Familial Hypercholesterolemia Medication

Updated: Mar 23, 2023
  • Author: Mose July, MD, CCD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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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)




FDA-Approved Dose


Expected LDLc Decrease


Dose Required for 30-40% LDLc Reduction


10-80 mg daily


10 mg


20-40 mg at bedtime


40 mg qd/bid

40 mg bid


40 mg bid

Extended-release fluvastatin

(Lescol XL)

80 mg at bedtime


80 mg at bedtime


20-80 mg at supper


40 mg at dinner

Extended-release lovastatin


20-60 mg at bedtime


60 mg at bedtime


40-80 mg at bedtime


40 mg at bedtime


10-40 mg daily


5 mg daily


20-80 mg daily at bedtime


20 mg at bedtime

Simvastatin + ezetimibe


10/20 mg

10/40 mg

10/80 mg

at bedtime


10/20 mg at bedtime


HMG-CoA reductase inhibitors (statins)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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.


Lipid-Lowering Agents, Other

Class Summary

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

Lomitapide (Juxtapid)

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.


Lipid-Lowering Agents, 2-Azetidinones

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.


PCSK9 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)

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)

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)

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.


Lipid-Lowering Agents, ACL Inhibitors

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)

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.


ANGPTL Inhibitors

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)

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. 


Combination Products

Class Summary

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

Simvastatin/ezetimibe (Vytorin)

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)

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.