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Clinical Trial
. 2024 Mar 19;331(11):920-929.
doi: 10.1001/jama.2024.1215.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial

Tracey G Simon  1   2   3 , Robert M Wilechansky  1   2   4 , Stefania Stoyanova  4 , Alessandra Grossman  4 , Laura E Dichtel  2   5 , Georg M Lauer  2   4 , Karen K Miller  2   5 , Yujin Hoshida  6 , Kathleen E Corey  1   2   4 , Rohit Loomba  7 , Raymond T Chung  1   2   4 , Andrew T Chan  1   2   4
Affiliations
Clinical Trial

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial

Tracey G Simon et al. JAMA. .

Abstract

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.

Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.

Design, setting, and participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.

Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.

Main outcomes and measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.

Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.

Conclusions and relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.

Trial registration: ClinicalTrials.gov Identifier: NCT04031729.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Simon reported grants from Amgen outside the submitted work. Dr Dichtel reported nonfinancial support from Perspectum Diagnostics (services in-kind; scan analysis donation) and from Pfizer (study drug donation for National Institutes of Health [NIH]–funded trial); other (serving as a fellow through the Mass General Brigham Innovation Fellows Program but remaining a full-time employee of Mass General Brigham during the course of this educational program [October 1, 2022-September 30, 2024]) from Third Rock Ventures; grants from Lumos Pharma (investigator-initiated research support), Novo Nordisk (site primary investigator for phase 4 postmarketing study), Recordati (site primary investigator for phase 4 postmarketing study); and other (stock owner) from Marea Therapeutics outside the submitted work. Dr Miller reported grants (investigator-initiated grant to institution) from Amgen; nonfinancial support (study drug donation) from Amgen and Pfizer; other (small amount of personal stock) from GE, Boston Scientific, Bristol-Myers Squibb, and Becton-Dickinson outside the submitted work. Dr Corey reported personal fees from Theratechnologies, Intercept, and Medscape; and grants from Bristol-Myers Squibb and Novartis outside the submitted work. Dr Loomba reported other (consulting) from Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse Bio, Inipharma, Intercept, Inventiva, Ionis, Janssen, Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics; grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; and other (cofounder and stock options) from LipoNexus during the conduct of the study. Dr Chan reported being an American Cancer Society professor; grants from Pfizer and Freenome; and personal fees from Pfizer and Boehringer Ingelheim outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Screening, Randomization, and Treatment
aPrescreening for potential eligibility was conducted by the investigator team (see study protocol in Supplement 1). bCommon reasons for which patients declined to participate included lack of time or childcare concerns. For additional details regarding reasons for early trial discontinuation, see Results section and eTable 1 in Supplement 2. cThe full analysis set included all 80 randomized participants. dThe per-protocol analysis set included all 71 randomized participants who provided consent, were randomized, and who completed the 6-month visit assessments for study outcomes. There were no missing data in this set. MASLD indicates metabolic dysfunction–associated steatotic liver disease.
Figure 2.
Figure 2.. Effect of Daily Aspirin 81 mg Compared With Placebo on Hepatic Fat Fraction
Data in the center of each panel present individual participant changes in the absolute hepatic fat fraction (HFF) by magnetic resonance spectroscopy and by treatment group. Box plots indicate the median (thick horizontal line), mean (circle), IQR (box top and bottom), and maximum and minimum changes in HFF (whiskers). The orange box plots on the left side in each panel show within-group changes in the aspirin group; the blue box plots on the right side in each panel show within-group changes in the placebo group; the orange and blue box plots at the far right show between-group absolute changes between baseline and month 6.
See this image and copyright information in PMC

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