Statins and stroke

An important issue for stroke prevention is the identification and treatment of risk factors such as hypercholesterolaemia. The 4 reasons to test if the statins have a role in stroke prevention are: (i) a statistical link between elevated low density lipoprotein-cholesterol or decreased high density lipoprotein-cholesterol and ischaemic stroke; (ii) a reduction in vascular risk with statins in randomised trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins; and (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e. with statins in secondary prevention trials). The question of whether statins also have a neuroprotective effect in humans and reduce the risk of post-stroke dementia remains unsettled.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann-Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann–Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

Selective cholesterol absorption inhibition: a novel strategy in lipid-lowering management

Many individuals throughout Europe have risk factors for coronary heart disease (CHD) and are non-compliant with recommended treatments, despite guidelines for the reduction of low-density lipoprotein cholesterol (LDL-C) and the prevention of CHD. Significant numbers who should receive pharmacotherapy for hypercholesterolaemia do not, and one-third of treated patients do not achieve recommended target LDL-C levels. Optimum doses of statins, which have demonstrated undisputed efficacy in the treatment of hypercholesterolaemia in clinical trials, are seldom used; the inconvenience of dosage adjustments and safety concerns, particularly myalgia, may constitute obstacles to their optimal use for LDL-C reduction in clinical practice. Ezetimibe is the first selective cholesterol absorption inhibitor that has demonstrated clinical benefits when used as either monotherapy or in combination with other lipid-modifying agents.     

Role of statin pleiotropism in acute coronary syndromes and stroke

Several landmark clinical trials have demonstrated the benefit of lipid-lowering with statins for the primary and secondary prevention of coronary heart disease. The clinical data in support of lowering cholesterol by statins are unequivocal. The established mechanism of action is via sterol regulatory element binding protein (SREBP) activation due to reduced hepatic cholesterol synthesis and secondary upregulation of the low-density lipoprotein (LDL)-receptor, leading to enhanced clearance of circulating cholesterol and lipids. Although it is widely accepted that most clinical benefit obtained with statins is a direct result of their lipid-lowering properties, there is still some debate as to whether the so-called 'pleiotropic effects' of statins contribute to the clinical outcome in vascular disease, or whether all the beneficial effects of statins are simply due to lipid-lowering. For example, these agents appear to display additional cholesterol-independent effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Thus, further studies are needed to understand the full impact of statin therapy on each of these processes and whether these effects contribute to the clinical benefits of statins in acute coronary syndromes and stroke.     

Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy

Abnormal lipid levels contribute significantly to the risk of coronary heart disease (CHD), which is increased further in the presence of other risk factors. The association between elevated low-density lipoprotein (LDL) cholesterol and CHD risk is well established, and large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) have shown conclusively that lowering LDL cholesterol levels reduces CHD events and total mortality. Regardless of the intervention used (diet, surgery, drugs), reduction of plasma cholesterol has consistently produced a reduction in cardiovascular risk. Absolute benefit is greatest in those who are at highest risk initially, and trial results suggest that the lower the LDL cholesterol level achieved, at least down to LDL of 3.0 mmol/l, then the lower is the CHD event risk. Epidemiological data also point to the negative impact of other lipids on CHD risk. Low levels of high-density lipoprotein (HDL) and high levels of triglycerides (particularly in conjunction with an LDL/HDL ratio >5) are particularly strong risk factors for CHD. Thus, although prevention trials to date have primarily assessed the impact of LDL lowering on CHD events, the initial assessment of CHD risk should consider a more detailed atherogenic profile including HDL and triglyceride levels. A general approach to preventing cardiovascular disease should include strategies to reduce the overall CHD risk by lifestyle modification and management of modifiable risk factors such as smoking, hypertension and diabetes. Based on data from recent prevention studies, and because they are the most potent lipid-lowering agents available for lowering LDL cholesterol, statins have appropriately become the drug of choice for most patients with hyperlipidaemia who require drug therapy.     

Antilipemics and prevention of cerebrovascular accidents. Meta-analysis

BACKGROUND: Previous overviews have suggested that the HMG-CoA reductase inhibitors (statins), but not other lipid lowering therapies (LLTs), may reduce stroke incidence in coronary patients. Our objective was to investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: A literature search was performed from 1966-2001 to identify all English-language published trials testing LLT. We then conducted a meta-analysis including randomised primary and secondary coronary heart disease prevention trials, which tested statins, nonstatins, diet or other interventions, and providing data on stroke incidence. RESULTS: The overall meta-analysis (38 individual trials, 83,161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLTs of 17% (p < 0.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary prevention) or type of LLT. Most demonstrative effects was obtained however with statins (RRR = 26%). Effect model analysis showed that the treatment benefits appeared constant whatever the risk of stroke, suggesting that LLTs may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between the RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol level allowed a clear separation between benefit (RRR > 0) and no effect (RRR < 0) of LLTs on stroke incidence, with a cut-off for benefit of 6.0 mmol/L. CONCLUSION: LLTs reduce stroke incidence in coronary patients, especially when total cholesterol is under 6.0 mmol/L, this explains the better results obtained with statins.     

Statins for everybody? New evidence on the efficacy and safety of the inhibitors of HMG Co-A reductase

Classically, the statins are the first choice drugs when treating dyslipidemias, especially in patients with hypercholesterolemia alone or accompanied by hypertriglyceridemia. The recent evidence of the effectiveness, safety and impact comes from hard endpoints, as demonstrated in 6 trials which included more than 40,000 subjects. The statins are being recommended for the treatment of a large number of patients with overt coronary heart disease, regardless of serum cholesterol levels, in patients with acute phases of coronary syndromes, and in patients without apparent coronary heart disease with moderate risk and average serum cholesterol and LDL cholesterol levels. These drugs are also being prescribed to patients with high-risk medical conditions that are "equivalent to coronary heart disease," like diabetes, lower limb atherosclerosis, or vascular cerebral disease, independent of the basal serum cholesterol levels or LDL cholesterol ranging from normal to high. Despite all the evidence collected as to the efficacy and safety of these drugs, the statins are not sufficiently used in daily practice, probably due to the ignorance of new concepts and the doubts related to the safety that may be cleared by careful analysis of 6 major studies with these drugs.     

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?     

The role of statins in heart failure

HMG CoA reductase inhibitors (statins) have an established place in the treatment of coronary artery disease. However, their role in the treatment of heart failure (HF), including HF due to coronary artery disease, has been controversial since beneficial as well as possible harmful effects may occur. Several recent studies lend support for a beneficial effect of the statins in HF. These include: (i) post hoc subgroup analyses of prospective randomized clinical trials of statin therapy among patients with stable coronary artery disease where statins reduce the incidence of new HF; (ii) subgroup analysis of the evidence of statin use in large HF trails with different medication and medical devices; (iii) retrospective observational studies of statin use in HF; and (iv) prospective randomized clinical trials of statins in non-ischemic. Beneficial effects include attenuation of cardiac hypertrophy, improvement in endothelial function, anti-inflammatory effects, reduction in the activity of matrix metalloproteinases, reduction in apoptosis, interference with neurohormones, and improved homeostasis. However, there are also theoretical concerns about statins in HF, and existing literature for their safety and efficacy in HF patients has been limited by the retrospective or observational nature of these analyses, examination of incompletely validated surrogate endpoints and small prospective studies in subgroups of HF subjects. In contrast with the normal population, low concentrations of LDL and total cholesterol are associated with a worse prognosis in HF patients and a possible mechanism is reduction in ubiquinone (coenzyme Q10) levels, which is required for oxidative phosphorylation in cells. The safety aspect of these drugs in HF patients needs to be answered before statins can be recommended as a routine drug. For the moment there are several large-scale prospective outcome studies in HF which probably will give us more definitive answers.     

Statin therapy: rationale for a new agent,rosuvastatin

Cardiovascular disease (CVD) remains a major cause of death in industrialised societies, and elevated serum lipids are a significant, highly prevalent and undertreated risk factor for this condition. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have revolutionised the treatment of hyperlipidaemia, and results from large-scale, long-term clinical trials have shown that the substantial reductions in low-density lipoprotein cholesterol (LDL-C) achieved with these drugs are associated with dramatic decreases in cardiovascular risk. Results from recent comparative clinical trials that have included a new drug in this class, rosuvastatin (Crestor), have demonstrated that it is significantly superior to atorvastatin, pravastatin and simvastatin in reducing total cholesterol, LDL-C and apolipoprotein B (Apo B). It is also significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I). Rosuvastatin was also superior to all these agents in helping patients meet European Atherosclerosis Society (EAS) and National Cholesterol Education Programme (NCEP) goals for LDL-C. The results of an increasing number of studies indicate that statins have a wide range of pleiotropic properties that almost certainly contribute to their ability to decrease cardiovascular risk and may also make them valuable for treatment of other diseases. These actions include plaque stabilisation, improvement of endothelial function, inhibition of smooth muscle cell proliferation and migration, reduction of expression of adhesion molecules, prevention of cholesterol esterification and accumulation, reduction of secretion of matrix metalloproteinases by macrophages, reduction of platelet activity, reduction of formation of thrombogenic factors, chemoprotection and induction of bone morphogenic protein-2 (BMP-2). Further exploration of these actions will provide key information about class effects and properties of specific members of this highly useful group of drugs.     

Statins: potent vascular anti-inflammatory agents

Atherosclerosis is a multifactorial condition that can result in cardiovascular disease. Statin therapy is thought to mediate cardioprotective effects that influence endothelial function, inflammatory responses, plaque stability and thrombus formation, processes involved in atherosclerosis. Although reduction in low-density lipoprotein cholesterol (LDL-C) potentially plays a role in all of these effects, several lines of evidence also implicate nonlipidmediated 'pleiotropic' effects. For example, statin therapy confers a lower risk for coronary heart disease than placebo in patients with comparable serum cholesterol levels, and confers a greater magnitude of clinical benefit than expected based on LDL-C levels alone. Moreover, while nonstatin lipid-lowering therapy does not necessarily reduce stroke risk, statins have shown a significant reduction in stroke. Statins exert their pleiotropic effects, in part, by improving endothelial function via up-regulation of endothelial nitric oxide synthase enzyme activity. Markers of inflammation such as high sensitivity C-reactive protein have been also shown to add further prognostic information about patients at risk of cardiovascular disease who may benefit from statin therapy. Further studies are still needed to determine whether statins have direct effects on inflammatory pathways.     

Ezetimibe for hypercholesterolemia

Ezetimibe (Zetia) is a novel, selective cholesterol absorption inhibitor. Ezetimibe blocks the absorption of dietary and biliary cholesterol within the brush-border enzyme system of the small intestine. Ezetimibe does not appear to alter or decrease the absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It is labeled for use in the treatment of primary hypercholesterolemia, either as monotherapy or in combination with statins. It also is labeled for the treatment of homozygous familial hypercholesterolemia in conjunction with statins and as adjunctive therapy to diet in the treatment of homozygous sitosterolemia (a rare, inherited, plant sterol storage disease).     

Statins,fibrates, nicotinic acid,cholesterol absorption inhibitors,anion‐exchange resins,omega‐3 fatty acids: which drugs for which patients?

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.     

Statins and osteoporosis: can these lipid-lowering drugs also bolster bones?

The statins may not only lower cholesterol, they may stimulate bone formation, as suggested by a number of observational studies and animal research. Whether these drugs will be of benefit in treating osteoporosis awaits further clinical trials.     

The need for increased utilization of statins after occlusive stroke

In registry data, among patients who have survived an occlusive stroke, only about half are treated with statins despite a large and persuasive totality of evidence, which includes large-scale randomized trials. In a comprehensive worldwide meta-analysis of 90,056 participants, statins conferred statistically significant and clinically important reductions in stroke and myocardial infarction, as well as cardiovascular and total mortality. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial of patients with prior stroke or transient ischemic attack, high-potency statins decreased risks of recurrent stroke and major cardiovascular events. In a nonrandomized subgroup analysis, patients who achieved a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) compared to those who achieved <50% had a statistically significant 31% reduction in risk of stroke. Finally, in a comprehensive, worldwide meta-analysis of all trials of cardiovascular disease, patients treated with intensive compared with conventional statin therapy had significantly reduced risks of stroke and myocardial infarction as well as any cardiovascular event or death. Based on this totality of evidence the US federal guidelines as well as those of the American Heart Association/American Stroke Association have been revised to recommend that patients with a prior occlusive stroke should have an optional goal for LDL of 70 mg/dL. All these considerations pose important and timely clinical and public health challenges concerning the need for wider utilization of statins in the treatment of patients with stroke.     

Effects of statins on renal function

Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population.     

Effects of atorvastatin in multiple sclerosis

Statins, 3-hydroxy-3 methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, are approved for cholesterol reduction and are commonly used to treat atherosclerosis and coronary disease. Statins may also be potent immunomodulatory agents and be beneficial in the treatment of autoimmune diseases. Statins have already been used to reduce the rejection of human heart transplants by the immune system, and there have been reports of a protective effect of injected statins in models of brain autoimmunity similar to experimental autoimmune encephalomyelitis. In vitro studies in multiple sclerosis(MS) revealed that statins reduced the expression of activation-induced adhesion molecules on T cells, modified Th1/Th2 cytokine balance, reduced matrix metalloproteinase(MMP)-9, and downregulated chemokine receptors on both B and T cells. Thus statins are effective immunomodulators in vitro that merit evaluation as treatment for MS. In vivo studies using three different animal models of MS revealed that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin has been shown to have pleiotropic immunomodulatory effects involving both antigen presenting cells and T cell compartment. Thus, statins may be beneficial for MS, and clinical trials of the effects of statins on MS are now in progress, hopefully in a favorable way.     

Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine

A statin is a cholesterol-lowering agent, which inhibits HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase and subsequently reduces the cholesterol precursor, and was first used commercially in 1987. The concept of cholesterol restriction leading to cancer cell dysfunction was proposed in 1992. The interruption of different signaling pathways has been proved in preclinical experiments to elucidate the anti-tumor mechanism of statins in pancreatic adenocarcinoma. Observational studies have shown that the clinical use of statins is beneficial in patients with pancreatic adenocarcinoma, including a chemoprevention effect, post-surgical resection follow-up and therapeutic prognosis of advanced cancer stage. Arrest of the cancer cell cycle by the combined use of gemcitabine and statin was observed in a cell line study. The effect of microbiota on the tumor microenvironment of pancreatic adenocarcinoma is a new therapeutic approach as statins can modulate the gut microbiota. Hence, further randomized trials of statins in pancreatic adenocarcinoma treatment will be warranted with application of precision medicine from microbiota-derived, cell cycle-based and signaling pathway-targeted research.