Statins and neuroprotection

The beneficial effect of β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in primary prevention of coronary artery disease in those with hypercholesterolaemia and in secondary prevention in those with established coronary vascular disease are now well known. A growing body of evidence suggests that statins also possess important additional clinical benefits, such as stroke risk reduction. In this article we review the evidence that statins may be neuroprotective, especially in the brain parenchyma during stroke. We also review the observational data that statins may prevent the onset of dementia.     

Synthetic Statins: More Data on Newer Lipid-lowering Agents

SUMMARY

Extensive trial evidence supports the use of hydroxy-methyl-glutaryl-CoA reductase inhibitors (HMG-CoA-RI; statins) in atherosclerotic disease. Statins can be divided into two broad groups: the ‘natural’ statins derived from a fungal metabolites, and synthetic compounds. Whether all statins have similar anti-atherosclerotic properties, or whether these actions are specific to the ‘natural’ statins, is controversial. This commentary reviews the differences between natural and synthetic statins with regard to including their action on the acute phase reactant C-reactive protein. Among the newer synthetic statins, fluvastatin has some positive end-point evidence while cerivastatin shares many biochemical properties with the ‘natural’ statins. Extensive clinical trial programmes are underway with both atorvastatin and cerivastatin. These trials will give a definitive answer to the question of whether synthetic statins are as equally efficacious as ‘natural’ statins in preventing atherosclerotic events.     

他汀类化合物构效关系研究进展

他汀类化合物是羟甲戊二酰辅酶A还原酶(HMGR)抑制剂,能够调节血浆中低密度脂蛋白胆固醇(LDL-C)水平。由于他汀类化合物安全有效,不良反应少,已成为目前临床上治疗高血脂症的首选药物。开发结构简单且安全有效的他汀类化合物一直是降血脂药物研究的热点。本文对近年他汀类化合物的母环和侧链两方面的构效关系进行综述。     

Statins and the risk of idiopathic venous thromboembolism

AIMS: To evaluate the association between current statin use and the risk of idiopathic venous thromboembolism (VTE). METHODS: A population-based retrospective follow-up with a nested case-control analysis using the General Practice Research Database. RESULTS: There were 72 cases of idiopathic VTE. Using normolipidaemic nonuse as the reference group, the adjusted relative risks for idiopathic VTE for current/recent statin use, past statin use, past other lipid-lowering drug use, and hyperlipidaemic nonuse were 0.8 (0.3, 2.7), 2.4 (0.6, 10.0), 1.8 (0.4, 7.4), and 0.9 (0.4, 2.0) in the follow-up analysis, and were 1.1 (0.3, 4.3), 3.7 (0.6, 24.1), 2.0 (0.3, 11.6), and 0.4 (0.2, 1.2) in the case-control analysis. CONCLUSIONS: Current statin use was not associated with a reduced risk of idiopathic VTE.     

他汀类药物对于阿尔茨海默病的疗效

流行病学和药理学研究结果显示，胆固醇在阿尔茨海默病(Alzheimer’s disease．AD)的发生中起着重要作用，他汀类药物对于AD具有潜在的治疗作用，今后这类药物可能被用来治疗AD。本综述了目前他汀类药物对AD的研究报道，并对他汀类药物、胆固醇、AD之间的作用机制进行了探讨，为AD的治疗和他汀类药物的新应用提供参考。     

Lovastatin and gemfibrozil in the treatment of type 2a and type 2b hyperlipoproteinemia

Summary Subanalyses of previous multicenter studies comparing lovastatin and gemfibrozil were carried out to evaluate the merits of these agents in patients with different serum lipid phenotypes (type 2a and 2b hyperlipoproteinemia). Regardless of phenotype, lovastatin was more effective in lowering LDL-cholesterol, while gemfibrozil had a greater triglyceride-lowering and HDL-cholesterol-increasing effect. Patients with type 2a phenotype benefited (in terms of serum lipid pattern) more from lovastatin. In type 2b hyperlipoproteinemia, more patients taking lovastatin than gemfibrozil reached both treatment goals defined by the European Atherosclerosis Society, (LDL-cholesterol4.0 mmol/Iandtriglycerides 2.3 mmol/1). In many patients these goals could not be met suggesting that multiple drug therapy may be indicated in part of the patients with type 2b hyperlipoproteinemia.     

Statins and fracture risk. A systematic review

PURPOSE: To summarize current evidence on statin use and fracture risk and to explore potential sources of heterogeneity among study results. METHODS: A computerized search was conducted on MEDLINE, EMBASE, and the Cochrane databases using the keywords HMG-CoA reductase inhibitor, osteoporosis, and fractures. A meta-analysis was performed to summarize results of studies identified. RESULTS: Statin use was associated with a 23% lower fracture risk (OR = 0.77, 95%CI: 0.66-0.90). An effect of statins was found in case-control (OR = 0.62, 0.45-0.85, n = 6) and cohort (OR = 0.77, 0.59-1.00, n = 8) studies, but not in post hoc analyses of randomized trials (OR = 1.03, 0.91-1.16, n = 4). A reduced risk with statin use was found for fractures of the hip (OR = 0.58, 0.46-0.74, n = 16), spine (OR = 0.65, 0.48-0.88, n = 8) and other sites (OR = 0.77, 0.60-1.00, n = 7), and both in women (OR = 0.80, 0.66-0.96, n = 11) and men (OR = 0.62, 0.36-1.08, n = 3). Among the observational studies that also evaluated the effect of other lipid-lowering drugs, no reduced fracture risk was found for these agents (OR = 0.96, 0.85-1.09, n = 10). The test for heterogeneity was significant for study results of statin use versus no-use (p < 0.01). Meta-regression analyses suggested that study design might partly account for the heterogeneity. There was an indication of publication bias by examining Begg's plot, although Egger's test was not significant (p = 0.13). CONCLUSIONS: Current evidence does not support an effect of statins in preventing fractures given (i) the lack of association in randomized trials, (ii) the heterogeneity among observational studies, (iii) the potential residual confounding, and (iv) the potential publication bias.     

Statins: balancing benefits,efficacy and safety

Coronary heart disease (CHD) is the leading cause of death in the US. The risk of CHD is substantially increased in people with elevated levels of low-density lipoprotein cholesterol (LDL-C). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective drug class for lowering LDL-C. Long-term prospective studies have shown that statin therapy significantly reduces the risk of CHD morbidity and mortality in patients without or with evidence of established CHD (primary and secondary prevention, respectively). In 1988, treatment guidelines were first issued by the National Cholesterol Education Program Adult Treatment Panel I (NCEP-ATP I), then revised in 1993 (ATP II), to provide recommendations for the prevention and management of high cholesterol in adults. Despite these guidelines, recent national surveys have shown that effective therapies are being under-utilised and they often fail to achieve LDL-C goals established by NCEP-ATP II. The reasons appear to be multifactorial but include issues related to efficacy, safety, the potential for adverse drug reactions, failure to prescribe appropriate medication or dose and noncompliance with therapy. In the first major update of NCEP guidelines in almost a decade, the current ATP III recommendations have placed an increased number of Americans in the high-risk category, inviting even more aggressive therapy and escalating the challenge of reaching NCEP goals. New statins that may have even greater efficacy and less potential for drug interactions may help address some concerns associated with the failure to achieve treatment goals.     

Current pharmacotherapy for the treatment of dyslipidemia associated with HIV infection

ABSTRACT

Introduction: Cardiovascular disease is an important cause of morbidity and mortality in persons with human immunodeficiency virus (PWH). The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in PWH compared to uninfected persons. Dyslipidemia is a critical link in the pathogenesis of ASCVD in PWH. Chronic inflammation associated with HIV infection may drive both dyslipidemia and ASCVD.

Areas covered: The authors review the evidence for using lipid-lowering therapy in PWH and includes an overview of the utility and complexity of using statins in PWH, in particular, drug interactions, safety, and efficacy. In addition, data covering alternate therapies like omega-3 fatty acids, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors are reviewed.

Expert opinion: Dyslipidemia is a common problem in PWH. The risk of ASCVD is higher in PWH. Lipid-lowering therapy reduces the risk of ASCVD, but clinical endpoint trials are lacking in PWH. Statin therapy is the mainstay of primary prevention for ASCVD. The timing of when to initiate primary prevention with statins in PWH is unclear. Beyond statins, there are limited data that other lipid-lowering agents have utility in PWH. Ongoing trials like the REPRIEVE trial will inform the community about the optimal approach to lipid-lowering therapy in PWH.     

Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.

Areas covered: This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.

Expert opinion: Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.     

Atorvastatin affects the tissue concentration of hydrogen sulfide in mouse kidneys and other organs

Hydrogen sulfide (H2S) is a crucial co-modulator of cardiovascular, nervous, digestive and excretory systems function. The pleiotropic action of atorvastatin exceeds simple 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition and involves multiple biological mechanisms. This study assesses the influence of atorvastatin on the H2S tissue concentration in mouse brain, liver, heart and kidney. Twenty-four female CBA strain mice received an intraperitoneal injection. The mice were given one of the following solutions: 0.1 mg atorvastatin (5 mg/kg of body weight (b.w.)/day--group D1, n=8), 0.4 mg atorvastatin (20 mg/kg b.w./day--group D2, n=8) or a saline physiological control (0.2 ml--group C, n=8). A modified Siegel spectrophotometric method was used for the H2S tissue concentration measurements. There was a remarkable rise in the H2S concentration [μg/g] in the kidney (C: 5.26±0.09, D1: 5.77±0.11, p=0.0003; D2: 7.48±0.09, p<0.0001). There were also slight H2S tissue level changes in the brain (C: 1.61±0.01, D1: 1.75±0.03, p=0.0001; D2: 1.78±0.03, p<0.0001), the heart (C: 4.54±0.08, D1: 4.86±0.10, p=0.0027; D2: 4.56±0.07, p=0.6997) and the liver (C: 3.45±0.03, D1: 3.27±0.02, p=0.0001; D2: 3.31±0.02, p=0.0003). Our study supports the influence of atorvastatin on H2S tissue concentration in kidneys and other mouse organs.     

老年帕金森病的临床护理

目的探讨老年帕金森病(PD)患者情感障碍的相关因素及临床护理干预的作用.方法对48例PD患者随机分为观察组28例,对照组20例.两组均给予内科药物治疗,而观察组同时进行系统的临床护理干预.入院前及出院时予以UPDRS第一分量表(UPDRS Subscale I)评分,进行统计学检验.结果观察组出院时评分改善明显优于对照组(P＜0.01)有显著性差异.结论 PD患者除药物治疗外,同时给予全方位人性化系统护理治疗,可提高患者的生活质量.     

Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present

PURPOSE: Our objective was to determine the association of clinically relevant adverse events from a systematic review and meta-analysis of statin randomized controlled trials (RCT). METHODS: We performed the meta-analysis in the manner of a Cochrane Collaboration systematic review. Outcomes were discontinuances of therapy or muscle-related symptoms due to adverse events. We searched for articles from 1982 through June 2006 in MEDLINE and other databases. The main inclusion criteria were double blind, placebo controlled RCTs with a monotherapy intervention of any marketed statin and active surveillance of adverse events. We excluded studies of drug interactions, organ transplants, or exercise, or those not meeting all of the study quality criteria. The primary analysis was a statin formulation stratified fixed-effect model using Peto odds-ratios (POR). Secondary analyses explored the stability of the primary results. RESULTS: Over 86,000 study participants from 119 studies were included. Available statins were associated with a lower POR of discontinuance (overall: 0.88 [0.84, 0.93], largest effect with pravastatin: 0.79 [0.74, 0.84]), an elevated POR of rhabdomyolysis (1.59 [0.54, 4.70]) and myositis (2.56 [1.12, 5.85]), and null odds of myalgia (1.09 [0.97, 1.23]). Cerivastatin by comparison demonstrated larger PORs for discontinuances and muscle-related adverse events. Secondary analyses demonstrated the stability of the results. CONCLUSIONS: Overall, discontinuation of statin therapy due to adverse events was no worse than placebo. The risks of muscle-related adverse events were in general agreement with the known risks of statins.     

Statin use and cancer risk: a comprehensive review

Importance of the field: HMG-CoA inhibitors (statins), a class of drugs that reduce cholesterol, are used to manage and prevent coronary heart disease. They are among the most commonly prescribed drugs worldwide. Contrary to early concerns over the carcinogenicity of statins, a growing body of evidence suggests statins may in fact have a chemopreventive potential against cancer.

Areas covered in this review: In this paper, we review evidence on the association between statin use and cancer risk. Specifically, we report on clinical trials and observational studies that measured all cancer or site-specific cancers of the breast, colorectal, lung, prostate and reproductive organs associated with statin use.

What the reader will gain: An understanding of the evidence, including strengths and limitations, to support an association between statins and cancer. Information on the current state of the field and future directions are also discussed.

Take home message: Few strong or consistent associations between statins and cancer incidence overall or for any of the sites reviewed were detected. Data for any effects of statins on cancer prognosis and secondary prevention are lacking; with the exception of consistent evidence that statins are associated with reduced risk of advanced/aggressive prostate cancer. Statins appear safe in relation to cancer risk but any chemopreventive effect in humans remains to be established and should not be recommended outside the context of clinical trials. It is encouraging that numerous trials are ongoing. The prospect of reducing the incidence and burden of some of the most prevalent cancers with safe, affordable and tolerable medication that already reduces the risk of the leading cause of death and cardiovascular disease warrants further exploration in clinical trials and observational studies of prognosis and survival.     

HMG-CoA reductase inhibitors improve heart rate variability in patients with a previous myocardial infarction

Statins decrease mortality in patients with coronary heart disease (CHD). The effect may begin early after initiation of therapy, but the mechanism(s) behind this has not been totally delineated. In the present study 304 patients referred for elective coronary angiography due to suspected CHD were included. Seventy-three of the patients had a previous myocardial infarction (MI). Twenty-four hours heart rate variability (HRV) was obtained in all the patients. In patients with a previous MI, HRV was significantly higher in patients who were treated with statins compared to patients not given statins. Matching of the patients with identical serum cholesterol levels (3.7 mmol l(-1) < or = s-cholesterol < or = 8.1 mmol l (-1)) also revealed a higher SDNN in patients who had a previous MI and were on statin treatment. Similar results were seen by matching for serum low-density-lipoprotein cholesterol levels. In line with this, step-wise multiple linear regression analysis revealed that treatment with statins had an independent and significant impact on HRV. Our data suggest that statins may increase HRV in patients with a previous MI, which could in part explain the early beneficial effect on clinical events observed in several trials.     

Chronic obstructive pulmonary disease: patho-physiology,current methods of treatment and the potential for simvastatin in disease management

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a severe disease that leads to a non-reversible obstruction of the small airways. The prevalence of this disease is rapidly increasing in developed countries, and in 2020 it has been predicted that this disease will reach the third cause of mortality worldwide. COPD patients do not respond well to current treatment modalities, such as bronchodilators and corticosteroids.

Areas covered: This review article focuses on the patho-physiology of COPD, explores current approaches to alleviate and treat the disease, and discusses the potential use of statins for treatment. Specifically, the mechanism of action and metabolism of simvastatin, the most known and studied molecule among the statin family, are critically reviewed.

Expert opinion: Various cellular pathways have been implicated in COPD, with alveolar macrophages emerging as pivotal inflammatory mediators in the COPD patho-physiology. Recently, emerging anti-cytokine therapies, such as PDE4 inhibitors and ACE inhibitors, have shown good anti-inflammatory properties that can be useful in COPD treatment. Recently, statins as a drug class have gained much interest with respect to COPD management, following studies which show simvastatin to exert effective anti-inflammatory effects, via inhibition of the mevalonic acid cascade in alveolar macrophages.