Blood Pressure and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: DELIVER

Senthil Selvaraj, Muthiah Vaduganathan, Brian L. Claggett, Zi Michael Miao, James C. Fang, Orly Vardeny, Akshay S. Desai, Sanjiv J. Shah, Carolyn S.P. Lam, Felipe A. Martinez, Silvio E. Inzucchi, Rudolf A. de Boer, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Optimizing systolic blood pressure (SBP) in heart failure (HF) with preserved ejection fraction carries a Class I recommendation but with limited evidence. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have antihypertensive effects across cardiovascular disease. Objectives: The authors examined the interplay between SBP and treatment effects of dapagliflozin on SBP and cardiovascular outcomes. Methods: The authors analyzed 6,263 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) participants and related baseline and mean achieved SBP categories (<120, 120-129, 130-139, ≥140 mm Hg) to the primary outcome (cardiovascular death or worsening HF), secondary outcomes, and safety events. They analyzed whether the blood pressure–lowering effects of dapagliflozin accounted for its treatment effects by adjusting for the change in SBP from baseline to 1 month. Results: The average age was 72 ± 10 years and 44% were women. SBP <120 mm Hg was associated with higher HF and mortality events, although amputation and stroke risk increased with higher SBP. Dapagliflozin reduced SBP by 1.8 (95% CI: 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and Kansas City Cardiomyopathy Questionnaire total symptom score was consistent across SBP (interaction P = 0.15 and P = 0.98, respectively). Adverse events between arms were similar across SBP categories. The treatment effect was not accounted for by reducing blood pressure. Conclusions: In DELIVER, risk by SBP was augmented in the lowest and highest categories and varied by endpoint examined. Dapagliflozin modestly decreased SBP compared with placebo. Dapagliflozin was similarly efficacious and safe across the range of baseline SBP. The beneficial effects of dapagliflozin were not accounted for the changes in SBP.

Original languageEnglish
Pages (from-to)76-89
Number of pages14
JournalJACC: Heart Failure
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 2023

Bibliographical note

FUNDING SUPPORT AND AUTHOR DISCLOSURES:
The DELIVER study was funded by AstraZeneca. Dr Selvaraj was
supported by the National Heart, Lung, and Blood Institute
(K23HL161348), American Heart Association (#935275), Doris Duke
Charitable Foundation (#2020061), and the Institute for Translational
Medicine and Therapeutics (Translational Bio-Imaging Center award).
Dr Vaduganathan has received research grant support from or served
on the advisory board for American Regent, Amgen, AstraZeneca,
Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics,
Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche
Diagnostics, Sanofi, and Tricog Health; had speaker engagements
with AstraZeneca, Novartis, and Roche Diagnostics; and served on the
clinical trial committee for studies sponsored by Galmed, Novartis,
Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received
consulting fees from Amgen, Cardurion, Corvia, and Novartis. Dr
Fang has received research grant support from the National Institutes
of Health; has served as a consultant for Novartis, Amgen,
AstraZeneca, Boehringer Ingelheim/Lilly, Abbott, Capricor, Windtree,
and LabCorp; and has provided support to the American Heart Association, National Institutes of Health, Heart Failure Society of
America, and Heart Rhythm Society. Dr Vardeny has received institutional research support for the DELIVER study from AstraZeneca
and has received institutional research support from Bayer. Dr Desai
has received institutional grant support from Abbott, Alnylam,
AstraZeneca, Bayer, and Novartis; and consulting fees from Abbott,
Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer,
Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck,
Novartis, Parxel, Regeneron, Roche, and Verily. Dr Shah has received
research grants from the National Institutes of Health (U54 HL160273,
R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion,
AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon
Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol
Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics,
Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia,
Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi,
Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Lam
was supported by a Clinician Scientist Award from the National
Medical Research Council of Singapore; has received research support
from Bayer and Roche Diagnostics; has served as a consultant or on
the advisory board/steering committee/executive committee for
Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB,
Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim,
Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly,
Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo
Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics,
Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Martinez has
received consultation fees and research grants from AstraZeneca,
Baliarda, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gador,
Milestone, Novartis, Pfizer, and St Luke’s University. Dr Inzucchi has
served on clinical trial committees or as a consultant to AstraZeneca,
Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv
Therapeutics, Abbott, and Esperion; and has given lectures sponsored
by AstraZeneca and Boehringer Ingelheim. Dr de Boer has received
research grants and/or fees from AstraZeneca, Abbott, Boehringer
Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals
Inc, Novo Nordisk, and Roche; and has had speaker engagements with
Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and
Roche. Drs Petersson and Langkilde are employees and shareholders
of AstraZeneca. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer
Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline,
Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director,
and Global Clinical Trial Partners. Dr Solomon has received research
grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon,
Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline,
Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/
National Heart, Lung, and Blood Institute, Neurotronik, Novartis,
NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and
has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen,
Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior,
Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline,
Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, SanofiPasteur, Dinaqor, Tremeau, CellProThera, Moderna, American
Regent, Sarepta, Lexicon, Anacardio, and Akros.


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