Real-World Resmetirom Data Look Promising in MASH: Naim Alkhouri, MD

Only about 5% of patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate to advanced fibrosis in his clinic need a liver biopsy before treatment, and real-world discontinuation of resmetirom (Rezdiffra; Madrigal Pharmaceuticals) is around 10% at 1 year, said Naim Alkhouri, MD, chief academic officer at Summit Clinical Research.

In part 1 of this interview with The American Journal of Managed Care® (AJMC®), Alkhouri discusses how real-world resmetirom data compare with the phase 3 MAESTRO-NASH trial,¹ when biopsy is still necessary, and how he chooses between resmetirom and semaglutide (Wegovy; Novo Nordisk), including adding resmetirom to a stable glucagon-like peptide 1 (GLP-1) regimen. He also explains how he counsels patients on gastrointestinal (GI) adverse events to support persistence and how prior authorizations and copays continue to limit access.

This interview has been edited for clarity.

AJMC: You led a real-world study of resmetirom in clinical practice, following patients after the 2024 approval. Can you talk about what you saw in your clinic compared with what the phase 3 trials had seen and predicted?

Alkhouri: The FDA approval of resmetirom in March 2024² was based on the results of the MAESTRO-NASH phase 3 trial.¹ In that study, we did biopsies on about 888 patients with F2, F3 fibrosis with MASH, and we had to do a second biopsy after 52 weeks to assess for MASH resolution and fibrosis improvement.

One of the concerns we had was, in clinical practice, are we going to identify the right patients without a liver biopsy? And what is the real-world data going to look like? We did a project where we pulled data from 6 academic centers that started to treat patients with resmetirom in the real world. We had around 650 patients that were treated, and we learned that about 90% were approved by insurance based on vibration-controlled transient elastography [VCTE; FibroScan], measuring liver stiffness. The cutoff that we used was liver stiffness more than 8 kPa to identify F2 and F3.

We also had about 15% of patients have the ELF [enhanced liver fibrosis] test available. Some patients had a historic biopsy that was done to rule out other etiologies, like autoimmune hepatitis, but they ended up having MASH with F2 or F3, so they qualified this way. There’s some overlap with some patients having a FibroScan and an ELF test, or a FibroScan and a biopsy. We learned that patients in the real world also had a heavy metabolic burden in terms of the metabolic comorbidities. About 50% of our patients had type 2 diabetes and about two-thirds had hypertension or dyslipidemia, which is very similar to what we saw in the MAESTRO-NASH trial.

Then we started to follow these patients over time and generate some data, and I presented some data at the last International Liver Congress from a different data set. This is the EASL [European Association for the Study of the Liver] meeting, where we had about 712 patients followed in the real world, and we had their baseline noninvasive test and then follow-up within 6 to 12 months.³

We showed that about 40% of patients achieved a reduction in VCTE liver stiffness by 30% or more. About 46% reduced stiffness by 25% or more, about 45% reduced their ALT [alanine aminotransferase] by 20% or more, and about 45% achieved a reduction in the FAST [FibroScan–AST] score. That includes liver stiffness, the CAP [controlled attenuation parameter] score, and AST [aspartate aminotransferase] levels. The efficacy data in the real world also is looking very promising.

In terms of tolerability, we also learned that most patients are able to remain on resmetirom after 1 year of treatment, with a discontinuation rate around 10% in the real world, which is pretty good for a drug for a chronic disease like MASH with F2/F3.

AJMC: How do you decide in the real world when a patient needs a biopsy confirmation before starting therapy versus relying on noninvasive tests?

Alkhouri: Most of the time, we are able to qualify patients for treatment based on noninvasive tests. There are 2 scenarios where we need to do the biopsy. One is if the noninvasive tests are completely discordant, like 1 test is showing F0, no fibrosis, and the next test is showing F3 fibrosis, and you cannot make an accurate decision if the patient has MASH with F2/F3. Then we do the biopsy sometimes.

Typically, in our clinics, we are doing the VCTE or the ELF, and we look at the patient characteristics, and we calculate the FIB-4 [Fibrosis-4] index. If there’s complete discordance, typically we go to another noninvasive test like MR elastography. But once in a while, the noninvasive tests are inconsistent, so we do a biopsy.

The second scenario is that you could have MASH overlap with another chronic liver disease, and the most common clinical scenario is potentially autoimmune hepatitis overlapping with MASH and F2/F3. We routinely test for autoimmune biomarkers, like autoantibodies, like smooth muscle antibodies, and when the titers are positive, especially if they have significant elevation in AST/ALT, then sometimes we do the biopsy to rule out the coexistence of autoimmune hepatitis.

When it’s all said and done in the clinic, we biopsy about 5% of patients. Then, we are able to determine if the patient has MASH with F2/F3, start treatment, and monitor the treatment without a biopsy in 95% of patients.

AJMC: Semaglutide (Wegovy) has joined resmetirom as an option for MASH with fibrosis. Can you talk about the clinical patient profiles or characteristics that may drive your decision to choose between the GLP-1 versus a liver-directed therapy like resmetirom?

Alkhouri: Semaglutide was approved in August 2025.⁴ This is based on the ESSENCE phase 3 trial,⁵ and similar to MAESTRO-NASH, we randomized, in the first part, 800 patients with biopsy-proven MASH with F2/F3, treated them with dose-escalation semaglutide to 2.4 mg weekly, and then we biopsied them after 72 weeks of total treatment duration, and we looked at MASH resolution and fibrosis improvement.

Because of the experience we had in the real world with resmetirom, we used the same noninvasive criteria to qualify patients for semaglutide. The majority of patients qualify based on VCTE or the ELF score, or a combination. Semaglutide has been on the market and had FDA approval for several years. It started with the type 2 diabetes indication, then the weight loss indication, and the cardiovascular indication. Clearly, we had a lot of real-world evidence in terms of tolerability and managing adverse events with semaglutide even before the FDA approval for MASH.

The way we think about it, typically we are looking at a few things to decide what is the best treatment option. We look at the metabolic burden. If the patient has severe obesity, uncontrolled type 2 diabetes, or other comorbidities that may benefit from a GLP-1, like obstructive sleep apnea, this may push us toward the GLP-1. If a patient has lean MASH, if a patient has contraindications to a GLP-1—like a history of medullary thyroid cancer or a history of recurrent pancreatitis—we go with resmetirom. We also ask the patient about their preference, if they prefer a once-a-day pill versus a weekly injection.

In my clinic, when I see patients with diabetes, between 35% and 50% of patients with type 2 diabetes are coming to us on a GLP-1. Sometimes it’s not semaglutide 2.4 mg weekly, but it could be semaglutide 2 mg weekly for diabetes. It could be tirzepatide [Mounjaro, Zepbound; Eli Lilly and Company], or it could be dulaglutide [Trulicity; Eli Lilly and Company]. If these patients have been on the GLP-1 for a while and their diabetes is under good control and they still have MASH with F2/F3, then what I do is typically add resmetirom on top of the stable GLP-1.

The good news is there are no drug-drug interactions between resmetirom and GLP-1. In the MAESTRO-NASH trial, about 15% were on a stable-dose GLP-1, and when we added resmetirom on top of it, these patients saw the same MASH resolution rates and the same fibrosis improvement rates.² It seems like there’s the added benefit of resmetirom on top of a stable GLP-1. When it’s all said and done in my practice, for newcomers, it’s almost a 50-50 split now between starting semaglutide or resmetirom.

AJMC: You mentioned earlier the tolerability of resmetirom. The rates of patients who discontinue GLP-1 therapy because of tolerability issues and insurance coverage challenges are substantial and well known at this point in the obesity space. What are we seeing for patients with MASH, and how do you counsel them up front to make sure they stay on their drugs and the persistence is there?

Alkhouri: The 2 most common adverse events with resmetirom are nausea and diarrhea, but typically they’re mild in severity and self-limited. After 3 to 4 weeks, typically, the patient is doing okay. While the main adverse events of resmetirom are gastrointestinal, they tend to be less severe than what we see with the GLP-1s.

With the GLP-1s, some studies show discontinuation rates as high as 50% or even 70% after the first year.⁶ Part of it, from earlier studies, was driven by insurance coverage and shortages and supply, so I suspect these rates will come down. But definitely there is a higher percentage of patients that do not tolerate semaglutide at the full dose of 2.4 mg. Often we are not able to dose escalate, and it seems like this is a bigger problem in the real world compared to the ESSENCE trial, where we were able to dose escalate to 2.4 mg in 83% of patients.⁵

Preemptive discussions about the potential for GI adverse events and how to manage them are crucial. Typically, we tell patients it’s very likely with the GLP-1 that you may develop nausea, and it’s part of the mechanism of action with delayed gastric emptying. You may end up having vomiting, sometimes constipation, and sometimes diarrhea. We counsel them on some simple things they can do, like taking probiotics and increasing fiber intake, and we tell them that we also have medications that we can prescribe, such as ondansetron [Zofran; GSK] for nausea. We can prescribe motility agents for diarrhea if needed or laxatives for constipation.

Communication is key. When they develop these adverse events, if they tell us about them early, we can act and potentially help them before the adverse events become too severe to the point that the patient wants to discontinue. Typically, we tell the patients to call us if they’re having significant adverse events, and then we check on them on a monthly basis until we dose escalate them to the full dose. If we realize that we need to keep them on a lower dose or if we realize we need to do something to mitigate some of the adverse events, we act on it proactively. That phone call or clinic visit on a monthly basis in the first 16 weeks when you’re dose escalating the GLP-1 is very important.

AJMC: Looking at real-world practice across multiple sites, where do access barriers and insurance hurdles actually affect treatment choices, such as the oral versus the injectable? How do you navigate any bottlenecks you hit?

Alkhouri: We still have to do prior authorizations. There’s paperwork involved and it is a process, and sometimes even with insurance coverage, the copays are still high for our patients and they cannot afford it. Even getting insurance approval is not a guarantee that the patient will be able to get the medicine and stay on the medicine, because if you respond, typically we want to keep them on the medicine.

There are some logistical issues. A practice sometimes has to hire someone to do all their prior authorizations. We are getting some help from artificial intelligence and some programs that can help with the prior authorization process and writing appeal letters. But again, the copays and the paperwork that goes with it are still a limiting factor for some patients and practices.

References

1. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
2. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC. March 14, 2024. Accessed October 26, 2026. https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis
3. Joszt L, Alkhouri N. Real-world resmetirom gains in MASH: Naim Alkhouri, MD. AJMC. June 12, 2026. Accessed October 26, 2026. https://www.ajmc.com/view/real-world-resmetirom-gains-in-mash-naim-alkhouri-md
4. Klein HE. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed October 26, 2026. https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis
5. Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258
6. Do D, Lee T, Peasah SK, Good CB, Inneh A, Patel U. GLP-1 receptor agonist discontinuation among patients with obesity and/or type 2 diabetes. JAMA Netw Open. 2024;7(5):e2413172. doi:10.1001/jamanetworkopen.2024.13172