Phenotypes of heart failure with preserved ejection fraction and effect of sodium-glucose cotransporter 2 inhibitors treatment

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Abstract Background Phenotypic heterogeneity of heart failure with preserved ejection fraction (HFpEF) has been reported, particularly among racial groups. While phenotype-specific treatment for HFpEF has attracted attention, the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in this context remains uncertain. Aims This study aimed to explore the phenotypic characteristics of HFpEF in Japanese patients and to evaluate the differential effects of SGLT2i treatment Methods In this multicentre study, a total of 3,588 hospitalised patients with HFpEF (median age, 76.3 years; 54.8% male) were categorised into three groups based on the phenotypes of HFpEF. Phenotype 1 was the youngest patient with a low burden of comorbidities. Phenotype 2 was the oldest patient with a high prevalence of atrial fibrillation. Phenotype 3 was mostly obese and diabetic with high burden of other co-morbidities. The primary outcome was a composite endpoint including kidney disease progression—defined as a decrease in estimated glomerular filtration rate (eGFR) to <10 ml/min/1.73 m², a sustained decline in eGFR of at least 40%, or end-stage kidney disease—along with heart failure readmission and all-cause mortality. Results HFpEF consisted of phenotype 1: 787/21.9%, phenotype 2: 2,323/64.7%, and phenotype 3: 478/13.4%. Over a median follow-up of 2 years, the primary outcome event occurred in 74 of 403 participants (18.4%) in the SGLT2i group and 796 of 3,185 participants (25.0%) in the non-SGLT2i group (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54 to 0.86; P = 0.002) (Figure). SGLT2i treatment was associated with a reduced risk of the primary outcome in phenotype 2 (HR: 0.68; 95% CI: 0.49–0.93; P = 0.014). The non-SGLT2i group showed progression of renal dysfunction over time, while the SGLT2i group preserved renal function across all phenotypes at 2 years. Conclusions Three distinct HFpEF phenotypes were identified among Japanese patients. SGLT2i treatment could improve clinical outcomes in a phenotype characterized by older age. The renoprotective effect was consistently observed regardless of phenotype.

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