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Fluvastatin Slow-Release Lowers Platelet-Activating Factor Acetyl Hydrolase Activity: A Placebo-Controlled Trial in Patients with Type 2 Diabetes

Division of Clinical Chemistry (K.W., I.F., M.M.H., H.W.), Department of Medicine, Albert Ludwigs-University, D-79106 Freiburg, Germany; Novartis Pharma GmbH (C.A.), D-90327 Nürnberg, Germany; and Department of Clinical Chemistry (W.M.), University of Graz, A-8036 Austria

Address all correspondence and requests for reprints to: Karl Winkler, M.D., Department of Medicine, Hugstetter Strasse 55, D-79106 Freiburg, Germany. E-mail: kwinkler{at}.ukl.uni-freiburg.de.

Fluvastatin reduces atherogenic dense low-density lipoprotein (dLDL) in patients with type 2 diabetes mellitus (T2DM). dLDLs are associated with platelet-activating factor acetyl hydrolase (PAF-AH), an enzyme involved in inflammation and related to coronary artery disease (CAD). The association of preexisting CAD and PAF-AH and the effect of fluvastatin on enzyme activity is investigated in a placebo-controlled trial in patients with T2DM.

A multicenter, double-blind, randomized comparison of fluvastatin XL (80 mg) (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with T2DM, was conducted. At baseline and on treatment, lipoproteins, including lipoprotein (a) [Lp(a)] and LDL subfractions, and the activity of PAF-AH were measured.

Increasing PAF-AH activity was significantly associated with a positive history of CAD (+0.7% per IU/liter PAH-AH; P = 0.010), the odds ratio estimate adjusted for age, gender, and body mass index of the highest quartile being 10.6 (P = 0.036). At baseline and at study end, PAF-AH activity was associated with the apolipoprotein B (apoB) content in dLDL (LDL-5 and LDL-6) (r = 0.447; P < 0.001 and r = 0.651; P < 0.001, respectively) and with non-HDL cholesterol at baseline (r = 0.485; P < 0.001). However, after additional adjustment for apoB in dLDL and non-HDL cholesterol at baseline, the odds ratio increment for CAD across PAF-AH quartiles was 2.09 (95% confidence interval, 1.02–4.29; P = 0.043). Fluvastatin treatment decreased the activity of PAF-AH by 22.8% compared with an increase of 0.4% in the placebo group (P < 0.001). This effect was independent of changes of Lp(a) concentrations.

In patients with T2DM, PAF-AH activity is associated with a positive history of CAD. Fluvastatin not only decreases atherogenic dLDL but also PAF-AH activity, emphasizing the significance of fluvastatin treatment in T2DM.

The antiatherogenic potential of fluvastatin in T2DM may thus be greater than expected from its effects on LDL-C and triglycerides alone.

This work was supported by Novartis Pharma GmbH, Nürnberg, Germany.

Abbreviations: apoB, Apolipoprotein B; CAD, coronary artery disease; CH, cholesterol; CI, confidence interval; CV, coefficient of variance; dLDL, dense LDL; FC, free cholesterol; GLM, general linear model; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); PAF-AH, platelet-activating factor acetyl hydrolase; PL, phospholipids; T2DM, type 2 diabetes mellitus; TG, triglycerides; WOSCOP Study, West of Scotland Coronary Prevention Study.

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