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Differential associations of circulating asymmetric dimethylarginine and cell adhesion molecules with metformin use in patients with type 2 diabetes mellitus and stable coronary artery disease

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Abstract

Metformin, the drug of first choice in type 2 diabetes mellitus (T2DM), reduces cardiovascular (CV) morbidity and mortality in part independently of improved glycemic control and changes in traditional risk factors. However, there are discordant reports on the effects of metformin on endothelial function in T2DM. Our aim was to compare biochemical endothelial markers in patients with stable coronary artery disease (CAD) and T2DM stratified by metformin use. We studied 70 patients (29 women, age 68 ± 9 years) with established T2DM referred for elective coronary angiography owing to stable angina who were receiving a standard CV medication and metformin or other oral antidiabetic drugs. Exclusion criteria included heart failure and other relevant coexistent disorders. Biochemical indices of endothelial dysfunction and activation at admission were compared according to metformin use for at least 1 year prior to index hospitalization. Clinical characteristics were similar in patients receiving metformin (n = 40) vs. those on other oral antidiabetic agents (n = 30). Plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) was lower (553 ± 148 vs. 668 ± 170 µg/L, P = 0.004) and asymmetric dimethylarginine (ADMA) higher (0.53 ± 0.09 vs. 0.48 ± 0.08 µM, P = 0.01) in subjects on metformin, which was maintained in multivariate analysis. Symmetric dimethylarginine, intercellular adhesion molecule-1, monocyte chemotactic protein-1 and E-selectin did not differ across the groups. The results were substantially unchanged after exclusion of insulin users. Thus, metformin use appears differentially associated with sVCAM-1 and ADMA in patients with T2DM and stable CAD. Whether this observation may reflect different prognostic effects of these endothelial markers in diabetes remains to be studied.

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Abbreviations

ACEI:

Angiotensin-converting enzyme inhibitors

ADMA:

Asymmetric dimethylarginine

ANCOVA:

Analysis of covariance

CAD:

Coronary artery disease

CV:

Cardiovascular

DDAH:

Dimethylarginine dimethylaminohydrolase

eGFR:

Estimated glomerular filtration rate

ELISA:

Enzyme-linked immunosorbent assay

eNOS:

Endothelial nitric oxide synthase

HbA1c:

Glycated hemoglobin

HDL:

High-density lipoproteins

LDL:

Low-density lipoproteins

MCP-1:

Monocyte chemotactic protein-1

NO:

Nitric oxide

SDMA:

Symmetric dimethylarginine

sICAM-1:

Soluble intercellular adhesion molecule-1

sVCAM-1:

Soluble vascular cell adhesion molecule-1

T2DM:

Type 2 diabetes mellitus

vWF:

von Willebrand factor

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Acknowledgments

An abstract based on this study was presented at the 21st Cardiology Update Course, Davos, Switzerland, February 9th, 2015. This work was supported by Jagiellonian University Medical College (research Grant No. K/ZDS/003761). The funding source had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Coronary Artery Disease and Heart Failure, John Paul II Hospital, 80 Prądnicka, 31-202, Cracow, Poland

    Olga Kruszelnicka

  2. Second Department of Cardiology, Jagiellonian University and University Hospital, Cracow, Poland

    Bernadeta Chyrchel & Andrzej Surdacki

  3. Department of Community Medicine, Service of Therapeutic Education for Chronic Diseases, WHO Collaborating Centre, University Hospitals of Geneva, Geneva, Switzerland

    Alain Golay

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  1. Olga Kruszelnicka
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  2. Bernadeta Chyrchel
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Correspondence to Olga Kruszelnicka.

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Kruszelnicka, O., Chyrchel, B., Golay, A. et al. Differential associations of circulating asymmetric dimethylarginine and cell adhesion molecules with metformin use in patients with type 2 diabetes mellitus and stable coronary artery disease. Amino Acids 47, 1951–1959 (2015). https://doi.org/10.1007/s00726-015-1976-3

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