Part2: Cardiovascular And Kidney Outcomes With Finerenone in Patients With Type2 Diabetes And Chronic Kidney Disease: The FIDELITY Pooled Analysis
May 26, 2022
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Results
From September 2015 through October 2018,33 292 patients from 48 countries were screened and 13 171 patients were randomized (Supplementary material online, Figure S3). Critical GCP violations related to the site or patient misconduct resulted in the prospective exclusion of 145 patients (see Supplementary material online, Appendix), leaving a population of 13026 patients on whom statistical analyses were performed.
Patient characteristics, medications, and demographics at baseline were balanced between patients randomized to finerenone and placebo (Table2 and Supplementary material online, Table S1; published previously）. The mean eGFR was 57.6mL/min/1.73 m²and the median UACR was 515mg/g. Overall,10.2%,41.0%, and 48.3% of patients had moderate, high, and very high Kidney Disease Improving Global Outcomes risk scores, respectively (Supplementary material online, Figure S4). A history of cardiovascular disease was reported in 45.6% of patients. Blood glucose(mean glycated haemoglobin 7.7%)and blood pressure (mean systolic blood pressure 136.7±14.2) were moderately well controlled. Baseline cardiovascular medications included statins, anti-platelets, and diuretics in 72.2%,56.0%, and 51.5% of patients, respectively, and renin-angiotensin system inhibition in 99.8% of patients. Glucagon-like peptide-1 receptor agonists(GLP-1RAs) and sodium-glucose co-transporter-2(SGLT-2) inhibitors were used by 7.2% and 6.7% of patients, respectively. Medications started after study drug initiation are summarized in Supplementary material online, Table S2. The median follow-up period was 3.0years [interquartile range (IQR) 2.3-3.8 years].
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The composite cardiovascular outcome(time to cardiovascular death, non-fatal M,non-fatal stroke,or HHF) occurred in 825 (12.7%) patients receiving finerenone and 939(14.4%) patients receiving placebo(HR,0.86;95%Cl,0.78-0.95;P=0.0018;Figures 1 and 2). Significantly lower incidences of HHF occurred with finer-none vs.placebo(HR,0.78;95% Cl,0.66-0.92[P=0.0030], Figures2 and 3).Cardiovascular death and non-fatal Ml incidences were directionally consistent with the cardiovascular composite outcome; non-fatal stroke was similar with finerenone and placebo(Figures 2 and 3). Based on a between-group risk difference of 2.2% after 3years,46 (95% Cl,29-109)patients would need to be treated with finerenone to prevent one composite cardiovascular outcome event. Consistent results were observed in prespecified subgroups(including those with SGLT-2 inhibitor or GLP-1RA baseline use; Supplementary material online, Figure S5), and a prespecified 'on-treatment sensitivity analysis(including all events from randomization up to 30 days after the last intake of study drug)confirmed the results of the main analysis (Supplementary material online, Table S3). Results for each of the cardiovascular and renal endpoints by individual trial in FIDELITY, including P interaction values, are presented in Supplementary material online, Figure S6.
The incidence of the composite kidney outcome(time to the first onset of kidney failure, sustained>57% decrease in eGFR from base-line over ≥4 weeks, or renal death) was significantly lower with finer-enone vs. placebo (Figures 1 and 2), occurring in 360(5.5%) patients receiving finerenone and 465(7.1%) patients receiving placebo (HR,0.77;95% Cl,0.67-0.88; P=0.0002); the number needed to treat based on a between-group risk difference of 1.7%at 3years was 60(95% Cl, 38-142).Analysis of the sustained ≥57% decrease in eGFR component showed a 30% risk reduction(HR, 0.70;95% Cl, 0.60-0.83;P<0.0001) and the ESKD component a 20% risk reduction with finerenone vs.placebo(HR,0.80;95% Cl,0.64-0.99;P=0.040). The prespecified 'on-treatment sensitivity analysis confirmed the results of the primary analysis (Supplementary material online, Table S3).
The composite kidney outcome of kidney failure, sustained ≥40%eGFR decrease, or renal death occurred in 854(13.1%) and 995 (15.3%) patients receiving finerenone and placebo, respectively (HR, 0.85;95%Cl,0.77-0.93; P=0.0004; Figures1and 2). Incidences of all-cause mortality(Figures 1 and 2) and hospitalization for any cause (Figure 2) with finerenone were not significantly different from placebo(P=0.051 and P=0.087, respectively). The mean change in UACR from baseline to 4months was 32% lower with finerenone vs. placebo(ratio of least-squares mean change from baseline, 0.68;95% Cl,0.66-0.70), an effect maintained throughout the trial (Supplementary material online, Figure S7A).
Similar incidences of investigator-reported treatment-emergent adverse events were observed between treatment groups(Table 3 and Supplementary material online, Table S4). Serious adverse events occurred in 31.6% of patients in the finerenone group and 33.7% of patients in the placebo group. Renal-related adverse events, including acute kidney injury, occurred in similar proportions of patients between groups. Hyperkalaemia-related adverse events occurred more frequently with finerenone(14.0%)vs. placebo(6.9%), but no hyperkalaemia-related adverse events were fatal and only a small proportion led to permanent treatment discontinuation [1.7%(incidence rate 0.66 per 100 patient-years) and 0.6% (incidence rate 0.22 per 100 patient-years), respectively] or hospitalization (0.9% and 0.2%, respectively). After the fourth month of treatment, the change in serum potassium from baseline was +0.21mmol/L [standard deviation(SD)0.47mmolL] with finerenone and +0.02 mmol L(SD 0.43mmol/L)with placebo; the mean serum potassium was stable over time thereafter (Supplementary material online, Figure S7B).
Hypokalaemia occurred less frequently with finerenone (1.1%) vs. placebo (2.3%), while gynecomastia was similar in the finerenone group (0.1%) and the placebo group (0.2%). Patients receiving finer-none had a modest reduction in mean systolic blood pressure compared with patients receiving placebo [change in mean systolic blood pressure at 4months was-3.2mmHg (SD 15.0mmHg) with fine-none and +0.5 mmHg(SD 14.6mmHg)with placebo; Supplementary material online.
Discussion
The pooled analysis of two complementary trials comprising 13 026 patients with a broad spectrum of CKD and type 2 diabetes, all treated with an optimized dose of an ACEi or ARB,7.10 provides robust evidence of both cardiovascular and kidney protection with finerenone vs. placebo. Based on the FIDELIO-DKD trial results, finerenone is currently indicated to reduce the risk of sustained eGFR decline, ESKD, cardiovascular death, non-fatal Ml, and HHF in adult patients with CKD associated with type 2 diabetes.7·16 Across the FIDELITY population, the relative risk reduction was 14% for the composite cardiovascular outcome and 23% for the composite kidney outcome; cardiovascular outcomes across subgroups by baseline demographics and clinical characteristics were generally consistent. The results of this ana-lysis provide reassurance regarding the safety and efficacy of finerenone across a wide spectrum of patients with CKD and type 2 diabetes with a degree of precision that was previously not possible to obtain by considering the two trials separately.
MRAs are indicated for the treatment of patients with chronicsymp-automatic heart failure with reduced ejection fraction18—such patients were excluded from the FIDELIO-DKD and FIGARO-DKD studies710—but data supporting the use of MRAs to reduce the risk of heart failure developing in patients with CKD and type 2 diabetes are limited. The FIDELITY analysis provides evidence that finerenone use in patients with CKD and type 2 diabetes, a population at high risk of developing heart failure, prevents HHF. In the FIDELITY analysis, HHF was the main driver of the cardiovascular benefit with finerenone, with a relative risk reduction of 22%vs.placebo(P=0.0030), in a population that excluded patients with chronic symptomatic heart failure with reduced ejection fraction at the run-in visit.710This finding is important because heart failure is a major source of morbidity and healthcare costs among patients with CKD and type 2 diabetes1-21; therefore, prevention of such events can improve patient outcomes and potentially reduce healthcare costs. Furthermore, the fact that finerenone lowers HHF risk across the CKD spectrum emphasizes the need to screen all patients with type 2 diabetes for this risk factor.
The FIDELITY analysis shows not only a 30% reduction in the risk of a sustained ≥57% decrease in eGFR on top of optimized ACEi or ARB therapy but also a relative risk reduction of 20% in ESKD with finerenone vs. placebo (P=0.0403). The relative risks of all components of the kidney composite outcome were reduced with finer-none vs. placebo, except for time to renal death (this finding was likely due to low event numbers, although the HR of 0.53 still favoured finerenone over placebo). The relative risk of a sustained>57% de-crease in eGFR was reduced by 30%, ESKD by 20%, sustained de-crease in eGFR to<15mLmin/1.73 m²by 19%， and kidney failure by 16%. The requirement for dialysis is one of the most dreaded complications of CKD progression2; it is associated with substantial morbidity and costs.23 Reduction of this outcome, which is of great relevance to both patients and payers, is therefore notable.
Prior trials of dual renin-angiotensin system blockade have failed to show cardiovascular or kidney protection among patients with CKD and type2diabetes, suggesting how the renin-angiotensin-aldosterone system is blocked important.42 The FIDELITYanalysis suggests a strong effect of MR overactivation in the pathogenesis of both cardiovascular disease and CKD progression in patients with CKD and type 2 diabetes.
Previous studies assessing SGLT-2 inhibitors in patients with CKD and type 2 diabetes, such as CREDENCE or DAPA-CKD, included patient populations representing a substantially smaller part of the CKD spectrum than the FIDELITYanalysis.27 Because the trials differed in population, design, and other aspects described previously, their results cannot be directly compared with the FIDELITY analysis.1In FIDELITY,877 patients(6.7%) received SGLT-2 inhibitors and 944 patients(7.2%)received GLP-1RAs at baseline, and the cardiovascular and kidney benefits of finerenone are at least as large in patients on SGLT-2 inhibitors or GLP-1RAs as in those without Preclinical data on the initial combination of finerenone and empagliflozin in a rat model of hypertension-induced end-organ damage also showed that the combination approach conferred a protective effect across various cardiorenal outcomes.28It is possible that there is an additive effect of the combination of finerenone on top of SGLT-2 inhibitors or GLP-1RAs, which may relate to their distinct mechanisms of action. However, this was not a randomized trial of finerenone and SGLT-2 inhibitor or GLP-1RA combination therapy, and the efficacy and safety of these agents in combination will be determined in future clinical trials and analyses.
Owing to its mechanism of action, finerenone treatment is expected to increase serum potassium concentration through MR antagonism. In FIDELITY, hyperkalaemia was more frequent with finerenone vs. placebo. However, the incidence of hyperkalaemia-related adverse events with clinical impact was low, with hyperkalaemia-related permanent treatment discontinuation in only 1.7% of patients receiving finerenone vs.0.6% with placebo over a median follow-up of 3.0years (IQR 2.3-3.8years). Hypokalaemia occurred less frequently in finerenone-treated patients than in placebo-treated patients.
Potassium intake was not restricted during the trials, but finerenone or placebo was withheld in cases where potassium concentrations >5.5 mmol/L were detected until potassium concentrations fell to <5.0mmoV/L. Therefore, finerenone improves cardiorenal outcomes in patients with CKD and type 2 diabetes with a manageable hyperkalaemia risk and a reduction in hypokalaemia. Hypokalaemia reduction is notable because it is causatively associated with adverse outcomes in heart failure.
Although this prespecified pooled analysis of two studies with similar protocols included a large patient population with CKD and type 2 diabetes, limitations are that it did not include patients with non-albuminuric CKD and only a small proportion of Black patients were included. Since the design of the FIGARO-DKD and FIDELIO-DKD studies, SGLT-2 inhibitors have emerged as therapeutic options for patients with CKD and type2 diabetes.30Some patients in the finer-none phase I rials also received these novel agents at study commencement, and consistent cardiovascular benefits were observed in these groups.
In conclusion, finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. The results highlight the importance of early treatment before CKD has progressed to improve outcomes in this patient population.
