Assessing the impact of PCSK9 inhibitors in steatotic liver disease: a prospective observational cohort study (SIMPLE)

Steatotic liver disease [SLD], characterised by an excess of triglyceride stored in hepatocytes, is an emerging global health challenge. The vast majority of SLD is a result of either metabolic dysfunction associated steatotic liver disease [MASLD], metabolic and alcohol related steatotic liver disease [MetALD] or alcohol related liver disease [ALD]. Whatever the underlying cause, SLD follows a common trajectory from simple steatosis through steatohepatitis and liver fibrosis to liver cirrhosis and hepatocellular carcinoma [HCC], in a minority of people. Treatment options in SLD are limited but multiple trials have shown the effectiveness of some existing drugs, used in the treatment of aspects of metabolic syndrome such as diabetes drugs [pioglitazone, GLP1-RA and SGLT2i], in improving histological features of MASLD. Treatments influencing normal cholesterol synthesis and lipid metabolism pathways have been targeted previously, with no apparent improvement in liver fibrosis.

Proprotein convertase subtilisin/kexin type-9 inhibitors [PCSK9i] (evolocumab, alirocumab, inclisiran) are drugs licensed for the treatment of hypercholesterolaemia, another aspect of the metabolic syndrome associated with SLD, however they may have other actions and benefits. PCSK9i have been shown to reduce liver steatosis (the hallmark of SLD) in a small number of studies. In addition, PCSK9i reduces cardiovascular risk and may reduce risk of malignancy (which are the most common causes of mortality in people with MASLD). Finally, alcohol excess increases PCSK9 levels and therefore there is a potential benefit of PCSK9i in steatosis associated with alcohol in MetALD and ALD. Therefore, PCSK9i may be an important therapeutic option for people with SLD. However, to date studies assessing the utility of PCSK9i in SLD have been in small numbers of people with MASLD only (not MetALD or ALD) and utilising non-invasive steatosis scores as outcomes.

This study aims to prospectively assess the impact of PCSK9i, being prescribed to people as part of their routine care, on liver steatosis, determined using transient elastography (Fibroscan) and non-invasive markers of liver steatosis and fibrosis.