Effects of canagliflozin versus finerenone on cardiorenal outcomes: exploratory post hoc analyses from FIDELIO-DKD compared to reported CREDENCE results

Abstract

Background The nonsteroidal mineralocorticoid receptor antagonist finerenone and the sodium-glucose co-transporter-2 inhibitor canagliflozin reduce cardiorenal risk in albuminuric patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). At first glance, the results of FIDELIO-DKD (ClinicalTrials.gov, NCT02540993) and CREDENCE appear disparate. In FIDELIO-DKD, the primary end-point had a 18% (95% CI 7% to 27%) relative risk reduction; in CREDENCE the primary end-point had a 30% (95% CI 18% to 41%) relative risk reduction. Unlike CREDENCE, FIDELIO-DKD trial included patients with high albuminuria but excluded patients with symptomatic heart failure with reduced ejection fraction. The primary end-point in the FIDELIO-DKD trial was kidney specific and included a sustained decline in eGFR of ≥40% from baseline. In contrast, the primary end-point in the CREDENCE trial was included a sustained decline in eGFR of ≥57% from baseline and cardiovascular death. This post-hoc exploratory analysis investigated how differences in trial design—inclusion/exclusion criteria and definition of primary outcomes— influenced observed treatment effects. Methods Patients from FIDELIO-DKD who met the CKD inclusion criteria of the CREDENCE study (urine albumin-to-creatinine ratio >300–5000 mg/g and an estimated glomerular filtration rate of 30–<90 ml/min/1.73 m2 at screening) were included in this analysis. The primary end point was a cardiorenal composite (cardiovascular death, kidney failure, estimated glomerular filtration rate decrease of ≥57% sustained for ≥4 weeks or renal death). Patients with symptomatic heart failure with reduced ejection fraction were excluded from FIDELIO-DKD. Therefore, in a sensitivity analysis, we further adjusted for the baseline prevalence of heart failure. Results Of 4619/5674 (81.4%) patients who met the subgroup inclusion criteria, 49.6% were treated with finerenone and 50.4% received placebo. The rate of the cardiorenal composite end point was 43.9/1000 patient years with finerenone compared to 59.5/1000 patient years with placebo. The relative risk was significantly reduced by 26% with finerenone versus placebo (hazard ratio 0.74, 95% CI 0.63–0.87).In CREDENCE, the rate of the cardiorenal composite end point was 43.2/1000 patient years with canagliflozin compared to 61.2/1000 patient years with placebo; a 30% risk reduction was observed with canagliflozin (hazard ratio 0.70, 95% CI 0.59–0.82). Conclusions This analysis highlights the pitfalls of direct comparisons between trials. When key differences in trial design are considered, FIDELIO-DKD and CREDENCE demonstrate cardiorenal benefits of a similar magnitude.

The changing trajectory of diabetic kidney disease

“…This allowed for a prespecified individual pooled patient-level analysis of both trials, the FIDELITY analysis [4 ▪▪ ]. The FIDELIO trial, with a primary renal outcome of end-stage kidney disease, yielded similar results to the SGLT2 inhibitor renal outcome trial, CREDENCE showing a reduction in the risk of a sustained more than 40% reduction in estimated GFR and renal death [20,21 ▪ ]. This later comparative analysis also demonstrated similar renal and cardiovascular outcomes in a subset of patients with advanced stage 3 and 4 kidney disease and high cardiovascular risk.…”

Renal Protection of Mineralocorticoid Receptor Antagonist, Finerenone, in Diabetic Kidney Disease

“…Co-administration of finerenone and empagliflozin in an animal model of hypertension-induced end-organ damage showed improvements in proteinuria, plasma creatinine and uric acid levels, blood pressure, renal and cardiac fibrotic lesions, and mortality [78]. In a post hoc analysis conducted on similar patient groups from Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CRE-DENCE) and FIDELIO-DKD, canagliflozin and finerenone showed similar results regarding the cardiorenal endpoint compared to the placebo group (canagliflozin vs. placebo: HR, 0.70; 95% CI, 0.59 to 0.82; P<0.0001; finerenone vs. placebo: HR, 0.74; 95% CI, 0.63 to 0.87; P=0.0003) [79]. In addition, in the FIDELITY analysis, 6.7% of the patients were already being administered SGLT2i, and there was no difference in the outcomes of these patients compared with those of participants who were not treated with SGLT2i.…”

Finerenone in SGLT-2 Inhibitors Era: Current Positioning in Diabetic Kidney Disease

“…These differences could be related to differences in the inclusion criteria and baseline characteristics of the patients across these trials (DAPA-CKD included CKD without T2D as well), however, v) Even in a post-hoc analysis that compared the cardiorenal outcomes of a "CREDENCE-like" equivalent cohort (matched baseline albuminuria and eGFR) of FI-DELIO-DKD to the CREDENCE trial there was -a. An insignificant benefit with finerenone on kidney failure (HR 0.81; 95% CI, 0.64-1.02) [16]. In the nearly equivalent "Diabetes-cohort" of DAPA-CKD, kidney failure was significantly reduced with dapagliflozin (HR 0.69; 95% CI 0.51-0.92), compared to the placebo [17,18], b. Cardiovascular risk reduction was less consistent with finerenone in the "CREDENCE-like" cohort of FIDELIO-DKD compared with CREDENCE and "Diabetic-cohort" of DAPA-CKD, and finally, c. mortality reduction (composite of CV death or HHF, and all-cause mortality) was not observed with finerenone ("CREDENCE-like" cohort in FIDELIO--DKD) unlike CREDENCE and "Diabetes-cohort" of DAPA-CKD.…”

“…No episode of hyperkalemia was noted with dapagliflozin (0%) [29]. An ongoing 6-month (n = 807), double-blind, three-arm study (CONFIDENCE, NCT052-54002) that is currently assessing the efficacy (change in UACR as the primary outcome and changes in eGFR as secondary outcome) and safety (incidence of hyperkalemia) of finerenone (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) [12]) ACEi -angiotensin-converting enzyme inhibitors, ARBs -angiotensin II receptor blockers; CI -confidence interval; CKDchronic kidney disease; CV -cardiovascular; HR -hazard ratio; MRA -mineralocorticoid receptor antagonists; RR -risk ratio; SGLT2i -sodium-glucose cotransporter-2 inhibitors 300-5000 mg/g) and T2DM will further enlighten the relative merits of these agents in near future [30].…”