Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins (original) (raw)
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Cardiovascular effects of statins, beyond lipid-lowering properties
Pharmacological Research, 2014
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as 'statins', are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid-lowering properties, which include enhancement of endothelial function, anti-inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits.
The lipid and non-lipid effects of statins
Pharmacology & Therapeutics, 2003
The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are a class of drug widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol; to a smaller degree, they also increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride concentrations. In recent years, however, there has been an increasing body of evidence that their effects on lipid profile cannot fully account for their cardiovascular protective actions: their beneficial effects are too rapid to be easily explained by their relatively slow effects on atherogenesis and too large to be accounted for by their relatively small effects on plaque regression. Experimental models have revealed that statins exert a variety of other cardiovascular effects, which would be predicted to be of clinical benefit: they possess anti-inflammatory properties, as evidenced by their ability to reduce the accumulation of inflammatory cells in atherosclerotic plaques; they inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis; they inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis; and they improve vascular endothelial function, largely through augmentation of nitric oxide (NO) generation. The relative importance of the lipid-and non-lipid-related effects of the statins in the clinical situation remains the subject of much continuing research.
Statins in the prevention of cardiovascular disease
2002
This article deals with the harmful effects of stopping treatment with statins on the cardiovascular progress of patients who need it. These statins are very effective cholesterol-lowering agents that are tolerated very well. Pravastatin and simvastatin competitively inhibit the enzyme that controls the cellular synthesis of cholesterol which brings about a drop in the intra-cellular cholesterol an increase in the cellular surface LDL receptors and a decrease in cholesterolemia. However these effects are reversible if the treatment is interrupted. Several clinical studies on cardiovascular prevention have revealed certain clarifications relating to good tolerance of statins and their therapeutic benefits namely primary prevention such as WOSCOPS which is the first study including 6595 men aged 45 to 64 with an average concentration of initial LDL cholesterol of 1.92 g/l and were randomly divided into two groups receiving 40 m per day of pravastatin or placebo. The result shows that ...
Circulation Journal, 2010
Once many epidemiological studies had proven an increase in coronary deaths and cardiac events associated with elevated levels of low-density lipoprotein-cholesterol (LDL-C), 1,2 the next clinical question became whether lowering LDL-C by drugs or diet would result in a reduction in cardiac events. This assessment was facilitated by the development of potent cholesterol-lowering drugs such as the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). In particular, statin therapy was proposed as a strategy to improve clinical outcomes and accordingly, large clinical trials using statin were started. By 2000, there had been many reports of the results of such large-scale clinical trials 3-8 and there was abundant evidence of the significant beneficial effects of lipid-lowering treatment using statin in reducing mortality and cardiovascular morbidity in patients with CAD as shown in Table 1. Interestingly, all the long-term clinical trials demonstrated that the beneficial effects of statin treatment were sustained and cumulative compared with placebo group as shown in Table 1. In the meta-analysis performed by The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.
STATINS FOR THE PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE
We included randomized controlled trials of statins versus placebo or usual case control with minimum treatment duration of one year and follow-up of six months, in adults with no restrictions on type of cholesterol -total, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels. Of these 10% or less had a history of CVD.
Clinical relevance of statins: their role in secondary prevention
Atherosclerosis Supplements, 2001
Five large randomized clinical trials show the benefits of lipid lowering with statins on cardiac morbidity and mortality. Three of these were secondary-prevention trials -the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, Cholesterol and Recurrent Events (CARE), and Scandinavian Simvastatin Survival Study (4S). The CARE and LIPID studies, performed with pravastatin, comprise populations that are representative of the majority of patients with coronary disease in that they included subjects with 'average' cholesterol levels. The 4S study, using simvastatin, comprised a patient population with elevated lipid levels. Pooled data from three trials, CARE, LIPID, and the West of Scotland Coronary Prevention Study (WOSCOPS), were examined in the Pravastatin Pooling Project (PPP). Individual patient data from these three event trials were pooled into a single database, permitting subgroup analyses and providing increased power. In the PPP, pravastatin-treated patients had significantly lower all-cause mortality (7.9, vs. 9.8% in those receiving placebo, a relative risk reduction of 20%). Pravastatin treatment was associated with a significant 24% reduction in CHD mortality and a nonsignificant difference in other vascular deaths (17%) and noncardiovascular deaths (12%). However, the reductions in absolute risk were much larger in those with a history of coronary heart disease than in those without. In the combined analysis of CARE and LIPID, there was also a uniform relative risk reduction in both men and women. In high-risk groups such as diabetics, smokers, hypertensives, and the elderly, there were also significant risk reductions in clinical end points. Finally, in the 598 participants, who had a stroke (90% of which were non-fatal), CARE and LIPID individually demonstrated reductions in non-fatal and total stroke. These data confirm that benefits of treatment in secondary prevention of coronary heart disease encompasses prevention of stroke as well as coronary heart disease events. The benefits are found in those who have had unstable angina as well as myocardial infarction. These findings strengthen even further the case for much more widespread use of statins in secondary prevention.
The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient
QJM: An International Journal of Medicine, 2005
The landmark HMG-CoA reductase inhibitor (statin) studies have practical lessons for clinicans. The 4S trial established the importance of treating the hypercholesterolaemic patient with cardiovascular heart disease. Next, WOSCOPS showed the benefit of treating healthy, high-risk hypercholesterolaemic men. CARE, a secondary prevention trial, showed the benefit of treating patients with cholesterol levels within normal limits. This was confirmed by the LIPID trial, another secondary prevention study, which enrolled patients with cholesterol levels 155-271 mg/dl (4-7 mmol/l). The importance of treating patients with established ischaemic heart disease, and those at high risk of developing heart disease, regardless of cholesterol level, was being realized. In the MIRACL trial, hypocholesterolaemic therapy was useful in the setting of an acute coronary syndrome, while the AVERT study showed that aggressive statin therapy is as good as angioplasty in reducing ischaemic events in patients with stable angina. By showing the value of fluvastatin after percutaneous intervention, LIPS confirmed that benefit is a class action of the statins. The HPS randomized over 20 000 patients, and showed beyond doubt the value of statins in reducing cardiovascular events in the high-risk patient. Although PROSPER showed benefit in treating the elderly patients above 70 years, statin therapy in this trial was associated with an increase in cancer incidence. The comparative statin trials, PROVE-IT, REVERSAL, Phase Z of the A to Z, ALLIANCE and TNT, all showed that highdose statins will better reduce cardiovascular events in the high-risk patient, although the adverse effects of therapy will also be increased. ALLHAT-LLT, ASCOT-LLA and CARDS showed that for statin therapy to demonstrate a significant benefit, hypertensive or diabetic patients must be at sufficiently high risk of cardiovascular events. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not the lipid level of the patient. No therapy is free of adverse effect. Treatment of those most at risk will bring the most benefit; treatment of those not at high risk of cardiovascular disease may expose patients who would not benefit much from therapy to its adverse effects.
The evolving role of statins in the management of atherosclerosis
Journal of the American College of Cardiology, 2000
Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors-"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebocontrolled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important antiischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.