Overview of a collaborative global effort to address the burden of familial hypercholesterolaemia.

This is an overview of the EAS Familial Hypercholesterolaemia (FH) Studies Collaboration (FHSC) global consortium and registry (established 2015), which broadly addresses the global burden of FH. Eighty-seven National Lead Investigators from 74 countries form this expanding global consortium, and this global registry currently includes pooled data on 70,000 participants from participating countries to facilitate FH surveillance. Published first results from this global registry concluded that FH is diagnosed late, and management of LDL-cholesterol falls below guideline recommendations, and therefore earlier detection of FH and wider use of combination therapy is required. Further FHSC studies will follow on updated data including new countries, participants and variables, and non-DNA genetic information, and on the remaining cohorts in the registry. FHSC cross-sectional collaborative global studies are expected to promote FH detection earlier in life to subsequently initiate early lipid lowering therapy to reduce lifelong exposure to cumulative LDL-cholesterol thus reducing cardiovascular disease risk.

Paediatric familial hypercholesterolaemia screening in Europe: public policy background and recommendations.

Familial hypercholesterolaemia (FH) is under-recognized and under-treated in Europe leading to significantly higher risk for premature heart disease in those affected. As treatment beginning early in life is highly effective in preventing heart disease and cost-effective in these patients, screening for FH is crucial. It has therefore now been recognized by the European Commission Public Health Best Practice Portal as an effective strategy. Model programmes exist in Europe to identify young individuals with FH, which are based on cascade screening of first-degree relatives of affected individuals, universal screening for high cholesterol, opportunistic screening of high-risk individuals, or a combination of the above approaches. Recommendations presented herein to improve identification of FH emphasize that every country should have an FH screening programme. These programmes should be adapted from existing strategies to best fit the individual country's healthcare system, governments should provide financial support for these programmes and related care, and further research to optimize care and implementations should be conducted.

A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia.

BACKGROUND AND AIMS: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. METHODS: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. RESULTS: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). CONCLUSIONS: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.

Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. METHODS: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. RESULTS: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P=0.60; across World Health Organization regions where data were available, P=0.29; and between population-based and electronic health records-based studies, P=0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P<0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (I2>95%). Tests assessing bias were nonsignificant (P>0.3). CONCLUSIONS: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia?

PURPOSE OF REVIEW: This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice. RECENT FINDINGS: Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia. SUMMARY: Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.

American Heart Association's Cholesterol CarePlan as a Smartphone-Delivered Web App for Patients Prescribed Cholesterol-Lowering Medication: Protocol for an Observational Feasibility Study.

BACKGROUND: Adoption of healthy lifestyle and compliance with cholesterol-lowering medication reduces the risk of cardiovascular disease (CVD). The use of digital tools and mobile technology may be important for sustaining positive behavioral change. OBJECTIVE: The primary objective of this study is to evaluate the feasibility and acceptability of administering the Cholesterol CarePlan Web app developed by the American Heart Association aimed at improving lifestyle and medication adherence among patients prescribed cholesterol-lowering medication. The secondary objective is to assess the Web app's efficacy. METHODS: A prospective, observational feasibility study will be conducted to demonstrate whether the Web app may be successfully taken up by patients and will be associated with improved clinical and behavioral outcomes. The study will aim to recruit 180 study participants being prescribed cholesterol-lowering medication for at least 30 days across 14 general practices in London, England. Potentially eligible patients will be invited to use the Web app on a smartphone and visit general practice for three 20-minute clinical assessments of blood pressure, height, weight, smoking, and nonfasting cholesterol over 24 weeks. The feasibility of administering the Web app will be judged by recruitment and dropout statistics and the sociodemographic and comorbidity profile of consenting study participants, consenting nonparticipants, and all potentially eligible patients. Acceptability will be assessed using patients' readiness to embrace new technologies, the usability of the Web app, and patient satisfaction. The efficacy of the Web app will be assessed by changes in medication adherence and clinical risk factors by levels of the Web app compliance. RESULTS: This study is currently funded by the American Heart Association. Initial study recruitment will take place between February and July 2018 followed by patient follow-up. Patient level data will be obtained in January 2019. Data analysis will be completed by February 2019. Results will be submitted for publication in March 2019. CONCLUSIONS: The potential of an app to improve patients' lifestyle and management of cholesterol may inform the design of a randomized controlled trial and the delivery of more effective CVD prevention programs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/9017.