Reviews/Heart Failure Management/SGLT2 inhibitors reduce heart failure hospitalisation in heart failure with preserved ejection fraction
HFPEF · HFM-HFPEF-01 · v2
Two large, carefully-run trials tested whether these drugs help people with heart failure whose heart still pumps relatively normally. One trial used empagliflozin [9] and the other used dapagliflozin [10], each enrolling roughly six thousand patients, and both found fewer combined events of hospitalisation for heart failure or death from heart causes. The benefit held whether or not patients had diabetes, and two further analyses of the same programmes pointed the same way [5] [11]. Most of the benefit came from preventing hospitalisations rather than from preventing cardiac deaths, which on its own was not clearly reduced. The trials also enrolled some patients with mildly-reduced rather than strictly preserved pumping function. The panel treated these as limits on how far the result stretches, not as reasons to doubt it, because two independent drugs from two independent sponsors agreed closely.
Two dedicated double-blind randomised trials in heart failure with ejection fraction over 40% each significantly reduced the composite of heart-failure hospitalisation or cardiovascular death: empagliflozin in EMPEROR-Preserved [9] (hazard ratio 0.79, 95% CI 0.69 to 0.90) and dapagliflozin in DELIVER [10] (hazard ratio 0.82, 95% CI 0.73 to 0.92). Both effects were consistent regardless of diabetes status [9] [10]. A prespecified DELIVER analysis of an expanded worsening-HF-or-CV-death composite reproduced the benefit [5] (hazard ratio 0.76, 95% CI 0.69 to 0.84), and the pooled EMPEROR dataset showed the HF-hospitalisation-or-CV-death benefit maintained across subgroups [11] (0.76 and 0.77). In both pivotal trials the composite was driven mainly by lower hospitalisation, with cardiovascular death alone not significantly reduced in DELIVER [10] (hazard ratio 0.88, 95% CI 0.74 to 1.05). The contested point: The division is over wording and scope rather than direction: the composite is carried by the heart-failure-hospitalisation component, while cardiovascular death alone was not significantly reduced in DELIVER [10] and was described as the minor contributor in EMPEROR-Preserved [9]. Both trials also enrolled ejection fraction over 40%, folding in mildly-reduced EF alongside strictly preserved (>=50%) EF, so the enrolled stratum is broader than the claim's 'preserved' wording.
All 12 papers behind this claim with their DOIs and what each does to it, the panel’s arbitration, the evidence gap map and the open research questions. Free, and sent to your inbox.
We’ll also send you other claims from Heart Failure Management, one at a time, and tell you when a release or a pivotal trial changes a grade. Unsubscribe by replying.
One reviewer's only job is to attack the finding. The challenges below were weighed before the grade was set.
The composite benefit is carried by the heart-failure hospitalisation component; cardiovascular death alone was not significantly reduced in DELIVER (HR 0.88, 95% CI 0.74-1.05) and EMPEROR-Preserved's effect was 'mainly related to a lower risk of hospitalization for heart failure'. The claim's composite wording is supported, but a reading that SGLT2i reduces CV death in HFpEF is not.
Population indirectness: both pivotal trials enrolled ejection fraction >40%, folding in HFmrEF rather than strictly preserved (LVEF >=50%). DELIVER's consistency for EF>=60% vs <60% mitigates this but the claim's 'preserved' wording is broader than the enrolled stratum.
Where it remains uncertain. The composite is driven by fewer hospitalisations; cardiovascular death alone was not significantly reduced in DELIVER [10] (HR 0.88, 0.74 to 1.05), and both trials enrolled EF over 40% rather than strictly >=50%.
Aleatory
Each pivotal estimate carries sampling uncertainty, e.g. DELIVER's composite spans 0.73 to 0.92 [10] and EMPEROR-Preserved's 0.69 to 0.90 [9].
The load-bearing papers from a corpus of 12, each classified by what it does to the claim. Every DOI is taken from the corpus the claim was graded on.
Prespecified DELIVER analysis reproducing the composite benefit in HFmrEF/HFpEF.
“when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84])”
Panel auditInternal validity: medium · scope of inference: Dapagliflozin effect on worsening HF events including ambulatory diuretic intensification in HF with mildly reduced or preserved EF.Key limitations: mixed HFmrEF and HFpEF population · composite broader than the claim · single agent (dapagliflozin)
Pivotal RCT (EF>40%) showing empagliflozin reduced the composite of CV death or HF hospitalization.
“Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes.”
Panel auditInternal validity: high · scope of inference: Empagliflozin in class II-IV heart failure with ejection fraction over 40%, with or without diabetes.Key limitations: EF >40% includes some mildly reduced EF · benefit mainly from hospitalisation component · single agent
Second independent pivotal RCT (different drug and sponsor) confirming reduction of worsening HF or CV death.
“Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction.”
Panel auditInternal validity: high · scope of inference: Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction (EF over 40%).Key limitations: EF >40% includes mildly reduced EF · worsening-HF definition includes urgent visits · CV death component alone HR 0.88 crossed 1
3 of 12 papers shown. The full review lists all of them, with the panel’s arbitration →
Claims are graded at each quarterly release, and re-graded between releases only when a pivotal trial lands. Every change is a new version of the claim.
Replicated, directly-on-claim, large double-blind RCT evidence with concordant effect size and direction supports the composite endpoint at an established level, held just below the ceiling by the CV-death-component and EF>40%-population qualifiers.
Release 2026-q4 re-graded every claim from its corpus under protocol v0.19. An earlier release's grade is shown for the record; it came from an earlier protocol and is not a movement.
Assumptions that carry weight but are not themselves established.
The panel records the gap that would most move the claim, and the study that would close it.
Cardiovascular death in preserved-EF heart failure. The composite is driven by hospitalisation while CV death alone was non-significant [10], leaving the mortality claim open. The panel rates this the highest-importance open gap for the claim, and names the study design that would close it: An adequately powered trial or pooled patient-level mortality analysis restricted to EF over 40% heart failure with cardiovascular death as a primary endpoint.
Open question: Do SGLT2 inhibitors reduce cardiovascular death, not just hospitalisation, in heart failure with preserved ejection fraction? Why it is still open: The CV-death component alone was not significantly reduced in DELIVER [10] (HR 0.88, 0.74 to 1.05) and was the minor contributor in EMPEROR-Preserved [9].
Priors is a sceptical first reader, not peer review, and not medical advice.
Release 2026-q4 · graded 21 Oct 2026 · protocol v0.19