Lipoprotein(a) and coronary artery calcium in comparison with other lipid biomarkers: The multi-ethnic study of atherosclerosis.

BACKGROUND: Coronary artery calcium (CAC) scoring is often used for atherosclerotic cardiovascular disease (ASCVD) risk stratification in individuals with elevated lipoprotein(a) [Lp(a)]. OBJECTIVE: To evaluate associations between Lp(a) and baseline CAC (volume/density) and CAC progression compared to other lipid biomarkers. METHODS: We utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of individuals without clinical ASCVD, excluding statin users. We evaluated the associations between Lp(a), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides, total cholesterol, apolipoprotein B, and non-HDL-C with baseline CAC and annual CAC progression using multivariable ordinal regression with adjustment for ASCVD risk factors. Analyses were also stratified by median age. RESULTS: In 5,597 participants (2,726 at median 9.5-year follow-up), Lp(a) was not associated with baseline CAC volume or density and was modestly associated with volume progression (OR 1.11, 95% CI 1.03-1.21). However, other biomarkers were positively associated with baseline volume and volume progression (LDL-C: OR 1.26, 95% CI: 1.19-1.33 and OR 1.22, 95% CI: 1.15-1.30, respectively), except HDL-C which was inversely associated. LDL-C, total cholesterol and non-HDL-C were inversely associated with baseline density. In participants <62 years of age, Lp(a) was modestly associated with baseline CAC volume (OR 1.10, 95% CI: 1.00-1.20) and volume progression (OR 1.16 95% CI: 1.04-1.30). CONCLUSIONS: In contrast to other lipid biomarkers, Lp(a) was not associated with baseline CAC volume or density and was only modestly associated with volume progression. Our findings suggest that Lp(a) is not as robustly associated with CAC as other lipid biomarkers.

Familial hypercholesterolemia in Southeast and East Asia.

Familial hypercholesterolemia (FH) is a relatively common autosomal dominant disorder associated with a significantly increased risk of coronary heart disease (CHD). Most (~85-90%) cases are due to pathogenic variants in the LDL-receptor gene (LDLR), while the remaining are due to pathogenic variants in the apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, though the proportion may vary depending on geographic location. Even though at least a quarter of the world's FH population lives in Southeast and East Asia, there are substantial gaps in knowledge regarding the epidemiology of FH due to low awareness, the absence of national screening programs, and limited availability of genetic testing. In this review, we discuss the most recent and relevant information available related to diagnostic criteria, prevalence, awareness, clinical characteristics, genetic epidemiology, and treatment in the FH population of Southeast and East Asia. Increasing awareness and improving the diagnosis and management of FH will reduce the burden of premature CHD in these regions of the world.

Proprotein convertase subtilisin/kexin type 9 inhibitor utilization and low-density lipoprotein-cholesterol control in familial hypercholesterolemia.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved in August 2015 as an adjunct to maximally tolerated statin treatment in those with familial hypercholesterolemia (FH). OBJECTIVE: To assess PCSK9 inhibitor utilization patterns and cholesterol control in the high-risk FH population. METHODS: This study was a retrospective analysis of a large administrative database that includes privately insured and Medicare Advantage patients. Individuals with diagnosis codes for FH from October 2016-September 2019 were identified. Differences in PCSK9 inhibitor utilization between various groups were evaluated using multivariable logistic regression. RESULTS: During the study period, 1:371 people enrolled in medical/pharmacy plans had a diagnosis of FH. While 62.5% (n = 33,649) had medication fills for statins (without PCSK9 inhibitors), only 2.0% (n = 1062) had medication fills for PCSK9 inhibitors (with or without other medications). Compared to men, women were more likely to be untreated (OR 1.23, 95% confidence interval (CI):1.18-1.28, p < 0.01) but more likely to be treated with PCSK9 inhibitors (OR 2.18, 95%CI:1.90-2.49, p < 0.01). Compared to those younger than 55 years of age, older individuals were more likely to be treated (OR 1.64, 95%CI:1.56-1.72, p < 0.01) but less likely to be treated with PCSK9 inhibitors (OR 0.40, 95%CI:0.34-0.47, p < 0.01). Lastly, those with household incomes ≥$40,000 were more likely to be treated with PCSK9 inhibitors than those with lower household incomes (OR 1.69, 95%CI:1.41-2.02, p < 0.01). CONCLUSION: PCSK9 inhibitor utilization in FH remains low. Significant differences exist based on demographic factors. Female sex, higher household incomes, and younger age were associated with increased PCSK9 inhibitor utilization.

Cost-effectiveness of cascade genetic testing for familial hypercholesterolemia in the United States: A simulation analysis.

Objective There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. Methods A simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. Results For 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. Conclusions Based on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.

The evaluation and management of patients with LDL-C ≥ 190 ​mg/dL in a large health care system.

OBJECTIVES: Patients with severe hyperlipidemia (low-density lipoprotein-cholesterol (LDL-C) ≥190 â€‹mg/dL) have a significantly increased risk of cardiovascular disease (CVD) and are more likely to have familial hypercholesterolemia (FH). We sought to determine how often health care providers recognize the implications of and adjust therapy for an LDL-C ≥190 â€‹mg/dL. METHODS: We conducted a retrospective review of patients with an LDL-C measurement in the medical record of a large health care system between November 2015 and June 2016. Patients were restricted to those with LDL-C ≥190 â€‹mg/dL and without secondary causes of dyslipidemia, with sensitivity analyses for those with LDL-C ≥220 â€‹mg/dL. RESULTS: Of 27,963 patients, 227 had LDL-C ≥190 â€‹mg/dL. Only 21% were on a statin at the time of LDL-C measurement. More than 90% had a follow-up clinic visit, but 41% had no change in treatment. FH was only included in the differential for 14%. The presence/absence of a family history of dyslipidemia, myocardial infarction, and premature CVD were documented in 26%, 29%, and 31%. Only 20.7% and 22.1% had documentation of the presence or absence of tendinous xanthomas or corneal arcus, respectively. Among those without prior specialist care (cardiologist or endocrinologist), only 13% were referred. These measures were only slightly better for those with LDL-C ≥220 â€‹mg/dL. CONCLUSION: In a large health care system, the possibility of FH was rarely acknowledged in those with residual LDL-C ≥190 â€‹mg/dL, few were referred to specialists, and therapeutic adjustments were suboptimal. Additional efforts are required to understand barriers to improving the evaluation and management of patients with LDL-C ≥190 â€‹mg/dL.

Identifying Familial Hypercholesterolemia Using a Blood Donor Screening Program With More Than 1 Million Volunteer Donors.

Importance: Familial hypercholesterolemia is an autosomal-dominant disorder that often causes premature coronary artery disease. Unfortunately, familial hypercholesterolemia remains largely undiagnosed. Objective: To estimate the prevalence of familial hypercholesterolemia in a population of blood donors. Design: This analysis of deidentified data from blood donors 16 years and older who donated to Carter BloodCare, one of the largest independent blood programs in the United States, between January 2002 and December 2016. Carter BloodCare, which serves a population of about 8 million in Texas, routinely measures total nonfasting serum cholesterol levels as part of a donor health screening program. Data analysis occurred from October 2017 to March 2019. Exposure: Blood donation. Main Outcomes and Measures: Familial hypercholesterolemia was defined using the Make Early Diagnosis to Prevent Early Death general population criteria, with total nonfasting serum cholesterol thresholds of 270, 290, 340, and 360 mg/dL for donors younger than 20 years, 20 to 29 years, 30 to 39 years, and 40 years or older, respectively (to convert cholesterol values to mmol/L, multiply by 0.0259). For repeated donors, the maximum observed total cholesterol level was used for analyses. Results: The study included 1 178 102 individual donors with a total of 3 038 420 blood donations. Of all individual donors (median total cholesterol level, 183 [interquartile range (IQR), 157-212] mg/dL; median age, 32 [IQR, 19-47] years; 619 583 [52.6%] women), a total of 3473 individuals (or 1 in every 339) met criteria for familial hypercholesterolemia. This group had a median (IQR) total cholesterol of 332 (297-377) mg/dL. Estimated prevalence was higher at younger ages (<30 years: 1:257) compared with older ages (≥30 years: 1:469; P < .001) and in men (1:327) compared with women (1:351; P = .03). Among 2219 repeated donors who met familial hypercholesterolemia criteria at least once, 3116 of 10 833 total donations (28.8%) met FH criteria. Conclusions and Relevance: The prevalence of familial hypercholesterolemia using the Make Early Diagnosis to Prevent Early Death criteria in a large cohort of blood donors was similar to the estimated prevalence of this disorder in the general population. The blood donor screening program could be a novel strategy to detect and notify individuals with potential familial hypercholesterolemia, particularly younger individuals in whom early detection and treatment is especially helpful, as well as guide cascade screening.