Research in context
Evidence before this study
We did a systematic search in PubMed for research articles published from inception to Feb 23, 2021, with no language restrictions. We included MeSH and free terms related to (“familial hypercholesterolaemia”) and (“registry”/“gender”/”sex”/“index case”), or variations of these terms thereof. We screened articles by title and abstract to identify relevant studies. Reference lists of eligible articles were also searched for additional studies. Articles that explored familial hypercholesterolaemia and registries to characterise familial hypercholesterolaemia and its burden, identification, and management were considered. We also reviewed the most recent guidelines and consensus statements on dyslipidaemias and familial hypercholesterolaemia.
In 2020, large meta-analyses showed that familial hypercholesterolaemia is a relatively common inherited condition, affecting about one in 300 individuals in the general population (approximately twice the prevalence historically estimated). Information on prevalence and burden of familial hypercholesterolaemia is scarce in many countries and regions. Low rates (<5–10%) of familial hypercholesterolaemia identification are consistently reported. Beyond opportunistic screening, family cascade screening and universal screening have been proposed; however, there is no consensus on the optimal strategy, and screening programmes are not widely implemented, with only few exceptions. Characterisation of index cases versus non-index cases could help inform optimal strategies, but information reported is insufficient. Familial hypercholesterolaemia increases the risk of (premature) cardiovascular disease, particularly of coronary disease, with data suggesting that outcomes could be prevented through early identification and intervention. However, undertreatment is consistently reported. Sex disparities in identification and management of familial hypercholesterolaemia have been suggested, but this requires additional characterisation.
Added value of this study
The Familial Hypercholesterolaemia Studies Collaboration provides an integrated approach to assess the global burden of familial hypercholesterolaemia by bringing together multiple sources and registries, which are standardised, harmonised, and merged into a single global Registry. The study included over 42 000 adults with heterozygous familial hypercholesterolaemia from 56 countries. Although familial hypercholesterolaemia occurs across all WHO regions, some regional variations exist. Familial hypercholesterolaemia is detected late, on average when individuals are in their 40s, with only about 40% of cases diagnosed before age 40 years. Prevalence of cardiovascular disease and cardiovascular risk factors increased with age of diagnosis, suggesting that late diagnosis potentially misses out on opportunities to address other future determinants of health in addition to LDL cholesterol. However, for non-index cases, who appeared to be diagnosed at an earlier age than index cases, the prevalence of cardiovascular disease and risk factors was lower, supporting the role of screening from index cases. Only 2·7% of patients receiving lipid-lowering medications achieved LDL cholesterol lower than 1·8 mmol/L, with low use of combination therapy. Goal attainment improved incrementally with the number of therapies used, particularly when including PCSK9 inhibitors. We observed important differences by sex, with implications for screening and treatment.
Implications of all the available evidence
Identification of familial hypercholesterolaemia needs to be improved to detect individuals affected much earlier in their life course. Greater use of combination therapy is probably required to improve familial hypercholesterolaemia management and reduce the gap between guideline recommendations and clinical practice. This point raises challenges about accessibility and cost, particularly in low-income and middle-income countries. Sex disparities in familial hypercholesterolaemia detection and management seem to be present, with potential implications for care and outcomes.