SGLT2 Inhibitor Shows Promise as MASH Treatment

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Trial reported MASH and fibrosis improvements with dapagliflozin

by
Kristen Monaco, Senior Staff Writer, MedPage Today
June 4, 2025 • 3 min read

An SGLT2 inhibitor helped improve metabolic dysfunction-associated steatohepatitis (MASH) in people with or without type 2 diabetes, a randomized trial in China found.

In 154 adults with biopsy-diagnosed MASH, improvement without worsening fibrosis occurred in 53% of people treated with dapagliflozin (Farxiga) versus 30% on placebo (risk ratio [RR] 1.73, 95% CI 1.16-2.58, P=0.006), reported Huijie Zhang, MD, PhD, of Southern Medical University in China, and colleagues.

MASH resolution without worsening of fibrosis occurred in 23% of those on dapagliflozin and 8% of those on placebo (RR 2.91, 95% CI 1.22-6.97, P=0.01), while fibrosis improvement by at least one stage without worsening of MASH was reported in 45% versus 20%, respectively (RR 2.25, 95% CI 1.35-3.75, P=0.001), they wrote in The BMJ.

MASH improvement was defined as a decrease of at least 2 points in nonalcoholic fatty liver disease activity score (NAS) or a NAS of ≤3 points. Resolution of MASH was defined as a hepatocellular ballooning score of 0 and lobular inflammation score of 0 or 1.

“Our findings indicate that dapagliflozin may affect key aspects of MASH by improving both steatohepatitis and fibrosis,” Zhang and co-authors wrote.

Therapeutic options for MASH are limited, they noted, despite the condition affecting more than 5% of adults and over 30% of individuals with diabetes or obesity.

Currently, the only approved treatment for MASH on the market is the thyroid hormone receptor β agonist resmetirom (Rezdiffra), said accompanying editorial authors Leila Haddad, MD, and Sebastián Marciano, MD, MSc, both of Hospital Italiano de Buenos Aires in Argentina.

Along with dapagliflozin, which holds indications for type 2 diabetes, heart failure, and chronic kidney disease, the GLP-1 receptor agonist semaglutide (Ozempic, Wegovy) has also shown improvements in liver histology in a phase III trial, Haddad and Marciano noted.

“For the outcome of MASH resolution without worsening fibrosis, the absolute differences in response rates versus placebo were 15% for dapagliflozin, 29% for semaglutide, and 20% for resmetirom,” the editorialists wrote. “For fibrosis improvement without worsening of steatohepatitis, the corresponding differences were 25% for dapagliflozin, 14% for semaglutide, and 12% for resmetirom.”

However, Haddad and Marciano pointed out that the dapagliflozin trial included younger patients who were predominantly male and of Asian descent, with a lower body mass index (BMI), a lower prevalence of type 2 diabetes, and less fibrosis than participants in the resmetirom and semaglutide trials.

“The coming years are expected to be particularly exciting in the field of pharmacological treatment for MASH,” said Haddad and Marciano. “As more drugs become available, therapeutic decisions will likely become increasingly tailored to individual patient profiles. Given the shared pathophysiological mechanisms linking MASLD [metabolic dysfunction-associated steatotic liver disease], type 2 diabetes, and obesity, particularly insulin resistance and lipotoxicity, identifying therapeutic drugs capable of improving overall metabolic control while also targeting liver disease remains a key goal.”

For the double-blind study, Zhang’s group recruited participants from six tertiary hospitals in China from November 2018 to March 2023. The 154 adults were randomized to receive 10 mg orally of dapagliflozin or matching placebo once daily for 48 weeks.

Average age was 35.1, 85% were male, and BMI was 29.2. Most (85%) had dyslipidemia and 45% had type 2 diabetes. A third had stage F1 fibrosis, 45% had stage F2, and 19% had stage F3. Main study results were consistent across people with the higher stages of fibrosis.

At baseline, average NAS was 6. After 48 weeks, dapagliflozin treated patients had an average 1.39-point lower NAS than the placebo group after adjusting for the diabetes status, baseline value, the intervention group, follow-up time, and the group-time interaction.

Dapagliflozin was also associated with reductions in liver steatosis and stiffness assessed by FibroScan, improvement in liver enzymes including γ-glutamyl transferase, and reductions in each subcomponent of histological features, including steatosis, ballooning, lobular inflammation, and fibrosis.

Worsening of fibrosis occurred in 5% in the dapagliflozin group and 22% of the placebo group. “Fibrosis is the most important prognosis factor in people with MASH, so that fibrosis regression is considered to improve long term clinical benefit for MASH progression (i.e., cirrhosis and hepatocellular carcinoma),” the researchers pointed out.

Common adverse events were COVID-19, insomnia, and gout. There were no serious adverse events in the dapagliflozin group. The proportion of participants who stopped treatment because of adverse events was 1% with dapagliflozin and 3% with placebo.