Dulaglutide Reduced Two Key Heart Disease Biomarkers in the REWIND Trial
In a large diabetes trial, dulaglutide reduced rises in NT-proBNP and GDF-15 — two biomarkers that were independently associated with cardiovascular events — suggesting these markers may help explain how GLP-1 drugs protect the heart.
Quick Facts
What This Study 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.
Key Numbers
How They Did This
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.
Why This Research 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.
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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- GDF-15: OR 1.94 for cardiovascular events Each standard deviation increase in GDF-15 nearly doubled the odds of a heart attack or stroke — and dulaglutide reduced GDF-15 rises
- Evidence Grade:
- 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.
- Study Age:
- 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.
- Original Title:
- Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis.
- Published In:
- Diabetes care, 46(5), 1046-1051 (2023)
- Authors:
- Gerstein, Hertzel C(4), 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
- Database ID:
- RPEP-06901
Evidence Hierarchy
Frequently Asked Questions
What are NT-proBNP and GDF-15?
NT-proBNP is a peptide released by the heart when it's under stress — higher levels indicate heart strain. GDF-15 is a protein that rises with cellular stress and inflammation throughout the body. Both are blood tests doctors can order, and higher levels predict worse cardiovascular outcomes.
Does this mean dulaglutide protects the heart through these biomarkers?
It's suggestive but not proven. The study shows dulaglutide reduces these markers AND that rising markers predict heart events — but this doesn't definitively prove one causes the other. Dulaglutide may protect the heart through multiple mechanisms, with these biomarker changes being one piece of the puzzle.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-06901APA
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
MLA
Gerstein, Hertzel C, et al. "Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis.." Diabetes care, 2023. https://doi.org/10.2337/dc22-2397
RethinkPeptides
RethinkPeptides Research Database. "Biomarker Changes Associated With Both Dulaglutide and Cardi..." RPEP-06901. Retrieved from https://rethinkpeptides.com/research/gerstein-2023-biomarker-changes-associated-with
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Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.