Effects of Metformin on Insulin Resistance, Risk Factors for Cardiovascular Disease, and Plasminogen Activator Inhibitor in NIDDM Subjects: A study of two ethnic groups

Abstract

OBJECTIVE To investigate the effects of metformin on glycemic control, insulin resistance, and risk factors for cardiovascular disease in NIDDM subjects from two ethnic groups (Caucasian and Asian) with different risks of cardiovascular disease. RESEARCH DESIGN AND METHODS A total of 27 subjects with NIDDM (17 Caucasian, 10 Asian) were given metformin and placebo each for a 12-wk period in a randomized, double-blind, placebo-controlled crossover study, and the dose was increased after 1 and 6 wk, up to a maximum of 850 mg three times a day. Insulin resistance, glycemic control, and cardiovascular risk factors were assessed before and after each treatment phase. The end of 12 wk of metformin treatment was compared with the end of 12 wk of placebo treatment. RESULTS Metformin treatment was associated with significant improvement in FPG at 6 and 12 wk (mean difference at 12 wk, −3.08 mM, 95% CI −4.12 to −2.04 mM, P < 0.0001) and MCR of glucose (median difference 0.40 ml · kg−1 · min−1, interquartile range −0.10 to 1.30 ml · kg−1 · min−1, P = 0.036). β-cell function calculated by HOMA also improved significantly (median difference 14%, interquartile range 7 to 23%, P < 0.001). Total triglyceride (median difference −0.2 mM, interquartile range −0.6 to 0.1 mM, P = 0.034), total cholesterol (mean difference −0.52 mM, 95% CI −0.83 to −0.22 mM, P = 0.002), and LDL cholesterol (mean difference −0.40 mM, 95% CI −0.64 to −0.16 mM, P = 0.002) fell significantly on metformin treatment, whereas no significant changes were observed in HDL cholesterol. PAI-1 activity fell significantly (mean difference −5.3 AU/ml, 95% CI −8.2 to −2.4 AU/ml, P = 0.001), but plasma fibrinogen concentrations and platelet function, spontaneous or agonist induced, were unaffected. UAE was lower on metformin treatment (median difference −2.4 μg/min, interquartile range −4.4 to −0.2 μg/min, P = 0.004), but metformin had no significant effect on BP. The effects of metformin on glycemic control and cardiovascular risk factors were generally similar in the two ethnic groups. CONCLUSIONS These findings indicate that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.