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

**Background:** Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) and early-onset atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Historically, untreated patients die by age 18. Contemporary data on HoFH in the United States are limited, and the extent of underdiagnosis and undertreatment is uncertain. This study aimed to describe the clinical characteristics, genetics, treatment patterns, and outcomes of patients with HoFH enrolled in the CASCADE FH Registry and to estimate the number of undiagnosed individuals with similar lipid profiles in a large US claims database.

**Methods:** Data were analyzed from 67 patients (51 adults, 16 children) with clinically diagnosed HoFH from 20 US lipid specialty clinics participating in the CASCADE FH Registry. Genetic diagnosis was confirmed in 43 patients. Untreated LDL-C levels, lipid-lowering treatments (LLTs), ASCVD events, and LDL-C goal attainment (goals: <100 mg/dL for adults without ASCVD, <130 mg/dL for children without ASCVD, <70 mg/dL for those with ASCVD) were assessed at enrollment and at most recent follow-up (median 3.8 years). Additionally, the Family Heart Database, an anonymized US payer health database of >81 million individuals, was queried to identify individuals with lipid profiles similar to genetically confirmed HoFH patients (using criteria including LDL-C ≥400 mg/dL, age ≤37 years, and exclusion of secondary causes).

**Key Results:** In the CASCADE FH Registry, median untreated LDL-C was significantly lower in adults than children (533 vs. 776 mg/dL; P=0.001). At enrollment, ASCVD was present in 78.4% of adults and 43.8% of children; aortic valve stenosis in 25.5% and 18.8%, respectively. Despite multiple LLTs, LDL-C goals were achieved at enrollment by only 3 (6.3%) adults and 2 (18.2%) children. At most recent follow-up, goal attainment improved to 32.4% of adults and 25.0% of children, but median LDL-C remained high (adults: 235 mg/dL at enrollment, 147 mg/dL at follow-up; children: 317 mg/dL at enrollment, 97 mg/dL at follow-up). The number of LLTs increased over follow-up, with 82.0% of adults and 87.5% of children on ≥3 LLTs at last visit. Six adults receiving evinacumab in an open-label trial achieved a mean 50% LDL-C reduction. In the Family Heart Database, 277 individuals were identified with lipid profiles similar to genetically confirmed HoFH patients (median maximum LDL-C 444 mg/dL). Of these, 40% were on no LLT, only 18% were on advanced LLTs (PCSK9 inhibitors, lomitapide, or apheresis), 20% had ASCVD, and only 26% had an ICD-10 diagnosis of FH.

**Clinical Implications:** HoFH remains severely underdiagnosed and undertreated in the United States. Only patients with the most extreme phenotypes are diagnosed in childhood, while many with less severe LDL-C elevations are diagnosed later or not at all, missing opportunities for early intervention. Even among diagnosed patients, LDL-C goals are rarely achieved despite multiple therapies. The availability of novel receptor-independent therapies like evinacumab offers hope for better LDL-C control. Universal pediatric screening for FH, as recommended by the American Academy of Pediatrics and NHLBI, and potentially neonatal screening, are urgently needed to identify patients early and prevent the devastating cardiovascular consequences of HoFH.