Statins For Treatment Of Hypercholesterolemia Research Articles

Von der kardiovaskulären Prävention zur Anti-Aging-Medizin: Einfluss auf Telomere und Zellalterung

The most important cardiovascular risk factors (hypercholesterolemia , hypertension, diabetes, chronic stress, physical inactivity, smoking, adipositas) were evaluated in the second half of the last century using placebo controlled trials. The mechanismen of action was not fully understood or remained unclear. In some studies not only the risk of atherosclerosis was reduced but life expectancy was improved. The length of telomeres is influenced by many of the cardiovascular risk factors and is a biomarker of age. Reduced telomere length are found in higher age, atherosclerosis, hypertension, adipositas, diabetes, smoking, physical inactivity, heart failure, maltreatment in childhood, exposure to traffic pollution, chronic infection, single life and dementia. A positive effect on telomerase and telomere length is found with increased physical activity, statins for treatment of hypercholesterolemia, and higher blood levels of omega-3 fatty acids. The probable mechanismen for this is an activation of telomerase activity. Many of the cardiovascular risk factors influence the cellular DNA by telomere shortening. These effects could be reduced by life style measures with prudent diet and drugs for good somatic fitness and healthy aging. By this mechanism cardiovascular prevention not only reduces the risk of atherosclerosis but also improves life exspectancy by anti-aging effects.

Statin‐induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells

Autophagy is a cellular process of degradation of macromolecules and organelles and activated under nutritional stress. Statins are a class of inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in synthesis of cholesterol. Epidemiological studies have shown that statin use decreases the incidence of advanced prostate cancer. We explored the idea that treatment of atorvastatin, a commonly prescribed statin for treatment of hypercholesterolemia, induces autophagy in prostate cancer cells. The atorvastatin-induced autophagic process in prostate cancer PC3 cells was determined by detection of cellular level of LC3-II, an autophagosomal marker, via immunoblotting and immunofluorescent staining. Atorvastatin treatment of PC3 cells for 40 hrs increased expression of LC3-II by more than 10 fold in a dose-dependent manner. Treatment of the cells with pepstatin A and E64-d, the autophagic protease inhibitors, dramatically increased atorvastatin-dependent LC3-II expression level, suggesting that atorvastatin induces autophagic flux. In addition, atorvastatin treatment caused rapid death of PC3 cells. Atorvastatin-induced autophagy and rapid cell death were reversed by addition of geranylgeraniol, not farnesol, into culture medium, indicating that atorvastatin-mediated inhibition of geranylgeranyl biosynthesis causes autophagy and cell death. Furthermore, atorvastatin did not induce autophagy or cell death in normal prostate RWPE1 cells, and induced only a minor autophagic response in AR-positive prostate cancer LNCaP cells. Our studies demonstrate that statins induce autophagy and autophagy-associated cell death in PC3 cells, likely through inhibition of geranylgeranylation, and suggest that autophagic response to statins may partially underlie the protective effects of statins on prostate cancer progression. Importantly, these findings highlight additional mechanisms by which statins might be used for prostate cancer therapy.

New azetidinone cholesterol absorption inhibitors

Since their initial discovery, azetidinones have been extensively studied as potent cholesterol absorption inhibitors. Ezetimibe is the first-in-class and only member in the clinics either as a monotherapy or in combination with statins for treatment of hypercholesterolemia. The recent identification of Niemann–Pick C1-like 1 protein in the brush border membrane of the small intestine as a possible molecular target has opened the door for the design and synthesis of new anticholesterol drugs. This article reviews the important literature and patents on cholesterol absorption inhibitors.

Consistency in Efficacy and Safety of Ezetimibe Coadministered with Statins for Treatment of Hypercholesterolemia in Women and Men

Women are often not treated as aggressively as men to control levels of low-density lipoprotein cholesterol (LDL-C), despite evidence that women and men realize comparable cardiovascular benefit from lipid-lowering therapy. Statins are the most effective drugs currently available for treating hypercholesterolemia. Despite the impressive cholesterol-lowering capacity of statins, however, many patients on statin therapy fail to reach established target levels of LDL-C. The cholesterol absorption inhibitor, ezetimibe, blocks the intestinal absorption of dietary and biliary cholesterol, a mechanism of action complementary to that of statins, which inhibit hepatic cholesterol synthesis. Ezetimibe coadministered with statins produces significant incremental reductions in LDL-C compared with statin monotherapy. Four randomized, double-blind, placebo-controlled, balanced-parallel group trials compared the efficacy and safety of statin monotherapy (lovastatin or pravastatin 10, 20, or 40 mg; simvastatin or atorvastatin 10, 20, 40, or 80 mg) vs. ezetimibe 10 mg plus statin (as above). A gender subset analysis (women, n = 1065; men, n = 796) on data pooled across these four trials was carried out to determine whether ezetimibe plus statin for the treatment of hypercholesterolemia is equally efficacious in women and men. Compared with statin monotherapy, ezetimibe plus statin demonstrated greater efficacy in reducing blood levels of LDL-C, apolipoprotein B, and triglycerides and raising high-density lipoprotein cholesterol. The beneficial effects of ezetimibe were comparable in women and men. The safety profile of subjects receiving ezetimibe plus statin was similar to that of patients receiving statin monotherapy and similar between the two sexes. Ezetimibe plus statin was more effective than statin alone in improving the lipid profile of patients with hypercholesterolemia and was equally efficacious in women and men. Ezetimibe plus statin was well tolerated and had a favorable safety profile in both patient subgroups. Ezetimibe coadministered with statins, a dual inhibition treatment strategy that targets both cholesterol absorption and synthesis, is an effective therapeutic option for women with hypercholesterolemia.