Liver Fat Reduction Varied Across Pharmacologic Treatments for MASH

Reducing liver fat has become a central target in the development of therapies for metabolic dysfunction–associated steatohepatitis (MASH), particularly as drug developers and regulators look for reliable noninvasive markers that may predict histologic response.¹

A new network meta-analysis suggested that several investigational and established agents differed meaningfully in their ability to lower hepatic fat as measured by MRI proton-density fat fraction (MRI-PDFF), a surrogate increasingly used in MASH clinical trials.

MASH, the inflammatory and progressive form of metabolic dysfunction–associated steatotic liver disease (MASLD), has been linked to rising rates of cirrhosis, hepatocellular carcinoma, and liver transplantation worldwide.² Although liver biopsy remains the diagnostic gold standard, its invasiveness and sampling variability have limited its routine use in clinical trials. As a result, MRI-PDFF has emerged as a validated, noninvasive tool for quantifying hepatic steatosis, with prior studies showing that a 30% relative decline in MRI-PDFF is associated with MASH resolution.¹

To better understand how pharmacologic agents compare on this imaging-based end point, investigators conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating therapies for MASH. The analysis included 39 trials enrolling 3311 adults with biopsy-proven or MRI-confirmed MASH and compared 41 pharmacologic interventions. Trials were identified through searches of MEDLINE and Embase from inception through December 26, 2023.

The primary outcome was absolute change in MRI-PDFF, and the secondary outcome was achievement of at least a 30% relative decline in MRI-PDFF. Treatments were ranked using surface under the cumulative ranking curve (SUCRA) scores, which estimate the probability that an intervention is among the most effective options.

Across studies, participants had a mean age of approximately 53 years, and just under half were male. Most trials were assessed as having a low risk of bias, although the authors noted that publication bias could not be formally evaluated because many drug comparisons were informed by single studies.

At 24 weeks, aldafermin, pegozafermin, and pioglitazone ranked highest for reducing liver fat content. Aldafermin demonstrated the largest absolute reduction in MRI-PDFF compared with placebo (log mean difference, −6.64; credible interval [CrI], −8.64 to −4.64), followed closely by pegozafermin (−6.60; CrI, −8.53 to −4.65). Pioglitazone was also associated with a significant reduction (−4.30; CrI, −5.88 to −2.71). By contrast, colesevelam and sitagliptin were associated with increases in MRI-PDFF relative to placebo.

When the outcome was defined as achieving at least a 30% decline in MRI-PDFF at 24 weeks, efinopegdutide ranked highest, followed by semaglutide combined with firsocostat and pegbelfermin. Combination therapies generally performed favorably in longer-term analyses, particularly at 48 weeks, where regimens pairing metabolic and antifibrotic mechanisms showed greater reductions in liver fat than monotherapy.

Shorter-term results at 12 weeks also highlighted differences among agents. Efruxifermin, aldafermin, and pegozafermin ranked highest for absolute MRI-PDFF reduction, and pegozafermin had the greatest likelihood of achieving a 30% relative decline at that time point.

According to the authors, the findings help contextualize a rapidly expanding therapeutic landscape. “This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat,” they wrote, adding that the results “may help inform the design and sample size calculation of future clinical trials and assist selection of combination therapy.”

The investigators emphasized that the analysis was not intended to establish clinical superiority or predict regulatory success. They noted that most included trials were early-phase studies, with limited head-to-head comparisons and relatively small sample sizes. In addition, many trials were conducted in the US, potentially limiting generalizability to other populations.

The authors also cautioned that improvements in MRI-PDFF do not always translate directly into fibrosis regression or long-term clinical benefit. “Changes in hepatic fat based on MRI-PDFF do not always correlate with the success of the drug in gaining FDA approval or in clinical practice,” they wrote, underscoring the multifactorial nature of MASH progression.

Still, the analysis reinforces MRI-PDFF as a useful tool for comparing therapeutic effects across trials and for informing combination strategies as the MASH pipeline continues to mature. For payers and clinicians, the results offer a structured view of how different mechanisms may perform on a shared, noninvasive end point while highlighting the need for longer-term outcomes tied to fibrosis and clinical events.

References

1. Koh B, Xiao J, Ng CH, et al. Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: Systematic review and network meta-analysis. Hepatology. 2026;83(1):117-126. doi:10.1097/HEP.0000000000001028

2. Huang DQ, Terrault NA, Tacke F, et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20(6):388-398. doi:10.1038/s41575-023-00759-2