Familial Hypercholesterolemia Treatment & Management

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). ^{[6, 7]}

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. ^[8]

The European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) have also released guidelines for the management of dyslipidemias, available at the ESC site. ^[27]  

In addition, the American College of Cardiology/American Heart Association (ACC/AHA) released updated blood cholesterol guidelines, in 2018; however, they do not address a specific approach to and management of FH. ^[28] .

CHD or CHD risk equivalent

See the list below:

• 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%

Determination of risk

Treatment of elevated LDLc levels is based upon the risk for a coronary heart disease (CHD) event (see Table 1). The 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) defined target LDLc levels and levels based on risk for CHD. ^[6] The 2004 update added optional lower LDLc goals to reflect the findings of several interventional trials demonstrating that more aggressive LDLc lowering further reduced coronary event rate. ^[8]

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

An HDLc level of 60 mg/dL or greater is a negative risk factor for CHD and its presence removes one risk factor from the total.

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 include the following:

• 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

Moderately high risk, more than 2 risk factors

See the list below:

• 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

See the list below:

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

Low risk

See the list below:

• 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 include the following:

• 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

Table 1. LDLc Target levels and levels Indicating Therapeutic Lifestyle Changes (TLC) and Drug Therapy (Open Table in a new window)

 

EAS guidelines for the screening and treatment of homozygous FH are summarized as follows: ^{[27, 29]}

• Treatment of homozygous FH involves a combination of lifestyle changes, statin therapy (first approach), and lipoprotein apheresis for severe cases, if available, and should be started as early as possible.

• LDL apheresis should begin as early as age 5 years and no later than age 8 years.

• For homozygous FH patients, the LDL cholesterol targets are < 100 mg/dL for adults, < 70 mg/dL for adults with clinical cardiovascular disease (CVD), and < 135 mg/dL for children.

• Other novel agents for LDL cholesterol lowering (eg, lomitapide with or without apheresis) can be considered as adjunctive treatments for patients who do not achieve the recommended LDL cholesterol targets and remain at high cardiovascular risk.

General treatment recommendations are discussed in more depth below.

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. ^{[9, 10]}

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. ^[11] 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. ^{[30, 31]}

A study by Drouin-Chartier et al indicated that in patients with homozygous FH, the level of serum triglycerides prior to the initiation of LDL apheresis is inversely proportional to the effectiveness of dextran sulfate adsorption in the reduction of LDLc. Dividing pre-apheresis triglyceride concentrations into quartiles, the investigators found that LDL apheresis with dextran sulfate adsorption was 3.9% less effective in acutely reducing LDLc concentrations for patients in the highest quartile (over 2.09 mmol/L) than for those in the lowest quartile (0.93 mmol/L or below). The study also found that for LDL apheresis using heparin-induced extracorporeal LDL precipitation, pre-apheresis serum triglyceride levels did not significantly affect LDLc removal. ^[32]

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

Evolocumab

Evolocumab (Repatha) was approved in August 2015. It is indicated as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous FH who require additional lowering of LDLc in adults and in children aged 10-17 years. It is also indicated for heterozygous FH in adults and in children aged 10 years or older.

Approval of evolocumab was based on the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDLc levels. ^{[33, 34]} Additionally, the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003) in a prespecified exploratory analysis. ^[33] Results of the ongoing FOURIER trial is looking at cardiovascular outcomes and will include more than 27,000 patients with clinically evident cardiovascular disease and is expected to be completed in late 2017. ^[35]

An interim subset analysis of the Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG) also indicated that evolocumab is effective in reducing LDLc in homozygous FH, even without apheresis. Patients in the study underwent treatment with evolocumab 420 mg subcutaneously either monthly or, if also undergoing apheresis, every 2 weeks, with an option, for patients not on apheresis, to increase dosing to every 2 weeks following 12 weeks of treatment. Among the results obtained, the investigators found that after 12 weeks, the mean LDLc level had been reduced by 20.6% and the mean HDLc level had been increased by 7.6%. Patients not on apheresis who increased dosing to every 2 weeks experienced an additional mean LDLc reduction of 8.3%. ^[36]  

Alirocumab

Alirocumab (Praluent) gained FDA approval in April 2021 for adjunctive use with other LDLc-lowering therapies in the treatment of homozygous FH. Approval was based on the ODYSSEY HoFH trial, which found alirocumab to be associated with significant LDLc reductions in patients with the disease. ^[37]  

Lomitapide

Lomitapide (Juxtapid) is a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor. It was approved by the US Food and Drug Administration (FDA) in December 2012 as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDLc, triglycerides, apoB, and non-HDLc in patients with homozygous familial hypercholesterolemia. Because lomitapide increases risk of hepatotoxicity, it is only available through a restricted access program. Approval was based on a small trial of 29 patients exposed to lomitapide, with 23 patients exposed to the drug for 1 year, 15 patients exposed for 2 years, and 5 patients exposed for 3 years. At baseline, the mean LDLc in the homozygous FH patients was 336 mg/dL, and this was reduced 50% after 26 weeks of treatment (P < 0.0001). ^[38]

A literature review by Liu et al reported that in patients with homozygous FH, lomitapide reduces LDLc, total cholesterol, apoB, and triglyceride levels, even without other lipid-lowering treatments, but also decreases HDLc and apoA-1 values. ^[39]  

Evinacumab

Evinacumab (Evkeeza) is a recombinant human monoclonal antibody that binds to and inhibits angiopoietin-like 3 (ANGPTL3). 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 trigyclerides (TG). 

The FDA approved evinacumab in February 2021 as an adjunct to other LDLc-lowering therapies for homozygous FH in adults and adolescents aged 12 years or older. (The indication was expanded in March 2023 to include children as young as 5 years.) Approval was based on the phase 3 ELIPSE trial (n = 65). The study found that patients undergoing stable lipid-lowering treatment in whom an intravenous (IV) infusion of evinacumab was administered every 4 weeks achieved, by week 24, a 47.1% relative reduction in their LDLc level, compared with a 1.9% increase seen in patients treated with a placebo. ^[40]

Probucol

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

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.

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. ^[10]

The 2013 European Atherosclerosis Society (EAS) consensus statement for screening and treatment of heterozygous FH includes the following treatment recommendations ^{[4, 5]} :

• An LDL target of < 3.5 mmol/L (< 135 mg/dL) for children with FH (age 8–10);

• An LDL target of < 2.5 mmol/L (< 100 mg/dL) for adults with FH; and

• An LDL target of < 1.8 mmol/L (< 70 mg/dL) for adults with known CHD or diabetes.

Lifestyle modifications include a diet that severely limits saturated fats, trans fats, and cholesterol (see Table 2). ^[9]

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. ^[9]

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. ^[11] 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. ^[41]

A pooled analysis of 5 statin trials revealed that intensive-dose therapy was associated with a greater risk of diabetes when compared with moderate dosing. ^[42]

In February 2020, the FDA approved bempedoic acid (Nexletol), the first adenosine triphosphate-citrate lyase (ACL) inhibitor. Reducing hepatic synthesis of LDLc, the enzyme ACL is upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway.

Bempedoic acid is 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.

Approval of bempedoic acid was based on the phase-3 trials CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Harmony and CLEAR Wisdom. The addition of bempedoic acid to maximally tolerated statin therapy resulted in an average placebo-corrected LDLc reduction of 18%. ^{[43, 44]}

Bempedoic acid was also approved in combination with ezetimibe (Nexlizet). A mean 38% reduction in LDLc (in comparison with placebo) was seen when the combination was added to maximally tolerated statins. ^[45]

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab (Praluent), was approved by the FDA in July 2015. It is indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDLc.

Alirocumab was approved before the completion of its CV-outcomes trial. The primary outcome measures for ODYSSEY-Outcomes, ^[46]  which is scheduled to finish by December 2017, include possible first occurrence of CHD death, any nonfatal MI, fatal and nonfatal ischemic stroke, and unstable angina requiring hospitalization. Secondary measures included time to first occurrence of any CHD event, major CHD event, any CV event, and all-cause mortality.

Alirocumab’s approval was based on data from the pivotal Phase 3 ODYSSEY program, which showed consistent, positive results for alirocumab compared to placebo and included current standard of care therapy (statins). The ODYSSEY LONG TERM trial evaluated alirocumab 150 mg SC every 2 weeks. Alirocumab reduced LDL cholesterol by 58% compared with placebo at week 24 when added to current standard of care, including maximally tolerated statins. ^[47] In ODYSSEY COMBO I, Praluent 75 mg every 2 weeks as an adjunct to statins reduced LDL cholesterol by an additional 45% compared with placebo at week 12. ^[48] At week 24 in the same trial, alirocumab reduced LDL cholesterol by an additional 44% compared with placebo. In this study, if additional LDL cholesterol lowering was required based on prespecified criteria at week 8, alirocumab was up-titrated to 150 mg at week 12 for the remainder of the trial. Eighty-three percent of patients remained on their initial 75 mg dose.

Evolocumab (Repatha) is the second PCSK9 inhibitor approved in the United States in 2015. It is approved as an adjunct to diet and other LDLc-lowering therapies for the treatment of adults and children aged 10 years or older with heterozygous FH or clinical atherosclerotic CVD who require additional lowering of LDLc. It is also approved for adults and for children aged 10-17 years, with homozygous FH.

Approval of evolocumab was based on the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels. ^{[33, 34]} Additionally, the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003) in a prespecified exploratory analysis. ^[33] Results of the ongoing FOURIER trial is looking at cardiovascular outcomes and will include more than 27,000 patients with clinically evident cardiovascular disease and is expected to be completed in late 2017. ^[35]  

The HAUSER-RCT affirmed evolocumab’s efficacy and safety in pediatric patients aged 10-17 years with heterozygous FH. Randomized patients were treated with evolocumab (104 patients) or placebo (53 patients). By week 24, the LDLc levels in the evolocumab group showed a mean change of -44.5%, compared with -6.2% in the placebo group. ^[49]

In December 2021, the FDA approved inclisiran (Leqvio) injection. A proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, inclisiran was approved as adjunctive treatment with diet and maximally tolerated statin therapy for adults with heterozygous FH or clinical atherosclerotic cardiovascular disease (ASCVD), when additional lowering of LDLc is required. ^[50]

In pediatric heterozygous FH, a study suggests that rosuvastatin slows atherosclerotic progression. In a randomized study (CHARON trial) of 196 children and adolescents (age range, 6-17 y) with heterozygous FH and 65 unaffected sibling controls, treatment with rosuvastatin in affected patients for two years slowed the progression of subclinical atherosclerosis. ^{[51, 52, 53]}  At baseline, the mean carotid intima-media thickness (IMT) was significantly higher among those with heterozygous FH (0.398 mm) compared with their healthy siblings (0.376 mm); following 2 years of treatment with rosuvastatin, there was no difference in the mean carotid IMT between the groups, and 38% of those receiving rosuvastatin met the target LDLc of less than 110 mg/dL. ^[51]  Over 85% of patients in the treatment group reported adverse events that the investigators considered as mild (eg, headaches, nasopharyngitis, influenzalike symptoms). All patients remained within the normal height and weight range for their age. ^[51]

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.

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

This may be indicated.

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.

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. ^[6] 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.

Table 2. Recommended Dietary Intake (Open Table in a 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. ^[26] 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.

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.