Total Cholesterol Management: Taking Complete Control

Supported by an educational grant from Merck & Co., Inc.

FACULTY:

Gina J. Ryan, PharmD, BCPS, CDE
Clinical Associate Professor
Director of Continuing Education Department of Pharmacy Practice
Mercer University, College of Pharmacy and Health Sciences,
Atlanta, GA

FACULTY DISCLOSURE STATEMENTS:

Dr. Ryan reports the following financial disclosures: clinical investigator, Merck; grant/research support, Solvay; speakers’ bureau, Bristol-Myers Squibb, Eli Lilly. U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own view-point. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program No.: 430-000-08-011-H01-P; 430-000-08-011-H01-T
Credits: 2.0 hours (0.20 ceu)

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 90 to 120 minutes.

METHOD OF PARTICIPATION:

There are no fees for participating and receiving CE credit for this activity. During the period July 1, 2008 through July 31, 2010, participants must: read the learning objectives and faculty disclosure; study the educational activity; complete the posttest by recording the best answer to each question in the answer key on the evaluation form; complete the evaluation form; and mail or fax the evaluation form with answer key to the address listed on the form. For faster service, enter your answers on the Internet at www.uspharmacist.com. A statement of credit will be issued upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists on the importance of and approach to maintaining complete control of cholesterol levels.

OBJECTIVES:

After completing this program, participants will be able to:

1. Describe the importance of achieving recommended target levels of blood pressure, blood glucose levels, low-density lipoprotein cholesterol levels, high-density lipoprotein cholesterol levels, and very-low-density lipoprotein cholesterol levels;*
2. List the mechanism of action, effect on lipoprotein levels, and common adverse events of statins, fibric acid derivatives, niacin, bile acid sequestrants, ezetimibe, and omega-3 ethyl acids;*
3. List at least one investigational agent used in the treatment of lipid disorders;*
4. Describe the effects of combination therapy for lipid disorders;* and
5. List at least three ways that a pharmacist can improve the treatment of lipid disorders.

*Also applies to pharmacy technicians.

In 2005, 16 million Americans had coronary heart disease (CHD) and 5.8 million suffered a stroke.¹ Despite an abundance of clinical interventions aimed at improving control of cardiac risk factors, cardiovascular disease (CVD) remains the leading cause of death in the United States. It is also the most frequent diagnosis at hospital discharge and resulted in direct and indirect costs of approximately 448 billion dollars in 2008.^1,2

Hypertension, elevated blood glucose levels, and dyslipidemia are well established risk factors for CVD.¹ In adults, increasing systolic blood pressure by 20 mm Hg or diastolic blood pressure by 10 mm Hg doubles the risk of developing CVD.³ Treatment with antihypertensive medications reduces the risk of myocardial infarction, stroke, and heart failure by 20% to 25%, 35% to 40%, and 50%, respectively.⁴ In an epidemiological study, every 1% decrease in glycosylated hemoglobin reduced fatal and nonfatal myocardial infarction (MI) by 18% in patients with uncontrolled diabetes compared to those with glycosylated hemoglobin close to goal at baseline.⁵ There is some evidence that controlling blood glucose levels in patients with type 1 diabetes reduces the risk of CVD.⁶ However, in one study, a statistically significant reduction in CVD risk was not observed when patients with type 1 diabetes received intensive treatment.⁶

Although elevated cholesterol levels are a modifiable risk factor for CVD, uncontrolled cholesterol levels remain prevalent. In 2005, 48.4% of Americans had a total cholesterol level over the recommended goal of 200 mg/dL.¹ Total cholesterol levels are comprised of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). All components of the total cholesterol level are carried through the body by lipoproteins. Lipoproteins are water-soluble spheres that transport lipids through the body. They are categorized by their size and function, as well as by the percentage of triglycerides, cholesterol, and phosopholipids they contain. There are three routinely monitored lipoproteins: very-low-density lipoprotein cholesterol (VLDL-C), LDL-C, and HDL-C. VLDL-C is commonly referred to as “triglycerides” because it predominately carries TG from the liver to the periphery. LDL-C is comprised primarily of cholesterol that it carries from the liver to the periphery. HDL-C, similar to LDL-C, is cholesterol rich but carries cholesterol from the periphery to the liver, a process called reverse cholesterol transport.

IMPORTANCE OF LDL-C CONTROL

The most recent report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) provides evidence-based recommendations on the management of dyslipidemia. ATP III recommends monitoring a fasting lipid profile that consists of LDL-C, HDL-C, and VLDL-C. ATP III identifies LDL-C as the primary target of lipid therapy.^7,8 The treatment goals for lipoprotein levels are based on risk stratification (TABLE 1).

TABLE 2 contains the ATP III recommended LDL-C levels based on patients’ risk levels. Numerous trials have demonstrated that lowering LDL-C levels will reduce the risk of CVD events and mortality.^9-14 A meta-analysis of 14 clinical trials showed that a 39-mg/dL reduction in LDL-C levels resulted in a 23% reduction in major vascular events.¹⁵ Aggregated data suggest that for every 1-mg/dL decrease in LDL-C levels, the risk of all-cause mortality, CHD-related mortality, and CVD-related mortality decreases by 15.6%, 28%, and 26.6%, respectively.¹⁶

Table 1
Adult Treatment Panel III Risk Categories7,8
Risk Level	Number of Risk Factorsa	10-year CHD Riskb
Very-High	CHD + multiple risk factors	N/A
High	≥2 risk factorsc or diagnosis of CHD or CHD risk equivalent	>20%
Moderate-High	≥2c	10% to 20%
Moderate	≥2c	<10%
Low	0-1	<10%
a Risk factors are cigarette smoking, hypertension, HDL-C level <40 mg/dL, family history of premature CHD death, men over age 45, and women over age 55. An HDL-C level >60 mg/dL reduces an individual’s risk by 1 risk factor. b A program for calculating the 10-year risk of CHD is available from the National Heart, Lung and Blood Institute (www.nhibi.nih.gov/guidelines/cholesterol) c Patients with ≥ 2 risk factors may be in 1 of 3 risk groups based on 10-year CHD risk.

Table 2
Adult Treatment Panel III Treatment Goals7,8
Risk Categorya	Goal LDL-C (mg/dL)	LDL-C (mg/dL) Start Lifestyle Changes	LDL-C (mg/dL) Add drug
Very-High	<70	≥70	≥ 70
High	<100	≥100	≥100
Moderate-High	<130	≥130	≥130
Moderate	<130	≥130	≥160
Low	<160	≥160	≥190
a See Table 1 for risk category

IMPORTANCE OF VLDL-C CONTROL

After patients reach their LDL-C goal, treatment for elevated TGs is recommended as a secondary goal.^7,8 According to the ATP III, a normal VLDL-C level is less than 150 mg/dL. If the VLDL-C level is over 200 mg/dL, drug therapy should be initiated. The results of several meta-analyses and cohort studies suggest an association between cardiovascular events and elevated TG levels. One meta-analysis evaluated approximately 46,000 men and 10,000 women for 8 to 11 years. When the results were adjusted for HDL-C levels, this study showed a 37% increase in CVD risk per 88 mg/dL increase in TG among women (p<0.05).¹⁷ A slightly lower but statistically significant 14% increase in CVD risk was also seen among men (p<0.05).¹⁷ A meta-analysis of 29 studies that included a total of 262,525 patients showed a 72% increase in CHD risk when comparing the upper third to the bottom third TG levels (p<0.05).¹⁸

In a prospective cohort study of 796,671 person years in 96,224 Asian patients, elevated serum TG levels were an independent risk factor for CVD.¹⁹ In the 26-year follow-up of a prospective cohort study of 7,587 women and 6,394 men, the lowest TG category was defined as 88.5 to 176.1 mg/dL and the highest TG category was defined as > 442.5 mg/dL. In the lowest TG category, the risk of ischemic heart disease increased by 30% in men. The risk increased by 50% in men in the highest TG category (p<0.001). In women, the risk of ischemic heart disease was 80% higher in the lowest TG category and 2.6 times higher in the highest TG category (p<0.05). There were similar results for myocardial infarction and death.²⁰

Although high TG levels are associated with increased CVD risks, the benefit of lowering TG levels has not been completely established. Several trials have demonstrated that TG-lowering agents reduce the risk of cardiovascular events, but these trials fail to establish the independent benefit of TG reduction.^21-23

IMPORTANCE OF HDL-C CONTROL

CVD risk is inversely correlated with low HDL-C levels.^24,25 For this reason, HDL-C is often called the “good cholesterol.” HDL-C levels below 40 mg/dL are considered to be low and HDL-C levels greater than 60 mg/dL are considered to be a negative risk factor. If the HDL-C level is greater than 60 mg/dL, then one is subtracted from the total number of risk factors (Table 1 footnote “a”).

HDL-C exerts its atheroprotective effect by reverse cholesterol transport. HDL extracts cholesterol from macrophages, foam cells, and atherosclerotic plaque and delivers it back to the liver for elimination as bile salts or biliary cholesterol and to steroidogenic organs, where it is converted to cholesterol-based hormones. CHD risk is reduced by increasing HDL-C levels. In the Helsinki Heart Study, a randomized, double-blind, five-year primary prevention study, a 1% increase in HDL-C levels was shown to reduce the risk of CVD by 3% in patients (p<0.05).²⁶ In a secondary prevention trial, an 11% reduction in CVD events was associated with every 5-mg/dL increase in HDL-C levels (p=0.02).^22,23

Lifestyle modifications and drug therapy are the primary treatments for dyslipidemia. To reduce the CVD risk, interventions aimed at increasing exercise for everyone and weight reduction, if applicable, should be employed. Weight loss will improve the lipid profile and reduce the risk of diabetes and hypertension. Even a modest 5% to 10% weight loss can reduce LDL-C levels. Ideally, patients should exercise at least 150 minutes a week or 30 minutes a day 5 days a week.²⁷ However, when LDL-C levels are significantly elevated above goal, drug treatment is warranted (TABLE 2). There are currently six classes of drugs with indications for the treatment of dyslipidemia (TABLE 3).

Table 3
Effects of Specific Agents on Lipid Profile23,26,46-55,82,85,135,149-166
Agent	Daily Dose	% change from baseline in
		TC	LDL-C	TG	HDL-C
HMG CoA Reductase Inhibitors (statins)
Atorvastatin	10-80 mg	↓29-45	↓39-60	↓19-37	↑5-9
Fluvastatin	20-80 mg	↓17-25	↓22-35	↓3-7	↑12-19
Lovastatin	10-80 mg	↓16-24	↓21-32	↑9 to↓10	↑2-8
Pravastatin	10-80 mg	↓16-27	↓22-34	↓15-24	↑7-12
Rosuvastatin	5-40 mg	↓33-46	↓46-63	↓10-35	↑10-13
Simvastatin	5-80 mg	↓19-36	↓26-47	↓12-33	↑8-16
Fibric Acid Derivatives (fibrates)
Fenofibrate	48-145 mg	↓9-14	↓20 to ↑45a	↓44-55	↑11-23
Gemfibrozil	1200 mg	↓4	↑2	↓31	↑6
Bile Acid Sequestrants (resins)
Cholestyramine	4-24 g	↓15-27	↓9-28	↑13-26	↑2-8
Colesevelam	1.5-4.5 g	↓2-10	↓2-19	↓1 to ↑15	↓1 to ↑9
Colestipol	2-16 g	↓3-17	↓5-26	↓1	↑10-15
Nicotinic Acid
Niacin ERb	500-2000 mg	↓ 4-10	↓2-18	↓3-36	↑8-26
Omega-3 Fatty Acids
Omega-3 ethyl esters	2-4 g	↓9	↑45	↓19- 45	↑9.1
Cholesterol Absorption Inhibitors
Ezetimibe	10 mg	↓12	↓13	↓11	↑4
aPatients with Type IV Fredrickson hyperlipidemia may have increased LDL-C levels with treatment of fenofibrate. bNiacin ER= niacin extended-release, not niacin sustained-release because the sustained-release preparation is associated with more hepatotoxicity

DRUG THERAPY’S ROLE IN COMPLETE CONTROL

Statins

Lovastatin was the first HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor (statin) approved in the United States. Currently, there are five other statins marketed in the United States (TABLE 3). HMG CoA reductase is an enzyme that catalyzes the rate-limiting step in hepatic cholesterol synthesis. Inhibition of this enzyme halts the liver’s biosynthesis of cholesterol. Since the liver requires cholesterol for hormone synthesis, reduction in cholesterol levels causes the liver to increase the number of LDL-C receptors on the surface of hepatocytes to increase cholesterol uptake from the serum. In summary, statins lower cholesterol synthesis and increase LDL-C catabolism.^28-31

The effects of statins on the lipid profile vary according to the agent and dose. They are primarily used to lower LDL-C levels, but high doses of atorvastatin, rosuvastatin, and simvastatin can lower TG levels significantly. Several large, randomized, controlled trials have shown that statins are effective in reducing the risk of CHD events (stroke and heart attacks) in patients without a history of CHD.^11,12,32,33 Four large, randomized, controlled trials have shown significant decreases in cardiovascular death, stroke, myocardial infarction, and the need for revascularization procedures in patients with pre-existing CHD.^10,13,34,35

Patients recently hospitalized with acute coronary syndrome (ACS) were evaluated to compare the effect of lowering LDL-C levels to less than 70 mg/dL with atorvastatin to a LDL-C level less than 100 mg/dL with pravastatin. A 16% reduction in the hazard ratio with the lower LDL-C target was demonstrated (p<0.05).³⁶ These results, along with additional trial data, resulted in the update to the current ATP III goal LDL-C level for high-risk patients (<70 mg/dL).^37-39 There is also evidence that statins are effective for secondary prevention of CHD.

In general, statins are well tolerated. The most frequent adverse events associated with statins include headaches and insomnia (0.5% to 10%), increased liver function enzymes (1% to 2%), increased creatine kinase levels (0.1% to 5%), myopathy (0% to 2.7%) and gastrointestinal (GI) upset (<2%).^28-31,40 The incidence of central nervous system (CNS)-related adverse events may be slightly higher with agents that cross the blood brain barrier, such as lovastatin and simvastatin.⁴⁰

Rhabdomyolysis is a rare but serious adverse effect associated with statin therapy. Myopathy and increased creatine kinase levels (greater than 10 times the upper limit of normal) are signs of potential rhabdomyolysis. Monitoring for these signs and symptoms is important. Patients with complaints of muscle weakness or pain should have their creatine kinase levels checked. If the levels are greater than 10 times the upper limit of normal, the drug should be discontinued. When the offending agent is a hydrophilic statin (eg, lovastatin, pravastatin, or rosuvastatin), then a trial of a lipophilic statin (simvastatin, atorvastatin, or fluvastatin) may be warranted. However, further studies are needed to prove this.

Fibric Acid Derivatives

Fibric acid derivatives (fibrates), such as gemfibrozil and micronized fenofibrate, are indicated for the treatment of elevated VLDL-C levels, but they also increase HDL-C levels and slightly decrease LDL-C levels (TABLE 3). Fibrates are peroxisome proliferator-activator receptor (PPARα´) agonists, which are transcription factors involved in the regulation of various metabolic processes. Activation of PPARα´ leads to increased production of lipoprotein lipase, the enzyme that degrades TG.⁴¹ Fibrates increase the genes that code for important HDL-C proteins, and as a result increase HDL-C levels. There is increased clearance of LDL-C because fibrates increase the affinity of hepatic LDL-C receptors.^42,43

The profound effect of fibrates on VLDL-C levels is the reason they are primarily used for the treatment of elevated VLDL-C levels. The Helsinki Heart Study is a randomized, controlled primary prevention trial in which gemfibrozil 600 mg twice a day was compared with placebo in 4,081 patients with dyslipidemia. The gemfibrozil group had an 8.7% increase in HDL-C levels, a 34.5% reduction in TG levels, and an 8.3% decrease in LDL-C levels, whereas the placebo group had virtually no changes in their lipid profile. After a 60-month follow-up, the gemfibrozil group had a 34% reduction in cardiac events (p<0.05).⁴⁴ In a different randomized, double-blind, placebo-controlled trial, 2,531 men with a history of CHD who had low HDL-C levels and low LDL-C levels were treated with gemfibrozil 1,200 mg/day or placebo for 5.1 years.²³ There was a 24% decrease in the combined risk of death from CHD, nonfatal myocardial infarction, and stroke (p<0.001). CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL increase in HDL-C levels (p=0.02).²²

Interestingly, although both trials found that gemfibrozil lowered VLDL-C levels to around 30%, there was no independent benefit of TG reduction. Although elevated baseline TG levels are an independent risk factor for CHD events, more studies on the benefits of lowering VLDL-C are warranted.^22,45

Similar to statins, fibrates are generally well tolerated. During clinical trials, there were no significant differences in withdrawal rates between treatment groups compared with placebo.^44,46 An increased liver function test (5.3%) was the most commonly reported adverse event that was significantly higher in the fenofibrate groups compared with the placebo group (1.5%).^44,46 The adverse events that occurred in the gemfibrozil-treated patients that were significantly higher than in those receiving placebo were dyspepsia (19.6%), abdominal pain (9.8%), acute appendicitis (1.2%), and atrial fibrillation (0.7%).⁴⁷ Fibrates (rarely) may cause myopathy and rhabdomyolysis; therefore, muscle pain and creatine protein kinase levels should be monitored.^46,47 When fibrates are initiated, patients should be instructed to report any muscle pain or weakness to the prescriber or pharmacist.

Bile Acid Sequestrants

Bile acid sequestrants include cholestyramine, colesevelam, and, colestipol. They are resins that bind cholesterol-rich bile and increase its elimination, resulting in lower cholesterol levels. Since the liver needs more cholesterol to increase bile production, more LDL-C receptors are sent to the cell surface of hepatocytes, and LDL-C clearance is increased. The Lipid Research Clinics Coronary Primary Prevention Trial was the largest trial to date (N=3,806) to examine the effectiveness of cholestyramine in lowering cholesterol and primary CHD events. In this trial, patients were randomized to either 24 gm daily of cholestyramine or placebo. There was a 20.3% decrease in LDL-C levels in patients receiving cholestyramine compared with a 12.6% decrease in patients receiving placebo (p<0.05). After 7.4 years, the cholestyramine-treated patients had a 19% reduction (p<0.05) in risk of cardiovascular death and MI. The cholestyramine group also had a 20% reduction in risk of angina and 21% reduction in the number of patients requiring a coronary artery bypass graft (p<0.05).⁴⁸

GI adverse events, mainly constipation, are the primary reason these agents are discontinued. In the Lipid Research Clinics Coronary Primary Prevention Trial, moderate-to-severe constipation was reported in 39% of patients receiving cholestyramine and in only 10% of patients receiving placebo (p>0.05).^38,48,49 Constipation was reported in 8.7% to 11%, dyspepsia in 4.1% to 8.3%, and nausea in 3.9% to 4.2% of patients taking colesevelam (p<0.05 versus placebo).^50-54 Colesevelam is administered at lower doses because of its higher bile-binding capacity and, therefore, is associated with fewer GI adverse effects.⁵⁵

Nicotinic Acid Derivatives

Nicotinic acid (niacin) decreases TG levels because it blocks lipolysis by inhibiting adenyl cyclase in adipocytes.⁵⁶ Since less fatty acids are extracted from adipose tissue, the liver production of VLDL-C decreases, which results in reduced LDL-C levels. Niacin increases serum HDL-C levels by inhibiting the uptake of HDL-C by the liver but does not attenuate the removal of cholesterol from HDL-C.⁵⁷ This results in increased circulating HDL-C available to take cholesterol from the periphery to the liver. Niacin is the only agent that has a clinically significant effect on all three lipoproteins (TABLE 3). In addition, niacin reduces another atherogenic lipoprotein, lipoprotein-a. Lipoprotein-a has been shown to correlate with CHD risk.⁵⁸

The efficacy of niacin in preventing coronary events has been demonstrated in the Coronary Drug Project.⁵⁹ In this 15-year, placebo-controlled trial, 8,341 patients with a history of myocardial infarction were assigned to treatment with estrogen, clofibrate, dextrothyroxine, niacin, or placebo. After a 15-year follow-up period, the niacin-treated group had a 11% lower mortality rate than the placebo group (p=0.0004). Niacin has been shown to reduce LDL-C levels by 2% to 18% and VLDL-C levels by 3% to 36% (see TABLE 3).

The major limitation to niacin therapy is its adverse event profile. Flushing and itching occur in almost all patients, usually within two hours of administration, and can last for hours.⁶⁰ These cutaneous symptoms do diminish after a few weeks of continued therapy.⁶¹ Slow dose titration also reduces the severity of the cutaneous reaction.

Flushing is stimulated by the rate of niacin absorption because flushing occurs when the serum concentrations are rising but stops once serum concentrations plateau.⁶² In one trial, the rate of niacin-induced flushing ranged between 32% to 53% in patients receiving immediate-release niacin compared with 12% to 22% in patients receiving sustained-release niacin.⁶³ Unfortunately, these early forms of sustained-release niacin were associated with hepatotoxicity.^63,64 A newer controlled-released prescription preparation, niacin extended-release, has not been associated with liver toxicity.^65-67 Pharmacists should not recommend over-the-counter sustained-release niacin.

Flushing is the result of niacin increasing the release of cutaneous prostaglandin D₂.⁶⁸ Pre-treatment with aspirin can reduce the incidence, frequency, and intensity of flushing. Oberwittler reviewed the evidence for use of aspirin to control niacin-related flushing. Pre-treatment with aspirin was associated with a lower discontinuation rate (7.7%) than when aspirin was not given (40%).⁶⁰ The optimal dose of aspirin for pre-treatment is not established. It is clear that 80 mg of aspirin may not be effective, but 160 mg was equally effective as a 325-mg dose for flushing prophylaxis.⁶⁹ Recently, coadministration of laropiprant, an investigational prostaglandin D₂ receptor antagonist, has been shown to reduce niacin-related flushing in patients by 47% to 74% when compared with those receiving placebo.^70,71 The use of laropiprant increased the tolerability of an expedited titration schedule.

Short-term studies indicate that immediate-release niacin can increase insulin resistance.^72-75 However, a 3% to 5% increase in blood glucose levels was seen during niacin therapy in three clinical trials.^59,65,66 Recent data found an increase of 0.3% in hemoglobin A_1c levels in patients with diabetes treated with niacin extended-release compared with those receiving placebo.^67,76 Regardless of any potential increases in blood glucose levels, niacin has proven to improve cardiovascular outcomes.⁵⁹ It should be noted that there have been case reports of myopathy related to niacin.^77,78 However, myopathy was not reported in clinical trials with monotherapy extended-release niacin.^65-67,79

Cholesterol Absorption Inhibitors

The most recently approved cholesterol-reducing agent, ezetimibe, decreases intestinal cholesterol absorption by inhibiting a brush boarder transporter.^80,81 At the time of this writing, there were no published trials examining the effects of ezetimibe monotherapy on CVD events or mortality. This agent has been studied in combination with statins and fenofibrate (see section on combination therapy). The effect of ezetimibe monotherapy is listed in TABLE 3. Very little of ezetimibe is absorbed, and reported adverse event rates are similar to placebo.^81,82

Omega-3 Acid Ethyl Esters

Omega-3 acid ethyl ester is FDA-approved for hypertriglyceridemia. Its mechanism for lowering VLDL-C levels is not clear. The three proposed mechanisms are (1) omega-3 fatty acids inhibit key enzymes in TG biosynthesis, (2) omega-3 fatty acid oxidation and TG biosynthesis compete with each other for the use of fatty acid substrates, and (3) omega-3 fatty acids increase activity of lipoprotein lipase, which increases TG clearance.^83-85

The effects of omega-3 fatty acids on mortality and event rates have varied in observational trials.^86-92 However, in a large, open-label, 3.5-year trial, 11,324 patients with CVD were randomized to 300 mg vitamin E, 850 mg omega-3 fatty acid ethyl esters, combination therapy, or placebo. There was a 15% reduction in the composite outcome of death, nonfatal MI, and nonfatal stroke (p<0.02). All-cause morality was 20% lower (p<0.01) and sudden death was 45% lower in the group receiving the fish oil supplement (p<0.001).^93,94

Similar to other cholesterol-lowering drugs, omega-3 ethyl esters are well tolerated. In clinical trials, the primary adverse events associated with prescription doses of omega-3 fatty ethyl esters were a “fishy taste” (2.7%) and eructation (4.9%).⁹⁵ It is important to note that omega-3 fatty ethyl esters have been reported to increase LDL-C levels significantly (see TABLE 3).^95,96

Investigational Agents

There are several agents that are being investigated for their cholesterol-lowering effects. Squalene sythase, another enzyme in the hepatic production of the cholesterol pathway, has been studied as a drug target. A squalene synthase inhibitor (TAK-475) has been shown to reduce LDL-C levels and is currently in phase III clinical trials.^97,98

Cholesteryl ester transfer protein (CETP) is a key enzyme in HDL-C metabolism. Two CETP inhibitors, anacetrapib and trocetrapib, have been shown to cause 30% to 60% increases in HDL-C levels and 17% to 38% decreases in LDL-C levels.^99-102 However, in a large (N=15,067), randomized, double-blind trial, trocetrapib increased the risk of CVD events (p=0.001) and death (p=0.006).¹⁰³ Obviously, anacetrapib’s safety will have to be assessed to determine if the results of the trial with trocetrapib were secondary to a “class effect.”

Combination Therapy

The use of statins is considered as first-line therapy for the treatment of LDL-C in both primary and secondary prevention of CHD.⁸ The intense lowering of LDL-C levels recommended by ATP III is not always achievable with statin monotherapy. In addition, monotherapy with a statin may not raise HDL-C levels and lower VLDL-C levels substantially (TABLE 3). Therefore, combination drug therapy may be warranted in some patients.⁸ The effects of combination statin therapy on the fasting lipid profile are listed in TABLE 4.

Table 4
Effects of Simultaneous Initiation of Statin-Based Combination Therapy53,104,117,122,124,129,131-133,135,136,167
Agent	% Change from baseline
	LDL-C	TG	HLDL-C
Niacin	↓51-57	↓25-47	↑7-24
Fibric Acid Derivatives	↓31	↓49	↑19
Ezetimibe	↓33-70	↓19-44	↑8-10
Bile Acid Sequestrants	↓21-48	↓12-↑18	↓3-↑4
Omega-3 Ethyl Esters	↑0.7	↓30-40	↑3

The addition of niacin to statin therapy offers the benefits of TG level reduction, increased HDL-C levels, and augmented LDL-C level reduction (TABLE 4). There is also evidence that this combination has positive effects on patient outcomes. In a randomized three-year, double-blind, placebo-controlled trial in 160 patients with CHD, the primary composite endpoint was death from coronary causes, confirmed MI or stroke, or revascularization for worsening ischemic symptoms. The combination of simvastatin and niacin reduced the risk of the primary composite endpoint compared with placebo (p=0.03).¹⁰⁴ There is a commercially available combination product of lovastatin and extended-release niacin.

There is some concern of overlapping toxicity with a combination of niacin and a statin because both can cause myopathy and increase liver enzymes. However, several studies have shown that the combination is well tolerated.^105-112

The effects of ezetimibe-statin combination therapy on lipid profiles have been studied extensively.^113-122 A meta-analysis showed that the combination is effective at enhancing the LDL-C reduction of statin therapy.¹²³ One double-blind, placebo-controlled, randomized two-year trial compared the effects of simvastatin versus simvastatin and ezetimibe in 720 patients with familial hypercholesterolemia, a rare genetic disorder characterized by high LDL-C levels. Although administration of ezetimibe resulted in a 16.5% lower LDL-C level (p<0.01), there was no difference in carotid artery thickness, a surrogate marker of CHD.¹²⁴ These results have raised concerns regarding the benefits of ezetimibe therapy. However, experts recommend that if statin therapy does not lower LDL-C levels to goal, nicotinic acid, fibrates, or bile acid sequestrants may be added since these agents have shown in clinical trials that they reduce event risk. Ezetimibe may be added if LDL-C levels are still not at goal.¹²⁵ Currently, ezetimibe is being studied in patients with degenerative aortic stenosis, chronic kidney disease, and acute coronary syndrome.¹²⁶

The other combination therapies are not as well studied and lack any positive outcome data. The combination of a fibrate and a statin is particularly effective in patients with metabolic syndrome or diabetes in which VLDL-C levels are often elevated, HDL-C levels are usually low, and LDL-C levels are not at goal (TABLE 4 for effects). There is an ongoing large-scale prospective outcome trial [Action to Control Cardiovascular Risk in Diabetes (ACCORD)] that examines a fenofibrate-statin combination.¹²⁷ This trial is scheduled to culminate in 2009. Fibrates and statins share the common toxicities of myopathy and adverse effects on liver enzymes. It has been shown that the actual incidence of increased toxicity is minimal but less when fenofibrate was used (0.5%) than when gemfibrozil was used (8.6%, no p value reported).¹²⁸

Resins in combination with statins can result in increased LDL-C lowering potency (TABLE 4).^129-133 However, there is minimal outcome data on resin-statin combination therapy. Studies do show that there is no risk of increased toxicity.

Omega-3 ethyl esters can also be used in combination with statin therapy. This combination results in enhanced VLDL-C reduction, but LDL-C levels may be adversely affected by the omega-3 fatty acid (TABLE 4).^134-136 Clinical outcomes studies of this combination have not been published.

PHARMACISTS’ ROLE IN COMPLETE CONTROL

Pharmacists need to be aware, and to make their patients aware, that controlling lipid abnormalities is directly related to total control of blood glucose levels, hypertension, and other risk factors for CVD. Since correction of lipid abnormalities is primarily accomplished with drug therapy, the role of a pharmacist is a vital part of this process. Assisting patients and prescribers with cost-effective drug selection and goal attainment is only part of the big picture. Providing patient education on the correct use of medications and warning of important adverse events are important to ensuring safe and effective therapy. Patients taking statins or fibrates should be told to report muscle pain and weakness. Patients should be informed not to take atorvastatin, lovastatin, and simvastatin with grapefruit products because of increased absorption of these agents and possible increased risk of toxicity. The effect, or lack of an effect, of food on statin therapy should be explained. Niacin-treated patients should be alerted to the possibility of cutaneous flushing and should be encouraged to pre-treat with aspirin.

The impact of pharmacist management of lipid-lowering therapy has been documented in both institutional and community settings.^137-146 Two retrospective studies compared lipid data from patients whose lipids were treated by a clinical pharmacist compared to other health care providers in Veteran’s Affairs (VA) clinics. Baseline values were not statistically different. However, in one study pharmacist-treated patients had a 12% lower LDL-C level.¹⁴⁵ The other study found similar results; the average LDL-C level was 34 mg/dL less in the group treated by pharmacists compared with the group treated by other health care providers.¹⁴¹

In a prospective, controlled trial in a health maintenance organization, 481 patients with CHD and elevated LDL-C levels were placed in a clinic in which a clinical pharmacist collaborated with physicians or in a clinic without a pharmacist (usual care). The patients in the usual care group had an average LDL-C reduction of 4.6% compared with a 27.5% reduction in patients in the clinical pharmacist group (p<0.001).¹⁴⁴

In a randomized, controlled trial conducted at nine VA medical centers, 437 patients were given pharmaceutical care or usual care. Patients receiving pharmaceutical care had a 23-mg/dL decrease in LDL-C levels compared with a 12.8-mg/dL decrease in patients in the control group (p=0.042).¹³⁹

Community pharmacists are well situated to identify and care for high-risk CVD patients. The effects of standardized medication education, regular pharmacist follow-up, and dispensing medication in time-specific blister packs were studied in a randomized controlled trial of 200 patients seen in an Army medical center.¹⁴⁷ Medication adherence increased during the period when patients were in the pharmacy care program.

The Study of Cardiovascular Risk Intervention by Pharmacists (SCRIP), a randomized controlled trial, examined the effect of a community pharmacy program on lipid management in 675 patients. Patients who were in the intervention group received education on CVD risk factors, had their cholesterol measured, were referred to their physician, and were followed closely. The primary endpoint was a composite of measurement of a fasting lipid profile by a physician or addition or increase in dose of lipid-lowering therapy. This study was stopped early because of the profound effect of the intervention. After four months, 57% of patients in the intervention group had improvement in the primary outcome compared with only 31% of patients in the usual care group (p<0.001).¹⁴⁸ A subsequent publication reported that extended follow-up care continued to maintain an effect on LDL-C levels.¹⁴⁶

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