Retatrutide 12 mg resolved steatosis in more than 90% of patients with obesity, MASLD
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Key takeaways:
- Retatrutide at its highest dose resolved steatosis in more than 90% of patients with obesity and MASLD.
- Mean relative liver fat reduction was greater than 80% at 8 mg and 12 mg doses.
BOSTON — Treatment with retatrutide at 8 mg and 12 mg resulted in substantial reductions in liver fat in patients with obesity and metabolic dysfunction-associated steatotic liver disease, according to a presenter at The Liver Meeting.
“Incretin-based therapies, including agonists of the [glucagon-like peptide 1] and [glucose-dependent insulinotropic polypeptide] receptors, have been shown to reduce liver fat and improve steatohepatitis-related biomarkers in patients with steatotic liver disease,” Arun J. Sanyal, MBBS, MD, director of the Stravitz-Sanyal Institute for Liver Disease & Metabolic Health and interim chair of the division of gastroenterology, hepatology and nutrition at Virginia Commonwealth University School of Medicine, told attendees.
He added: “Preliminary data show that tri-agonists of GIP, GLP-1 and glucagon may have greater effects than mono- and dual-agonists in reducing liver fat.”
Sanyal and colleagues conducted a randomized, double-blind, phase 2 study of retatrutide, a novel triple agonist of GIP, GLP-1 and glucagon receptors, vs. placebo in 338 adult patients with obesity, as well as an MASLD substudy of 98 participants with at least 10% liver fat assessed via MRI-PDFF.
Participants were randomized to once-weekly subcutaneous retatrutide 1 mg (n = 20), 4 mg (n = 19), 8 mg (n = 22), 12 mg (n = 18) or placebo (n = 19). Baseline demographics and clinical characteristics were similar between the main study group and the MASLD subset, although there were fewer Black patients in the MASLD subset.
The study’s primary outcome was relative liver fat change from baseline at 24 weeks, while secondary outcomes included relative liver fat change from baseline at 48 weeks, absolute liver fat change and percent of participants achieving at least 30% liver fat reduction at weeks 24 and 48.
Exploratory endpoints included percent of participants achieving liver fat content less than 5%, as well as at least 50% and 70% liver fat reductions, and correlations between changes in liver fat and body weight, waist circumference and fasting metabolic biomarkers.
According to Sanyal, who presented results of the MASLD substudy, baseline liver fat was 19% for the overall cohort, with greater relative change in liver fat for all doses of retatrutide vs. placebo. Further, relative mean liver fat reduction exceeded 80% with retatrutide 8 mg and 12 mg.
At week 24, 100% of participants on retatrutide 8 mg and 12 mg achieved relative liver fat reduction of at least 30%, with similar trends reported for participants who achieved at least 50% reduction (95% and 100%, respectively) and at least 70% reduction (86% and 80%).
Further, 79% to 86% of patients in the 8 mg and 12 mg groups, respectively, achieved liver fat content below the 5% threshold at week 24, with 89% and 93% achieving this endpoint at week 48.
“So, almost 90% of patients, or nine out of 10 patients, no longer met criteria to have steatotic liver disease by the end of the study,” Sanyal said.
Results also showed dose-dependent reductions at week 24 in abdominal and visceral adipose tissue volume with retatrutide, with further declines reaching 45% to 50% by week 48 at the two highest doses.
Further, Sanyal noted that retatrutide doses greater than 4 mg improved insulin sensitivity, increased adiponectin and reduced serum triglycerides and leptin compared with placebo. Near-maximal liver fat reductions were achieved at about 20% reduction in body weight and at about 40% reduction in abdominal subcutaneous and visceral adipose tissue.
The safety profile of retatrutide in the MASLD subset was similar to the obesity trial population, with no hepatoxicity signals reported in either population at 48 weeks. The most common adverse events were nausea, vomiting and diarrhea.
“We are excited to demonstrate that in those with MASLD, retatrutide was able to clear steatosis in over 90% of individuals,” Sanyal told Healio. “One can effectively defat the liver with anti-obesity therapy using retatrutide, and it is hoped this will prevent more serious MASH and fibrosis from developing. This remains to be shown and will be an important topic for future analysis.”
He added, “[The study] also provides a rationale to evaluate retatrutide in those with established fibrosis to determine if it will prevent progression to cirrhosis and clinical outcomes.”