Biomarker Changes Associated with both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control post hoc Analysis

Background: The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. The relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE) is unknown. 

Methods: In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE.

Results: Compared to placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), and high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared to placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P<0.001). Increases from baseline in 2 of the proteins (but neither metabolite) were associated with MACE including NT-proBNP (OR 1.267; 95%CI 1.119, 1.435; P<0.001), and GDF-15 (OR 1.937; 95%CI 1.424, 2.634; P <0.001). 

Conclusion: Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.