Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights From DAPA-HF

Carly Adamson, Kieran F. Docherty, Hiddo J.L. Heerspink, Rudolf A. De Boer, Kevin Damman, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Mark C. Petrie, Piotr Ponikowski, Marc S. Sabatine, Morten Schou, Scott D. Solomon, Subodh Verma, Olof Bengtsson, Anna Maria Langkilde, Mikaela Sjöstrand, Muthiah Vaduganathan, Pardeep S. JhundJohn J.V. McMurray

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66 Citations (Scopus)

Abstract

Background: In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial. Methods: Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min-1·1.73 m-2 were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models. Results: The mean change in eGFR between day 0 and 14 was-1.1 mL·min-1·1.73 m-2 (95% CI,-1.5 to-0.7) with placebo and-4.2 mL·min-1·1.73 m-2 (95% CI,-4.6 to-3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min-1·1.73 m-2 (95% CI, 2.6-3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07-2.69; P<0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59-0.91; Pinteraction<0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events. Conclusions: The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin.

Original languageEnglish
Pages (from-to)438-449
Number of pages12
JournalCirculation
Volume146
Issue number6
DOIs
Publication statusPublished - 9 Aug 2022
Externally publishedYes

Bibliographical note

Funding Information:
The DAPA-HF trial was funded by AstraZeneca. Dr McMurray and C. Adamson are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.

Funding Information:
K.F. Docherty received funding for the University of Glasgow, UK, from AstraZeneca for DAPA-HF and has received honoraria for lectures from AstraZeneca and Eli Lilly. Dr Heerspink reports grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial paid to his institution from AstraZeneca; research grants paid to his employer from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk for clinical trials; consulting fees paid to his employer from Abbvie, Boehringer Ingelheim, Travere Pharmaceuticals, and Novo Nordisk; fees for steering committee membership paid to his employer from Bayer, Chinook, CSL Pharma, Janssen, and Gilead; honoraria for lectures from AstraZeneca and Mitsubishi Tanabe; and honoraria for advisory board participation from Merck (paid to his employer), Mitsubishi Tanabe, and Mundipharma. Dr de Boer reports grants from Cardior Pharmaceuticals GmbH to other; compensation for other services from Novartis, AstraZeneca, Roche Diagnostics GmbH, Bayer, and Abbott Fund; and grants from AstraZeneca, Ionis Pharmaceuticals, Inc, Roche Diagnostics GmbH, Boehringer Ingelheim, Novo Nordisk, and Abbott Fund to other. Dr Damman has received consultancy fees from Abbott. Dr Inzucchi received funding from AstraZeneca for participating in the steering committee for DAPA-HF; has received consultancy fees from Abbott, VTV Therapeutics, Esperion, Pfizer, and Merck; and reports fees for clinical trial committee participation, advisory roles, and travel costs from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk, as well as honoraria for lectures from Merck and AstraZeneca. Dr Køber reports speaker honoraria from Novo Nordisk, Novartis, AstraZeneca, and Boehringer Ingleheim; support from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. Dr Kosiborod reports payment to his institution for participation in DAPA-HF; has received grant payment to his institution from Boehringer Ingelheim; has received personal fees, fees to his institution, or both for consultancy from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma; has received personal honoraria and honoraria to his institution for lectures from AstraZeneca, Boeringer Ingelheim, and Novo Nordisk; has received personal honoraria and honoraria to his institution from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma for participation on Data Safety Monitoring Boards; and has received study drug for a clinical trial from AstraZeneca and Boehringer Ingelheim. Dr Martinez reports personal fees from AstraZeneca. Dr Petrie reports compensation from Bayer, Boehringer Ingelheim, Takeda California, Inc, and Novo Nordisk for end point review committee services; compensation from Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Novartis, and SQ Innovation for consultant services; grants from Boehringer Ingelheim; and grants from Novartis, SQ, and AstraZeneca to other. Dr Ponikowski reports personal fees for consultancy and speaker bureau from AstraZeneca, Boehringer Ingelheim, Vifor Pharma, Servier, Bayer, Bristol Myers Squibb, Respocardia, Berlin-Chemie, Cibiem, Novartis, and RenalGuard; other support for participation in clinical trials from Boehringer Ingelheim, Amgen, Vifor Pharma, Bayer, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; and research grants to his institution from Vifor Pharma. Dr Sabatine reports grants from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis. Dr Sabatine received an institutional research grant from AstraZeneca for DAPA-HF and received institutional research grants from Abbott, Amgen, Anthos Therapeutics, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. Dr Sabatine is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Regeneron, Roche, and Zora Biosciences. Dr Schou reports no conflicts. Dr Solomon received payment to his institution for participation in DAPA-HF; received grants to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, 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; received fees for consultancy from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta; and received honoraria for lectures from Novartis and AstraZeneca. Dr Verma has received research and/or speaking honoraria from Amgen, Amarin, AstraZeneca, Bayer, CMS, Janssen, HLS, Sanofi, Novo Nordisk, Novartis, Merck, and PhaseBio. He is also the president of the Canadian Medical and Surgical Knowledge Translation Research Group and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Drs Bengtsson, Langkilde, and Sjöstrand are employees and stockholders of AstraZeneca. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health National Center for Advancing Translational Sciences Award UL 1TR002541); serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa; and has participated on clinical end point committees for studies sponsored by Novartis (including the PARAGON-HF trial) and the National Institutes of Health. Dr Jhund reports payment to the University of Glasgow by AstraZeneca for his time working on the DAPA-HF and DELIVER trials, from Novartis for work on the PARADIGM-HF and PARAGON-HF trials, and Novo Nordisk; reports speaker and advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and reports research funding from Boehringer Ingelheim and Analog Devices. Dr McMurray reports payment to Glasgow University by AstraZeneca for time spent as principal investigator of DAPA-HF and coprincipal investigator of DELIVER and DETERMINE in HF and meetings and other activities related to these trials; AstraZeneca has also paid travel and accommodation for these meetings. These payments were made through a consultancy with Glasgow University, and he did not receive personal payments in relation to this trial or drug. He has received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and reports steering committee and travel fees from Cytokinetics and Amgen, advisor and travel fees from KBP Biosciences, steering committee fees from Bayer, DalCor, and Bristol Myers Squibb, investigator and travel fees from Theracos, consultancy and travel fees from IONIS, investigator, steering committee, and travel fees from Novartis and GlaxoSmithKline, consultancy fees from Boehringer Ingelheim, and advisory board fees from Cardurion and Alnylam, all paid to the University of Glasgow. C. Adamson reports no conflicts.

Publisher Copyright:
© 2022 the Author(s). Published by Wolters Kluwer Health, Inc.

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