Sex Differences in Diabetic Cardiomyopathy and Treatment Response to AT-001

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a significant cause of heart failure (HF) in individuals with type 2 diabetes mellitus. Although sex differences are noted in HF patients, it is unclear if such differences exist in those with DbCM and whether sex-based differences affect treatment responses. OBJECTIVES: This analysis focuses on sex differences in baseline characteristics of study participants with DbCM at high risk for progression to overt HF and sex-based treatment responses to high-dose AT-001, a novel aldose reductase inhibitor. METHODS: The ARISE-HF trial was a Phase 3, randomized, international, placebo-controlled study designed to evaluate the efficacy and safety of AT-001 in study participants with DbCM. RESULTS: Of 691 participants, 348 (50.4%) were women. At baseline, women had higher N-terminal pro-B-type natriuretic peptide concentrations (92 vs 60 ng/L; P < 0.001), lower peak oxygen uptake (13.87 vs 17.59 mL/kg/min; P < 0.001), shorter cardiopulmonary exercise testing durations (8.47 vs 11.05 minutes; P < 0.001), and worse quality of life and health status (Kansas City Cardiomyopathy Questionnaire overall summary score 87.79 vs 92.55; P < 0.001; Physical Activity Scale for the Elderly score 137.87 vs 171.09; P < 0.001) compared with men. Despite these differences, there were no significant sex differences in the efficacy or tolerability of high-dose AT-001 compared with placebo. The placebo-corrected oxygen uptake change was 0.26 for women and 0.27 for men (P = 0.58), and changes from baseline to month 15 in Kansas City Cardiomyopathy Questionnaire and Physical Activity Scale for the Elderly scores showed no significant sex differences (all P > 0.05). CONCLUSIONS: Despite baseline differences between women and men with DbCM, the efficacy and safety of high-dose AT-001 are comparable across sexes. These findings highlight the presence of sex-specific characteristics in DbCM and underscore the importance of further research to understand potential sex-specific mechanisms. (Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial [ARISE-HF]; NCT04083339).