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Page 8 of 19 Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26

Heart failure with preserved ejection fraction
The use of SGLT2 inhibitors, although now established in reduced ejection fraction, still has not been fully
confirmed in those with preserved ejection fraction. The first SGLT2 inhibitor trial to provide some
evidence of potential benefit in HFpEF was the SOLOIST-WHF and SCORED trials involving sotagliflozin,
a dual SGLT2/SGLT1 inhibitor - though both were terminated early and their primary endpoints were
altered in the trial. The SOLOIST -WHF trial showed that regardless of ejection fraction < 50% or > 50%,
sotagliflozin was associated with reductions in a composite of CV death, hospitalization for worsening heart
[27]
failure, and urgent visits for heart failure (HR 0.67, P < 0.001) . Additionally, pooled analysis from both
trials looking at patients with preserved ejection fraction (LVEF > 50%) found that sotagliflozin was
[27]
associated with benefit in terms of the primary outcome (HR 0.63, P = 0.009) .
More recently, the Emperor Preserved trial compared empagliflozin 10mg to placebo in patients with
preserved ejection fraction with and without type 2 diabetes. The primary outcome of cardiovascular
mortality or hospitalization for heart failure was achieved with a hazard ratio of 0.73 (P < 0.001) though this
was driven by the hospitalization for heart failure . Additionally, Empagliflozin was associated with
[28]
improvements in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
scores, and this occurred regardless of baseline scores . The lack of hard endpoints in terms of mortality
[29]
benefit must be balanced against the benefits seen in reduced hospitalization and QOL, and this has been
reflected in approval from the FDA and SmPC for chronic heart failure (irrespective of ejection
fraction) [30-31] . It is worth noting that the benefits of empagliflozin were seen in those with ejection fraction <
60%, which has led to a debate on what constitutes HFpEF and whether EF < 50% is just a continuum and
given the benefits seen at higher EF with Empagliflozin, perhaps these classifications should be revised or
re-considered when deciding therapy benefit .
[32]
This may be further explored with the Dapagliflozin Evaluation to Improve the LIVEs of Patients With
PReserved Ejection Fraction Heart Failure (DELIVER) trial. This trial assessed the primary outcome of
cardiovascular mortality or worsening heart failure with dapagliflozin 10mg in patients with heart failure
and mildly reduced or preserved ejection fraction (LVEF > 40%) and was stopped early due to the
achievement of its primary endpoint. The trial met its primary endpoint with an HR of 0.82 (CI 0.73-0.92, P
< 0.001), largely driven by worsening heart failure (HR 0.79, CI 0.69-0.91) . It is likely that soon SGLT2
[33]
inhibitors will be considered in some form across the spectrum of reduced and preserved ejection fraction;
however, there may be a review of classification and evidence-based benefit depending on ejection fraction
given the variation in trial findings.

Inpatient initiation of SGLT2s
Although SGLT2 inhibitors have been largely outpatient-initiated medications, the overwhelming evidence
of benefit and early benefit within weeks with regard to heart failure outcomes has started to draw the
conversation to earlier initiation in the acute setting. A post hoc analysis of empagliflozin from the EMPA-
REG trial showed primary outcome benefit by day 59 and hHF benefit by day 17 . Similarly, data from
[34]
DAPA-HF and EMPEROR-REDUCED showed benefits in primary outcome by day 28 and day 12,
respectively, highlighting the potential benefits of early initiation [35,36] . The previously mentioned SOLOIST-
WHF trial first looked at this consideration and showed benefits of sotagliflozin in patients with recent
worsening heart failure, with just under half of patients (48.8%) given the first dose prior to discharge and
[27]
the remainder within a median of two days post discharge .

The EMPULSE study provided some further focus on patients with acute or newly decompensated heart
failure, who, regardless of ejection fraction, started either empagliflozin 10mg or placebo for 90 days. The
primary outcome was clinical benefit defined by a composite of all-cause mortality, number of heart failure