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Daily low-dose aspirin reduced hepatic fat in patients with noncirrhotic metabolic dysfunction-associated steatotic liver disease (MASLD), a randomized phase II trial showed.

Among the 80 patients in the single-center study, 6 months of aspirin led to a 6.6% mean absolute reduction in liver fat content on magnetic resonance spectroscopy (MRS), as compared with a 3.6% increase with placebo (P=0.009), reported researchers led by Tracey Simon, MD, MPH, of Massachusetts General Hospital in Boston.

Given as a once-daily 81-mg dose, the aspirin was safe and well-tolerated during the short study period, they detailed in , with no bleeding events or drug-related serious adverse events (AEs).

For key secondary outcomes, 42.5% of the patients assigned to the intervention had at least a 30% reduction in liver fat versus 12.5% of those on placebo (P=0.006), and aspirin produced greater reductions in other measurements of hepatic fat content via MRS or MRI proton density fat fraction (PDFF) as well.

"MRI is well-established as an accepted measure for quantifying hepatic fat," wrote Simon and co-authors. "Reducing hepatic fat by 30 percentage points or more has been defined as a meaningful treatment effect in early-phase MASLD trials, based on substantial corresponding histological improvements in steatohepatitis and fibrosis" -- that latter two of which are endpoints used in late-stage trials, as FDA has indicated they are likely to predict clinical benefit in this patient population.

MASLD, formerly nonalcoholic fatty liver disease, is the most common cause of chronic liver disease and is defined by fatty infiltration of the hepatic tissue in the absence of excessive alcohol consumption. The condition is often associated with type 2 diabetes and hypertension, and up to a third of MASLD patients go on to develop progressive steatohepatitis and fibrosis, increasing their risk for cirrhosis, hepatocellular carcinoma (HCC), and liver-related death.

Simon and colleagues said the current results are preliminary and should be confirmed in larger trials that include histological and clinical outcomes and that investigate the optimal dosing and durability of aspirin's effect.

Treatments are lacking for the disease, the researchers noted, though just last week the FDA granted accelerated approval to the first-ever drug for a severe form of MASLD -- metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis.

Evaluating aspirin as a treatment for MASLD was supported by preclinical work, observational data, and a small nonrandomized trial that hinted at a potential benefit.

"In of steatohepatitis, platelets were the first cells to infiltrate the liver, promoting inflammation by activating Kupffer cells and releasing proinflammatory α-granules," explained Simon and co-authors. "In those models, aspirin reversed steatosis and necroinflammation, and prevented fibrosis and hepatocellular carcinoma through glycoprotein 1b α-mediated inhibition of platelet activation and immune cell signaling. Aspirin also exhibited anti-inflammatory and antitumor effects by inhibiting proinflammatory cyclooxygenase-2 and platelet-derived growth factor signaling, and it modulated bioactive lipids."

In the , researchers found that individuals with biopsy-proven MASLD who took aspirin daily had lower rates of progression to advanced fibrosis, HCC, and liver-related death.

The current was a double-blind randomized trial that assigned 80 adults with MASLD without cirrhosis at a single hospital in Boston in a 1:1 ratio to either low-dose aspirin (81 mg) or placebo once-daily for 6 months.

At baseline, participants had an average age of 48 years, 55% were women, and more than three-fourths were white. Patients had a mean body mass index of 33.4-34.0, while 39% had type 2 diabetes and 36% had hypertension. Patients' had an average liver fat content of 35%, which indicates moderate steatosis, and of those with a liver biopsy, 84% had steatohepatitis.

Other key secondary endpoints in the trial showed that low-dose aspirin led to significant reductions in relative liver fat content on MRS (-8.8 vs 30 percentage points, P=0.007), as well as in absolute liver fat content (-2.7% vs 0.9%, P=0.004) and relative liver fat content (-11.7 vs 15.7 percentage points, P=0.003) on MRI-PDFF.

In the 32 participants with significant stage 2 or greater fibrosis at baseline, aspirin led to an 11.7% reduction in mean absolute liver fat fraction, as compared with a 1.9% increase with placebo (P=0.03) and a relative 23.3-percentage point reduction in liver fat versus a 33-percentage point increase with placebo (P=0.02).

For other secondary endpoints, aspirin significantly reduced alanine transaminase and aspartate aminotransferase levels, corrected T1-estimated inflammation and fibrosis, and vibration-controlled transient elastography-estimated fibrosis. No significant differences were observed between groups when it came to changes in weight.

The AE rate was an identical 32.5% in the aspirin and placebo arms, with the most common AEs being upper respiratory tract infections (10.0% for each arm) and arthralgias (5.0% and 7.5%, respectively). One patient (2.5%) in the aspirin arm had drug-related heartburn, but none of the AEs met criteria for discontinuation.

The researchers noted that the analyses were adjusted for baseline values and that no minimal clinically important differences for outcomes were predefined. In their limitations, they cautioned that some baseline differences, including in liver fat measures, "may have introduced confounding and favored the aspirin intervention."

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