SYNERGY: Tirzepatide for NASH

Dr. Tashko presents the SYNERGY trial results, revealing Tirzepatide's significant benefits in treating NASH and liver fibrosis, offering promising advancements in managing these liver conditions.

June 2024 NEJM

Introduction – Diabetes & Obesity Care, Maryland

As a diabetologist and weight loss specialist with extensive clinical and research experience, I emphasize staying current with the latest advancements. My goal is to offer our community the highest standard of care using personalized and integrative approaches.

Conveniently located in Rockville, my practice offers virtual and in-person services, extending support to nearby areas such as Chevy Chase, Bethesda, North Bethesda, Potomac, North Potomac, Gaithersburg, Germantown, Frederick, Silver Spring, Northern Virginia, Howard County, Anne Arundel, and the Eastern Shore of Maryland, ensuring comprehensive care.

Here, I provide a brief summary of the SYNERGY study on Tirzepatide’s effects in liver disease. This study highlights the benefits of Tirzepatide in improving NASH and fibrosis scores in patients with obesity and type 2 diabetes. We will delve into the key findings and results published in the New England Journal of Medicine in June 2024.

What is MASH or NASH?

Metabolic dysfunction–associated steatohepatitis (MASH), formerly called nonalcoholic steatohepatitis (NASH), is a severe liver disease. MASH involves fat buildup, liver inflammation, and cell injury, often leading to fibrosis. With rising obesity and type 2 diabetes, MASH cases are growing globally. It was the second leading reason for liver transplants in 2019. Today, the FDA has approved only one medication for NASH treatment: Rezdiffra (resmetirom), along with diet and exercise.

Testing Tirzepatide

Researchers conducted a phase 2 clinical trial to assess tirzepatide’s effectiveness. Tirzepatide is a new drug that targets two receptors, GIP and GLP-1, known to help with insulin production and reducing appetite. The trial included 190 participants with confirmed MASH and moderate to severe fibrosis. They were randomly assigned to receive either tirzepatide (at 5 mg, 10 mg, or 15 mg) or a placebo once a week for 52 weeks. The main goal was to see if tirzepatide could resolve MASH without worsening fibrosis.

Dr. Tashko presents the baseline characteristics of the SYNERGY trial, published in NEJM in June 2024, highlighting key patient demographics and study parameters.

Promising Results

By the end of the trial, 157 participants had biopsy results available for analysis. The study found that tirzepatide significantly outperformed the placebo.

  • MASH Resolution:
    • Placebo: 10% success rate
    • 5 mg tirzepatide: 44% success rate
    • 10 mg tirzepatide: 56% success rate
    • 15 mg tirzepatide: 62% success rate
  • Fibrosis Improvement:
    • Placebo: 30% success rate
    • 5 mg tirzepatide: 55% success rate
    • 10 mg tirzepatide: 51% success rate
    • 15 mg tirzepatide: 51% success rate
Dr. Tashko presents SYNERGY trial results published in NEJM, June 2024. Tirzepatide outperforms placebo in enhancing MASH and Fibrosis scores.

Secondary Benefits and Side Effects of Tirzepatide

Tirzepatide also improved liver function markers, including ALT, AST, and GGT levels. Participants experienced weight loss and reduced liver fat. However, the most common side effects were mild to moderate gastrointestinal issues like nausea, diarrhea, and constipation.

Weight Loss as a Key Factor

Weight reduction plays a critical role in managing MASH. Both lifestyle changes and bariatric surgery have shown benefits. Tirzepatide’s ability to induce significant weight loss makes it a promising treatment. It could potentially prevent major liver complications and improve overall liver health.

Why These Results Matter

Previous treatments for MASH (or NASH), like GLP-1 receptor agonists, mainly reduced liver fat and inflammation but didn’t improve fibrosis. Tirzepatide’s dual action on GIP and GLP-1 receptors not only reduces body weight more effectively but also improves insulin sensitivity and liver function.

While this study shows promising results, it had limitations. The trial was relatively short (52 weeks), and the sample size was small. Longer and larger studies are needed to fully understand tirzepatide’s long-term effects and safety. Researchers also need to explore its effectiveness in patients with advanced liver disease, including cirrhosis.


Tirzepatide offers a new hope for MASH patients, showing significant improvements in liver health and fibrosis. With further research, it could become a key treatment option, helping to reduce the global burden of this progressive liver disease.

Dr. Tashko

Weight Loss Specialist or Obesity Expert