Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more rapidly progressive variant steatohepatitis (MASH) are widespread chronic liver conditions linked to obesity and other common metabolic disorders. The emergence of tirzepatide, a dual incretin receptor agonist targeting both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, presents major therapeutic potential for MASLD.
The SYNERGY-NASH trial provides compelling evidence for tirzepatide’s liver benefits. Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group, 56% in the 10-mg tirzepatide group, and 62% in the 15-mg tirzepatide group (P<0.001 for all three comparisons).
At week 52, MASH resolution without worsening fibrosis was achieved in 44% of participants in the tirzepatide 5 mg arm, 56% in the tirzepatide 10 mg arm and 62% in the tirzepatide 15 mg arm compared to 10% in the placebo arm. Regarding the secondary endpoint of improvement by at least 1 fibrosis stage without worsening of MASH, this occurred in 55%, 51% and 51% of participants in the tirzepatide 5 mg, 10 mg, and 15 mg arms, respectively, compared to 30% in the placebo arm.
Evaluation of additional secondary endpoints showed tirzepatide was associated with improvements in body weight, blood markers of liver injury, and biomarkers of liver fat, inflammation and fibrosis.
Evidence shows these medications typically improve liver enzyme levels rather than harm them, particularly in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Clinical trials demonstrate reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—key markers of liver health—often correlating with decreased hepatic fat accumulation.
Tirzepatide delays gastric emptying, impacting the absorption of concurrently administered oral medications. This is particularly significant in those with preexisting delayed gastric emptying, as it can exacerbate these symptoms. Caution is advised when using oral medications dependent on threshold concentrations or with a narrow therapeutic index (TI) and tirzepatide.
The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.
