Combination of dietary phytosterols plus niacin or fenofibrate: effects on lipid profile and atherosclerosis in apo E-KO mice

Patients with mixed dyslipidemias (increased LDL cholesterol and triglyceride as well as low HDL cholesterol levels) benefit from a combination of lipid-modifying drugs such as statins, niacin, fibrates and ezetemibe. However, safety, tolerability and cost are a concern in drug combination therapy. Dietary phytosterols reduce LDL cholesterol, and niacin or fenofibrate primarily reduces triglyceride and increases HDL-cholesterol levels. Thus, we hypothesized that a combination of phytosterols with niacin or fenofibrate will synergistically impact lipoprotein profile and atherogenesis in apo E-KO mice. Phytosterols alone significantly reduced plasma total cholesterol levels (14.1 vs. 16.9 mmol/L, P<.05) and the extent of atherosclerosis (0.42 vs. 0.15 mm2, P<.05). The addition of fenofibrate to phytosterols increased plasma total cholesterol levels by >50% (14.1 vs. 21.6 mmol/L, P<.05) and decreased HDL-cholesterol concentrations by 50% (0.8 vs. 0.4 mmol/L). These changes were accompanied by slight reductions in the extent of atherosclerosis (0.42 vs. 0.34 mm2, P>0.05) as compared to controls, suggesting other potential anti-atherogenic effects of fenofibrate. Unlike fenofibrate, niacin caused an increase of 150% (P<.05) in HDL-cholesterol concentrations and a decrease of 22% (P<.05) in total cholesterol levels which were associated with significant reductions (65%, P<.05) in atherosclerotic lesion size as compared to controls. Neither the addition of niacin nor of fenofibrate reduced plasma triglyceride levels. In conclusion, the addition of niacin to phytosterols synergistically increases HDL-cholesterol levels, while a combination of phytosterols and fenofibrate results in no synergistic effects in apo E-KO mice. Further studies in other animal models are needed to establish synergetic effects between these lipid-modifying dietary and pharmacological agents.