Assessment of LDL receptor-dependent lipid lowering therapies in patients with homozygous familial hypercholesterolemia according to functional genotype

BACKGROUND AND AIMS: Patients with homozygous familial hypercholesterolemia (HoFH) respond to standard lipid lowering therapy (LLT) poorly due to biallelic abnormalities affecting low-density lipoprotein receptor (LDLR) function. Relatively little information stratified by functional genotyping is available. METHODS: We evaluated lowering of low-density lipoprotein cholesterol (LDL-C) with statins, statins plus ezetimibe or add-on proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in 175 patients with HoFH according to LDLR functional genotyping (defective/defective = 119, defective/null = 38, null/null = 18). RESULTS: LLT resulted in significant LDL-C percent reductions in all 3 subgroups ranging from 17 ± 19 % (mean ± SD) in the null/null subgroup to 29 ± 21 % in the defective/defective subgroup. Achievement of ≥50 % LDL-C reduction was not seen in the null/null subgroup. Achievement of this plus LDL-C < 2.6 mmol/L was seen only in the defective/defective subgroup but rarely (2.5 %, 3/119 patients). While responses to statin plus ezetimibe and add-on PCSK9 inhibitors were progressively and significantly attenuated in the defective/null and null/null subgroups, there was no difference according to functional genotyping in the response to statins. All 3 subgroups showed mean LDL-C lowering in the range of 25-29 % in response to statins. CONCLUSIONS: LDLR-dependent LLT achieves significant LDL-C lowering in patients with HoFH which is modulated by functional genotyping except in the case of statins, possibly because of potential non-LDLR-dependent mechanisms of action. However, optimization of LDL-C remains rare and underscores the need for accessible and non-LDLR-dependent LDL-C lowering therapies.