Sex differences in cardio-kidney metabolic syndrome: insights from the FINE-HEART pooled analysis of 18,000 trial participants

Abstract Introduction While the prevalence, drivers and impact of obesity are known to differ between women and men, less is known about sex differences in the cardio-kidney metabolic (CKM) syndrome. Understanding sex-specific differences in CKM syndrome is essential to guide treatment strategies. We investigate sex-specific differences in clinical profiles, outcomes, and treatment responses to the non-steroidal MRA finerenone. Methods FINE-HEART pooled participants from 2 trials of chronic kidney disease and type 2 diabetes (FIDELIO-DKD and FIGARO-DKD) and a trial of heart failure (HF) with mildly reduced or preserved ejection fraction (FINEARTS-HF). The risk of first HF hospitalization, cardiovascular death, major adverse cardiovascular event (composite of non-fatal myocardial infarction, non-fatal stroke, HF hospitalization, or CV death), and kidney composite outcome (sustained decrease in eGFR to ≥50% from baseline, sustained decline in eGFR to 15 ml/min/1.73 m2, kidney failure, or death due to kidney failure), was compared between men and women using Cox regression models adjusted for clinical covariates. Treatment effect heterogeneity in response to finerenone was evaluated using interaction analyses. Results Of the 18,991 participants of FINE-HEART, 6,664 (35%) were women. Compared with men, women were slightly older (68 vs. 66 years) and had a lower median urine albumin-creatinine ratio (UACR, 183 vs. 337 mg/g). Women were less likely to receive medical therapies commonly indicated in the management of CKM conditions at baseline (Figure 1). During a median follow-up of 2.9 years, women experienced a trend toward lower HF hospitalization rates compared to men, though this did not reach statistical significance (adjusted HR (aHR) 0.91, 95% CI 0.82, 1.01, p=0.08). The risk of kidney composite endpoint was similar between women and men (aHR 0.98, 95% CI 0.87, 1.11, p=0.77). Men and women were at high risk for MACE and CV death in follow-up, but women faced lower adjusted risks of these outcomes: MACE (aHR 0.85, 95% CI 0.79, 0.92, p0.001) and CV death (aHR 0.80, 95% CI 0.69, 0.92, p=0.002) (Figure 2). Finerenone was beneficial in reducing CV, kidney, and mortality outcomes, regardless of sex (all Pinteraction0.05). Conclusions In this high-risk CKM syndrome cohort, despite heightened risks of a range of CV and kidney outcomes, women were less likely to be treated with commonly indicated CKM therapies than men. The beneficial effects of finerenone in reducing adverse outcomes were consistent regardless of sex.Baseline medication use by sex among FIN Hazard ratios (HR) compare women vs. men