eMedicine Specialties > Endocrinology > Metabolic Disorders

Hypercholesterolemia, Polygenic

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
William L Isley, MD, Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester

Updated: Nov 17, 2009

Introduction

Background

Polygenic hypercholesterolemia is the most common cause of elevated serum cholesterol concentrations. Low-density lipoprotein cholesterol (LDL-C) elevations are moderate (140-300 mg/dL) with serum triglyceride concentrations within the reference range. However, practically speaking, the material in this article is also relevant to patients with mixed dyslipidemias with triglyceride levels of less than 350 mg/dL.

This condition is caused by a susceptible genotype aggravated by 1 or more factors, including atherogenic diet (excessive intake of saturated fat, trans fat, and, to a lesser extent, cholesterol), obesity, and sedentary lifestyle. The involved genes have yet to be discovered. Polygenic hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD), as displayed in the image below and in Image 1.

Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago Heart Association Detection Project in Industry, PG is Chicago Peoples Gas Company, and MRFIT is Multiple Risk Factor Intervention Trial. Adapted from Stamler, 2000.

Pathophysiology

Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, in patients with normal or minimally elevated triglyceride levels and average high-density cholesterol levels (HDL-C), the total serum cholesterol measurement can be used as a surrogate for the LDL-C level. Hypertriglyceridemia is caused by excessive numbers of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and/or chylomicron particles; and in this situation the total cholesterol level is not a reflection of the LDL-C level. For a simplified diagram of cholesterol metabolism, see the image below and Image 2. Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL hepatic uptake. Diets high in saturated fat, trans fat, and cholesterol cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.^6,7

Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediate-density lipoprotein, HDL is high-density lipoprotein, and LPL is lipoprotein lipase.

Frequency

United States

The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of greater than or equal to 240 mg/dL. Desirable cholesterol concentrations are less than 200 mg/dL. The National Health and Nutrition Examination Survey III, performed from 1988-1991, found that 26% of American adults had high blood cholesterol concentrations and 49% had desirable values. According to the NCEP ATP III guidelines, all adults aged 20 years or older should have a fasting lipid profile determined at least every 5 years to assess CHD risk. Sixty-five million American adults qualify for therapeutic lifestyle changes, while 36 million US adults need pharmacologic therapy to reach NCEP ATP III goals.

International

Serum cholesterol concentrations vary widely throughout the world. Generally, countries associated with low serum cholesterol concentrations (eg, Japan) have lower CHD event rates, while countries associated with very high serum cholesterol concentrations (eg, Finland) have very high CHD event rates. However, some populations with similar total cholesterol levels have very different CHD event rates, as would be expected given that other risk factors (e.g. prevalence of smoking or diabetes mellitus) also influence CHD risk. The cholesterol levels in developing countries tend to increase as western dietary habits (the MacDonald's syndrome) replace traditional diets.

Mortality/Morbidity

The primary manifestation of hypercholesterolemia is increased CHD risk.⁸ Data from epidemiological studies (eg, the Multiple Risk Factor Intervention Trial and the Framingham Heart Study) show a relationship between elevated LDL-C concentrations and CHD events and CHD mortality rates. In the prestatin era, randomized clinical trials showed a clear correlation between CHD morbidity and mortality but not total mortality. The advent of the statins, medications that are more easily tolerated and substantially more powerful than older cholesterol-lowering medications, increased the likelihood of substantial LDL-C lowering (increased power). Thus, the statins showed benefits that drugs used in previous studies had not.

Placebo-controlled statin trials have demonstrated not only reduced coronary morbidity and mortality in primary and secondary prevention populations, but also decreased total mortality. 

The causative relationship between LDL-C levels and ischemic stroke and transient ischemic attack (TIA) was suggested by decreased cerebrovascular events in several major statin trials in which stroke was a secondary endpoint. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study definitively showed that in patients who had suffered a recent stroke or TIA but who had no CHD, high-dose statin reduced the overall incidence of stroke and cardiovascular events despite a small, but statistically significant, increase in the incidence of hemorrhagic stroke.⁹

Race

Among adults, National Health and Nutrition Examination Survey III data (1988-1992) show more frank hypercholesterolemia among non-Hispanic white persons (19%) than Mexican Americans (15%) or non-Hispanic black persons (16%).

Sex

Hypercholesterolemia is more common in men younger than 55 years and in women older than 55 years.

Age

In adults, hypercholesterolemia increases with advancing age (see image below and Image 3).

National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.

Clinical

History

Hypercholesterolemia is usually discovered during routine screening and does not produce symptoms. Hypercholesterolemia is more common in individuals with a family history of the condition, but lifestyle factors (eg, a diet high in saturated fat) clearly play a major role.

Physical

Tendon xanthomas are not present in persons with polygenic hypercholesterolemia. If tendon xanthomas are present, familial hypercholesterolemia or familial defective apoprotein B-100 is the correct diagnosis. Eruptive xanthomas signify extreme hypertriglyceridemia. Xanthelasmas may be present but do not necessarily indicate hypercholesterolemia. Secondary hypercholesterolemia is suggested by stigmata of liver disease, hypothyroidism, hypopituitarism, nephrotic syndrome, and chronic renal disease.

Causes

The risk factors for coronary heart disease (CHD), other than LDL-C, in the US National Cholesterol Education Program (NCEP) screening and treatment algorithm are as follows:

• Age and sex
  • Men aged 45 years or older
  • Women aged 55 years or older
• Family history of premature CHD (male first-degree relative <55 y, female first-degree relative <65 y)
• Current cigarette smoking
• Hypertension - Blood pressure greater than or equal to 140/90 mm Hg or current antihypertensive drug therapy
• Low HDL-C concentration - Less than 40 mg/dL, but 1 risk factor subtracted if HDL-C concentration is more than 60 mg/dL (This level has been increased from <35 mg/dL compared with the value from the NCEP Adult Treatment Panel II [NCEP ATP II].)

Differential Diagnoses

Other Problems to Be Considered

Biliary cirrhosis
Coronary heart disease

Workup

Laboratory Studies

• The US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) suggests screening asymptomatic individuals with a fasting lipid panel every 5 years.
• Practically speaking, performing a risk factor analysis prior to obtaining screening blood test results is preferable. Patients can have risk factors for coronary heart disease (CHD) other than low-density lipoprotein cholesterol (LDL-C; see Causes).
  • A full lipid profile is obtained after the patient fasts for 9-12 hours.
  • Chylomicrons must be absent and the total triglyceride level must be less than 400 mg/dL in order to use the Friedewald formula to calculate LDL-C. The Friedewald formula is LDL-C = total cholesterol - high-density lipoprotein cholesterol (HDL-C) + triglycerides/5.
  • Direct LDL-C measurements do not offer any greater use, except in patients with marked hypertriglyceridemia. Direct LDL-C measurements can be performed while the patient is in the nonfasting state.
• To perform a careful medical evaluation, the practitioner must ascertain all medication intake (both prescription and over-the-counter medications) and perform tests of serum thyroid-stimulating hormone, liver function, creatinine, and urinalysis to rule out secondary dyslipidemias.

Treatment

Medical Care

During the 1990s, the cholesterol revolution occurred. Numerous studies documented the efficacy of low-density lipoprotein cholesterol (LDL-C) reduction in the reduction of coronary heart disease (CHD) events and, in some situations, the reduction of CHD and total mortality rates.

• Medical therapy involves lifestyle modification and pharmacologic therapy.
  • For patients with known atherosclerosis (clinical CHD, symptomatic carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm), the LDL-C goal is less than 100 mg/dL, although an LDL-C goal of less than 70 mg/dL is now considered a therapeutic option in patients considered to be at very high risk (acute coronary syndrome patients, diabetes mellitus, multiple risk factors with uncorrected risk factors such as continued smoking).
  • For patients with 2 or more risk factors, the LDL-C goal is less than 130 mg/dL, with recommendations for drug therapy that depend on the estimated 10-year risk of a CHD event based on the modified Framingham equation (see below).
  • For patients at low risk (0-1 risk factors), the LDL-C goal is less than 160 mg/dL.
  • The LDL-C goal for patients with CHD equivalent risk, including patients with diabetes mellitus, should also be less than 100 mg/dL. In patients considered to be very high risk, a goal of less than 70 mg/dL is an acceptable option
• The evaluation generally begins with a risk-factor analysis. Patients are then categorized according to CHD or CHD risk equivalent (particularly diabetes), ie, those with multiple risk factors and those at low risk (<2 risk factors). Patients with CHD or CHD equivalent risk have a greater than 20% 10-year risk for CHD events. Low-risk patients generally have a 10-year CHD risk of less than 10%. Patients with multiple risk factors may or may not be at high risk.
• The new National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend calculating a Framingham risk score in patients with multiple risk factors to quantify risk and set LDL-C goals. The Framingham score calculator is available through the NCEP and the US National Heart, Lung, and Blood Institute (see Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD).
  • Patients with CHD or CHD equivalent are prescribed drug therapy simultaneously with therapeutic lifestyle changes if their LDL-C concentration is greater than or equal to 130 mg/dL. Drug therapy is optional for patients whose LDL-C value is 100-129 mg/dL.
  • For patients with multiple risk factors, the LDL-C level at which drug treatment is recommended depends on the Framingham score. The LDL-C goal is less than 130 mg/dL. For patients with multiple risk factors and a 10-year risk of greater than 20%, the treatment is similar to that of patients with CHD. For patients with a 10-year risk of 10-20%, drug treatment is considered if their LDL-C level is greater than or equal to 130 mg/dL. For patients with multiple risk factors and a 10-year risk of less than 10%, drug therapy is considered if their LDL-C levels are greater than or equal to 160 mg/dL.
  • For patients at low risk, the LDL-C goal is less than 160 mg/dL, with therapeutic lifestyle changes for patients with higher values and drug therapy considered at LDL-C levels of greater than or equal to 190 mg/dL.
  • Therapeutic lifestyle treatment (ie, dietary changes and exercise) is recommended for patients whose LDL-C concentrations are greater than their goal LDL-C.
• The new NCEP guidelines also recommend trying to identify patients with what has been called the metabolic syndrome. Such patients in particular should be targeted for therapeutic lifestyle changes. These patients meet at least 3 of the following criteria:
  • Abdominal obesity (waist >40 in for men, >35 in for women)
  • High triglyceride level (>150 mg/dL)
  • Low high-density lipoprotein cholesterol (HDL-C) value (<40 mg/dL for men, <50 mg/dL for women)
  • High blood pressure (>130/85 mm Hg)
  • Impaired fasting glucose (IFG) value (plasma glucose level >110 mg/dL, although the lower limit now generally used in the American Diabetes Association IFG cutpoint of 100 mg/dL or greater)
• If the patient's serum triglyceride level remains greater than or equal to 200 mg/dL after the LDL-C goal is reached, a secondary non–HDL-C goal is set. The non–HDL-C goal is the LDL-C goal plus 30 mg/dL. This goal may be achieved with an increase in the statin dose, a more efficacious statin, or the addition of another agent (eg, fibrate, niacin, fish oil). Fenofibrate has less of a propensity for drug interactions; therefore, it is preferred in most situations. If fish oil is used, the correct dose is at least 2-3 g of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) daily. Because most 1-g fish oil capsules contain only approximately 300 mg of DHA and EPA, a patient must consume 10 1-g fish oil capsules daily to reach the goal. More highly concentrated fish oil capsules or liquids can be used, but the patient usually cannot find these in local pharmacies.
• Screen all patients via a fasting lipid profile every 5 years beginning at age 20 years. Patients with CHD should undergo a lipid profile determination at least yearly. Patients with multiple risk factors should have their lipid profiles determined at least every other year.
• In 3 months, recheck the lipid profiles of patients treated with therapeutic lifestyle intervention. In 6-12 weeks, recheck the lipid profiles of patients treated with drugs.
• Liver function testing is indicated periodically for patients taking statins or fibrates, although the risk for hepatotoxicity is very low. Liver function abnormalities are more common at the highest doses of each of the approved statins. Checking liver test results 6-12 weeks after an increase in the dose is reasonable, particularly in patients on high-dose statins.
• The dosage and approximate LDL-C lowering of various statins is as follows:
  • For atorvastatin at 10-80 mg/d, the LDL-C level is lowered by 39-60%.
  • For fluvastatin at 20-80 mg every bedtime or 40 mg twice daily, the LDL-C level is lowered by 22-36%.
  • For lovastatin at 20-40 mg every evening or 40 mg twice daily, the LDL-C level is lowered by 24-42%.
  • For pravastatin at 10-80 mg every bedtime, the LDL-C level is lowered by 22-34%.
  • For rosuvastatin at 5-40 mg/d, the LDL-C level is lowered by 45-63%.
  • For simvastatin at 20-80 mg every bedtime, the LDL-C level is lowered by 38-47%.¹⁰
• Statin intolerance creates a treatment dilemma for patients and practitioners in terms of selecting therapeutic options to treat hypercholesterolemia. Red yeast rice is an herbal supplement known to decrease LDL-C levels. Becker et al randomly assigned 62 patients (1:1 ratio) who discontinued statin therapy because of myalgias to receive either red yeast rice (1800 mg) or placebo twice daily for 6 months.¹¹ During the study, all patients also took part in a 12-week therapeutic lifestyle change program.
  
  LDL-C levels were significantly lower in the red yeast rice group compared with the placebo group at 12 weeks and 24 weeks (P <0.001 and P=0.011, respectively). Compared with the placebo group, the red yeast rice group also had a significant decrease in total cholesterol levels at 12 weeks and 24 weeks (P <0.001 and P=0.016, respectively). The study was small, but the results indicated that red yeast rice, along with a therapeutic lifestyle change, lowers LDL-C and total cholesterol levels. (It should be noted that red yeast rice contains a small amount of lovastatin.) Additional study is warranted to examine treatment alternatives for statin intolerance.

Diet

The NCEP has created dietary guidelines for all people older than 2 years. The reduction of saturated fat intake is vitally related to reduced low-density lipoprotein cholesterol (LDL-C) levels. In general, replacing fat with complex carbohydrates is helpful. Because carbohydrates are less calorically dense than fat, this substitution may also help prevent obesity. Adopting an appropriate diet may help patients reduce their LDL-C value by approximately 10-15%.⁶ However, in real-world studies, a 5% reduction is more likely. Reduction in trans fat intake also helps to reduce LDL-C levels and may help to raise high-density lipoprotein cholesterol (HDL-C) levels.

• NCEP dietary guidelines are as follows:
  • Total fat - Less than 30% of energy intake (calories)
  • Saturated fat - Less than 7% of energy intake
  • Polyunsaturated fat - Less than or equal to 10% of energy intake
  • Monounsaturated fat - From 10-15% of energy intake
  • Cholesterol - Less than 200 mg/dL
  • Carbohydrates - From 50-60% of energy intake
• Extreme fat and cholesterol restriction has been achieved with vegetarian diets, as demonstrated by the 1990 studies performed by Ornish and colleagues. This type of dietary restriction has resulted in a marked reduction in LDL-C levels and improvement in CHD symptoms. Whether these dietary restrictions are realistic for most Americans is debatable. Moreover, such a diet also reduces HDL-C levels and raises triglyceride levels.
• Plant sterols and plant stanol esters can be included in the diet and may reduce LDL-C values by approximately 10-15%. Commercial preparations are available as margarine substitutes (eg, Benecol, Take Control).⁷
• After years of lay promotion, small, short-term (6 mo) studies have suggested that high-fat, low-carbohydrate diets (eg, the Atkins diet) may facilitate weight loss without adversely affected serum lipid concentrations. However, the long-term effects of such diets remain to be determined.

Activity

Although exercise has little effect on low-density lipoprotein cholesterol (LDL-C) concentrations, aerobic exercise may improve insulin sensitivity, high-density lipoprotein cholesterol (HDL-C) concentrations, and triglyceride levels and, thus, may help reduce CHD risk. Patients who exercise and adhere to an appropriate diet appear to be more successful in long-term lifestyle modifications that improve their CHD risk profile.

Medication

The statin (HMG-CoA reductase inhibitor) class of drugs has revolutionized the treatment of hypercholesterolemia. Statins are highly efficacious and very well tolerated.⁵ Thus, other drugs are often not needed for low-density lipoprotein cholesterol (LDL-C) reduction.

Statins

Studies have shown the efficacy of statin drugs in reducing coronary heart disease (CHD) events, CHD death, and total mortality rates (see images below and Images 4-5). Efficacy for LDL-C lowering at approved doses of statins is listed in Medical Care under Dosage and approximate LDL-C lowering of various statins. Primary prevention implies the use of statins in an asymptomatic population, which may include some people with clinically occult disease. Secondary prevention implies the use of statins in patients with clinically apparent disease.^5,10

Angiographic and clinical endpoint trials with statins.

Major coronary heart disease (CHD) clinical endpoint studies of primary prevention and stable CHD with statins versus placebo. *not statistically significant. + atorvastatin 10 mg is the comparator rather than placebo. ++ LDL-C in the atorvastatin 80 mg group/LDL-C in the atorvastatin 10 mg group.

The West of Scotland Coronary Prevention Study (WOSCOPS) studied high-risk male subjects who had no history of CHD events (primary prevention).¹⁴ Pravastatin was administered at a dose of 40 mg/d for 4.9 years. Cardiovascular events were reduced by 31%, and the treatment caused a borderline statistically significant reduction of 31% in the total mortality rate compared with placebo.

The Cholesterol and Recurrent Events (CARE) study of subjects with CHD and cholesterol concentrations within the reference range (mean LDL-C level of 138 mg/dL) examined the effects of pravastatin at a dose of 40 mg/d. Compared with placebo, the CHD events were reduced by 24% at 5 years, with no significant change in total mortality.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) enrolled more than 6000 subjects with average LDL-C concentrations and below-average high-density lipoprotein cholesterol (HDL-C) values. Lovastatin was administered at a dose of 20-40 mg/d for approximately 5 years, resulting in a 37% reduction in first major acute coronary events compared with placebo therapy.¹⁵

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study used pravastatin at a dose of 40 mg/d for an average of 6.2 years in subjects with CHD; the CHD mortality rate decreased by 24%, and the total mortality rate decreased by 22% compared with placebo treatment.¹⁶

The Atorvastatin versus Revascularization Treatment (AVERT) study compared 80 mg atorvastatin daily with standard therapy and angioplasty in subjects with CHD. Although event rates at 18 months were the same between both groups, the time until the first CHD event was longer, with aggressive LDL-C lowering. Angioplasty alone has not been proven to prevent events, so this is not necessarily tantamount to a no-therapy comparison trial.¹⁷

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial showed borderline significant reduction in coronary events in subjects treated with atorvastatin (80 mg/d) who presented with an acute coronary syndrome, although significant abnormalities revealed via liver function test were common. The major positive finding from this study was a 61% reduction in stroke in the atorvastatin-treated group.

In the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study that compared pravastatin 40 mg/d versus placebo in subjects aged 70-82 years with a history of CHD or risk factors for CHD, active therapy reduced cardiovascular events by 15%.¹⁸

The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) assessed the effects of simvastatin (40 mg/d) versus placebo in approximately 20,000 subjects with vascular disease or at high risk for CHD with total cholesterol levels greater than 135 mg/dL, including approximately 6000 subjects with diabetes mellitus. CHD endpoints were reduced by approximately 24% and were effective in multiple subgroups, including subjects with diabetes. The mortality rate was reduced by approximately 15%.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) used 10 mg of atorvastatin versus placebo in approximately 10,000 subjects with hypertension. CHD event rates were reduced approximately 36%. However, most subgroups, including subjects with diabetes mellitus or metabolic syndrome, did not return positive results, perhaps because of the short duration (3.3 y) of the study.¹⁹

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared treatment with atorvastatin (80 mg) with treatment with pravastatin (40 mg) in subjects with CHD. After 18 months, the atorvastatin treatment group had a slight decrease in atheroma volume based on intravascular ultrasonography evaluations, and the pravastatin group had a slightly increased atheroma volume.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study also compared atorvastatin therapy (80 mg/d) with pravastatin therapy (40 mg/d) in subjects who had been hospitalized for acute coronary syndromes. The baseline LDL-C level was approximately 106 mg/dL. After a mean follow-up of 2 years, the intensively treated group had LDL-C levels of approximately 62 mg/dL, compared with approximately 95 mg/dL in the pravastatin group. Cardiovascular events were reduced by 16%.

Unfortunately, the study had a dropout rate of approximately one third. The number of patients needed to treat was 26, but the number needed to cause transaminase values to exceed 3 times the upper limit of normal was only 46 patients. In this scenario, 26 patients would have to be treated to prevent one clinical event, and 46 patients would have to be treated to see one case of transaminases >3 X ULN (and possibly end up stopping therapy). Interestingly, subjects pretreated with statins or those with baseline LDL-C levels of less than 125 mg/dL did not show a benefit from high-dose atorvastatin therapy compared with pravastatin therapy (40 mg).

The Treating to New Targets (TNT) study assessed the effect of therapy with atorvastatin 80 mg/d versus atorvastatin 10 mg/d in patients with stable CHD for a period of 4.9 years. The mean on-treatment LDL-C level was 77 mg/dL in the former group and 101 mg/dL in the latter group. The relative risk of cardiovascular events was reduced by 22%. Mortality was higher but not significantly statistically different in the high-dose atorvastatin group, although persistent transaminase elevations were 6 times higher in this group.

The statins lower LDL-C by inhibiting HMG-CoA reductase, the enzyme that regulates the rate-limiting step in cholesterol synthesis. The amount of the intermediate (ie, mevalonate) is lowered, and, subsequently, cholesterol levels are reduced in hepatic cells. This, in turn, results in up-regulation of LDL receptors and increased hepatic uptake of LDL from the circulation.

Atorvastatin (Lipitor)

Highly efficacious at high doses, resulting in as much as a 60% reduction in LDL-C. Inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism. Half-lives of atorvastatin and its active metabolites are longer than those of all other statins (ie, approximately 17 h for native drug, approximately 48 h for active metabolites, compared with 3-4 h for other drugs).
Used for primary prevention (10-mg dose) in the ASCOT trial of subjects with hypertension and at the 80-mg dose in the AVERT, MIRACL, REVERSAL, PROVE-IT, and TNT trials.

Dosing

Adult

10 mg PO qd; titrate to a maximum 80 mg/d

Pediatric

10-20 mg qd in familial hypercholesterolemia patients

Interactions

Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, and mibefradil; increases action of anticoagulants and levothyroxine

Contraindications

Documented hypersensitivity; significant hepatic impairment; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not exceed daily dose; caution in patients receiving drugs that prolong QRS or QT interval; monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo; stop or decrease doses for elevations of >3 times the upper limit of normal; elevations generally resolve upon withdrawal; if symptoms of myopathy and rhabdomyolysis occur, stop drug and obtain creatine kinase (CK) value

Fluvastatin (Lescol)

Least potent of statin drugs. The Lescol Intervention Prevention Study showed that in subjects with CHD monitored after a first percutaneous intervention, fluvastatin at 80 mg/d reduced CHD events compared with placebo. Synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, structurally distinct and has different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration). Fluvastatin has been shown to reduce CHD events after revascularization.

Dosing

Adult

20-40 mg PO qhs; 40 mg PO bid; 80 mg of the SR preparation qhs

Pediatric

Not established

Interactions

Increased risk of developing myopathy with cyclosporine, erythromycin, clofibrate, gemfibrozil, fenofibrate, azole antifungals (eg, fluconazole, itraconazole, ketoconazole), or antilipemic doses of niacin

Contraindications

Documented hypersensitivity; hepatic disease; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo; stop or decrease dose for elevations >3 times the upper limit of normal; elevations generally resolve upon withdrawal; if symptoms of myopathy and rhabdomyolysis occur, stop drug and obtain CK value

Lovastatin (Mevacor, Altocor)

First statin approved by the FDA. Has been shown to retard atherosclerosis in angiographic and carotid ultrasound trials and to reduce clinical events in primary prevention (AFCAPS/TexCAPS). Prodrug hydrolyzed in vivo to mevinolinic acid, one of several active metabolites. Once hydrolyzed, it competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, thus reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol can also be taken up by the liver from LDL by endocytosis. The diminishing de novo synthesis of cholesterol leads to increased clearance of circulating LDL. In the AFCAPS/TexCAPS study, 20-40 mg lovastatin daily reduced the incidence of CHD events in a relatively low-risk primary prevention population. Available as IR (Mevacor and generic) and SR (Altocor) dosage forms.

Dosing

Adult

IR: 20-40 mg PO at evening meal as a single dose or bid; dosage range 10-80 mg/d
SR: 10-20 mg PO hs initially; may increase dose q4wk, not to exceed 60 mg/d

Pediatric

For heterozygous familial hypercholesterolemia only: 10-40 mg PO qd

Interactions

Increased risk of developing myopathy with antiretroviral protease inhibitors, cyclosporine, erythromycin, clofibrate, gemfibrozil, fenofibrate, azole antifungals (eg, fluconazole, itraconazole, ketoconazole), or antilipemic doses of niacin

Contraindications

Documented hypersensitivity; severe hepatic disease; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo; after 1 y of therapy on a stable dose, transaminases no longer need to be monitored; stop drug or decrease dose for elevations of transaminases >3 times the upper limit of normal; elevations generally resolve upon withdrawal; if symptoms of myopathy and rhabdomyolysis occur, stop drug and obtain CK value

Pravastatin (Pravachol)

Reduces CHD events when used in primary prevention in patients with marked LDL-C elevations (WOSCOPS). Also reduces CHD events and mortality rates in patients with CHD and moderate increases in LDL-C (LIPID study). Reduces CHD events in patients with cholesterol levels within reference range and known CHD (CARE study). Reduces cardiovascular events in elderly persons (PROSPER).

Dosing

Adult

10-80 mg PO qd, usually given hs

Pediatric

For heterozygous familial hypercholesterolemia only
<8 years: Not established
8-13 years: 20 mg PO qd
14-18 years: 40 mg PO qd
>18 years: Administer as in adults

Interactions

Increased risk of developing myopathy with antiretroviral protease inhibitors, cyclosporine, erythromycin, clofibrate, gemfibrozil, fenofibrate, azole antifungals (eg, fluconazole, itraconazole, ketoconazole), or antilipemic doses of niacin (vitamin B-3)

Contraindications

Documented hypersensitivity; severe hepatic disease; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor for myopathy and rhabdomyolysis; associated with elevated hepatic enzyme levels, which generally resolve upon withdrawal; perform LFTs before treatment, at 6 wk and 12 wk, then q6mo; if symptoms of myopathy occur, stop drug and obtain CK value

Simvastatin (Zocor)

First drug shown to reduce total mortality rate by reducing LDL-C concentrations in patients with CHD with marked LDL-C elevations at baseline (4S). Markedly affects mortality rates and CHD events in patients with CHD and marked hypercholesterolemia (4S). Also reduces CHD events by >40% in similar patients with type 2 diabetes mellitus. Has also been shown to reduce CHD events in patients with a wide variety of cholesterol concentrations (>135 mg/dL) at baseline, ie, in the HPS. Adverse effects, including LFT abnormalities and myalgia, were minimal at this dose.

Dosing

Adult

20-80 mg PO qhs

Pediatric

Not established

Interactions

Rifampin; nicotinic acid may decrease effects; clofibrate, itraconazole, erythromycin, cyclosporine, and niacin increase toxicity; coadministration of verapamil or amiodarone may increase risk for myopathy; protease inhibitors may increase risk for myopathy

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevation of liver enzymes; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo; stop drug or decrease dose for elevations of transaminases >3 times the upper limit of normal; elevations generally resolve upon withdrawal; after 1 y of therapy on a stable dose, transaminases no longer need to be monitored; if symptoms of myopathy and rhabdomyolysis occur, stop drug and obtain a CK value; discontinue therapy if symptoms of myopathy or renal failure develop; caution in patients with a history of liver disease and patients who consume excessive amounts of alcohol

Rosuvastatin (Crestor)

HMG-CoA reductase inhibitor that decreases cholesterol synthesis and increases cholesterol metabolism. Reduces total cholesterol, LDL-C, and triglyceride levels and increases HDL-C level. Used adjunctively with diet and exercise to treat hypercholesterolemia. Most efficacious of the statins. May raise HDL-C at higher doses than equally effective doses of atorvastatin. Not metabolized by cytochrome P450 system. Dose of 40 mg associated with hematuria and proteinuria, which is of unknown clinical significance. No clinical outcome studies completed as yet.

Dosing

Adult

5-10 mg PO qd initially; may increase dose if needed, not to exceed 40 mg/d; for marked hypercholesterolemia (ie, LDL-C >190 mg/dL), initiate with 20 mg/d PO

Pediatric

Not established

Interactions

Cyclosporine or gemfibrozil significantly increase C _max and AUC, thereby increasing myopathy and rhabdomyolysis risk; limit dose to 5 mg/d when coadministered with cyclosporine and 10 mg/d when coadministered with gemfibrozil; coadministration with aluminum and magnesium hydroxide antacids decrease plasma concentrations (administer antacids 2 h after rosuvastatin); may increase oral contraceptive plasma concentrations; alcohol may increase hepatotoxic risk

Contraindications

Documented hypersensitivity; active liver disease; unexplained serum transaminase elevation

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include muscle aches, stomach pain, constipation, nausea, and weakness; may cause myopathy, rhabdomyolysis, and kidney failure; monitor LFTs (ie, baseline, 12 wk after drug initiation and any dose elevation, semiannually); discontinue if elevation persists; decrease dose with CrCl <30 mL/min; doses >40 mg are associated with hematuria and proteinuria

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.

Dosing

Adult

2 mg PO qd; not to exceed 4 mg/d

Pediatric

Not established

Interactions

Data limited; CYP2C9 substrate; OATP1B1 transporter substrate; 4-fold increase in AUC when coadministered with cyclosporine (an OATP1B1 inhibitor); coadministration with other drugs that cause myopathy (eg, gemfibrozil) may increase risk; CYP2C9 inhibitors (eg, fluconazole, gemfibrozil, nevirapine, sulfisoxazole) may decrease metabolism and thereby increase serum concentration

Contraindications

Documented hypersensitivity; active liver disease; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include myalgias and myopathy, joint pain, back pain, and constipation; caution with history of liver/renal impairment

Cholesterol absorption inhibitors

These drugs inhibit dietary cholesterol absorption. Ezetimibe (Zetia) is the only medication in this class with FDA approval. It selectively inhibits cholesterol absorption in the intestine by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Alone or with a statin, ezetimibe lowers LDL-C levels by 12-19%.¹⁰ In individuals who hyperabsorb cholesterol, LDL-C reduction of as much as 40% has been documented.

Two studies have brought national media attention to ezetimibe. The first study, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial,²⁰ was undertaken to demonstrate that progression of atherosclerosis reflected by changes in carotid intima-media thickness (CIMT) would be reduced if ezetimibe was added to 80 mg of simvastatin in patients with heterozygous familial hypercholesterolemia. At the end of the 24-month study, however, no significant difference in CIMT was found between patients using ezetimibe in combination with simvastatin and those using simvastatin alone, despite greater reductions in LDL-C and C-reactive protein levels in the ezetimibe/simvastatin combination group.

Prominent investigators weighed in, stating that if ezetimibe could not improve CIMT, then it had no role in cholesterol management. It should be noted, however, that the cholesterol levels in the study subjects had been aggressively managed for many years, and they did not have increased CIMT at baseline. The study sought to show increased regression and decreased progression in subjects receiving both simvastatin and ezetimibe, compared with simvastatin alone. But regression cannot occur in subjects whose CIMT is normal, and therefore no difference in regression between the 2 treatment groups would have been possible at the end of the study. In order to demonstrate reduced progression, the CIMT in the simvastatin-only arm would have had to increase. In fact, no progression occurred in this group. Therefore, the simvastatin-ezetimibe subjects could not have benefited from decreased progression because no progression occurred in thesimvastatin-onlysubjects.

The second trial, SEAS (Simvastatin and Ezetimibe in Aortic Stenosis),²¹ was meant to demonstrate that intensive LDL-C lowering through administration of a daily dose of 40 mg of simvastatin plus 10 mg of ezetimibe would reduce the incidence of major cardiovascular events and also reduce the number of events related to aortic stenosis. As expected, cardiovascular endpoints were clinically and statistically lower in patients using the combination therapy than they were in in placebo-treated patients. However, events related to aortic stenosis were not reduced in the combination group. In addition, the investigators made an unexpected finding, that the incidence of cancer was significantly greater in the ezetimibe/simvastatin group than it was in the patients using placebo (11.1% vs 7.5% [P = 0.01]).

An expert statistician, Richard Peto, with special expertise in analyzing cancer data was invited to analyze the SEAS findings.^22,23 He was also given access to data from 2 much larger, ongoing clinical trials—SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)—with a total of 20,617 randomized patients. SHARP was designed to compare results from the use of simvastatin 20 mg plus ezetimibe to those from placebo, and IMPROVE-IT was designed to compare the results from the administration of simvastatin 40 mg plus ezetimibe to simvastatin 80 mg.

In the combined data from the SHARP and IMPROVE-IT trials, more cancer deaths and fewer cases of cancer were found in the patients assigned to ezetimibe; neither difference was statistically significant. Several features of the data suggested lack of credibility: cancer incidence and death were not prespecified endpoints in SEAS; no excess of cancers at any particular site (more that 15 different sites were involved) were observed; and longer duration of follow-up did not result in an increased trend in cancer incidence or death. The final conclusion by Peto et al was that the available data from the SHARP, IMPROVE-IT, and SEAS trials did not "provide credible evidence of any adverse effect of ezetimibe on rates of cancer." A more definitive answer will be possible when the SHARP and IMPROVE-IT trials are analyzed after a longer follow-up period.

Ezetimibe (Zetia); Ezetimibe and simvastatin (Vytorin)

First in a new class of cholesterol-lowering agents that inhibits cholesterol intestinal absorption. Approved as monotherapy or in addition to HMG-CoA reductase inhibitors. Reduces LDL-C by approximately 18-20% as monotherapy, and lowers approximately 15% more when added to statin. No clinical endpoint trials completed yet.
Combination product lowers LDL-C levels 45-60%. Effect on CHD events compared with statin alone is unknown.

Dosing

Adult

Ezetimibe 10 mg PO qd
Ezetimibe and simvastatin: 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, and 10 mg/80 mg (ezetimibe/simvastatin, respectively)

Pediatric

Ezetimibe:
<10 years: Not established
>10 years: Limited data; administer as in adults
Ezetimibe and simvastatin: Not established

Interactions

Ezetimibe: Cholestyramine decreases bioavailability; fenofibrate and gemfibrozil increase bioavailability; cyclosporine may increase bioavailability
Simvastatin: Effects increase with cholestyramine; increases toxicity of gemfibrozil, clofibrate, niacin, cyclosporine, and oral anticoagulants; itraconazole and ketoconazole increase toxicity of lovastatin; concurrent use with erythromycin may increase risk of rhabdomyolysis
When coadministered with fibrates (eg, gemfibrozil), niacin (>1 g/d), or cyclosporine, do not exceed 10 mg/d; when coadministered with verapamil or amiodarone, do not exceed 20 mg/d

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Initiate treatment at lower dose with severe renal insufficiency and discontinue if renal function worsens; discontinue therapy if symptoms of myopathy develop; caution in moderate-to-severe hepatic impairment and in patients who consume excessive amounts of alcohol

Nicotinic Acid

Nicotinic acid/niacin is the most effective agent for raising HDL-C levels. It lowers triglycerides as effectively as fibrates do and is more reliable for lowering LDL-C. It is an effective add-on to statin therapy and is available in a single tablet (Advicor), in combination with simvastatin (Zocor), and as extended-release niacin (Niaspan).

Niacin has several features that make it the most difficult lipid agent to prescribe:

• Niacin at doses greater than 2 grams or in time-release formulations can cause significant hepatotoxicity. Immediate-release niacin is the least likely to cause hepatic injury, and time-release niacin is the most likely to cause it. Extended-release niacin has an intermediate risk, and if the FDA maximum approved dose for Niaspan, 2000 mg/day, is not exceeded, the risk of serious hepatic injury is minimal.
• Niacin inhibits urate metabolism and can precipitate an acute gouty attack. Patients with a history of gout whose uric acid levels have been normalized with allopurinol have minimal, if any, risk.
• Niacin may increase insulin resistance but is not contraindicated in the treatment of patients with diabetes.²⁴
• Patient tolerability limits niacin's use, the most common side effect being flushing, sometimes accompanied by pruritus and/or rash. Several techniques can lessen or, in some cases, prevent these symptoms, which are prostaglandin-mediated. Time itself will usually decrease symptoms; therefore, to enhance tachyphylaxis and, more importantly, to decrease the risk of hepatotoxicity, niacin should always be started at a low dose and gradually increased ("start low, go slow").
  
  Many patients who will be treated with niacin are already on prophylactic aspirin, 81 mg/day. Aspirin taken 30-60 minutes before niacin may lessen symptoms, but 325 mg is often necessary. Taking niacin with a small, low-fat snack slows absorption and thereby decreases symptoms. Activities that might cause vasodilation (hot food or beverages, spicy food, hot showers) should be avoided. Benadryl is sometimes effective in decreasing a severe reaction.

Niacin is used primarily to treat hypertriglyceridemia, but it also has a beneficial impact on HDL-C and LDL-C levels, and it is the only lipid medication that lowers lipoprotein (a). Niacin has been shown to retard progression of atherosclerosis and reduce CHD events when used in conjunction with a bile acid sequestrant or lovastatin.

The ARBITER 6–HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies) trial compared the effects of 2 lipid-lowering combination therapies on CIMT.²⁵ In a prospective, randomized, parallel-group, open-label study, patients received either extended-release niacin (2 g/d target dose) or ezetimibe (10 mg/d) in addition to their long-term statin therapy. All participants (n=363) had been treated with statin monotherapy at a consistent dose. Inclusion required that lipid panels were obtained within 3 months before enrollment showing an LDL cholesterol level of less than 100 mg/dL (2.6 mmol/L), as well as an HDL cholesterol level of less than 50 mg/dL (men) or 55 mg/dL (women) (1.3 or 1.4 mmol/L, respectively). The mean common CIMT change from baseline after 14 months was the study’sprimary end point.

Following a prespecified interim analysis conducted after 208 patients (mean age 65 y, 80% men) had completed the trial, the trial was terminated early on the basis of efficacy. The results are described for these 208 patients. In the niacin group, HDL cholesterol level were increased by 18.4% to 50 mg/dL (P <0.001). Niacin also significantly reduced LDL cholesterol and triglyceride levels. The ezetimibe group showed a 19.2% decrease in LDL cholesterol, 66 mg/dL (1.7 mmol/L) (P <0.001). Ezetimibe did not increase HDL cholesterol (HDL levels were actually reduced), but it did reduce triglycerides. Niacin was more effective than ezetimibe in changing mean CIMT over 14 months (P = 0.003), leading to a significant reduction of mean (P = 0.001) and maximal CIMT (P £ 0.001 for all comparisons).

This trial concluded that niacin is superior to ezetimibe for combination therapy in high-risk patients taking statin monotherapy. Two editorials stated that the early termination of and small number of patients in the study, along with the limited duration of follow-up, do not yet merit changes in cholesterol therapy guidelines, but they did support niacin as the preferred agent for statin combination therapy until the completion of clinical trials with clinical end points can be completed.^26,27

Two well-powered studies of clinical end points — AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes; NCT00120289) and HPS2-THRIVE (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events; NCT00461630) — will, it is hoped, determine if adding niacin to statin therapy leads to a further risk reduction in patients with hypercholesterolemia.²⁷

Niacin and lovastatin (Advicor)

Niacin: Niacin functions in the body after conversion to NAD in the NAD coenzyme system. Niacin in gram doses reduces levels of total cholesterol, LDL-C, and triglycerides and increases HDL-C levels. The severity and type of underlying lipid abnormality may influence the magnitude of individual lipid and lipoprotein responses may be influenced.
Lovastatin: Competitively inhibits HMG-CoA reductase, which catalyzes rate limiting step in cholesterol synthesis.
Formulation contains lovastatin and niacin in pills of 20 mg lovastatin, with 500 mg, 750 mg, or 1000 mg of niacin (Niaspan). Not indicated for initial therapy of dyslipidemia. Combination therapy causes greater increases in HDL-C levels than statins alone.

Dosing

Adult

20 mg/500 mg (lovastatin/niacin) PO up to 40 mg/2000 mg

Pediatric

Not established

Interactions

Niacin: HMG-CoA reductase inhibitors increase the risk of rhabdomyolysis; cutaneous vasodilation may be a problem if high dose is used with peripheral dilators such as nitroglycerin; taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated side effects of niacin (eg, flushing, itching); clonidine may inhibit niacin-induced flushing; separate dosing of bile acid sequestrants by at least 4-6 h; may increase PT when coadministered with warfarin
Lovastatin: Coadministration with potent CYP3A4 inhibitors (eg, cyclosporine, ketoconazole, itraconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, large quantities of grapefruit juice [>1 quart/d]), gemfibrozil, clofibrate, lipid-lowering doses (>1 g/d) of niacin, verapamil, or amiodarone increases myopathy or rhabdomyolysis risk (decrease lovastatin dose by 50-75%)

Contraindications

Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; substantial alcohol consumption; active peptic ulcer disease; active gout; hyperuricemia

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in patients with gallbladder disease or diabetes or in those predisposed to gout; monitor blood glucose; may elevate uric acid levels and lower blood phosphate levels; pregnancy category C when used at doses greater than RDA; may elevate aminotransferases; perform LFTs before therapy and every 4-6 wk for 12-15 mo, periodically thereafter

Niacin (Niaspan, Niacor, Slo-Niacin)

Immediate release dosage form is less hepatotoxic than sustained-release (SR) form but not as well tolerated by patients because of prostaglandin-mediated flushing, itching, or rash. Immediate-release (IR) niacin started at low doses and gradually increased over several weeks allows some patients to accommodate to these adverse effects.
Higher doses (4-6 g/d) can be used more safely than SR niacin.

Niacor and Nicolar are prescription formulations of IR niacin that, while more expensive than over-the-counter brands, may make it less likely that patient will switch brands. Changing formulation of niacin while on high doses may increase risk of hepatotoxicity.

Sustained-release (SR) dosage form is more hepatotoxic than IR niacin; therefore, strongly advise against switching formulations or brands during treatment. Over-the-counter and prescription SR niacin are available. Over-the-counter brands cost less, but if using this option, recommend only reliable manufacturers.

Slo-Niacin is an over-the-counter formulation available in 250-mg, 500-mg, and 750-mg tabs. Sundown also is a manufacturer of over-the-counter SR niacin. Prescription SR niacin, Niaspan, is available in 375-mg, 500-mg, and 1000-mg tabs.

Niaspan with nocturnal dosing may be more tolerable than the other preparations. Niacin has no real utility in treating pure hypercholesterolemia because of the availability of statins. It is questionable whether adding it to statins to increase a low serum HDL-C reduces CHD risk beyond that observed with a statin alone.

Dosing

Adult

1-2 g PO qd divided bid/tid with meals or pc

Niaspan recommended dosage schedule:
500 mg PO qhs with small snack for 1 mo
1000 mg PO qhs with small snack for 1 mo
1500 mg PO qhs with small snack for 1 mo
2000 mg PO qhs with small snack for 1 mo
Other SR formulations usually require bid dosing beginning with smallest dose available and gradually increasing to a total dose not to exceed 3 g/d

Pediatric

Not established

Interactions

HMG-CoA reductase inhibitors increase the risk of rhabdomyolysis; cutaneous vasodilation may be a problem if high dose is used with peripheral dilators such as nitroglycerine; taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated side effects of niacin (eg, flushing, itching); clonidine may inhibit niacin-induced flushing; separate dosing of bile acid sequestrants by at least 4-6 h; may increase PT when coadministered with warfarin

Contraindications

Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; substantial alcohol consumption; active peptic ulcer disease; active gout; hyperuricemia

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category C when used at doses greater than RDA; caution in patients with gallbladder disease or diabetes or in those predisposed to gout; monitor blood glucose; may elevate uric acid levels and lower blood phosphate levels

Antilipemic agent, fibric acid

Older fibrates (eg, clofibrate, gemfibrozil) are used primarily for triglyceride lowering. The Helsinki Heart Study, published in 1987, showed a decrease in CHD events in patients with elevated non–HDL-C concentrations when used in primary prevention. With the advent of statins, fibrates have largely fallen out of favor when pure LDL-C lowering is needed. However, fenofibrate is more efficacious for LDL-C lowering than earlier fibrates. Ongoing studies may help determine if fenofibrate is useful in patients with mixed dyslipidemia, particularly subjects with type 2 diabetes mellitus. The Diabetes Atherosclerosis Intervention Study showed that such subjects with CHD have stabilization of angiographic findings when treated with fenofibrate compared with placebo. This trial was inadequately powered to assess an effect on CHD events. Currently, fenofibrate should probably be relegated to second-line therapy for LDL-C reduction in patients intolerant of statins.

The publication of the Veterans Affairs HDL Intervention Trial is notable. This trial consisted of male subjects with CHD, relatively low LDL-C concentrations (mean of 112 mg/dL), and low HDL-C concentrations (mean of 32 mg/dL). Coronary events were reduced 22% with gemfibrozil treatment compared with placebo treatment. This effect was thought to be due to an increase (6%) in HDL-C levels; however, the almost 30% decrease in triglyceride levels in subjects treated with gemfibrozil may also have played a role in risk reduction.

Fenofibrate (Tricor, Lofibra, generics)

Lowers LDL-C better than older fibrate drugs. Presently used primarily for triglyceride reduction and in mixed dyslipidemias. Induces lipoprotein lipase and decreases hepatic production of apolipoprotein CIII (an inhibitor of LPL) via PPAR alpha activity, which enhances plasma catabolism and clearance of triglyceride-rich particles. Fatty acid oxidation is enhanced by fenofibrate activation of acyl-CoA synthetase and other enzymes. Inhibition of acetyl-CoA carboxylase and fatty acid synthetase activity by fenofibrate further decreases synthesis of triglycerides. Result is a marked reduction in plasma triglyceride and VLDL levels and an increase in HDL-C levels. Diabetes Atherosclerosis Intervention Study associated with decreased progression of coronary atherosclerosis in subjects with type 2 diabetes mellitus.

Dosing

Adult

145 mg (Tricor) PO qd with a meal; 160 mg or 200 mg (other preparations) PO qd with a meal; lower doses (48-67 mg [depending on preparation] PO qd/bid) in renal insufficiency

Pediatric

Not established

Interactions

Increased risk of rhabdomyolysis and myoglobinuria, resulting in renal failure, when used with HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin); potentiates effects of warfarin and other oral anticoagulants

Contraindications

Documented hypersensitivity; breastfeeding; hepatic disease; renal disease; gallbladder disease; biliary cirrhosis; cholelithiasis

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Instruct patients to report myalgia, muscle tenderness, and myasthenia; perform CK determinations and renal function assessment, including serum creatinine

Gemfibrozil (Lopid)

Used primarily to lower serum triglyceride levels. Statin clinical endpoint trials have largely made use for pure cholesterol lowering obsolete. The Veterans Affairs HDL Intervention Trial suggests that gemfibrozil (and probably other fibrates) may be used in patients with CHD, low LDL-C, and low HDL-C. Mechanism of action is unknown but probably similar to fenofibrate. May inhibit lipolysis and secretion of VLDL and decrease hepatic fatty acid uptake.

Dosing

Adult

600 mg PO bid 30 min prior to breakfast and dinner

Pediatric

Not established

Interactions

Increased risk of rhabdomyolysis and myoglobinuria, resulting in renal failure, when used with HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin [recalled from US market 8/8/01]); potentiates effects of warfarin and other oral anticoagulants

Contraindications

Documented hypersensitivity; gallbladder disease; renal or hepatic insufficiencies

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Discontinue drug if no reduction in triglyceride levels observed after 3 mo of therapy; monitor for abnormal elevation of ALT, AST, LDH, bilirubin, and alkaline phosphatase serum levels; prevalence of myositis is higher among patients with renal impairment

Bile acid sequestrants

These agents are also called resins. Bile acid sequestrants are used primarily as additional therapy in patients with familial hypercholesterolemia who experience inadequate LDL-C lowering with statins. These agents are also useful in pediatric hypercholesterolemia. Several studies show that LDL-C lowering with resins retards the progression of atherosclerosis. The Lipid Research Clinics Coronary Primary Prevention Trial showed that cholestyramine therapy could reduce the risk for CHD events.

Interference with anionic drug absorption and patient compliance are major problems with this class of drugs. Resins may be used as an adjunct in primary hypercholesterolemia. These drugs form a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Cholestyramine (Questran, Questran Light)

Flavored to improve palatability. Light version is sweetened with aspartame and is more palatable to some patients.

Dosing

Adult

4 g PO qd/bid; not to exceed 24 g/d or 6 doses/d; dose refers to anhydrous cholestyramine content

Pediatric

240 mg/kg/d PO divided tid; not to exceed 2 scoops or packets qd

Interactions

Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, and statins

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in patients with constipation and phenylketonuria

Colesevelam (WelChol)

New high-capacity bile acid sequestrant. Better tolerated than older agents (eg, cholestyramine and colestipol), and drug interactions are less of a problem. Can lower LDL-C levels by 15-18% as monotherapy. Useful in patients who cannot tolerate statins, have contraindications for statin therapy, or request nonsystemic therapy. Can also be used in combination with a statin for additive LDL-C lowering. Has no effect on serum triglyceride levels and a modest beneficial effect on HDL-C.

Dosing

Adult

6 tab (625 mg each) PO qd or divided bid with meals

Pediatric

Not established

Interactions

None reported; decreases AUC for SR verapamil (clinical significance is unknown)

Contraindications

Documented hypersensitivity; complete biliary or bowel obstruction

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Safety has not been established in dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal surgery

Colestipol (Colestid)

Available in tabs, powder form, and flavored and unflavored varieties. Interference with anionic drug absorption and patient compliance are major problems. Forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound LDL-C.

Dosing

Adult

Granules: 5-30 g/d PO qd or divided bid/qid; increase dose by 5 g at 1- to 2-mo intervals
Tabs: 2-16 g/d PO initial dose, 2 g PO qd/bid; increase dose by 2 g at 1- to 2-mo intervals

Pediatric

240 mg/kg/d PO divided tid; not to exceed 2 scoops or packets qd

Interactions

Decreases absorption of methotrexate, glipizide, imipramine, phenytoin, tolbutamide, niacin, clindamycin, NSAIDs, gemfibrozil, ursodiol, clofibrate, phenobarbital, warfarin, digitalis glycosides, propranolol, phenobarbital, hydrocortisone, statins, and other drugs by inhibiting absorption in intestine

Contraindications

Documented hypersensitivity; complete biliary obstruction; severe constipation

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May be associated with increase in bleeding tendencies from hypoprothrombinemia that results from decrease in vitamin K absorption; severe constipation

Follow-up

Deterrence/Prevention

• Obviously, the adoption of a healthier lifestyle that included aerobic exercise and a low-fat diet would probably reduce the prevalence of obesity, hypercholesterolemia, and, ultimately, the risk of coronary heart disease (CHD). Hopefully, younger Americans will adopt these measures to reduce CHD events in the coming years.

Prognosis

• The statin era has revolutionized the treatment of hypercholesterolemia. Coupled with the treatment of hypertension and the use of beta-blockers, angiotensin-converting enzyme inhibitors, and aspirin, the potential for reduction of CHD events in patients with known atherosclerosis is significant.
• Cholesterol reduction is certainly useful as a CHD risk-reduction strategy and for primary prevention in individuals who are at high risk for CHD or other forms of atherosclerosis.

Patient Education

• Dietary education about a low-fat (especially saturated fat and trans fat), low-cholesterol diet is of paramount importance.
• For excellent patient education resources, visit eMedicine's Cholesterol Center and Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, Cholesterol Lowering Medications, and Statins and Cholesterol.

Miscellaneous

Medicolegal Pitfalls

• High total cholesterol levels can be due to a very high high-density lipoprotein cholesterol (HDL-C) level, particularly in women. If the low-density lipoprotein cholesterol (LDL-C) level is not elevated, no treatment is needed.
• Patients with marked hypertriglyceridemia (>1000 mg/dL) have very high cholesterol concentrations (300-600 mg/dL), but this situation is due to large numbers of chylomicrons and very low-density lipoprotein (VLDL), not LDL. Therefore, do not treat these patients with statins; treat them with agents that lower triglycerides (eg, fibrates, niacin, fish oils).
• Obtain serum thyroid-stimulating hormone levels, liver function test results, creatinine values, and urinalysis results to help rule out secondary dyslipidemias.

Special Concerns

• Therapeutic controversies
  • Post hoc analysis of some studies (eg, Cholesterol and Recurrent Events, West of Scotland Coronary Prevention Study¹⁴ ) has been interpreted to indicate the presence of a lower limit for LDL-C, and, beyond this level, lowering the LDL-C is no longer beneficial. Similar analyses of other studies (eg, Scandinavian Simvastatin Survival Study,^12,13 Air Force/Texas Coronary Atherosclerosis Prevention Study¹⁵ ) have failed to indicate an LDL-C therapeutic threshold.
  • The Medical Research Council/British Heart Foundation Heart Protection Study enrolled subjects at high risk for CHD and total cholesterol (not LDL-C) concentrations greater than 135 mg/dL. CHD event reduction was observed in the total patient population and in the subgroup with the lowest tertile of LDL-C.
  • The completed Pravastatin or Atorvastatin Evaluation and Infection Therapy trial showed CHD event reduction when postacute coronary syndrome patients were treated with atorvastatin at 80 mg/d (LDL-C level at treatment was approximately 62 mg/dL) compared with pravastatin at 40 mg/d (LDL-C level at treatment was approximately 95 mg/dL). The study was plagued by high dropout (approximately one third of subjects in both groups at 2 y), and the fact that liver function test abnormalities (transaminase levels >3 times the upper limit normal) were common. The number needed to treat to prevent a CHD event was 26, and the number needed to treat to potentially harm (transaminases >3 times the upper limit normal) was 45.
  • The Post Coronary Artery Bypass Graft Trial showed less progression of the disease in bypass grafts with attainment of an LDL-C value of approximately 95 mg/dL (achieved with lovastatin) compared with less aggressive treatment, with an LDL-C value of approximately 135 mg/dL.²⁸
  • The Reversal of Atherosclerosis with Aggressive Lipid Lowering trial showed minimal regression of atherosclerosis in CHD subjects treated with 80 mg of atorvastatin for 18 months compared with minimal progression in CHD subjects treated with 40 mg of pravastatin.
  • The Atorvastatin versus Revascularization Treatment trial showed no difference in CHD events in patients treated to achieve an LDL-C level of approximately 77 mg/dL compared with patients with an LDL-C level of approximately 115 mg/dL who had angioplasty.¹⁷
  • The Treating to New Targets Study showed a reduction in cardiovascular events, but not mortality, in patients with stable CHD who were given atorvastatin 80 mg/d compared with atorvastatin 10 mg/d (LDL-C 77 mg/dL vs 101 mg/dL). Persistent transaminase elevations were 6 times as common in the former group.
  • Because the epidemiologic data suggest a curvilinear relationship between LDL-C values and CHD events, an LDL-C level below which no benefit may accrue is probable; however, that actual level is unknown. The National Cholesterol Education Program (NCEP) guidelines probably provide an adequate estimate of an appropriate LDL-C target, except perhaps in patients with diabetes. 
  • The author believes that lower targets (<70 mg/dL) may be reasonable in patients who can be treated with low-to-moderate dose statin. However, the author feels that the risk/benefit ratio for high-dose statin (atorvastatin 80 mg/d is what has been tested so far) across the board to try to achieve an LDL-C level of less than 70 mg/dL (many patients will not achieve this level despite this therapy) is not yet proven definitely to be acceptable and achieve extra added benefit. The question of achieving lower LDL-C values with combination therapy (statin plus ezetimibe), in terms of showing further CHD risk reduction, remains unanswered at this point.
  • Whether patients with low HDL-C and high LDL-C values should use a drug (eg, niacin) to raise their HDL-C levels, in addition to using a drug to lower LDL-C levels, is questionable. The HDL Atherosclerosis Treatment Study showed positive effects of low-dose (10 mg) simvastatin and niacin on angiographic measures. However, no outcome studies have been performed with more conventionally used doses of statins. Statins often raise HDL-C levels a small amount. Some statin trials show a marked diminution of increased CHD risk in patients treated with statins who have lower HDL-C levels compared with individuals with higher HDL-C levels. The results of the Veterans Affairs HDL Intervention Trial may not be applicable to patients with high baseline LDL-C concentrations.
• Patients with mixed dyslipidemias
  • Patients with insulin resistance and those with type 2 diabetes mellitus are likely to have mild-to-moderate triglyceride elevations.
  • Whether lipid therapy beyond statins is beneficial is debatable, although combination therapy with statins plus niacin or fibrates improves lipid parameters. Such therapy clearly increases the potential for adverse effects. The author believes that most patients should be treated with monotherapy. If a fibrate is given with a statin, fenofibrate is probably safer than gemfibrozil.
  • A potentially more benign nutraceutical is fish oil. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglyceride levels if at least 3 g/d is administered. Unfortunately, many preparations contain large amounts of fish oil that is not DHA or EPA. These preparations just supply fat, with little positive effect on the lipid profile. The author always insists on personally examining the fish oil bottle that his patients use to ensure that such patients will benefit from this therapy.
• Women who are postmenopausal
  • Although epidemiologic studies have suggested that estrogen therapy is associated with better lipid profiles and lower CHD risk, recent intervention trials with estrogen have generated considerable controversy.
  • Currently, therapy with estrogens plus progestins is considered potentially harmful long-term therapy in postmenopausal women. This drug combination may still be useful for short-term therapy soon after menopause for vasomotor symptoms in women with an intact uterus.
  • In women who do not have a uterus, therapy with estrogen alone is of no proven benefit for CHD prevention.
  • Statin therapy, rather than estrogens, should be used for primary lipid modification and for CHD prevention in women who are postmenopausal, particularly in women with atherosclerosis. 
• Patients with diabetes
  • The post hoc analysis of the Scandinavian Simvastatin Survival Study trial in patients with type 2 diabetes mellitus showed dramatic event reduction in patients who received simvastatin. Unfortunately, this trial did not include patients with high triglyceride levels, which is a common lipid abnormality in persons with type 2 diabetes mellitus.^12,13
  • The Medical Research Council/British Heart Foundation Heart Protection Study (of simvastatin 40 mg/d) showed a similar reduction in CHD event rates in patients with type 2 diabetes mellitus compared with patients without diabetes.¹³
  • Epidemiologic work suggests that patients with diabetes who have not had a previous known myocardial infarction may be at the same risk for CHD events and mortality as patients with diabetes who have not had a previous known myocardial infarction, compared with patients without diabetes who have had a previous coronary event. These data led the American Diabetes Association to advocate an LDL-C level of less than 100 mg/dL for patients with diabetes. American Diabetes Association treatment based on LDL-C levels is as follows:
    • Medical nutrition therapy
      • Patients without coronary heart disease, peripheral vascular disease, or cardiovascular disease and an LDL-C level of greater than 100 mg/dL: Goal level of LDL-C is less than 100 mg/dL (<70 mg/dL is considered an option).
      • Patients with coronary heart disease, peripheral vascular disease, or cardiovascular disease and an LDL-C level higher than 100 mg/dL: Goal level of LDL-C is less than 100 mg/dL (<70 mg/dL is considered an option).
    • Drug treatment
      • Patients without coronary heart disease, peripheral vascular disease, or cardiovascular disease and an LDL-C level higher than 130 mg/dL: Goal level of LDL-C is less than 100 mg/dL. Additionally, for patients with diabetes who have multiple CHD risk factors (eg, low HDL-C level, hypertension, smoking, family history of cardiovascular disease, microalbuminuria or proteinuria), most authorities recommend drug therapy for LDL-C levels of 100-130 mg/dL. Age and sex are not risk factors because women and men have equal CHD risk.
      • Patients with CHD, peripheral vascular disease, or cardiovascular disease and an LDL-C level of greater than 100 mg/dL: Goal level of LDL-C is less than 100 mg/dL (goal of <70 mg/dL is an option).
  • The NCEP ATP III now considers diabetes mellitus a CHD risk equivalent, with the same LDL-C goal (<100 mg/dL, or if considered appropriate, <70 mg/dL) as patients with known CHD. 
• Risk of myopathy
  • With statin monotherapy, the risk of myopathy is low and is increased with the concomitant use of fibrates, niacin, macrolides, protease inhibitors, and imidazoles. The fibrate effect appears to relate to inhibition of glucuronidation of statins, rather than an effect on cytochrome P450 metabolism, because it is observed with all statins.
  • Routine CK monitoring has no proven value in the prevention of myopathy. Because muscle aches are common, even in placebo-treated patients, a check of serum CK values, once the patient has myalgias, may be helpful. Many patients with myalgias have CK values within the reference range.
  • Sometimes, changing the statin is necessary to eliminate the problem. Anecdotal reports suggest that coenzyme Q supplements in patients with muscle aches and CK values within the reference range may reduce myalgias.
  • Reports suggest that histologic myopathy may occur in the absence of CK elevations. Whether this is a widespread phenomenon is debatable.

Multimedia

Media file 1: Relative risk of coronary heart disease (CHD) mortality versus baseline serum cholesterol over time in 3 large cohorts of young men. CHA is Chicago Heart Association Detection Project in Industry, PG is Chicago Peoples Gas Company, and MRFIT is Multiple Risk Factor Intervention Trial. Adapted from Stamler, 2000.

Media file 2: Simplified diagram of cholesterol metabolism. LDL is low-density lipoprotein, VLDL is very low-density lipoprotein, IDL is intermediate-density lipoprotein, HDL is high-density lipoprotein, and LPL is lipoprotein lipase.

Media file 3: National Health and Nutrition Examination Survey data for hypercholesterolemia among American adults.

Media file 4: Angiographic and clinical endpoint trials with statins.

Media file 5: Major coronary heart disease (CHD) clinical endpoint studies of primary prevention and stable CHD with statins versus placebo. *not statistically significant. + atorvastatin 10 mg is the comparator rather than placebo. ++ LDL-C in the atorvastatin 80 mg group/LDL-C in the atorvastatin 10 mg group.

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Keywords

polygenic hypercholesterolemia, hypercholesterolemia, hyperlipidemia, cholesterol level, high cholesterol, cholesterol lowering foods, familial hypercholesterolemia, nonfamilial hypercholesterolemia, non-familial hypercholesterolemia cholesterol, statins, statin therapy, simvastatin, pravastatin, atorvastatin, coronary heart disease, CHD, atherothrombotic stroke, atherosclerosis, heart disease

Contributor Information and Disclosures

Author

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

William L Isley, MD, Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester
William L Isley, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Related eMedicine topics:
High HDL Cholesterol (Hyperalphalipoproteinemia)
Hypercholesterolemia, Familial
Hypoglycemia [Emergency Medicine]
Hypoglycemia [Endocrinology]
Hypoglycemia [Pediatrics: General Medicine]
Renal Vein Thrombosis [Radiology]
Renal Vein Thrombosis [Vascular Surgery]

Clinical guidelines:
Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia.
National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]. 2007 Nov. 30 pages. NGC:006202

Cardiometabolic risk management in primary care.
Qatif Primary Health Care - National Government Agency [Non-U.S.].  2008. Various pagings. NGC:006689 

Diagnosis and treatment of childhood hypercholesterolaemia.
Finnish Medical Society Duodecim - Professional Association.  2004 Jun 14 (revised 2007 Feb 13). Various pagings. NGC:005813

Clinical trials:
Pediatric Study to Evaluate the Efficacy and Safety of Ezetimibe Monotherapy in Children With Primary Hypercholesterolemia (Study P05522)

Efficacy and Safety Study of Pitavastatin Compared to atoRvastatin in Type 2 dIabeTes Mellitus With Hypercholesterolemia (ESPRIT)

Combination Treatment With Green Tea Extract and Statins in Patients With Hypercholesterolemia (GTE-Stat)

Evaluation of Ezetimibe and Atorvastatin Coadministration Versus Atorvastatin or Rosuvastatin Monotherapy in Japanese Patients With Hypercholesterolemia (Study P06027)

Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE

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