SGLT1/2 Inhibitor in NASH Improved Liver Biomarkers

BOSTON -- Licogliflozin, a sodium-glucose cotransporter (SGLT)1/2 inhibitor, was associated with improvements in biomarkers for liver health in patients with non-alcoholic steatohepatitis (NASH), and showed modest evidence of weight loss, a researcher said here.

Patients randomized to licogliflozin had a dose-dependent reduction in alanine transaminase (ALT) levels from baseline through week 12 compared with the placebo group, reported Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio.

Moreover, he noted a placebo-adjusted reduction in body weight at both doses of the drug of around 4% as a secondary outcome.

At a late-breaking presentation at the Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases, Harrison explained that earlier research found that licogliflozin led to "significant weight loss and favorable changes in metabolic parameters" in patients with type 2 diabetes and/or obesity.

One clinician commenter at the presentation pointed out that licogliflozin acts on the kidneys, not the liver, and asked if its effect was through weight loss.

"We know the effects of weight loss on diabetes and fatty liver," Harrison said. "By blocking gut absorption of glucose, upregulation of [glucagon-like peptide-1 and peptide YY, which are associated with anti-diabetic and anti-obesity actions] and downregulation of some mechanisms attributed to weight loss ... I think that plays a role. But as far as a direct effect on the liver as a result of this, I'm not sure we can tease that out in weight loss."

Amon Asgharpour, MD, of Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the research, characterized his response to the trial as "very optimistic, but very skeptical."

"Whenever you see body weight reduction, that's what gets me excited more than anything else," he told MedPage Today. "But these are short studies -- we need to look at long-term studies to see if it's durable. I've seen it a ton now -- where something looks fantastic, then you look at it long-term and it doesn't work or all the signals aren't there, as you'd hope."

The most recent high-profile SGLT1/2 dual inhibitor has arguably been sotagliflozin, which had been developed as an adjunct therapy to insulin for patients with type 1 diabetes, but after a split advisory committee meeting in Jan 2019, the FDA declined to approve the drug to treat type 1 diabetes in March 2019.

Harrison and colleagues outlined two criteria for study inclusion -- patients had to have either histologically confirmed NASH and an elevated alanine aminotransferase (ALT) level or a phenotypic diagnosis of NASH, based on ALT level, body mass index (BMI), and diagnosis of type 2 diabetes by hemoglobin A1c.

This interim analysis contained 110 patients -- 33 from a phase Ia trial to test futility (comparing the highest dose of licogliflozin with placebo) and an additional 44 completers from phase II (where 77 patients were randomized to either licogliflozin at 30 mg or 150 mg or placebo). There were 31 patients in the licogliflozin 150 mg group, 24 in the licogliflozin 30 group, and 16 placebo patients who completed their 12 week visit.

The mean age of patients ranged from 49 to 53, about 80-90% were Caucasian, and only 11-18% were women. BMI was about 35-36. Mean ALT and aspartate aminotransferase (AST) were higher in the 30 mg group, though Harrison noted that cohort was mainly enrolled later in "ex-U.S. sites."

Researchers saw a dose-response relationship with a drop in ALT compared with placebo, with similar findings for AST and gamma-glutamyl transferase. Notably, the 150 mg group had a significant reduction in liver fat content versus placebo.

Diarrhea was the most commonly reported adverse event. Harrison said that this is a known side effect associated with this drug, and that nearly all patients had mild grade 1 diarrhea. There was one serious adverse event reported due to gastroenteritis and a new diagnosis of cirrhosis in the placebo group, he noted, but overall there were no significant changes in cholesterol or triglycerides.

Asgharpour called ALT a "softer endpoint," but said it is "promising" that licogliflozin is reducing inflammation, and may hold potential as part of a combination therapy.

"We're realizing none of these drugs is a standalone drug, so if you have one that [shows] weight loss, improvement in diabetes, improvement in ALT/AST, it could definitely be one of the tools to use, perhaps in conjunction with something else," he said.

Harrison said that licogliflozin is currently being evaluated in the ELIVATE study along with tropifexor as combination therapy in patients with NASH and liver fibrosis, to help better define its role in the treatment of NASH.

Comment