MASH Outcomes Hinge on Risk Stratification, Coverage: Zobair Younossi, MD

Routine fibrosis screening in primary care, built into electronic health record (EHR) prompts and backed by payers, could catch metabolic dysfunction–associated steatohepatitis (MASH) before it progresses to cirrhosis or liver cancer, according to Zobair Younossi, MD, MPH, professor of medicine and founding chair of the Global Center for Liver Outcomes and Policy Research at Georgetown University School of Medicine, in an interview with The American Journal of Managed Care^® (AJMC^®).

Younossi also explained how he chooses between resmetirom (Rezdiffra; Madrigal Pharmaceuticals) and semaglutide (Wegovy; Novo Nordisk) based on whether a patient has obesity or diabetes, and why he doesn’t yet start both drugs at once. He described what future trials should show on combination therapy, new drug classes, and better noninvasive tests (NITs). He also compared what a better coverage framework could do for MASH with what happened in hepatitis C, where liver transplants have dropped sharply.

In part 1 of the interview with AJMC, Younossi explained why fibrosis, rather than steatohepatitis resolution, is the better end point for MASH clinical trials.

This interview has been edited for clarity.

AJMC: MASH is often diagnosed late, sometimes after patients have already developed advanced disease or liver cancer. What gaps do you see in how at-risk patients are identified, and how should risk stratification work in practice?

Younossi: The problem right now that we face is lack of awareness at all levels of care. We routinely see in clinical practice patients who present with MASH and very advanced disease, sometimes with liver cancer. A lot of times minor elevation of liver enzymes or MASLD [metabolic dysfunction–associated steatotic liver disease] has been dismissed as not a “serious” liver disease. In fact, MASH is the most common liver disease in the world and the second indication for liver transplantation in both Europe and the United States.¹ But awareness about this, especially in the primary care setting, is still low.² A lot of these patients are not captured early enough, and they end up coming with very advanced liver disease.

The message is that you need to find those patients who are at risk for progressive liver disease. Not everyone will progress, obviously. Of the 30% of the US population with MASLD,³ not everyone will progress, but a group will progress, and you find them through risk stratification, through algorithms that are now standard because they’re part of guidelines.⁴ What does that mean? That means that if you’re diabetic, or you have complicated obesity—obesity with another complication of metabolic syndrome—or your liver enzymes are elevated, you need to have an FIB-4 [Fibrosis-4 Index] score, which is a blood-based test, and if that score is more than 1.3, you need to get the second-line test, which is either an ELF test, an enhanced liver fibrosis test, or a transient elastography, which is an imaging test to show liver stiffness, and that will tell you if you’re at risk of progression. If you have a liver stiffness score of more than 8 [kPa] or an ELF test of more than 9.2, you’re at risk, and that means that you should be treated with changes in lifestyle concurrently with approved medication, you should be followed closely, and you should be managed carefully.

Using these tests, you can go from a very large number of patients and can filter the group down to some group that is manageable, but that risk stratification must happen. If it doesn’t happen, then you cannot really capture the high-risk patient so that you can intervene early.

AJMC: Resmetirom and semaglutide differ in mechanism, administration, and cost, and they treat overlapping but not identical patient populations. How do you decide which to use, and where does coverage factor in?

Younossi: I think the drugs are both fantastic advances in our field. The biggest difference between semaglutide and resmetirom is that semaglutide is a metabolic drug. It’s already been approved for diabetes, it’s already been approved for obesity, and now it’s approved for MASH, and resmetirom is a liver-directed drug, which means that you can only use it for MASH.^5,6

What happens is that in most practices, at least in my practice, a lot of my patients come to see us who are already on a GLP-1 [glucagon-like peptide-1] receptor agonist or a dual agonist for obesity or type 2 diabetes, and they still have MASH. They get treated for MASH with the addition of resmetirom. That’s what we do when the patients are already on a GLP-1 receptor agonist. Now, if you have a patient who’s coming in fresh, you look at the patient profile. If a patient is not obese or has overt diabetes, then resmetirom is the first drug to choose. Of course, if the patient comes in and they need to be treated for their diabetes and their obesity with a GLP-1 receptor agonist, then I would probably choose semaglutide in that context. But I wouldn’t wait a year or so to see if the drug is working. If I’m putting somebody on one or the other drug and it’s not working, I can either add the second drug or I can replace it, depending on the situation.

Starting 2 drugs at the same time is probably not a good idea currently because we don’t have the data as of yet. But it probably will be something we will do in the future. For the moment, we start one drug at a time and then monitor the patients to see if they are responding. If they are responding, then that’s fine. We’ll continue that one drug. If they are not responding, we either switch or actually add, depending on the insurance and coverage, obviously.

AJMC: You mentioned that there are not yet data on starting 2 drugs at the same time. Looking ahead, what is missing right now that future trials should address?

Younossi: There are multiple future opportunities we have. First, although we have good NITs, noninvasive tests, for risk stratification, they’re not perfect. A good opportunity is to develop better NITs or use the power of AI [artificial intelligence] and bring in clinical data, genomic data, and biomarker data and really get those patients the best predictive opportunity to predict what they’re going to look like so that you can do this stratification better. These NITs should also get better so that we know who’s responding and who’s not responding. We now have an idea that if somebody’s liver stiffness decreases by 30% or if ELF decreases by 0.5, they’re responding, but these need to be validated.⁴ We need better tools.

Second, we are developing new classes of drugs. They’re in phase 3: FXR [farnesoid X receptor] agonists, pan-PPAR [peroxisome proliferator–activated receptor] agonists, and other dual and triple agonists with GLP-1 receptor agonists. Having different families of drugs will be important. I also think that there’s going to be a combination of drugs. You can look at a patient’s profile and their clinical characteristics and use 2 drugs. Ultimately, treatment of MASH will be based on personalized medicine, in my view. Taken together, clinical data, laboratory data, genomic data, and environmental data will give us a profile of each patient. That may be where AI can help us most with this disease: identifying the best regimen for each individual patient. That could mean choosing a combination of 2, or possibly 3, drugs to treat patients for a shorter period of time.

The way I look at this disease is that you can start having multiple drugs initially as a first step of induction so that you can calm the disease down, and then you maintain that response or improvement that you achieve. If they are improving their fibrosis, you probably need to use at least 1 drug to keep them so that they don’t progress over time. One of the drugs will probably ultimately be used like you treat high cholesterol or diabetes, meaning that the patient will be on it for a long time, probably lifelong, unless they lose significant weight and they change their metabolic profile so that they’re no longer at risk. In general, that would be the treatment approach and innovation in the future.

AJMC: If you could design a coverage framework for MASH therapies from scratch, what would an ideal, evidence-based framework look like?

Younossi: I think there has to be a health system approach where the electronic health record is connected to the first-line assessment of at-risk patients, which is, "Are you diabetic? Do you have abnormal liver enzymes? Do you have complicated obesity?” If they do, automatically that will calculate a FIB-4 test, which is basically a very easy test from labs and from clinical data. If the FIB-4 is high, automatically that patient gets either a transient elastography or an order for a blood test, the ELF test. If that meets a certain threshold, that automatically goes into a care pathway that will connect the patient to the right provider experienced in managing and treating these patients. The payers will have to buy into this being a package payment where you get these patients who are at risk to be risk stratified for the liver disease, the same way that they do this for a patient with diabetes with eye or kidney examinations. It’s included in the assessment, so you get that assessment for those patients.

Once the patients get to the specialist or to the provider—because there are primary care providers who may want to use these drugs to treat patients with MASH—then the coverage should be there so that the patient can start treatment as early as possible. There is no reason to wait if somebody has stage 2 to 3 fibrosis from MASH, which is really precirrhosis. You don’t want to wait for too long because they can form complications. They can go into cirrhosis with its complications.

That’s the ideal situation: a lot of these patients are risk stratified automatically through the electronic health record, through AI, or through algorithms that then find the patients who are at high risk and connect them to the right provider, and all that spectrum of assessments is not only accepted by the health systems but also covered by the payers.

AJMC: Looking ahead 5 to 10 years, what might MASH treatment, outcomes, and societal impact look like?

Younossi: I think one of the important issues is not only to raise awareness about this within the primary care community but also with patients, and specifically with policy makers, to dedicate some resources to better manage this important liver disease. MASH is part of a metabolic package that is connected to other metabolic diseases such as heart disease, kidney disease, etc. In this context, MASH is the liver manifestation of these metabolic diseases.

In the next 5 to 10 years, I would hope to see better tools to risk stratify patients and better treatment that’s available. If we do this early and we intervene and we make these care pathways seamless to connect, I suspect that we will see improvement in outcomes. We’ve seen it already with semaglutide or GLP-1s for obesity. We’re already seeing it in the treatment of hepatitis C, where we can cure hepatitis C, and now the number of patients requiring liver transplantation because of hepatitis C has plummeted substantially.⁷ It was because of a very good drug and also a very good approach to coverage and policy. I think if we do this in the next five to 10 years, we will see a decline in the complications related to this disease.

References

1. Younossi ZM, Germano G, Wong R, et al. Steatotic liver disease is the dominant indication for liver transplantation in both Europe and the United States: trends and outcomes in the past 2 decades. Liver Transpl. 2026;32(4):549-557. doi:10.1097/LVT.0000000000000688
2. Lazarus JV, White TM, Allen AM, et al. Awareness of metabolic dysfunction-associated steatotic liver disease (MASLD) in 4 major cities in the United States. Hepatol Commun. 2025;9(5):e0704. doi:10.1097/HC9.0000000000000704
3. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-1347. doi:10.1097/HEP.0000000000000004
4. Younossi ZM, Kalligeros M, Wong VW-S, et al. Updated global consensus recommendations for risk stratification, treatment initiation, and response monitoring in metabolic dysfunction-associated steatotic liver disease. Clin Gastroenterol Hepatol. 2026;24(9):2333-2347. doi:10.1016/j.cgh.2026.03.030
5. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC. March 14, 2024. Accessed October 2, 2026.https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis
6. Klein HE. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed October 2, 2026.https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis
7. Richards S. Hepatitis C cure means many liver failure patients have a better chance at transplantation and recovery. University of Chicago. July 22, 2020. Accessed October 3, 2026. https://www.uchicagomedicine.org/forefront/research-and-discoveries-articles/hepatitis-c-cure-means-many-liver-failure-patients-have-a-better-chance-at-transplantation-and-recovery