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Randomized Controlled Trial
. 2024 Feb 1;9(2):144-152.
doi: 10.1001/jamacardio.2023.4664.

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial

Finnian R Mc Causland  1   2 , Brian L Claggett  2   3 , Muthiah Vaduganathan  2   3 , Akshay Desai  2   3 , Pardeep Jhund  4 , Orly Vardeny  5 , James C Fang  6 , Rudolf A de Boer  7 , Kieran F Docherty  4 , Adrian F Hernandez  8 , Silvio E Inzucchi  9 , Mikhail N Kosiborod  10 , Carolyn S P Lam  11 , Felipe Martinez  12 , Jose F Kerr Saraiva  13 , Martina M McGrath  1   2 , Sanjiv J Shah  14 , Subodh Verma  15 , Anna Maria Langkilde  16 , Magnus Petersson  16 , John J V McMurray  4 , Scott D Solomon  2   3
Affiliations
Randomized Controlled Trial

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial

Finnian R Mc Causland et al. JAMA Cardiol. .

Erratum in

  • Change to Open Access Status.
    [No authors listed] [No authors listed] JAMA Cardiol. 2024 Jul 1;9(7):674. doi: 10.1001/jamacardio.2024.1234. JAMA Cardiol. 2024. PMID: 38776071 Free PMC article. No abstract available.

Abstract

Importance: An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure.

Objective: To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.

Design, setting, and participants: This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023.

Intervention: Dapagliflozin, 10 mg per day, or placebo.

Main outcomes and measures: In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes.

Results: Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82).

Conclusions and relevance: Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline.

Trial registration: ClinicalTrials.gov Identifier: NCT03619213.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McCausland reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, Lexicon, Novartis, Fifth Eye, and Satellite Healthcare and personal fees from Rubin Anders Scientific, GSK, and Zydus Therapeutics outside the submitted work. Dr Claggett reported receiving consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, Rocket, and CVRX outside the submitted work. Dr Vaduganathan reported receiving personal fees from American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health and grants from AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics outside the submitted work. Dr Desai reported receiving grants and consulting fees from AstraZeneca, Abbott, Alnylam, Bayer, and Novartis; consulting fees from Axon, Avidity BioPharma, GlaxoSmithKline, Merck, Medpace, Parexel, Regeneron, Roche, River2Renal, Veristat, Verily, and Zydus outside the submitted work. Dr Jhund reported being employed by and receiving research fees from AstraZeneca; speaker and advisory board fees from Novartis; grants from Boehringer Ingelheim, Roche Diagnostics, Analog Devices Inc; research fees from Bayer, Novo Nordisk; personal fees from ProAdwise, Sun Pharmaceuticals, and Intas Pharma outside the submitted work; and being director GCTP Ltd. Dr Vardeny reported receiving research support from AstraZeneca, Bayer, and Cardurion outside the submitted work. Dr Fang reported receiving steering committee fees from AstraZeneca, serving as deputy editor for the American Heart Association, grants from the National Institutes of Health, and data safety monitoring committee fees from Windtree and Amgen during the conduct of the study. Dr de Boer reported receiving grants from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche and speaker fees from Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, Novartis, and Roche outside the submitted work. Dr Docherty reported receiving nonfinancial support, grants, and personal fees from AstraZeneca; grants from Boehringer Ingelheim and Roche; personal fees from Pharmacosmos; and advisory board fees from Us2.ai and Bayer outside the submitted work. Dr Hernandez reported receiving grants from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Lilly outside the submitted work. Dr Inzucchi reported receiving personal fees from Astra Zeneca, Boehringer Ingelheim, Merck, Pfizer, and Novo Nordisk outside the submitted work. Dr Kosiborod reported receiving personal fees from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; and grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; and stock options from Artera Health and Saghmos Therapeutics outside the submitted work. Dr Lam reported receiving research support from Novo Nordisk and Roche Diagnostics; consultant or committee fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; being cofounder/nonexecutive director of Us2.ai; having a patent pending for a method for diagnosis and prognosis of chronic heart failure; and having patents for an automated clinical workflow that recognizes and analyzes 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction, and prognosis of heart disease. Dr Martinez reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Saraiva reported receiving advisory board fees from AstraZeneca, Novartis, Novo Nordisk, Lilly, Merck Sharp Dhome, and Boehringer Ingelheim; grants from AstraZeneca, Novartis, Novo Nordisk, Lilly, Merck Sharp Dhome, and Boehringer Ingelheim outside the submitted work. Dr Shah reported receiving consulting/committee fees and research grants from AstraZeneca during the conduct of the study. Dr Verma reported receiving personal fees from AstraZeneca, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi and grants from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, and PhaseBio outside the submitted work. Dr Langkilde reported being a full-time employee and shareholder of AstraZeneca during the conduct of the study. Dr Petersson reported being a full-time employee and shareholder of AstraZeneca outside the submitted work. Dr McMurray reported receiving institutional research support from AstraZeneca, Bayer, Cardurion, and Novartis; steering committee and travel fees paid to institution from Amgen, Cytokinetics, GSK, and Novartis; advisory fees paid to institution from KBP Biosciences; data safety monitoring board fees from George Clinical PTY Ltd; personal fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; lecture fees from Alynylam Pharmaceuticals, Bayer, BMS, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; consultancy fees from Global Clinical Trial Partners Ltd; and being a director outside the submitted work. Dr Solomon reported receiving grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai and consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Risk of Primary Cardiovascular Outcome
Kaplan-Meier curve showing the risk of the primary cardiovascular outcome according to the presence or absence of an initial decline in estimated glomerular filtration rate greater than 10% vs not and assignment to dapagliflozin vs placebo.
Figure 2.
Figure 2.. Incidence Rates of the Primary Outcome
Adjusted incidence rates of the primary outcome occurring after 1 month (landmark analysis) according to change in estimated glomerular filtration rate (eGFR) from baseline to month 1 within randomized treatment groups. A, Absolute change in eGFR. B, Percentage change in eGFR. The shaded regions represent 95% CIs.
See this image and copyright information in PMC

Comment in

  • SGLT2-Hemmer nützt auch bei GFR-Abfall.
    Schwinger RHG. Schwinger RHG. MMW Fortschr Med. 2024 Sep;166(15):29. doi: 10.1007/s15006-024-4287-3. MMW Fortschr Med. 2024. PMID: 39266835 Review. German. No abstract available.

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