Clinical impact of early vs. late treatment in familial hypercholesterolaemia: a systematic review

Background

Familial hypercholesterolaemia (FH) is an inherited condition characterised by very high lifelong levels of low-density lipoprotein cholesterol (LDL-C), leading to an increased risk of atherosclerotic cardiovascular disease (ASCVD). FH has a high prevalence yet is underdiagnosed. Unless detected by cascade testing or opportunistically, FH is commonly only identified after a cardiovascular (CV) event. To inform decision-making on preventive public health measures for FH in Ireland, and given a lack of direct universal screening evidence in children, a systematic review of the clinical effectiveness and safety of early compared with late diagnosis and or treatment was undertaken.

Methods

Electronic searches were conducted in November 2025 across seven databases, from inception with no language restrictions, supplemented by grey literature searches. Outcomes of interest were morbidity, mortality, surrogate markers, quality of life. Screening, data extraction and quality appraisal were performed independently by two reviewers.

Reviewers

Of 7,758 records identified and 299 full texts screened, 12 observational studies met the inclusion criteria. Heterogeneity in defining early versus late treatment limited comparability between studies. Studies reported that earlier diagnosis and treatment was associated with improved clinical outcomes such as a reduced risk of ASCVD and probability of, or death from, a major CV event. Studies reported that treatment in childhood was protective against ASCVD events and or death compared with later treatment as an adult. Studies identified a positive association between surrogate outcomes in children, such as thinner carotid intima media thickness and lower cumulative LDL-C exposure, and earlier treatment.

Conclusions

The direction of effect across multiple studies suggests that earlier diagnosis and or treatment of FH is associated with improved surrogate outcomes in children and improved CV outcomes in adulthood.

Key messages

• Evidence suggests that earlier diagnosis and or treatment of FH, as a proxy for screening evidence, is associated with improved surrogate outcomes in children and cardiovascular outcomes in adults.

• There was substantial heterogeneity in the study contexts and the applied definition of early versus late diagnosis or treatment, limiting comparability between studies.