Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58

Thomas A. Zelniker; David A. Morrow; Ofri Mosenzon; Erica L. Goodrich; Petr Jarolim; Sabina A. Murphy; Deepak L. Bhatt; Lawrence A. Leiter; Darren K. McGuire; John Wilding; Christoph Bode; Basil S. Lewis; Ingrid Gause-Nilsson; Anna Maria Langkilde; Martin Fredriksson; Itamar Raz; Marc S. Sabatine; Stephen D. Wiviott

doi:10.1002/ejhf.2073

Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58

Thomas A. Zelniker, David A. Morrow, Ofri Mosenzon, Erica L. Goodrich, Petr Jarolim, Sabina A. Murphy, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John Wilding, Christoph Bode, Basil S. Lewis, Ingrid Gause-Nilsson, Anna Maria Langkilde, Martin Fredriksson, Itamar Raz, Marc S. Sabatine, Stephen D. Wiviott

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. Methods and results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35–165] and 10.2 pg/mL (IQR 6.9–15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan–Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.

Original language	English (US)
Pages (from-to)	1026-1036
Number of pages	11
Journal	European Journal of Heart Failure
Volume	23
Issue number	6
DOIs	https://doi.org/10.1002/ejhf.2073
State	Published - Jun 2021

Keywords

Biomarker
Dapagliflozin
High-sensitivity troponin T
NT-proBNP
Sodium–glucose co-transporter 2 inhibitors
Type 2 diabetes mellitus

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

Access to Document

10.1002/ejhf.2073

Cite this

Zelniker, T. A., Morrow, D. A., Mosenzon, O., Goodrich, E. L., Jarolim, P., Murphy, S. A., Bhatt, D. L., Leiter, L. A., McGuire, D. K., Wilding, J., Bode, C., Lewis, B. S., Gause-Nilsson, I., Langkilde, A. M., Fredriksson, M., Raz, I., Sabatine, M. S., & Wiviott, S. D. (2021). Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58. European Journal of Heart Failure, 23(6), 1026-1036. https://doi.org/10.1002/ejhf.2073

Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58. / Zelniker, Thomas A.; Morrow, David A.; Mosenzon, Ofri et al.
In: European Journal of Heart Failure, Vol. 23, No. 6, 06.2021, p. 1026-1036.

Research output: Contribution to journal › Article › peer-review

Zelniker, TA, Morrow, DA, Mosenzon, O, Goodrich, EL, Jarolim, P, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, J, Bode, C, Lewis, BS, Gause-Nilsson, I, Langkilde, AM, Fredriksson, M, Raz, I, Sabatine, MS & Wiviott, SD 2021, 'Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58', European Journal of Heart Failure, vol. 23, no. 6, pp. 1026-1036. https://doi.org/10.1002/ejhf.2073

@article{cb180a93a0464cb6a62c60067411e4b7,

title = "Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58",

abstract = "Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. Methods and results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35–165] and 10.2 pg/mL (IQR 6.9–15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan–Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.",

keywords = "Biomarker, Dapagliflozin, High-sensitivity troponin T, NT-proBNP, Sodium–glucose co-transporter 2 inhibitors, Type 2 diabetes mellitus",

author = "Zelniker, {Thomas A.} and Morrow, {David A.} and Ofri Mosenzon and Goodrich, {Erica L.} and Petr Jarolim and Murphy, {Sabina A.} and Bhatt, {Deepak L.} and Leiter, {Lawrence A.} and McGuire, {Darren K.} and John Wilding and Christoph Bode and Lewis, {Basil S.} and Ingrid Gause-Nilsson and Langkilde, {Anna Maria} and Martin Fredriksson and Itamar Raz and Sabatine, {Marc S.} and Wiviott, {Stephen D.}",

note = "Funding Information: The DECLARE‐TIMI 58 trial was initially supported by AstraZeneca and Bristol‐Myers Squibb, and by the end of the trial by AstraZeneca alone. T.A.Z. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft ZE 1109/1‐1 to T.A.Z.). D.A.M., M.S.S. and S.D.W. were supported in part by a research grant from the American Heart Association (20SFRN35120087 to M.S.S.). The funding sources had no role in data collection, analysis, writing of the manuscript or the decision to submit for publication. All statistical analyses were performed at the TIMI Study Group. S.D.W. is the guarantor of this work and all authors take responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: TAZ reports research grants from the Austrian Science Fund and the German Research Foundation, served on advisory boards for Boehringer Ingelheim and received personal honoraria from AstraZeneca and Boehringer Ingelheim. D.A.M. reports grants to the TIMI Study Group from Abbott Laboratories, Amgen, AstraZeneca, BRAHMS, Eisai, Glaxosmithkline, Medicines Co, Merck, Novartis, Pfizer, Roche Diagnostics, Quark, Takeda, and consultant fees from Abbott Laboratories, Aralez, AstraZeneca, Bayer Pharma, InCardia, Pfizer, and Roche Diagnostics. O.M. reports grants and personal fees from AstraZeneca, Bristol‐Myers Squibb, and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson, and Novartis. P.J. reports research support through his institution from Abbott Laboratories, AstraZeneca, LP, Daiichi‐Sankyo, Inc., GlaxoSmithKline, Merck & Co., Inc., Roche Diagnostics Corporation, Takeda Global Research and Development Center, and Waters Technologies Corporation; and consulting fees from Roche Diagnostics Corporation. E.L.G. and S.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. D.L.B. discloses the following relationships—Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, Takeda. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; personal fees from Merck and Servier; and grants from GlaxoSmithKline. D.K.G. has provided clinical trial leadership for AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Lilly US, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, and Esperion, and consultancy for AstraZeneca, Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Afimmune, Metavant and Merck Sharp & Dohme. J.P.H.W. reports grants, consultancy fees (paid to his institution), and personal fees for lectures and trial steering committee participation from AstraZeneca; grants, consultancy fees (paid to his institution), and personal fees for lectures from Novo Nordisk; consultancy fees (paid to his institution) and personal fees for lectures from Boehringer Ingelheim, Janssen, Napp, Mundipharma, Lilly, Takeda, and Sanofi; and consultancy fees (paid to his institution) from Wilmington Healthcare. C.B. reports speaker's honoraria from Bayer, Bristol‐Myers Squibb/Pfizer, Daiichi‐Sankyo, Boehringer Ingelheim. B.S.L. reports grant support from AstraZeneca, Kowa, Resverlogix; grants and personal fees from Pfizer, Merck and Bayer Healthcare. I.G.N., M.F., and A.M.L. are employees of AstraZeneca. I.R. reports personal fees from AstraZeneca, Bristol‐Myers Squibb, Boehringer Ingelheim, Concenter BioPharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. M.S.S. reports grants from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, AstraZeneca, and Anthos Therapeutics, personal fees from Althera, Bristol‐Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis, grants from Bayer, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, Takeda, grants and personal fees from Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eisai, Eli Lilly, Janssen, Merck and Sanofi‐Aventis, consulting fees from ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, Xoma; his spouse, Dr. Caroline Fox is an employee of Merck; and is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. Conflict of interest: Publisher Copyright: {\textcopyright} 2020 European Society of Cardiology",

year = "2021",

month = jun,

doi = "10.1002/ejhf.2073",

language = "English (US)",

volume = "23",

pages = "1026--1036",

journal = "European Journal of Heart Failure",

issn = "1388-9842",

publisher = "Oxford University Press",

number = "6",

}

TY - JOUR

T1 - Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58

AU - Zelniker, Thomas A.

AU - Morrow, David A.

AU - Mosenzon, Ofri

AU - Goodrich, Erica L.

AU - Jarolim, Petr

AU - Murphy, Sabina A.

AU - Bhatt, Deepak L.

AU - Leiter, Lawrence A.

AU - McGuire, Darren K.

AU - Wilding, John

AU - Bode, Christoph

AU - Lewis, Basil S.

AU - Gause-Nilsson, Ingrid

AU - Langkilde, Anna Maria

AU - Fredriksson, Martin

AU - Raz, Itamar

AU - Sabatine, Marc S.

AU - Wiviott, Stephen D.

N1 - Funding Information: The DECLARE‐TIMI 58 trial was initially supported by AstraZeneca and Bristol‐Myers Squibb, and by the end of the trial by AstraZeneca alone. T.A.Z. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft ZE 1109/1‐1 to T.A.Z.). D.A.M., M.S.S. and S.D.W. were supported in part by a research grant from the American Heart Association (20SFRN35120087 to M.S.S.). The funding sources had no role in data collection, analysis, writing of the manuscript or the decision to submit for publication. All statistical analyses were performed at the TIMI Study Group. S.D.W. is the guarantor of this work and all authors take responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: TAZ reports research grants from the Austrian Science Fund and the German Research Foundation, served on advisory boards for Boehringer Ingelheim and received personal honoraria from AstraZeneca and Boehringer Ingelheim. D.A.M. reports grants to the TIMI Study Group from Abbott Laboratories, Amgen, AstraZeneca, BRAHMS, Eisai, Glaxosmithkline, Medicines Co, Merck, Novartis, Pfizer, Roche Diagnostics, Quark, Takeda, and consultant fees from Abbott Laboratories, Aralez, AstraZeneca, Bayer Pharma, InCardia, Pfizer, and Roche Diagnostics. O.M. reports grants and personal fees from AstraZeneca, Bristol‐Myers Squibb, and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson, and Novartis. P.J. reports research support through his institution from Abbott Laboratories, AstraZeneca, LP, Daiichi‐Sankyo, Inc., GlaxoSmithKline, Merck & Co., Inc., Roche Diagnostics Corporation, Takeda Global Research and Development Center, and Waters Technologies Corporation; and consulting fees from Roche Diagnostics Corporation. E.L.G. and S.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. D.L.B. discloses the following relationships—Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, Takeda. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; personal fees from Merck and Servier; and grants from GlaxoSmithKline. D.K.G. has provided clinical trial leadership for AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Lilly US, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, and Esperion, and consultancy for AstraZeneca, Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Afimmune, Metavant and Merck Sharp & Dohme. J.P.H.W. reports grants, consultancy fees (paid to his institution), and personal fees for lectures and trial steering committee participation from AstraZeneca; grants, consultancy fees (paid to his institution), and personal fees for lectures from Novo Nordisk; consultancy fees (paid to his institution) and personal fees for lectures from Boehringer Ingelheim, Janssen, Napp, Mundipharma, Lilly, Takeda, and Sanofi; and consultancy fees (paid to his institution) from Wilmington Healthcare. C.B. reports speaker's honoraria from Bayer, Bristol‐Myers Squibb/Pfizer, Daiichi‐Sankyo, Boehringer Ingelheim. B.S.L. reports grant support from AstraZeneca, Kowa, Resverlogix; grants and personal fees from Pfizer, Merck and Bayer Healthcare. I.G.N., M.F., and A.M.L. are employees of AstraZeneca. I.R. reports personal fees from AstraZeneca, Bristol‐Myers Squibb, Boehringer Ingelheim, Concenter BioPharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. M.S.S. reports grants from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, AstraZeneca, and Anthos Therapeutics, personal fees from Althera, Bristol‐Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis, grants from Bayer, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, Takeda, grants and personal fees from Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eisai, Eli Lilly, Janssen, Merck and Sanofi‐Aventis, consulting fees from ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, Xoma; his spouse, Dr. Caroline Fox is an employee of Merck; and is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. Conflict of interest: Publisher Copyright: © 2020 European Society of Cardiology

PY - 2021/6

Y1 - 2021/6

N2 - Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. Methods and results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35–165] and 10.2 pg/mL (IQR 6.9–15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan–Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.

AB - Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. Methods and results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35–165] and 10.2 pg/mL (IQR 6.9–15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan–Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.

KW - Biomarker

KW - Dapagliflozin

KW - High-sensitivity troponin T

KW - NT-proBNP

KW - Sodium–glucose co-transporter 2 inhibitors

KW - Type 2 diabetes mellitus

UR - http://www.scopus.com/inward/record.url?scp=85098132746&partnerID=8YFLogxK

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U2 - 10.1002/ejhf.2073

DO - 10.1002/ejhf.2073

M3 - Article

C2 - 33269486

AN - SCOPUS:85098132746

SN - 1388-9842

VL - 23

SP - 1026

EP - 1036

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 6

ER -

Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58

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