Survodutide in MASH

Credits
- Section Writer: ChatGPT 4o
- Section Editor: Dr. Om J Lakhani

Support us:

Support you by Becoming a YouTube member (Click here).
- Premium Membership- Download PDF version of Notes, Get ad free video and more
- Consultant Membership- Above plus Download Powerpoint presentation of the notes
Support us by purchasing our book - Click here for more details:
- Volume 1- THE BEST OF NOTES IN ENDOCRINOLOGY BOOK SERIES
- Volume 2- THE BEST OF NOTES IN ENDOCRINOLOGY - DIABETES SPECIAL
For more such updates follow our WhatsApp Channel: https://whatsapp.com/channel/0029VaFyQnfHbFUz0LVdBO3h

1. Title of the article:*
- A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
2. First two Authors followed by et al:*
- Arun J. Sanyal, M.D., Pierre Bedossa, M.D., Ph.D., et al
3. One line summary of the article:*
- This phase 2 trial evaluates the efficacy and safety of survodutide, a dual agonist of the glucagon receptor and GLP-1 receptor, in treating metabolic dysfunction–associated steatohepatitis (MASH) and liver fibrosis.
4. Six key points from the article in a numbered format:*
- 1. Survodutide showed significant improvement in MASH with no worsening of fibrosis compared to placebo.
- 1. The trial included 293 participants who were randomly assigned to different doses of survodutide or a placebo.
- 1. Improvement in liver conditions was dose-dependent, with the 4.8 mg group showing the highest efficacy.
- 1. Secondary outcomes like decreased liver fat content and fibrosis stage improvement were also favorable in the survodutide groups.
- 1. Adverse events were more common with survodutide, including nausea, diarrhea, and vomiting, leading to some trial discontinuations.
- 1. Despite gastrointestinal side effects, survodutide demonstrates potential as a therapeutic agent for MASH, warranting further phase 3 trials.
5. Practical take home message:*
- Survodutide, a dual glucagon and GLP-1 receptor agonist, shows promise in improving liver conditions in patients with MASH and fibrosis, though gastrointestinal side effects need careful management.
6. Citation for the article in vancouver format:*
- Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024; DOI: 10.1056/NEJMoa2401755.
  ===
Q. _What exactly is Survodutide ?
- Survodutide (BI 456906) is a pharmacological compound designed as a dual agonist for both the glucagon receptor and the glucagon-like peptide-1 (GLP-1) receptor. Here’s an overview to provide clarity on its function and purpose:
1. Dual Receptor Agonist:
  - Glucagon Receptor Agonism: Glucagon is a hormone involved in regulating glucose and fat metabolism. Agonizing the glucagon receptor can enhance energy expenditure, increase lipolysis (the breakdown of fats), and mobilize hepatic (liver) fat.
  - GLP-1 Receptor Agonism: GLP-1 is an incretin hormone that enhances insulin secretion, inhibits glucagon release, slows gastric emptying, and reduces appetite.
2. Potential Therapeutic Benefits:
  - Liver and Metabolic Effects: The combination effect of glucagon and GLP-1 receptor agonism aims to address multiple facets of metabolic dysfunction. While GLP-1 receptor agonism helps with glucose control, reducing appetite, and promoting weight loss, glucagon receptor agonism contributes by directly affecting liver metabolism, boosting energy expenditure, and reducing hepatic fat accumulation.
  - MASH and Fibrosis: Specifically designed to treat metabolic dysfunction–associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), and associated liver fibrosis, survodutide helps in reducing liver inflammation, steatosis (accumulation of fats in the liver), and fibrosis (scarring).
3. Administration and Dosage:
  - Survodutide is administered subcutaneously (under the skin) once weekly.
  - In clinical trials, it has been tested in different dosing regimens to establish the optimal balance between efficacy and safety (e.g., 2.4 mg, 4.8 mg, and 6.0 mg doses).
4. Clinical Trial Findings:
  - Survodutide has shown promise in improving histological markers of MASH and liver fibrosis.
  - It has demonstrated dose-dependent effects on reducing liver fat content and improving liver histology.
  - Common adverse events include gastrointestinal disturbances like nausea, vomiting, and diarrhea.
  In essence, survodutide represents an innovative approach in the treatment of complex metabolic and liver diseases by leveraging dual agonism to target both metabolic and hepatic pathways.
Q. What dose of the agent was found to be most effective in this trial ?
- In the phase 2 trial, the dose of survodutide that was found to be most effective in achieving histologic improvement in metabolic dysfunction–associated steatohepatitis (MASH) without worsening of fibrosis was the 4.8 mg dose. Here are some key findings that highlight its efficacy:
1. Primary End Point - Improvement in MASH:
  - 47% in the 2.4 mg group
  - 62% in the 4.8 mg group
  - 43% in the 6.0 mg group
  - 14% in the placebo group
  The 4.8 mg dose group showed the highest improvement rate, with 62% of participants meeting the primary end point, compared to 14% in the placebo group.
2. Secondary End Points:
  - For the reduction of liver fat content by at least 30%, the proportions were:
    - 63% in the 2.4 mg group
    - 67% in the 4.8 mg group
    - 57% in the 6.0 mg group
    - 14% in the placebo group
  Again, the 4.8 mg group had the highest percentage of participants achieving significant reduction in liver fat content.
3. Improvement in Fibrosis:
  - While the improvement in fibrosis was similar across all survodutide groups (34% to 36%), it was still superior to the placebo group (22%).
  Overall, the 4.8 mg dose was identified as the most effective in balancing efficacy and safety, showing the highest rates of improvement in key outcomes without a significant increase in adverse events compared to other doses.
Q. How was fibrosis recognized ? Was a biopsy done ?
- Yes, fibrosis was recognized through biopsy. In the described study, liver biopsies were performed to confirm the diagnosis of metabolic dysfunction–associated steatohepatitis (MASH) and to assess the stage of liver fibrosis. Here are the relevant details:
1. Biopsy Confirmation:
  - Participants included in the study had biopsy-confirmed MASH with fibrosis stages F1 through F3 prior to randomization. This means that initial liver biopsies were used to determine eligibility for the trial based on fibrosis staging.
2. Assessment at Baseline and End of Treatment:
  - A baseline liver biopsy was used to establish the participants' initial fibrosis stage and other histologic features relevant to MASH.
  - An end-of-treatment liver biopsy was conducted after 48 weeks of treatment to evaluate the primary end point, which was histologic improvement in MASH without worsening of fibrosis.
3. Histologic Scoring:
  - The histologic assessment was performed by a central pathologist, who evaluated both the NAFLD (non-alcoholic fatty liver disease) activity score and fibrosis stage.
  - The NAFLD activity score is a composite score that includes components like steatosis, lobular inflammation, and hepatocellular ballooning. Higher scores indicate more severe disease.
4. End Points:
  - The primary end point was defined as improvement in MASH (at least a 2-point decrease in the NAFLD activity score with a decrease of at least 1 point in either lobular inflammation or hepatocellular ballooning) without any increase in fibrosis stage.
  - Improving fibrosis by at least one stage and a decrease in liver fat content by at least 30% were secondary end points.
  - Participants who did not have an end-of-treatment biopsy were considered nonresponders for the purposes of the primary analysis.
  This biopsy-centric method ensures a precise and objective assessment of liver histology, which is crucial for evaluating the efficacy of treatments for liver conditions such as MASH and fibrosis.