Diabetes drug dapagliflozin shows benefits for MASH in Phase 3 trial
Treatment associated with reductions in liver fat and stiffness
Daily treatment with the diabetes medication dapagliflozin eased disease severity for people with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease, in a Phase 3 clinical trial. Benefits included reductions in liver fat and scarring.
“These results support the potential for dapagliflozin to provide benefit to patients with MASH and liver fibrosis [scarring],” researchers wrote. “Large scale and long term trials are needed to further confirm these effects.”
The trial results were detailed in a study, titled “Effect of dapagliflozin on metabolic dysfunction-associated steatohepatitis: multicentre, double blind, randomised, placebo controlled trial,” which was recently published in the British Medical Journal.
MASH is a serious form of fatty liver disease where excessive fat accumulation in the liver gives rise to inflammation and fibrosis that can eventually cause serious liver damage.
The disease generally occurs in the context of cardiometabolic risk factors such as obesity or type 2 diabetes, which is marked by persistently high blood sugar (glucose) levels. Treatment has traditionally consisted of lifestyle changes aimed at promoting weight loss and reducing associated cardiometabolic risk factors.
Trial tests safety, efficacy of dapagliflozin in adults with MASH
Dapagliflozin belongs to a class of oral medications called sodium-glucose cotransporter 2 (SGLT-2) inhibitors that are widely used to treat type 2 diabetes, as well as for reducing the risk of complications in people with heart failure and chronic kidney disease. It’s sold in the U.S. under the brand name Farxiga.
As the name suggests, SGLT-2 inhibitors block SGLT-2, a protein found in the kidneys that normally helps reabsorb glucose back into the bloodstream. In doing so, they facilitate glucose excretion in the urine and help lower blood sugar levels.
Studies have shown these medications also reduce liver fat, help normalize liver enzymes (which are a marker of liver damage), and lower liver stiffness — an indicator of fibrosis — making them of interest for treating fatty liver disease. Still, their exact benefits in people with MASH are not fully established.
The multicenter Phase 3 DEAN trial (NCT03723252) was designed to test the safety and efficacy of dapagliflozin in adults with biopsy-confirmed MASH, with or without type 2 diabetes. It enrolled 154 participants in China (85% men) who were randomly assigned to receive either dapagliflozin (10 mg) or a placebo once daily for 48 weeks, or nearly a year.
These participants had a mean age of 35.1, and 45% of them had type 2 diabetes. Nearly all had at least mild liver fibrosis.
Reductions seen in body weight, waist circumference, abdominal fat
The study’s main goal was to evaluate the proportion of participants who achieved a MASH improvement, a reduction in MASH severity, without worsening liver fibrosis at week 48.
This was achieved by a significantly higher proportion of people on dapagliflozin compared with those on the placebo group (53% vs. 30%), meeting the main goal.
Several confirmatory secondary goals were also met, with significantly more dapagliflozin-treated people achieving MASH resolution without fibrosis worsening (23% vs. 8% of those on the placebo) and fibrosis reduction without MASH worsening (45% vs. 20%).
Such improvements are “consistent with the [outcome goals] that the US Food and Drug Administration (FDA) proposed as reasonably likely to predict long term clinical benefit for MASH,” the scientists wrote.
These benefits were also observed in the subgroup of participants with moderate or severe liver scarring, as well as regardless of MASH severity at the study’s start and the presence of diabetes or obesity.
Overall, our findings indicated that dapagliflozin may modulate key aspects of the [disease processes] of MASH.
Other secondary goals, related to disease severity and liver fibrosis, also tended to favor dapagliflozin over the placebo. Fibrosis worsening occurred in 5% of the dapagliflozin group and 22% of the placebo group, while the proportion of participants with both MASH resolution and fibrosis reduction was 21% with dapagliflozin and 1% with the placebo.
Dapagliflozin treatment was also associated with reductions in liver fat and stiffness, as well as in blood levels of liver enzymes, compared with the placebo. Metabolic factors linked to MASH were similarly improved, including reductions in body weight, waist circumference, and abdominal fat, as well as improvements in indicators of blood sugar and fats in the blood.
“Overall, our findings indicated that dapagliflozin may modulate key aspects of the [disease processes] of MASH,” the researchers wrote.
Additional analyses suggested the effects of dapagliflozin on MASH reductions or resolution — but not on fibrosis lessening — could be largely explained by weight loss. However, exactly how SGLT2 inhibitors ease features of MASH is “largely unknown and requires further research,” the researchers wrote.
The most common side effects included COVID-19 infection, insomnia, and gout, a type of inflammatory arthritis that’s common in people with diabetes. The occurrence of adverse events known to be linked to SGLT-2 inhibitors were generally mild and similar between the two groups.
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