Abstract
OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P<0.001).AriskscoreusingthesethreevariablesidentifiedagradientofHHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (20.2 to 8.9) (P-trend <0.001). CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NTproBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2573-2581 |
| Number of pages | 9 |
| Journal | Diabetes care |
| Volume | 44 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2021 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Advanced and Specialized Nursing
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In: Diabetes care, Vol. 44, No. 11, 01.11.2021, p. 2573-2581.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A biomarker-based score for risk of hospitalization for heart failure in patients with diabetes
AU - Berg, David D.
AU - Wiviott, Stephen D.
AU - Scirica, Benjamin M.
AU - Zelniker, Thomas A.
AU - Goodrich, Erica L.
AU - Jarolim, Petr
AU - Mosenzon, Ofri
AU - Cahn, Avivit
AU - Bhatt, Deepak L.
AU - Leiter, Lawrence A.
AU - McGuire, Darren K.
AU - Wilding, John P.H.
AU - Johanson, Per
AU - Langkilde, Anna Maria
AU - Raz, Itamar
AU - Braunwald, Eugene
AU - Sabatine, Marc S.
AU - Morrow, David A.
N1 - Funding Information: Funding. D.D.B., S.D.W., B.M.S., M.S.S., and D.A.M., were supported for the present analysis by the American Heart Association Cardiometabolic Health & Type 2 Diabetes Mellitus Strategically Focused Research Network (20SFRN35120087). The SAVOR-TIMI 53 and DECLARE-TIMI 58 trials were supported by institutional research grants to Brigham and Women’s Hospital from AstraZeneca. Biomarker testing was supported by grants from Roche Diagnostics (reagent only). D.D.B. is supported by Harvard Catalyst KL2/CMeRIT (National Institutes of Health, National Center for Advancing Translational Sciences grant UL 1TR002541). T.A.Z. reports research grants from the German Research Foundation, and Austrian Science Funds. Duality of Interest. D.D.B. has received research grant support to his institution from AstraZeneca and Pfizer, and consulting fees from AstraZeneca. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi, and 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, and Xoma. His spouse, Dr. Caroline Fox, is an employee of Merck. B.M.S. reports research grants via Brigham and Women's Hospital from AstraZeneca, Eisai, Novartis, and Merck, consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr. Reddy's Laboratory, Eisai, Elsevier Practi-ceUpdate Cardiology, GlaxoSmithKline, Lexicon, Merck, Novo Nordisk, Sanofi, and St. Jude's Medical, and equity in Health [at] Scale. T.A.Z. reports honoraria from AstraZe-neca and Boehringer Ingelheim. E.L.G. reports grants from AstraZeneca during the conduct of the study. P.Ja. has received research support from Abbott Laboratories, Amgen Inc., AstraZeneca, Daiichi Sankyo, Inc., Eisai, Inc., GlaxoSmith Kline, Merck & Co., Inc., Regen-eron Pharmaceuticals, Inc., Roche Diagnostics Corp., Siemens Healthineers, Takeda Global Research and Development Center, and Waters Technologies Corp., and consulting fees from Roche Diagnostics. O.M. sits on advisory boards for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, and BOL Pharma, has received research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and has received speaker’s fees from AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, and Jansen. A.C. reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Medial Early-Sign, and GlucoMe. D.L.B. discloses the following relationships: advisory board for Cardax, CellProthera, Cereno Scientific, Elsev-ier PracticeUpdate Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Nir-vaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences; board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; inaugural chair, American Heart Association Quality Oversight Committee; data monitoring committees for 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 CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis [ExCEED] trial, funded by Edwards), Contego Medical (Chair, Protection Against Emboli During Carotid Artery Stenting Using the Neuro-guard IEP System [PERFORMANCE 2]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation [ENVISAGE] trial, funded by Daiichi Sankyo), Novartis, and Population Health Research Institute; honoraria from Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting [RE-DUAL PCI] clinical trial steering committee funded by Boehringer Ingelheim, Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome [AEGIS-II] executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [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), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education steering committees), MJH Life Sciences, Population Health Research Institute (for the Cardiovascular OutcoMes for People Using Anticoagulation StrategieS [COMPASS] operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (Continuing Medical Education steering committees); and other for Clinical Cardiology (Deputy Editor), National Cardiovascular Data Registry-Acute Coronary Treatment and Intervention Outcomes Network [NCDR-ACTION] Registry Steering Committee (Chair), Veterans Health Administration Clinical Assessment, Reporting and Tracking System for Cath Labs [VA CART] Research and Publications Committee (Chair); research funding from Abbott, Afimmune, Amarin, Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Eli Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, and 89Bio; royalties from Elsevier (Editor, Funding Information: for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, and Svelte; trustee for American College of Cardiology; and unfunded research for FlowCo, Merck, and Takeda. L.A.L. reports speaker’s bureau/honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier, consulting Fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier, and participation in clinical trials funded by AstraZeneca, Boehringer Ingel-heim, Eli Lilly, GlaxoSmithKline, Janssen, Novo Nordisk, and Sanofi. D.K.M. has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Lexicon, Merck, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Eisai, Esperion, GlaxoSmithKline, Eli Lilly, Pfizer, Metavant, Applied Therapeutics, Afimmune, and CSL Behring. 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, Eli Lilly, Takeda, and Sanofi, and consultancy fees (paid to his institution) from Wilmington Healthcare. P.Jo. and A.M.L. are employees and shareholders 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. E.B. reports grants to his institution from AstraZeneca, Daiichi Sankyo, Merck, and Novartis, and personal fees for consultancies with Amgen, Cardurion, Myo-Kardia, Novo Nordisk, and Verve. M.S.S. reports research grant support through Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda, and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr. Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis. D.A.M. reports grants to the TIMI Study Group from Abbott Laboratories, Amgen Anthos Therapeutics, AstraZeneca, BRAHMS, Eisai, GlaxoSmithKline, Medicines Co., Merck, Novartis, Pfizer, Roche Diagnostics, Quark, Siemens, and Takeda, and consultant fees from InCardia, Merck & Co, Novartis, and Roche Diagnostics. D.D.B., S.D.W., B.M.S., E.L.G., E.B., M.S.S., and D.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, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daii-chi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. No other potential conflicts of interest relevant to this article were reported. Author Contributions. D.D.B. drafted the manuscript. D.D.B., S.D.W., M.S.S., and D.A.M. developed the study concept and design and interpreted the data. S.D.W., B.M.S., T.A.Z., E.L.G., P.Ja., O.M., A.C., D.L.B., L.A.L., D.K.M., J.P.H.W., P.Jo., A.M.L., I.R., E.B., M.S.S., and D.A.M. critically revised the manuscript. E.L.G. performed the statistical analyses. D.D.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the American Heart Association Virtual Scientific Sessions, 13–17 November 2020. Publisher Copyright: © 2021 by the American Diabetes Association.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P<0.001).AriskscoreusingthesethreevariablesidentifiedagradientofHHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (20.2 to 8.9) (P-trend <0.001). CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NTproBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.
AB - OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P<0.001).AriskscoreusingthesethreevariablesidentifiedagradientofHHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (20.2 to 8.9) (P-trend <0.001). CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NTproBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.
UR - http://www.scopus.com/inward/record.url?scp=85120091792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120091792&partnerID=8YFLogxK
U2 - 10.2337/dc21-1170
DO - 10.2337/dc21-1170
M3 - Article
C2 - 34535469
AN - SCOPUS:85120091792
SN - 0149-5992
VL - 44
SP - 2573
EP - 2581
JO - Diabetes care
JF - Diabetes care
IS - 11
ER -