Broad enrollment, not phenotypic heterogeneity, drives **HFpEF** treatment success; **obesity** emerges as a central factor.

Heart failure with preserved ejection fraction (HFpEF) remains a complex syndrome with no unifying hypothesis and limited broadly effective treatments. Historically, it was proposed that HFpEF represented a multitude of different disorders, leading to extensive efforts to characterize phenotypic heterogeneity. The goal was to identify novel causal pathways for new drugs and discern specific patient subgroups that would selectively benefit from targeted therapies, addressing the significant unmet need in this patient population.

This review critically analyzed a decade of research on heart failure with preserved ejection fraction (HFpEF), focusing on efforts to characterize phenotypic diversity and their impact on treatment response. The authors examined outcomes from subgroup analyses of neutral HFpEF trials, as well as studies employing advanced techniques like proteomics and unsupervised cluster analysis across multiple phenotypic domains. These findings were contrasted with the success of large-scale HFpEF trials that utilized broad eligibility criteria for established treatments.

Efforts over the past decade to characterize phenotypic diversity in HFpEF proved unsuccessful in achieving their goals. Subgroup analyses of neutral HFpEF trials consistently failed to reliably identify responders to treatments. Furthermore, advanced methods such as proteomics and unsupervised cluster analysis across multiple phenotypic domains did not yield reproducible results (even within the same dataset), elucidate novel mechanistic pathways for drug development, or identify patients most likely to benefit from treatment.

In marked contrast, large-scale HFpEF trials enrolling patients with broad eligibility criteria successfully established the benefits of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists without evidence for subgroup effects.

A key observation was the general uniformity of patients in these successful trials regarding excess adiposity, with central obesity being a feature in the vast majority of enrolled participants. Notably, patients with obesity showed particularly large benefits when treated with effective drugs for HFpEF. These findings suggest that if trials had included patients with class III obesity or lower natriuretic peptide levels, the magnitude of observed treatment effects might have been even greater.