Long-Term Effects of Metformin on Endothelial Function in Type 2 Diabetes: A Randomized Controlled Trial
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OBJECTIVES: We investigated whether metformin can improve endothelial function and decrease inflammatory activity, and thereby decrease the risk of atherothrombotic disease. SUBJECTS AND DESIGN: A randomized, placebo-controlled trial with a follow-up period of 4.3 years set in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden Hospitals, the Netherlands). A total of 390 patients with type 2 diabetes treated with insulin were included. Either metformin 850 mg or placebo (one to three times daily) was added to insulin therapy. Urinary albumin excretion and plasma levels of von Willebrand factor (vWf), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured at baseline and after 4, 17, 30, 43 and 52 months. RESULTS: Metformin significantly reduced levels of vWF, sVCAM-1, t-PA, PAI-1, CRP and sICAM-1, which, except for CRP, remained significant after adjustment for baseline differences in age, sex, smoking and severity of previous cardiovascular (CV) disease. No effects on urinary albumin excretion or sE-selectin were observed. The improvements in vWf and sVCAM-1 statistically explained about 34% of the reduction in the risk of CV morbidity and mortality associated with metformin treatment in this study. CONCLUSIONS: Metformin is associated with improvement in some (vWF and sVCAM-1) but not all markers of endothelial function, which may explain why it is associated with a decreased risk of CV disease in type 2 diabetes.
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- Authors
- de Jager, J., Kooy, A., Schalkwijk, C., van der Kolk, J., Lehert, P., Bets, D., Wulffelé, M. G., Donker, A. J., & Stehouwer, C. D. A.
- Affiliations
- Bethesda Diabetes Research Center Hoogeveen The Netherlands
- Ziekenhuis Bethesda (NL)
- Maastricht University Medical Centre (NL)
- Clinical Laboratory Bethesda Hospital Hoogeveen The Netherlands
- Department of Statistics Faculty of Economics FUCAM Louvain Academy Leuven Belgium
- Merck B.V. (Netherlands) (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Kooy, A.
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2013-09-16
- Volume
- 275
- Issue
- 1
- Pages
- 59-70
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- OpenAlex
- W2065995883
- Cited by
- 129
- References
- 40
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 4 · 2022: 24 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 10 · 2017: 12 · 2016: 9 · 2015: 9 · 2014: 5 · 2013: 1
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Journal of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Altana
- Lifescan
- Merck Serono
- Merck Sharp & Dohme
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- metformin, endothelial function, type 2 diabetes, insulin therapy, atherothrombosis, inflammation, von Willebrand factor, soluble VCAM-1, plasminogen activator inhibitor-1, tissue plasminogen activator, C-reactive protein, soluble ICAM-1, soluble E-selectin, urinary albumin excretion, cardiovascular risk
- MeSH terms
- Aged, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Endothelium, Vascular, Female, Humans, Hypoglycemic Agents, Insulin, Male, Metformin, Middle Aged, Time, von Willebrand Factor, Biomarkers, Treatment Outcome, Drug Monitoring, Intercellular Adhesion Molecule-1
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