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Ezetimibe, a cholesterol absorption inhibitor, can be combined with statins to lower low-density lipoprotein (LDL) cholesterol. We have previously shown that ezetimibe can decrease LDL cholesterol by 16% even in patients treated by regular LDL apheresis and statins (Atherosclerosis. 2005;180:107-112). However, it is unclear whether ezetimibe decreases all LDL subfractions equally in patients with hypercholesterolemia. We therefore evaluated the effect of ezetimibe (5 weeks, 10 mg/d) on LDL subtype distribution in a placebo-controlled, double-blind randomized crossover study in 20 patients (age, 56+/-9 years; body mass index, 27.5+/-4 kg/m2) with severe hyperlipoproteinemia and coronary heart disease who are treated by statins and regular LDL apheresis. Both treatment periods (placebo and ezetimibe) were separated by a 5-week washout period. Low-density lipoprotein subtype distribution was determined at the end of each treatment period before apheresis by density gradient ultracentrifugation (LDL1, 1.020-1.024; LDL2, 1.025-1.029; LDL3, 1.030-1.034; LDL4, 1.035-1.040; LDL5, 1.041-1.047; LDL6, 1.048-1.057; LDL7, 1.058-1.066 g/mL). Overall, the LDL subtype distribution did not change significantly (large-buoyant LDL [LDL1+LDL2], 17.2%+/-6.4% vs 16.3%+/-7.1%; intermediate LDL [LDL3+LDL4], 49.3%+/-4.5% vs 48.2%+/-5.2%; small-dense LDL [LDL5+LDL6+LDL7], 33.5%+/-8.0% vs 35.5%+/-10% during placebo and ezetimibe treatments, respectively). With respect to the individual LDL subfractions, cholesterol was significantly (P<.05, Wilcoxon test) reduced by ezetimibe in LDL1 to LDL5 with a somewhat more pronounced reduction in larger LDL (mean+/-SD, -20%+/-28%, -17%+/-32%, -14%+/-25%, -13%+/-27%, -11%+/-21%, -7%+/-21%, -4%+/-19%; median, -28%, -12%, -18%, -16%, -4%, -4%, -2% for LDL subfractions 1-7, respectively). We therefore conclude that ezetimibe decreases cholesterol in nearly all LDL subfractions. Although this was established in patients concomitantly treated with statins and apheresis, this may also hold true in other clinically relevant situations.

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BACKGROUND: Increased C-reactive protein (CRP) concentration is an independent risk predictor for coronary heart disease (CHD). A therapeutic reduction of CRP might, therefore, reduce the risk of cardiovascular events. A single LDL apheresis lowers LDL cholesterol by 45-70%, and CRP by 20-65%, however, less is known about the long-term effects of LDL apheresis on CRP levels. METHODS: We investigated 34 CHD patients (20 males, 14 females, 52 +/- 10 years) on statin therapy who were regularly treated by LDL apheresis because of drug-resistant hypercholesterolemia. Measurements of CRP (ultrasensitive nephelometric assay) were performed before the first apheresis, before a current apheresis (1 or 2 weeks after the last apheresis), and after a current apheresis (treatment period: 5.3 +/- 4.2 years, range: 0.25-12.5 years). LDL apheresis was performed by immunoadsorption (n = 6), dextran sulfate adsorption (n = 13), heparin-induced extracorporal LDL precipitation (HELP, n = 9), or direct adsorption of lipoproteins (DALI, n = 6). RESULTS: CRP was significantly lower before a current apheresis (median: 0.75 mg/l, range: 0.16-4.33 mg/l) compared to before the first apheresis (median: 0.85 mg/l, range: 0.16-7.02 mg/l; P < 0.05). As expected, total and LDL cholesterol were lower before a current apheresis compared to before the initial apheresis while fibrinogen concentration did not differ significantly. CONCLUSION: Over the period of more than 5 years LDL apheresis slightly, but significantly reduced CRP concentrations in patients with CHD on statin therapy, which may contribute to the stabilization of atherosclerosis in hypercholesterolemic patients treated with LDL apheresis. These results are even more impressive when the known age-related increase in CRP over the treatment period is taken into account.

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BACKGROUND: Diabetic dyslipoproteinemia is characterized by hypertriglyceridemia, low HDL-cholesterol and often elevated LDL-cholesterol and is a strong risk factor for atherosclerosis. Adhesion molecule levels are elevated both in hyperlipoproteinemia and diabetes mellitus. It is unclear whether fibrate or statin therapy has more beneficial effects on adhesion molecule concentrations. METHODS: Atorvastatin (10 mg/d) was compared to fenofibrate (200 mg/d) each for 6 weeks separated by a 6 week washout period in 11 patients (6 male, 5 female; 61.8 +/- 8.2 years; body mass index 29.8 +/- 3.1 kg/m2) with type 2 diabetes mellitus (HbA1c 7.3 +/- 1.1%) and mixed hyperlipoproteinemia using a randomized, cross-over design. Fasting blood glucose, HbA1c, lipid parameters, E-selectin, ICAM-1, VCAM-1, and fibrinogen concentrations were determined before and after each drug. RESULTS: Glucose and HbA1c concentrations remained unchanged during the whole study period. LDL cholesterol was reduced during atorvastatin therapy, triglycerides were lowered more effectively with fenofibrate. Comparison of pre- and postreatment concentrations of E-selectin showed a reduction during atorvastatin (-7%, p = 0.11) and fenofibrate (-10%, p < 0.05) therapy. Atorvastatin treatment reduced VCAM-1 levels by 4% (p < 0.05), while VCAM-1 concentrations remained unchanged (+1%, ns) during fenofibate therapy. However, direct comparisons of post-treatment levels during both forms of therapy were not of statistical significance. ICAM-1 levels were not influenced by either form of therapy. CONCLUSIONS: In addition to the different beneficial effects on lipid metabolism, both drugs appear to lower adhesion molecule plasma concentrations in a different manner in patients with type 2 diabetes and mixed hyperlipoproteinemia. Our observations should be confirmed in a larger cohort of such patients.

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Direct adsorption of lipoproteins (DALI) apheresis has been shown to reduce effectively low-density lipoprotein (LDL) cholesterol and lipoprotein (a) concentrations. However, the effects on nontraditional risk indicators such as hemorheology and LDL subtypes have not been investigated so far. Five patients (2 women, 3 men, age 53 +/- 8 years) with coronary artery disease and severe LDL hypercholesterolemia regularly treated with other LDL apheresis devices entered the study and were then treated with DALI for the first time. Hemorheological and lipoprotein parameters were measured before and immediately after the initial DALI apheresis as well as before the fourth DALI apheresis. Compared to baseline (before the first DALI apheresis), the following parameters were significantly improved (p < 0.05) after the first DALI apheresis: LDL cholesterol (69 +/- 28 versus 208 +/- 82 mg/dl) and cholesterol in each LDL subfraction as well as plasma viscosity (1.23 +/- 0.04 versus 1.37 +/- 0.06 mPa), C-reactive protein, native blood viscosity, red cell aggregation, and red cell deformability. When parameters before the fourth DALI apheresis were compared to baseline, LDL cholesterol was still lower, and red cell deformability was still improved while cholesterol in each subfraction showed a statistical trend to lower concentrations (0.08 < p < 0.14). In conclusion, DALI apheresis not only reduces LDL cholesterol but also induced a significant reduction of cholesterol in all LDL subfractions and improved various hemorheological parameters.

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