Novel tri-agonist confers significant gains for MASLD patients

In a substudy of a phase II obesity trial, individuals with MASLD* and obesity benefited significantly from retatrutide, a once-weekly, injectable, novel synthetic molecule that has shown potent agonist action at GIP**, GLP-1***, and glucagon receptors.

“Retatrutide treatment resulted in a substantial reduction in liver fat in MASLD patients,” said Dr Arun Sanyal from the Virginia Commonwealth University School of Medicine, Richmond, Virginia, US, at The Liver Meeting 2023.

Relative mean hepatic fat fraction changes were greater with all retatrutide doses compared with placebo at week 24, with the two highest doses (8 and 12 mg) rendering the greatest benefit (-81.4 percent and -82.4 percent vs 0.3 percent). For the 1- and 4-mg doses, the corresponding reductions were -42.9 percent and -57.0 percent. Comparisons between retatrutide and placebo yielded p-values of <0.001 across all retatrutide doses.

“Retatrutide was maxing out liver fat cleanup by week 24, which was sustained until week 48,” said Sanyal.

Secondary, exploratory, safety outcomes

Four retatrutide doses (1, 4, 8, and 12 mg) were compared against placebo. Of the 338 patients in the full study set, 98 comprised the MASLD subset (mean age 46.6 years, 53 percent female). Mean liver fat was higher across all retatrutide groups relative to the placebo arm (20.0 percent vs 15.6 percent). [The Liver Meeting 2023, abstract 148]

All participants on the two higher retatrutide doses achieved relative liver fat reduction of ≥30 percent, 95–100 percent achieved ≥50-percent reduction, while 80–86 percent achieved ≥70-percent reduction.

Between 79 and 86 percent of those on retatrutide 8 and 12 mg achieved liver fat content <5 percent by week 24. By week 48, these numbers rose to 89 and 93 percent, meaning that about 90 percent of participants on high-dose retatrutide had resolution of hepatic steatosis at this point. “This means that nine out of ten patients on the two higher retatrutide doses no longer met the criteria for steatotic liver disease by end of study,” Sanyal explained.

“Retatrutide doses ≥4 mg also improved insulin sensitivity, increased adiponectin, and reduced serum triglycerides and leptin,” he added.

Sanyal said that they wanted to ascertain “if there was a signal for liver toxicity because retatrutide had glucagon and glucagon can target the liver,” but none were seen in the full cohort. The overall safety profile of retatrutide was similar between the MASLD subset and the overall cohort. The most common adverse events were nausea, vomiting, and diarrhoea.

Waist, weight changes

Retatrutide also rendered significant dose-dependent reductions in visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) volumes relative to placebo at week 48. Again, the greatest reductions were observed with the 8- and 12-mg doses.

“The [ASAT and VAT] stores kept dropping, with almost 50-percent reduction with the two higher doses by week 48,” added Sanyal. The percent changes in ASAT volume with retatrutide 8 and 12 mg were -41.4 percent and -43.5 percent, respectively. In terms of VAT volume, the corresponding values were -48.3 percent and -44.5 percent. All comparisons against placebo were significant (p<0.001).

The VAT and ASAT volume reductions from baseline to week 48 corresponded to body weight reductions: those on high-dose retatrutide lost about a quarter of their body weight; the lower two doses rendered reductions between 9 and 16 percent.

Improved efficacy with tri-agonism

Preliminary evidence shows that agonists of the GIP, GLP-1, and glucagon receptors may have greater effects than mono or dual agonists in cutting liver fat in MASLD patients. The current study shows that the addition of glucagon agonism to GIP and/or GLP-1 agonism may improve efficacy in MASLD/MASH* patients. [J Hepatol 2020;73;S124; Contemp Clin Trials 2023;130:107176]

“The current pilot data, along with the weight loss findings from the main phase II trial, support further evaluation of retatrutide in individuals with histologically or more deeply phenotyped steatohepatitis and fibrosis,” said Sanyal.