Licogliflozin, a SGLT-1/2 Inhibitor, Shows Potential for Treatment of NASH

The sodium-glucose cotransporter 1/2 inhibitor at 150 mg was associated with a significant 32% reduction in liver enzyme levels in a phase 2a clinical trial.

Treatment with licogliflozin, a sodium-glucose cotransporter (SGLT)1/2 inhibitor, lowered serum alanine aminotransferase (ALT) levels by approximately 32% in patients with nonalcoholic steatohepatitis (NASH), according to findings from a phase 2a trial published online June 20, in Nature Medicine.

Led by Stephen Harrison, MD, a hepatologist and medical director at Pinnacle Clinical Research in San Antonio, the research team enrolled 107 adults (mean age 50 years, 55% women, ~20% with diabetes) with a histologic or phenotypic diagnosis of NASH. The participants were randomized in a 1:2:2 fashion to receive either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks.

The primary outcome measure for the study ( ID: NCT03205150) was change from baseline in ALT at 12 weeks; secondary outcomes included change from baseline in percent liver fat, body weight, and noninvasive markers of hepatic fibrosis; findings from the first are reported.

At 12 weeks of treatment Harrison et al found the higher dose of licogliflozin – 150 mg/day – resulted in a significant 32% (80% confidence interval (CI): 21–43%; P = 0.002) reduction in serum ALT versus placebo. Analysis found absolute reductions of 30.41 U/L for licogliflozin vs 8.77 U/L for placebo. The 30-mg dose did not reach the primary endpoint. Researchers also reported significant reductions with the SGLT1/2 inhibitor in aspartate aminotransferase and gamma-glutamyl transferase.

Harrison and coauthors found an average reduction in liver fat of 38.7% among licogliflozin-treated participants, a significantly greater reduction than seen with placebo, although at 21%, the investigators observe the latter to be an “unusually robust” response.

Diarrhea was the most frequent adverse event, reported by 76.7% of those in the licogliflozin 150 mg group versus 42.9% in the placebo group. Inhibition of SGLT-1 in the gut is likely the reason for the higher rate with the study drug, explain authors and they note that only 1 participant discontinued treatment because of diarrhea.

The team concludes, “Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of [sic] licogliflozin as a therapeutic option for NASH.”

Reference: Harrison S, Manghi FP, Smith WB, et al. Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Nat Med 2022; doi:10.1038/s41591-022-01861-9