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Retatrutide, an investigational triple-agonist therapy, may help resolve liver fat prior to progression to severe disease.
Novel triple agonist therapy retatrutide was associated with steatosis resolution in nearly 9 of 10 treated patients with metabolic dysfunction-associated steatotic liver disease (MASLD), according to new trial data.1
In findings from an additional analysis of a 48-week phase 2 trial, once-weekly 8 mg and 12 mg subcutaneous doses of retatrutide—an agonist of the GIP, GLP-1 and glucagon receptors—resolved fatty liver disease in >85% of treated patients with MASLD and obesity. The data, presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend, come at a time when nomenclature regarding fatty liver disease is evolving to reflect the metabolic characteristics that which agents like retatrutide are showing capability to effectively treat.2
Presented by Arun J. Sanyal, MD, chair of the division of gastroenterology, hepatology and nutrition at VCU Health, The Liver Meeting data readout for retatrutide involved patient data from a recent 48-week, phase 2 obesity trial that which showed up to 24.2% overall weight loss in patients receiving 1 of the 2 treatment doses. Sanyal and colleagues used the available data to interpret retatrutide’s impact on liver fat and correlated metabolic outcomes in trial participants with MASLD.1
Eligible patients were 18 – 75 years old with body mass index (BMI) >30 kg/m2 and a weight-related condition excluding type 2 diabetes, as well as ≥10% liver fat per magnetic resonance imaging. In the original trial, participants were randomized to a once-weekly regimen of either 1, 4, 8 or 12 mg retatrutide, or placebo, for 48 weeks.
Investigators sought a primary outcome of relative liver fat change from baseline at 24 weeks, as well as liver fat percent change from baseline at 48 weeks, and proportion of subjects to achieve <5% liver fat composition at 48 weeks. The team additionally observed relationships between relative liver fat CFB and changes in body weight, waist circumference and fasting metabolic biomarkers.
Among the 338 subjects in the trial, 98 (46.9%) were female and mean patient age was 46.6 years old. Mean BMI was 38.4 kg/m2; waist circumference was 118.3 cm. Mean liver fat ranged from 15.6 – 21.0% across the treatment arms at baseline.
Investigators observed a mean relative liver fat change of -81.4% and -82.4% from baseline to 24 weeks with retatrutide 8 mg and 12 mg, respectively—versus a 0.3% increase in placebo. At 48 weeks, the higher-dosage groups reported changes of -81.7% and -86.0%, versus a 4.6% increase with placebo (P <.001).
Another 89% and 93% of patients receiving retatrutide 8 mg and 12 mg, respectively, achieved <5% liver fat at 48 weeks (P <.001). Investigators additionally observed a significant correlation between percent change in liver fat from baseline and patient body weight and waist circumference (P <.001), as well as nonlinear relationship between near-maximal liver fat .reduction achieved at approximate 20% body weight loss in treated individuals (P = .002).
In an interview with HCPLive during The Liver Meeting, Sanyal said the new findings immediately put retatrutide near “the top of the class” across molecules being investigated to treat liver fat reduction.
“Between 80 - 90% of patients—and actually by week 48, at the high dose, 93% of patients—lost so much fat in the liver that they were below the cutoff for having fatty liver disease...which is quite dramatic, because in the overweight-obese population, we first said that 70 - 75% of them will have excess fat in the liver,” Sanyal said. “But now we have a treatment that can treat obesity, and you can wipe out the liver fat in 90% of these people.”
The caveat with these impressive findings, Sanyal said, is that the trial population is comprised of early disease stage patients—not individuals at imminent risk of liver disease. He anticipates future research will separately address the effect of retatrutide on those patients.
“But here, the implication is that by treating the underlying obese state and by getting rid of all the fat in the liver, there's at least a reasonable assumption that you might in the future be able to say that this population that no longer has fat in the liver, they're not going to progress to significant scarring of the liver, or they will not develop fibrosis or fibrosis-related outcomes,” Sanyal said.
The current armamentarium in investigation to treat metabolic fatty liver disease does not necessarily address early disease, Sanyal said. The findings for retatrutide now raise the question: if there’s an opportunity to effectively treat a patient early, why wouldn’t you?
“So, here's a new concept, which is bottom-up therapy, where you just treat the systemic obesity and get rid of the liver disease altogether and prevent it from developing into real liver disease,’ Sanyal said. “But it's a theoretical construct that comes out of this study that will need to be verified in further studies with longer follow up.”