Tirzepatide’s Potential in Reducing Liver Inflammation and Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on September 4th, 2024
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Metabolic dysfunction-associated steatohepatitis (MASH) is linked to an elevated risk of cardiovascular and liver-related complications. Obesity is a significant risk factor for MASH, and previous studies have shown that weight reduction can help resolve the condition. Tirzepatide, a GLP-1 receptor agonist commonly used for diabetes management, also aids in weight loss. To explore its potential in treating MASH, Eli Lilly sponsored a study to investigate the effects of tirzepatide in managing this condition.
The phase 2 clinical trial involved 190 participants with an average body mass index (BMI) of 36.1 kg/m². Histological analysis of liver biopsies revealed that 43% of participants were in the F2 stage of liver fibrosis, while 57% were in the F3 stage; individuals in the least severe and most severe F1 and F4 stages were excluded from the study. The average NAFLD activity score among participants was 5.3, with 8 representing the most severe disease. Baseline biochemical analysis showed average alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 61.8 U/L and 50.6 U/L, respectively. Liver fat content, measured via MRI-PDFF, averaged 18.4%. Participants were randomly assigned to receive weekly subcutaneous injections of either a placebo or one of three tirzepatide doses: 5 mg, 10 mg, or 15 mg. After 52 weeks of treatment, tirzepatide proved more effective than the placebo in reducing liver inflammation and steatosis, with the 15 mg dose showing the greatest efficacy. Additionally, tirzepatide significantly improved fibrosis, with over 50% of treated participants experiencing at least a one-stage regression, compared to 30% in the placebo group. Tirzepatide also led to substantial reductions in ALT, AST, and liver fat content, among other biomarkers. The incidence and severity of adverse events were similar across all groups. The researchers suggested that tirzepatide may prevent hepatic fat accumulation by enhancing lipid storage in white adipose tissue and increasing fat oxidation. They also recommended that future studies should be longer, include more participants, and involve individuals with cirrhosis to better assess liver outcomes.
The phase 2 clinical trial involved 190 participants with an average body mass index (BMI) of 36.1 kg/m². Histological analysis of liver biopsies revealed that 43% of participants were in the F2 stage of liver fibrosis, while 57% were in the F3 stage; individuals in the least severe and most severe F1 and F4 stages were excluded from the study. The average NAFLD activity score among participants was 5.3, with 8 representing the most severe disease. Baseline biochemical analysis showed average alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 61.8 U/L and 50.6 U/L, respectively. Liver fat content, measured via MRI-PDFF, averaged 18.4%. Participants were randomly assigned to receive weekly subcutaneous injections of either a placebo or one of three tirzepatide doses: 5 mg, 10 mg, or 15 mg. After 52 weeks of treatment, tirzepatide proved more effective than the placebo in reducing liver inflammation and steatosis, with the 15 mg dose showing the greatest efficacy. Additionally, tirzepatide significantly improved fibrosis, with over 50% of treated participants experiencing at least a one-stage regression, compared to 30% in the placebo group. Tirzepatide also led to substantial reductions in ALT, AST, and liver fat content, among other biomarkers. The incidence and severity of adverse events were similar across all groups. The researchers suggested that tirzepatide may prevent hepatic fat accumulation by enhancing lipid storage in white adipose tissue and increasing fat oxidation. They also recommended that future studies should be longer, include more participants, and involve individuals with cirrhosis to better assess liver outcomes.