Rationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis
Open accessAbstract
Background Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.Design The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants.Summary CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.
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GLP-1RAs reduce the levels of systemic inflammatory markers.
“GLP-1RAs have been shown to reduce the levels of systemic inflammatory markers.457,458”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [458]
The Clinical Evidence that Treating Inflammation Matters section says statins lower inflammation, while the Type 2 Diabetes, Metabolic Syndrome, and Inflammation section discusses elevated inflammatory biomarkers in people with diabetes or metabolic syndrome. Searches for GLP-1 receptor agonists and glucagon-like peptide-1 found no passage in our copy addressing whether those drugs reduce systemic inflammatory markers. Page numbers were not available in the indexed passages. (LLM, conf=0.76)
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“By contrast, the National Heart, Lung, and Blood Institute–funded CIRT was designed to address whether an alternative broad-spectrum anti-inflammatory approach using LDM might also reduce vascular event rates.(5,79) LDM is Figure 4.”
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- Authors
- Everett, B. M., Pradhan, A. D., Solomon, D. H., Paynter, N., MacFadyen, J., Zaharris, E., Gupta, M., Clearfield, M., Libby, P., Hasan, A. A. K., Glynn, R. J., & Ridker, P. M.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Toronto (CA)
- Touro University California (US)
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Everett, Brendan M.
- ORCID
- Venue
- American Heart Journal
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 166
- Issue
- 2
- Pages
- 199-207.e15
- ISSN
- 0002-8703 (ISSN-L)
- PMC
- PMC3888829
- OpenAlex
- W2126384096
- Cited by
- 368
- References
- 51
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 8 · 2021: 16 · 2020: 16 · 2019: 34 · 2018: 67 · 2017: 57 · 2016: 49 · 2015: 61 · 2014: 28 · 2013: 5
- FWCI
- 26.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL101422, U01HL101389)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- low-dose methotrexate, atherothrombosis, inflammation, inflammatory hypothesis, old myocardial infarction, type 2 diabetes, metabolic syndrome, secondary prevention, cardiovascular events, coronary revascularization, congestive heart failure, all-cause mortality, anti-inflammatory therapy
- MeSH terms
- Algorithms, Anti-Inflammatory Agents, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Humans, Inflammation, Methotrexate, Myocardial Infarction, Research Design, Metabolic Syndrome, Atherosclerosis
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