REFERCHOL study of 2,979 heterozygous FH patients finds extreme Lp(a) confers cardiovascular risk equivalent to secondary prevention (J Clin Lipidol 2025)

Background: Extreme elevations in lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are both monogenic diseases associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). The identification of high Lp(a) risk thresholds would help to improve risk assessment in subjects with heterozygous FH (HeFH).

Objective: To find the Lp(a) value at which the observed 10-year ASCVD risk corresponds to a cardiovascular risk equivalent in a cohort of HeFH patients in primary cardiovascular prevention.

Methods: This multinational observational study used data from 3 prospective cohorts from France, UK, and Canada. A total of 2979 adult patients with HeFH in primary prevention diagnosed using genetic or clinical criteria (Dutch Lipid Clinic Network score ≥6) and 10,521 non-FH control participants in secondary cardiovascular prevention were included in the study. The 10-year risk of incident ASCVD was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models.

Results: The 90th percentile of Lp(a) in the group of FH subjects in primary prevention corresponds to ≥100 mg/dL (≥250 nmol/L). The observed 10-year risk of ASCVD associated with an Lp(a) ≥100 mg/dL (≥250 nmol/L) vs <100 mg/dL (<250 nmol/L) was 28.7% and 11.0%, respectively, compared to 34.9% in non-FH individuals in secondary cardiovascular prevention.

Conclusion: This study showed that 10% of HeFH in primary cardiovascular prevention have an extreme cardiovascular risk associated with the presence of a double monogenic dyslipidemia. These individuals should be treated more aggressively to prevent ASCVD and may greatly benefit from novel therapeutics targeting Lp(a).