Steatotic liver disease (SLD) includes a set of diseases where fat, inflammation, and scar-tissue builds-up in the liver. SLD can lead to severe disease and death. No medical treatment is available for the most common forms of SLD, metabolic SLD and alcohol related SLD. Thus, there is a great need for new treatments that can help these patients.
The aim of this feasibility study is to understand more about the severe diseases and deaths seen in SLD. This knowledge will be used to use improve clinical trials where new treatments for SLD are tested.
In clinical practice, SLD is often diagnosed after findings from liver function tests and clinical evaluations. We will therefore define our SLD population as patients with alanine transaminase and platelets recorded in CPRD AURUM. These two tests are commonly used to measure liver function among general practitioners in England. We will add information on obesity, blood sugar, blood pressure, blood lipids, alcohol, and other liver diseases to classify SLD into metabolic SLD and alcohol related SLD.
In patients with the two liver function tests recorded, we will study the occurrence of severe liver disease, severe heart disease and deaths. The occurrence will also be studied in the metabolic SLD and the alcohol related SLD, and in different age and ethnicity groups.
The study results will help us to improve the clinical trials where new treatments for SLD are tested. Better trials increase the chance of finding a treatment for people with SLD.
Steatotic liver disease (SLD) includes a spectrum of liver diseases classified according to aetiology. Progression of SLD increases the risk of severe clinical outcomes and death. No pharmacotherapy is approved for the most common forms of SLD, metabolic SLD (MASLD) and alcohol related SLD (ALD), and there is a significant unmet need for treating these conditions. Regulatory authorities require outcomes trials for approval of new treatments in MASLD/ALD. The aim of this feasibility study is to gain insights about outcome-events in MASLD/ALD to inform planning/design of clinical trials where new treatments for MASLD/ALD are investigated.
Biopsy-confirmed liver fibrosis predicts clinical outcomes in SLD and is often mandated as inclusion-criteria in trials. Biopsies are not performed in routine clinical practice where SLD is often diagnosed after findings from liver function tests (aminotransferases, GGT, platelets) and clinical evaluations.
We will define our SLD-population as patients with alanine transaminase (ALT) and platelets recorded in CPRD AURUM, as these are commonly used to measure liver function among general practitioners in England. We will add information on metabolic risk factors (anthropometry, blood glucose/diabetes, blood pressure, cholesterols, lipids), alcohol consumption and other liver diseases (autoimmune/viral/biliary/drug-induced) to classify SLD into MASLD/ALD and use fibrosis-4-index as indicator of fibrosis.
In the SLD-population with ALT and platelets, we will investigate occurrence of liver events, CV events, and all-cause mortality by calculating incidence rates and Aalen-Johannsen cumulative incidences. Occurrence will also be investigated in MASLD/ALD subpopulations, according to fibrosis-4-index and factors as age, sex, ethnicity, and socio-demography.
Linkage is used to capture outcome-events (Hospital Episode Statistics/Office for National Statistics) and ethnicity/socio-demography (Practice/Patient Level Index of Multiple Deprivation data/CPRD AURUM Ethnicity Record).
The study will improve planning of new MASLD/ALD trials increasing the likelihood of finding treatments for people with MASLD/ALD, which improves healthcare for many patients with significant unmet needs.
Severe liver events defined as a composite endpoint of; liver mortality; hepatocellular carcinoma; liver transplant; chronic liver failure; liver cirrhosis; portal hypertension; jaundice; and decompensated liver events (ascites; transjugular intrahepatic portal shunt; hepatorenal syndrome; hepatic encephalopathy; gastro-oesophageal varices with/without bleeding). Components may also be investigated individually.
Severe cardiovascular events defined as a composite endpoint of; cardiovascular mortality; stroke; acute myocardial infarction; unstable angina; heart failure; coronary revascularisation. Components may also be investigated individually.
All-cause mortality
Tina Landsvig Berentzen - Chief Investigator - Novo Nordisk A/S
Tina Landsvig Berentzen - Corresponding Applicant - Novo Nordisk A/S
Katrine Grau - Collaborator - Novo Nordisk A/S
Mads Jeppe Tarp-Johansen - Collaborator - Novo Nordisk A/S
Mette Skalshøi Kjær - Collaborator - Novo Nordisk A/S
Michelle Long - Collaborator - Novo Nordisk Denmark A/S
Sune Boris Nygård - Collaborator - Novo Nordisk A/S
Timothy Stone - Collaborator - Novo Nordisk A/S
HES Accident and Emergency;HES Admitted Patient Care;HES Diagnostic Imaging Dataset;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;CPRD Aurum Ethnicity Record;Practice Level Index of Multiple Deprivation (Standard)