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

Abstract

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.

Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia

“…PAF-AH hydrolyzes the sn-2 position of the substrate [1-myristoyl-2-(4-nitrophenyl succinyl) phosphatidylcholine], producing 4-nitrophenylsuccinate, which is immediately degraded to 4-nitrophenol and subsequently measured spectrophotometrically 24) .…”

Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial

“…However, the decreases in LDL-C (54 [31] vs 57 [32] mg/dL), TG (176 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between treatment groups.…”

LDL-Related Intolerance to Glucose, Diastolic Hypertension and Additive Effects of Smoking Were Found with Three Female Study Groups

“…The rates of LDL-C did not change here over the course of time while hypercholesterolemic women with diastolic hypertension were currently about ten years older and needed phramcotherapy in the presence of additive risk factors in respect to the medical guidelines [82]. Statins can then inhibit cholesterol synthesis (e.g.…”

“…Statins can then inhibit cholesterol synthesis (e.g. to 70 -100 mg/dl) and also accelerated synthesis of phospholipases as shown with benefit during diabetes [82] [83]. Ezetimibe or plant-derived oxysterols can inhibit intestinal adsorption of cholesterol [84] [85].…”