Early vascular benefits of statin therapy

SUMMARY

Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration.

Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment.

These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid-lowering properties of statins.     

Non-lipid effects of statins: emerging new indications

Statins are beneficial both in the primary and secondary prevention of atherosclerotic vascular disease and acute events in a broad spectrum of patient subgroups. However, the observed clinical benefit with statin therapy is much greater than expected through the reduction of cholesterol levels alone. Clinical and experimental studies suggested that several antiatherosclerotic effects other than lipid lowering also contribute to the observed benefit of statin therapy. These 'pleiotropic effects' include improvement of endothelial function, antitrombotic actions, plaque stabilization, reduction of the vascular inflammatory process and anti-oxidation. Statins may also exhibit a wide variety of actions other than antiatherosclerotic effects. Recent observational data documented a potential association between statin use and improvement of fracture risk in osteoporosis. Despite the lack of randomized trials, epidemiological and limited clinical data suggested that statins might retard the pathogenesis of Alzheimer's disease. Observational data indicated that the progression of aortic stenosis and valvular calcification might be delayed in statin users. In addition, the deterioration of congestive heart failure may be delayed with statins via anti-inflammatory, vascular endothelial and antiatherosclerotic actions. Furthermore, preliminary clinical studies suggested that, by their immunosuppressive actions statins might reduce the incidence of rejection following organ transplantation. Currently, there is not enough evidence to prescribe therapy for such patients. However, ongoing studies are exploring the role of statin therapy for these new indications. This review will discuss several non-lipid effects of statin therapy currently under investigation.     

Statins and the Response to Myocardial Injury

The benefits of long-term statin (HMG-CoA reductase inhibitor) treatment for preventing coronary events have been well documented in several large-scale prospective clinical trials. By influencing the determinants of myocardial injury, statins may produce direct cardioprotective effects in the ischemic myocardium and prevent further damaging recurrent events. Although not proven fully in a clinical setting, cholesterol-independent or 'pleiotropic' effects of statins are thought to protect against myocardial injury and may occur via a number of mechanisms. Endothelial dysfunction occurs early in the development of atherosclerosis and is associated with a reduction in endothelial nitric oxide (NO) production. Statins have been shown to increase the expression of endothelial NO synthase, with subsequent augmentation of NO in the vasculature. Statins have also been reported to have anti-inflammatory effects, reducing the release of cytokines and chemokines, decreasing the expression of pro-inflammatory cell adhesion molecules, and reducing the accumulation of neutrophils in myocardial tissue following ischemia and reperfusion. Indeed, the role of statins in reducing infarct size is supported by data from a number of preclinical studies. Statin treatment, administered at the onset of reperfusion, has been shown to reduce infarct size by approximately 50% following ischemia in various animal models, and this may be an NO-dependent effect. Randomized clinical trials have indicated that early initiation of statin treatment is associated with a reduction in both the rate of recurrence of cardiovascular events and death in patients with acute coronary syndrome. In addition, decreased rates of myocardial infarction and mortality were demonstrated in several retrospective studies where statin treatment was administered before an interventional procedure. There is a need for further clinical trials to fully elucidate the importance of pre-procedural statin therapy and to determine the extent and mechanisms by which statins exert their cardioprotective effects.     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug-drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.     

The antiplatelet and antithrombotic actions of statins

Several studies over the last years have demonstrated that statins exhibit actions beyond that of lipid-lowering (pleiotropic effects) ranging from improving endothelial function, modulating the inflammatory response, maintaining plaque stability and preventing thrombus formation. Since the interplay among platelets, cells and other components of atherosclerotic lesions as well as the coagulation system play an important role in the progression of atherosclerosis and in the development of acute coronary syndromes, these non-lipid properties of statins may help to explain the early and significant reduction of cardiovascular events reported in several clinical trials of statin therapy. This review focuses on the experimental and clinical results regarding the antiplatelet/antithrombotic effects of statins.     

Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis

Statins are highly effective at reducing coronary disease risk. The main side effects of these medications are a variety of skeletal muscle complaints ranging from mild myalgia to frank rhabdomyolysis. To search for physiologic factors possibly influencing statin muscle toxicity, we screened for genetic associations with serum creatine kinase (CK) levels in 102 patients receiving statin therapy for hypercholesteremia. A total of 19 single nucleotide polymorphism (SNPs) were selected from ten candidate genes involved in vascular homeostasis. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. SNPs in the angiotensin II Type 1 receptor (AGTR1) and nitric oxide synthase 3 (NOS3) genes were significantly associated with CK activity. These results demonstrate a strong association between CK activity during statin treatment and variability in genes related to vascular function, and suggest that vascular smooth muscle function may contribute to the muscle side effects of statins.     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

1. Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events.

2. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug–drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use.

3. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

     

Statins for diabetic cardiovascular complications

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with >or= 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL approximately 100 - 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with ≥ 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL ～ 100 – 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

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.     

Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.     

HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins

1. The results of several clinical studies investigating the effect of statin therapy on the fibrinolytic system in vivo are inconclusive. We compared the effect of six different statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin) on components of the fibrinolytic system expressed by human vascular endothelial cells and smooth muscle cells and by the human hepatoma cell line HepG2. 2. All statins used except pravastatin significantly decreased PAI-1 production in human endothelial and smooth muscle cells. This effect was also seen in the presence of IL-1 alpha and TNF-alpha. All statins except pravastatin increased t-PA production in human smooth muscle cells. On a molar basis cerivastatin was the most effective HMG CoA reductase inhibitor used. Only simvastatin and lovastatin increased t-PA production in endothelial cells. The effects on the fibrinolytic system were reversed by mevalonate. Statins decreased mRNA levels for PAI-1 in endothelial and smooth muscle cells and increased mRNA levels for t-PA in smooth muscle cells. Statins did not affect PAI-1 expression in HepG2 cells. Cell viability was not influenced by statins in endothelial cells and HepG2 cells whereas in smooth muscle cells a cytotoxic effect was seen at high concentrations. 3. If the effects on the fibrinolytic system of vascular cells in vitro shown in this study are also operative in vivo one could speculate that by increasing t-PA and decreasing PAI-1 at sites of vascular lesions statins might reduce fibrin formation and thrombus development. Such an effect might contribute to the clinically proven benefits of statin therapy.     

Modulation of the inflammatory process by statins

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.     

Peripheral arterial disease: a missed opportunity to administer statins so as to reduce cardiac morbidity and mortality

Peripheral arterial disease (PAD) is a common condition associated with an increased risk of coronary heart disease, myocardial infarction and stroke. It follows that PAD merits aggressive preventive treatment that includes lipid lowering drugs (mainly statins). This review summarises the current knowledge concerning the use and mechanisms of action of statins in patients with PAD. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. There is also evidence that statins reduce surgical mortality and improve graft patency and limb salvage. Because of the high risk, a more aggressive goal [i.e. low density lipoprotein cholesterol (LDL-C) of 70 mg/dl; 1.8 mmol/l] [National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), revised guidelines 2004] should be considered to maximally reduce the atheroma burden and related events. Not all statins can achieve this LDL-C target. Furthermore, there may be a need to use an additional lipid lowering drug so as to achieve the LDL-C goal and benefit from the different modes of action. Statins exert beneficial pleiotropic effects on haemostasis, the vasculature and inflammatory markers. There is also evidence that statins improve renal function (the plasma creatinine level is considered as an emerging vascular risk factor). Since PAD patients often take several drugs, there is a need to carefully consider their selection so as to maximize benefits and minimize adverse effects. Patients with PAD often do not receive adequate lipid lowering treatment. This situation needs to change.     

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.     

Simvastatin reduces serum level of vascular endothelial growth factor in hypercholesterolemic patients

Vascular endothelial growth factor plays a pivotal role in the progression of atherosclerotic lesions and causes instability of atherosclerotic plaques by inducing neoangiogenesis inside the current plaque. The pro-inflammatory cytokine interleukin (IL-) 6 induces vascular endothelial growth factor in smooth muscle cells (SMC). HMG-CoA reductase inhibitors (statins), display beside their lipid-lowering potency various pleiotropic effects. Such pleiotropic effects include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. In this study we investigate the influence of statin treatment on the serum levels of VEGF in hypercholesterolemic patients. One hundred and seven hypercholesterolemic patients were treated with 20 (n = 52) or 40 mg (n = 55) simvastatin daily. Six weeks of treatment resulted in a significant decrease of VEGF from 1017.1 +/- 297.8 pg/mL at baseline to 543.5 +/- 317.4 pg/mL after 6 weeks (-47.7%) and to 211.8 +/- 155.3 pg/mL after 6 months (-79.7%; all P < 0.001). IL-6 induced the expression of vascular endothelial growth factor in human SMC as analyzed by rt-PCR and flow cytometry. Statins decreased the stimulatory effect of IL-6 on mRNA and protein levels. This effect could be inhibited by co-incubation with mevalonate acid. This study contributes in understanding the pleiotropic effects of statins particularly with regard to their use in treatment and prevention of cardiovascular disease.     

Atorvastatin and diabetic vascular complications

Statins inhibit 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol synthesis, and share the common mechanism of lowering circulating levels of low-density lipoprotein cholesterol. Among various statins, atorvastatin is the most widely used statin for the treatment of hypercholesterolemia. Recent clinical trials show that atorvastatin reduces the risk of cardiovascular events and slows the progression of atherosclerosis in patients with coronary artery diseases. Further, intensive therapy with atorvastatin is also associated with an early clinical benefit in patients with acute coronary syndrome. These observations support the concept that beyond lipid-lowering effects of atorvastatin, that is, pleiotropic effects, could contribute at least in part to cardiovascular event reduction. Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. However, whether atorvastatin therapy decreases the risk for the development and progression of diabetic vascular complications and the way that it might achieve these effects are not fully elucidated. In this paper, we focus on diabetic vascular complications and review the efficacy and safety of atorvastatin in the treatment of these devastating disorders. We further discuss here the possible vasculoprotective properties of atorvastatin in patients with diabetes.     

Defining the Role of High-Dose Statins in PCI

Several studies have reported a significant reduction in morbidity and mortality in patients with acute coronary syndrome (ACS) or in patients with stable ischemic heart disease with the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Based on these findings, current guidelines recommend the use of statin therapy before hospital discharge for all patients with ACS regardless of the baseline low-density lipoprotein level. Statins are also recommended to patients at high risk for cardiovascular disease. Statins have been introduced in the clinical arena to reduce the low-density lipoprotein (LDL) cholesterol level that is associated with coronary atherosclerosis; however, a growing body of evidence suggests that other mechanisms of action beyond the modification of the lipid profile may come into action. In particular, statins exert antiinflammatory effects, modulate endothelial function, and inhibit the thrombotic signaling cascade. All together the non-LDL cholesterol-lowering effects of statins are called pleiotropic effects. In this article we will review the evidence supporting the use of high-dose statins in patients undergoing percutaneous coronary intervention, and we will also attempt to highlight the possible mechanisms of action.