Advanced Glycation End Products, Oxidation Products, and Incident Cardiovascular Events in Patients With Type 2 Diabetes
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OBJECTIVE: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: 1) a subcohort of the Veterans Affairs Diabetes Trial (VADT) (n = 445) and 2) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n = 271). RESULTS: Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A1c. In the VADT, increased risk of incident CVD events (n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28–0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events (n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event (P = 0.002). CONCLUSIONS: Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.
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Higher levels of circulating AGEs are positively correlated with the incidence of cardiovascular disorders and severity of coronary atherosclerosis and coronary artery disease independent of diabetic status.
“Additionally, higher levels of circulating AGEs are positively correlated with the incidence of cardiovascular disorders and severity of coronary atherosclerosis and coronary artery disease independent of diabetic status62–64, suggesting a causal role of AGEs in cardiovascular diseases.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [63]
AGEs have a causal role in cardiovascular diseases.
“Additionally, higher levels of circulating AGEs are positively correlated with the incidence of cardiovascular disorders and severity of coronary atherosclerosis and coronary artery disease independent of diabetic status62–64, suggesting a causal role of AGEs in cardiovascular diseases.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [63]
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- Authors
- Koska, J., Saremi, A., Howell, S., Bahn, G., De Courten, B., Ginsberg, H., Beisswenger, P. J., Reaven, P. D., & for the VADT Investigators
- Affiliations
- Phoenix VA Health Care System, Phoenix, AZ
- Phoenix VA Health Care System (US)
- PreventAGE Health Care (United States) (US)
- Edward Hines, Jr. VA Hospital (US)
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia
- Columbia University (US)
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2017-12-05
- Volume
- 41
- Issue
- 3
- Pages
- 570-576
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC5829965
- OpenAlex
- W2771721456
- Cited by
- 134
- References
- 35
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 11 · 2023: 15 · 2022: 26 · 2021: 15 · 2020: 15 · 2019: 19 · 2018: 7
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes Care (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion, other-oa)
- Figshare (submittedVersion)
- Funders
- Veterans Affairs Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development
- National Institutes of Health (R01-HL110418, R01-067690, 5R01-094775)
- American Diabetes Association
- National Institute of Diabetes and Digestive and Kidney Diseases (4R44-DK101226-01A1)
- National Heart Foundation Future Leader Fellowship (100864)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- advanced glycation end products, oxidation products, type 2 diabetes, cardiovascular disease incidence, methionine sulfoxide, carboxymethyllysine, 2-aminoadipic acid, tight glycemic control, cardiovascular risk prediction
- MeSH terms
- Aged, Cardiovascular Diseases, Cholesterol, Deoxyglucose, Diabetes Mellitus, Type 2, Glycated Hemoglobin, Humans, Imidazoles, Lysine, Male, Methionine, Middle Aged, Oxidation-Reduction, Pyruvaldehyde, Risk Factors, Triglycerides, 2-Aminoadipic Acid, Cohort Studies, Body Mass Index, Incidence, Case-Control Studies, Glycation End Products, Advanced
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