Importance of trial design when investigating cardiorenal outcomes in patients with CKD and T2D: Focus on CREDENCE and FIDELIO-DKD

Abstract

BackgroundRecent trials investigating novel therapies in chronic kidney disease (CKD) and type 2 diabetes (T2D) include the randomized, placebo-controlled phase III FIDELIO-DKD and CREDENCE studies of finerenone (selective, nonsteroidal mineralocorticoid receptor antagonist) and canagliflozin (sodium-glucose co-transporter-2 inhibitor), respectively. This analysis investigated how differences in trial design between FIDELIO-DKD and CREDENCE influence the treatment effects of the two drugs. MethodsThis was a post hoc analysis of FIDELIO-DKD that included patients meeting the CKD inclusion criteria of the CREDENCE study (urine albumin-to-creatinine ratio >300–5000 mg/g and estimated glomerular filtration rate [eGFR] 30–<90 mL/min/1.73 m2 at screening). The cardiorenal composite endpoint comprised kidney failure, eGFR decrease of ≥57% from baseline sustained for ≥4 weeks, or renal or cardiovascular death (equivalent to the CREDENCE primary endpoint). ResultsOverall, 81.4% (4619/5674) of patients were eligible for this analysis; 2291 (49.6%) received finerenone and 2328 (50.4%) received placebo. The cardiorenal composite endpoint risk was significantly reduced by 26% with finerenone versus placebo (hazard ratio 0.74, 95% confidence interval 0.63–0.87; p=0.0003); after adjusting for history of heart failure, the risk was reduced by 28%. In CREDENCE, the cardiorenal endpoint risk reduction was 30% with canagliflozin versus placebo (see Figure for all results). ConclusionThe results of this analysis highlight the pitfalls of direct comparisons between trials, and how subtle differences in patient eligibility criteria and endpoint definitions can lead to meaningful differences in outcomes. Both the FIDELIO-DKD and CREDENCE studies demonstrate cardiorenal benefits of a similar magnitude when these differences are considered.