LDL-C reduction and residual cardiovascular risk in heterozygous familial hypercholesterolemia: a matched cohort study in South Wales

Abstract Background Heterozygous familial hypercholesterolemia (HeFH) is characterized by lifelong elevated LDL-C and increased atherosclerotic cardiovascular disease (ASCVD) risk. While LDL-C reduction remains the cornerstone of treatment, many patients experience ASCVD events despite achieving substantial LDL reductions. Whether LDL-C lowering alone sufficiently reduces ASCVD risk or if additional factors contribute remains uncertain. This study evaluates LDL-C reduction and residual ASCVD risk in a genetically confirmed cohort of FH mutation-positive and mutation-negative individuals in South Wales. Methods This retrospective, matched-cohort study included 425 mutation-positive individuals (LDLR, APOB, or PCSK9) and 1,210 FH/M- relatives. The inclusion of first-degree relatives minimized selection bias, enabling a real-world genetic comparison. Lipid-lowering therapy was classified according to NHS guidelines. ASCVD events were defined as myocardial infarction (MI), stroke, coronary revascularization, or peripheral vascular disease (PVD). All analyses were adjusted for age at event or follow-up to account for ASCVD risk progression. Analysis: Kaplan-Meier survival analysis compared ASCVD-free survival between FH/M+ and FH/M-individuals, stratified by LDL-C reduction. Multivariable logistic regression assessed whether LDL-C reduction alone predicted ASCVD risk, adjusting for age,smoking, DM, mutation status, and lipid-lowering therapy. Results FH/M+individuals had significantly higher baseline LDL-C than mutation-negative relatives (p0.001), yet LDL-C reductions varied despite intensive therapy. Kaplan-Meier analysis showed that greater LDL-C reduction correlated with improved ASCVD-free survival (p0.001); however, substantial ASCVD events occurred despite LDL-C lowering. Logistic regression found that LDL-C reduction alone was not the strongest predictor of ASCVD: LDL-C reduction (per 1 mmol/L decrease): OR = 0.72, p = 0.002 High-intensity statin use: OR = 0.65, p = 0.01 Mutation status alone: No longer statistically significant after age correction (p = 0.12) Notably, even patients achieving ≥50% LDL-C reduction exhibited significant residual ASCVD risk, suggesting that LDL-C lowering alone does not fully mitigate cardiovascular risk. Further analysis of mutation subgroups (LDLR, APOB, PCSK9) revealed no significant differences in LDL response or ASCVD risk, reinforcing the need for additional risk markers. Conclusion This study provides strong evidence that LDL-C reduction alone is insufficient to eliminate ASCVD risk in FH patients. While lower LDL-C levels correlate with improved outcomes, persistent ASCVD events suggest additional contributors to risk. The findings highlight the need for a broader risk stratification approach beyond LDL-C.This study emphasizes the importance of refining risk prediction models and exploring novel lipid-lowering strategies to further reduce cardiovascular risk.Kaplan-Meire Curve for MACE free Matched LDL-C levels across mutation gro