‘Whether or not we like it,’ GLP-1s are part of hepatology, treatment of MASH
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To put it simply, diabetes and steatotic liver disease are joined at the hip. They are part of the same biological process that involves multiple organs, connected by the concept of metabolic flexibility — or lack thereof.
Diabetes occurs late in the course of steatotic liver disease when individuals have enough insulin resistance that the pancreas can no longer adapt and cope with it. Therefore, patients start losing beta cells. These patients tend to also have more disease in the liver, heart and other places, which may lead to enhanced adverse effects. Conversely, patients with the most aggressive metabolic dysfunction-associated steatohepatitis often have diabetes as a comorbid condition.
This linkage between obesity, insulin resistance, diabetes and liver disease makes it conceptually obvious why the use of glucagon-like peptide 1 in MASH has improved liver fat. But it does not capture the full treatment effect because one of the important measures we are interested in is the fibrosis stage.
Concerns If GLP-1s Can ‘Deliver’ on Treating Fibrosis
If we can clear up the fat in patients with early-stage disease with an effective therapy for underlying obesity and diabetes before there is any liver scarring, then GLP-1 use is a good thing. However, for patients with advanced fibrosis, concerns remain about whether GLP-1 therapies can deliver on treating fibrosis.
Although we do not have data to show a clear-cut reversal of fibrosis, GLP-1 does slow it down. So far, published data suggests that a GLP-1 alone can make progress on steatosis in MASH within a 72-week time frame. But no studies were designed to address this in a definitive manner.
The phase 3 trial with semaglutide (Ozempic, Wegovy; Novo Nordisk), a GLP-1 agonist, is going to provide important data about both progression and regression. Further, tirzepatide (Mounjaro, Zepbound; Lilly), a glucose-dependent insulinotropic polypeptide/GLP-1; survodutide (Boehringer Ingelheim); and retatrutide (Lilly), a novel triple agonist of GIP, GLP-1 and glucagon receptors, have considerable potential because they are potent at inducing weight loss.
The advent of GLP-1 use in MASH has impacted drug development because it has affected our ability to get patients into trials. Many patients are being put on GLP-1-anchored therapies for weight loss by their primary care physicians, so their weight is unstable because it’s dropping. By the time they see the specialist, their bodies are in flux — their weight and their whole biology is shifting, they are not in a steady state and, therefore, they do not meet criteria to go into clinical trials for drug development.
GLP-1s ‘Coming Down the Road’ in Hepatology
The field continues to evolve rapidly, but we have not established whether there is a ceiling effect that, when beyond a certain level, there is no further improvement in liver disease with increasing weight loss. Where is the line drawn? I think we are getting close to seeing that.
We need to be able to identify patient populations that can be solely managed with a GLP-1 and populations that need a liver-targeted therapy in addition to weight loss therapy. This is particularly relevant with the recent approval of Rezdiffra (resmetirom, Madrigal Pharmaceuticals), which has both a fibrosis and MASH benefit. In my opinion, a combination therapy would make sense in patients who have significant fibrosis and active disease. But those are the patients for whom liver-targeted therapeutics will be important.
Many of our patients are already on GLP-1s; however, hepatologists are not as familiar with GLP-1s because they are not historically within the portfolio of drugs that hepatologists routinely use.
There is some level of anxiety about how to best use GLP-1s and manage the side effects related to nausea. We should learn from our colleagues in diabetology, who have been using GLP-1s for much longer and have worked out best practices to manage side effects. The key is to go slow. I advise patients to stop eating as soon as they start feeling full, because otherwise it leads to nausea and vomiting. There are other ways to minimize the side effects profile to maximize retention of patients on the drug, because the drugs do not work if patients do not take them.
The use of GLP-1s must be part of what hepatologists do because they are coming down the road — whether or not we like it.
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- Arun Sanyal, MD, is director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine. He can be reached at arun.sanyal@vcuhealth.org.
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