The evolving role of statins in the management of atherosclerosis

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 placebo-controlled 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 anti-ischemic 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.     

Cholesterol 2001. Rationale for lipid-lowering in older patients with or without CAD

Statin treatment of men and women age > or = 50 with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg/dL in older patients with CAD, prior stroke, peripheral arterial disease, or extracranial carotid arterial disease and serum LDL cholesterol > 125 mg/dL despite diet therapy. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia but without cardiovascular disease. Consider using statins in patients age 50 to 80 without cardiovascular disease, serum LDL cholesterol > 130 mg/dL, and serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL.     

Is there a better marker of cardiovascular risk than LDL cholesterol? Apolipoproteins B and A-I – new risk factors and targets for therapy

LDL (Low Density Lipoprotein) is considered the major atherogenic lipoprotein whereas HDL (High Density Lipoprotein) is anti-atherogenic. In recent years also non-HDL cholesterol as well as TG (triglycerides) are included in guidelines defining cardiovascular (CV) risk and target values during lipid lowering treatment. In recent years apolipoproteins (apo) B, reflecting atherogenic, and apoA-I reflecting anti-atherogenic lipoproteins, have been shown to be superior to conventional lipids in predicting risk and reduction of events in lipid lowering trials using statins. These new data are reviewed. The apoB/apoA-I ratio, which reflects the cholesterol balance of the “bad” and “good” lipids, is a simple and accurate summary index of CV risk and it is better than the conventional LDL and other lipids as a risk marker and taget for therapy.     

Current questions regarding the use of statins in patients with coronary heart disease

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their "pleiotropic" action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (<2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels <100 mg/dL, preferably in the range of 70-80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50-70 mg/dL.     

Are lower levels of low-density lipoprotein cholesterol beneficial? A review of recent data

In the 1960s, epidemiologic studies established a link between elevated serum cholesterol and increased risk of cardiovascular events. Extensive clinical trial data subsequently highlighted 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) as the most effective pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol, and showed that statin-mediated LDL cholesterol reductions were associated with significant improvements in cardiovascular outcomes. Such findings are reflected in current cardiovascular disease management guidelines, which focus on LDL cholesterol as the primary therapeutic target. These guidelines recommend target LDL cholesterol levels. However, a number of clinical trials have failed to identify an LDL cholesterol threshold level below which no further cardiovascular risk reduction occurs. Such findings suggest that optimal risk reduction may require greater reductions in LDL cholesterol than are currently being achieved. This review examines recent data highlighting the benefits of more pronounced LDL cholesterol reductions and considers how this could be achieved in clinical practice when many patients are not even reaching current targets.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease

OBJECTIVES: The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). BACKGROUND: Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. METHODS: Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. RESULTS: Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). CONCLUSIONS: Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.     

hsCRP and HDL effects of statins trial (CHEST): rapid effect of statin therapy on C-reactive protein and high-density lipoprotein levels A clinical investigation

Inflammation contributes to the pathogenesis of coronary heart disease and elevated serum levels of C-reactive protein (CRP) are independently associated with increased coronary risk. This study assessed whether there were differences in the effects on CRP and high-density lipoprotein (HDL) cholesterol levels among patients treated with three common statins. In a prospective, observational study, 80 dyslipidemic adults without evidence of cardiovascular disease were treated with 10 mg atorvastatin (A), 20 mg simvastatin (S), or 40 mg pravastatin (P) daily. CRP and lipid profiles were assayed before and after 12 weeks of therapy; in 21 patients, CRP levels were also measured after 1 and 4 weeks. The three treatment groups experienced comparable reductions in CRP (A: 33%, S: 42%, and P: 30%) and statistically insignificant changes in HDL cholesterol levels. CRP began to decrease after 1 week of treatment, and decreased further at 4 and 12 weeks of therapy. The change in the log-transformed CRP concentration correlated with the change in the log-transformed LDL cholesterol concentration. Subjects had similar baseline CRP levels, lipid profiles, and coronary risk factors. The authors conclude that at doses achieving similar reductions in LDL cholesterol, the three statins were associated with comparable decreases in CRP without significant changes in HDL cholesterol levels. The correlation between the reductions in CRP and LDL cholesterol differs from the findings of other published studies, and should prompt further investigation of the mechanism by which statins reduce CRP.     

Models for describing relations among the various statin drugs, low-density lipoprotein cholesterol lowering, pleiotropic effects, and cardiovascular risk

Five models are proposed to describe the relations among statins, pleiotropic effects, low-density lipoprotein (LDL) cholesterol lowering, and cardiovascular risk reduction. On the basis of the evidence available, the pleiotropic effects of statins do not appear to reduce cardiovascular risk more than would be predicted from LDL cholesterol lowering alone, which suggests that model 1 is not a valid model. Although most attention has focused on models 2 through 4, most data to date support model 3 for describing the relation between statins, inflammation, and cardiovascular risk. Stronger consideration should also be given to model 5, in which pleiotropic effects are the result of cardiovascular risk reduction in and of itself. It may be that other models are operative for nonatherosclerotic inflammatory disorders. However, beneficial effects of statins on rheumatologic or other noncardiovascular may still be due to effects of cholesterol reduction on the immune system, as in model 3. More high-quality research is needed to determine the role of statin pleiotropic effects in cardiovascular risk reduction. Well-designed animal studies can help elucidate potential mechanisms, which will then require confirmation in human studies with cardiovascular event outcomes. Substudies of cardiovascular end point trials and mechanistic studies should be methodologically sound and designed to test specific models. To sort out the independence of pleiotropic effects from LDL cholesterol lowering, studies will need to achieve similar LDL cholesterol reductions in each treatment group. It may be that the biologic impact of a specific pleiotropic effect is mediated by >1 model. Ultimately, once a predominant model has been identified for a given pleiotropic effect, long-term studies would be needed to evaluate the relative contributions of various pleiotropic effects to cardiovascular risk reduction. These findings may reveal new targets for the development of new agents that will prove effective for reducing cardiovascular events when added to LDL cholesterol lowering. To date, little evidence supports consideration of statin pleiotropic effects in clinical decision making. In conclusion, LDL cholesterol is currently the only reliable marker for statin effects on cardiovascular risk reduction. The focus should remain on closing the treatment gap and improving adherence to therapies directed at lowering LDL cholesterol and non-high-density lipoprotein cholesterol to reduce the burden of cardiovascular disease.     

Lipidapherese

Lipid apheresis is an extracorporeal elimination procedure to reduce the blood concentration of low density lipoprotein (LDL) cholesterol and lipoprotein(a). There are three indications for this therapy: it is the treatment of choice for homozygous familial hypercholesterolemia, secondly it is applied in severe hypercholesterolemia that cannot be treated by changes in lifestyle or cannot be managed pharmacologically either because of intolerance of statins or insufficient reduction of LDL cholesterol and thirdly, it is indicated if atherosclerosis is progressive even after sufficient lowering of LDL cholesterol and if the concentration of lipoprotein(a) exceeds 60 mg/dl. Together with pleiotropic effects, long-term lowering of LDL cholesterol and lipoprotein(a) by lipid apheresis has been shown to reduce the risk of cardiovascular events by approximately 80% [1].     

Effect of withdrawal of pravastatin therapy on C-reactive protein and low-density lipoprotein cholesterol

In addition to lowering cholesterol, statins effectively lower C-reactive protein (CRP) levels. The effects of withdrawal from long-term statin therapy on CRP are unknown. This study examined the effect of withdrawal from 4 years of statin treatment on CRP. We prospectively evaluated the effects of withdrawal from pravastatin (40 mg) treatment on CRP levels in 566 subjects who participated in a randomized, placebo-controlled trial. Median (interquartile range) CRP levels before randomization were 1.29 mg/L (0.63 to 2.73) and mean low-density lipoprotein (LDL) cholesterol was 4.06 +/- 0.92 mmol/L. Four years after randomization, placebo-treated patients (n = 266) had a nonsignificant 9% increase in CRP, whereas there was a 12% decrease (p = 0.001) in the pravastatin-treated patients (n = 300). LDL cholesterol only decreased in pravastatin-treated patients (-27%; p <0.001). Withdrawal from pravastatin led to a significant increase in both CRP and LDL cholesterol to approximately pretreatment levels (p <0.05 and <0.001, respectively). Changes in CRP after withdrawal from pravastatin could not be predicted by the change in LDL cholesterol. The difference between the pravastatin and placebo groups in terms of change in CRP by withdrawal was consistent and persisted in analysis corrected for body mass index, smoking status, blood pressure, and baseline levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triglycerides. In conclusion, withdrawal from pravastatin treatment resulted in an increase in CRP to approximately baseline levels, which is not related to the increase in LDL cholesterol.     

Clinical significance of plasma lipid levels

Epidemiologic studies have established that elevated low-density lipoprotein (LDL) cholesterol values and decreased levels of high-density lipoprotein (HDL) cholesterol are risk factors for coronary artery disease (CAD). Results from clinical trials indicate that reduction in LDL cholesterol decreases the incidence of and reduces the risk of CAD. The National Cholesterol Education Program recently developed guidelines for the evaluation of plasma cholesterol in adults. Initial classification is categorized and based on the following values: less than 200 mg/dl is "desirable" blood cholesterol; from 200 through 239 mg/dl is classified as "moderate-high" blood cholesterol; and greater than or equal to 240 mg/dl is "high" blood cholesterol. Decision-making regarding therapeutic intervention is influenced by the presence of other lipoprotein risk factors, such as reduced HDL cholesterol and elevated lipoprotein (a), and nonlipid factors, including age, sex, hypertension, obesity, smoking, diabetes mellitus, and family or patient history of CAD. Persons with borderline-high blood cholesterol and established CAD or 2 other risk factors as well as those with high blood cholesterol should undergo lipoprotein analysis. LDL cholesterol is the primary lipoprotein to consider when determining treatment goals. Patients with LDL cholesterol levels greater than 160 mg/dl without CAD or 2 other risk factors and those patients with LDL cholesterol greater than 130 mg/dl with CAD or 2 other risk factors are initially managed with dietary therapy. The goal of treatment of hyperlipidemia is to reduce LDL cholesterol to less than 160 mg/dl or to less than 130 mg/dl in patients with established CAD or with 2 other risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypercholesterolemia. The evidence supports use of statins

Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.     

Determinants of Achieved LDL Cholesterol and “Non-HDL” Cholesterol in the Management of Dyslipidemias

Purpose of Review

The advent of combination therapy to provide LDL lowering beyond that achieved with statins necessitates the development of greater understanding of how drugs work together, what changes occur in key lipoprotein fractions, and what residual risk remains.

Recent Findings

Clinical trials of agents that, when added to statins, generate profound LDL lowering have been successful in reducing further the risk of cardiovascular disease. LDL cholesterol can be now decreased to unprecedented levels, so the focus of attention then shifts to other apolipoprotein B-containing, atherogenic lipoprotein classes such as lipoprotein(a) and remnants of the metabolism of triglyceride-rich particles. “Non-HDL cholesterol” is used increasingly (especially if measured in the non-fasting state) as a more comprehensive index of risk.

Summary

Metabolic studies reveal how current drugs act in combination to achieve profound lipid lowering. However, care is needed in interpreting achieved LDLc and non-HDLc levels in the emerging treatment paradigm.

     

Isoprenoid metabolism and the pleiotropic effects of statins

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. Indeed, in animal studies many of the cholesterol-independent or pleiotropic effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol, synthesis. Thus, with the recent findings of the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.     

Meaning of Low‐Density Lipoprotein‐Apheresis for Hypercholesterolemic Patients at High Risk for Recurrence of Coronary Heart Disease

Abstract: The goal of cholesterol‐lowering therapy in hypercholesterolemic patients at high risk for recurrence of coronary heart disease (CHD) is the prevention of acute coronary syndrome by stabilization of coronary atheromatous plaque. We often encounter patients in whom it is difficult to maintain the serum cholesterol level at a desirable level with dietary therapy and drug treatment, despite the development and use of statins. For secondary prevention in patients who are at high risk for the recurrence of CHD and whose cholesterol level cannot be controlled by drugs alone, low‐density lipoprotein (LDL)‐apheresis therapy, which involves removal of LDL through extracorporeal circulation, is now available. Many reports concerning improvement of vascular endothelial function, improvement of myocardial ischemia, regression of coronary atherosclerotic lesions, stabilization of coronary plaque, and reduction in the incidence of cardiac events as a result of LDL‐apheresis treatment have been published in various countries. We believe that LDL‐apheresis should be performed on hypercholesterolemic patients with existing CHD for whom diet and maximum cholesterol‐lowering drug therapies have been ineffective or not tolerated and whose LDL cholesterol level is 160 mg/dL or higher.     

Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates

Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.     

Therapies to increase high-density lipoprotein cholesterol and their effect on cardiovascular outcomes and regression of atherosclerosis

Epidemiological studies have shown that decreased level of high-density lipoprotein (HDL) cholesterol (C) is an independent inverse predictor of coronary artery disease (CAD) even in patients with normal levels of low-density lipoprotein (LDL)-C. There is an abundance of evidence in favor of statins and aggressive LDL-C lowering therapy for both primary and secondary prevention of CAD. In contrast, the evidence for reduction of CAD risk with HDL-C raising therapy is relatively thin, partly due to the paucity of effective and safe drugs for increasing HDL-C level. However, there are emerging new therapies for raising HDL-C level and growing evidence in favor of pharmacologic therapies to raise HDL-C level. We present in this article a review of pharmacologic therapies that are currently available to increase HDL-C level, their safety and efficacy in relation to cardiovascular endpoints.     

The role of statins in the treatment of the metabolic syndrome

The metabolic syndrome is a cluster of cardiometabolic risk factors associated with higher risk for atherosclerotic cardiovascular (CV) disease and diabetes. Its prevalence is about 20% to 30% among adults worldwide and is increasing. The primary goal is reduction of CV risk through lifestyle changes and drug therapy if required. Post hoc analyses of prospective trials showed the benefit of lowering low-density lipoprotein (LDL) cholesterol in patients with the metabolic syndrome. Statin therapy exerts beneficial effects not only by lowering LDL cholesterol but also via its so-called pleiotropic effects. These effects seem particularly important for reducing risk of CV disease in patients with the metabolic syndrome. Thus, evidence is accumulating that statins are very effective therapeutic agents in the treatment of individuals with the metabolic syndrome.