829-P: Outcomes with Finerenone in People with CKD and T2D by Baseline Insulin Resistance—A FIDELITY Subgroup Analysis

Abstract

Introduction Insulin resistance (IR) is associated with increased risk of T2D, CV disease and CKD. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has shown cardiorenal benefits in people with CKD and T2D. We investigated if IR is associated with risk of cardiorenal outcomes and if IR modifies finerenone efficacy in the pooled FIDELITY dataset. Methods People with T2D and CKD (UACR ≥30-<300 mg/g + eGFR ≥25-≤90 mL/min/1.73 m2 or UACR ≥300-≤5000 mg/g + eGFR ≥25 mL/min/1.73 m2) and optimized RAS blockade were randomized to finerenone or placebo. Estimated glucose disposal rate (eGDR), an inverse marker of IR, was calculated by 21.158 + (-0.09 × waist circumference [cm]) + (-3.407 × presence of hypertension) + (-0.551 × HbA1c [%]). Risk of CV (time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (time to kidney failure, sustained ≥57% eGFR decline, or renal death) composite outcomes, and safety, were assessed by eGDR. Results Median baseline eGDR was 4.1 mg/kg/min in 12,964 participants. Analysis by continuous baseline eGDR showed a significantly lower risk of CV events at 3.5 years with increasing eGDR (HR 0.88 [95% CI 0.86-0.91] p<0.01); whereas eGDR was not associated with kidney outcomes. Analyses by eGDR subgroups showed no significant heterogeneity for the effect of finerenone on CV (eGDR <median: HR 0.82 [95% CI 0.72-0.92]; eGDR ≥median: HR 0.91 [95% CI 0.78-1.06]; p-interaction=0.29) or kidney outcomes (eGDR <median: HR 0.85 [95% CI 0.70-1.04]; eGDR ≥median: HR 0.69 [95% CI 0.57-0.84]; p-interaction=0.18). Consistent strength and direction of the associations were observed across sensitivity analyses. Adverse events were similar across eGDR subgroups; hyperkalaemia events were higher with finerenone than placebo. Conclusions A higher risk of CV, but not kidney, outcomes was observed with greater IR in people with T2D and CKD. Finerenone efficacy and safety were not modified by baseline IR. Disclosure T.Ebert: Advisory Panel; Sanofi, Bayer Inc., Research Support; AstraZeneca, Speaker's Bureau; CME-Verlag, Santis, Fresenius Medical Care. K.Rohwedder: Employee; Bayer Inc., AstraZeneca. P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. S.Anker: Advisory Panel; AstraZeneca, Novartis AG, Consultant; Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Vifor Pharma Management Ltd., Research Support; Abbott, Vifor Pharma Management Ltd. L.M.Ruilope: Advisory Panel; Bayer Inc. P.Fioretto: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Bayer Inc. V.Fonseca: Consultant; Abbott, Corcept Therapeutics, Eli Lilly and Company, Other Relationship; BRAVO4HEALTH, LLC, Research Support; Fractyl Health, Inc., Stock/Shareholder; Amgen Inc. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. A.L.Birkenfeld: None. R.Lawatscheck: Employee; Bayer Inc. C.Scott: None.