.Z.I. Sodium glucose cotransporter 2 inhibition and renal ischemia: implications for future clinical trials.Kidney Int. 2018; 94: 459-462Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,8Sridhar VS, Tuttle KR, Cherney DZI. We can finally stop worrying about SGLT2 inhibitors and acute kidney injury. Am J Kidney Dis. 2020;76:454–456.Google Scholar Understanding the relationship between SGLT2 inhibition and risk of AKI in patients with CKD and albuminuria is important, as patients with CKD experience higher rates of AKI than patients with normal or near-normal kidney function. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial demonstrated that the SGLT2 inhibitor dapagliflozin reduced the risk of kidney failure and heart failure hospitalization, and prolonged survival in patients with CKD with and without type 2 diabetes.9Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (886) Google Scholar In this analysis, we report the effect of dapagliflozin on abrupt declines in kidney function. These events were captured in the DAPA-CKD trial as a pre-specified exploratory outcome, defined as the doubling of serum creatinine between 2 subsequent visits. We also compare the frequency of serious AKI adverse events (as reported by investigators) in patients randomized to receive either dapagliflozin or placebo. DAPA-CKD was a randomized, double-blind, placebo-controlled, multicenter, international trial conducted in 21 countries at 386 study sites. The study design and the primary results have been published previously.9Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (886) Google Scholar Briefly, DAPA-CKD participants were ≥18 years of age, with an estimated GFR (eGFR) ≥25 and <75 ml/min per 1.73 m2, and a urinary albumin:creatinine ratio (UACR) ≥200 and <5000 mg/g. Patients either with or without type 2 diabetes were eligible for participation. Patients with type 1 diabetes, polycystic kidney disease, lupus nephritis, or anti-neutrophil cytoplasmic antibody–associated vasculitis, as well as those receiving immunotherapy for primary or secondary kidney disease within 6 months prior to enrollment, were excluded. All participants were receiving treatment with a stable dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for ≥4 weeks prior to randomization, unless they had a documented intolerance to these agents. The trial protocol was approved by a central or local ethics committee at each trial site, and all participants provided written informed consent. This study was prospectively registered on ClinicalTrials.gov (NCT03036150) and was posted online on January 30, 2017, prior to enrollment of the first patient. Eligible participants were randomly assigned to receive either dapagliflozin, 10 mg daily, or matching placebo. This treatment was to be continued until the occurrence of diabetic ketoacidosis, pregnancy, receipt of disallowed therapy, or study completion. Following randomization, in-person study visits were performed after 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter. At each follow-up visit, vital signs were recorded, blood and urine samples were sent for laboratory assessment, and information on potential study endpoints, adverse events, concomitant therapies, and study drug adherence was collected. The primary pre-specified outcome of the current analysis was an abrupt decline in kidney function, defined as a doubling of serum creatinine (measured by either a local or central laboratory) compared with the most recent central laboratory serum creatinine value, assessed in the intent-to-treat population. The doubling of serum creatinine was adjudicated by the independent event-adjudication committee, which was blinded to study treatment allocation. The event adjudication committee determined whether the doubling of serum creatinine reflected progression of the underlying CKD or was an abrupt deterioration unrelated to the underlying disease, due rather to another cause, such as infection, volume depletion, or cardiovascular disease events. AKI reported by investigators as a serious adverse event (SAE; i.e., an adverse event that required hospitalization, led to prolongation of hospitalization, or was associated with death) was assessed in the safety population. SAEs were derived from a predefined list of kidney-related events from the preferred terms in the Medical Dictionary for Regulatory Activities. These events were not prospectively adjudicated by the event-adjudication committee. However, 2 independent reviewers who were blinded to study drug assignment determined the most likely cause of AKI SAEs by reviewing narratives submitted by study investigators. Any disagreement was resolved by a third reviewer. We also evaluated all episodes of dialysis, institution of maintenance dialysis (for at least 28 days), and mortality following a doubling of serum creatinine or an AKI SAE. Finally, we assessed the proportion of patients with end-stage kidney disease (ESKD) or renal death, and all-cause mortality from the time of an abrupt decline in kidney function event until the end of the trial. We performed all efficacy analyses in accordance with the intention-to-treat principle. We determined the risk of abrupt declines in kidney function (dapagliflozin vs. placebo) by calculating the time-to-first inter-visit doubling of serum creatinine, applying proportional hazards (Cox) regression, stratified by diabetes status and UACR (≤1000 vs. >1000 mg/g). We tested for homogeneity of treatment effects across pre-specified subgroups, defined by patient’s demographics and laboratory measurements, by adding interaction terms to the relevant Cox models. We assessed the validity of the proportional hazards assumption by inspection of the log-cumulative hazard function of each treatment group and by including a term for the interaction between treatment assignment and time as a time-varying covariate. We applied the Fine–Gray modification of the Cox model to determine the subdistribution hazard ratio (HR) of an abrupt decline in kidney function, with death as a competing risk. Factors associated with an abrupt decline in kidney function were collected during the trial and summarized by treatment groups. In addition, dialysis and death outcomes after an abrupt decline in kidney function were collected and summarized by treatment group. The relative hazard of ESKD or renal death, or mortality, following an abrupt decline in kidney function, was determined in a companion Cox model into which an indicator of the abrupt decline in kidney function event was fitted as a time-varying covariate (with follow-up time starting at the time of randomization). The period of risk prior to the abrupt decline in kidney function event was attributed to the group with no event, so that calculation of incidence rates would reflect patients’ time-updated event status. The model was adjusted for treatment assignment, age, sex, race/ethnicity, HbA1c, eGFR, log-transformed UACR, systolic blood pressure, hemoglobin, body mass index, and history of cardiovascular disease. In an additional analysis, we performed a causal mediation analysis to examine whether the effect of dapagliflozin in reducing the relative risks of ESKD or renal death, or all-cause mortality, could be explained by the prevention of abrupt declines in kidney function. We used study treatment as the exposure variable, and inter-visit doubling of serum creatinine as a binary mediator. We included age, sex, race, type 2 diabetes status, cardiovascular disease, eGFR, UACR, systolic and diastolic blood pressure, body mass index, and hemoglobin as additional covariates in both the outcome model (a Cox proportional hazards model) and the mediator model (a binary logistic regression model).10VanderWeele T.J. Causal mediation analysis with survival data.Epidemiology. 2011; 22: 582-585Crossref PubMed Scopus (191) Google Scholar We determined point estimates for the natural direct effect, the natural indirect effect, and the total effect of dapagliflozin using the estimators provided by Valeri and VanderWeele.11Valeri L. VanderWeele T.J. SAS macro for causal mediation analysis with survival data.Epidemiology. 2015; 26: e23-e24Crossref PubMed Scopus (96) Google Scholar We obtained 95% confidence intervals (CIs) through bootstrapping with 1000 bootstrap samples. Effects were calculated for the mean level of the continuous confounders and for the mode of the categorical confounders. We performed all analyses with R, version 4.0.2 (R Foundation for Statistical Computing) or Stata, version 15 (StataCorp). A total of 4304 participants were enrolled in the DAPA-CKD trial, of whom 2152 were randomly assigned to receive dapagliflozin, 10 mg once daily, and 2152 to receive placebo, comprising the intent-to-treat population (Supplementary Figure S1). Three patients in each group were randomized but not treated, comprising the safety population (dapagliflozin, n = 2149; placebo, n = 2149). Mean (SD) age was 62 (12) years; 2906 of 4304 (68%) of the cohort had type 2 diabetes; mean eGFR was 43 (12) ml/min per 1.73 m2; and median UACR was 949 (interquartile range: 477 to 1885) mg/g. Baseline characteristics were balanced between the dapagliflozin and placebo groups (Table 1).Table 1Baseline characteristics of patients randomized to receive dapagliflozin or placeboVariableDapagliflozin (n = 2152)Placebo (n = 2152)Age, yr, mean (SD)61.8 (12.1)61.9 (12.1) ≤651247 (57.9)1239 (57.6) >65905 (42.1)913 (42.4)Sex Male1443 (67.1)1436 (66.7) Female709 (32.9)716 (33.3)Race White1124 (52.2)1166 (54.2) Black or African American104 (4.8)87 (4) Asian749 (34.8)718 (33.4) Other175 (8.1)181 (8.4)Type 2 diabetes1455 (67.6)1451 (67.4)HbA1c, %, mean (SD)7.1 (1.7)7.0 (1.7)Blood pressure, mm Hg, mean (SD) Systolic136.7 (17.5)137.4 (17.3) Diastolic77.5 (10.7)77.5 (10.3)eGFR, ml/min per 1.73 m2, mean (SD)43.2 (12.3)43.0 (12.4) ≥45880 (40.9)902 (41.9) <451272 (59.1)1250 (58.1)Urinary albumin-to-creatinine ratio, mg/g, median (IQR)965 (472–1903)934 (482–1868) ≤10001104 (51.3)1121 (52.1) >10001048 (48.7)1031 (47.9)Cardiovascular disease diagnosis813 (37.8)797 (37.0)Heart failure diagnosis235 (10.9)233 (10.8)Diuretic use at baseline928 (43.1)954 (44.3)ACEi or ARB use at baseline2094 (97.3)2080 (96.7)ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; IQR, interquartile range.Values are n (%), unless otherwise indicated. Open table in a new tab ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; IQR, interquartile range. Values are n (%), unless otherwise indicated. During a median of 2.4 years (interquartile range, 2.0–2.7 years) of follow-up, there were 166 abrupt decline in kidney-function events, with a median time interval between visits of 100 days (interquartile range, 48–130 days) recorded in 154 patients (Supplementary Figure S2)—63 of 2152 patients (2.9%; event rate 1.4 [95% CI, 1.1–1.7] per 100 patient-years) in the dapagliflozin group, and 91 of 2152 patients (4.2%; event rate 2.0 [95% CI, 1.6–2.5] per 100 patient-years) in the placebo group (HR, 0.68 [95% CI, 0.49–0.94; P = 0.02]; incidence rate difference 0.64 [95% CI, 0.09–1.20]). Results were similar using the Fine–Gray model, which accounted for the competing risk of death (subdistribution HR, 0.69 [95% CI, 0.50–0.95; P = 0.02]; Figure 1). There was no heterogeneity in the effect of dapagliflozin, compared with placebo, on an abrupt decline in kidney function in pre-specified subgroups. Notably, the effects were consistent in patients with versus without type 2 diabetes and were remarkably similar in patients with a baseline eGFR above versus below 45 ml/min per 1.73 m2, and those with a UACR above versus below 1000 mg/g (Figure 2). Effects were also similar in subgroups created post hoc, of those with baseline diuretic use and those with presence of heart failure at baseline (Figure 2).Figure 2Forest plot shows the incidence of an abrupt decline in kidney function (at least a doubling of serum creatinine between visits separated by a median of 100 days), by subgroups. CI, confidence interval; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Participants who developed abrupt declines in kidney function were more likely to be White and less likely to be Asian, had higher systolic blood pressure, HbA1c level, and UACR, were more likely to report a diagnosis of type 2 diabetes, have a history of cardiovascular disease or heart failure, and have a prescription for diuretics at baseline (Supplementary Table S1). During follow-up, volume depletion, dehydration, and infections were the most frequently reported factors associated with abrupt declines in kidney function (Table 2).Table 2Factors associated with abrupt decline-in-kidney-function eventsTotalDapagliflozinPlaceboPatients who had an event154 (3.6)63 (2.9)91 (4.2)Predisposing factors associated with eventaPredisposing factors are reported for patients with available data and in whom the event was unrelated to underlying kidney disease as adjudicated by the independent event-adjudication committee.Event adjudicated to be related to underlying disease, n381325Event adjudicated to be unrelated to underlying disease,bFour participants in the placebo group had more than 1 predisposing factor. n1165066 Dehydration/volume depletion21 (20.2)9 (21.4)12 (19.4) Medication-associated11 (10.6)2 (4.8)9 (14.5) Trauma1 (1.0)0 (0.0)1 (1.6) Cardiovascular event6 (5.8)2 (4.8)4 (6.5) Infection/septic shock24 (23.1)12 (28.6)12 (19.4) Acute exacerbation of existing kidney disease2 (1.9)1 (2.4)1 (1.6) Other5 (4.8)2 (4.8)3 (4.8) Unknown50 (43.1)22 (44.0)28 (42.4)EventRequiring dialysis59 (38.3)23 (36.5)36 (39.6)Requiring maintenance dialysis after AKI32 (20.8)13 (20.6)19 (20.9)Death after AKI43 (27.9)16 (25.9)27 (29.7)Recovery of kidney function: Δ serum creatinine at next central laboratory measurement,cSerum creatinine data at the next central laboratory measurement were available in 98 participants. %>25 (no recovery)55 (56.1)23 (54.8)32 (57.1)0 to ≤25 (partial recovery)27 (27.6)12 (28.6)15 (26.8)≥0 (full recovery)16 (16.3)7 (16.6)9 (16.1)AKI, acute kidney injury.Seven patients (2 in the dapagliflozin and 5 in the placebo group) discontinued study medication within 28 days after the abrupt decline-in-kidney-function event.Values are n (%), unless otherwise indicated.a Predisposing factors are reported for patients with available data and in whom the event was unrelated to underlying kidney disease as adjudicated by the independent event-adjudication committee.b Four participants in the placebo group had more than 1 predisposing factor.c Serum creatinine data at the next central laboratory measurement were available in 98 participants. Open table in a new tab AKI, acute kidney injury. Seven patients (2 in the dapagliflozin and 5 in the placebo group) discontinued study medication within 28 days after the abrupt decline-in-kidney-function event. Values are n (%), unless otherwise indicated. Following an abrupt decline in kidney function, the rate of ESKD or renal death was 48.7 per 100 patient-years, compared with 2.7 per 100 patient-years for those who did not experience an abrupt decline in kidney function. The risk of death was also increased in those who experienced an abrupt decline in kidney function (Table 3). In a multivariable model including selected baseline variables and treatment assignment, the strong association persisted between doubling of serum creatinine and ESKD or renal death (HR, 13.7 [95% CI, 9.7–19.3]) and mortality (HR, 9.3 [95% CI, 6.6–13.2]; Table 3).Table 3Association between an abrupt decline in kidney function and ESKD/renal death and mortalityOutcomeWithout an abrupt decline in kidney functionWith an abrupt decline in kidney functionHazard ratio (95% CI)EventsEvent rate, 95% CI(events per 100 patient-year)EventsEvent rate, 95% CI(events per 100 patient-year)ESKD or renal death2282.7 (2.4–3.1)4448.7 (35.4–65.4)13.7 (9.7–19.3)Mortality2042.2 (1.9–2.6)4333.3 (24.1–44.8)9.3 (6.6–13.2)CI, confidence interval; ESKD, end-stage kidney disease.The multivariable adjusted hazard ratio for the association between doubling of serum creatinine events that were not attributed to the underlying disease (n = 116 patients) and subsequent ESKD or renal death was 7.0 (95% CI, 4.4–11.3) and 9.9 (95% CI, 6.8–14.3) for the association with mortality. Open table in a new tab CI, confidence interval; ESKD, end-stage kidney disease. The multivariable adjusted hazard ratio for the association between doubling of serum creatinine events that were not attributed to the underlying disease (n = 116 patients) and subsequent ESKD or renal death was 7.0 (95% CI, 4.4–11.3) and 9.9 (95% CI, 6.8–14.3) for the association with mortality. Given that there were fewer doubling of serum creatinine events in the dapagliflozin group compared to the placebo group, and that these events were associated with ESKD and mortality, we explored whether the beneficial effect of dapagliflozin on ESKD and mortality could be explained by its reduction in risk of abrupt declines in kidney function. In a causal mediation analysis model, the direct effect of dapagliflozin (transition from “No AKI” to “ESKD/renal death or mortality” in Figure 3) approximated the total effects, indicating that almost all of the benefit of dapagliflozin on these clinical endpoints occurred through mechanisms distinct from abrupt declines in kidney function (Figure 3). Overall, investigator-reported AKI-related SAEs occurred in 54 of 2149 participants (2.5%; event rate 1.2 per 100 patient-years) in the dapagliflozin group, and 69 of 2149 participants (3.2%; event rate 1.5 per 100 patient-years) in the placebo group (HR, 0.77 [95% CI, 0.54–1.10; P = 0.15]; incidence rate difference 0.35 [95% CI, −0.14 to 0.86]). Accounting for the competing risk of mortality did not alter our findings; the effect size for AKI-related SAEs using the Fine–Gray modification of the Cox model was identical (subdistribution HR, 0.77 [95% CI, 0.54–1.10; P = 0.16]; Supplementary Figure S3). Initiation of SGLT2 inhibitors is associated12Cherney 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 (69) Google Scholar,13Kraus B.J. Weir M.R. Bakris G.L. et al.Characterization and implications of the initial estimated glomerular filtration rate 'dip' upon sodium-glucose co-transporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.Kidney Int. 2021; 99: 752-760Abstract Full Text Full Text PDF Scopus (31) Google Scholar with an abrupt rise in serum creatinine and a corresponding decline in eGFR of 3–5 ml/min per 1.73 m2. Prior to the availability of data from cardiovascular safety trials, there was concern among some clinicians that the abrupt rise in creatinine might be a signal of harm related to AKI that had a deleterious effect on survival—an effect amplified in the presence of CKD and increased albuminuria.4James M.T. Grams M.E. Woodward M. et al.A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury.Am J Kidney Dis. 2015; 66: 602-612Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar,5Vallon V. Do tubular changes in the diabetic kidney affect the susceptibility to acute kidney injury?.Nephron Clin Pract. 2014; 127: 133-138Crossref PubMed Scopus (19) Google Scholar In this analysis from the DAPA-CKD trial, we demonstrated that dapagliflozin, compared with placebo, was associated with a lower risk of an abrupt decline in kidney function. In addition, investigator-reported AKI SAEs occurred less frequently with dapagliflozin, compared with placebo. These data support the favorable benefit–risk profile of dapagliflozin, and endorse the revised clinical practice guidelines recommending the use of SGLT2 inhibitors in patients with CKD.14Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work GroupKDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.Kidney Int. 2020; 98: S1-S115Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Long-term safety data from other cardiovascular outcome trials (starting with the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME] and subsequently endorsed by other cardiovascular outcome trials) have demonstrated the safety of SGLT2 inhibitors with respect to AKI, and in fact, they have suggested that AKI risk is reduced with these therapies in patients with type 2 diabetes and preserved kidney function.15Neuen B.L. Young T. Heerspink H.J.L. et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2019; 7: 845-854Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar Our observations are also consistent with analyses in patients with type 2 diabetes and CKD from the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Patients With Diabetic Nephropathy (CREDENCE) trial, in which the HR for AKI SAEs was 0.79 (95% CI, 0.52–1.19).15Neuen B.L. Young T. Heerspink H.J.L. et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2019; 7: 845-854Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar In addition, a network meta-analysis comparing the risk of AKI across different classes of glucose-lowering agents showed that, compared to placebo, SGLT2 inhibitors reduce the risk of AKI, whereas effects were neutral for glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.16Zhao M. Sun S. Huang Z. et al.Network meta-analysis of novel glucose-lowering drugs on risk of acute kidney injury.Clin J Am Soc Nephrol. 2020; 16: 70-78Crossref PubMed Scopus (26) Google Scholar Important to note is that the signal for protection against AKI risk was consistent across a range of subgroups, indicating that dapagliflozin is protective even in higher-risk patients, such as those with type 2 diabetes, heart failure, more severe albuminuria, or those already using diuretics. Our results are also in keeping with findings from a