Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab) or with small-interfering RNAs (inclisiran) lowers plasma low-density lipoprotein cholesterol (LDL-C) levels, a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD).1,2 So far, the pharmacologic inhibition of PCSK9 presents with a favorable safety profile, but longer-term safety remains to be proven. Studies in preclinical models and in humans have suggested a potential link between PCSK9 deficiency and the risk of nonalcoholic fatty liver disease (NAFLD),3,4 a spectrum of progressive liver diseases ranging from simple steatosis to fibrosis that can lead to cirrhosis and hepatocellular carcinoma. Notably, it has been shown that PCSK9 knockout mice are more prone to develop severe hepatic steatosis and fibrosis when receiving a high-fat diet.3
Rimbert A, Smati S, Dijk W, Le May C, Cariou B. Genetic Inhibition of PCSK9 and Liver Function. JAMA Cardiol. 2021;6(3):353–354. doi:10.1001/jamacardio.2020.5341
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