FH genotype stratifies LDL-C–lowering response and improves diagnostic discrimination in severe hypercholesterolemia
J Bernhard, L Galli, I Undt, B Ruth, P Haider, C Hengstenberg, K A Krychtiuk, W S SpeidlAbstract
Introduction
Severe hypercholesterolemia encompasses a broad range of phenotypes and treatment responses. Whether lipid-lowering therapy (LLT) effectiveness differs in patients with versus without pathogenic heterozygous familial hypercholesterolemia (FH) variants is not well defined, and it is uncertain if response patterns can enhance identification of monogenic FH beyond clinical criteria.
Methods
In a cross-sectional study, we evaluated patients with severe hypercholesterolemia (untreated LDL-C >170mg/dl) referred for genetic testing at a tertiary lipid clinic. Individuals with a pathogenic or likely pathogenic mutation (ACMG > 3) were classified as mutation-positive (mut+), those without pathogenic mutations were classified as mutation-negative (mut-). We then compared untreated lipid levels and LDL-C changes achieved with predefined LLT regimens between these two groups. For each therapy value, we calculated an observed-to-expected (O/E) LDL-C–lowering ratio, quantified response variability within and between individuals, and used logistic regression to determine whether adding categorical or continuous O/E metrics improved discrimination of genetically confirmed FH beyond the Dutch Lipid Clinic Network (DLCN) score.
Results
Among 399 patients, 83 (20.8%) carried a pathogenic FH variant. Variant carriers had higher untreated LDL-C than non-carriers. Across LLT intensities, LDL-C reductions were consistently smaller in mutation-positive than mutation-negative patients, with the largest separation for high-intensity statin plus ezetimibe (59.2% vs 72.2% reduction; p<0.001). We found no significant genotype-potency interaction. Nonetheless, O/E ratios were generally lower and less variable among mutation-positive individuals. Incorporating O/E ratios - either as categorical groupings or continuous values - into the DLCN score significantly improved discrimination of genetically confirmed FH (AUC 0.68 to 0.76–0.79; p<0.001).
Conclusion
In severe hypercholesterolemia, pathogenic FH variant status is associated with higher baseline LDL-C and attenuated LDL-C lowering across multiple LLT regimens. Integrating individualized LDL-C response measures meaningfully improves identification of monogenic FH beyond clinical scoring alone.Figure 1:Difference in LLT ResponseFigure 2:Diagnostic performance