Efficacy of Survodutide in Treating Metabolic Dysfunction-Associated Steatohepatitis
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on September 11th, 2024
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Given the role of obesity as a risk factor for metabolic dysfunction-associated steatohepatitis (MASH), GLP-1 receptor agonists have emerged as promising therapies due to their glucose control and appetite suppression effects. However, since hepatocytes lack GLP-1 receptors, targeting additional pathways, such as glucagon receptors, could enhance treatment effectiveness by promoting lipolysis and mobilizing hepatic fat. Survodutide, a dual agonist targeting both GLP-1 and glucagon receptors, is currently under investigation in a study funded by Boehringer Ingelheim for its potential to manage MASH.
The phase 2 clinical trial involved 293 participants with biopsy-confirmed MASH and liver fibrosis ranging from F1 to F3 stages. The cohort had an average nonalcoholic fatty liver disease (NAFLD) activity score of 5.2, where 8 indicates the most severe disease. Baseline liver fat content was measured at 19.57% using MRI-PDFF, and biochemical analysis revealed average alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 57.8 and 47.3 U/liter, respectively. Participants were randomly assigned to receive weekly subcutaneous injections of either a placebo or one of three doses of survodutide: 2.4 mg, 4.8 mg, or 6.0 mg. After 48 weeks of treatment, survodutide was found to be superior to placebo in improving MASH and managing fibrosis, defined by a minimum 2-point decrease on the NAFLD activity score scale without an increase in fibrosis score. Additionally, survodutide significantly reduced liver fat content, ALT, and AST levels. The study reported minimal differences in the rate of adverse events between the survodutide and placebo groups. The authors noted that previous studies on other dual agonists of glucagon and GLP-1 receptors (cotadutide, SAR425899, and NNC9204-1177) reported more severe adverse events leading to treatment discontinuation. They hypothesized that the lower rate of side effects associated with survodutide might be due to the ratio of its action on GLP-1 to glucagon receptors; survodutide targets 8 GLP-1 receptors for every 1 glucagon receptor, whereas other agents have ratios of 5:1 and 3:1, favoring the glucagon receptor more frequently.
The phase 2 clinical trial involved 293 participants with biopsy-confirmed MASH and liver fibrosis ranging from F1 to F3 stages. The cohort had an average nonalcoholic fatty liver disease (NAFLD) activity score of 5.2, where 8 indicates the most severe disease. Baseline liver fat content was measured at 19.57% using MRI-PDFF, and biochemical analysis revealed average alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 57.8 and 47.3 U/liter, respectively. Participants were randomly assigned to receive weekly subcutaneous injections of either a placebo or one of three doses of survodutide: 2.4 mg, 4.8 mg, or 6.0 mg. After 48 weeks of treatment, survodutide was found to be superior to placebo in improving MASH and managing fibrosis, defined by a minimum 2-point decrease on the NAFLD activity score scale without an increase in fibrosis score. Additionally, survodutide significantly reduced liver fat content, ALT, and AST levels. The study reported minimal differences in the rate of adverse events between the survodutide and placebo groups. The authors noted that previous studies on other dual agonists of glucagon and GLP-1 receptors (cotadutide, SAR425899, and NNC9204-1177) reported more severe adverse events leading to treatment discontinuation. They hypothesized that the lower rate of side effects associated with survodutide might be due to the ratio of its action on GLP-1 to glucagon receptors; survodutide targets 8 GLP-1 receptors for every 1 glucagon receptor, whereas other agents have ratios of 5:1 and 3:1, favoring the glucagon receptor more frequently.