Approved Medications for MASLD/MASH

In Part 5 of this roundtable discussion, Drs Afdhal, Bansal, and Younossi review the approved medications resmetirom and GLP-1 receptor agonists for MASLD/MASH, including how they work, selecting patients best suited for each, using dual therapy, and shared decision-making with patients.
 

MASH (MASLD) Treatment Update: Resmetirom, Semaglutide, and Real-World Combination Use

• Resmetirom (thyroid hormone receptor beta agonist for F2–F3 noncirrhotic MASH improves mitochondrial function and lipid metabolism, achieving fibrosis regression ≥1 stage without MASH worsening and MASH resolution without fibrosis worsening; also reduces LDL by ~16–20% and improves atherogenic lipids (Lp(a), ApoB). It is an oral once-daily therapy with mild GI side effects (nausea/diarrhea early, resolving by ~12 weeks) and high adherence (~85–90% at 1 year).
• Semaglutide improves MASH outcomes indirectly via weight loss and insulin resistance reduction (no direct hepatic receptor effect). It has established use in obesity and type 2 diabetes, with additional cardiometabolic and behavioral benefits (weight loss, reduced alcohol cravings), and can be used earlier across fibrosis stages.
• Treatment selection and real-world practice: GLP-1s are often first-line in patients with obesity and/or diabetes; resmetirom is favored for higher fibrosis burden or added when fibrosis persists despite GLP-1 therapy. Combination therapy is common (≈40% in one clinic), with many patients already on GLP-1s at presentation and resmetirom added based on fibrosis criteria and shared decision-making.

Nezam Afdhal, MD, is Chief of Gastroenterology and Hepatology at Beth Israel Deaconess Medical Center and a professor of medicine at Harvard Medical School in Boston, Massachusetts. Meena Bansal, MD, is Chief of the division of Liver Diseases and Director of the MASH Center of Excellence at Mt Sinai Medical Center in New York, New York. Zobair Younossi, MD, is chairman and professor of the Liver and Obesity Research Program at INOVA Health in Fairfax, Virginia, and chairman of the Global NASH Council.

TRANSCRIPT:

Dr Afdhal: So we've done the lifestyle modification. We've discussed all these issues. So Meena, I'm going to turn to you to tell us a bit about the two approved treatments that we have today, the GLP-1 agonist, the semaglutide, and also the thyroid beta agonist, resmetirom.

I want you to tell us a little bit about each one, and then I'm going to put you a little bit on the spot and ask you to tell us a little bit about how you might choose which one of these therapies to use based on some of the clinical characteristics of the patient population that you see.

Dr Bansal:

Sure, sure. So I'll start with resmetirom, which was the first FDA-approved therapy in March of 2024, and that is a thyroid hormone receptor beta agonist. And it works under the pretense that one of the driving factors in MASLD/MASH is intrahepatic hypothyroidism, which leads to accumulation of excess triglycerides and fat. And so the idea is that this thyroid hormone receptor beta has some very positive beneficial effects on mitochondria, which are really the workhorse of the hepatocyte and help burn the excess fat in the hepatocyte. So this thyroid hormone receptor beta does two things. One, it kind of causes mitochondrial biogenesis or the replication of new fresh mitochondria in an effort to increase the beta oxidation capacity of the hepatocyte. It also promotes the mitophagy or the removal of the tired mitochondria that have been working so hard for many years to kind of keep up with that kind of excess fat.

So by replenishing, if you will, the fat burning factory, this drug works. It also has a beneficial effect at increasing the expression of LDL receptors on hepatocytes. So you see about a 16 to 20% reduction of LDL in patients on this drug. And to Zobair’s point that we need to be lipidologists, we need to think about cardiovascular outcomes as well. So there is that potential benefit of having that LDL, and it actually has beneficial effects on LP little a, ApoB—so other atherogenic lipids that might have important implications for decreasing cardiovascular risk down the line.

So as we know, that was approved for F2-F3 noncirrhotic MASH, hit the 2 endpoints of fibrosis regression by greater than 1 stage without worsening of MASH and MASH resolution without worsening of fibrosis. The range of kind of 8 to 15 kPa was the AASLD guidance. Zobair, I think we're part of the expert consensus that felt 10 to 15 was a better sweet spot. Eight, you're going to catch, I think, some with less than F2 fibrosis, which is less of an issue, I think, when you talk about semaglutide or GLP-1, because there's a lot of other reasons that we can get into that, that you may want to start that even at earlier stages of fibrosis.

So those are the key indications for resmetirom oral once a day with or without food. So I think from an ease of delivery, it's very easy. The side effect profile is excellent. A little bit of nausea and diarrhea in the first 4 weeks, which generally resolves by 12 weeks and rarely causes medication discontinuation. I think in the real-world data after a year, 85, 90% are still adherent and able to stay on therapy. Then we get to the GLP-1 semaglutide, which got the approval in August of this year [2025]. And I think the advantage to GLPs is they've been around for a while.

So we have a lot of ... They've been around— liraglutide 10 plus years. So we have a lot of data in this class of drugs, and we know that it's already FDA-approved for patients with obesity and cardiovascular complications and those with type 2 diabetes. So it's already been a drug that's out there. And in the formulation of Wegovy, getting to that 2.4 dose, you saw weight loss. And along with that weight loss, you have the reduction in fibrosis and MASH resolution. Keep in mind that unlike resmetirom, where there are receptors in the liver for the drug, there are no GLP-1 receptors in the liver. There is some suggestion that infiltrating T-cell subsets might express the GLP-1 receptors and maybe sinusoidal endothelial cells, but really the bulk, there's really no expression. So the effects that you're seeing in the liver are really secondary to the improvement in insulin resistance and weight

Dr Afdhal:

Loss. Fantastic. So you mentioned it in the discussion, and we've kind of talked about it before, that this is a disease of spectrum, that as hepatologists, we're always talking about F stages. And most of the times that's relatively irrelevant. There's early disease, there's more advanced disease, and then there's cirrhosis. And obviously cirrhosis is a critical diagnosis because of the various screening things you have to put in once cirrhosis is there. But you also mentioned the fact that the GLP-1 class of agents, and I know Wegovy is approved, but really many of the newer GLP-1 agents are kind of, because there is no liver-specific effect, they're kind of interchangeable in many ways. You talked a lot about their cardiometabolic benefits and the fact that they've been used. They also improve mortality in people with obesity and diabetes. They have a lot of secondary benefits on the factors that patients worry about.

I mean, our patients are often worried about things like their weight, and weight loss makes patients extremely happy. There's also the additional benefit that the cravings for alcohol are reduced by agents like GLP-1 agonists, and that we will often hear our patients say, "Oh, I started the GLP-1 and I don't feel like drinking anymore and I can no longer drink beer. I feel full and I don't have a desire for it. " So lots and lots of secondary benefits. So if you were to say who in a patient spectrum you might choose one versus the other, what would you say? And it may be that there really isn't a patient that one is better than the other 4.

Dr Bansal:

Yeah. I mean, I think that as you point out, if you can kill more than one bird with a stone in certain patients, you might choose that approach as a first line. So if you have somebody who's living with obesity, perhaps their diabetes is not fully controlled and they have MASH with significant fibrosis, you need to deal with the diabetes and the obesity anyway. So if you have a secondary and an additional benefit on the liver, certainly that seems like a good first-line therapy for that individual patient provided they're also interested in that approach.

I think one thing to keep in mind is many patients come to us already on a GLP-1, which is also a really important thing. So many are already on it for the indication that already exists such as diabetes or obesity. And so if despite that, they still have significant fibrosis, then it's a different conversation because then you're going to be wanting to add on something like resmetirom or Rezdiffra.

But in somebody who is tackling, as you said, it has all of these other benefits, this is where shared decision-making I think is really important in discussing with the patients what their goals are and what their interest would be. Some people, like you said, losing weight is usually something many people want to do, and so it certainly is, and they've struggled and people have told them to do this diet and this exercise for many, many years, and they haven't been successful at that. So I think that looking at the patient holistically, if their diabetes is well-controlled and their weight is not a huge concern, maybe they're just in the overweight category, for example, then perhaps I might go and their kPa is on the higher side, then I might go with a resmetirom.

Dr Afdhal:

Fantastic. Just listening to you there, and I'll bring Zobair in on this one, when we analyzed our data at BIDMC on the patients that we treat in the MASH clinic with either a GLP-1 that we prescribe as the prescribers, not necessarily those that are coming to us already on GLP-1s and looked at that in resmetirom, we found that actually 40% of our patients are now on dual therapy. They're actually on dual therapy. And I think this is an important point because as we get to newer treatments, we're going to talk about where new treatments come in and how they can help. So Zobair, you have a big MASH clinic. What do you see now in terms of already using a multi-treatment type approach?

Dr Younossi:

Yeah, to be honest with you, the vast majority of my patients, when I see them, they are already on a GLP-1. They come in with that because folks in the primary care and even endocrinology are not still, they're not case finding for MASH per se. So the first thing they do, and they go first and instead of going to metformin as a first-line treatment for diabetes, they now start a lot of these patients on GLP-1 receptor agonist. So by the time I get them, the vast majority are already on a GLP-1 receptor agonist. So the issue for me is that do I add a second drug or not? And if I have a patient that meets the criteria with either a VCT or an ELF test, I'm starting actually resmetirom. And to me, when this is really ... The question is, do we have data with combination therapy?

Well, we don't have combinations starting de novo, but we do have patients who were on GLP-1 receptor agonist in the MAESTRO NASH trial who came in and actually got the resmetirom. And there was not an increased efficacy, but that may have been because of the fact that they had gotten some benefit from their GLP-1 before. So I'm in a complete agreement that a lot of our patients would be on both. They will be on ... The number of patients that I had to start completely de novo on a GLP-1 were basically patients who could not get insurance coverage for obesity indication, and now they could get it for MASH indication. Otherwise, our diabetics get it, for most of them are on a GLP-1 or a dual agonist for weight loss. And my job is really relatively easy because I'm going to add resmetirom to those patients.

And at the end of the day, the question ultimately will be a clinical decision. It's really clinicians that are going to have to decide. It's not going to be just a recipe that we have to always follow because we have to think about what drugs available, what's the coverage, what's the side effect? Is the pain all the patients may not like injection, although these injections are pretty simple, but oral is always a bit superior to, at least in terms of route of administration. Although I can tell you that the injection itself is not an issue, but side effects may be an issue in the real-world setting. When you look at how many patients were still on GLP-1 receptor agonists a year after they started, and why they stopped? Was it because there was no coverage? Was it because of side effects or people just stopped because of whatever reasons?

So I think those are the issues that come together. But then reality in practice is that as you say, Ned, most of our patients are now for MASH, they will be on a GLP-1 receptor agonist or dual agonist, and we just add resmetirom to those patients.

Dr Bansal:

I would just add that one of the things that we see is they come in on the 1 milligram dose. So they got the diabetes indication for the 1 milligram dose, but then we can dose escalate that to get to the 1.7, 2.4 ideally, see how that gives them additional benefit and then reassess and then add resmetirom if they need it.