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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

For patients with severe elevations in low-density lipoprotein (LDL) cholesterol (≥190 mg/dL) and a combination of clinical signs and family history to suggest familial hypercholesterolemia (FH) or the genetic results to prove it, treatment is warranted for adults and children alike regardless of atherosclerotic cardiovascular disease (ASCVD) risk-predictor scores.

That starts with the same dietary and lifestyle modifications recommended for LDL‐cholesterol lowering in patients without FH, along with treating other ASCVD risk factors and comorbidities, such as hypertension and diabetes mellitus.

But bringing cholesterol down to a more adequate level in FH usually also takes multidrug treatment.

Adult FH

Maximally tolerated statin treatment has a class I recommendation for patients ages 20-75 when LDL is 190 mg/dL or higher in the American Heart Association/American College of Cardiology (AHA/ACC) . If that doesn't bring LDL levels down by at least 50% or to less than 100 mg/dL, ezetimibe (Zetia) is recommended as reasonable to add on. If LDL still doesn't drop below 50% of baseline, a bile acid sequestrant can be added on. However, bile acid sequestrants must be used cautiously with regular monitoring for patients with fasting triglyceride levels approaching 300 mg/dL and are not recommended at fasting triglycerides above 300 mg/dL so as not to cause pancreatitis.

PCSK9 inhibitors -- monoclonal antibodies alirocumab (Praluent) and evolocumab (Repatha) and small interfering RNA agent inclisiran (Leqvio) -- have class IIb recommendation to add on to the statin and ezetimibe for patients 30-75 years of age with heterozygous FH when LDL cholesterol remains 100 mg/dL or higher and for those ages 40-75 who start at an LDL level of 220 mg/dL or higher and still have a level 130 mg/dL or higher on treatment.

Severe hypercholesterolemia that continues to be inadequately controlled with drug therapy can be treated with LDL apheresis for selected patients. AHA/ACC guidelines don't spell out a threshold for starting apheresis and indications by country, but adequate LDL control is generally considered a level under 100 mg/dL without ASCVD and under 70 mg/dL in high-risk patients with it. "Referral to a lipid specialist may be indicated," the guidelines note.

Lomitapide (Juxtapid) is also approved for treatment of homozygous FH, but is subject to a Risk Evaluation and Mitigation Strategy program due to significant liver toxicity risk.

Pediatric Familial Hypercholesterolemia

The roots of ASCVD can start in childhood, with especially high lifetime risks for FH.

All statins are approved for children with FH, although usually prescribed at reduced doses. After lifestyle management is tried for 3-6 months, statins are also considered reasonable for those age 10 or older who have LDL cholesterol (LDL-C) persistently at 190 mg/dL or higher or at least 160 mg/dL if the clinical presentation is consistent with FH.

Use could even start by age 8 years "in the presence of concerning family history, extremely elevated LDL-C level, or elevated Lp(a) [lipoprotein(a)] in the context of informed shared decision-making and counseling with the patient and family," the guidelines added. Dose intensity should be based on how severely elevated cholesterol levels are and take into consideration patient and family preferences.

"A smaller group, but even at higher risk, are young adults with persistent, moderate hypercholesterolemia (LDL-C 160-189 mg/dL), especially when risk-enhancing factors, such as a family history of premature ASCVD, are present," the guidelines pointed out. "Since there is increased probability of genetic FH in this LDL-C range, clinical judgment would suggest that these high-risk young adults will benefit from long-term statin therapy. Indeed, it has been shown that those with higher LDL-C can gain as much or more benefit from cholesterol reduction as do those with lower pretreatment LDL-C but at higher risk."

of the original placebo-controlled statin trial in youth with FH showed that those who started taking a statin at age 8-18 years had slower progression of carotid intima-media thickening over 20 years and a lower incidence of cardiovascular events and death from cardiovascular causes (1% vs 26% and 0% vs 7%, respectively) by age 39 compared with their FH-affected parents for whom statins weren't available until later in life.

Along with long-term safety data in children and adults, those data on hard outcome benefits "affirm the importance of initiating statins in childhood in the setting of FH," a 2019 in the Journal of the American Heart Association noted.

What scant data there is on use of ezetimibe in children with severe hypercholesterolemia suggests "reasonable" LDL-lowering with no significant adverse effects, the guidelines state. While bile acid sequestrants can be useful to lower LDL as well, tolerability is an issue, with gastrointestinal side effects common.

PCSK9 inhibitors are also approved for use in pediatric FH as an add-on to statin and lifestyle treatment, but have not yet been incorporated into the guidelines.

Evolocumab (Repatha) was approved for children ages 10 and older with heterozygous and homozygous FH based on a showing a 38.3 percentage point greater reduction in LDL cholesterol over 24 weeks compared with placebo.

And in March 2024, the FDA extended the approval for alirocumab (Praluent) to patients ages 8 and older with heterozygous FH based on findings from an of 153 patients ages 8-17 years. Those randomized to receive alirocumab had a 43.3 and 33.8 percentage point greater reduction in LDL cholesterol than seen with placebo when dosed every 2 and 4 weeks, respectively.

The angiopoietin-like 3 inhibitor evinacumab (Evkeeza) is also approved for children ages 5-11 with homozygous FH based on a showing that children in that age range had a 48.3% reduction in LDL cholesterol over 24 weeks.

to correct the most common genetic causes of FH is under development and could hold promise for even greater cardiovascular protection.

Read previous installments in this series:

Part 1: Hypercholesterolemia: A Complex System

Part 2: Consequences of Hypercholesterolemia

Part 3: Genetics of Hypercholesterolemia

Part 4: Case Study: High Lipoprotein(a) Levels in Younger Patients Are Not So Clear Cut

Part 5: The Shifting Epidemiology of Hypercholesterolemia

Part 6: Diagnosing Hypercholesterolemia

Part 7: Primary Prevention in Hypercholesterolemia

Part 8: Case Study: Teenage Girl's Shortness of Breath and Chest Pain

Part 9: Options for Treating Non-Familial Hypercholesterolemia

Up next: Hypercholesterolemia in Special Populations