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

Author:

Agarwal Rajiv1ORCID,Anker Stefan D2,Filippatos Gerasimos3,Pitt Bertram4,Rossing Peter56ORCID,Ruilope Luis M789,Boletis John10,Toto Robert11,Umpierrez Guillermo E12,Wanner Christoph13ORCID,Wada Takashi14ORCID,Scott Charlie15,Joseph Amer16,Ogbaa Ike17,Roberts Luke18,Scheerer Markus F19,Bakris George L20

Affiliation:

1. Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, Indiana, USA

2. Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany

3. National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital, Athens, Greece

4. Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI

5. Steno Diabetes Center Copenhagen, Gentofte, Denmark

6. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

7. Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid, Spain

8. CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain

9. Faculty of Sport Sciences, European University of Madrid, Madrid, Spain

10. Faculty of Medicine, Laiko General Hospital, University of Athens, Greece

11. Department of Internal Medicine, UT Southwestern, Dallas, Texas, USA

12. Division of Endocrinology, Metabolism, Emory University School of Medicine, Atlanta, Georgia, USA

13. Medizinische Klinik und Poliklinik 1, Schwerpunkt Nephrologie, Universitätsklinik Würzburg, Germany

14. Department of Nephrology, Kanazawa Medical University, Ishikawa, Japan

15. Data Science and Analytics, Bayer PLC, Reading, UK

16. Cardiology and Nephrology Clinical Development, Bayer AG, Berlin, Germany

17. US Medical Affairs - Cardiovascular and Renal, Bayer U.S. LLC

18. Study Medical Experts, Bayer PLC, Reading, UK

19. Global Medical Affairs & Pharmacovigilance, Pharmaceuticals, Bayer AG, Berlin, Germany

20. Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA

Abstract

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.

Publisher

Oxford University Press (OUP)

Subject

Transplantation,Nephrology

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