Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance

Cardiovascular disease (CVD) risk associated with fat redistribution seen a mong HIV-infected individuals remains unknown, but: may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prot hrombotic state associated with these metabolic abnormalities. In this stud y we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-typ e plasminogen activator (tPA) antigen levels, markers of fibrinolysis and i ncreased CVD risk, in HIV lipodystrophic patients compared to controls. Fur thermore, we investigated the effect of treatment with metformin on PAI-1 a nd tPA antigen levels in patients with HIV-associated fat redistribution. E ighty-six patients age 43+/-1 yr, BMI 26.1+/-0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin > 15 muU/mL [104 pmol/L] or impaired glu cose tolerance, but without diabetes mellitus were enrolled in a placebo-co ntrolled treatment study of metformin 500mg twice dairy. PAI-1 and tPA anti gen levels were significantly increased in patients with HIV related fat re distribution compared to Framingham control subjects (46.1+/-1.4 vs 18.9+/- 0.9 mug/L PAI-1, 16.6+/-0.8 vs. 8.0+/-0.3 mug/L tPA, P=0.0001). Among patie nts with HIV infection, a multivariate regression analysis including age, s ex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and ins ulin area under the curve (AUC), found gender and insulin AUC were signific ant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9+/-1.4 vs +1.4+/-1.0 mug/L in the pla cebo-treated group P=0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7+/-2.3 vs +1.7+/-2.9 mug/L, P=0.03). Change in insulin A UC correlated significantly with change in tPA antigen (r=0.43, P=0.03). PA I-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD ris k, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrati ons in these patients and may ultimately improve associated CVD risk.