Dapagliflozin in HFpEF &

mild HFrEF

Journal Club
Raquel Weinberg

DELIVER trial, published in NEJM on

August 27, 2022

DOI: 10.1056/NEJMoa2206286
2022
Table of contents

01 Background
SGLT2 inhibitors
HFrEF vs HFpEF
02 Methods
Study design
Subpopulations
Outcomes of interest

03 Results 04 Conclusions
 01

Background
SGLT2 inhibitors
HFpEF vs. HFrEF
SGLT2
inhibitors
- MOA: blocks the Na+/glucose transporter in
the PCT, which → ↓ glucose absorption.

- Since approval for use in DM management,

started using in more scenarios, w/wo dx of
DM:
- HFrEF → DAPA-HF, 2019.
- CKD → DAPA-CKD, 2020 stopped early d/t
overwhelming benefit of the drug, same w/ EMPA-
KIDNEY & CREDENCE.

Dapagliflozin Farxiga
- Adverse effects:
- Dehydration → hypotension. Empagliflozin Jardiance
- Glucosuria → genitourinal fungal infex.
- Ketoacidosis → can be “euglycemic.” Canagliflozin Invokana
- Limb amputation → controversial, particularly w/ canagliflozin.
(systolic) (diastolic)

Image source
 02

Methods
Study design
Outcomes of interest
Subpopulations
Study design 10,418 pts
screened
- “Phase 3, international, multicenter, parallel-
group, event-driven.”
- Screening occurred @ 353 centers in ➔ ≥ 40 y/o
➔ ± T2DM
20 countries. ➔ LVEF >40%
- Double-blind RCT. ➔ ↑ ANP/BNP
- Collab w/ sponsor AstraZeneca.
6,363 pts
- Attrition:
- Dapagliflozin was d/c in 444 pts for
reasons other than death.
- Placebo was d/c in 442 pts for reasons
other than death.
dapagliflozin 10 mg matching placebo
- Mean duration of f/u: 2.3 years 3,131 pts 3,132 pts
Primary outcomes of interest
“Composite of worsening heart
failure”

Unplanned
Urgent visit for HF Cardiovascular death
hospitalization for HF
Secondary outcomes of interest

Total # of worsening Total # of Δ from baseline in

HF events cardiovascular deaths total sx score on the
KCCQ*

*KCCQ: Kansas City Cardiomyopathy Questionnaire

 Subpopulations investigated
H/o HFrEF
T2DM HTN
≤40%*
Dapa Placebo Dapa Placebo Dapa Placebo

1,401 (44.7%) 1,405 (44.9%) 2,755 (88%) 2,798 (89.3%) 572 (18.3%) 579 (18.5%)

Mean EF 54.0% Mean EF 54.3%

(±8.6) (±8.9)
dapagliflozin 10 mg placebo
3,131 pts 3,132 pts

*All of these pts had EF >40% by time of enrollment.

 03

Results
Results interpretation
Effect of dapagliflozin on primary outcome was similar across various groups;
- In pts w/wo T2DM.
- In pts who were enrolled during or w/in 30 days after hospitalization for HF & pts
who were not enrolled during this time range.
- In pts w/wo previous HFrEF (≤40%) that had improved by the time of enrollment.
- Among pts w/wo COVID-19 diagnosis (this was censored to the investigators).

Overall results were similar when death from noncardiac causes was taken into account
as a competing risk.
 04

Conclusions
Main discussion points
● Compared to placebo, the dapagliflozin group had:
○ Fewer total worsening HF events.
○ Lower rates of cardiovascular death.
○ Lower sx burden.

● Also had broad inclusion criteria and ∴ can generalize to greater population :
○ Pts who were hospitalized or recently-hospitalized.
○ Pts w/ previous HFrEF that had improved to >40%.
○ Pts for whom evidence-based tx is limited.
Expansion on prior studies
- DAPA-HF: 2019, Dapagliflozin in Patients with Heart Failure and Reduced
Ejection Fraction.
- DELIVER shows benefit for pts w/ EF >40%.

- EMPEROR-Preserved: 2021, Empagliflozin Outcome Trial in Patients with

Chronic Heart Failure with Preserved Ejection Fraction.
- Similarly, pts w/ EF >40%, but w/ empagliflozin.
- Noted w/ EMPEROR that there was attenuation of benefit in the highest
range of EF, which was not seen in the DELIVER trial.
Limitations
- The study design was not created to assess whether dapagliflozin directly
prevents mortality alone, ∴ additional studies will follow.

- Mentioned by the authors; only 5% of the patients enrolled were Black.

- Noted, however, that this was representative of particular regions studied.

- D/t COVID-19, the KCCQ sx burden assessment occurred before March 11,
2020. Thus, some pts did not have this data available.
 ‫תכלס‬
Further support for the use of SGLT2i as
essential tx in pts w/ HF, regardless of:
- Presence of absence of T2DM
- Ejection fraction
References
DAPA-HF
DAPA-CKD
EMPEROR-Preserved
EMPA-KIDNEY
CREDENCE

UptoDate: Dapagliflozin
UptoDate: HFpEF

Harding, E., Marques, S. C., Mes, M., Murphy, M. (2020). Spotlight on HFpEF: heart failure with
preserved ejection fraction. Heart Failure Policy Network. Available here.
 Questions?
Raquel Weinberg
raquelw@post.bgu.ac.il
WhatsApp +1 (301) 525-5229
SMS +972 (058) 696-7625

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Appendix A
ESC 2022 Guidelines for
HFrEF
Appendix B
Levels of evidence/
recommendations