A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

Abstract

To the Editor: The study by Fitzgerald et al. poses the question as to whether inclisiran is suitable for long-term treatment of hyperlipidemia. In contrast with PCSK9 antibodies, which target plasma PCSK9, inclisiran inhibits PCSK9 synthesis intracellularly. The high prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in obese patients with diabetes may warrant special consideration; perhaps inclisiran should be contraindicated in these patients.1 The involvement of PCSK9 in livercell metabolism goes beyond regulation of the LDL receptor and facilitates liver-cell regeneration after hepatic damage.2 PCSK9 also attenuates the expression of CD81,3 which has been implicated in hepatitis C and Plasmodium falciparum infections. Long-term hepatic silencing of PCSK9 expression by inclisiran may be worrisome in patients with hyperlipidemia in whom hepatic health is already challenged by NAFLD or NASH and in those living in regions in which the incidence of hepatitis C infection is high, such as in Central Asia and East Asia, North Africa, and the Middle East. In such settings, inclisiran may augment the risk of liver disease and could potentially lead to irreparable liver damage.