| Summary: | Despite evidence of SGLT2 inhibitors in improving cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF), the heterogenous mechanism and characteristic multimorbidity of HFpEF require a phenotypic approach. Metabolic phenotype, one common HFpEF phenotype, has various presentations and prognoses worldwide. We aimed to identify different phenotypes of hypertensive-diabetic HFpEF, their phenotype-related outcomes, and treatment responses. The primary endpoint was time to the first event of all-cause mortality or hospitalization for heart failure (HHF). Among 233 recruited patients, 24.9% experienced primary outcomes within 12 months. A total of 3.9% was lost to follow-up. Three phenotypes were identified. Phenotype 1 (n = 126) consisted of lean, elderly females with chronic kidney disease, anemia, and concentric hypertrophy. Phenotype 2 (n = 62) included younger males with coronary artery disease. Phenotype 3 (n = 45) comprised of obese elderly with atrial fibrillation. Phenotype 1 and 2 reported higher primary outcomes than phenotype 3 (<i>p</i> = 0.002). Regarding treatment responses, SGLT2 inhibitor was associated with fewer primary endpoints in phenotype 1 (<i>p</i> = 0.003) and 2 (<i>p</i> = 0.001). RAAS inhibitor was associated with fewer all-cause mortality in phenotype 1 (<i>p</i> = 0.003). Beta blocker was associated with fewer all-cause mortality in phenotype 1 (<i>p</i> = 0.024) and fewer HHF in phenotype 2 (<i>p</i> = 0.011). Our pioneering study supports the personalized approach to optimize HFpEF management in hypertensive-diabetic patients.
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