What's Ahead for MASLD and MASH?

The expert roundtable on MASH and MASLD wraps up as Drs Fontana, Abdelmalek, and Arab consider treatment advances in progress and encourage gastroenterologists to make use of the tools available today to risk assess, treat, and monitor their patients with MASLD or MASH.

Robert Fontana, MD, is a professor of medicine and director of the Transplant Hepatology Fellowship Program at University of Michigan Medicine in Ann Arbor, Michigan. Manal Abdelmalek, MD, FAASLD, is a professor of medicine and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) Clinical Research Program at Mayo Clinic in Rochester, Minnesota. Juan Pablo Arab, MD, is associate professor of medicine and the inaugural director of Alcohol Sciences at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University (VCU) Health in Richmond, Virginia.

Steatotic Liver Disease: Risk Stratification and Treatment in GI Practice

• MASH with F2–F3 fibrosis: Consider treatment now with resmetirom or semaglutide rather than waiting for newer therapies. Assess fibrosis, cardiovascular risk factors, alcohol use, and alcohol use disorder.
• ALD and MetALD: Address alcohol use through counseling and medications. In a MAESTRO-NASH sample analysis, 10% were heavy drinkers; resmetirom response rates were similar to those in other participants and may help reduce the craving for alcohol. 
• GLP-1 therapy: Dr Fontana recommends starting low and increasing slowly; he described waiting 6 weeks before dose escalation and involving a dietitian to support tolerability.

Dr Fontana:

Certainly lots for all of us to do and work on to move the field forward. But I think one of the take home points I'm hearing is we don't need to wait for something better to come. We should be able to risk stratify patients. We should be able to immediately intervene on the alcohol access, whether it's through counseling, medications are coming more into vogue and prescribed by nonmental health providers like ourselves for patients with MetALD and ALD. And then certainly I think in most medical centers, resmetirom and semaglutide for MASH falls in the hands of GI and liver specialists. I don't get the sense, maybe it may vary from center, that endocrinologists are taking this on. Is that your experience?

Dr Abdelmalek:

I think the endocrinologists are very comfortable with GLP-1s and are prescribing it agnostic to the underlying liver disease. So they are certainly doing a great job with use of the GLP-1s and likely treating underlying fatty liver disease as well, steatotic liver disease. So we are adding liver directed therapies on in the right cohorts.

Dr Fontana:

Great. Well, before we close here, any other thoughts again for the practicing GI doc of pearls or things to be aware of in the next year or two? So let me first start with you, JP. Anything else coming down the pike, guidelines, major studies that people should be looking for, that kind of thing?

Dr Arab:

Yeah, so probably the only thing in those lines, although it's very important to assess for alcohol and identify people with alcohol use disorder, is many of these drugs have also been testing in ALD or MetALD. So I think down the road we may come up with opportunities where we can treat independent if this is more MASLD or more ALD. So Naim Khoury actually presented the data for resmetirom where they analyzed the samples of the MAESTRO-NASH trial and they found that 10% were actually heavy drinkers and the response rates were very similar. So there is some data that this may work even if you are on the heavier drinker side. And this year actually in May was published in Lancet, the paper for the use of semaglutide for alcohol use disorder. It's not a liver trial. The liver trial is likely going to be presented by the end of the year, but the use of semaglutide reduced the drinking, so the heavy drinking days.

So I think there is evidence to support that some of these drugs may be working in both sides. So my final thoughts to the GI doctors is don't be afraid. Sometimes we like to overly complicate things, but I think under this umbrella of steatotic liver disease, we care about fibrosis. If the patient has fibrosis, we need to act quickly and we want to stratify cardiovascular risk factors because sometimes these patients die from cardiovascular events, not necessarily due to the liver. We want to look at the alcohol part too, and that can give you the full picture. So that will be my final thoughts.

Dr Fontana:

I think that's good advice. Don't be afraid to try these. And I think to your point, many of us who've been around for a while used interferon for Hep C, that was a much more toxic drug than the GLP-1s. And my experience also has been that if you start the GLP-1s, you should start low and go slow. In other words, don't go from zero to a hundred miles an hour full dose. And I find oftentimes that some patients have been tried on them before and they're very hesitant to try them again. But then if I start low and I wait 6 weeks before I do a dose increase and also have the dietician in almost for reassurance, patients seem to be able to do it with that. So Manal, one final thing. Again, looking more forward, JP said we're probably going to have triple drugs, dual drugs, more potent, more weight loss, FGF21.

One thing that we didn't talk about, and I'm curious to know since you've done a lot of research, is what about the personalized medicine? Will genetics or a microbiome profile become part of clinical practice in the near future? Or is that just not there yet and the drugs are going to trump genetics and/or microbiome? I mean, what's your gestalt there for the practicing GI doc?

Dr Abdelmalek:

That's a great question and a very challenging one. I am not convinced as of yet that genetics is going to trump everything. So this is a gene-environment interaction, and there probably is certainly more than one gene polymorphism that influences not only the acquisition, but the risk of progression. So to think that we can target just one gene in this complex physiology, maybe a little shortsighted as of yet. I mean, the data with the PNPLA-3 that was presented by Rohit Loomba at EASL was really kind of eye-opening. We weren't expecting that not targeting that gene would not have an influence on this, which speaks to the multifaceted nature of this disease. I also think that the heterogeneity of the gut microbiome may really make that a very difficult target for therapeutics at this juncture. So targeting metabolic syndrome and insulin resistance is a driver and partnering.

I think we're going to see a lot more data with regards to combination therapies in the upcoming year. The top line results of the Pan-PPAR agonist lanifibranor will come out, and certainly we're going to see data on the dual and triple agonists in the upcoming year. So if the antifibrotic effect and antisteatohepatitis effect of these therapies is incrementally increasing, then we have a one-size-fits-all approach to therapy. We need a safe, bigger gun, in which case the genetics may not be as relevant in the disease.

Dr Fontana:

Right. Well, I really appreciate the time you've spent and giving us your perspective because I think that's what we all need is just some sort of creating realistic expectations as practitioners in what we tell our patients. And now's the time when there's no need to wait for better therapeutics. We can offer them. And that in the near future, we may have even more to offer that may be more potent, more effective, but now's the time certainly for your F2, F3 patients to consider treating them.

So on behalf of the GI Learning Network, I'd like to thank all of our audience for listening in to us. Certainly, if any of you have any questions or follow up from what we discussed today, you can feel free to reach out to any of the three of us. We can provide our information. We hope to see you soon, either at one of the upcoming liver meetings or one of the GI meetings, DDW, in the near future, and certainly hope you have a great day.

Thank you.