Cumulative clinical trial data on atorvastatin for reducing cardiovascular events: the clinical impact of atorvastatin

ABSTRACT

Background: Since the 1990s a multitude of statin trials have definitively demonstrated the ability of statin therapy to reduce the risk of adverse coronary heart disease (CHD) events. Among these, the Atorvastatin Landmarks program – a group of 32 major atorvastatin trials – has assessed the efficacy and safety of atorvastatin across its full dose range and has helped illustrate its effectiveness in treatment of cardiovascular disease and its related disorders and also in non-cardiovascular outcomes.

Scope: This paper will review the major atorvastatin clinical trials and report the important findings and their clinical significance.

Findings: Clinical trials with atorvastatin have established significant reductions in cardiovascular events in patients with and without CHD. Studies show that high-dose atorvastatin will reduce LDL to ≈?70?mg/dL in many patients and improve cardiac outcomes. Current evidence suggests that high-dose atorvastatin can halt and, in some cases, reverse atherosclerotic progression. A study of diabetic patients showed atorvastatin decreased the occurrence of acute CHD events, coronary revascularizations, and stroke. Atorvastatin has been found to be effective for reducing nonfatal myocardial infarctions and fatal CHD in hypertensive patients with three or more additional risk factors. High-dose atorvastatin was found to be effective in reducing risk of recurrent stroke in patients with prior cerebrovascular events, has been shown to benefit patients suffering a recent acute coronary syndrome, and to slow cognitive decline in preliminary studies of patients with Alzheimer's disease. Atorvastatin has been associated with reduced progression of mild chronic kidney disease; however, in a randomized trial of patients with end stage renal disease on hemodialysis, atorvastatin showed no statistically significant benefit. Limitations of this review include lack of generalizablity of the atorvastatin trial data to other statins, lack of head to head outcome trials involving the newer more potent statins, and the relatively short study durations (none exceeded 5 years) when atherosclerosis is typically a decades-long disease.

Conclusion: A compelling body of evidence documents that atorvastatin reduces major cardiovascular events in both secondary and primary prevention of CHD and in a broad range of patients and disease conditions. Furthermore, throughout its dose range, atorvastatin is safe and well tolerated.     

Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis

Abstract

Objective:

To systematically review and analyse evidence for cholesterol-lowering efficacy of at least 4 weeks of add-on ezetimibe vs doubling statin dose, in adults with primary hypercholesterolaemia.     

Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolaemia with simvastatin

Summary Thirty-six patients with total serum cholesterol levels above 6.5 mmol/l and Lipoprotein(a) levels above 100 mg · 1^–1 were evaluated in a 24 week double-blind, placebo controlled, cross-over study to assess the possible changes in Lp(a) during treatment with the HMG CoA reductase inhibitor simvastatin.The median plasma Lp(a) increased from 359 to 464 mg·l^–1 during simvastin treatment as compared to placebo (not significant). Individual changes in Lp(a) varied. In a multivariate linear regression analysis the individual change in Lp(a) was correlated with the baseline Lp(a) (r = 0.64), the change in serum triglycerides (r = 0.48) and the baseline apolipoprotein B (r = 0.36). Differences between the Lp(a) phenotypes may explain some of the varied Lp(a) responses. It appears that the effect of simvastatin on the Lp(a) level in individuals is usually insignificant, but in patients with a high Lp(a) simvastatin may further increase it.     

Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on

Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated enzyme displaying esterase and lactonase activity. PON1 hydrolyzes several organophosphorus (OP) insecticides and nerve agents, a number of exogenous and endogenous lactones, and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. As such, PON1 plays a relevant role in determining susceptibility to OP toxicity, cardiovascular diseases and several other diseases. Serum PON1 activity in a given population can vary by at least 40-fold. Most of this variation can be accounted for by genetic polymorphisms in the coding region (Q192R, L55M) and in the promoter region (T-108C). However, exogenous factors may also modulate PON1 activity and/or level of expression. This paper examines various factors that have been found to positively modulate PON1. Certain drugs (e.g. hypolipemic and anti-diabetic compounds), dietary factors (antioxidants, polyphenols), and life-style factors (moderate alcohol consumption) appear to increase PON1 activity. Given the relevance of PON1 in protecting from certain environmental exposure and from cardiovascular and other diseases, there is a need for further mechanistic, animal, and clinical research in this area, and for consideration of possible alternative strategies for increasing the levels and activity of PON1.     

Comparison of the efficacy of rosuvastatin versus atorvastatin,simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial

SUMMARY

In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor) was compared with that of atorvastatin (Lipitor ), simvastatin (Zocor), and pravastatin (Pravachol) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20,40, or 80?mg, atorvastatin 10, 20,40, or 80?mg, simvastatin 10,20,40, or 80?mg, or pravastatin 10, 20, or 40?mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels <100?mg?dl^?1 (<2.6?mmol?l^?1), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of <100?mg?dl^?1 (<2.6?mmol?l^?1) (55% to 77% compared with 0 to 64%), <3.0?mmol?l^?1 (<116?mg?dl^?1) (76% to 94% compared with 6% to 81%), and <2.5?mmol?l^?1 (<97mg?dl^?1) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides >200?mg?dl^?1 (>2.3?mmol?l^?1), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of <2.5 (<97?mg?dl^?1) to <5.0?mmol?l^?1 (< 193mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (<3.0?mmol?l^?1 [< 266?mg?dl^?1] to < 2.0?mmol?l^?1 [<177?g?dl^?1]), and the total cholesterol/high-density lipoprotein-cholesterol ratio (<4 to <7) (70% to 83% versus 35% to 79%).     

Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015)

Introduction: The identification by Abifadel et al. in 2003 of the first mutations of PCSK9 was the major breakthrough in the cholesterol field that led to a new therapeutic target. This discovery paved the way to new lipid lowering drugs reducing LDL-cholesterol levels through the inhibition of PCSK9. Two anti-PCSK9 monoclonal antibodies have received FDA and EMA approvals: Alirocumab and Evolocumab.

Areas covered: This article reviews the different strategies that are pursued to modulate the functional activity of PCSK9 for lowering LDL-cholesterol levels. It also provides a brief overview of the patents related to PCSK9 from 2011 until the end of 2015. This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9, focusing on anti-PCSK9 monoclonal antibodies and the related clinical trials.

Expert opinion: Anti-PCSK9 antibodies are a new class of lipid lowering drugs with promising results in reducing LDL-cholesterol. Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are eagerly awaited.     

Effect of atorvastatin on highdensity lipoprotein cholesteroland its relationship withcoronary events: a subgroupanalysis of the GREekAtorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

SUMMARY

Objective: To investigate the relationship between changes in high density lipoprotein cholesterol (HDL-C) levels after statin treatment and the risk for coronary heart disease (CHD)-related events in the secondary CHD prevention GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. These findings suggested that dose titration

with atorvastatin (10-80mg/day, mean 24mg/day) achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality, in comparison to usual care.

Methods: Analysis of variance was used to assess the effect of atorvastatin on HDL-C over

time (up to 48 months) in 1600 CHD patients. The time-dependent multivariate Cox predictive model, involving backward stepwise logistic regression, was used to evaluate the relation between coronary events and HDL-C changes.

Results: The mean increase in HDL-C levels during the study was 7%. All doses of atorvastatin significantly increased HDL-C levels. Increases were greater in men (7.8 vs 6.1%; p?=?0.02), in combined hyperlipidaemia (7.9 vs 6.4% for hypercholesterol-aemia; p?=?0.04), and in the lower baseline HDL-C quartile (9.2 vs 5.3%, 1st vs 4th quartile; p?=?0.001). After adjustment for 24 predictors of coronary events, multivariate analysis revealed a Hazards Ratio of 0.85 (95% confidence

interval 0.76-0.94; p?=?0.002) for every 4?mg/dL (0.1?mmol/L) increase in HDL-C.

Conclusions: There was a significant beneficial effect on HDL-C levels across the dose range of atorvastatin. Clinical outcomes in the structured care arm of GREACE were determined in part by the extent of atorvastatin-induced HDL-C increase. This effect was independent from benefit induced by low density lipoprotein cholesterol (LDL-C) reduction, suggesting that the CHD risk reduction associated with a rise in a low HDL-C at baseline remains significant under aggressive (-46%) LDL-C lowering conditions. However, the relationship between HDL-C and vascular risk may be weaker when LDL-C levels are aggressively lowered.     

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for pulmonary application: A review of the state of the art

Drug delivery by inhalation is a noninvasive means of administration that has following advantages for local treatment for airway diseases: reaching the epithelium directly, circumventing first pass metabolism and avoiding systemic toxicity. Moreover, from the physiological point of view, the lung provides advantages for systemic delivery of drugs including its large surface area, a thin alveolar epithelium and extensive vasculature which allow rapid and effective drug absorption. Therefore, pulmonary application is considered frequently for both, the local and the systemic delivery of drugs. Lipid nanoparticles – Solid Lipid Nanoparticles and Nanostructured Lipid Carriers – are nanosized carrier systems in which solid particles consisting of a lipid matrix are stabilized by surfactants in an aqueous phase. Advantages of lipid nanoparticles for the pulmonary application are the possibility of a deep lung deposition as they can be incorporated into respirables carriers due to their small size, prolonged release and low toxicity. This paper will give an overview of the existing literature about lipid nanoparticles for pulmonary application. Moreover, it will provide the reader with some background information for pulmonary drug delivery, i.e., anatomy and physiology of the respiratory system, formulation requirements, application forms, clearance from the lung, pharmacological benefits and nanotoxicity.     

ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials

Introduction: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity.

Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.     

Correlates of Salvia divinorum use in a national sample: findings from the 2009 National Survey on Drug Use and Health

Salvia, a hallucinogenic plant legally available in most of the United States, has become a widely discussed drug in the media. The extant research on Salvia use relies on non-probability samples and studies of college students. There is a clear need for research that identifies the correlates of Salvia use using data from a large sample that is nationally representative. The current study fills this important gap in the literature by using data from the 2009 National Survey on Drug Use and Health. This survey includes data from nearly 70,000 respondents ages 12 and older living in all 50 U.S. states and the District of Columbia. Due to survey design, separate analyses are conducted among adolescents and adults. Findings indicate that 1.66% of adolescents (respondents ages 12 to 17) and 5.08% of adults (respondents ages 18-34) report the use of Salvia at some point in their lifetime. Correlates of use among adolescents include age, gender, income, peer and parent attitudes toward substance use, and other forms of drug use. Correlates of use among adults include age, gender, race, religiosity, marital status, criminal involvement, and other forms of substance use. Implications of the findings and limitations of the current study are discussed.     

Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN)

Abstract

Background:

Previous imaging studies have demonstrated that the beneficial impact of high-dose statins on the progression of coronary atherosclerosis associates with their ability to lower levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) and to raise high-density lipoprotein cholesterol (HDL-C). The Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN (SATURN, NCT00620542) aims to compare the effects of high-dose atorvastatin and rosuvastatin on disease progression.     

Anti-inflammatory activity of a lipid fraction (lyprinol) from the NZ green-lipped mussel

A lipid-rich extract, preparared by supercritical fluid extraction of fresh stabilized mussel powder (Lyprinol), showed significant anti-inflammatory (AI) activity given therapeutically and prophylactically po to Wistar and Dark Agouti rats developing either (a) adjuvant-induced polyarthritis or (b) collagen(II)-induced autoallergic arthritis, with ED₅₀≤15 mg/kg; c.f. naproxen≥25 mg/kg or various therapeutic oils (flaxseed, evening primrose, fish)≥1800 mg/kg given orally. Lyprinol showed little or no activity in acute irritation assays (carrageenan, kaolin, histamine) indicating it is not mimicking rapid-acting NSAIDs. Incorporating Lyprinol into arthritigenic adjuvants composed of heat-killed Mycobacterium. tuberculosis suspended in olive oil or squalane, effectively prevented arthritis development at a dose of 5 mg/rat. By contrast, ‘dummy adjuvants’ prepared with Mycobacterium tuberculosis and flaxseed, evening primrose or fish oils were still arthritigenic in Dark Agouti rats (doses of oil=90 mg/rat). Lyprinol subfractions inhibited leukotriene-B₄ biosynthesis by stimulated human polymorphonuclear leukocytes in vitro, and prostaglandin-E₂ production by activated human macrophages in vitro. Much of this AI activity was associated with polyunsaturated fatty acids and natural antoxidants (carotenoids, etc.). In contrast to NSAIDs, Lyprinol is non-gastrotoxic in disease-stressed rats at 300 mg/kg po and does not seem to affect platelet aggregation (human, rat). These data show Lyprinol to be a reproducible, relatively stable, source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.     

Centralized intravenous additive services (CIVAS): the state of the art in 2010

In hospitals, the major part of the drugs is administered by intravenous way and the majority of the reconstitution of injectable drugs are carried out right before the administration to the patient by the nursing staff. The risks and errors related to the preparation and the administration of the injectable drugs are numerous. The standardization then the centralization of the preparations and reconstitution by the hospital pharmacy make it possible to reduce these various risks and errors. In addition to the preparation of the mixtures of parenteral nutrition as well as doses of anticancer chemotherapy, many other treatments can be taken in charge, such as antibiotics, antiemetics and pain treatments. Consequent equipment is necessary but the realization of these treatments proves non-overdrawn insofar as a certain quantity of production is reached. The reconstitution of the intravenous treatments by a centralized intravenous admixture service guarantees the chemical stability and the microbiological quality of the ready-to-use injectable drugs and contributes to the quality and the total management of the care of the patient.     

瑞舒伐他汀强化调脂对不稳定型心绞痛患者氧化应激的影响

摘 要 目的： 探讨瑞舒伐他汀强化调脂对不稳定型心绞痛(UAP)患者氧化应激的影响。方法: 选取92例UAP患者随机分为观察组和对照组各46例。两组均予以阿司匹林、β-受体阻断药、硝酸酯类和血管紧张素转换酶抑制药等基础治疗;对照组加用瑞舒伐他汀片10 mg,qd,睡前口服,观察组加用瑞舒伐他汀片20 mg,qd,睡前口服。两组疗程均为8周。观察两组患者治疗前后血清超氧化物歧化酶(SOD)、丙二醛(MDA)和脂质过氧化物(LPO)水平变化,比较药品不良反应发生情况。结果: 观察组和对照组失访率比较差异无统计学意义(P>0.05)。治疗8周后,两组血清MDA和LPO水平较前明显下降,SOD水平较前明显上升(P<0.05或P<0.01),且观察组变化幅度较对照组更明显(P<0.05)。两组药品不良反应发生率比较差异无统计学意义(P>0.05)。结论:瑞舒伐他汀强化调脂治疗UAP患者的安全性较佳,作用可能与其降低血清MDA和LPO水平,提高SOD水平,抑制脂质过氧化反应与增加其抗氧化能力密切相关。