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Randomized Controlled Trial
. 2023 May 1;8(5):503-509.
doi: 10.1001/jamacardio.2023.0019.

Association of Cardiac Biomarkers With Major Adverse Cardiovascular Events in High-risk Patients With Diabetes: A Secondary Analysis of the DECLARE-TIMI 58 Trial

Thomas A Zelniker  1 , Stephen D Wiviott  2 , Ofri Mosenzon  3 , Erica L Goodrich  2 , Petr Jarolim  4 , Avivit Cahn  3 , Deepak L Bhatt  5 , Lawrence A Leiter  6 , Darren K McGuire  7 , John Wilding  8 , Oleg Averkov  9 , Andrzej Budaj  10 , Alexander Parkhomenko  11 , Kausik K Ray  12 , Ingrid Gause-Nilsson  13 , Anna Maria Langkilde  13 , Martin Fredriksson  13 , Itamar Raz  3 , Marc S Sabatine  2   14 , David A Morrow  2
Affiliations
Randomized Controlled Trial

Association of Cardiac Biomarkers With Major Adverse Cardiovascular Events in High-risk Patients With Diabetes: A Secondary Analysis of the DECLARE-TIMI 58 Trial

Thomas A Zelniker et al. JAMA Cardiol. .

Abstract

Importance: Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear.

Objective: To explore whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events.

Design, setting, and participants: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022.

Interventions: Dapagliflozin vs placebo.

Main outcomes and measures: Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial.

Results: Of 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%).

Conclusions and relevance: In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin.

Trial registration: ClinicalTrials.gov Identifier: NCT01730534.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Zelniker reported grants from AstraZeneca during the conduct of the study; grants from Austrian Science Funds, German Research Foundation, and Eli Lilly and Co; and personal fees from AstraZeneca, Boehringer Ingelheim, Alkem Lab, Bayer AG, and Sun Pharmaceuticals outside the submitted work. Dr Wiviott reported grants from AstraZeneca during the conduct of the study; grants from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Janssen, Merck, and Pfizer; and personal fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and Novo Nordisk outside the submitted work; and his spouse is an employee of Merck. Dr Mosenzon reported grants from AstraZeneca and personal fees from AstraZeneca during the conduct of the study; grants from Novo Nordisk; and personal fees from Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Sanofi, and Merck Sharp & Dohme outside the submitted work. Dr Goodrich reported grants from AstraZeneca during the conduct of the study. Dr Jarolim reported grants from AstraZeneca, Abbott Laboratories, Amgen, Roche Diagnostics, Siemens Healthineers, and Merck during the conduct of the study. Dr Cahn reported grants and personal fees from AstraZeneca during the conduct of the study as well as personal fees from Novo Nordisk, Eli Lilly, Sanofi, Boehringer Ingelheim, and Medial EarlySign outside the submitted work. Dr Bhatt reported grants from AstraZeneca during the conduct of the study; grants from Boehringer Ingelheim, Lexicon, and Sanofi outside the submitted work; research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; honoraria from American College of Cardiology, Arnold and Porter Law Firm, Baim Institute for Clinical Research, Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, Clinical Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, and Wiley; royalties from Elsevier; unfunded research support from FlowCo and Takeda; has consulted for Broadview Ventures; serves on an advisory board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; serves on a board of directors for AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; serves on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, and Rutgers University; is chair for the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; is a site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical, Philips, SpectraWAVE, Svelte, and Vascular Solutions; and has a patent for Lexicon pending. Dr Leiter reported personal fees from AstraZeneca during the conduct of the study as well as personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lexicon, Merck, Novo Nordisk, Pfizer, Sanofi, and Servier outside the submitted work. Dr McGuire reported personal fees from AstraZeneca during the conduct of the study as well as personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Novo Nordisk, Esperion, Lilly, CSL Behring, Applied Therapeutics, Metavant, Sanofi, Afimmune, Bayer, GlaxoSmithKline, Lexicon, Altimmune, Intercept Pharmaceuticals, and Kirkland & Ellis outside the submitted work. Dr Wilding reported institutional fees from AstraZeneca during the conduct of the study; personal fees from Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Sanofi; and institutional fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lilly, Mundipharma, Pfizer, Rhythm, Saniona, and Ysopia outside the submitted work. Dr Averkov reported personal fees from AstraZeneca, Sanofi-Aventis, Bayer, Bristol Myers Squibb, Pfizer, Aspen, and Servier outside the submitted work. Dr Budaj reported personal fees from AstraZeneca during the conduct of the study as well as personal fees from Bristol Myers Squibb/Pfizer, Sanofi-Aventis, GlaxoSmithKline, Eisai, Bayer, Amgen, Novartis, and Novo Nordisk outside the submitted work. Dr Parkhomenko reported grants and personal fees from AstraZeneca as well as personal fees from Sanofi-Aventis, Novo Nordisk, Boehringer Ingelheim, Novartis, ACINO, Bayer, and Amgen outside the submitted work. Dr Ray reported personal fees from AstraZeneca during the conduct of the study; grants from Sanofi, Daiichi Sankyo, Regeneron, and Amgen; personal fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Novartis, Esperion, Eli Lilly, Silence Therapeutics, Kowa, Bayer, Amgen, Sanofi, Cargene, New Amsterdam, Daiichi Sankyo, Vaxxinity, Scribe Therapeutics, Abbott, and Pemi31 outside the submitted work. Dr Sabatine reported grants and personal fees from AstraZeneca during the conduct of the study; grants from Abbott, Amgen, Pfizer, Novartis, Ionis, Merck, Intarcia, Daiichi Sankyo, Eisai, and Anthos Therapeutics; and personal fees from Althera, Amgen, Anthos Therapeutics, Beren Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics outside the submitted work. Dr Morrow reported grants from AstraZeneca and Roche Diagnostics during the conduct of the study; grants from Abbott Laboratories, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Merck, Novartis, Pfizer, Regeneron, and Siemens; and personal fees from Abbott Laboratories, ARCA Biopharma, InCarda Therapeutics, Inflammatix, Merck, Novartis, and Roche Diagnostics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier (KM) Event Rates of the Composite of Myocardial Infarction, Ischemic Stroke, or Cardiovascular Death by Baseline Biomarker Quartiles
Four-year KM event rates are reported. P for trend < .001 for each panel. As previously reported, the median (IQR) biomarker concentrations were 75 (35-165) pg/mL for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and 10.2 (6.9-15.5) ng/L for high-sensitivity cardiac troponin T (hsTnT). Among patients with both biomarker levels available (N = 14 548, 99.9%), 4755 patients (32.7%) had either hsTnT concentrations of 14 ng/L or greater or NT-proBNP levels of 450 pg/mL or greater, and 830 patients (5.7%) had both biomarkers elevated. ASCVD indicates atherosclerotic cardiovascular disease.
Figure 2.
Figure 2.. Association Between Cardiac Biomarkers and the Composite of Myocardial Infarction, Ischemic Stroke, or Cardiovascular Death in Placebo-Treated Patients With Multiple Risk Factors for or Established Atherosclerotic Cardiovascular Disease (ASCVD)
Adjusted for age, sex, race, smoking, baseline estimated glomerular filtration rate, body mass index, diabetes duration, insulin use, history of coronary artery disease, myocardial infarction, ischemic stroke, peripheral artery disease, heart failure, dyslipidemia, and hypertension. HR indicates hazard ratio; hsTnT, high-sensitivity cardiac troponin T; MACE, major adverse cardiovascular events; NT-proBNP, N-terminal pro–B-type natriuretic peptide.
Figure 3.
Figure 3.. Outcomes of Dapagliflozin vs Placebo According to Baseline Biomarker Level
A and B, Probability of the composite of myocardial infarction, ischemic stroke, or cardiovascular death by treatment arm and N-terminal pro–B-type natriuretic peptide (NT-ProBNP) and high-sensitivity cardiac troponin T (hsTnT) levels. C and D, Hazard ratio of dapagliflozin vs placebo for the composite of myocardial infarction, ischemic stroke, or cardiovascular death by treatment arm and NT-proBNP and hsTnT levels. The dashed vertical lines indicate the median and IQR of the biomarker levels, and the shaded area indicates 95% CIs. ASCVD indicates atherosclerotic cardiovascular disease; MACE, major adverse cardiovascular events.
See this image and copyright information in PMC

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