Breakthrough Clinical Results
Novo Nordisk announced that the FDA has approved Wegovy® (semaglutide 2.4 mg) for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) in adults with moderate to advanced liver fibrosis. This accelerated approval is based on part 1 of the ESSENCE phase 3 trial, which showed Wegovy® significantly improved liver fibrosis and resolved steatohepatitis compared to placebo. Wegovy® is now the first and only GLP-1 treatment approved for MASH. The approval expands Wegovy's indications beyond weight loss and cardiovascular risk reduction. Novo Nordisk has also filed for regulatory approval in the EU and Japan.
Key Highlights
- FDA approves Wegovy® for MASH treatment in adults with moderate to advanced liver fibrosis.
- Wegovy® is the first GLP-1 receptor agonist approved for MASH.
- Approval based on positive results from part 1 of the ESSENCE phase 3 trial.
- Novo Nordisk has filed for regulatory approval in the EU and Japan.
Incidence and Prevalence
Global Prevalence and Incidence of Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Metabolic dysfunction-associated steatohepatitis (MASH) is the current terminology for what was previously known as nonalcoholic steatohepatitis (NASH). It represents the most severe manifestation of Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by distinctive hepatocellular injury, inflammation, and fibrosis.
Global Prevalence Data
Recent epidemiological data from 2024 indicates that MASLD has a global prevalence of up to 30% among the general population. More specifically, a 2024 publication estimates that MASLD affects approximately 32% of the world's adult population. This prevalence is projected to continue rising alongside increasing rates of obesity, type 2 diabetes, and metabolic syndrome.
According to a 2024 cross-sectional analysis of 40,189 patients from the UK Biobank who underwent liver MRI: - 27.0% (10,886 patients) had a proton density fat fraction (PDFF) ≥5%, indicating steatotic liver disease (SLD) - Among patients with SLD, 2.2% had at-risk MASH - The at-risk MASH group represented approximately 0.6% of the general population
Projected Disease Burden
The burden of MASLD is projected to affect over 100 million people in the U.S. and 20 million in Europe by 2030. While these projections primarily address MASLD, they have implications for MASH prevalence as well, since MASH represents the progressive form of MASLD.
Demographic and Risk Factor Variations
The prevalence of steatotic liver disorders shows different sex- and BMI-specific patterns: - MASLD prevalence was significantly higher among men with a BMI ≥30 kg/m² - Non-obese women showed only a 12% risk of MASLD - The at-risk MASH group had the highest mean liver fat on MRI and the highest BMI
Clinical Significance
While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. MASH progression into advanced fibrosis may lead to decompensated cirrhosis and development of liver-related events, hepatocellular carcinoma, and death.
Risk Factors
Predisposing risk factors for MASH include: - Obesity - Type 2 diabetes - Dyslipidemia - Metabolic syndrome
The global prevalence of MASLD as a risk factor for hepatocarcinogenesis is on the rise, highlighting the growing public health concern represented by this spectrum of liver diseases.
Drug used in other indications
Indications for Wegovy® (Semaglutide 2.4 mg) Beyond MASH
Type 1 Diabetes (T1D)
Semaglutide 2.4 mg is being investigated for Type 1 diabetes through an off-label use study. This investigation employed a retrospective chart review methodology comparing semaglutide users to matched controls who did not receive weight loss medications. Patients were followed for up to 1 year, with data collected at baseline and throughout the study period. Results showed weight loss of 9.1% (-19.2 ± standard error 2.9 lbs) and improved glucose control with HbA1c decreases of -0.54 ± SE 0.14% (P = 0.0001) over 12 months. The increasing off-label use of semaglutide in T1D patients suggests a need for "larger, prospective safety and efficacy trials" in this population.
Obesity Without Type 2 Diabetes
The STEP-1 trial investigated semaglutide 2.4 mg for obesity without type 2 diabetes in obese or overweight individuals. This study utilized a randomized controlled trial (RCT) intervention model as part of the Phase 3 clinical development program, designed to assess both efficacy and safety outcomes compared to other agents or placebo.
Obesity With Type 2 Diabetes
For patients with obesity with type 2 diabetes, the STEP-2 trial evaluated semaglutide 2.4 mg specifically in this population. Like STEP-1, this study employed a randomized controlled trial (RCT) intervention model as part of the Phase 3 clinical development program, focusing on efficacy and safety outcomes.
Metabolic-dysfunction-associated steatotic liver disease (MASLD)
Semaglutide has demonstrated efficacy in treating MASLD. In a study with leptin-receptor-deficient mice, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. The treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition.
Cardiovascular Outcomes
Semaglutide has shown improvement in cardiovascular outcomes in patients with type 2 diabetes. Cardiovascular efficacy and safety of oral semaglutide are currently being assessed in a dedicated outcomes trial (as of 2022).
Real-World Applications
In a real-world study in Wales, both oral and subcutaneous formulations of semaglutide provided clinically and statistically significant reductions in HbA1c and weight. At 6-month follow-up, improvements were observed in HbA1c, body weight, and BMI for both formulations.
The intervention models for these trials range from retrospective chart reviews for off-label use in T1D to rigorous randomized controlled trials for the STEP program, highlighting the varying levels of evidence being generated for different indications of semaglutide 2.4 mg.