OBJECTIVE: To explore whether insulin resistance, assessed by estimated glucose disposal rate (eGDR), is associated with cardiorenal risk and whether it modifies finerenone efficacy.

RESEARCH DESIGN AND METHODS: In FIDELITY (N = 13,026), patients with type 2 diabetes, either 1) urine albumin-to-creatinine ratio (UACR) of ≥30 to <300 mg/g and estimated glomerular filtration rate (eGFR) of ≥25 to ≤90 mL/min/1.73 m2 or 2) UACR of ≥300 to ≤5,000 mg/g and eGFR of ≥25 mL/min/1.73 m2, who also received optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. Outcomes included cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained decrease of ≥57% in eGFR from baseline, or renal death) composites. eGDR was calculated using waist circumference, hypertension status, and glycated hemoglobin for 12,964 patients.

RESULTS: Median eGDR was 4.1 mg/kg/min. eGDR <median (insulin resistant) was associated with higher cardiovascular event incidence regardless of treatment versus ≥median (insulin sensitive) (incidence rate/100 patient-years of 5.18 and 6.34 [for finerenone and placebo] vs. 3.47 and 3.76 [for finerenone and placebo], respectively). However, eGDR was not associated with kidney outcomes. There was no significant heterogeneity for effects of finerenone by eGDR on cardiovascular (<median: hazard ratio [HR] 0.81, 95% CI 0.72-0.92; ≥median: HR = 0.92, 95% CI 0.79-1.06; P interaction = 0.23) or kidney outcomes (<median: HR = 0.84, 95% CI 0.68-1.02; ≥median: HR = 0.70, 95% CI 0.58-0.85; P interaction = 0.28). Overall, finerenone demonstrated similar safety between subgroups. Sensitivity analyses were consistent.

CONCLUSIONS: Insulin resistance was associated with increased cardiovascular (but not kidney) risk and did not modify finerenone efficacy.