Dulaglutide Reduced Two Key Heart Disease Biomarkers in the REWIND Trial

What the researchers found

Compared to placebo over 2 years, dulaglutide was associated with greater reductions or lesser rises in NT-proBNP, GDF-15, high-sensitivity CRP, and a greater rise in C-peptide. It also reduced 2-hydroxybutyric acid and increased threonine levels.

Critically, of these biomarkers, only NT-proBNP and GDF-15 were also independently associated with cardiovascular events (MACE). NT-proBNP: OR 1.267 (95% CI 1.119–1.435, p<0.001); GDF-15: OR 1.937 (95% CI 1.424–2.634, p<0.001). This dual association — reduced by dulaglutide AND predictive of heart events — suggests these markers may mediate the drug's cardiovascular protection.

Why it matters

GLP-1 drugs clearly reduce heart disease risk in diabetes, but the mechanism remains debated. This study identifies NT-proBNP and GDF-15 as potential mediators — they're reduced by dulaglutide and independently predict cardiovascular events. This could guide development of better cardiovascular risk markers and help explain which patients benefit most from GLP-1 therapy.

How the study worked

Nested case-control post-hoc analysis of the REWIND randomized controlled trial. Fasting plasma samples from baseline and 2 years were analyzed in 824 participants who experienced MACE and 845 matched controls. 19 protein biomarkers were measured in the full cohort; 135 metabolites were measured in a subset of 1,201 participants. Linear and logistic regression models identified biomarkers associated with both dulaglutide treatment and cardiovascular events.

What this study cannot tell us

This is a post-hoc analysis, not a pre-specified endpoint, so the findings are hypothesis-generating rather than definitive. Biomarker associations don't prove causation — dulaglutide could reduce these markers without that being the mechanism of cardiovascular protection. Only baseline and 2-year samples were analyzed, so biomarker trajectories between those time points are unknown.

How to read the evidence

This is a post-hoc nested case-control analysis of a large, well-conducted randomized controlled trial (REWIND). While the RCT itself is high-quality evidence, post-hoc biomarker analyses are hypothesis-generating and considered moderate-strength evidence.

When this study was published

Published in 2023, this is recent analysis of the REWIND trial (completed 2018). The biomarker findings are current and relevant to ongoing research on GLP-1 cardiovascular mechanisms.

The bigger picture

This adds to a growing body of evidence that GLP-1 agonists do more than lower blood sugar — they appear to directly reduce cardiovascular stress and inflammation. The identification of NT-proBNP and GDF-15 as dual biomarkers (affected by dulaglutide AND predictive of events) strengthens the case that GLP-1 drugs have direct cardioprotective mechanisms beyond glucose control and weight loss.

Questions still open

• Do other GLP-1 agonists like semaglutide show the same pattern of NT-proBNP and GDF-15 reduction?
• Could NT-proBNP and GDF-15 levels be used to identify which diabetes patients would benefit most from GLP-1 therapy?
• Is dulaglutide's effect on these biomarkers a cause of cardiovascular protection or just a correlated response?

Common questions

Read the original research

Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis.

Diabetes care, 46(5), 1046-1051

Citation

Gerstein, Hertzel C; Lee, Shun-Fu; Paré, Guillaume; Bethel, M Angelyn; Colhoun, Helen M; Hoover, Anastasia; Lakshmanan, Mark; Lin, Yanzhu; Pirro, Valentina; Qian, Hui-Rong; Ruotolo, Giacomo; Ryden, Lars; Wilson, Jonathan M; Duffin, Kevin L. (2023). Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis.. Diabetes care, 46(5), 1046-1051. https://doi.org/10.2337/dc22-2397