Finerenone according to insulin resistance in heart failure: the FINEARTS-HF trial

Abstract Background Insulin resistance is a common metabolic risk factor for heart failure (HF) onset and progression. The estimated glucose disposal rate (eGDR) is a simple and noninvasive three-variable measure of insulin sensitivity, where lower eGDR levels reflect greater insulin resistance. However, whether eGDR is associated with adverse outcomes in individuals with HF is uncertain. Purpose To explore clinical outcomes and treatment effects of finerenone according to baseline eGDR in the FINEARTS-HF trial. Methods FINEARTS-HF enrolled individuals with chronic, symptomatic HF with mildly reduced or preserved ejection fraction (HFpEF/HFmrEF), with or without diabetes. Using an established algorithm, eGDR was calculated using baseline waist circumference, glycated hemoglobin (HbA1c), and hypertension status (history of hypertension or baseline blood pressure ≥140/90 mm Hg). Clinical outcomes and treatment effects of finerenone according to baseline eGDR were examined categorically ( median or ≥ median) through multivariable-adjusted Cox proportional hazards regression models and continuously through Poisson regression with restricted cubic splines. Results Among 5,851 (98%) FINEARTS-HF participants with a calculable eGDR, the median eGDR was 5.1 mg/kg/min. Lower eGDR at baseline was associated with female sex, Asian race, worse health status, and kidney dysfunction. Participants with eGDR 5.1 mg/kg/min experienced a 60% higher rate of cardiovascular death and total HF events compared with those with eGDR ≥5.1 mg/kg/min (adjusted hazard ratio aHR, 1.60; 95% CI, 1.39-1.84; P0.001). Similar findings were observed in participants with diabetes (aHR, 1.61; 95% CI, 1.31-1.98) and without diabetes (aHR, 1.30; 95% CI, 1.04-1.63; Pinteraction=0.09). When evaluated continuously, lower eGDR was associated with an increased risk for a wide range of cardiovascular, kidney, and mortality outcomes (Figure 1). Lower baseline eGDR was additionally associated with a higher rate of new-onset diabetes (P0.001) (Figure 2). Treatment benefits of finerenone on cardiovascular death and total HF events (Pinteraction=0.63) and new-onset diabetes (Pinteraction=0.37) were consistent irrespective of baseline eGDR category. The safety profile of finerenone was similar among participants with eGDR versus ≥5.1 mg/kg/min. Conclusions In this FINEARTS-HF analysis, greater eGDR-defined insulin resistance among individuals with HFmrEF/HFpEF was associated with a wide range of adverse cardiovascular-kidney-metabolic outcomes, and did not appear to modify benefits of finerenone. These findings suggest eGDR may enhance risk stratification among individuals with HFmrEF/HFpEF, with or without diabetes.Figure 1 Figure 2