Serial Assessment of NT-proBNP and High-Sensitivity Cardiac Troponin with Glucagon-Like Peptide-1 Receptor Agonist Therapy in Type 2 Diabetes: Insights from EXSCEL.
In the EXSCEL trial, exenatide did not reduce major adverse cardiovascular events (MACE), but heterogeneity of benefit and the role of cardiac biomarkers remain uncertain. We evaluated the prognostic value of baseline and 1-year changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI), and whether baseline biomarker concentrations modified exenatide effects.
EXSCEL randomized 14,752 adults with type 2 diabetes to exenatide 2 mg weekly (EQW) or placebo. In a biomarker cohort, 4,292 participants had serial NT-proBNP or cTnI at baseline and 1 year. Biomarkers were log transformed and Cox models related baseline concentrations and 1-year change to MACE, all-cause mortality (ACM), cardiovascular (CV) death, hospitalization for heart failure (hHF), adjusting for clinical covariates and the alternate biomarker. Treatment interaction was tested with biomarker by treatment terms.
Over median 1,480 days follow-up, 529 MACE, 310 all cause deaths, 193 CV deaths, and 157 hHF events occurred. Baseline NT-proBNP was strongly prognostic (adjusted HR per 1 integer unit 1.63 for MACE, 1.85 for ACM, 2.17 for CV death, and 2.17 for hHF; all p<0.001). Baseline cTnI was also prognostic with a nonlinear pattern, with risk rising mainly above the median. Per SD rise in NT-proBNP over 1 year predicted later MACE (HR 1.85) and CV death (HR 2.81; both p<0.001). Baseline NT-proBNP didn't modify treatment effects. Baseline cTnI didn't modify EQW treatment effect on MACE but lower rates of CV deaths and hHF with EQW were observed at higher cTnI concentrations.
NT-proBNP and cTnI were strong prognostic markers of adverse outcomes in patients with type 2 diabetes and their 1-year increases signaled higher subsequent risk. Baseline cTnI may mark heterogeneity of EQW response, but mortality interactions are hypothesis generating and require confirmation.
EXSCEL randomized 14,752 adults with type 2 diabetes to exenatide 2 mg weekly (EQW) or placebo. In a biomarker cohort, 4,292 participants had serial NT-proBNP or cTnI at baseline and 1 year. Biomarkers were log transformed and Cox models related baseline concentrations and 1-year change to MACE, all-cause mortality (ACM), cardiovascular (CV) death, hospitalization for heart failure (hHF), adjusting for clinical covariates and the alternate biomarker. Treatment interaction was tested with biomarker by treatment terms.
Over median 1,480 days follow-up, 529 MACE, 310 all cause deaths, 193 CV deaths, and 157 hHF events occurred. Baseline NT-proBNP was strongly prognostic (adjusted HR per 1 integer unit 1.63 for MACE, 1.85 for ACM, 2.17 for CV death, and 2.17 for hHF; all p<0.001). Baseline cTnI was also prognostic with a nonlinear pattern, with risk rising mainly above the median. Per SD rise in NT-proBNP over 1 year predicted later MACE (HR 1.85) and CV death (HR 2.81; both p<0.001). Baseline NT-proBNP didn't modify treatment effects. Baseline cTnI didn't modify EQW treatment effect on MACE but lower rates of CV deaths and hHF with EQW were observed at higher cTnI concentrations.
NT-proBNP and cTnI were strong prognostic markers of adverse outcomes in patients with type 2 diabetes and their 1-year increases signaled higher subsequent risk. Baseline cTnI may mark heterogeneity of EQW response, but mortality interactions are hypothesis generating and require confirmation.
Authors
Kittipibul Kittipibul, Nguyen Nguyen, Welsh Welsh, Buse Buse, Sourij Sourij, Hernandez Hernandez, Holman Holman, Shah Shah, Mentz Mentz
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