Effects of newer kidney protective agents on kidney endpoints provide implications for future clinical trials

Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds. Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds. Lay SummaryThe established endpoint for clinical trials in nephrology includes a large decline in estimated glomerular filtration rate (eGFR; 57%). To assess drug effects, the established endpoint requires large sample sizes and trials of long duration. Alternative endpoints that include smaller declines in eGFR have been proposed and applied in recent clinical trials. In this new study, we demonstrate in 4 recently completed clinical trials that the effects of newer nephroprotective agents are generally similar across endpoints using varying eGFR declines. Because endpoints based on smaller declines in eGFR occur more often, the sample size needed to detect treatment effects would be smaller if less-stringent eGFR thresholds are used, thereby facilitating conduct of clinical trials. The established endpoint for clinical trials in nephrology includes a large decline in estimated glomerular filtration rate (eGFR; 57%). To assess drug effects, the established endpoint requires large sample sizes and trials of long duration. Alternative endpoints that include smaller declines in eGFR have been proposed and applied in recent clinical trials. In this new study, we demonstrate in 4 recently completed clinical trials that the effects of newer nephroprotective agents are generally similar across endpoints using varying eGFR declines. Because endpoints based on smaller declines in eGFR occur more often, the sample size needed to detect treatment effects would be smaller if less-stringent eGFR thresholds are used, thereby facilitating conduct of clinical trials. Kidney failure is the most significant long-term complication of chronic kidney disease (CKD), for clinicians, patients, and caregivers.1Webster A.C. Nagler E.V. Morton R.L. Masson P. Chronic kidney disease.Lancet. 2017; 389: 1238-1252Abstract Full Text Full Text PDF PubMed Scopus (1755) Google Scholar Given this, clinical trials aiming to develop new therapies for CKD have traditionally used kidney failure as a component of a composite endpoint, together with a relatively large decline in kidney function (e.g., doubling of serum creatinine). Because kidney failure and doubling of serum creatinine are late manifestations of CKD progression, drug development for CKD has historically focused on patients with more advanced disease, to avoid protracted follow-up times and mitigate operational complexities. Surrogate endpoints that can reliably reflect longer-term, well-established endpoints could facilitate the conduct of clinical trials at earlier stages of CKD.2Levey A.S. Gansevoort R.T. Coresh J. et al.Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in Collaboration with the US Food and Drug Administration and European Medicines Agency.Am J Kidney Dis. 2020; 75: 84-104Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar In the past decade, significant progress has been made in validating surrogate endpoints. Initial studies focused on the validity of using declines in eGFR of less than 57% (equivalent to a doubling of serum creatinine) as a component of a composite endpoint.3Heerspink H.J.L. Weldegiorgis M. Inker L.A. et al.Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT).Am J Kidney Dis. 2014; 63: 244-250PubMed Google Scholar, 4Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an endpoint for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug and Administration.Am J Kidney Dis. 2014; 64: 821-835Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 5Levin A. Agarwal R. Herrington W.G. et al.International consensus definitions of clinical trial outcomes for kidney failure: 2020.Kidney Int. 2020; 98: 849-859Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar A meta-analysis of clinical trials supported the validity of using a 30% eGFR decline in some circumstances, and a 40% decline in eGFR could be more broadly acceptable as a surrogate endpoint. However, for both surrogate endpoints, the pattern of acute effects on eGFR should be examined, specifically because the acute eGFR lowering effects can attenuate the treatment effect estimate in confirmatory phase 3 trials.6Inker L.A. Lambers Heerspink H.J. Mondal H. et al.GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.Am J Kidney Dis. 2014; 64: 848-859Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The validity of kidney endpoints defined by smaller declines in eGFR was demonstrated with established therapies, using data from clinical trials conducted mostly in the 1990s and early 2000s, with the majority being agents that inhibit the renin–angiotensin system. Newer classes of agents for attenuating CKD progression have emerged since then, including sodium–glucose co-transporter-2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, and empagliflozin); a nonsteroidal mineralocorticoid receptor antagonist (finerenone); and an endothelin receptor antagonist (atrasentan).7Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2918) Google Scholar, 8Heerspink 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 (1631) Google Scholar, 9Heerspink H.J.L. Parving H.-H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 10Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (701) Google Scholar These newer interventions all have acute eGFR-lowering effects, although of varying magnitude; whereas atrasentan exerts a modest eGFR-lowering acute effect (–0.8 ml/min per 1.73 m2), the acute effect is 3- to 4-fold larger with finerenone and SGLT2 inhibitors. Understanding the implications of alternative eGFR decline thresholds on the relative (and absolute) effects of these and other therapeutic agents will help inform clinical decision making in the near term, and the design of future clinical trials. In this study, we used data from pivotal placebo-controlled randomized clinical trials that assessed the efficacy and safety of either an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist, or an endothelin receptor antagonist on composite endpoints of kidney failure or death due to kidney disease, with eGFR decline thresholds of 40%, 50%, and 57%. We selected pivotal phase 3 clinical trials enrolling patients with type 2 diabetes and CKD that demonstrated a significant risk reduction in the respective composite kidney endpoint with the newer pharmacologic intervention. We therefore included the following trials: Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE [clinicaltrials.gov NCT02065791]); Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD [NCT03036150]); Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD [NCT02540993]); and the Study of Diabetic Nephropathy with Atrasentan (SONAR [NCT01858532]). Between 2014 and 2017, the CREDENCE trial randomized 4401 patients who were at least 30 years of age, had a diagnosis of type 2 diabetes, an eGFR between 30 and 90 ml/min per 1.73 m2, and a urinary albumin:creatinine ratio (UACR) between 300 and 5000 mg/g (>33.9–565.6 mg/mmol).7Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2918) Google Scholar Eligible patients were prescribed an angiotensin-converting enzyme (ACE)–inhibitor or an angiotensin receptor blocker (ARB). Eligible participants were randomly assigned to receive either canagliflozin at a dose of 100 mg daily or placebo and were followed for a median duration of 2.6 years. Between 2017 and 2020, the DAPA-CKD trial enrolled 4304 patients aged 18 years or older who had CKD, with or without a diagnosis of type 2 diabetes, an eGFR between 25 and 75 ml/min per 1.73 m2, and a UACR between 200 and 5000 mg/g (>22.6–565.6 mg/mmol).8Heerspink 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 (1631) Google Scholar Eligible patients were prescribed an ACE-inhibitor or ARB if tolerated. Participants were randomly assigned to receive either dapagliflozin at a dose of 10 mg once daily or placebo and were followed for a median of 2.4 years.2Levey A.S. Gansevoort R.T. Coresh J. et al.Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in Collaboration with the US Food and Drug Administration and European Medicines Agency.Am J Kidney Dis. 2020; 75: 84-104Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar Between 2015 and 2018, the FIDELIO-DKD trial enrolled 5734 patients aged 18 years or older who had CKD and a diagnosis of type 2 diabetes.10Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (701) Google Scholar Participants had an eGFR of 25 to <60 ml/min per 1.73 m2, a UACR of 30 to <300 mg/g (3.9–<33.9 mg/mmol), and diabetic retinopathy; or an eGFR of 25 to <75 ml/min per 1.73 m2 and a UACR between 300 and 5000 mg/g (33.9–565.6 mg/mmol). Eligible patients were prescribed an ACE-inhibitor or ARB and were randomized to receive either finerenone or placebo and were followed for a median duration of 2.6 years. Between 2013 and 2017, the SONAR trial enrolled 5117 patients aged 18 to 85 years who had a diagnosis of type 2 diabetes, an eGFR between 25 and 75 ml/min per 1.73 m2, and a UACR between 300 and 5000 mg/g (>33.9–565.6 mg/mmol).9Heerspink H.J.L. Parving H.-H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar All patients were prescribed an ACE-inhibitor or ARB. All eligible participants received atrasentan at a dose of 0.75 mg during an open-label active run-in “enrichment period” aimed to select patients who were likely to respond to atrasentan, defined as a reduction in UACR of 30% or more, and exclude patients prone to atrasentan-induced fluid retention, defined as an increase of at least 3 kg in body weight or an increase in brain natriuretic peptide to at least 300 pg/ml. All responder patients who tolerated atrasentan (n = 2648) and a selection of nonresponder patients (n = 1020) proceeded to the randomization visit and were assigned in a 1:1 ratio to either continue receiving atrasentan at a dose of 0.75 mg/d or transition to receiving placebo. For the current analysis, we combined the responder and nonresponder strata, as no evidence indicated that the effect of atrasentan on the primary composite kidney outcome was different in responders and nonresponders. The median duration of follow-up was 2.2 years. The kidney endpoints evaluated in this analysis were a composite of kidney failure (defined as requiring maintenance dialysis for at least 28 days [90 days in the FIDELIO-DKD trial], having undergone kidney transplantation, or having an eGFR <15 ml/min per 1.73 m2 sustained for at least 28 days), death due to kidney failure, or decline in eGFR sustained for at least 28 days (thresholds of ≥40%, ≥50%, and ≥57%). A sustained eGFR <15 ml/min per 1.73 m2 was not a component of the kidney failure definition in the FIDELIO-DKD trial. We performed all statistical analyses following the intention-to-treat principle. We used proportional hazards (Cox) regression models to assess the effect of the active intervention, compared to placebo, on the risk for first relevant composite kidney endpoint. The kidney endpoint in each analysis was defined as kidney failure, death due to kidney failure, or varying eGFR thresholds—57%, 50%, or 40% decline in eGFR from baseline. We also assessed the effects of the interventions on the composite endpoint of kidney failure or death due to kidney failure. We adjusted Cox models for stratification factors used at randomization as originally defined in each clinical trial. To estimate treatment effects on the acute and chronic eGFR slope, we used a shared parameter mixed-effects model, as previously described, based on a linear eGFR slope starting at 3 months postrandomization, while accounting for informative censoring due to kidney failure or death.11Inker L.A. Heerspink H.J.L. Tighiouart H. et al.GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.J Am Soc Nephrol. 2019; 30: 1735-1745Crossref PubMed Scopus (102) Google Scholar, 12Vonesh E. Tighiouart H. Ying J. et al.Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease.Stat Med. 2019; 38: 4218-4239Crossref PubMed Scopus (20) Google Scholar, 13Vonesh E.F. Greene T. Biased estimation with shared parameter models in the presence of competing dropout mechanisms.Biometrics. 2022; 78: 399-406Crossref PubMed Scopus (1) Google Scholar The model adjusts for baseline eGFR and accounts for different sources of variation in eGFR between and within participants and treatment arms. Differences between the randomized groups in the mean eGFR at the 3-months follow-up, and the mean slopes from 3 months onward factored by the follow-up duration, represented the treatment effects on the acute and chronic eGFR slopes, respectively. We calculated required sample sizes for future kidney outcome trials with PASS version 14.07.6 (PASS NCSS, LLC). We used observed hazard ratios as the assumed relative risk reduction for each composite endpoint and the event rate for that endpoint in participants assigned to placebo. We calculated the required sample size to provide 90% power at a 2-sided α-level of 0.05 with an allocation ratio of 1, assuming 18 months of enrollment and 48 months of total trial duration. Patient characteristics of the CREDENCE, DAPA-CKD, FIDELIO-DKD, and SONAR trials are shown in Table 1. Mean age ranged between 61.8 and 65.6 years; mean eGFR ranged between 42.3 and 56.2 ml/min per 1.73 m2, and median UACR ranged between 828 and 949 mg/g. An ACEi or ARB was prescribed for all participants in the SONAR, CREDENCE, and FIDELIO-DKD trials, and for 97% of participants in the DAPA-CKD trial. In all clinical trials, baseline characteristics were well balanced across randomized patient groups.Table 1Baseline characteristicsCharacteristicCREDENCE (N = 4401)DAPA-CKD (N = 4304)FIDELIO-DKD (N = 5674)SONAR (N = 3668)Enrollment period2014–20172016–20182015–20182013–2018Age, yr63.0 (9)61.8 (12)65.6 (9)64.5 (8.8)Female sex494 (33.9)1425 (33.1)1691 (29.8)946 (25.8)Race Asian877 (19.9)1467 (34.1)1440 (25.4)1198 (32.7) Black224 (5.1)191 (4.4)264 (4.7)224 (6.1) Other369 (8.4)356 (8.3)378 (6.7)136 (3.7) White2931 (66.6)2290 (53.2)3592 (63.3)2110 (57.5)Blood pressure, mm Hg Systolic140.0 (16)137.1 (17)138.0 (14)133.3 (15) Diastolic78.3 (9)77.5 (11)75.8 (10)71.5 (10)Body weight, kg87.1 (20.7)81.7 (21)87.2 (20)85.7 (20)Hba1c, %8.3 (1.3)7.06 (1.7)7.7 (1.3)7.8 (1.5)eGFR, ml/min per 1.73 m256.2 (18)43.1 (12)44.3 (13)42.3 (14)eGFR, ml/min per 1.73 m2 >601769 (40.2)454 (10.5)656 (11.6)468 (12.8) <602632 (59.8)3850 (89.5)5016 (88.4)3191 (87.0)UACR, mg/g927 (463–1833)949 (477–1885)852 (446–1634)828 (458–1556)UACR, mg/g ≥10002053 (46.7)2079 (48.3)2480 (43.7)892 (24.5) ≤10002348 (53.3)2225 (51.7)3191 (56.2)2771 (75.5)Baseline medicationsACEi1922 (43.7)1353 (31.4)1942 (34.2)1319 (36.0)ARB2480 (56.4)2870 (66.7)3725 (65.7)2391 (65.2)Diuretics2057 (46.7)1882 (43.7)3214 (56.6)3157 (86.1)Insulin2884 (65.5)1598 (37.1)3637 (64.1)2315 (63.1)Statins3036 (69.0)2794 (64.9)4215 (74.3)2707 (73.8)ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; HbA1c, hemoglobin A1c; SONAR, Study of Diabetic Nephropathy with Atrasentan; UACR, urinary albumin-to-creatinine ratio.Values are presented as mean (SD) or n (%), except for UACR, which is presented as median (25th–75th percentile). Open table in a new tab ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; HbA1c, hemoglobin A1c; SONAR, Study of Diabetic Nephropathy with Atrasentan; UACR, urinary albumin-to-creatinine ratio. Values are presented as mean (SD) or n (%), except for UACR, which is presented as median (25th–75th percentile). Initiation of canagliflozin, dapagliflozin, or finerenone led to larger acute eGFR-lowering effects, compared to atrasentan (Table 2). During follow-up, the chronic eGFR slope was significantly reduced, with all interventions with numerically larger effects observed with canagliflozin (Table 2).Table 2Acute and chronic effects of the interventions on eGFR declineAcute eGFR change, ml/min per 1.73 m2 per moChronic eGFR slope, ml/min per 1.73 m2 per yrClinical trialInterventionActivePlaceboDifference (95% CI)ActivePlaceboDifference (95% CI)CREDENCECanagliflozin–0.93 (0.06)–0.33 (0.07)–0.60 (–0.78, –0.42)–2.5 (0.14)–5.0 (0.15)2.5 (2.1, 2.8)DAPA-CKDDapagliflozin–0.88 (0.05)–0.45 (0.05)–0.43 (–0.57, –0.30)–2.4 (0.16)–3.9 (0.11)1.5 (1.2, 1.8)FIDELIO-DKDFinerenone–0.95 (0.04)–0.19 (0.04)–0.76 (–0.88, –0.64)–3.1 (0.08)–4.4 (0.09)1.3 (1.1, 1.6)SONARAtrasentan–0.20 (0.05)–0.11 (0.05)–0.09 (–0.23, 0.05)–3.0 (0.13)–3.7 (0.13)0.7 (0.3, 1.1)CI, confidence interval; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; SONAR, Study of Diabetic Nephropathy with Atrasentan. Open table in a new tab CI, confidence interval; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; SONAR, Study of Diabetic Nephropathy with Atrasentan. During follow-up, 284 (6.5%), 272 (6.3%), 444 (7.8%), and 287 (7.8%) kidney failure or death due to kidney failure events occurred in the CREDENCE, DAPA-CKD, FIDELIO-DKD, and SONAR trials, respectively. The composite endpoint of 57% eGFR decline, end-stage kidney disease, or death due to kidney failure occurred in 319 (7.2%), 313 (7.3%), 578 (10.2%), and 323 (8.8%) participants during the follow-up of the respective trials. As expected, incorporating lesser declines in eGFR within the composite kidney endpoint increased the number of events (Figure 1). The number of 40% eGFR decline endpoints during the first 3 to 6 months of follow-up was higher in the canagliflozin and finerenone groups, compared to the placebo group, of the relevant trials, triggered by the initial decline, an effect not observed with dapagliflozin or atrasentan (Supplementary Table S1). Treatment effects of the active, compared to placebo, groups in each trial are shown in Figure 1. The precision of the treatment effect increased for endpoints with lesser declines in eGFR, as reflected by the narrower 95% confidence interval and decreased standard error (for example, the standard error of the log hazard ratio was 0.058 for 57% eGFR decline, compared to 0.043 for 40% eGFR decline in the DAPA-CKD trial). The magnitudes of the treatment effects of canagliflozin, dapagliflozin, and atrasentan on the composite endpoint of end-stage kidney disease or death due to kidney failure were similar, compared to the composite endpoint of kidney failure, death due to kidney failure, or 57% eGFR decline (Figure 1). The effect of finerenone on the composite endpoint of end-stage kidney disease or death due to kidney failure was somewhat smaller, compared to the composite endpoints that included an eGFR decline threshold. Overall, the direction and magnitude of these effect sizes in all 4 trials remained generally similar when the 57% eGFR decline was replaced by a 50% or 40% eGFR reduction. Figure 2 shows the impact on the statistical power for the composite kidney endpoints based on each of the eGFR thresholds to detect the observed relative risk reduction. As a result of higher event rates and similar relative risk reductions, required sample sizes would have been smaller in all trials if less-stringent eGFR thresholds had been used. This analysis of 4 recently completed clinical trials in CKD primarily associated with type 2 diabetes compared event rates, treatment effect sizes, and required sample sizes of different kidney endpoints, including different eGFR decline thresholds. The results demonstrated that the SGLT2 inhibitors canagliflozin and dapagliflozin, the nonsteroidal mineralocorticoid receptor antagonist finerenone, and the endothelin receptor antagonist atrasentan showed benefit on all kidney endpoints irrespective of the eGFR threshold included in this analysis. Because the number of endpoints was higher, with no appreciable difference in relative risk reduction, the required sample size to detect the observed treatment effect would be smaller if less-stringent thresholds were used. Many treatments that affect CKD progression cause acute effects on eGFR that differ from their long-term effects.14Neuen B.L. Tighiouart H. Heerspink H.J.L. et al.Acute treatment effects on GFR in randomized clinical trials of kidney disease progression.J Am Soc Nephrol. 2022; 33: 291-303Crossref PubMed Scopus (3) Google Scholar Analyses prepared for a workshop organized by the National Kidney Foundation and the US Food and Drug Administration concluded that for interventions that cause large acute reductions in eGFR (such as use of SGLT2 inhibitors and mineralocorticoid receptor antagonists), a 50% or 57% eGFR decline is the preferred endpoint.6Inker L.A. Lambers Heerspink H.J. Mondal H. et al.GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.Am J Kidney Dis. 2014; 64: 848-859Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,15Greene T. Teng C.C. Inker L.A. et al.Utility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study.Am J Kidney Dis. 2014; 64: 867-879Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar These recommendations were made based on clinical trial results and simulations that demonstrated that the acute decline in eGFR contributes to additional endpoints in the active treatment arm. Presumably, this impact is at least in part due to random variations in eGFR over time, which can periodically exceed the eGFR endpoint threshold. Consistent with these prior findings, our results also showed a higher number of events in the active treatment arm in the canagliflozin and finerenone trials early in follow-up. In contrast to prior analyses demonstrating that the treatment effects of ACE inhibitors and ARBs are attenuated when lower eGFR decline thresholds are used,3Heerspink H.J.L. Weldegiorgis M. Inker L.A. et al.Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT).Am J Kidney Dis. 2014; 63: 244-250PubMed Google Scholar our analyses show generally similar treatment effects across eGFR decline thresholds. This similarity is most likely explained by the balance between the magnitude of the acute and chronic treatment effects on eGFR. The SGLT2 inhibitors and finerenone exert relatively large acute reductions in eGFR but also show a profound stabilization of the rate of eGFR decline during maintenance treatment, which appears to be sufficient to overcome the acute reduction in eGFR.7Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabet