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INTRODUCTION

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in a broad population of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the FIDELITY prespecified pooled analysis¹ of the FIDELIO-DKD² and FIGARO-DKD³ clinical trials
This post hoc analysis aimed to explore whether insulin resistance, measured by estimated glucose disposal rate (eGDR), is associated with an increased risk of cardiorenal outcomes and if insulin resistance modifies the cardiorenal efficacy of finerenone

METHODS

This analysis combines individual patient-level data from the FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) phase 3 clinical trials^2,3
FIDELITY study design and efficacy outcomes are shown in Figure 1 and study population information in Figure 2
Insulin resistance was estimated using the eGDR
Composite outcomes were analyzed by defined categorical subgroups: eGDR <median and eGDR ≥median
Safety was also assessed

eGFR, estimated glomerular filtration rate; IQR, interquartile range; od, once daily.

Patients included in this FIDELITY post hoc analysis were stratified according to baseline insulin resistance, estimated by eGDR

eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; K+, potassium; RAS, renin-angiotensin system; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio.

RESULTS

Overall, baseline characteristics were well balanced between groups (Figure 3). However, there were some notable differences:
- Patients with insulin resistance had a longer mean duration of diabetes and a higher urine albumin-to-creatinine ratio (UACR) and mean weight versus those with eGDR ≥median

eGDR, estimated glucose disposal rate; eGFR, estimated glomerular filtration rate; SD, standard deviation; UACR, urine albumin-to-creatinine ratio.

EFFICACY OUTCOMES (OVERALL GROUP) (FIGURE 4)

There was a significantly lower risk of CV events at 3.5 years with increasing eGDR (as continuous variable) in the overall group (placebo plus finerenone) (HR 0.88 [95% CI, 0.86-0.91; P<0.01])
However, for kidney outcome events, baseline eGDR had no effect

CI, confidence interval; CV, cardiovascular; eGDR, estimated glucose disposal rate.

EFFICACY OUTCOMES BY eGDR SUBGROUPS (FIGURE 5)

CV and kidney composite outcome incidence rates (IR) were measured per 100 patient-years
- Similar to the overall group, the IR for CV events was greater if baseline eGDR <median versus IR if baseline eGDR ≥median following either finerenone or placebo treatment
- The IR of the composite kidney outcome was similar (and therefore followed the trend for the overall population) across eGDR subgroups for both finerenone- or placebo-treated patients
- The difference in IR between finerenone versus placebo showed no significant heterogeneity by baseline eGFR on the CV outcomes or kidney outcomes (P>0.05 for the interaction)

CI, confidence interval; CV, cardiovascular; eGDR, estimated glucose disposal rate; HR, hazard ratio; PY, patient-years.

SAFETY OUTCOMES

Overall, the incidences of treatment-emergent adverse events and severe adverse events were balanced between the finerenone and placebo groups and between eGDR subgroups
The incidence of investigator-reported, treatment-emergent hyperkalemia events was higher in patients treated with finerenone versus placebo in both eGDR subgroups, but discontinuations due to hyperkalemia were low (Figure 6)

AE, adverse event; eGDR, estimated glucose disposal rate; SAE, severe adverse event.

CONCLUSIONS

In this post hoc analysis of the FIDELITY prespecified pooled analysis, the efficacy and safety of finerenone were not modified by baseline insulin resistance
A higher risk of CV outcomes, but not kidney outcomes, was observed in people with T2D and CKD who had greater baseline insulin resistance
The safety profile of finerenone was generally consistent irrespective of baseline insulin resistance

REFERENCES

Agarwal R, et al. Eur Heart J. 2022;43(6):474-484.
Bakris GL, et al. N Engl J Med. 2020;383(23):2219-2229.
Pitt B, et al. N Engl J Med. 2021;385(24):2252-2263.

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INSULIN RESISTANCE

Introduction 1 — CKD, chronic kidney disease; T2D, type 2 diabetes

REFERENCES

Whaley-Connell A, Sowers JR. Cardiorenal Med. 2017;8(1):41-49.
Schrauben SJ, et al. BMC Nephrol. 2019;20(1):60.
Nakashima A, et al. Nutrients. 2021;13.
Lee SH, et al. Diabetes Metab J. 2022;46(1):15-37

THE ESTIMATED GLUCOSE DISPOSAL RATE (eGDR)

The eGDR is an inverse marker of insulin action (in vivo) and was originally developed as a validated score to measure insulin resistance in patients with type 1 diabetes based on waist circumference, hypertension, and glycated hemoglobin level (HbA1c)^1-3
In this post hoc analysis, insulin resistance was estimated using the eGDR and was calculated as follows: 21.158 + (−0.09 x waist circumference [cm]) + (−3.407 x presence of hypertension) + (−0.551 x HbA1c [%])
- A lower eGDR is associated with greater insulin resistance and increased risk of CV disease and progression to end-stage kidney disease versus a higher eGDR^4-6

REFERENCES

Nystrom T, et al. Diabetes Obes Metab. 2018;20(3):556-563.
Williams KV, et al. Diabetes. 2000;49(4):626-632.
Lu Z, et al. Cardiovasc Diabetol. 2023;22(1):225 (also based on overview provided by Ebert T, et al. Diabetes Care. 2023).
Whaley-Connell A, Sowers JR. Cardiorenal Med. 2017;8(1):41-49.
Schrauben SJ, et al. BMC Nephrol. 2019;20(1):60.
Nakashima A, et al. Nutrients. 2021;13.

ACKNOWLEDGMENTS

Funded by Bayer AG; FIDELIO-DKD and FIGARO-DKD clinicaltrials.gov numbers are NCT02540993 and NCT02545049, respectively. Medical writing assistance was provided by Envision Pharma Group and was funded by Bayer AG

DISCLOSURES

TE reports personal fees from Bayer, Fresenius Medical Care Deutschland, Sanofi, and Santis. He has received research support from the European Foundation for the Study of Diabetes (EFSD Mentorship Programme supported by AstraZeneca). SDA has received research support from Abbott Vascular and Vifor International, and personal fees from Abbott Vascular, Bayer, Boehringer Ingelheim, BRAHMS, Cardiac Dimensions, Impulse Dynamics, Novartis, Servier, and Vifor Pharma. LMR reports receipt of consultancy fees from Bayer. PF has served as an advisory board member and speaker for AstraZeneca, Eli-Lilly, Bayer, Novo Nordisk, and Mundipharma. VF has served as a paid consultant or Abbott, Asahi, AstraZeneca, Bayer, Novo Nordisk, and Sanofi. He has patent and ownership interests in BRAVO4Health. GEU has received research support (to Emory University) from AstraZeneca, Bayer, Abbott, and Dexcom Inc. ALB reports personal fees from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk during the conduct of the study; all fees are given to the University Clinic Tübingen. RL, CS, and KR are full-time employees of Bayer. PR reports personal fees from Bayer during the conduct of the study. He has received research support and personal fees from AstraZeneca and Novo Nordisk, and personal fees from Astellas Pharma, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma, Sanofi, and Vifor Pharma; all fees are given to Steno Diabetes Center Copenhagen.

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Outcomes With Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Baseline Insulin Resistance: A FIDELITY Subgroup Analysis

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