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. 2023 Mar 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,
PMCID: PMC9979005  PMID: 36857035

Key Points

Question

Can cardiac biomarkers identify patients with type 2 diabetes (T2D) at higher risk and who benefit more from dapagliflozin for atherosclerotic events?

Findings

In this substudy of the DECLARE-TIMI 58 trial including 14 565 patients, baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) concentrations did not modify the relative treatment effect of dapagliflozin vs placebo on major adverse cardiovascular events (MACE). However, event rates were lower in dapagliflozin-treated vs placebo-treated patients with biomarker levels in the top quartile, whereas event rates did not differ between treatment groups in patients with biomarkers levels in quartiles 1 to 3.

Meaning

In this study, NT-proBNP and hsTnT were associated with MACE in patients with T2D at high risk of atherosclerotic events, and in individuals with high levels of both biomarkers, dapagliflozin was associated with reduced MACE event rates.


This secondary analysis of the DECLARE-TIMI 58 trial evaluates whether N-terminal pro–B-type natriuretic peptide and high-sensitivity cardiac troponin T levels can identify a subset of patients with type 2 diabetes at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events.

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

Introduction

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce hospitalizations for heart failure (HF) and progression of chronic kidney disease (CKD) in patients with and without type 2 diabetes (T2D).1,2 However, their effects on reducing atherosclerotic events appear modest across the population of patients with T2D with heterogeneity observed among studied populations.3,4,5,6,7

The Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial tested the SGLT2i dapagliflozin in 17 160 patients with T2D with preserved kidney function and either multiple risk factors (ie, men 55 years and older or women 60 years and older who had at least 1 of the following risk factors: hypertension, dyslipidemia, or smoking) or established atherosclerotic cardiovascular disease (ASCVD; defined as clinically evident ischemic heart disease, cerebrovascular disease, or peripheral artery disease) over a median follow-up of 4.2 years. Dapagliflozin reduced the risk of cardiovascular death and hospitalization for HF (HHF) but, in the overall population, did not reduce the risk of major adverse cardiovascular events (MACE; hazard ratio [HR], 0.93; 95% CI, 0.84-1.03).8 This finding was consistent in patients with multiple risk factors and ASCVD, although a nominally significant reduction of MACE was observed in patients with prior myocardial infarction (MI) and those with long-standing diabetes.9,10

We previously reported the association of cardiac biomarkers and the risk of cardiovascular death and HHF.11 Treatment with dapagliflozin reduced the risk of cardiovascular death and HHF irrespective of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) concentrations, but NT-proBNP and hsTnT identified cohorts with higher biomarker concentrations who derived greater absolute risk reductions. Here, we assessed the association between NT-proBNP and hsTnT and ASCVD outcomes and whether these biomarkers identified a subset of patients with T2D who benefit from SGLT2i with regard to atherosclerotic events.

Methods

Study Population

This was a nested biomarker study from DECLARE-TIMI 58.8,12,13 As described previously,11 NT-proBNP (n = 14 562) and hsTnT (n = 14 551) were measured among all patients with available randomization blood samples in the TIMI Clinical Trials Laboratory, Boston, Massachusetts. The trial and this analysis were approved by the institutional review boards of all participating sites, including at Brigham and Women’s Hospital as the supervising coordinating center. Written informed consent was obtained from all trial participants.

Outcomes of Interest

The primary outcome of interest for these analyses was MACE, the composite of MI, ischemic stroke, and cardiovascular death, which was one of the dual primary outcomes of the trial. We previously reported the relationship of cardiac biomarkers and the other dual primary outcome, the risk for cardiovascular death and HHF.11 All outcome events were adjudicated by a masked clinical events committee.

Biomarker Levels

Serum NT-proBNP concentrations were measured at the first thaw using an electrochemiluminescent immunoassay on the cobas e601 analyzer (proBNP II; Roche Diagnostics). This assay has a measuring range of 10 to 35 000 pg/mL. Reference limits for NT-proBNP levels are less than 125 pg/mL in people younger than 75 years and less than 450 pg/mL in people 75 years and older. hsTnT was measured with a high-sensitivity electrochemiluminescent immunoassay on the Roche cobas 601 analyzer (Elecsys Troponin T Gen 5 STAT; Roche Diagnostics). The limit of quantitation of the assay is 6 ng/L. We applied a 99th percentile upper reference limit for hsTnT of 14 ng/L.

Statistical Analysis

Kaplan-Meier event rates at 4 years are reported and illustrated using cumulative incidence curves. Log-rank tests for trend were used to compare event rates across biomarker quartiles. We used Cox models adjusted for age, sex, race, smoking, estimated glomerular filtration rate, body mass index, diabetes duration, insulin use, prior coronary artery disease, MI, ischemic stroke, peripheral artery disease, HF, dyslipidemia, and hypertension to assess the association between baseline biomarker concentrations and incident MACE. We added an interaction term along with the main effects for each biomarker and the treatment effect of dapagliflozin to test for treatment effect modification by biomarker values. To explore a nonlinear association between biomarker concentrations and the treatment effect of dapagliflozin, we further fitted adjusted Cox models with biomarker concentrations as cubic splines. All analyses were performed using R version 3.6.0 (The R Foundation) or SAS version 9.4 (SAS Institute). Two-sided P values < .05 were considered to indicate nominal statistical significance.

Results

Study Population

Among 14 565 included patients, 9143 patients (62.8%) were male, the mean (SD) age was 63.9 (6.8) years, and the median (IQR) duration of diabetes was 11 (6-16) years. A total of 5974 (41.0%) had established ASCVD, and 3101 (21.3%) had a prior MI. The median (IQR) NT-proBNP and hsTnT levels were 75 (35-165) pg/mL and 10.2 (6.9-15.5) ng/L, respectively. The baseline characteristics by biomarker quartile are shown in eTables 1 and 2 in Supplement 2.

Association Between Baseline Cardiac Biomarkers and MACE Within the Placebo Arm

Among those allocated to placebo, patients with higher baseline biomarker concentrations had higher rates of MACE (Figure 1). A stepwise gradient of risk from quartiles 1 to 3 with a steep increase in quartile 4 was observed in both patients with established ASCVD (quartile 4 vs quartile 1: NT-proBNP, 22.9% vs 8.5%; P for trend < .001; hsTnT, 24.2% vs 7.2%; P for trend < .001) as well as multiple risk factors (quartile 4 vs quartile 1: NT-proBNP, 11.4% vs 3.0%; P for trend < .001; hsTnT, 10.1% vs 3.1%; P for trend < .001) (Figure 1). Patients with multiple risk factors and biomarker levels in quartile 4 had similar event rates compared with patients with ASCVD with low biomarker concentrations.

Figure 1. Kaplan-Meier (KM) Event Rates of the Composite of Myocardial Infarction, Ischemic Stroke, or Cardiovascular Death by Baseline Biomarker Quartiles.

Figure 1.

Four-year KM event rates are reported. P for trend < .001 for each panel. As previously reported,11 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.

This association remained apparent after multivariable adjustment (adjusted HR [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) (Figure 2). The magnitude of the association was similar in patients with ASCVD (aHR per 1 SD in log-transformed biomarker: NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and patients with multiple risk factors (adjusted HR [aHR] per 1 SD in log-transformed biomarker: 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 (and the individual components) when combined in the multivariable model in the total patient population (adjusted HR [aHR] per 1 SD in log-transformed biomarker: NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53) as well as in patients with ASCVD and multiple risk factors (Figure 2; eFigure 1 in Supplement 1).

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).

Figure 2.

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.

Treatment Effect of Dapagliflozin According to Baseline Biomarker Levels

Consistent with the results of the main trial, the HR for MACE with dapagliflozin in the present biomarker cohort was 0.92 (95% CI, 0.83-1.03). The probabilities of MACE stratified by baseline biomarker concentrations and treatment arm in ASCVD and multiple risk factors are shown in Figure 3A and B. In patients with NT-proBNP and hsTnT concentrations in quartile 4, dapagliflozin-treated patients had lower MACE rates than those taking placebo, yielding 17% (95% CI, 3-29) and 15% (95% CI, 1-28) relative reductions in the hazard of MACE, respectively. The absolute risk reductions observed in patients with NT-proBNP and hsTnT in the top quartiles were 2.4% and 2.7%, respectively, at 4 years. In contrast, there was no nominally significant association in patients with quartile 1 to quartile 3 levels of NT-proBNP (HR, 1.02; 95% CI, 0.88-1.18) or hsTnT (HR, 0.97; 95% CI, 0.84-1.13) (eFigure 2 in Supplement 1). However, formal interaction testing did not reveal significant heterogeneity of the association of dapagliflozin based on either baseline biomarker (Figure 3C and D; eFigures 2-6 in Supplement 1).

Figure 3. Outcomes of Dapagliflozin vs Placebo According to Baseline Biomarker Level.

Figure 3.

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.

Discussion

The main findings of the present study are that both NT-proBNP and hsTnT stratify (individually and complementarily) risk for future atherosclerotic events in both patients with and without established ASCVD. Moreover, in patients at high risk identified by biomarker concentrations in the top quartile (ie, NT-proBNP greater than 165 pg/mL and hsTnT greater than 15.5 ng/L), we observed lower rates of MACE with dapagliflozin than placebo. Our findings suggest the possibility that these cardiovascular biomarkers identify patients with T2D among whom treatment with dapagliflozin may confer a benefit with respect to MACE in addition to the established reductions in future HF and kidney events that are conferred irrespective of cardiac biomarker levels. In light of the global burden of T2D, these smaller effects on MACE may have clinical and public health implications (particularly in those with ASCVD and higher biomarker levels).

Results from the present study expand on findings from biomarker analyses of the CANVAS trial.14 That study of 3503 patients with baseline hsTnT levels measured, which had a higher proportion of patients with hsTnT concentrations of 14 ng/L or higher (38% vs 30%) and a longer follow-up (6 vs 4.2 years), indicated that patients with hsTnT concentrations of 14 ng/L or higher derived greater benefit from treatment with canagliflozin for MACE.

Limitations

These analyses are subject to the known limitations of subgroup analyses, including their exploratory nature and limited statistical power. As reflected in the distribution of the baseline concentrations with only approximately one-third of the patient population having either hsTnT concentrations of 14 ng/L or greater or NT-proBNP levels of 450 pg/mL or greater, the included patient population represents a lower-risk patient cohort compared with other SGLT2i cardiovascular outcomes trials in patients with T2D.3,5

Conclusions

In this study, NT-proBNP and hsTnT levels had unique, independent prognostic value and were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers are helpful to identify patients at very high risk of atherosclerotic events who may derive clinical benefit from dapagliflozin with regard to MACE.

Supplement 1.

eTable 1. Baseline Characteristics According to NT-proBNP Quartiles

eTable 2. Baseline Characteristics According to hsTnT Quartiles

eFigure 1. Relationship Between Cardiac Biomarkers and Cardiovascular Events in Patients With Multiple Risk Factors for or Established Atherosclerotic Cardiovascular Disease Within the Placebo Arm

eFigure 2. Effect of Dapagliflozin vs Placebo on the Composite of Myocardial Infarction, Ischemic Stroke, and Cardiovascular Death by Biomarker Q1-3 vs Q4

eFigure 3. Effect of Dapagliflozin vs Placebo on Myocardial Infarction by Baseline Biomarker Quartiles

eFigure 4. Effect of Dapagliflozin vs Placebo on Ischemic Stroke by Baseline Biomarker Quartiles

eFigure 5. Effect of Dapagliflozin vs Placebo on Cardiovascular Death by Baseline Biomarker Quartiles

eFigure 6. Effect of Dapagliflozin vs Placebo on the Composite of Myocardial Infarction, Ischemic Stroke, and Cardiovascular Death by Biomarker Quartiles

Supplement 2.

Data Sharing Statement

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Baseline Characteristics According to NT-proBNP Quartiles

eTable 2. Baseline Characteristics According to hsTnT Quartiles

eFigure 1. Relationship Between Cardiac Biomarkers and Cardiovascular Events in Patients With Multiple Risk Factors for or Established Atherosclerotic Cardiovascular Disease Within the Placebo Arm

eFigure 2. Effect of Dapagliflozin vs Placebo on the Composite of Myocardial Infarction, Ischemic Stroke, and Cardiovascular Death by Biomarker Q1-3 vs Q4

eFigure 3. Effect of Dapagliflozin vs Placebo on Myocardial Infarction by Baseline Biomarker Quartiles

eFigure 4. Effect of Dapagliflozin vs Placebo on Ischemic Stroke by Baseline Biomarker Quartiles

eFigure 5. Effect of Dapagliflozin vs Placebo on Cardiovascular Death by Baseline Biomarker Quartiles

eFigure 6. Effect of Dapagliflozin vs Placebo on the Composite of Myocardial Infarction, Ischemic Stroke, and Cardiovascular Death by Biomarker Quartiles

Supplement 2.

Data Sharing Statement


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