medwireNews: The sodium-glucose cotransporter (SGLT)2 inhibitor dapagliflozin improves outcomes in patients with metabolic dysfunction-associated steatohepatitis (MASH), concludes the DEAN trial.
“Overall, our findings indicated that dapagliflozin may modulate key aspects of the pathophysiology of MASH, including steatohepatitis and fibrosis,” write Huijie Zhang (Southern Medical University, Guangzhou, China) and colleagues in The BMJ. But they add that “the mechanism of SGLT2 inhibitors on MASH is largely unknown and requires further research.”
The phase 3 trial enrolled adult patients from six hospitals in China with a score of 4 points or higher out of a possible 8 points on the nonalcoholic fatty liver disease activity score (NAS), where higher scores indicate more severe disease. Eligible patients had subscores of at least 1 point on all the components of NAS including steatosis, hepatocellular ballooning, and lobular inflammation, which range from 0 to 3 points, 0 to 2 points, and 0 to 3 points, respectively.
The researchers randomly assigned 154 participants to receive oral dapagliflozin 10 mg (n=78) or placebo (n=76) once daily for 48 weeks, alongside health education sessions semi-annually. The participants had undergone an initial liver biopsy within 6 months of entering the trial and another at week 48.
The mean age was 35.1 years, 85% of patients were men, and their mean BMI was 29.2 kg/m², and their mean NAS was 6.0 points. A third had mild fibrosis (stage F1), 45% had significant fibrosis (stage F2), and the remaining 19% had advanced fibrosis (stage F3). The majority (85%) had dyslipidemia, and 45% had type 2 diabetes.
At week 48, Zhang et al found that significantly more of the dapagliflozin group had achieved the primary endpoint of the trial – MASH improvement with no worsening of fibrosis – than the placebo group, at 53% versus 30% and a risk ratio (RR) of 1.73. MASH improvement was defined as at least a 2-point decrease in NAS or an NAS of 3 points or less, while worsening of liver fibrosis was defined as an increase in fibrosis stage.
The investigators also observed that the dapagliflozin group was significantly more likely than the placebo group to achieve the first and second confirmatory secondary endpoints of the study by week 48.
These were MASH resolution (hepatocellular ballooning score of 0 points and lobular inflammation score of 0–1 point) without worsening of fibrosis, with rates of 23% and 8%, respectively (RR=2.91), and fibrosis improvement without worsening of MASH, at 45% versus 20% (RR=2.25).
The results were similar when analyzing participants with F2 and F3 fibrosis and when stratifying by characteristics including metabolic factors and NAS.
Zhang and colleagues note that the dapagliflozin-treated patients had a significantly lower NAS than their placebo-treated counterparts at week 48, with a mean difference of −1.39 after adjusting for baseline NAS, diabetes status, and other factors.
Dapagliflozin was also associated with significant improvements in secondary liver endpoints including steatosis, ballooning, lobular inflammation, and fibrosis, with worsening of fibrosis at week 48 occurring in fewer dapagliflozin- than placebo-treated patients (5 vs 22%).
In addition, patients given dapagliflozin had significant improvements in secondary metabolic endpoints relative to the placebo group, both in patients with and without type 2 diabetes, including a reduction in body weight that the researchers say “was found to largely mediate the total effect of dapagliflozin on the higher proportion of MASH improvement and MASH resolution,” but not fibrosis improvement.
However, there was no significant difference in the quality of life between the two treatment arms, according to the Short-Form Health Survey.
The dapagliflozin group had a similar rate of adverse events (AEs) as the placebo group (56 vs 64%). The most common AEs, which were mostly mild, included COVID-19, insomnia, and gout. No serious AEs occurred in the dapagliflozin group, while one patient in the placebo group went to hospital due to diabetic ketoacidosis; there were no cases of cardiovascular disease events, cancer, severe hypoglycemia, or deaths.
The authors acknowledge limitations to the study, including the generalizability to populations outside of China, and the underrepresentation of women and older patients, noting that young men “may be more willing to accept liver biopsy at screening.”
In a related editorial, Leila Haddad and Sebastián Marciano, both at Hospital Italiano de Buenos Aires in Argentina, write that, “[g]iven the shared pathophysiological mechanisms linking [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.”
As therapeutic decisions are likely to become increasingly tailored to individual patient profiles, they conclude: “The coming years are expected to be particularly exciting in the field of pharmacological treatment for MASH.”
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BMJ 2025; 389: e083735
BMJ 2025; 389: r1101