Inclisiran Response in a Patient With Familial Hypercholesterolemia After Suboptimal Response to Evolocumab.

backgroundThe discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) has transformed dyslipidemia management. Monoclonal antibodies (PCSK9 inhibitors [PCSK9i]) and small interfering RNA therapy (inclisiran) offer substantial low-density lipoprotein cholesterol reduction in patients intolerant of statins or those requiring intensification beyond conventional lipid-lowering therapy, including individuals with familial hypercholesterolemia. CASE SUMMARY: We report a 34-year-old woman with familial hypercholesterolemia due to a heterozygous LDLR mutation (Afrikaner-2 variant) who had inadequate response to evolocumab but subsequently responded well to inclisiran. DISCUSSION: To our knowledge, this is the second reported case of this phenomenon. Data from ORION-3 and real-world German cohorts show that inclisiran achieves a more modest low-density lipoprotein cholesterol reduction compared to PCSK9i, likely because it selectively suppresses hepatic PCSK9 synthesis, whereas PCSK9i also neutralize circulating PCSK9 from extrahepatic tissues. TAKE-HOME MESSAGE: This case underscores the importance of clinical persistence and highlights the need for further research into pharmacogenomic determinants of variable interindividual responses to therapy.