Can statins put the brakes on Alzheimer’s disease?

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which initiates the syntheses of cholesterol and isoprenoid lipids that are needed to provide amyloid peptides for the amyloid cascade. This cascade is believed to induce sporadic or late-onset Alzheimer’s disease, which accounts for 90 – 95% of Alzheimer’s disease sufferers. Cholesterol is also the prime driver of cerebrovascular disease that (along with amyloid peptides) increasingly appears to be linked to the cognitive deterioration of Alzheimer’s disease. Cholesterol is needed to make the lipid rafts that are the platforms for isoprenoid-dependent assembly and activation of raftophilic β- and γ-secretases that work in tandem to excise dangerous 40 and 42 amino acid amyloid-β (Aβ) fragments from amyloid precursor protein, the transmembrane amyloid precursor glycoprotein. When they are excessively produced and can no longer be effectively destroyed or otherwise cleared from the hypoperfused ageing brain, the Aβ42 fragments released from the active synaptic terminals of normally busy neurons (and from stressed neurons unsuccessfully trying to proliferate and producing disruptive tangles of hyperphosphorylated τ-proteins) aggregate into neuritic plaques, which activate glial cells. The pro-inflammatory cytokines and growth factors from the glial cells further damage and kill neurons. As statins strike at several parts of the Alzheimer’s disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer’s disease development) should slow or even prevent the progression of Alzheimer’s disease. Indeed, there is some evidence of a significantly reduced incidence of Alzheimer’s disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects. To be certain of this, there must be more multi-year trials to specifically assess the effects of statins on sporadic Alzheimer’s disease.     

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

Drug–drug interaction with statins

3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (the so-called statins: atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin and simvastatin) are a well-established class of drugs in the treatment of hypercholesterolemia. Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Since statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. Moreover, a combination of therapy between statins and other classes of lipid-lowering agents (e.g., ezetimibe, fibrates, resins and nicotinic acid) is recommended for some patients by current guidelines. Therefore, the potential for drug–drug interactions emerges as a relevant factor in determining the safety profile of statins. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.     

Can statins put the brakes on Alzheimer's disease?

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which initiates the syntheses of cholesterol and isoprenoid lipids that are needed to provide amyloid peptides for the amyloid cascade. This cascade is believed to induce sporadic or late-onset Alzheimer's disease, which accounts for 90 - 95% of Alzheimer's disease sufferers. Cholesterol is also the prime driver of cerebrovascular disease that (along with amyloid peptides) increasingly appears to be linked to the cognitive deterioration of Alzheimer's disease. Cholesterol is needed to make the lipid rafts that are the platforms for isoprenoid-dependent assembly and activation of raftophilic beta- and gamma-secretases that work in tandem to excise dangerous 40 and 42 amino acid amyloid-beta (Abeta) fragments from amyloid precursor protein, the transmembrane amyloid precursor glycoprotein. When they are excessively produced and can no longer be effectively destroyed or otherwise cleared from the hypoperfused ageing brain, the Abeta42 fragments released from the active synaptic terminals of normally busy neurons (and from stressed neurons unsuccessfully trying to proliferate and producing disruptive tangles of hyperphosphorylated tau-proteins) aggregate into neuritic plaques, which activate glial cells. The pro-inflammatory cytokines and growth factors from the glial cells further damage and kill neurons. As statins strike at several parts of the Alzheimer's disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer's disease development) should slow or even prevent the progression of Alzheimer's disease. Indeed, there is some evidence of a significantly reduced incidence of Alzheimer's disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects. To be certain of this, there must be more multi-year trials to specifically assess the effects of statins on sporadic Alzheimer's disease.     

Modulation of cardiovascular remodeling with statins: fact or fiction?

The concept of cardiac remodeling implies a complex mixture of myocardial ischemia, and increased wall stress that results in molecular, cellular and interstitial changes in the heart. Clinically, cardiac remodeling is manifested as a change in size, shape and function of the heart. Morphologically the key feature of remodeling is myocyte hypertrophy, myocyte loss from necrosis or apoptosis, as well as interstitial cell growth especially fibroblast proliferation leading to myocardial fibrosis. Cardiac remodeling is influenced by hemodynamic load, neurohumoral activation, and other factors that can further affect the remodeling process. Despite advances in the management of heart failure, morbidity and mortality still present major health care issues in these patients. Statins (HMG Coenzyme A reductase inhibitors) play a key role in the management of ischemic heart disease. Recent studies indicate that statins may modulate cardiac remodeling by affecting signals that cause fibroblast growth, and myocyte hypertrophy and loss. In this paper we review the mechanisms of cardiac remodeling and the mechanisms of potential beneficial effects of statins on cardiac remodeling.     

Pleiotropic effects of statins: stabilization of the vulnerable atherosclerotic plaque?

Acute coronary syndromes (ACS), i.e. unstable angina and myocardial infarction, are the leading causes of death in developed countries and developing countries alike. Lipid lowering intervention studies have demonstrated a 30% risk reduction in recurrent cardiovascular events and death, despite only modest improvement in angiographic stenosis. This discrepancy suggested that cholesterol lowering by statins may lead to stabilization of vulnerable plaques rather than reducing stenosis per sé. The predominant effect of statins is to lower lipid levels by inhibiting cholesterol biosynthesis. Besides the lipid lowering effects, statins have also been shown to modulate the inflammatory status and improve endothelial function amongst others, commonly referred to as "pleiotropic effects". In the present review we will discuss different determinants which lead to plaque vulnerability and subsequently we will expand on the plaque stabilizing or "pleiotropic" effects of statin treatment.     

Do statins afford neuroprotection in patients with cerebral ischaemia and stroke?

An emerging body of evidence indicates that beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or 'statins', provide neuroprotection in addition to reducing ischaemic stroke. Statins reduce the incidence of ischaemic stroke by stabilising atherosclerotic plaques in the precerebral vasculature and through antithrombotic actions, and the neuroprotective effects of statins may confer significant clinical benefit. Some of these neuroprotective effects are likely to be cholesterol independent and mediated by the interruption of isoprenoid biosynthesis. Therapy with statins may modulate endothelial function and preserve blood flow to regions exposed to an ischaemic insult. In particular, statin-mediated preservation of endothelial nitric oxide synthase activity in cerebral vasculature, especially in the ischaemic penumbra, may limit neurological deficit. Moreover, putative anti-inflammatory and antioxidant properties of statins may confer additional neuroprotection. Further large clinical trials are necessary to address the role of statin therapy in the primary prevention of stroke, small vessel cerebrovascular disease and vascular dementia.     

Telomere/Telomerase system: a new target of statins pleiotropic effect?

Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named "pleiotropic effects" and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function. Recently, additional pleiotropic effects of statins on "cellular senescence" have been seen in different cell types, including endothelial progenitor cells (EPC), endothelial cells (EC), VSMC and chondrocytes. At the molecular level, the effect of statins on cellular senescence could be mediated by their interaction with the telomere/telomerase system. Recent evidence suggests that the anti-aging effects of statins are linked to their ability to inhibit telomere shortening by reducing either directly and indirectly oxidative telomeric DNA damage, as well as by a telomere capping proteins dependent mechanism. In this review, we discuss the pleiotropic effects of statins, focusing on the telomere/telomerase system. We will also present our current findings regarding leukocyte telomere length in very old people with myocardial infarction on statin therapy.     

Combination of clopidogrel and statins: a hypothetical interaction or therapeutic dilemma?

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and clopidogrel are frequently used in the treatment of patients with various cardiovascular disorders. The possibility of a drug-drug interaction between certain statins and clopidogrel has been extensively investigated in the literature recently. Investigators have proposed that the use of statins that are metabolized by the cytochrome P450 (CYP) system may diminish the conversion of clopidogrel to its active form by inhibiting the CYP3A4 isoenzyme. This inhibition could result in a decreased antiplatelet effect of clopidogrel, which could translate into an increased risk of cardiovascular events. METHODS: We performed a MEDLINE search of the literature from 1993-2005 to evaluate and discuss the existing data on a possible interaction between clopidogrel and statins and to provide clinicians with relevant and practical recommendations. Additional studies were identified from the bibliographies of the reviewed literature. RESULTS: Several articles were discovered that discuss this potential drug-drug interaction. Whereas some studies indicated that there was not a relevant interaction between statins and clopidogrel, other studies demonstrated that the concomitant administration of some statins with clopidogrel resulted in diminished platelet inhibition activity of clopidogrel. CONCLUSIONS: Although the interaction between certain statins and clopidogrel seems to be a pharmacologic certainty, the clinical relevance of this interaction needs further clarification. While investigators continue to evaluate the clinical relevance, we provide several recommendations for clinicians responsible for treating patients who require combination therapy with statins and clopidogrel.     

他汀类药物（statins）通过抑制内源性胆固醇合成限速酶还原酶

他汀类药物（statins）通过抑制内源性胆固醇合成限速酶还原酶,使细胞内胆固醇合成减少,是治疗动脉粥样硬化（atherosclerosis, AS）的基本药物。研究表明,他汀类药物还存在着非胆固醇依赖的多效性,包括改善血管内皮功能,抑制血管平滑肌增殖,促进血管新生,抗炎,抗氧化以及减轻血管和心肌重构等。本文就他汀类药物临床应用作一综述。