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

The 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.

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.

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.

This case underscores the importance of clinical persistence and highlights the need for further research into pharmacogenomic determinants of variable interindividual responses to therapy.