CLINICAL STUDY: ENDOTHELIAL FUNCTION
Improved endothelial function with metformin in type 2 diabetes mellitus
Kieren J. Mather, MD*,
Subodh Verma, MD, PhD and
Todd J. Anderson, MD
* Division of Endocrinology and Metabolism, Indiana University, Indianapolis, Indiana, USA
Division of Cardiac Surgery, University of Toronto, Toronto, Canada
Division of Cardiology, University of Calgary, Calgary, Canada
Manuscript received August 11, 2000;
revised manuscript received November 17, 2000,
accepted December 21, 2000.
Reprint requests and correspondence: Dr. Todd J. Anderson, Division of Cardiology, Faculty of Medicine, University of Calgary, c849, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada.
todd.anderson{at}crha-health.ab.ca
OBJECTIVES
This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus.
BACKGROUND
Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported.
METHODS
Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR).
RESULTS
Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = –0.659, p = 0.0012).
CONCLUSIONS
Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.
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Abbreviations and Acronyms
| | Ach | = acetylcholine | | ANCOVA | = analysis of covariance | | ANOVA | = analysis of variance | | BMI | = body mass index | | CV | = coefficient of variation | | DM | = diabetes mellitus | | FBF | = forearm blood flow | | FFA | = free fatty acid | | HOMA-IR | = homeostasis model assessment of insulin resistance | | IR | = insulin resistance | | LDL | = low density lipoprotein | | SNP | = sodium nitroprusside | | VER | = verapamil |
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