OBJECTIVES: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) from birth and early cardiovascular disease (CVD) onset. However, quantitative assessment of the association between FH and CVD risk has not been reported. We performed a systematic literature review (SLR) and meta-analysis of observational studies to quantify the association between FH and risk of CVD.

METHODS: MEDLINE and EMBASE databases were searched through June 2022, along with reference scrutiny of relevant articles, to identify studies that include any measure of CVD risk (risk ratio (RR), odds ratio (OR), hazard ratio (HR), or ratios of incidence, mortality, and morbidity) in FH patients. Hazard ratio (HR) and 95% confidence interval (CI) were pooled using a random effect model. Quality assessment of studies was conducted using the modified Newcastle-Ottawa tool.

RESULTS: Twenty-five studies, comparing FH patients versus non-FH patients, met the inclusion criteria. Across these studies, the RR (95% CI) for CVD ranged from 3.0 (2.2-4.1) to 8.5 (5.3-13.8), HR (95% CI) ranged from 1.3 (1.0-1.5) to 8.7 (4.8-15.8), and OR (95% CI) ranged from 1.5 (0.8-2.8) to 13.2 (10.6-17.4). The risk of CVD was markedly high in men and in patients younger than 40 years. Out of 25 studies, 12 studies were meta-analyzed. Pooling of individual risk estimates showed a significant association between FH and risk of CVD (HR 1.72; 95% CI 1.35-2.19; p<0.00001; I²=97%). The overall risk of bias was deemed low across the included studies.

CONCLUSIONS: The current meta-analysis suggests that FH significantly increases CVD risk. Consequently, patients with FH should be routinely screened for CVD. Age and sex also appeared to have an impact on CVD risk in FH patients. Further studies are needed to determine how these factors interact with FH to influence the risk of CVD.