Sections

Sections Familial Hypercholesterolemia
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Guidelines
Medication
Follow-up
Questions & Answers
Tables
References

Medication

Medication Summary

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%.^{[11, 55, 56, 57, 58]}

The ATPIII update advises that the starting dose of a statin be sufficient to lower the LDLc 30-40% (see Table 3).^[8]

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. ACL inhibitors^{[43, 44]} and PCSK9 inhibitors^{[33, 34, 46, 47]}are now available in the United States to add to maximally tolerated statins or other LDLc-lowering therapies for patients with heterozygous FH.

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).

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.

An extended follow-up of the Heart Protection Study examined the long-term efficacy and safety of LDLc-lowering with simvastatin treatment. In-trial cardiovascular benefits began after the first year and increased with each subsequent year of statin therapy and persisted 6 years beyond the end of the study. No difference in nonvascular morbidity or mortality was observed either during 5 years of statin therapy or in 6-year follow-up. The investigators recommend prompt initiation and long-term statin treatment in patients who are at increased risk for vascular events.^[59]

Table 3. Statin and Statin Combination Approved Doses, Expected LDLc Decrease, and Dose Required for 30-40% LDLc Reduction (Open Table in a new window)

Statin	FDA-Approved Dose	Expected LDLc Decrease	Dose Required for 30-40% LDLc Reduction
Atorvastatin	10-80 mg daily	35-60%	10 mg
Fluvastatin	20-40 mg at bedtime	20-30%	40 mg qd/bid
Fluvastatin	40 mg bid	35%	40 mg bid
Extended-release fluvastatin (Lescol XL)	80 mg at bedtime	35-38%	80 mg at bedtime
Lovastatin	20-80 mg at supper	25-48%	40 mg at dinner
Extended-release lovastatin (Altoprev)	20-60 mg at bedtime	25-45%	60 mg at bedtime
Pravastatin	40-80 mg at bedtime	30-40%	40 mg at bedtime
Rosuvastatin	10-40 mg daily	40-60%	5 mg daily
Simvastatin	20-80 mg daily at bedtime	35-50%	20 mg at bedtime
Simvastatin + ezetimibe (Vytorin)	10/20 mg 10/40 mg 10/80 mg at bedtime	50-60%	10/20 mg at bedtime

Class Summary

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)^[60]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)

View full drug information

Second strongest LDL-lowering statin 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 primary hypercholesterolemia (heterozygous FH and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb); decrease triglycerides in patients with type IV; and treat patients with type III dysbetalipoproteinemia.

It is approved for treatment of adults with homozygous FH as an adjunct to other LDL-lowering measures (eg, LDL apheresis) or if other treatments are not available.

It is approved for children and adolescents aged ≥10 y if after an adequate trial of diet, LDLc remains ≥190 mg/dL, or if LDLc remains ≥160 mg/dL and there is a positive family history of premature CVD or the patient has >2 other CVD risk factors.

Simvastatin (Zocor)

View full drug information

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 in adults for homozygous FH and heterozygous FH, 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)

View full drug information

Rosuvastatin has the strongest lipid-lowering potential of all the statins currently available. It is indicated for adults with primary hyperlipidemia and mixed dyslipidemia, homozygous FH, primary dysbetalipoproteinemia, and hypertriglyceridemia. In children and adolescents, it is indicated for homozygous FH and heterozygous FH.

Pitavastatin (Livalo)

View full drug information

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia in adults. In clinical trials, 2 mg/d reduced total cholesterol and LDLc similar to atorvastatin 10 mg/d and simvastatin 20 mg/d. It is also indicated for the reduction of elevated total cholesterol, LDLc, and apoB, in children aged 8 years or older with heterozygous FH.

Pravastatin (Pravachol)

View full drug information

Pravastatin is indicated for heterozygous FH in children and adolescents aged ≥8 y if after an adequate trial of diet, LDLc remains ≥190 mg/dL, or if LDLc remains ≥160 mg/dL and there is a positive family history of premature CVD or the patient has >2 other CVD risk factors.

Lovastatin (Altoprev, Mevacor)

View full drug information

Lovastatin is indicated for heterozygous FH in adults and in children and adolescents aged ≥10 y if after an adequate trial of diet, LDLc remains ≥190 mg/dL, or if LDLc remains ≥160 mg/dL and there is a positive family history of premature CVD or the patient has >2 other CVD risk factors.

Fluvastatin (Lescol, Lescol XL)

View full drug information

Fluvastatin is indicated for heterozygous FH in adults and in children and adolescents aged ≥10 y if after an adequate trial of diet, LDLc remains ≥190 mg/dL, or if LDLc remains ≥160 mg/dL and there is a positive family history of premature CVD or the patient has >2 other CVD risk factors.

Class Summary

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 a dose 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.

On April 15, 2016, the FDA announced that it was withdrawing approval for the new drug applications (NDAs) for the use of niacin ER with statins. The action stemmed from the results of several large cardiovascular outcome trials, including AIM-HIGH, ACCORD, and HPS2-THRIVE, with the FDA determining that "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events."^[61]

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

View full drug information

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)

View full drug information

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.

Class Summary

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)

View full drug information

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)

View full drug information

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)

View full drug information

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.

Class Summary

A variety of agents are emerging on the market as adjuncts to existing drugs and other therapies.

Lomitapide (Juxtapid)

View full drug information

Lomitapide directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing apo B-containing lipoproteins assembly in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL; inhibition of VLDL synthesis leads to reduced LDLc plasma levels. This agent is indicated as an adjunct to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce LDLc, triglycerides, apo B, and non-HDLc in patients with homozygous familial hypercholesterolemia.

Ezetimibe (Zetia)

View full drug information

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

Class Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors decrease LDLR degradation by PCSK9, and thereby improve LDLc clearance and lower plasma LDLc.

Alirocumab (Praluent)

View full drug information

Alirocumab is a monoclonal antibody that binds to PCSK9. LDLc is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. PCSK9 is a serine protease that destroys LDLR in the liver, resulting in decreased LDLc clearance and increased plasma LDLc. PCSK9 inhibitors decrease LDLR degradation by PCSK9.

Indicated for adults as an adjunct to diet, alirocumab is administered either alone or in combination with other lipid-lowering therapies (eg, statins, ezetimibe), being employed for the reduction of LDLc in primary hyperlipidemia, including heterozygous FH. It is also FDA approved as an adjunctive treatment for homozygous FH.

Another indication for alirocumab is for the prevention of CV events, with the drug having been found to lower the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established CV disease.

Evolocumab (Repatha)

View full drug information

Evolocumab is a monoclonal antibody that inhibits the serine protease PCSK9. PCSK9 destroys the LDL receptor in the liver, thereby decreasing LDLc clearance. It is indicated as an adjunct to diet and other LDLc-lowering therapies for adults and for children aged 10 years or older, with heterozygous FH or clinical atherosclerotic CVD, who require additional lowering of LDLc. Evolocumab is also indicated as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for adults and for children aged 10-17 y, with homozygous FH, who require additional lowering of LDLc.

Inclisiran (Leqvio)

View full drug information

Inclisiran is a small interfering RNA (siRNA) that inhibits hepatic translation of PCKS9 via mRNA interference. This inhibition increases upregulation of LDLc, with LDLc decreasing in the circulation. Inclisiran is indicated as adjunctive treatment with diet and maximally tolerated statin therapy for adults with heterozygous FH or clinical ASCVD, when additional lowering of LDLc is required.

Class Summary

Adenosine triphosphate-citrate lyase (ACL) inhibitors lower LDLc by inhibiting cholesterol synthesis in the liver. In the cholesterol biosynthesis pathway, the enzyme ACL is upstream of HMG-CoA reductase.

Bempedoic acid (Nexletol)

View full drug information

Indicated for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease when additional LDLc reduction is needed, serving as an adjunct to diet and maximally tolerated statin therapy.

Class Summary

Lipoprotein lipase and endothelial lipase are inhibited by ANGPTL3, resulting in reduced lipid metabolism. Inhibition of ANGPTL3 by evinacumab allows increased lipid metabolism, leading to decreased LDLc, HDLc, and triglycerides.

Evinacumab (Evkeeza)

View full drug information

Recombinant human monoclonal antibody that binds to and inhibits angiopoietin-like 3 (ANGPTL3). Indicated as an adjunct to other LDLc-lowering therapies for homozygous FH in adults and adolescents aged 5 years and older.

Class Summary

Clinicians may consider these products to provide additive effects in LDLc reduction and improve adherence to medication regimens.

Simvastatin/ezetimibe (Vytorin)

View full drug information

Contains the HMG-CoA inhibitor simvastatin, which reduces cholesterol synthesis, and the 2-azetidione ezetimibe, which inhibits cholesterol intestinal absorption. It is indicated for the reduction of elevated total cholesterol, LDLc, apoB, triglycerides, and non-HDLc, and for the increase of HDLc, in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia. Additionally, serving as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or a replacement if such treatments are unavailable, it is indicated for the reduction of elevated total cholesterol and LDLc in patients with homozygous familial hypercholesterolemia.

Bempedoic acid/ezetimibe (Nexlizet)

View full drug information

Contains the ACL inhibitor bempedoic acid, which inhibits hepatic cholesterol synthesis, and the 2-azetidione ezetimibe, which inhibits cholesterol intestinal absorption. Indicated for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease when additional LDLc reduction is needed, serving as an adjunct to diet and maximally tolerated statin therapy.

Follow-up

Illingworth DR, Duell PB, Connor WE. Disorders of lipid metabolism. Felig P, Baxter JD, Frohmin LA, eds. Endocrinology and Metabolism. 1315-1403.
Ueda M. Familial hypercholesterolemia. Mol Genet Metab. 2005 Dec. 86(4):423-6. [QxMD MEDLINE Link].
Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003 May. 168(1):1-14. [QxMD MEDLINE Link].
Wood S. New EAS Consensus Document Tackles Familial Hypercholesterolemia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/805252. Accessed: September 5, 2013.
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J. 2013 Aug 15. [QxMD MEDLINE Link].
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16. 285 (19):2486-97. [QxMD MEDLINE Link].
National Cholesterol Education Program Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988 Jan. 148(1):36-69. [QxMD MEDLINE Link].
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13. 110(2):227-39. [QxMD MEDLINE Link].
Connor WE, Connor SL. Dietary treatment of familial hypercholesterolemia. Arteriosclerosis. 1989 Jan-Feb. 9(1 Suppl):I91-105. [QxMD MEDLINE Link].
Illingworth DR. Management of hypercholesterolemia. Med Clin North Am. 2000 Jan. 84(1):23-42. [QxMD MEDLINE Link].
Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29. 345(22):1583-92. [QxMD MEDLINE Link].
Toklu B, Amirian J, Giugliano RP. Current indications, cost, and clinical use of anti-PCSK9 monoclonal antibodies. American College of Cardiology. Available at http://www.acc.org/latest-in-cardiology/articles/2016/05/18/14/34/current-indications-cost-and-clinical-use-of-anti-pcsk9-monoclonal-antibodies. May 19, 2016; Accessed: July 10, 2016.
Wiegman A et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21. 36 (36):2425-37. [QxMD MEDLINE Link]. [Full Text].
Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004 Sep 1. 160(5):421-9. [QxMD MEDLINE Link].
Sibley C, Stone NJ. Familial hypercholesterolemia: a challenge of diagnosis and therapy. Cleve Clin J Med. 2006 Jan. 73(1):57-64. [QxMD MEDLINE Link].
Bjorkhem I, Boberg KM. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 2073-2099.
Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001 May 18. 292(5520):1394-8. [QxMD MEDLINE Link].
Kane JP, Havel RJ. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 2717-2752.
Goldstein JL, Brown MS. Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep. 76(3):504-7. [QxMD MEDLINE Link].
Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science. 2001 May 18. 292(5520):1310-2. [QxMD MEDLINE Link].
Hammond E, Watts GF, Rubinstein Y, et al. Role of international registries in enhancing the care of familial hypercholesterolaemia. Int J Evid Based Healthc. 2013 Jun. 11(2):134-9. [QxMD MEDLINE Link]. [Full Text].
de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016 Mar 15. 133 (11):1067-72. [QxMD MEDLINE Link].
Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab. 1973. 15(1):132-40. [QxMD MEDLINE Link].
Pisciotta L, Priore Oliva C, Pes GM, Di Scala L, Bellocchio A, Fresa R, et al. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis. 2006 Oct. 188(2):398-405. [QxMD MEDLINE Link].
Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993 Jul 15. 72(2):171-6. [QxMD MEDLINE Link].
Patel MD, Thompson PD. Phytosterols and vascular disease. Atherosclerosis. 2006 May. 186(1):12-9.
[Guideline] Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1. 41 (1):111-88. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18. 139 (25):e1082-143. [QxMD MEDLINE Link]. [Full Text].
Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: guidelines and new therapies. Atherosclerosis. 2018 Oct. 277:483-92. [QxMD MEDLINE Link]. [Full Text].
Richter WO, Donner MG, Hofling B, Schwandt P. Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia. Metabolism. 47(7):863-8. [QxMD MEDLINE Link].
Thompsen J, Thompson PD. A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis. 2006 Mar 16. [Epub ahead of print].
Drouin-Chartier JP, Tremblay AJ, Bergeron J, Lamarche B, Couture P. High serum triglyceride concentrations in patients with homozygous familial hypercholesterolemia attenuate the efficacy of lipoprotein apheresis by dextran sulfate adsorption. Atherosclerosis. 2018 Mar. 270:26-32. [QxMD MEDLINE Link].
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16. 372 (16):1500-9. [QxMD MEDLINE Link]. [Full Text].
Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014 Jan 14. 129 (2):234-43. [QxMD MEDLINE Link]. [Full Text].
Langslet G, Emery M, Wasserman SM. Evolocumab (AMG 145) for primary hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015 May. 13 (5):477-88. [QxMD MEDLINE Link].
Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017 Apr. 5 (4):280-290. [QxMD MEDLINE Link].
Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020 Jul 14. 76 (2):131-42. [QxMD MEDLINE Link]. [Full Text].
Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2012 Nov 1. [QxMD MEDLINE Link].
Liu X, Men P, Wang Y, Zhai S, Zhao Z, Liu G. Efficacy and safety of lomitapide in hypercholesterolemia. Am J Cardiovasc Drugs. 2017 Mar 2. [QxMD MEDLINE Link].
Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug 20. 383 (8):711-20. [QxMD MEDLINE Link]. [Full Text].
Kane JP, Malloy MJ, Tun P, Phillips NR, Freedman DD, Williams ML, et al. Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. N Engl J Med. 1981 Jan 29. 304(5):251-8. [QxMD MEDLINE Link].
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22. 305(24):2556-64. [QxMD MEDLINE Link].
Ray KK, Bays HE, Catapano AL, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14. 380 (11):1022-32. [QxMD MEDLINE Link]. [Full Text].
Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019 Nov 12. 322 (18):1780-8. [QxMD MEDLINE Link].
Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2019 Jul 29. 2047487319864671. [QxMD MEDLINE Link]. [Full Text].
ODYSSEY outcomes: Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727). ClinicalTrials.gov. NCT01663402. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT01663402. 2015 Jul 10; Accessed: July 27, 2015.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16. 372 (16):1489-99. [QxMD MEDLINE Link].
Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun. 169 (6):906-915.e13. [QxMD MEDLINE Link]. [Full Text].
Santos RD, Ruzza A, Hovingh GK, et al. Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Oct 1. 383 (14):1317-27. [QxMD MEDLINE Link]. [Full Text].
Leqvio (inclisiran) [package insert]. East Hanover, NJ: Novartis Pharmaceutical Companies. December 2021. Available at [Full Text].
O'Riordan M. Rosuvastatin slows atherosclerosis in FH kids. Heartwire. June 6, 2014. [Full Text].
Braamskamp M, Langslet G, McCrindle BW, et al. Efficacy and safety of rosuvastatin in children aged 6–17 years with familial hypercholesterolemia: findings from the CHARON study (abstract M140). Presented at EAS 2014: The 82nd European Atherosclerosis Society Congress; June 2, 2014; Madrid, Spain.
Braamskamp MJAM, Langslet G, McCrindle BW, et al. Effect of rosuvastatin therapy on carotid intima media thickness in children with familial hypercholesterolemia: findings from the CHARON study. Presented at EAS 2014: The 82nd European Atherosclerosis Society Congress; June 3, 2014; Madrid, Spain.
[Guideline] Harada-Shiba M, Ohta T, Ohtake A, et al. Guidance for Pediatric Familial Hypercholesterolemia 2017. J Atheroscler Thromb. 2018 Feb 6. [QxMD MEDLINE Link]. [Full Text].
Cohen DE, Anania FA, Chalasani N,. An assessment of statin safety by hepatologists. Am J Cardiol. 2006 Apr 17. 97(8A):77C-81C. [QxMD MEDLINE Link].
Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19. 344(8934):1383-9. [QxMD MEDLINE Link].
Jones PH, Davidson MH, Stein EA. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003 Jul 15. 92(2):152-60. [QxMD MEDLINE Link].
Thompson PD, Clarkson PM, Rosenson RS, National Lipid Association Statin Safety Task Force Liver Exert Panel. An assessment of statin safety by muscle experts. Am J Cardiol. 2006 Apr 17. 97(8A):69C-76C.
Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011 Dec 10. 378(9808):2013-20. [QxMD MEDLINE Link]. [Full Text].
McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Task Force Liver Expert Panel. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006 Apr 17. 97(8A):89C-94C.
Wending P. FDA pulls approval of niacin, fibrate in combo with statins. Heartwire. 2016 Apr 15. Available at http://www.medscape.com/viewarticle/862022.

Media Gallery

Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.

of 1

Table 1. LDLc Target levels and levels Indicating Therapeutic Lifestyle Changes (TLC) and Drug Therapy

Risk Category

LDLc Target level,

mg/dL

LDLc level Indicating TLC,

mg/dL

LDLc level for Considering Drug Therapy,

mg/dL*

High risk:

CHD or CHD risk equivalent

(10-y risk >20%)

< 100

Optional goal < 70

>100

Moderately high risk:

More than 2 risk factors

(10-y risk 10-20%)

130

Optional goal < 100

>130

(100-129 may consider drug options)

Moderate risk:

More than 2 risk factors

(10-y risk 10%)

< 130

>130

>160

Lower risk:

0-1 risk factor

< 160

>160

>190

(160-189 LDL-lowering drug optional)

*The 2004 update recommended that when statin therapy is initiated in patients at high or moderately high risk, a dose and strength should be chosen that achieves at least a 30-40% LDLc reduction (see Table 3).

Table 2. Recommended Dietary Intake

Food Category	Typical US Diet	NCEP Diet	Diet for FH
Cholesterol, mg/d	500	< 200	100
Total fat, % energy (calories)	40	25-35	20
Saturated fat, % energy (calories)	14	< 7	< 6
Carbohydrate, % energy (calories)	45	50-60	65
Protein, % energy (calories)	Approximately 15	15	N/A

Table 3. Statin and Statin Combination Approved Doses, Expected LDLc Decrease, and Dose Required for 30-40% LDLc Reduction

Statin	FDA-Approved Dose	Expected LDLc Decrease	Dose Required for 30-40% LDLc Reduction
Atorvastatin	10-80 mg daily	35-60%	10 mg
Fluvastatin	20-40 mg at bedtime	20-30%	40 mg qd/bid
Fluvastatin	40 mg bid	35%	40 mg bid
Extended-release fluvastatin (Lescol XL)	80 mg at bedtime	35-38%	80 mg at bedtime
Lovastatin	20-80 mg at supper	25-48%	40 mg at dinner
Extended-release lovastatin (Altoprev)	20-60 mg at bedtime	25-45%	60 mg at bedtime
Pravastatin	40-80 mg at bedtime	30-40%	40 mg at bedtime
Rosuvastatin	10-40 mg daily	40-60%	5 mg daily
Simvastatin	20-80 mg daily at bedtime	35-50%	20 mg at bedtime
Simvastatin + ezetimibe (Vytorin)	10/20 mg 10/40 mg 10/80 mg at bedtime	50-60%	10/20 mg at bedtime

Back to List

Author

Mose July, MD, CCD Endocrinologist and Certified Clinical Densitometrist, Kymera Independent Physicians

Mose July, MD, CCD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Coauthor(s)

Omolola Bolaji Olajide, MD, FACE Associate Professor, Consultant, Department of Internal Medicine, Program Director, Fellowship Program, Section of Endocrinology, Joan C Edwards School of Medicine at Marshall University

Omolola Bolaji Olajide, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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 and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Gregory William Rutecki, MD Professor of Medicine, Fellow of The Center for Bioethics and Human Dignity, University of South Alabama College of Medicine

Gregory William Rutecki, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Nephrology, National Kidney Foundation, Society of General Internal Medicine

Disclosure: Nothing to disclose.

Sections Familial Hypercholesterolemia
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Guidelines
Medication
Follow-up
Questions & Answers
Tables
References

Familial Hypercholesterolemia Medication

Medication Summary

HMG-CoA reductase inhibitors (statins)

Class Summary

Atorvastatin (Lipitor)

Simvastatin (Zocor)

Rosuvastatin (Crestor)

Pitavastatin (Livalo)

Pravastatin (Pravachol)

Lovastatin (Altoprev, Mevacor)

Fluvastatin (Lescol, Lescol XL)

Vitamins

Class Summary

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

SR niacin (Slo-Niacin, Niaspan)

Bile acid sequestrants (resins)

Class Summary

Cholestyramine (Questran)

Colestipol (Colestid)

Colesevelam (WelChol)

Lipid-Lowering Agents, Other

Class Summary

Lomitapide (Juxtapid)

Lipid-Lowering Agents, 2-Azetidinones

Ezetimibe (Zetia)

PCSK9 Inhibitors

Class Summary

Alirocumab (Praluent)

Evolocumab (Repatha)

Inclisiran (Leqvio)

Lipid-Lowering Agents, ACL Inhibitors

Class Summary

Bempedoic acid (Nexletol)

ANGPTL Inhibitors

Class Summary

Evinacumab (Evkeeza)

Combination Products

Class Summary

Simvastatin/ezetimibe (Vytorin)

Bempedoic acid/ezetimibe (Nexlizet)

References

Tables

Contributor Information and Disclosures

What would you like to print?