Therapeutic implications of recent ATP III guidelines and the important role of combination therapy in total dyslipidemia management

The Adult Treatment Panel III report reemphasized the importance of reducing elevated levels of low-density lipoprotein cholesterol as the most efficacious treatment target to reducing coronary heart disease morbidity and mortality, which is the leading cause of disability and death in the United States. Although the etiologic role of elevated levels of low-density lipoprotein cholesterol in atherosclerosis is well established, treatment with statins still leaves a large proportion of patients vulnerable to cardiovascular events. The role of high-density lipoprotein cholesterol in atherosclerosis is increasingly recognized because of its strong inverse association with coronary heart disease in epidemiologic studies, and the observed high prevalence of low high-density lipoprotein cholesterol that occurs in populations with coronary heart disease, with or without elevated low-density lipoprotein cholesterol, especially among patients with diabetes and metabolic syndrome. This report highlights some of the therapeutic implications of the Adult Treatment Panel III report and various therapeutic approaches to both lowering elevated low-density lipoprotein cholesterol and triglycerides as well as increasing low levels of high-density lipoprotein cholesterol to optimize clinical event rate reduction in patients with coronary heart disease. Among available dyslipidemic therapies, although statins remain the mainstay for lowering low-density lipoprotein cholesterol and clinical events, niacin is currently the most effective agent for increasing low high-density lipoprotein cholesterol levels. The importance of combination dyslipidemic therapy, such as a statin plus niacin, in treating more optimally the entire lipid profile has been demonstrated not only to decrease progression and increase regression of atherosclerotic lesions, but to enhance event-free survival compared with statin monotherapy. Combination dyslipidemic therapy affords the most efficacious approach to controlling the multiple lipid abnormalities associated with atherosclerotic cardiovascular disease and optimizing cardiovascular event rate reduction in patients with coronary heart disease.     

REVIEW: Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia

CONTEXT: The Adult Treatment Panel III recommends 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, as first-line lipid-altering therapy for all adult patients with diabetes mellitus. This is based on the well-characterized efficacy and safety profiles of this class of agents as well as several clinical trials demonstrating that statin treatment reduces the risk of cardiovascular events. EVIDENCE ACQUISITION: This review provides an overview of the effectiveness and mechanisms of action of statins in patients with diabetes mellitus using small efficacy trials and large clinical outcomes trials as well as studies of the effects of statins on apolipoprotein B (apoB) metabolism. EVIDENCE SYNTHESIS: The major findings presented are a review of mechanistic studies of selected subjects with diabetes mellitus and dyslipidemia and a compilation of results from large-scale clinical trials of patients with diabetes. CONCLUSIONS: Statins are highly efficacious as low-density lipoprotein cholesterol-lowering agents and have more modest effects on very low-density lipoprotein triglyceride and high-density lipoprotein cholesterol levels. The effects of statins on plasma lipids and lipoproteins result from their ability to both increase the efficiency with which very low-density lipoprotein and low-density lipoprotein are cleared from the circulation and reduce the production of apoB-containing lipoproteins by the liver. Additional investigations are needed to clarify the mechanisms by which statins reduce apoB secretion from the liver.     

Monotherapy vs combination therapy for dyslipidemia in the elderly

Dyslipidemia conveys a major increased risk of future cardiovascular events in older persons. Data from large randomized controlled trials confirm that statin therapy is as beneficial in older adults as it is in younger persons in both primary and secondary prevention. National guidelines support the use of statin therapy to reduce low-density lipoprotein cholesterol in older adults, with the recommended goal of <100 mg/dL in high-risk patients and an optional goal of <70 mg/dL in very high-risk patients. In the majority of high-risk older patients, these levels of low-density lipoprotein cholesterol can be achieved with initial low doses of an efficacious statin, but in some clinical situations, combination therapy may be considered. Moreover, statins appear to be safe and well tolerated in older age groups. Because of heightened risks of drug-drug interactions, the likelihood of polypharmacy in seniors, and issues of tolerability and convenience, monotherapy with low doses of an efficacious statin may be preferable to combination therapy in elderly individuals.     

The Use of Fibric Acid Derivatives in Cardiovascular Prevention

Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol–lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.     

Management of hyperlipidemia with statins in the older patient

Numerous randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins decrease mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study found that statins decreased mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dl is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary heart disease of 10% to 20%), the serum LDL cholesterol should be decreased to <100 mg/dl. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be decreased at least 30% to 40%.     

Beneficial effects of ezetimibe-based therapy in patients with dyslipidemia

Treatment of dyslipidemia is important for the primary and secondary prevention of cardiovascular events. Although statins induce the intensive lowering of low-density lipoprotein (LDL) cholesterol levels, two-thirds of cardiovascular events are not prevented. Ezetimibe has been shown to be a selective inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) transporter of cholesterol across the intestinal wall. Ezetimibe-based therapy may hold the promise of more intensive lowering of LDL cholesterol. This review will address the beneficial effects of ezetimibe in patients with dyslipidemia.     

Evolocumab: Considerations for the Management of Hyperlipidemia

Purpose of Review

To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Recent Findings

PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non–high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins.

Summary

Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.

     

Statins for stroke prevention

Unlike coronary heart disease, epidemiologic studies find a weak and inconsistent relationship between cholesterol levels and overall stroke risk. There does, however, appear to be a positive relationship between total and low-density lipoprotein cholesterol levels and the risk of ischemic stroke, with an inverse relationship between cholesterol levels and hemorrhagic stroke. Treatment with statins is associated with the reduction in the risk of a first stroke in various populations of patients at increased risk of cardiovascular events. Treatment of patients with prior cerebrovascular disease is associated with a reduction in major cardiovascular events and, in a single study, with a reduction in fatal and nonfatal stroke in patients with prior stroke or transient ischemic attack and no known coronary heart disease. Whether the benefit of statins in reducing the risk of stroke is due to their potent lipid-lowering effects, pleiotropic effects, or a combination of the two cannot be determined based on data available from clinical trials.     

Achieving optimum lipid-lowering goals in patients with vascular disease

Individuals with established cardiovascular disease are at high risk for serious adverse ischemic events. Fortunately, effective control of serum cholesterol levels, especially low-density lipoprotein (LDL), can significantly reduce cardiovascular morbidity and mortality. To achieve these benefits, the evidence-based National Cholesterol Education Program-Adult Treatment Panel III Guidelines recommend an LDL goal of less than 100 mg/dL with a secondary non-high-density lipoprotein (HDL) goal of less than 130 mg/dL. The more aggressive optional goals are an LDL less than 70 mg/dL and a non-HDL of less than 100 mg/dL. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert potent LDL-lowering as well as pleiotropic effects, and these agents have consistently reduced cardiac mortality and myocardial infarction in trials of secondary prevention. Should a statin drug alone fail to achieve the goal due to resistance or patient intolerance, combination drug therapy can be used. Combination therapy may also help achieve secondary goals for the reduction of non-HDL cholesterol levels.     

Is a statin as part of a polypill the answer?

Statins are a necessary component of a polypill. Almost all patients have the potential to benefit from low-density lipoprotein cholesterol reduction with statins, although absolute benefits due to the reduction in coronary heart disease and stroke vary by risk level. The reduction in coronary heart disease and stroke from antihypertensive therapy is additive to the reduction in risk from statins. Used in combination with antihypertensive therapy, a moderate-dose statin would be expected to reduce cardiovascular risk by at least 50%, and a high-dose statin would be expected to reduce risk by at least 60% over an approximately 5-year period. A polypill containing aspirin in addition to a statin and antihypertensive therapy would be appropriate for most men over age 55 years, but not for high-risk women until age 65 years and moderately high-risk women until age 75 years. Polypills in development hold great promise for reducing the global burden of cardiovascular disease.     

Reducing cardiovascular risk by targeting high-density lipoprotein cholesterol

Although lowering low-density lipoprotein (LDL) cholesterol with statins can substantially reduce cardiovascular morbidity and mortality, many treated patients retain a residual risk for cardiovascular events. Low levels of high-density lipoprotein (HDL) cholesterol may underpin this residual risk and may represent an additional target for intervention. Several new therapies for substantially increasing HDL cholesterol levels are under investigation, including cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I mimetics and recombinant HDL, liver X receptor (LXR) agonists, and peroxisome proliferator-activated receptor (PPAR) agonists. Combining new HDL cholesterol-elevating agents with existing LDL cholesterol-lowering agents may improve the cardiovascular risk reductions currently attainable.     

Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials

Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis.     

Statin Effects on Both Low-Density Lipoproteins and High-Density Lipoproteins: Is There a Dual Benefit?

Considerable evidence has demonstrated that use of statins has a beneficial impact on both progression of atherosclerosis and cardiovascular events. Accordingly, statins have been increasingly used in preventive strategies to reduce cardiovascular risk. More recent reports have demonstrated an incremental benefit with use of higher doses of statins and when used early in the setting of acute ischemic syndromes. Although lowering levels of low-density lipoprotein cholesterol is likely to underscore the majority of the clinical benefit, emerging evidence suggests that additional properties may also be important. In particular, a number of reports have demonstrated that modest elevations in levels of high-density lipoprotein cholesterol are likely to contribute to the benefit of statins. As a result, a favorable influence on the ratio of atherogenic and protective lipid species is likely to have the most profound impact on cardiovascular risk in statin-treated individuals.     

Emerging importance of HDL cholesterol in developing high-risk coronary plaques in acute coronary syndromes

Cardiovascular disease is the principal cause of death in industrialized countries. Hyperlipidemia, with high low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol levels (<40 mg/dL in men and <45 mg/dL in women), is a known major cardiovascular risk factor. Statins are considered the most potent and effective agents to reduce low-density lipoprotein cholesterol, but they have a variable effect on high-density lipoprotein cholesterol and triglycerides. Different clinical trials with statins have shown a decrease in low-density lipoprotein cholesterol by 35% and a reduction of the incidence of coronary events by as much as 30%. However, 60 to 70% of events still occur, despite remarkable reduction of low-density lipoprotein cholesterol concentration. Recent National Cholesterol Education Program guidelines highlighted the importance of high-density lipoprotein cholesterol concentration in the prevention and treatment of cardiovascular disease. High-density lipoprotein cholesterol is considered an independent risk factor and has an inverse relation with coronary events. The association of low levels of high-density lipoprotein cholesterol with an increased incidence of cardiovascular events implies a critical role of high-density lipoprotein in the protection against atherosclerotic disease and in the progression of coronary atherosclerotic disease. High-density lipoprotein cholesterol appears to exert this protective effect through multiple mechanisms. High-density lipoprotein is not only involved in reverse cholesterol transport, but also prevents endothelial dysfunction; inhibits the homing of monocytes, apoptosis, platelet activation, and factor X activation; and has antioxidant properties. In this article the authors review the available experimental and clinical evidence supporting the importance of high-density lipoprotein cholesterol as a protective factor in coronary artery disease, and the strategies developed to increase high-density lipoprotein cholesterol.     

Clinical and public health assessment of benefits and risks of statins in primary prevention of coronary events: resolved and unresolved issues

Peer-reviewed, evidence-based recommendations for statin use in primary prevention of cardiovascular events are limited. A narrative review of published randomized controlled trials and meta-analyses was conducted to critically appraise the benefits and risks of statins in primary prevention. Statins effectively reduce plasma concentrations of low-density lipoprotein cholesterol, and reduce the risk of cardiovascular events and death. The greatest benefits are observed in high-risk subjects, such as patients with diabetes or hypertension. Serious cardiovascular events should not be included among serious adverse events because they are efficacy outcomes and are dependent on the baseline risk of patients. Rates of specific serious adverse events, such as cancer and rhabdomyolysis, seem to be similar between the statin and control arms of the clinical trials examined. Thus, the benefits of statins in primary prevention outweigh the risks, particularly among high-risk patients. However, the benefit-risk ratio would likely be optimized through interventions designed to increase persistence and adherence in a real-life setting.     

Intensive lipid lowering in the cardiovascular patient: Who, how low, and for how long?

Clinical trials have unequivocally demonstrated that lowering levels of low-density lipoprotein cholesterol with statins prevents cardiovascular events. As a result, statins have become an integral component of therapeutic strategies to reduce cardiovascular risk. A number of important issues remain to be defined with regard to the optimal use of statin therapy in clinical practice. In particular, the ideal does, when to initiate therapy in relation to an acute ischemic event, and the duration of treatment remain uncertain. Results from a number of recently reported trials that investigate the impact of statin therapy on atherosclerotic plaque and clinical events provide further clarification with regard to these issues.     

C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus

Over 20 large-scale prospective studies show that the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is an independent predictor of future cardiovascular events that additionally predicts risk of incident hypertension and diabetes. In many studies, the relative impact of hsCRP is at least as large as that individually of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, or smoking, and knowledge of hsCRP correctly reclassifies a substantial proportion of "intermediate-risk" individuals into clinically relevant higher- or lower-risk categories. Other studies show the relative benefit of statins to be greater among those with increased hsCRP and that achieved hsCRP levels after statin therapy predict recurrent event rates as much as achieved levels of low-density lipoprotein cholesterol. Nonetheless, it remains controversial whether the time has come to modify traditional algorithms used for global risk detection. As described here, 6 areas of controversy regarding hsCRP are resolvable with a consensus position that focuses in primary prevention on selective use among individuals with 5% to 20% 10-year risk as estimated by Adult Treatment Panel III, and focuses in secondary prevention on high-risk patients being treated with statin therapy. Forthcoming trial data could expand or contract this "screen selectively" policy, and investigators should be open to the possibility that second-generation inflammatory biomarkers may be developed that supplant hsCRP altogether. In the meantime, however, this consensus position on hsCRP should be one to which both advocates and critics of the inflammatory hypothesis of atherosclerosis can adhere because it is one that can immediately improve patient care.     

Statins and biomarkers of inflammation

Clinical and epidemiologic studies convincingly demonstrate that increased levels of low-density lipoprotein cholesterol promote premature atherosclerosis. Several large clinical trials have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease cardiovascular events. The beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Evidence for the pleiotropic effects of statins is provided by recent clinical trials in which the benefit of statin drugs is manifest early in the course of lipid-lowering therapy, well before plaque regression could occur. Inflammation is pivotal in all stages of atherosclerosis, and C-reactive protein (CRP), the prototypic marker of inflammation, has emerged as a cardiovascular risk marker. Statins reduce CRP levels, and this reduction in most studies does not correlate to reduction in cholesterol. In addition, statins have beneficial effects on endothelial function, monocytemacrophages, and platelets. In this review we discuss the role of inflammation in atherosclerosis, the role of CRP as a risk marker, the clinical evidence implicating the anti-inflammatory effects of statins, and the cellular and molecular basis underlying the anti-inflammatory effects of statins.     

Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease.

Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the risk of atherothrombotic cardiovascular disease (CVD). Yet, despite the success of statins in reducing cardiovascular event rates in at-risk patients, many will still experience further events. There is, therefore, a need to develop suitable therapies to reduce this residual risk. Low high-density lipoprotein cholesterol (HDL-C) levels are an important independent risk factor for CVD. Though fibrates, niacin, and statins have been shown to modestly raise HDL-C, there is increasing recognition of the need to develop therapies that can increase HDL-C more robustly. Such therapies may help supplement the LDL-C-lowering benefits of statins. Inhibition of cholesteryl ester transfer protein (CETP) has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy, in terms of increasing HDL-C, in preliminary clinical trials, and clinical trials based on outcomes are ongoing. Two CETP inhibitors, JTT-705 and torcetrapib, are now being evaluated more extensively.     

How safe is aggressive statin therapy?

The most recent guidelines of the National Cholesterol Education Program recommend more aggressive low-density lipoprotein cholesterol goals: <100 mg/dL for patients at moderate or high risk of cardiovascular disease, and <70 mg/dL for patients at very high risk. These lower goals are more likely to be achieved using the more powerful statins--atorvastatin, rosuvastatin, and simvastatin. Although statins are widely used, extensively studied, and known to have an excellent safety profile, the perception of many health care providers and patients is that safety concerns about the more efficacious statins, especially at high doses, limit their use. However, clinical data consistently support the view that adverse events are uncommon even when intensive therapy is used to reach aggressive low-density lipoprotein cholesterol goals. Overall, the more potent statins have similar safety profiles. The benefits of aggressive statin treatment in reducing the risk of cardiovascular events appear to far outweigh any potential risks of adverse events.