SYNERGY-NASH: Tirzepatide, a GIP/GLP-1 RA, Resolves MASH Without Worsening Fibrosis

Use of tirzepatide was associated with statistically significant improvements in metabolic dysfunction-associated steatohepatitis (MASH) without worsening fibrosis in a phase 2 trial of patients with MASH and moderate to severe fibrosis.¹

Presented at the European Association for the Study of the Liver (EASL) Congress in Milan, Italy, and published in the New England Journal of Medicine, the data showed treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, for 52 weeks was superior to placebo for MASH resolution without worsening of fibrosis.¹

"MASH is the second most common contributor to liver transplantation in the US, highlighting the need for novel therapies1," said Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at University of California San Diego School of Medicine. "The study is significant, given the urgent need for treatment options that are capable of slowing the progression of the disease and potentially reducing serious health complications."

Weight loss has historically served as the cornerstone of MASH management, especially prior to the landmark FDA approval of resmetirom (Rezdiffra) in March of 2024 when the oral thyroid hormone receptor-β selective agonist became the first FDA-approved MASH therapeutic.³ Although GLP-1 RAs have emerged as efficacious weight management tools, their apparent lack of direct impact on fibrosis limits their utility in MASH.⁴

A phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis, SYNERGY-NASH was conducted at 130 sites in 10 countries to investigate the efficacy and safety of tirzepatide in this patient population.¹

For inclusion, patients were required to be 18-80 years of age with a body mass index (BMI) between 27-50 kg/m2 and with or without type 2 diabetes mellitus. Histologically confirmed inclusion criteria were a diagnosis of MASH with stage 2 or 3 fibrosis and a nonalcoholic fatty liver disease (NAFLD) activity score of ≥ 4.¹

Participants were randomly assigned in a 1:1:1:1 ratio to receive once-weekly subcutaneous tirzepatide 5 mg, 10 mg, or 15 mg, or placebo for 52 weeks, stratified by type 2 diabetes mellitus status and geographic region. The primary endpoint was resolution of MASH, defined as no steatotic liver disease (NAFLD activity steatosis score of 0) or simple steatosis (NAFLD activity steatosis score of 1, 2, or 3) without steatohepatitis and an inflammation score of 0 or 1 and a ballooning score of 0, without worsening of fibrosis at 52 weeks. A key secondary endpoint, also assessed at week 52, was an improvement of ≥ 1 fibrosis stage without worsening of MASH.¹

Among 190 patients who underwent randomization, 165 (87%) completed the trial, 161 (85%) completed the trial regimen, and 157 (83%) had liver biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. Among the cohort, most participants were White (86%), female (57%), and had type 2 diabetes (58%) and F3 fibrosis (57%).¹

Upon analysis, 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 (difference vs placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50); 56% in the 10 mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62); and 62% in the 15 mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (all P <.001).¹

The percentage of participants who had an improvement of ≥ 1 fibrosis stage without worsening of MASH was 30% in the placebo group; 55% in the 5 mg tirzepatide group (difference vs placebo, 25 percentage points; 95% CI, 5 to 46); 51% in the 10 mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42); and 51% in the 15 mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42).¹

Further analysis revealed that at week 52, a decrease of ≥ 2 points in the NAFLD activity score with a reduction of ≥ 1 point in at least 2 NAFLD activity score components occurred in 72 - 78% of participants across the 3 tirzepatide groups and in 37% of those in the placebo group. In the overall trial population, the mean percentage change in body weight was −10.7%, −13.3%, and −15.6% in the 5 mg, 10 mg, and 15 mg tirzepatide groups, respectively, as compared with −0.8% in the placebo group.¹

Overall, adverse events were reported in 92% of participants in the tirzepatide groups and 83% of those in the placebo group. The most common adverse events in the tirzepatide groups were gastrointestinal events, and most (96%) were mild or moderate in severity. Serious adverse events were reported in 9 (6%) participants in the tirzepatide groups and 3 (6%) participants in the placebo group.¹

Investigators were careful to note several potential limitations to these findings, including the inadequate sample size for evaluating the effect of tirzepatide on fibrosis while controlling for multiple comparisons; the short trial duration; the lack of safety and efficacy assessments in patients with MASH who had progressed to cirrhosis; the lack of adjustment for multiplicity made in the calculation of the sample size and confidence intervals; and the underrepresentation of certain ethnicities.¹

“In this trial, treatment with tirzepatide, a GIP and GLP-1 receptor agonist, was more effective than placebo with respect to resolution of MASH without worsening of fibrosis in patients with MASH and moderate or severe fibrosis,” investigators concluded.¹ “Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH with liver fibrosis and to determine whether tirzepatide treatment could reduce the risk of major adverse liver outcomes.”

References:

1. ^{Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. doi:10.1056/NEJMoa2401943.}
2. ^{Eli Lilly and Company. Lilly’s tirzepatide was superior to placebo for MASH resolution, and more than half of patients achieved improvement in fibrosis at 52 weeks. Eli Lilly and Company. June 8, 2024. Accessed June 8, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-was-superior-placebo-mash-resolution-and-more.}
3. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed June 7, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
4. ^{Brooks, A. Stephen Harrison, MD: The Role of Weight Loss, Resmetirom in NASH Management. HCPLive. March 18, 2024. Accessed June 7, 2024. https://www.hcplive.com/view/stephen-harrison-md-weight-loss-resmetirom-nash-management}