Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study

Background 29% of subjects had T2DM. At Week 12, relative reductions in LFC from baseline were (1.2 mg) 46.6% 95% CI -63.7 to -29.6, (1.8 mg) 68.5% 95% CI -84.4 to -52.5, and (2.4 mg) 57.1% 95% CI -76.1 to -38.1 versus 4.4% 95% CI -20.2 to 11.3 in placebo subjects (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of subjects achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events.ConclusionsIn subjects with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.Impact and implicationsMASLD, and MASH, are strongly associated with overweight and obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content (LFC) reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, to significantly reduce LFC, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both MASH and obesity.Clinical Trial NumberNCT05006885.