GLP-1s, Resmetirom, Dual Therapy and More: Roundtable Continued

Continuing their discussion on treatment for MASLD/MASH, the expert roundtable members delve into treatment of early-stage cirrhosis and the utility of bariatric surgery for a subset of patients with these liver diseases. 

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.

CLINICAL PRACTICE SUMMARY

MASH (Metabolic Dysfunction–Associated Steatohepatitis) in Cirrhosis: Limited Pharmacotherapy, Role of GLP-1 RAs and Bariatric Surgery

• MASH + GLP-1 receptor agonists (clinical response, noncirrhotic baseline context): In patients with MASH (often overweight/obese with type 2 diabetes, FibroScan 10–15), GLP-1 receptor agonists show ~20% response rates for improvement, meaning ~80% are nonresponders; this supports a rationale for combination or dual-agonist approaches targeting multiple disease pathways.
• MASH-induced cirrhosis (no approved therapy; cautious off-label use): There is currently no approved treatment for MASH cirrhosis, and labeled therapies (including resmetirom) are not recommended in known cirrhosis. GLP-1 receptor agonists may be considered for comorbid type 2 diabetes or obesity in early (compensated) cirrhosis per ADA guidance, but not specifically for MASH treatment; clinicians emphasize caution pending efficacy/safety data, prioritize lifestyle management, metabolic control, sarcopenia prevention (e.g., adequate protein intake ~1.5 g/kg/day), and routine cirrhosis surveillance (HCC, varices), with referral to clinical trials when available.
• Bariatric surgery (selected patients, early/compensated cirrhosis): Bariatric surgery is described as highly effective for MASH, with evidence of improved steatohepatitis/fibrosis and reported cirrhosis reversal in compensated cases (e.g., Cleveland Clinic data); it is considered in carefully selected patients (younger, severe obesity, cardiometabolic disease) and should be performed at experienced centers, often favoring less aggressive (restrictive) procedures and avoiding patients with decompensated disease.
•  

TRANSCRIPT:

Dr Afdhal:

I do think it's worth pointing out that even in the best-case scenario, and what we're talking about is evaluating these patients. When you see these people that come in initially on a GLP-1, you're right, Meena, they're often on the diabetes dose, but also even if they were on the full dose, the response rate in terms of improvements and reductions is in the best case scenario, to make it simple, we could say 20%. That means that 80% of these patients are actually not responding. So the rationale for combination, if you want, or dual agonism to attack 2 components of MASH is absolutely there. I mean, we actually expect when we see somebody that comes to us who's on a GLP-1, that they won't be responding. I mean, that's the odds. It's a 4 to 1 odds that they won't respond. So that's all really good. And remember, we've been talking mostly about the kind of virtual patient we said who's a kind of Fibroscan between 10 and 15, obese or overweight, got a little bit of type 2 diabetes.

I want to ask you a different question. I want to switch to the patients that we actually in our clinic see more frequently, which is the cirrhotic patient. All right? So let's turn to the cirrhotic patient with the understanding that there is currently no approved treatment for MASH-induced cirrhosis. I just want to get your trends on what you're doing for these patients to help us and our audience understand how we're approaching these particular patients. And obviously, when you're not biopsying everybody, some of the patients that we have will have cirrhosis, we'll be saying that they're stage 3, but they may well be stage 4 at that time. And of course, there is some literature that's available out there, both on the safety of GLP-1s in patients with cirrhosis and also a little bit of data on efficacy of resmetirom in patients with cirrhosis. So I'll start off with Zobair. How do you approach these people?

Dr Younossi:

I think coming back to what we were just discussing, if we're going to think of this as a chronic disease like type two diabetes, there is no rationale to think that a single drug will work here. It doesn't work in diabetes. We always use multiple different drugs to treat the patient with diabetes. This is a similar story and basically we use multiple drugs. Now, patients with cirrhosis is challenging, at least for the moment from a MASH standpoint. And the reason is that both drugs are really, if you follow the label, they are not to be used in patients with known cirrhosis. But I know that the patients and clinical practice and other scenarios they have actually received when they were cirrhotics, I would say that from the context of GLP-1 receptor agonist, unless they have very advanced cirrhosis that I would then really recommend not to use these drugs for management of diabetes or obesity and patients who have early cirrhosis for diabetes or obesity management, just following the guidance, the guideline that came from ADA, there's a very nice table, how to manage a figure, how to manage diabetes and obesity in patients with different stages of fibrosis, including cirrhosis. And for obesity and for type 2 diabetes, you can consider GLP-1 receptor agonist. But at this point, until we have better data, the use of GLP-1 receptor agonist and actual resmetirom specifically to manage and treatment match is something that I do not recommend. That's basically, I'm cautious until I have better data. Am I actually going to be very uncomfortable if I see a patient? I am not. I think this is my own sort of personal feeling and from the data that I've seen that these drugs may not be as bad as I would've thought in the context of cirrhosis, but we need to see data to be comfortable that efficacy and safety is there before we recommend it to all patients.

So those are the patients that I manage very, very aggressively with lifestyle. I want to make sure that if their diabetes is out of control, that they're controlled well, you can use other drugs obviously in that context. I want to make sure they don't develop sarcopenia because sarcopenia in the context of MASLD is an independent predictor of mortality. And so lots of other things. And by the way, we have a number of clinical trials that exist in every region of the country that patients who have cirrhosis, at least early cirrhosis, can enroll. So I think for those patients, I just have to follow their preventative hepatology sort of things in terms of screening for HCC and varices, but in terms of treatment, we're limited. We are really limited to what we can do with lifestyle at the moment because I personally don't prescribe resmetirom or even GLP-1 specifically for treatment of MASH.

Dr Afdhal:

Meena, would you like to comment?

Dr Bansal:

Yeah, I mean, I don't prescribe it for cirrhosis, especially resmetirom, there's an ongoing trial in patients with cirrhosis and we don't need an OCA situation on our hands where there's like a random complication in the real world because people are not qualified to really understand cirrhosis very well, and then you have a black box warning all of a sudden and we've just kind of killed a leading drug. So with resmetirom, it's an absolute not for me.

However, with the GLP-1s, if I have patients with other indications, I'm not writing it as a liver indication, but if they have diabetes that's not well controlled or they have obesity and they have other things that would benefit from the GLP-1, with the caveat being that I'm watchful for sarcopenia, I make sure they're having adequate protein intake, 1.5 grams per kilogram per day. I make sure the resistance testing is there, et cetera. I am okay with them getting them because the safety has been shown that it's relatively safe in that population and I'm kind of watching, but I feel like it's going to help in some of the other ways. So with GLP-1s, I'm a little bit more liberal in patients with cirrhosis, not flagrant decompensated cirrhosis, but kind of the earlier stages of cirrhosis, I think there could be some benefit.

Dr Afdhal:

Great. I'm going to go to one last therapeutic modality that's available for our patients and just get maybe a short answer of, do you ever consider it and do you ever use it or recommend it? And that would be bariatric surgery. All right. So I mean, that's always been an option for our patients. Again, improved cardiometabolic outcomes, improved survival in some patients, and a kind of mixed evidence on reversibility of cirrhosis and reversibility of fibrosis. And there are some patients, particularly younger patients who have really got significant issues related to cardiometabolic disease, obesity, and diabetes that we certainly will discuss bariatric surgery. I'd like to just get your viewpoint on that.

Dr Younossi:

Yeah. I've been actively involved in some of this research for 27 years, and I can tell you that's probably one of the best treatment for MASH, especially if diabetes reverses and patients lose weight, bariatric surgery works very, very well, especially if the weight is maintained. And of course, one of the complications post-bariatric surgery is alcohol and consumption, so you just have to watch out for that. But in terms of efficacy of bariatric surgery, in terms of the improvement of steatohepatitis or fibrosis, the data is there. I've actually sent patients with even compensated cirrhosis, as long as there is no evidence of poor hypertension or any other sort of complication. I've sent patients to bariatric surgery, but I've made sure that these go to the bariatric surgery centers with a lot of experience because you need experienced surgeons to do this.

The other thing that I've done this, and this was based on my own sort of caveat and experience, not a lot of data when I was doing this, is that I elected to do less aggressive surgery or recommended less aggressive surgery. Instead of malabsorptive type of bariatric surgery, I recommended maybe more of a restrictive surgeries that you don't lose the massive weight that could sometimes potentially induce some complication in these patients. And I've seen actually improvement of cirrhosis as long as it's really just histologic well compensated, no evidence of clinical evidence of cirrhosis that has regressed over after a year period of time. But that's anecdote, that's from my own experience. And there is some data, as you say, on both sides for patient with more advanced liver disease, but earlier patients, those who are noncirrhotic, bariatric surgery, if it's done in a good center with good professional sort of surgeons that can have good outcomes, works like a charm.

Dr Bansal:

I agree. I agree. I discuss it with my patients, especially those who may not tolerate GLP-1 or have multiple things in the younger patients who are really morbidly obese, I think that that is where bariatric surgery definitely plays a great role. And there was a paper published in December from the Cleveland Clinic in patients that showed cirrhosis reversal in patients. Obviously they were compensated, but it's selecting for that because you're not doing it in patients who have more advanced cirrhosis anyway. So they clearly have early cirrhosis. Nevertheless, they showed that bariatric surgery showed cirrhosis reversal and improved liver-related outcomes. So I think it's a great option for a subset of our population.