{"product_id":"tirzepatide-for-fatty-liver-disease-with-liver-scarring-results-of-the-synergy-nash-trial","title":"Tirzepatide for Fatty Liver Disease with Liver Scarring: Results of the SYNERGY-NASH Trial","description":"\u003cp\u003eIn a 52-week phase 2 trial, all three doses of tirzepatide were significantly better than placebo at resolving metabolic dysfunction–associated steatohepatitis (MASH, a progressive fatty liver disease). The three doses were 5 mg, 10 mg, or 15 mg given once weekly by injection. This resolution occurred without making liver fibrosis worse. Among 190 randomized participants with moderate or severe fibrosis, MASH resolved without worsening fibrosis in 44%, 56%, and 62% of the tirzepatide groups versus 10% with placebo. At least one stage of fibrosis improvement without worsening MASH occurred in 51–55% of tirzepatide-treated participants versus 30% with placebo. The most common side effects were gastrointestinal, and most were mild or moderate.\u003c\/p\u003e\n\n\u003ch1\u003eTirzepatide for Fatty Liver Disease with Liver Scarring: Results of the SYNERGY-NASH Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: What Is MASH and Why Does It Matter?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#study-methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#participants\"\u003eWho Took Part in the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#key-findings\"\u003eKey Findings: MASH Resolution and Fibrosis Improvement\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#liver-enzymes\"\u003eChanges in Liver Enzymes and Other Markers\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#weight\"\u003eWeight Loss Results\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a 52-week phase 2 trial of 190 people with MASH and moderate or severe fibrosis, all three tirzepatide doses resolved MASH without worsening fibrosis more often than placebo.\u003c\/li\u003e\n\u003cli\u003eMASH resolution without worsening fibrosis occurred in 44%, 56%, and 62% with 5 mg, 10 mg, and 15 mg tirzepatide, versus 10% with placebo.\u003c\/li\u003e\n\u003cli\u003eAt least one stage of fibrosis improvement without worsening MASH occurred in 51–55% of tirzepatide-treated participants versus 30% with placebo.\u003c\/li\u003e\n\u003cli\u003eThe most common side effects were gastrointestinal; 96% were mild or moderate, and discontinuation due to side effects was 4% in both groups.\u003c\/li\u003e\n\u003cli\u003eThis was an early-stage trial; larger and longer studies are needed before tirzepatide can be considered for routine clinical use for MASH.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: What Is MASH and Why Does It Matter?\u003c\/h2\u003e\n\n\u003cp\u003eMetabolic dysfunction–associated steatohepatitis (MASH) is a progressive liver disease. It was formerly known as nonalcoholic steatohepatitis (NASH). MASH is characterized by three features: excess fat accumulation in the liver, liver inflammation, and hepatocyte injury (liver cell damage confirmed by biopsy showing ballooning of cells). These features may occur with or without fibrosis (liver scarring).\u003c\/p\u003e\n\n\u003cp\u003eMASH is associated with an increased risk of cardiovascular disease (heart and blood vessel disease). In patients who also have clinically significant liver fibrosis, MASH carries a higher risk of liver-related complications and death. The prevalence of MASH is increasing globally, in parallel with rising rates of obesity and type 2 diabetes mellitus.\u003c\/p\u003e\n\n\u003cp\u003eIn 2019, MASH was the second most common indication for liver transplantation. It was also the most rapidly increasing indication for liver transplantation.\u003c\/p\u003e\n\n\u003cp\u003eThe beneficial effects of weight reduction on MASH are well documented. Higher rates of MASH resolution and regression (reversal) of liver fibrosis have been observed when patients achieve a weight reduction of 10% or more. This weight reduction can be achieved through lifestyle modification or bariatric metabolic surgery (weight-loss surgery).\u003c\/p\u003e\n\n\u003cp\u003eIn phase 2 trials with 48-week and 72-week treatment periods, glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to be effective for the resolution of MASH. However, these drugs were not effective for regression of fibrosis.\u003c\/p\u003e\n\n\u003cp\u003eTirzepatide is a once-weekly injectable drug. It is an agonist (activator) of two receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor. Tirzepatide has been shown to induce substantial weight reduction in placebo-controlled trials involving persons with type 2 diabetes mellitus, obesity, or both. In patients with type 2 diabetes mellitus, treatment with tirzepatide resulted in a reduction in liver fat and improvement in biomarkers of MASH and fibrosis.\u003c\/p\u003e\n\n\u003cp\u003eThe SYNERGY-NASH trial was designed to investigate the efficacy and safety of tirzepatide in patients with biopsy-confirmed MASH and moderate or severe fibrosis.\u003c\/p\u003e\n\n\u003ch2 id=\"study-methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThe SYNERGY-NASH trial was a phase 2, multicenter, double-blind, randomized, placebo-controlled trial. It was conducted at 130 sites in 10 countries. The trial protocol was approved by the ethical review board at each site. The trial was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations. All participants provided written informed consent.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was designed by the sponsor (Eli Lilly) in collaboration with two academic authors. Site monitoring, data collection, and data analysis were performed by the sponsor. The first draft of the manuscript was written by the first and second authors. All authors participated in interpreting the data, provided critical review of the manuscript, and vouched for the accuracy and completeness of the data.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEligibility criteria:\u003c\/strong\u003e Eligible participants were 18 to 80 years of age. They had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) between 27 and 50. They could have type 2 diabetes mellitus or not.\u003c\/p\u003e\n\n\u003cp\u003eHistologically confirmed inclusion criteria were a diagnosis of MASH with stage 2 (F2) or stage 3 (F3) fibrosis. Fibrosis was measured on a scale of 0 (no fibrosis) to 4 (cirrhosis). Participants also had a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher. The NAFLD activity score is measured on a scale of 0 to 8, with higher scores indicating more severe disease. Participants had a score of 1 or higher for each subcomponent. The subcomponents were steatosis (fat accumulation, on a scale of 0 to 3). The subcomponents were hepatocellular ballooning (liver cell swelling, on a scale of 0 to 2). The subcomponents were lobular inflammation (liver inflammation, on a scale of 0 to 3).\u003c\/p\u003e\n\n\u003cp\u003eThese criteria were evaluated by two central pathologists using the NASH Clinical Research Network scoring system. The evaluation was based on a liver biopsy performed at screening or no more than 6 months before screening.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eKey exclusion criteria\u003c\/strong\u003e were:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eChronic liver disease other than MASH\u003c\/li\u003e\n  \u003cli\u003eCirrhosis\u003c\/li\u003e\n  \u003cli\u003eEvidence of hepatic decompensation (liver failure)\u003c\/li\u003e\n  \u003cli\u003eExcessive alcohol consumption (defined as more than 14 standard drinks per week for women and more than 21 standard drinks per week for men)\u003c\/li\u003e\n  \u003cli\u003eUncontrolled type 2 diabetes mellitus (defined by a glycated hemoglobin level above 9.5%)\u003c\/li\u003e\n  \u003cli\u003eUse of confounding concomitant medication, including GLP-1 receptor agonists or medications intended to promote weight reduction\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eTreatment procedures:\u003c\/strong\u003e Participants were randomly assigned in a 1:1:1:1 ratio to receive maintenance treatment with tirzepatide at doses of 5 mg, 10 mg, or 15 mg, or to receive placebo. All doses were administered subcutaneously (under the skin) once weekly for 52 weeks.\u003c\/p\u003e\n\n\u003cp\u003eRandomization was performed using an interactive Web-response system (IWRS). Randomization was stratified according to type 2 diabetes mellitus status (present versus absent) and geographic region (Japan versus United States or Mexico versus Europe or Israel).\u003c\/p\u003e\n\n\u003cp\u003eThe starting dose of tirzepatide or placebo was 2.5 mg. The dose was increased by 2.5 mg every 4 weeks in a blinded manner using the IWRS, until the target maintenance dose was attained. If dose escalation resulted in adverse events, the investigators could reduce the dose to the next lower maintenance dose. Throughout the trial, all participants received counseling regarding nutrition and physical activity in accordance with site programs.\u003c\/p\u003e\n\n\u003cp\u003eA liver biopsy was planned at the end of the 52-week treatment period. The results were evaluated by central pathologists who were unaware of the trial-group assignments and the clinical characteristics of the participants. In some cases, the biopsy was performed before or after week 52 owing to early withdrawal from the trial, participant availability, or delays in scheduling, particularly during the coronavirus disease 2019 pandemic.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEnd points and assessments:\u003c\/strong\u003e The primary end point was resolution of MASH without worsening of fibrosis (defined as no increase in the fibrosis stage) at week 52. MASH resolution was defined as no steatotic liver disease (steatosis score of 0) or simple steatosis (a steatosis score of 1, 2, or 3) without steatohepatitis. MASH resolution also required an inflammation score of 0 or 1 and a ballooning score of 0.\u003c\/p\u003e\n\n\u003cp\u003eSecondary end points, all assessed at week 52, were:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eA decrease of at least one fibrosis stage without worsening of MASH (defined as no increase in the NAFLD activity score)\u003c\/li\u003e\n  \u003cli\u003eAn increase of at least one fibrosis stage\u003c\/li\u003e\n  \u003cli\u003eThis was a decrease of at least 2 points in the NAFLD activity score. It also required a reduction of at least 1 point in at least two NAFLD activity score components. Those components were steatosis, hepatocellular ballooning, and lobular inflammation.\u003c\/li\u003e\n  \u003cli\u003eChanges in liver fat content (assessed by magnetic resonance imaging proton density fat fraction, or MRI-PDFF) and body weight\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMRI images were transmitted to a reader at a central facility (Perspectum) for evaluation.\u003c\/p\u003e\n\n\u003cp\u003eExploratory end points included change in extracellular hepatic water content (which provides an indication of hepatic fibroinflammation, or liver scarring and inflammation) as assessed by iron-corrected T1-weighted MRI. Other exploratory end points included change in liver stiffness as measured by vibration-controlled transient elastography (FibroScan), changes in liver-enzyme levels, and changes in serum biomarkers of steatohepatitis and fibrosis. These biomarkers included cytokeratin 18 and N-terminal type III collagen propeptide (Pro-C3) levels. They also included scores on the Enhanced Liver Fibrosis test and the Fibrosis-4 index. They also included the result of a noninvasive diagnostic blood test known as NIS4.\u003c\/p\u003e\n\n\u003cp\u003eSafety assessments included adverse events, vital signs, clinical laboratory assessments, and electrocardiograms. Selected clinical events were adjudicated by an independent, external adjudication committee whose members were unaware of the trial-group assignments.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c\/strong\u003e Researchers estimated that a sample of 196 participants would provide the trial with at least 80% power to show the superiority of each tirzepatide dose level to placebo with respect to resolution of MASH without worsening of fibrosis at a two-sided significance level of 0.05. The sample size was based on the assumption that 42.5% of participants in the tirzepatide groups would have a response. The sample size also assumed that 12.5% of those in the placebo group would have a response. It also assumed that 20% of participants would withdraw from the trial.\u003c\/p\u003e\n\n\u003cp\u003eEfficacy end points were analyzed using a treatment-regimen estimand that included data from all participants who had undergone randomization. Multiple imputation was used to handle missing data. A prespecified analysis of the primary end point was performed. In this analysis, data from all randomly assigned participants were included. The exception was data obtained after permanent discontinuation of tirzepatide or placebo.\u003c\/p\u003e\n\n\u003cp\u003eSafety analyses included data obtained from all randomly assigned participants during the 52-week treatment period and a 4-week safety follow-up period. Logistic regression was used to analyze all binary end points. Comparisons among trial groups for continuous variables assessed over time were analyzed using either an analysis of covariance model or a mixed model for repeated measures. Analyses were adjusted for the stratification factors (type 2 diabetes mellitus status and geographic region).\u003c\/p\u003e\n\n\u003cp\u003eAll statistical analyses were performed using SAS software, version 9.4, or R software, version 4.2.2. No prespecified plan was made to adjust for multiple comparisons. The P values reported for the primary end point reflect a post hoc adjustment to accommodate three dose comparisons against placebo. All other end points are reported with point estimates and 95% confidence intervals. The confidence intervals have not been adjusted for multiple comparisons and should not be used to infer definitive treatment effects. An interim analysis for futility was performed, and on the basis of the results, the trial was continued without modification.\u003c\/p\u003e\n\n\u003ch2 id=\"participants\"\u003eWho Took Part in the Study\u003c\/h2\u003e\n\n\u003cp\u003eBetween January 24, 2020, and January 10, 2023, a total of 190 participants underwent randomization. Overall, 165 participants (87%) completed the trial, 161 (85%) completed the trial regimen, and 157 (83%) had end-of-treatment liver-biopsy results that could be evaluated.\u003c\/p\u003e\n\n\u003cp\u003eThe percentage of participants who ultimately received the randomly assigned dose with dose escalation was 96% in the 5-mg tirzepatide group, 96% in the 10-mg group, and 85% in the 15-mg group. After the target dose was reached, the dose was reduced in 0 participants in the 5-mg group, 9 participants (20%) in the 10-mg group, and 3 participants (7%) in the 15-mg group.\u003c\/p\u003e\n\n\u003cp\u003eThe demographic and clinical characteristics of the participants at baseline were generally similar across the trial groups. One exception was the mean γ-glutamyltransferase (GGT) level, which was higher in the placebo group than in the tirzepatide groups.\u003c\/p\u003e\n\n\u003cp\u003eMost participants were White (86%) or Asian (12%). A total of 36% identified as Hispanic or Latino. The mean age was 54.4 years, and the mean body-mass index was 36.1. A total of 57% were women, and 58% had type 2 diabetes mellitus. Overall, 57% had stage F3 fibrosis. The incidence of stage F3 fibrosis was higher in the placebo and 5-mg tirzepatide groups than in the other groups.\u003c\/p\u003e\n\n\u003cp\u003eBaseline characteristics by group were as follows:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAge:\u003c\/strong\u003e 55.0 years (5-mg group), 54.3 years (10-mg group), 54.9 years (15-mg group), 53.5 years (placebo group)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFemale sex:\u003c\/strong\u003e 57% (5-mg), 55% (10-mg), 60% (15-mg), 56% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eType 2 diabetes:\u003c\/strong\u003e 55% (5-mg), 57% (10-mg), 60% (15-mg), 60% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eStage F2 fibrosis:\u003c\/strong\u003e 36% (5-mg), 53% (10-mg), 46% (15-mg), 35% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eStage F3 fibrosis:\u003c\/strong\u003e 64% (5-mg), 47% (10-mg), 54% (15-mg), 65% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNAFLD activity score:\u003c\/strong\u003e 5.4 (5-mg), 5.3 (10-mg), 5.0 (15-mg), 5.3 (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAlanine aminotransferase (ALT):\u003c\/strong\u003e 67.9 U\/liter (5-mg), 61.2 U\/liter (10-mg), 58.7 U\/liter (15-mg), 59.7 U\/liter (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAspartate aminotransferase (AST):\u003c\/strong\u003e 55.5 U\/liter (5-mg), 47.0 U\/liter (10-mg), 47.5 U\/liter (15-mg), 52.3 U\/liter (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGlycated hemoglobin:\u003c\/strong\u003e 6.6% (5-mg), 6.4% (10-mg), 6.4% (15-mg), 6.8% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLiver fat content:\u003c\/strong\u003e 19.0% (5-mg), 17.6% (10-mg), 18.8% (15-mg), 18.2% (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eExtracellular hepatic water content:\u003c\/strong\u003e 920.5 msec (5-mg), 894.1 msec (10-mg), 923.3 msec (15-mg), 917.7 msec (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLiver stiffness:\u003c\/strong\u003e 12.6 kPa (5-mg), 11.1 kPa (10-mg), 11.4 kPa (15-mg), 12.0 kPa (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFibrosis-4 index score:\u003c\/strong\u003e 1.8 (5-mg), 1.5 (10-mg)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"key-findings\"\u003eKey Findings: MASH Resolution and Fibrosis Improvement\u003c\/h2\u003e\n\n\u003cp\u003eThe primary end point was the percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis. This percentage was significantly higher in all three tirzepatide groups than in the placebo group. In the placebo group, 10% of participants met this end point.\u003c\/p\u003e\n\n\u003cp\u003eThe results by dose were:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e5-mg tirzepatide group:\u003c\/strong\u003e 44% (difference versus placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e10-mg tirzepatide group:\u003c\/strong\u003e 56% (difference, 46 percentage points; 95% CI, 29 to 62)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e15-mg tirzepatide group:\u003c\/strong\u003e 62% (difference, 53 percentage points; 95% CI, 37 to 69)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe P value was less than 0.001 for all three comparisons. This means there is less than a 0.1% probability that these results were due to random chance.\u003c\/p\u003e\n\n\u003cp\u003eThe percentage of participants who had an improvement (decrease) of at least one fibrosis stage without worsening of MASH (a key secondary end point) was 30% in the placebo group. The results by dose were:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e5-mg tirzepatide group:\u003c\/strong\u003e 55% (difference versus placebo, 25 percentage points; 95% CI, 5 to 46)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e10-mg tirzepatide group:\u003c\/strong\u003e 51% (difference, 22 percentage points; 95% CI, 1 to 42)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e15-mg tirzepatide group:\u003c\/strong\u003e 51% (difference, 21 percentage points; 95% CI, 1 to 42)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eReduction in fibrosis was more apparent among participants with stage F3 fibrosis than among those with stage F2 fibrosis. This difference may be due to a lower placebo response in the F3 group.\u003c\/p\u003e\n\n\u003cp\u003eTirzepatide treatment did not have an apparent effect on the percentage of participants who had a decrease of at least two fibrosis stages without worsening of MASH. Tirzepatide treatment also did not have an apparent effect on the percentage of participants who had an increase of at least one fibrosis stage. Tirzepatide treatment also did not have an apparent effect on the percentage of participants with an absence of fibrosis at week 52.\u003c\/p\u003e\n\n\u003cp\u003eThis was a decrease of at least 2 points in the NAFLD activity score. It also required a reduction of at least 1 point in at least two NAFLD activity score components at week 52. This occurred in 72% to 78% of participants across the three tirzepatide groups. This compared with 37% of participants in the placebo group.\u003c\/p\u003e\n\n\u003cp\u003eChanges in the three components of the NAFLD activity score at week 52 were evaluated as an exploratory end point:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e1-point improvements in the steatosis score:\u003c\/strong\u003e 62% to 75% of participants in the tirzepatide groups versus 32% in the placebo group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e1-point improvements in the lobular inflammation score:\u003c\/strong\u003e 61% to 62% of participants in the tirzepatide groups versus 36% in the placebo group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e1-point improvements in the hepatocellular ballooning score:\u003c\/strong\u003e 77% to 82% of participants in the tirzepatide groups versus 54% in the placebo group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"liver-enzymes\"\u003eChanges in Liver Enzymes and Other Markers\u003c\/h2\u003e\n\n\u003cp\u003eAcross the three doses of tirzepatide, reductions at week 52 were observed for several serum liver enzyme levels. Alanine aminotransferase (ALT) decreased by a mean of 51.6% to 56.7%. Aspartate aminotransferase (AST) decreased by a mean of 42.1% to 47.7%. γ-glutamyltransferase (GGT) decreased by a mean of 39.3% to 49.0%.\u003c\/p\u003e\n\n\u003cp\u003eIn a post hoc analysis, ALT levels had normalized in the following percentages of participants. Normalization was defined as a level of 30 U per liter or lower at week 52 in participants with a baseline level above 30 U per liter.\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e5-mg tirzepatide group:\u003c\/strong\u003e 47%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e10-mg tirzepatide group:\u003c\/strong\u003e 64%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e15-mg tirzepatide group:\u003c\/strong\u003e 75%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePlacebo group:\u003c\/strong\u003e 12%\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eChanges were also observed in biomarkers of liver fat, inflammation, and fibrosis. These included liver fat content (as assessed by MRI-PDFF) and extracellular hepatic water content (as assessed by iron-corrected T1-weighted MRI). These included liver stiffness, NIS4 test results, and the score on the Enhanced Liver Fibrosis test. These included the Pro-C3 level, the cytokeratin 18 level, and the score on the Fibrosis-4 index.\u003c\/p\u003e\n\n\u003ch2 id=\"weight\"\u003eWeight Loss Results\u003c\/h2\u003e\n\n\u003cp\u003eIn the overall trial population, the mean percentage change in body weight after 52 weeks was:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e5-mg tirzepatide group:\u003c\/strong\u003e −10.7%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e10-mg tirzepatide group:\u003c\/strong\u003e −13.3%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e15-mg tirzepatide group:\u003c\/strong\u003e −15.6%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePlacebo group:\u003c\/strong\u003e −0.8%\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThere appeared to be an association between greater degrees of weight reduction and higher incidences of MASH resolution without worsening of fibrosis. However, the relationship with weight reduction was less apparent for reduction in fibrosis without worsening of MASH.\u003c\/p\u003e\n\n\u003cp\u003eChanges in serum lipid levels and glycated hemoglobin levels were also measured during the trial.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\n\u003cp\u003eOverall, adverse events were reported in 92% of participants in the tirzepatide groups and in 83% of participants in the placebo group.\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse events reported with tirzepatide were gastrointestinal events. Most of these events (96%) were mild or moderate in severity.\u003c\/p\u003e\n\n\u003cp\u003eDiscontinuation of tirzepatide or placebo because of an adverse event occurred in 4% of participants in the tirzepatide groups and also in 4% of participants in the placebo group.\u003c\/p\u003e\n\n\u003cp\u003eSerious adverse events were reported in nine participants (6%) in the tirzepatide groups and in three participants (6%) in the placebo group.\u003c\/p\u003e\n\n\u003cp\u003eAdjudicated cases of progression to cirrhosis occurred in four participants (3%) in the tirzepatide groups and in two participants (4%) in the placebo group. There was no evidence of drug-induced liver injury.\u003c\/p\u003e\n\n\u003cp\u003eOne adjudicated major adverse cardiovascular event (a transient ischemic attack) occurred in the 5-mg tirzepatide group.\u003c\/p\u003e\n\n\u003cp\u003eGallbladder-related adverse events were reported in four participants (3%) in the tirzepatide groups and in one participant (2%) in the placebo group. No cases of acute pancreatitis were reported.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/h2\u003e\n\n\u003cp\u003eAt 52 weeks, all three doses of tirzepatide were superior to placebo with respect to resolution of MASH without worsening of fibrosis, the primary end point. Tirzepatide treatment was associated with changes in fibrosis, the NAFLD activity score, and the subscores for the individual components of the NAFLD activity score. These components included steatosis, lobular inflammation, and hepatocellular ballooning.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, changes were observed in body weight and in blood markers of liver injury. These blood markers included serum levels of ALT, AST, GGT, and cytokeratin 18. Changes were also observed in biomarkers of liver fat, inflammation, and fibrosis. These biomarkers included liver fat content (as assessed by MRI-PDFF) and extracellular hepatic water content (as assessed by iron-corrected T1-weighted MRI). These biomarkers included liver stiffness, NIS4 test results, and the score on the Enhanced Liver Fibrosis test. These biomarkers included the Pro-C3 level, the cytokeratin 18 level, and the score on the Fibrosis-4 index.\u003c\/p\u003e\n\n\u003cp\u003eThis means that patients with MASH and moderate or severe fibrosis who received tirzepatide were substantially more likely to have their MASH resolve without their liver scarring getting worse. Patients who received tirzepatide were also more likely to see at least one stage of fibrosis improvement without their MASH getting worse.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThis was a phase 2 trial, which is an early-stage study designed primarily to assess whether a treatment shows promise and to find the right dose. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH.\u003c\/p\u003e\n\n\u003cp\u003eThe trial included 190 participants, which is a relatively small number. The treatment period was 52 weeks, which is relatively short for a chronic, progressive liver disease.\u003c\/p\u003e\n\n\u003cp\u003eSome participants did not have end-of-treatment liver-biopsy results that could be evaluated. Missing values were imputed under the assumption that they would follow the pattern of results in the placebo group.\u003c\/p\u003e\n\n\u003cp\u003eNo prespecified plan was made to adjust for multiple comparisons. The confidence intervals for secondary and exploratory end points have not been adjusted for multiple comparisons and should not be used to infer definitive treatment effects.\u003c\/p\u003e\n\n\u003cp\u003eThe trial population was mostly White (86%) or Asian (12%), so the results may not apply equally to all racial and ethnic groups.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on these results, tirzepatide shows promise as a treatment for MASH with moderate or severe fibrosis. However, this was a phase 2 trial, and larger and longer trials are needed before tirzepatide can be considered for routine clinical use for MASH.\u003c\/p\u003e\n\n\u003cp\u003ePatients with MASH and liver fibrosis should discuss treatment options with their healthcare provider. Current approaches include weight reduction through lifestyle modification or bariatric metabolic surgery, which have been shown to improve MASH and liver fibrosis.\u003c\/p\u003e\n\n\u003cp\u003ePatients who are interested in participating in clinical trials of tirzepatide or other treatments for MASH should ask their healthcare provider about available studies.\u003c\/p\u003e\n\n\u003cp\u003eThe most common side effects of tirzepatide were gastrointestinal events, and most were mild or moderate. Patients considering tirzepatide should discuss the potential benefits and risks with their healthcare provider.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is MASH and why is it serious?\u003c\/h3\u003e\n\u003cp\u003eMASH, formerly called NASH, is a progressive fatty liver disease with three features: excess liver fat, liver inflammation, and liver cell damage. It may occur with or without liver scarring. In patients who also have significant liver scarring, MASH carries a higher risk of liver-related complications and death, and it is linked to increased cardiovascular risk.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible for the SYNERGY-NASH trial?\u003c\/h3\u003e\n\u003cp\u003eEligible participants were 18 to 80 years old with a body-mass index between 27 and 50, with or without type 2 diabetes. They needed biopsy-confirmed MASH with stage F2 or F3 liver fibrosis and a NAFLD activity score of 4 or higher. People with cirrhosis, other chronic liver disease, or excessive alcohol use were excluded.\u003c\/p\u003e\n\u003ch3\u003eDid tirzepatide improve liver scarring?\u003c\/h3\u003e\n\u003cp\u003eAt least one stage of fibrosis improvement without worsening MASH occurred in 51% to 55% of tirzepatide-treated participants, compared with 30% with placebo. The improvement was more apparent in participants with stage F3 fibrosis than stage F2. Tirzepatide did not appear to affect the percentage of participants with a two-stage fibrosis decrease.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects did participants report?\u003c\/h3\u003e\n\u003cp\u003eAdverse events were reported in 92% of tirzepatide participants and 83% of placebo participants. The most common were gastrointestinal, and 96% of these were mild or moderate. Discontinuation due to side effects was 4% in both groups. Serious adverse events occurred in 6% of each group, with no drug-induced liver injury.\u003c\/p\u003e\n\u003ch3\u003eHow much weight did participants lose?\u003c\/h3\u003e\n\u003cp\u003eAfter 52 weeks, average body weight decreased by 10.7% with 5 mg, 13.3% with 10 mg, and 15.6% with 15 mg of tirzepatide, compared with 0.8% with placebo. Greater weight reduction appeared associated with higher rates of MASH resolution without worsening fibrosis, though this link was less clear for fibrosis improvement.\u003c\/p\u003e\n\u003ch3\u003eWhat are the limitations of these results?\u003c\/h3\u003e\n\u003cp\u003eThis was a phase 2 trial of 190 participants over 52 weeks, which is relatively small and short for a chronic liver disease. Some biopsy results were missing and were imputed. The population was mostly White or Asian. Larger, longer trials are needed before tirzepatide can be considered for routine clinical use for MASH.\u003c\/p\u003e\n\u003ch3\u003eI have MASH with stage F2 or F3 liver fibrosis — when should I get a second opinion on my treatment options?\u003c\/h3\u003e\n\u003cp\u003eA diagnosis of MASH with moderate or severe fibrosis is a decision point worth reviewing. In a 52-week trial, MASH resolved without worsening fibrosis in 44% to 62% of participants receiving tirzepatide versus 10% with placebo, and at least one stage of fibrosis improvement occurred in 51% to 55% versus 30%. This was a phase 2 trial, so larger and longer trials are needed before routine use. A second opinion can help confirm fibrosis staging and weigh current options, including weight reduction through lifestyle modification or bariatric metabolic surgery. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Tirzepatide for Metabolic DysfunctionAssociated Steatohepatitis with Liver Fibrosis NEJM 2024\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e R. Loomba, M.L. Hartman, E.J. Lawitz, R. Vuppalanchi, J. Boursier, E. Bugianesi, M. Yoneda, C. Behling, O.W. Cummings, Y. Tang, B. Brouwers, D.A. Robins, A. Nikooie, M.C. Bunck, A. Haupt, and A.J. Sanyal, for the SYNERGY-NASH Investigators\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e The New England Journal of Medicine, July 25, 2024, Volume 391, Number 4, pages 299–310. The article was published on June 8, 2024, and updated on September 4, 2025.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2401943\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinicalTrials.gov number:\u003c\/strong\u003e NCT04166773\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Eli Lilly\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919023030428,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/he\/products\/tirzepatide-for-fatty-liver-disease-with-liver-scarring-results-of-the-synergy-nash-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}