Shared Decision-Making Shapes MASH Therapy Choices: Naim Alkhouri, MD

Response to therapy in metabolic dysfunction–associated steatohepatitis (MASH) should be judged after about 1 year on a stable dose, and treatment should not be stopped at 6 months unless tolerability is a problem, said Naim Alkhouri, MD, chief academic officer at Summit Clinical Research.

Alkhouri discusses how he defines a great, partial, or absent response at 1 year, how he sets expectations on weight loss and muscle loss with glucagon-like peptide 1 (GLP-1) therapy, and what primary care needs to change to screen for fibrosis with the Fibrosis-4 (FIB-4) index. He also explains how FDA openness to noninvasive surrogate end points could reshape future MASH trials.

In part 1 of the interview with The American Journal of Managed Care® (AJMC®), Alkhouri explained that noninvasive tests allow most patients to start resmetirom (Rezdiffra; Madrigal Pharmaceuticals) without a liver biopsy and discussed how he chooses between resmetirom and semaglutide (Wegovy; Novo Nordisk).

This interview has been edited for clarity.

AJMC: How long do you typically wait before determining a therapy isn’t working, and what prompts a decision to switch mechanisms?

Alkhouri: For simplicity, I would say 1 year. With resmetirom, we treated 52 weeks in the trial,¹ so that’s why we check at 1 year. With semaglutide, forget about the dose escalation, which is about 16 weeks. It’s really 1 year once the patient is on the stable dose.

After 1 year of treatment, I think it’s fair to do VCTE [vibration-controlled transient elastography], look at the liver stiffness measurement for fibrosis, look at the CAP [controlled attenuation parameter] score for steatosis, and look at AST [aspartate aminotransferase] and ALT [alanine aminotransferase]. All of that will give you an idea about liver inflammation and disease activity. If you see improvement in all of them, especially if you achieve a reduction in liver stiffness by 30% after 1 year of treatment, a reduction in the CAP score by 30 units, and a reduction in ALT/AST by 20%, this is a great response, and this patient should continue on treatment. This happens in about 40% to 45% of patients in the real world.

There are about 45% of patients that have a partial response, so you may see a reduction in the ALT/AST and a reduction in the CAP score, but the liver stiffness doesn’t drop by 30%. This is a partial response. Typically, we like to continue treatment. In about 10% of patients we see an increase in the noninvasive tests. At that point, you have to say that the medicine didn’t work for them. We stop treatment for futility, and typically we switch to the other agent that’s available to us.

AJMC: What have you learned from tracking your own patient population that helps you identify likely GLP-1 responders in MASH before you get to 1 year? Are you able to tell who’s more likely to respond than others at this point?

Alkhouri: We don’t recommend doing this, because we just don’t have a test that is accurate enough to say, “Hey, this is an early nonresponder.” There are some preliminary studies, and some people are looking at dynamic changes of noninvasive tests as early as 3 or 6 months. But at this point, I do not recommend that these are used because we need larger studies. We also need to make sure that we are not missing a response on histology that is not being picked up by noninvasive tests. I would recommend against stopping treatment after 6 months, unless it’s for a tolerability issue.

AJMC: For these treatments, the goal is liver health, not necessarily weight loss or the other effects that you might see while someone is on a GLP-1. How do you manage patient expectations around those other things they might expect when they hear about being on a GLP-1 and the injection burden they might face?

Alkhouri: It’s all about shared decision-making. At the end of the day, I always tell my patients, “I’m not an old-fashioned doctor. It’s not my way or the highway. I’m going to present you with the data, I’ll try to answer all questions for you, and let’s make a decision together.” If we do shared decision-making, they have ownership of the decision, they feel like they’re part of the process, and they’re more likely to stay engaged with you, share adverse events with you, and figure out a way to actually remain on their medication.

With GLP-1, obviously, weight loss is an expectation. Many patients are motivated by this. Sometimes the patient has already potentially 2 indications for GLP-1, like MASH and class 2 or 3 obesity. When you start them on semaglutide, if they lose a lot of weight and the MASH is not responding the way I want, I’m not going to stop the GLP-1. I would continue because I would want to maintain that weight loss.

The other thing that we get asked about a lot now is the muscle loss that happens when you lose weight with GLP-1. There are studies showing that up to potentially 40% of the weight you lose is muscle mass.² This is very important as part of counseling to talk about it and tell patients that they need to be on a high-protein diet. This could be animal protein but could also be protein from nonanimal sources, which is perfectly fine. They need to increase their exercise and talk about the GLP-1 as part of a lifestyle intervention and not just an injection by itself.

Again, shared decision-making, talking about things outside of the gastrointestinal side effects, and understanding that we’re treating the whole patient and not just the liver. In my clinic, my focus is on MASH resolution, fibrosis improvement, and improvement in the noninvasive tests. But if I see other beneficial effects of the medicine, even if I don’t see the response I want in the liver, I will add the resmetirom for its liver-directed effect but will not stop the GLP-1 if the patient loses weight and we see improvement in their [hemoglobin] A_1C. They feel much better on the GLP-1, because we know once you stop a GLP-1, there’s rapid weight regain and you lose most of the benefits.

AJMC: Given how asymptomatic early MASH is, what needs to change in primary care screening workflows so that we can catch patients with significant fibrosis before they ever reach the specialist’s office?

Alkhouri: We just need to implement the guidelines.³ We learned that patients with type 2 diabetes, metabolic syndrome, and elevated ALT/AST all need to have a FIB-4 index calculated, and if the FIB-4 is more than 1.3, then either you order the ELF [enhanced liver fibrosis] test in primary care, or you just send them to get VCTE with liver stiffness measurement.

We are nowhere near implementing this on a large scale in primary care offices. In my practice, unfortunately, we still see the patients for the 2 most common referral reasons. One is elevated liver enzymes, but no one calculated the FIB-4. The second one is the incidental finding of steatotic liver on imaging. A patient goes because of abdominal pain; they do a CAT scan at the emergency department, and they see that they have steatotic liver disease. We’re not getting many referrals coming to our clinics because the primary care doctor calculated the FIB-4, and it was more than 1.3.

Number 1 is implementing the guidelines. Number 2 is potentially making it a quality metric: if you have a patient with type 2 diabetes, the same way you have to do an eye exam and document that you did a foot exam, or you send them to get a foot exam, you have to document that FIB-4 was calculated for that patient. Then if the FIB-4 is more than 1.3, you have to document that you referred them to get VCTE done, or you ordered a blood test to risk stratify that patient.

That would be the main message for primary care doctors: that you have to screen, and if you find a patient has MASH, you need to stage with FIB-4, followed by another test if the score is more than 1.3. Then the specialist can start treatment. I always talk about this 3 S’s approach: screen, stage, and start treatment.

AJMC: As we look forward to future trials in MASH, what needs to change in trial end points to better match what clinicians and payers care about? For instance, the trials used liver biopsies, but in the real world only about 5% of patients get liver biopsies because you’re using noninvasive tests. What else needs to change to match up with the real world a little better?

Alkhouri: There is a big push now, and the FDA is on board, to see if we can replace biopsy in clinical trials completely with noninvasive tests that become what we call reasonably likely surrogate end points. The FDA published a paper in Hepatology within the last year or so providing guidance to industry on what is required for the NITs [noninvasive tests] to become reasonably likely surrogate end points.⁴ We want the NIT to be linked to disease pathogenesis. We want to understand what magnitude change in the NIT can predict the response. We want to make sure that this NIT, when it changes, predicts outcomes more important than predicting MASH resolution or fibrosis improvement.

Based on this paper and announcement by the FDA, several what we call letters of intent (LOIs) were submitted to the FDA to start this qualification process for NITs as reasonably likely surrogate end points in clinical trials. The first NIT that submitted an LOI was VCTE liver stiffness, followed by MR elastography,⁵ and I think other NITs are following now, so we may see more announcements with, for example, the ELF score, corrected T1.

Probably the highest unmet need is to design trials and get to the accelerated approval quickly using NITs without a biopsy. The FDA is open to the idea now that you can enroll your study without needing a biopsy, but then you have to follow these patients to hard clinical outcomes and show a reduction in progression to cirrhosis, decompensating liver events, overall mortality, liver transplant, and worsening in the MELD [Model for End-Stage Liver Disease] score. These are the hard end points.

One pharma company that decided to go that route is Eli Lilly. They have a very large study called the SYNERGY-Outcomes trial,⁶ where the plan is to randomize 4500 patients based on noninvasive tests and follow them to a prespecified number of clinical events. That study is planned for potentially 4 or 5 years, and it’s a very large sample size. Not all companies are following that pathway. Most companies today are still designing their trials to do the biopsy, do interim analysis after 1 year of treatment, try to get the accelerated approval, and then follow patients for hard outcomes for the full approval.

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. Mechanick JI, Butsch WS, Christensen SM, et al. Strategies for minimizing muscle loss during use of incretin-mimetic drugs for treatment of obesity. Obes Rev. 2025;26(1):e13841. doi:10.1111/obr.13841
3. Clinical assessment and management of metabolic dysfunction-associated steatotic liver disease. AASLD. Accessed October 26, 2026. https://www.aasld.org/practice-guidelines/clinical-assessment-and-management-metabolic-dysfunction-associated-steatotic
4. Anania FA, Hager R, Higgins K, Makar GA, Siegel J, Tran TT. Non-invasive tests: establishing efficacy for metabolic dysfunction-associated steatohepatitis beyond the biopsy—current perspectives from the Division of Hepatology and Nutrition, US Food and Drug Administration. Hepatology. 2026;84(1):321-327. doi:10.1097/HEP.0000000000001509
5. FDA accepts proposal for reasonably likely surrogate endpoint for ‘MASH’ all-cause mortality or liver-related events. US Food and Drug Administration. August 27, 2025. Accessed October 26, 2026. https://www.fda.gov/drugs/drug-alerts-and-statements/fda-accepts-proposal-reasonably-likely-surrogate-endpoint-mash-all-cause-mortality-or-liver-related
6. A master protocol of multiple agents in adults with metabolic dysfunction-associated steatotic liver disease (SYNERGY-Outcomes). ClinicalTrials.gov identifier: NCT07165028. Eli Lilly and Company. Accessed October 26, 2026. https://trials.lilly.com/en-US/trial/651596