Sex‐related differences in premature cardiovascular disease in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an inherited condition marked by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) starting in utero due most often to a monogenic mutation in the LDL-receptor. Frequency is approximately 1 in 250 in the general population and higher in several founder groups. It is well established that individuals with FH have an elevated lifetime risk of atherosclerotic cardiovascular disease (ASCVD) and are also at an increased risk of premature ASCVD (defined as <55 years in men and <65 years in women). However, less is known about sex differences in those with FH who develop early ASCVD, including age, relative impact of other risk factors, and treatment outcomes. This is clinically relevant because a large burden of traditional risk factors has been observed in general in individuals with premature ASCVD. Additionally, it is well known that some ASCVD risk factors impart greater relative risks in women and are even ‘risk equalizers’ (i.e. diabetes, a very high total cholesterol to HDL cholesterol ratio ≥ 7.5, and LVH), and yet ASCVD risk in women is generally undertreated compared to men.^{,  ,  ,}  This sex-related gap has been attributed to a lower perceived risk of ASCVD by both female patients and their clinicians even when traditional ASCVD risk factors are present. The aim of this study was to characterize sex-specific risk factor burdens and lipid treatment outcomes in individuals with FH and premature ASCVD.

Study Design: We retrospectively collected data on 782 adult patients receiving care for heterozygous FH at 5 US-based lipid and genetics clinics: Washington University in St Louis, Baylor College of Medicine, University of Texas Southwestern Medical Center at Dallas, Geisinger Health, and the Brown University Lifespan Hospital system. All data extraction was performed by trained research assistants who collected de-identified data for importation into a dedicated study database. Demographic data were self-reported. Patients were diagnosed with either heterozygous FH based on validated clinical criteria or genetic testing. Clinical criteria included, but were not limited to, Simon Broome, Dutch Lipid Clinic Network, Make Early Diagnosis to Prevent Early Death (MEDPED) and/or the American Heart Association schema for possible, probable, or definite FH. Genetically confirmed FH included mutations in the LDLR, APOB, or PCSK9 genes. Given the heterogeneous means of diagnoses, patients with either a clinical or genetic diagnosis were characterized as having FH; and no distinction was made between patients who had a clinical or genetic diagnosis for the scope of this analysis. The institutional review boards at each site approved of the protocol, and waivers were obtained for retrospective data collection.

Clinical characteristics of the 280 men and 502 women included in this analysis are shown in Table 1. Women were well represented in our cohort. Women in the cohort tended to be older than the men (mean age 55±15 years vs. 52±14 years, p<0.001). A total of 187 patients had a diagnosis of premature ASCVD. The incidence of premature ASCVD in men n = 98 was 35% and in women n= 89 was 18%. Treated LDL-C levels across all individuals with FH were significantly higher in women than in men (125 ± 48 mg/dL vs. 116 ± 51 mg/dL respectively, p =0.02).

Traditional risk factors in those with premature ASCVD are shown in Table 2. The prevalence of hypertension, current smoking, and diabetes mellitus were two-fold greater amongst those with premature ASCVD as compared to those without premature ASCVD, N=148 (80%) vs. N=213 (40%), p <0.001 for hypertension, N=29 (16%) vs. N= 40 (8%), p= 0.002 for current smoking, and N= 60(32%) vs. N=91 (15%), p<0.001 for diabetes. No difference was noted in treated LDL-C levels in patients with and without premature ASCVD respectively mean value 122 mg/dL mg/dL in both group, p=0.28.

Analysis by sex (Tables 3 and 4) further highlights the nearly two-fold higher prevalence of traditional ASCVD risk factors in both men and women with premature ASCVD. The prevalence of hypertension was N=80 (83%) vs. N= 69 (45%), p <0.001 in men with and without premature ASCVD respectively and N= 68 (77%) vs. N= 144 (39%), p<0.001 in women with and without premature ASCVD respectively. Women, but not men, with premature ASCVD vs. those without were more likely to be current smokers, N=15 (17%) vs. N=27 (7%), p=0.009 in women and N= 14 (15%) vs. N= 13(9%), p= 0.192 in men. Men and women with premature ASCVD had significantly higher BMI compared to their counterparts without ASCVD.

A comparison of clinical characteristics and ASCVD risk factors is shown in Table 5. Women with premature ASCVD had higher on-treatment total cholesterol (216 vs. 179 mg/dl, p<0.001) and LDL-C (135 vs. 109 mg/dl, p= 0.005). The strongest predictors of premature ASCVD in all individuals with FH were smoking [OR 2.40 (95% CI 1.41, 4.05) p=0.001] and hypertension [OR 4.36 (95% CI 2.91, 6.67) p<0.001] (Table 6). Sex-stratified analyses further highlighted differences in predictors of premature ASCVD in men and women. In men, the strongest predictors of premature ASCVD were hypertension (OR 3.83, 95% CI 2.09, 7.90, p<0.001) and diabetes mellitus (OR 1.89 95% CI 1.04, 3.43, p=0.036). In women, the strongest predictors of premature ASCVD were hypertension (OR 4.25, 95% CI 2.47, 7.57, p<0.001) and smoking (OR 2.54, 95% CI 1.25, 5.00, p < 0.001). Treated LDL-C was not a significant predictor of ASCVD in either men or women (Table 6).

In this cohort of 782 men and women with FH cared for by lipid or genetic specialists across several regions of the U.S. we found the prevalence of premature ASCVD to be around 24% overall and 35% in men vs. 18% in women. These findings are comparable to those previously published through the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH®) registry that demonstrated the prevalence of premature ASCVD to be 36% and 12% in men and women respectively. The prevalence of premature ASCVD is estimated at around 11% according to a study of over 1.2 million patients seen in the US Department of Veterans Affairs healthcare system. The prevalence of premature ASCVD in our cohort of patients with FH is approximately 2-3-fold higher than that in the general U.S. population. These data confirm that a diagnosis of FH confers substantially elevated risk for premature ASCVD compared to the general population.

In our cohort, women had significantly higher treated LDL-C levels compared to men regardless of ASCVD status. In previously published data through the CASCADE-FH registry women were less likely than men to receive statin therapy, high-intensity statin therapy, and achieve their LDL-C goals. When compared to men with premature ASCVD, women with premature ASCVD had significantly higher on treatment total and LDL-C values despite the lack of difference in high-intensity statin, ezetimibe, and PCSK9 inhibitor use. The reason behind the discrepancy in LDL-C merits further investigation. It is important to note that some of the patients in our cohort may have been co-enrolled in the CASCADE-FH registry, contributing to an overlap in the patients used for these studies. This overlap may limit how these data sets are compared to each other. However, there are limited data on women with FH and CASCADE is one of the very few large registries available that allows for these data to be compared. Electronic health record data from other cohorts including patients without a diagnosis of FH, show that women with coronary artery disease are not prescribed adequate doses of lipid lowering therapy and are less likely to reach their LDL-C therapeutic threshold.^, The UK Simon Broom FH registry reported that women between the ages of 30-50 years had a significantly higher CVD related morbidity when compared to men. These findings, in addition to the ones in our study highlight the importance of optimization of lipid lowering therapy and risk factor reduction, particularly in young women. Notably, men and women with premature ASCVD were more likely to be obese than those without premature ASCVD. Taken together, these findings shed light on multifactorial drivers for premature ASCVD beyond LDL-C in men and women with FH. Importantly, the risk of premature ASCVD appears to be exacerbated by modifiable risk factors (i.e. hypertension, diabetes mellitus, and smoking), suggesting that early and aggressive treatment of hypertension and diabetes, and interventions to target smoking cessation may reduce the burden of ASCVD in these individuals who are already at heightened risk of ASCVD due to their lifelong exposure to elevated LDL-C. While optimizing lifestyle measures of diet and exercise will not adequately control LDL-C levels in individuals with FH, these measures can have a robust impact on controlling blood pressure and preventing or controlling diabetes mellitus, which should also be important goals, in addition to smoking prevention and/or cessation, in the treatment of FH.

FH is a common genetic disorder with an estimated prevalence of 1 in 250 U.S. adults, in whom the relative risks of cardiovascular morbidity and mortality including premature ASCVD, surpass that of the general population. The present study has demonstrated sex-related disparities in risk factors for ASCVD and in lipid control in individuals with FH, which have important implications for primary and secondary prevention in this high-risk group. Premature ASCVD in individuals with FH appears to be driven by risk factors beyond just LDL-C. Comprehensive evaluation and management of all ASCVD risk factors in in men and women alike, is key to reducing ASCVD burden.

Anandita Agarwala: Conceptualization, Project administration, Writing – review & editing. Elena Deych: Conceptualization, Project administration, Writing – review & editing. Laney K. Jones: Conceptualization, Project administration, Writing – review & editing. Amy C. Sturm: Conceptualization, Project administration, Writing – review & editing. Karen Aspry: Conceptualization, Project administration, Writing – review & editing. Zahid Ahmad: Conceptualization, Project administration, Writing – review & editing. Christie M. Ballantyne: Conceptualization, Project administration, Writing – review & editing. Anne C. Goldberg: Conceptualization, Project administration, Writing – review & editing.