Blumer V; Baim Institute for Clinical Research, Boston, Massachusetts, USA.
Januzzi JL Jr; Liu Y; Butler J; Ezekowitz JA; et al

JACC Heart Failure. 14(1):102433, 2026 Jan.

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).