CLINICAL QUESTION: Does tirzepatide improve the rate of resolution of Metabolic Dysfunction-Associated Steatohepatitis (MASH) or decrease the fibrosis stage in patients with steatohepatitis and moderate to severe (F2 to F3) fibrosis?
BACKGROUND: Prior studies have shown the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists for treating MASH but they have not shown benefit in reducing fibrosis. Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and GLP-1 receptor agonist, has not previously been studied in its effect on MASH. GIP receptor activation leads to improved lipid storage in white adipose tissue and thereby may decrease lipid deposition in the liver.
STUDY DESIGN: Prospective, phase 2, randomized, double-blinded, placebo-controlled trial
SETTING: Multicenter (Japan, U.S., Mexico, Europe, and Israel)
SYNOPSIS: Across all sites, 157 patients were randomized to either treatment with weekly tirzepatide versus placebo. Those treated with tirzepatide showed significantly higher rates of MASH resolution (44% to 62%) compared to placebo (10%) over a 52-week period (P <0.001) as assessed by liver biopsy. Higher doses of tirzepatide showed higher rates of resolution in a dose-dependent response. However, although suggestive of decreasing fibrosis stage, this relationship was not statistically significant. This study is limited by its relatively small size and the results are similar to the data already known showing efficacy of GLP-1 receptor agonists in reducing MASH. It may need a longer follow-up period to see if there are meaningful changes in the degree of fibrotic disease imparted by the added GIP receptor activation of tirzepatide.
BOTTOM LINE: Tirzepatide was effective at decreasing MASH but does not clearly reduce the fibrosis stage over a one-year period.
CITATION: Loomba R, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299- 310. doi: 10.1056/NEJMoa2401943
Dr. Hilbert
Dr. Hilbert is a hospitalist in the department of hospital medicine at Duke Regional Hospital and a medical instructor at Duke University School of Medicine, both in Durham, N.C.