Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry

Abstract

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Keywords: atherosclerotic cardiovascular disease; homozygous familial hypercholesterolemia; lipid‐lowering treatments; low‐density lipoprotein cholesterol; xanthomas.

Figure 1. Lipid values and status of individuals with HoFH living in the United States.

ASCVD indicates atherosclerotic cardiovascular disease; CASCADE, Cascade Screening for Awareness and Detection; FH, familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; IQR, interquartile range; LDL‐C, low‐density lipoprotein cholesterol; LLT, lipid‐lowering treatement; TC, total cholesterol; and TG, triglycerides.

Figure 2. Untreated LDL‐C levels and age at diagnosis in patients enrolled in the CASCADE FH Registry as children (red symbols) and as adults (black symbols). CASCADE indicates Cascade Screening for Awareness and Detection; FH, familial hypercholesterolemia; and LDL‐C, low‐density lipoprotein cholesterol.

Figure 3. Distribution of treated LDL‐C levels by number of LLTs among patients with homozygous familial hypercholesterolemia at time of enrollment in the CASCADE FH Registry (A; n=59) and at the last follow‐up visit (B; n=45).

Patients with liver transplants were excluded. CASCADE indicates Cascade Screening for Awareness and Detection; FH, familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; and LLTs, lipid‐lowering treatments.