Abstract Body (Do not enter title and authors here): Introduction: Familial hypercholesterolemia (FH) is a genetic disorder affecting 4 in 1000 people, resulting in lifelong elevated low-density lipoprotein cholesterol (LDL) and increased atherosclerotic cardiovascular disease (ASCVD) risk. This study assessed patterns of lipid-lowering therapy and ASCVD outcomes in patients with and without FH using real-world electronic health record (EHR) data.

Methods: We analyzed EHR data from 287,012 individuals in the All of Us Controlled Tier Dataset version 7, identifying 708 with an FH diagnosis. Among the 15,804 people with documented lipid-lowering therapy, 116 had FH. A multivariable proportional hazards (PH) model assessed age of first ASCVD, defined as either myocardial infarction, cerebrovascular accident, coronary or peripheral artery disease, by FH status, adjusting for sex, race, and number of lipid-lowering agents used.

Results: In this treated cohort (54.3% male; 74.3% White), patients with FH began therapy at a similar age as those without FH (57.1±12.9 vs 60.0±10.8 years; p=0.12) and had similar maximum baseline LDL (146.1±40.8 vs 134.3±38.8 mg/dL; p=0.14) but were prescribed more agents (1.6±1.0 vs 1.3±0.6; p=0.0004). Most received statins (98.3% FH vs 95.4% non-FH), but there was greater use of ezetimibe (13.8% vs 6.5%; p=0.002), PCSK9 inhibitors (12.9% vs 1.1%; p<0.0001), and bile acid sequestrants (11.2% vs 6.1%; p=0.02) among those with FH. No differences were found in use of fibrates, niacin, or omega-3 fatty acids (all p>0.15). LDL remained higher after at least 3 months (mean 1.7±0.5 yrs) of treatment in people with FH (110.4 ± 54.1 mg/dL vs 99.2 ± 35.6 mg/dL; p=0.02). Hypertension was common but less prevalent in FH (70.7% vs 82.1%; p=0.001). Neither BMI (30.8±7.8 kg/m²) nor prevalence of diabetes (44.0%), heart failure (15.6%), chronic kidney disease (19.6%), or ASCVD (41.1%) differed between groups. People with FH experienced their first ASCVD event earlier (62.2±13.5 vs 65.3±11.3 years; p=0.01). However, in the PH model, while male sex (HR = 1.28), Black race (HR = 1.69), and number of medications (HR = 1.39; all p<0.0001) predicted an earlier age of ASCVD event, treated FH did not (HR = 1.19; p = 0.21).

Conclusion: Even with more intensive regimens, people with FH have higher post-treatment LDL. Although our study is limited by a small sample size, these real-world data suggest modern lipid-lowering therapy can reduce ASCVD risk in FH to levels comparable to the general population.