More data needed on GLP-1s, dual agonists to reach ‘optimal’ management of MASH, diabetes
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Metabolic dysfunction-associated steatohepatitis is significantly more common in patients with type 2 diabetes, and most patients with MASH — formerly known as NASH — experience metabolic abnormalities, including obesity.
We also know that fibrosis progression is much faster in patients with diabetes based on data from a study in Gastroenterology, and the risk for cirrhosis and liver cancer is significantly higher in patients with diabetes compared with those without diabetes. In another study, advanced MRIs showed the prevalence of metabolic dysfunction-associated steatotic liver disease can be up to 70% in patients with type 2 diabetes, and presence of advanced fibrosis is 14%. We also found that approximately 5% to 6% of patients had cirrhosis and did not know it.
Recently, an innovative disruption in the treatment of patients with type 2 diabetes and obesity has been the use of glucagon-like peptide-1 receptor agonists. Things are already changing both in the metabolic sphere and in MASH.
GLP-1 Alone vs. Dual Agonists
We have observed improvements in liver histology and a significantly higher rate of MASH resolution in patients with biopsy-proven MASH treated for up to 72 weeks with semaglutide (Ozempic, Wegovy; Novo Nordisk), a GLP-1 agonist.
More recently, placebo-controlled trials have looked at dual agonists such as tirzepatide (Mounjaro, Zepbound; Lilly), a glucose-dependent insulinotropic polypeptide/GLP-1, where even greater weight loss has been observed compared with GLP-1 analogs alone, as well as numerically higher rates of MASH resolution. Within 1 year of treatment, we noticed improvements in biomarkers of inflammation and of fibrosis and MRI proton density fat fraction (MRI-PDFF). There has been a lot of excitement with this response.
We are also looking at GLP-1 analogs combined with glucagon agonists, and these drugs have been shown to have higher rates of improvements on liver fat via MRI-PDFF compared with GLP-1 analogs alone. Among these dual agonists are survodutide (Boehringer Ingelheim), which to date has shown robust reduction in MRI-PDFF and histology, with numerically higher placebo-subtracted rates in MASH resolution and potential improvements in fibrosis.
With a combination of glucagon/GLP-1 analogs, the glucagon acts directly in the liver by increasing hepatic glucose production and can lead to gluconeogenesis, which is further helpful in reducing liver fat. Glucagon can be liver centric and may help improve liver pathophysiology on top of what we see with GLP-1 analogs alone.
Currently, there are no head-to-head trials comparing GLP-1s with dual agonists for treatment of MASH. Further studies are needed to examine relative efficacy of these compounds in improving fibrosis improvements.
‘Encouraging Data,’ But Research Still Needed
Although the full data is not available yet, what we have are encouraging, and we are starting to see improvements with combination approaches.
One issue with weight loss-associated improvements is that there are not only improvements in adiposity, or fat loss, but muscle loss may be induced as well. In future studies, the long-term impact of muscle loss in our patients who may already have sarcopenia and who have more advanced disease, such as stage 3 fibrosis or cirrhosis, needs to be evaluated, as well as safety, how long the therapy needs to be continued and what happens when patients stop.
Once we have more data on GLP-1s and dual agonists, we will be able to develop an optimal personalized approach for the management of obesity, type 2 diabetes and MASH-related fibrosis. The most important thing would be treatment to reverse cirrhosis. The verdict is still out on how we would approach this and what sort of therapies would be needed for this.
- References:
- Ajmera V, et al. J Hepatol. 2022;doi:10.1016/j.jhep.2022.11.010.
- El-Serag HB, et al. Gastroenterology. 2004;doi:10.1053/j.gastro.2003.10.065
- Lilly reports strong fourth-quarter 2023 financial results and provides 2024 guidance. https://investor.lilly.com/news-releases/news-release-details/lilly-reports-strong-fourth-quarter-2023-financial-results-and. Published Feb. 6, 2024. Accessed March 26, 2024.
- Newsome PN, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2028395.
- Survodutide phase 2 trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH, with significant improvements in fibrosis. https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/survodutide-top-line-results-mash-fibrosis. Published Feb. 26, 2024. Accessed March 26, 2024.
- For more information:
- Rohit Loomba, MD, MHSc, is founding director of the MASLD Research Center and chief of the division of gastroenterology and hepatology at the University of California, San Diego. He can be reached at roloomba@health.ucsd.edu.
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