SGLT2 inhibitors in heart failure with preserved EF - what changed.

For two decades, heart failure with preserved ejection fraction (HFpEF) was the harder, less-evidence-supported sibling of HFrEF. Neither ACE inhibitors, ARBs, beta blockers, nor MRAs delivered the kind of mortality-and-hospitalization benefit that defined treatment in reduced-EF disease. Then in 2021, empagliflozin reduced the combined endpoint of cardiovascular death and HF hospitalization by 21% in patients with EF above 40%, spanning HFmrEF and HFpEF.^[1] A year later, dapagliflozin replicated the result across mildly-reduced and preserved EF in DELIVER.^[2]

The mechanism remains debated - natriuresis, hemoconcentration, reductions in epicardial fat, direct cardiomyocyte effects on calcium handling - but the outcome data have, for the first time in HFpEF, the kind of effect size and consistency that guidelines respond to.^[3]

For the first time in HFpEF, a class of drug delivers the kind of effect size and consistency guidelines respond to.- Section synthesis

What the trials established

EMPEROR-Preserved enrolled 5,988 patients with LVEF >40%, so the population included both HFmrEF and HFpEF by ACC/AHA definitions. Participants were randomized to empagliflozin 10 mg or placebo on top of standard care. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. The hazard ratio was 0.79 (95% CI 0.69 to 0.90), driven primarily by reduced HF hospitalization. CV death alone was not significantly reduced.^[1,4]

DELIVER enrolled 6,263 patients with LVEF >40% and randomized them to dapagliflozin 10 mg or placebo. The composite primary outcome of worsening heart failure or cardiovascular death occurred in 16.4% vs 19.5% (HR 0.82; 95% CI 0.73 to 0.92). The benefit was mainly a reduction in worsening heart failure events, not a standalone cardiovascular-death signal.^[2]

What guidelines now say

Guideline language should separate definitions from trial entry criteria: ACC/AHA defines HFmrEF as LVEF 41 to 49% and HFpEF as LVEF at least 50%. SGLT2 inhibitors are recommended across these higher-EF heart-failure categories to reduce heart-failure events, with the strongest signal being fewer hospitalizations or worsening-HF episodes.^[4,5] The 2023 ESC focused update is similar.^[5]

The practical question is eligibility and tolerance: volume status, kidney function, and the product label for the chosen agent matter more than diabetes status.

At the bedside

For a typical HFpEF patient - symptomatic, on a diuretic, regardless of diabetes status - both empagliflozin and dapagliflozin are reasonable. The FDA labels carry the HF indication and do not require diabetes for use.^[6,7] Start at 10 mg daily; do not titrate. Hold during acute illness with volume loss. Counsel on euglycemic ketoacidosis risk (rare, but consequential).^[8]

Cost remains a practical barrier in much of the world; check formulary status before committing. Where covered, the bar to start is now the patient's tolerance and renal function, not their A1c.