eMedicine Specialties > Endocrinology > Metabolic Disorders

Hypercholesterolemia, Familial: Treatment & Medication

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
Contributor Information and Disclosures

Updated: Aug 4, 2009

Treatment

Medical Care

The National Cholesterol Education Program (NCEP) ATPIII defined LDLc goals and cutpoints for therapeutic intervention based on risk for CHD (see Table 2 and Table 3).

The guidelines were updated in 2004 to reflect the findings of several interventional trials demonstrating that coronary event rate was reduced after lowering the LDLc well below 100 mg/dL.

Risk categories

• Clinical CHD
• Symptomatic carotid artery disease or carotid stenosis greater than 70%
• Peripheral artery disease
• Abdominal aortic aneurysm
• Diabetes
• Global 10-year risk of major CHD event (ie, fatal or nonfatal myocardial infarction) greater than 20%

In patients without atherosclerotic disease, the risk for developing CHD is defined by the number of major risk factors for CHD and by the following:

• Hypertension (blood pressure >140/90 mm Hg or treatment for hypertension)
• Cigarette smoking (any within the past mo)
• HDLc level below 40 mg/dL
• Male sex and age 45 years or older
• Female sex and age 55 years or older
• Family history of premature CHD: Clinical CHD or sudden death in first-degree male relative younger than 55 years or first-degree female relative younger than 65 years

Percent risk for developing CHD or having a major CHD event (ie, fatal or nonfatal myocardial infarction) is determined by calculating the Framingham risk score, which is available through the US National Heart, Lung, and Blood Institute (see Risk Assessment Tool for Estimating 10-Year Risk of Developing Hard CHD).

• LDLc goal less than 100 mg/dL
• Therapeutic lifestyle changes (TLC) instituted at LDL 100 mg/dL or more
• Medical therapy initiated at LDL 100 mg/dL or more  (new 2004 cut off point)
• Optional LDLc goal less than 70 mg/dL, especially for very high risk patients:

• Patients with CHD and multiple other major risk factors for CHD, especially diabetes
• Severe, poorly controlled risk factors, especially continued cigarette smoking
• Multiple risk factors of the metabolic syndrome
• Patients admitted with an acute coronary syndrome

• See Table 2
• Global risk 10-20%
  • LDLc goal less than 130 mg/dL
  • Optional LDLc goal less than 100 mg/dL
• Consider medical therapy for LDL 100-129

Moderate risk, 2 risk factors or more

• Global risk less than 10% 
  • LDLc goal less than 130 mg/dL

• None to 1 major risk factor for CHD
• LDLc goal less than 160 mg/dL
• Low-risk patients have fewer than 2 risk factors and a 10-year risk for a major CHD event that is almost always less than 10%. The goal LDLc is less than 160 mg/dL.
• Moderate risk patients have 2 or more factors and a 10-year risk for CHD of less than 10%. The goal LDLc is less than 130 mg/dL.
• Moderately high risk patients have 2 or more risk factors and a 10-year risk of 10-20%. The goal LDLc is less than 130 mg/dL and the update suggested an optional goal LDLc of less than 100 mg/dL.
• The highest category of risk includes CHD and CHD risk equivalents
  • Clinical CHD
  • Symptomatic carotid artery disease (transient ischemic attack or stroke of carotid origin)
  • Peripheral artery disease
  • Abdominal aortic aneurysm
  • Diabetes
  • 10-year risk less than 20%
• The LDLc goal for high-risk patients is less than 100 mg/dL and the 10-year risk is greater than 20%. In addition to lifestyle changes, institution of medication is recommended if LDLc level is greater than 100 mg/dL. Patients at high or very high risk have an optional LDLc goal of less than 70 mg/dL.
• Patients with cardiovascular disease who are at very high risk have an optional LDLc goal of less than 70 mg/dL.
• Very high risk is defined as the presence of the following:
  • Multiple other major risk factors for CHD, especially diabetes
  • Severe, poorly controlled risk factors, especially continued cigarette smoking
  • Multiple risk factors for the metabolic syndrome (especially triglycerides >200 mg/dL, non-HDLc >130 mg/dL, and HDLc <40 mg/dL)
  • Patients with acute coronary syndromes

Open table in new window

• Healthy diet, regular exercise, and maintenance of desirable weight
• Because of improved diet normally results in upregulation of LDL receptors, the impact of diet changes on LDLc levels in homozygous patients is negligible (there are no receptors to upregulate), but lifestyle changes have other cardiovascular benefits and should be strongly encouraged.
• Because of the severity of CHD and lack of response, homozygous FH patients require heroic intervention.
• Occasionally, the LDL receptors retain some degree of function and diet control and high doses of HMG-CoA reductase inhibitors combined with bile acid sequestrants, ezetimibe, and niacin can be effective. Estrogen replacement therapy in postmenopausal women is also effective, but this therapy is not recommended because of its adverse effects in older women. However, in some women the benefits may outweigh risks.
• When the LDL receptors are absent or nonfunctional, one of the following is necessary:
  • LDL apheresis for homozygous FH involves selective removal of lipoproteins that contain apo-B by heparin precipitation, dextran sulfate cellulose columns, or immunoadsorption columns.
    • All methods reduce LDLc levels more than 50% and also lower lipoprotein (a), VLDL, and triglyceride levels. HDL is spared.
    • The procedure takes 3 or more hours and is performed at 1- to 2-week intervals. Few adverse events are experienced, most of which are noncritical episodes of hypotension.
    • LDL apheresis is an extremely expensive procedure and is not readily available.
  • Portacaval anastomosis
    • Compared to liver transplantation (see Surgical Care), this procedure is less hazardous and requires no immunosuppression.
    • Although cholesterol levels are not reduced as dramatically when compared with transplantation or apheresis, the clinical benefits appear comparable.
    • LDLc reductions  50% have been reported; regression of coronary lesions, aortic lesions, and xanthomas have been documented.
    • The exact mechanism by which LDLc is lowered is unclear. 
• Other treatments for homozygous FH
  
  
  • Probucol, a medication with only mild LDL-lowering effects and an undesirable HDL-lowering impact, has been shown to cause regression of cutaneous and tendon xanthomas in patients with both homozygous and heterozygous FH. An animal model has demonstrated reduced coronary atherosclerosis. No long-term benefits have been documented for patients with FH.
  • Gene therapy is still at the investigational stage. Initially, expectations were high that genetic manipulation would be a less hazardous method for providing functional LDL receptors compared with liver transplantation; however, advances have been slow.

Treatment for heterozygous FH

In patients with heterozygous FH, lifestyle modification should always be instituted but is unlikely to result in acceptable LDLc levels; therefore, cholesterol-lowering medication (usually more than one) is necessary.

• A diet that severely limits saturated fats, trans fats, and cholesterol (see Table 2) 
• Desirable weight should be attained. Significant weight loss should improve all lipid parameters (LDLc, HDLc, triglycerides).
• Aerobic and toning exercises improve blood lipid levels if performed for longer than 30 minutes, 4 or more days per week.
• While these efforts often have only a modest impact on LDLc levels, rigorous dietary intervention works synergistically with lipid-lowering medications, especially diet.
• With 50% functional LDL receptors, heterozygous FH patients have an excellent response to the usual cholesterol-lowering drugs, but treatment still remains difficult.
• To approach the recommended LDLc goals, a high dose of one of the 3 strongest HMG-CoA reductase inhibitors (statins), simvastatin, atorvastatin, or rosuvastatin, and one or more other LDL lowering medications, bile acid sequestrants, ezetimibe, or niacin, is recommended. To decrease the risk of myopathy, one step below the maximum dose of the statin should be considered. For additional resources, please visit Landmark Statin Trials.
• Because doubling the dose of any statin lowers the LDLc only 6-7%, adding a second, third, or even fourth agent is more effective.
• Fibrates have no place in treatment of patients with FH unless triglyceride levels are elevated.
• Estrogen replacement therapy in postmenopausal women also helps lower LDLc levels, but this therapy is not recommended because of its adverse effects in older women, although the benefits may sometimes outweigh risks.
• Patients with documented CHD whose LDLc level cannot be lowered below 200 mg/dL by conventional therapy are candidates for LDL apheresis. Patients without CHD but with an LDLc level of higher than 300 mg/dL also qualify for this intervention. However, health insurance coverage is not automatic, and decisions are made on a case-by-case basis because of the costs, which approach $3000 for each treatment, every 2 weeks, for the patient's lifetime.

Surgical Care

• Liver transplantation for homozygous FH
  
  
  • Liver transplantation is rarely performed because of the considerable risks associated with the surgery itself and long-term immunosuppression. But a new liver provides functional LDL receptors and causes dramatic decreases in LDLc levels.
  • If not normalized, LDLc levels then can be treated with the usual LDL-lowering medications. 
• Portacaval anastomosis for homozygous FH

Consultations

• Homozygous FH
  • Because the risk of sudden death or nonfatal myocardial infarction is so high, early or highly specialized treatment is necessary.
  • As soon as a child is diagnosed with homozygous FH, a referral should be made to a medical center specializing in severe lipid disorders.
  • Referral to center providing LDL apheresis
• Heterozygous FH
  • Refer to qualified nutritionist to provide guidance in reducing intake of saturated and trans fats and cholesterol and assist in weight reduction if indicated.
  • If patients do not reach recommended treatment goals under the care of their primary care physicians, they should be referred to an endocrinologist or lipid specialist and to a qualified nutritionist.
  • If patients are considered candidates for LDL apheresis and are willing to undertake this arduous procedure, referral should be made to a medical facility offering this procedure.

Diet

• Predicting the degree of improvement in an individual's lipids levels with dietary change is difficult because many variables affect the response, including the makeup of the baseline diet, the degree of patient compliance, and the individual's LDL responsiveness to the diet, which is genetically determined. A decrease of at least 15% can be expected in heterozygous patients who are willing to make significant dietary changes.
• The 2001 NCEP ATPIII guidelines emphasize a multifaceted approach to the prevention of CHD. Designated therapeutic lifestyle changes (TLC), its features include increased physical activity, weight reduction, and diet modification. The same diet is recommended for all patients with lipid abnormalities.
• The NCEP recommendations for the dietary management of hypercholesterolemia are not highly restrictive, but a more stringent regimen may have a greater impact on lipid levels (see Table 2).
• Restricting total fat is less important than reducing the intake of saturated fat, trans fat, and cholesterol. Moreover, diets very low in total fat are high in carbohydrates, which may increase triglyceride levels and lower HDLc levels. Substituting monounsaturated fats (eg, olive and canola oils, avocados, nuts) for carbohydrates does not increase LDLc levels and, in the absence of weight gain, may increase HDLc levels and lower triglyceride levels in patients who have maintained a diet very low in fat.
• Diets should be rich in whole grains, whole fruit, and legumes and other vegetables. These foods are high in soluble fiber, which has a small (approximately 5%) cholesterol-lowering effect; they are also high in antioxidants and flavonoids, which may be cardioprotective.

Open table in new window

• Other features of the NCEP diet are as follows:
  
  
  • Fiber (soluble fiber): Intake should be 20-30 g/d.
  • Carbohydrates: Intake should be 50-60% of total energy (caloric) intake. Carbohydrates should be derived predominantly from foods rich in complex carbohydrates, including grains, especially whole grains, fruits, and vegetables.
  • Plant sterols and stanols: Intake should be 2 g/d. These are present in commercial margarines (eg, Benacol, Take Control).
  • Total energy (caloric) intake: Balance energy intake and expenditure to maintain desirable body weight and prevent weight gain. Daily energy expenditure should include at least moderate physical activity, contributing approximately 200 Kcal/d (eg, a brisk walk of 2 miles or more).
  • Trans- fatty acids (trans fats): Intake should be avoided. Products made with hydrogenated fats contain variable amounts of trans fats. Similar to saturated fats, trans fats increase LDLc levels. However, unlike saturated fats, trans fats decrease HDLc levels. Hydrogenated fats and trans fats are found in many margarines, cakes, cookies, crackers, and frosting.

Activity

• Exercise has many cardiovascular benefits and can improve blood lipid levels. Although a greater proportion of time should be spent doing aerobic exercise because of its greater impact on lowering blood pressure and decreasing insulin resistance, resistance training also has benefits.

• Patients with CAD or symptoms suggestive of ischemic heart disease should undergo a symptom-limited exercise stress test before undertaking a new program of vigorous exercise.

Medication

HMG-CoA reductase inhibitors (statins) are the medications of choice for the treatment of LDLc elevations in patients with heterozygous FH because they have the greatest efficacy and are easily tolerated and because multiple randomized, placebo-controlled trials have shown that lowering LDLc levels with statins reduces coronary morbidity and mortality and, in some cases, total mortality. The strongest statins, rosuvastatin and atorvastatin, at their maximum approved doses, can be expected to reduce LDLc levels 50-60%.

The ATPIII update advises that the starting dose of a statin be sufficient to lower the LDLc 30-40% (see Table 3).

Even the maximum doses of the strongest statins are usually inadequate for patients with FH, and the addition of one or more nonstatin cholesterol-lowering medications is necessary.

Bile acid sequestrants (eg, cholestyramine, colestipol, colesevelam) can be added with no risk of drug interaction, with the exception of absorption of the statin (and many other medications) if taken at the same time. Bile acid sequestrants modestly decrease LDLc levels with a small  increase in HDLc and triglyceride levels. Other medications should be taken 1 hour before or 4 hours after a bile acid sequestrant. Colesevelam, which is a polymer, has less gastrointestinal side effects than the older resins and is effective at a lower dose (maximum 7 tabs/d).

Nicotinic acid (niacin) not only lowers LDLc levels but also has significant HDL-raising and triglyceride-lowering effects. There are few data to support the belief that niacin increases the risk of myopathy if combined with a statin.

Fibric acid derivatives include gemfibrozil (Lopid) and fenofibrate (Tricor). Outside of the United States, bezafibrate is also available. The fibrates lower triglyceride levels and raise HDLc levels, but they do not reliably lower LDLc levels. They increase the risk of statin-induced myositis more so than niacin. Therefore, this class of drugs is not usually useful in patients with FH.

Ezetimibe reduces LDLc levels approximately 18%, with small HDLc-raising and triglyceride-lowering effects. Because the mechanism by which it inhibits cholesterol absorption is quite specific, it does not interfere with the absorption of other drugs and does not cause the constipation associated with bile acid sequestrants. This medication has a major role in LDL-lowering when a statin alone is not sufficient and can be administered as a single tablet when combined with simvastatin (Vytorin).

Another useful statin combination is lovastatin combined with extended-release niacin (Advicor). 

These statin combinations are particularly appropriate for patients with FH, most of whom will require 2 or more drugs to reach their LDLc goals.  In addition, significantly greater than expected decreases in the LDLc level are frequently observed. 

Open table in new window

HMG-CoA reductase inhibitors (statins)

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Reduction in hepatocyte cholesterol causes up-regulation of LDL (B,E) receptors, which, in turn, reduces plasma LDL levels. Statins are used adjunctively with diet and exercise to treat hypercholesterolemia and are the most potent LDL-lowering medications. All statins have modest triglyceride-lowering and HDL-raising effects. Randomized, double-blind, placebo-controlled trials demonstrate regression of coronary atherosclerosis but, even more importantly, reduction in rates of total mortality, coronary events, and stroke.

• Because hepatic cholesterol synthesis is greatest at night, most of the statins should be taken at bedtime. Lovastatin is better absorbed with food and is most effective taken with supper. Rosuvastatin and atorvastatin are the strongest statins because they have long half-lives.
• Atorvastatin, simvastatin, and lovastatin are metabolized by the P450 cytochrome 3A4, which is inhibited by many other drugs and may thereby increase the risk of myopathy. Rosuvastatin, fluvastatin, and pravastatin are metabolized by other pathways.
• The weaker statins (pravastatin, fluvastatin, lovastatin) do not lower LDLc levels as much and, therefore, are not the statins of choice for patients with FH. However, myopathy is dose and strength-related and thus these statins may not be as likely to cause severe myopathy.
• The Report of the National Lipid Association's Statin Safety Task Force published in the American Journal of Cardiology (Volume 97, Issue 8, Supplement 1, pages S1-S98, 17 April 2006) provides the results of a rigorous, unbiased assessment of statin safety. It includes specific reports on the muscle, liver, renal, and neurologic effects of statins; as well as addressing drug interactions and other safety issues.

Atorvastatin and rosuvastatin are long-acting statins and do not require evening dosing.  Simvastatin is the third strongest statin and should be administered at bedtime.  The three weaker statins (pravastatin, fluvastatin, lovastatin) are not the statins of choice for patients with FH.  Rosuvastatin, unlike atorvastatin and simvastatin is not metabolized by the cytochrome 3A4; and, therefore, may have fewer drug interactions.

Atorvastatin (Lipitor)

Second strongest LDL-lowering drug approved to date. Long half-life. Clinical trial has shown reduction in CHD events.
As an adjunct to diet, approved indications are to reduce total cholesterol, LDLc, triglycerides, and apoB; increase HDLc in patients with Fredrickson types IIa and IIB; decrease triglycerides in patients with type IV; and treat patients with type III dysbetalipoproteinemia.
Only statin approved for treatment of patients with homozygous FH as an adjunct to other LDL-lowering measures (eg, LDL apheresis) or if other treatments are not available.

Simvastatin (Zocor)

Third strongest LDL-lowering drug approved to date. Several randomized clinical trials in patients with and without CHD have shown clinically significant reductions in CHD morbidity and mortality rates and, in some cases, total mortality rates.
In addition to its multiple effects in improving lipid profiles (decrease in total cholesterol, LDLc, triglycerides, and apoB and increase in HDLc), has been approved for reducing risk of total mortality by reducing CHD death, reducing risk of nonfatal MI and stroke, reducing need for coronary and noncoronary revascularization procedures, and for adolescents with heterozygous FH.

Rosuvastatin (CRESTOR)

Strongest cholesterol-lowering medication released to date.

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.

Vitamins

Niacin at doses of at least 1-1.5 g/d lowers LDLc levels 10-25%. HDLc levels can increase substantially, 30% or more, particularly at higher doses. Triglyceride levels decrease approximately 50%. Niacin, whether OTC or by prescription, costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, more so with time-release niacin than with regular niacin, particularly at does of 3 g/d or more. Nicotinamide, while acceptable treatment for vitamin B-3 deficiency, does not affect lipid levels, nor do most of the "no flush" niacin preparations, including inositol hexaniacinate.

Immediate-release niacin/vitamin B-3 (nicotinic acid, Niacor, Nicolar)

Less hepatotoxic than SR niacin but not as well tolerated by patients because of prostaglandin-mediated flushing, itching, or rash. IR niacin started at low doses and gradually increased over several wk allows some patients to accommodate to these adverse effects.
Higher doses (4-6 g/d) can be used more safely than those of SR niacin.
Niacor and Nicolar are prescription formulations of IR niacin that, while more expensive than OTC brands, may decrease likelihood of patient switching brands. Changing formulation of niacin while on high doses may increase risk of hepatotoxicity.

SR niacin (Slo-Niacin, Niaspan)

More hepatotoxic than IR niacin; therefore, strongly advise against switching formulations or brands during treatment. Both OTC and prescription SR niacin is available. OTC brands cost less, but if using this option, only recommend reliable manufacturers.
Slo-Niacin is an OTC formulation available in 250-, 500-, and 750-mg tabs. Sundown also manufactures OTC SR niacin. Prescription SR niacin, Niaspan, is available in 375-, 500-, and 1000-mg tabs.

Bile acid sequestrants (resins)

Anion-exchange compounds that work by preventing reabsorption of bile in the intestine. Modestly lower LDLc and increase HDLc levels but can raise triglyceride levels. When used with a statin, the LDLc-lowering effects are additive. Not absorbed systemically and, therefore, are safer than most medications. Powder should never be taken in dry form. Combine with water, other noncarbonated fluid, or soft food (eg, applesauce, soup). Probably more effective at mealtime. Colestipol is formulated both as a powder and a tablet; however, 1 tablet contains only 1 g of colestipol. Given that the maximum dose of colestipol powder is 30 g, taking an even 10 tablets (which most patients will object to) will have only minimal LDL-lowering impact.

Because resins can decrease absorption of many other medications, those medications should be taken 1 h before or 4 h after the resin. Major adverse effect is constipation, and patient compliance is often an issue.

WelChol is a polymer (not a resin) and is the newest bile acid sequestrant to enter the market. It is formulated as a tablet, and the maximum number is 7 tab/d, which may improve compliance. Reportedly causes fewer adverse GI effects and fewer drug interactions. Added to a statin, further LDLc reductions of as much as 20% can be expected.

Cholestyramine (Questran)

Orange-flavored and sweetened with either sucrose (Questran) or aspartame (Questran Light). Must be mixed with fluids or soft, high-moisture foods.
Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.
Safer than most medications.

Colestipol (Colestid)

Formulated as dry, flavorless powder and as a tab. Otherwise, similar to cholestyramine. Because contains no flavoring or sweeteners, can be mixed with a wider variety of liquid foods (eg, soup, tomato juice).

Colesevelam (WelChol)

Better tolerated than older agents (eg, cholestyramine, colestipol), and drug interactions are less of a problem. Can lower LDLc 15-18% as monotherapy. Useful in patients who cannot tolerate statins, who have contraindications for statin therapy, or who request nonsystemic therapy. Can also be used in combination with a statin for additive LDLc lowering. Has no effect on serum triglycerides or beneficial effects on HDLc. Available in a 643-mg tab.

Cholesterol inhibitors

Inhibits intestinal absorption of cholesterol.

Ezetimibe (Zetia)

First in a new class of cholesterol-lowering agents. Inhibits cholesterol intestinal absorption. Approved as monotherapy or in combination with HMG-CoA reductase inhibitors.

• Search for CME/CE on This Topic »

• Hypercholesterolemia, Polygenic (Endocrinology)
• Sitosterolemia (Pediatrics: Genetics and Metabolic Disease)
• High HDL Cholesterol (Hyperalphalipoproteinemia) (Endocrinology)
• Obesity (Pediatrics: General Medicine)

• Understanding Your Cholesterol Level
• Lifestyle Cholesterol Management
• Cholesterol Center
• High Cholesterol Overview
• Understanding Cholesterol-Lowering Medications
• Statins Center
• Statins Overview

• FDA Approves Colesevelam for Children With Familial Hypercholesterolemia
• Rosuvastatin Cleared for Pediatric FH
• Hyperlipidemia Phenotype Is a Risk Factor for Early Myocardial Infarction

• Inhibition of Microsomal Triglyceride Transfer Protein Alone or With Ezetimibe in Patients With Moderate Hypercholesterolemia
• Approaches To Dyslipidemia Treatment in Children and Adolescents
• Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects (CAPTIVATE)

• Cardiometabolic Risk Factor Management (Metabolic Syndrome) Resource Center
• Testicular Cancer Resource Center
• Chronic Leukemia Resource Center