Welcome to the EAS 2023 Interactive Program
The congress will officially run on CET time zone (Central European Time)
Introduction by chair (ID 1655)
O041 - SPATIAL IMPACT ON LIFE EXPECTANCY DOES NOT CORRECT FOR FAMILIAL HYPERCHOLESTEROLEMIA (ID 164)
Abstract
Background and Aims
After diagnosis, patients with familial hypercholesterolemia (FH) are advised lifelong cholesterol-lowering treatment. Although without trial evidence, we always propose to combine a healthy lifestyle with statins as the first line of therapy. The geographic variation of life expectancy in the Netherlands has enabled a trial by nature of the same untreated FH mutation in a beneficial and general environment.
Methods
We performed a nationwide cascade screening and obtained a large pedigree with the S306L mutation in the low-density lipoprotein receptor (LDLR ) gene. Before the statins became available in 1990, we determined the all-cause standardized mortality ratio (SMR). Patients and spouses were compared with Poisson regression (relative risk).
Results
Between 1800 and 1989, 147 deaths occurred in 14,152 person-years. Overall, the SMR was 1.25 (95% CI 1.05-1.46; P = 0.0056). The spouses in a beneficial environment had an SMR of 0.75 (95% CI 0.55-0.99; P =0.0547). The mortality in this beneficial environment was not increased (SMR 1.16; 95% CI 0.85-1.54 ; P =0.1794), while other parts confirmed the known overall excess mortality from untreated FH (SMR 1.29; 95% CI 1.05-1.57; P = 0.0076). However, the FH patients in the beneficial environment had 1.5 times more deaths relative to their spouses (RR 1.46; 95% CI 0.96-2.22; P =0.07388).
Conclusions
A favorable local environment decreased excess mortality significantly. However, the S306L mutation in the LDLR gene still caused the expected excess mortality locally. Our findings show that a beneficial lifestyle is an add-on but not an alternative for the immediate start of cholesterol-lowering treatment.
O042 - FGF-5 UNIQUELY IDENTIFIES SUBJECTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: RESULTS FROM A PROTEOMICS STUDY (ID 1231)
Abstract
Background and Aims
Targeted proteomics can identify subjects at high Atherosclerotic Cardiovascular Diseases (ACVD) risk in the general populations beyond the known risk factors. Familial Hypercholesterolemia (FH), is a genetically determined disease that exposes to a lifelong high burden of LDL cholesterol (LDL-C) resulting in premature cardiovascular disease. We aimed to address the question whether targeted proteomics could differentiate subjects with FH from the general population even with similar levels of LDL-C.
Methods
We compared the plasma relative abundance of 264 proteins (Proximity Extension Assay) in 133 heterozygous FH, in 586 normocholesterolemic subjects (“controls”) from the “PLIC” study cohort and in 55 subjects with high LDL cholesterol, but not diagnosed as FH, from the same population (LDL-C 190-220 mg/dL not on statins). A Machine Learning (ML) boosting prediction model identified the protein markers representative of FH (Random Forest classifiers).
Results
FGF-5 resulted as the most powerful plasma protein in differentiating FH subjects from the controls, with an excellent performance (Area Under the Curve (AUC)=0.995 (0.985-1.000); sensitivity=100%; specificity=99.54%; P<0.0001). Of note, FGF-5 also emerged as the top, unique, protein in differentiating FH subjects from subject with elevated LDL-C (AUC= 1.000 (0.914-1.000; sensitivity=100%, specificity=100% and P<0.001) also when matched with FH for plasma LDL-C levels.
Conclusions
Specific plasma proteomics markers allow a clear-cut identification of FH patients as compared to controls and the finding that FH proven subjects with relatively low LDL-C can be easily distinguished from non-FH with the same LDL-C strongly suggests that the LDL-C burden might be responsible for our findings.
O043 - GLOBAL PREVALENCE OF OVERWEIGHT AND OBESITY AMONG PAEDIATRIC AND ADULT PATIENTS WITH HOMOZYGOUS OR HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA, AND ASSOCIATION WITH CORONARY ARTERY DISEASE (ID 81)
Abstract
Background and Aims
Overweight and obesity are modifiable risk factors for coronary artery disease (CAD) in the general population, but their prevalence in patients with familial hypercholesterolaemia (FH) and whether they confer additional risk of CAD independent of LDL-cholesterol in FH is largely unknown.
Methods
Cross-sectional analysis on 35,919 patients across 46 countries, included in the EAS FH Studies Collaboration (FHSC) Registry. We assessed body mass index distribution (adults: underweight:<18.5, normal weight:18.5-<25.0, overweight:25.0-<30.0, obesity:≥30 kg/m2; children: z-scores) in patients with homozygous (HoFH; n=57 children/adolescents [<18 years], n=325 adults) or heterozygous FH (HeFH; n=6275 children/adolescents, n=29,262 adults), overall and by geographic region, and whether obesity was independently associated with CAD independent of LDL-cholesterol levels.
Results
Among patients with HoFH, 55% of adults and 25% of children were overweight or obese; corresponding proportions for HeFH were 52% and 27%; Figure-top. By region, prevalence of overweight/obesity was highest in Northern-Africa/Western-Asia. In HeFH and HoFH, CAD was more prevalent in patients with vs. without obesity; Figure-middle. After adjusting for age, sex, LDL-cholesterol and lipid-lowering medication, being obese vs. non-obese was associated with higher odds of CAD in patients with HeFH (OR, adults: 2.16 [95%CI: 1.97,2.36]; children/adolescents: 6.87 [1.55,30.46]), but not in patients with HoFH; Figure-bottom. Results remained similar after further adjustment for diabetes.
Conclusions
Obesity is independently associated with the presence of CAD in adults and children with HeFH, with similar trends in HoFH. In addition to LDL-cholesterol control, preventing and treating obesity are required to reduce the risk of CAD among those with FH.
O044 - EVOLOCUMAB TREATMENT IN PAEDIATRIC PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: DATA FROM THREE POOLED OPEN-LABEL STUDIES (ID 165)
Abstract
Background and Aims
Patients with homozygous familial hypercholesterolaemia (HoFH) have a premature, high risk for ASCVD, and treatment should be initiated as early as possible. We evaluated paediatric HoFH patients from three pooled trials to describe safety and efficacy of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor monoclonal antibody) and the relationship between LDL-C lowering and genetic mutations.
Methods
HoFH patients (aged 10-17 years) participated in the TAUSSIG, RAMAN, or HAUSER-OLE studies and received open-label subcutaneous evolocumab (420 mg QM or Q2W) with background lipid-lowering therapy for 12 to 260 weeks. Patients receiving lipoprotein apheresis (n=4) were analyzed separately. The primary endpoint for this analysis was TEAEs, analyzed per 100 patient-years. Efficacy endpoints were percent change in lipids at week 12 and LDL-C change by LDLR mutation type.
Results
Of 39 patients in the pooled analysis set, 69% were male, mean age was 13.5 (SD=1.8) years, and 82% had genotyped HoFH (Table). Overall, median (Q1, Q3) evolocumab exposure was 18.2 months (3.0, 18.5). TEAEs with exposure-adjusted incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%). The rate for serious TEAEs was 13.3%. At week 12, mean percent change from baseline LDL-C was –10.0% (SD=21.2) in non-apheresis patients, with high variability depending on residual LDLR activity (Figure).
Conclusions
In paediatric patients with HoFH, LDL-C reduction achieved during 12 weeks of PCSK9 inhibitor therapy was variable, depending on residual LDLR activity. However, several patients achieved a clinically meaningful reduction in LDL-C. Safety findings were consistent with previous studies of evolocumab.