A Four-Phenotype Model for Risk Stratification in Heart Failure with Preserved and Mildly Reduced Ejection Fraction: The Role of Sex and Diabetes

Background/Objectives: Sex and diabetes are important determinants of risk in heart failure with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF), yet their combined effects have not been systematically evaluated. This study examined how sex–diabetes phenotypes influence clinical characteristics and the risk of heart failure rehospitalization. Methods: We retrospectively analyzed 1018 HFmrEF/HFpEF patients (2019–2023), classified into four sex–diabetes phenotypes, and performed group comparisons. The primary endpoint was heart failure rehospitalization. Results: Over a mean follow-up of 1463 ± 496 days, 307 patients (30.1%) were rehospitalized for heart failure decompensation. The four phenotypes differed significantly in age, renal function, LV mass, LV dimensions, glycemia, and comorbidity burden (all p < 0.05). Men—particularly those with diabetes—had greater structural remodeling and higher prevalence of smoking, hypercholesterolemia, and atrial fibrillation. In univariate analysis, male sex, diabetes, smoking, NYHA class, lower TAPSE, and lower LVEF were associated with increased risk of rehospitalization. After adjustment for LVEF and NYHA class, male sex (HR 1.28; p = 0.035) and diabetes (HR 1.28; p = 0.036) remained independent predictors. Kaplan–Meier curves demonstrated a clear gradient in event-free survival (log-rank p = 0.015), with women without diabetes showing the best prognosis and diabetic men the worst. Conclusions: Sex and diabetes interact to define distinct risk profiles in HFmrEF/HFpEF. Women without diabetes represent a low-risk phenotype, whereas diabetic men exhibit the highest risk of recurrent heart failure decompensation. These findings support incorporating sex–diabetes phenotyping into routine risk stratification and personalized management.