Evaluating optimal lipid levels in patients with mixed dyslipidemia following short- and long-term treatment with fenofibric acid and statin combination therapy: a post hoc analysis.

OBJECTIVE: To evaluate the achievement of individual and combined lipid and lipoprotein/biomarker targets as specified by treatment guidelines with the combination of fenofibric acid and statin therapy in patients with mixed dyslipidemia. METHODS: Data for the post hoc analyses were derived from three 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; low-, moderate-, or high-dose statin (rosuvastatin 10, 20, or 40 mg; atorvastatin 20, 40, or 80 mg; or simvastatin 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin in the controlled studies; and with fenofibric acid + moderate-dose statin in the extension study. Achievement of risk-stratified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (ApoB) targets; and optimal levels of ApoB <90 mg/dL, HDL-C >40/50 mg/dL in men/women, triglycerides (TG) < 150 mg/dL, and high-sensitivity C-reactive protein <2 mg/L were assessed. RESULTS: In the controlled studies, significantly lower percentage of high-risk patients treated with fenofibric acid + moderate-dose statin, and significantly higher percentage of high-risk patients treated with fenofibric acid + low-dose statin, compared with corresponding-dose statin monotherapies, achieved their LDL-C (51.3% vs. 72.9%, p < 0.001) and non-HDL-C targets (53% vs. 38%, p = 0.02), respectively. Among all patients, optimal levels of ApoB, HDL-C, TG, and the combined target of LDL-C + non-HDL-C + ApoB + HDL-C + TG were achieved by higher percentage of patients treated with fenofibric acid + low- and moderate-dose statin versus corresponding dose-statin monotherapies (p ≤ 0.04 for all comparisons). In the extension study, significantly (p < 0.001 for all comparisons) higher percentage of patients had achieved individual and combined targets at final visit, compared with baseline. CONCLUSIONS: In patients with mixed dyslipidemia, short-term treatment with the combination of fenofibric acid and low- or moderate-dose statin resulted in comparable or more patients achieving individual targets of non-HDL-C, ApoB, HDL-C, and TG, and combined targets for these parameters and LDL-C, compared with corresponding-dose statin monotherapy. In the long-term study, the proportion meeting these targets was significant, compared with baseline. Limitations include the post hoc nature of the analysis, and the fact that all patients had mixed dyslipidemia and majority were white, which limits generalization to other populations.

Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1.

Statins and gamma-tocotrienol (a rare isoform of vitamin E) both inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase activity and display anticancer activity. However, clinical application of statins has been limited by high dose toxicity. Previous studies showed that combined statin and gamma-tocotrienol treatment synergistically inhibits growth of highly malignant +SA mammary epithelial cells in culture. To investigate the mechanism mediating this growth inhibition, studies were conducted to determine the effect of combination low dose gamma-tocotrienol and statin treatment on +SA mammary tumor cell cycle progression. Treatment with 0.25 microM simvastatin, lovastatin, mevastatin, 10 microM pravastatin or 2.0 microM gamma-tocotrienol alone had no effect, while combined treatment of individual statins with gamma-tocotrienol significantly inhibited +SA cell proliferation during the 4-day culture period. Flow cytometric analysis demonstrated that combined treatment induced cell cycle arrest in G1. Additional studies showed that treatment with 0.25 microM simvastatin or 2 microM gamma-tocotrienol alone had no effect on the relative intracellular levels of cyclin D1, CDK2, CDK4 and CDK6, but combined treatment caused a large reduction in cyclin D1 and CDK2 levels. Combined treatments also caused a relatively large increase in p27, but had no effect on p21 and p15 levels, and resulted in a large reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. Similar effects were observed following combined treatment of gamma-tocotrienol with low doses of lovastatin, mevastatin and pravastatin. These findings demonstrate that combination low dose statin and gamma-tocotrienol treatment induced mammary tumor cell cycle arrest at G1, resulting from an increase in p27 expression, and a corresponding decrease in cyclin D1, CDK2, and hypophosphorylation of Rb protein. These findings suggest that combined treatment of statins with gamma-tocotrienol may provide significant health benefits in the treatment of breast cancer in women, while avoiding myotoxicity associated with high dose statin monotherapy.

Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the membrane anchorage and biologic functions of growth-related proteins. Contrary to preclinical studies showing the growth-suppressive activity of statins, competitive inhibitors of HMG CoA reductase, clinical application of statins in cancer is precluded by their lack of activity at levels prescribed for the prevention of cardiovascular disease and by their dose-limiting toxicities at high doses. The dysregulated and elevated HMG CoA reductase activity in tumors retains sensitivity to the isoprenoid-mediated posttranscriptional down-regulation, an action that complements the statin-mediated inhibition and may lead to synergistic impact of blends of isoprenoids and lovastatin on tumor HMG CoA reductase activity and consequently tumor growth. d-gamma- and d-delta-tocotrienols, vitamin E isomers containing an isoprenoid moiety, and lovastatin-induced concentration-dependent inhibition of the 48-hr proliferation of murine B16 melanoma cells with IC50 values of 20 +/- 3, 14 +/- 3, and 1.5 +/- 0.4 microM respectively. A blend of lovastatin (1 microM) and d-gamma-tocotrienol (5 microM) totally blocked cell growth, an impact far exceeding the sum of inhibitions induced by lovastatin (12%) and d-gamma-tocotrienol (8%) individually. Synergistic impact of these two agents was also shown in human DU145 prostate carcinoma and human A549 lung carcinoma cells. C57BL6 mice were fed diets supplemented with 12.5 mg lovastatin/kg body weight, 62.5 mg d-delta-tocotrienol/kg body weight, or a blend of both agents for 22 days following B16 cell implantation; only the latter had significantly lower tumor weight than those with no supplementation. Co-administration of isoprenoids that posttranscriptionally down-regulate tumor reductase may lower the effective dose of statins and offer a novel approach to cancer chemo-prevention and/or therapy.