‘Triple-G’ obesity drug also targets NAFLD in phase II trial

In a subanalysis of a phase II trial on obesity, retatrutide, a triagonist of GIP*, GLP**, and glucagon receptors, also demonstrated multiple favourable signals for nonalcoholic fatty liver disease (NAFLD).

“[In this substudy, we] put into perspective what it means for the obese patient to receive retatrutide in terms of liver health,” said Dr Arun Sanyal from the Virginia Commonwealth University School of Medicine, Richmond, Virginia, US, at ADA 2023.

Sanyal and colleagues sought to evaluate the efficacy of once-weekly retatrutide in a subset of participants from the parent study (n=338) who had NAFLD (n=98; mean age 46.6 years, 53 percent male). The substudy had four active arms representing four retatrutide doses (1, 4, 8, and 12 mg) and a placebo arm. Those on retatrutide 4, 8, and 12 mg initially received 2 or 4 mg Q4W. The doses were uptitrated up to week 12. The initial-dose subgroups were pooled for this analysis due to the small sample size.

 

Relative liver fat reduction

At week 24, there was a stepwise, dose-dependent reduction in relative liver fat with retatrutide. Mean relative liver fat reduction was >80 percent for the two highest retatrutide doses (p<0.001 for both). This was sustained at week 48 (relative mean hepatic fat fraction change, –82 percent [8 mg] and –86 percent [12 mg]; p<0.001 for both).

All patients receiving the two highest retatrutide doses achieved relative liver fat reduction of ≥30 percent. “This is the threshold [denoting that a patient is] likely to be clear of steatohepatitis,” Sanyal explained.

The numbers were similar in terms of the fraction of participants achieving liver fat reduction of ≥50 percent with retatrutide 8 and 12 mg (95 percent and 100 percent, respectively). Although the figures dropped when looking at those achieving liver fat reduction of ≥70 percent, it is “still very high considering that these are in the 80–86 percent range. This is still remarkable,” Sanyal said.

 

Resolution of disease

“Even more remarkable is resolution of the disease, and that is when liver fat drops below 5 percent. This is what we saw at [weeks 24 and 48],” said Sanyal.

At week 24, 79 percent of patients on retatrutide 8 mg had complete resolution of NAFLD, escalating to 89 percent at week 48 (p<0.001 for both timepoints). The corresponding percentages were higher with the 12-mg dose (86 percent and 93 percent; p<0.001 for both).

Sanyal highlighted the importance of the 5-percent mark. “A patient is only considered to have NAFLD when liver fat exceeds 5 percent. Therefore, achieving <5 percent of liver fat means the fatty liver has resolved.”

 

Other endpoints

There were no hepatotoxicity signals in the main study cohort based on the eDISH plot. “Both ALT*** and bilirubin were low in this plot,” said Sanyal. There were a few patients who had ALT excursions, but these all came down, he continued. The plot showed no signal for drug-induced liver injury. “Therefore, retatrutide is very safe from a hepatic perspective,” he added.

There were significant reductions in K-18 levels (hepatic apoptosis marker) with retatrutide 8 and 12 mg at week 48 (–49.6 and –47.5; p<0.05 for both doses).

Pro-C3, a fibrogenesis marker, also dropped with retatrutide vs placebo. The doses that particularly stood out in reducing this marker were the 4-mg (–23.3; p<0.001 [week 24] and –21.1; p<0.001 [week 48]) and 8-mg doses (–22.7; p<0.001 and –15.4; p<0.05, respectively). Albeit significant at week 24, the reduction with the 12-mg dose lost its significance at week 48.

 

Implications

In sum, these findings suggest that adding glucagon agonism to GIP and/or GLP-1 agonism may lead to greater efficacy in people with NAFLD/NASH^#.

“There are currently no approved pharmacologic therapies for the treatment of NASH … Along with the weight loss findings from the main phase II trial, the current pilot data further support the use of retatrutide in people with NASH,” Sanyal concluded.