AIMS: Pharmacotherapy for metabolic associated steatotic liver disease (MASLD) is reserved for steatohepatitis (MASH) with moderate Fibrosis Grades 2-3. Randomised controlled trials (RCT) of clinically available medications with biopsy data were evaluated for treatment benefits in steatohepatitis.
MATERIALS AND METHODS: PUBMED, Cochrane, and Scopus databases were searched for 'MASH/NASH/NAFLD/randomised-controlled trials/liver biopsy' (N = 848 publications) which provided 14 publications with biopsy data. Outcomes were changes in biopsy MASLD Activity Scores (MAS), Fibrosis Grades, resolution of MASH with no worsening of liver fibrosis (RSw/oF) or reduction =1 fibrosis stage with no worsening of steatohepatitis (RFw/oS). Meta-analyses and meta-regression analyses were performed.
RESULTS: There were 3173 subjects (age 53.1 ± 5.8 SD years). Steatohepatitis scores (MAS) improved with treatment versus placebo by mean difference (md) = -1.27 ± 0.16 SD Units, p < 0.001. MAS sub scores improved for steatosis, lobar inflammation, and ballooning for dapagliflozin, semaglutide, and pioglitazone (all p < 0.002). Fibrosis Grades improved compared to placebo (md = -0.352 ± 0.03 Units, p < 0.001). Relative rates (rr) of RSw/oF and RFw/oS were found with resmetirom, semaglutide, tirzepatide, and dapagliflozin (all p < 0.015). Changes in RSw/oF and RFw/oS inversely correlated with the baseline levels of Fibrosis Grades (p = 0.025, and p = 0.076 respectively), with greater improvements of both at lower Fibrosis Grades.
CONCLUSIONS: Clinically available medications are beneficial in reversing MASH. Improvements in RSw/oF and RFw/oS were greater at earlier stages of fibrosis. Future analyses of drug effects should include assessments adjusted for baseline study characteristics of Fibrosis Grades and may evaluate whether preventive therapy will have long term benefits if started at earlier stages of MASLD.
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Endocrine | |
| Internal Medicine | |
| Gastroenterology |  |
Important to note the larger benefits of treating at an earlier stage of steatohepatitis and fibrosis. Also notable evidence of reduction in actual fibrosis when starting at an earlier stage. Despite differences in baseline levels of both steatosis and fibrosis, the benefits of all these metabolically acting agents would support earlier use in persons who have diabetes with any degree of steatosis and favour requesting them for all MASH patients with elevated fib-4 levels even without a substantive degree of fibrosis on non-invasive testing such as elastography given the epidemic of MASLD. Careful patient selection and education is required and further evolution of generalist involvement is key. Limitations in level of evidence or head-to-head comparisons or the longer-term outcomes are outweighed by using pre-post biopsy comparisons and not just biochemical or imaging metrics. Dense but important analysis.
Not definitively relevant until research confirms clinical impact of improvements in staging; however, this does provide some data despite this uncertainty.
A dangerous paper as it pushes using drugs, some of which have been around for fatty liver disease for years, while underplaying the NEED for a MDT approach to the management of fatty liver disease. The focus is too narrow and too late in our understanding of MASLD /MAFLD /Met ALD.
Meta-analysis of MASLD/MASH treatment that is limited by the small number of studies for individual agents and its heterogeneity.
