Key result
Pathogenic FH variants linked to ~13-point smaller LDL-C reductions on statin-ezetimibe therapy vs non-carriers.
Why the study?
In severe hypercholesterolemia, differences in lipid-lowering therapy effectiveness between patients with and without pathogenic heterozygous FH variants are poorly defined, and whether treatment response patterns can improve monogenic FH identification beyond clinical criteria remained uncertain.
Does pathogenic FH variant status affect LDL-C lowering response to lipid-lowering therapy, and does incorporating observed-to-expected LDL-C response ratios improve the diagnostic discrimination of monogenic FH beyond clinical criteria in patients with severe hypercholesterolemia?
Cross-Sectional (n=399)
No
Does pathogenic FH variant status affect LDL-C lowering response to lipid-lowering therapy, and does incorporating observed-to-expected LDL-C response ratios improve the diagnostic discrimination of monogenic FH beyond clinical criteria in patients with severe hypercholesterolemia?
In patients with severe hypercholesterolemia, carrying a pathogenic FH variant is associated with an attenuated LDL-C response to lipid-lowering therapy, and incorporating this treatment response metric into the DLCN score significantly improves the diagnostic identification of monogenic FH.
May warrant caution interpreting LDL-C response in suspected FH; leaves open whether genetic testing refines therapy selection.
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.
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Bernhard et al. (2026) conducted a cross-sectional in Severe hypercholesterolemia (n=399). Pathogenic or likely pathogenic FH mutation (mut+) vs. Mutation-negative (mut-) was evaluated on LDL-C reduction with high-intensity statin plus ezetimibe (p=<0.001). Pathogenic FH variant carriers had smaller LDL-C reductions with high-intensity statin plus ezetimibe vs non-carriers (59.2% vs 72.2%; p<0.001), and response ratios improved FH discrimination.
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