MASH Matters: Multidisciplinary Strategies for Translating the Latest Evidence Into Practice

Basic Concepts

Dr. Kenneth Cusi (University of Florida): Welcome all. We are very excited about this program, and we are going to, very soon, try to cover in my role of discussing a little bit the basic mechanisms of disease. If I can, I still have Jay in the main thing.

Okay. While we wait for the slides to become available, what is really important here is to understand some basic concepts. The number one is to identify those who are at risk of MASH.

There is a term that is becoming more mainstream, what we call at-risk MASH. For nonhepatologists, think about at risk of cirrhosis MASH. These are individuals who would have steatohepatitis or MASH and have a degree of fibrosis that is clinically significant, which is for the pathologist F2 or greater.

With that clinically significant fibrosis is that we are going to be concerned and trying to identify them. We send to Dr. Noureddin, who is our hepatologist in the group, the right candidates.

Okay. The first thing that has been a big change has been the nomenclature, the name. We used to call it nonalcoholic fatty liver disease in a nutshell. It was felt that it was not really addressing the metabolic basis of the disease, which is insulin resistance and cardiometabolic risk factors.

Second, there was a concern that a significant minority felt that fatty, at least in the English language, could be stigmatizing. With that background, there was international agreement among experts to change it to steatotic liver disease as the umbrella for any condition in which there is excessive triglycerides, actually, in the liver. What we called NAFLD is now called metabolic dysfunction–associated steatotic liver disease on the left of your panel. Again, when you have steatohepatitis, the inflammation associated with this fat deposition with this steatosis, we call it metabolic dysfunction–associated steatohepatitis.

On the other end, what is important is that all of you are aware of alcohol-associated liver disease. But there was a sense that there was an overlap syndrome of people who were not drinking as much as alcohol to a level considered alcoholic liver disease, but could not be really considered drinking less than what we define as MASH. That is that MET/ALK. I do not want to spend too much time on cutoffs and values, but perhaps this is an important distinction in your clinic.

Now, going through the classification, just focus on the left part of the panel. What you have to ask yourself is a patient has a cardiometabolic criteria that would meet the condition for MASLD. Of course, you had to rule out secondary causes for nonhepatologists, at least, excessive alcohol intake and viral hepatitis. Then if your patient you believe is steatosis-associated with elevated liver enzymes, this is persistent over time, consider a referral to hepatology. But if the patient has metabolic circumstances, well then, what you would consider their secondary causes could be MET/ALK or other things. If not, consider that your patient may have MASLD.

Cardiometabolic criteria

Now, the cardiometabolic criteria. You are very familiar with the metabolic syndrome there on the right. Now, if the patient does not have cardiometabolic criteria, well, you have another laundry list of causes of steatosis. If not, I mean, it could be early steatosis, early MASLD in individuals that perhaps are young and do not have cardiometabolic risk factors. This is the overall picture.

I have to say that cardiometabolic risk factors are not very specific. 85% of people, 50 or older, without steatosis may have cardiometabolic risk factors, particularly overweight or prediabetes. But again, this is something that helps us think about the metabolic origins of the disease.

For you just to have a general sense of the prevalence in the general population, it is about 25%. One in 4 individuals have steatosis. Minority will have MASH or cirrhosis. But what is more important for you, whether you are a hepatologist or endocrinologist or primary care, that in people with obesity, 70% of individuals have steatosis, and higher if you have type 2 diabetes and obesity. If you have type 2 diabetes and obesity, about half of those individuals will have steatohepatitis, and as many as 1 in 5 or 6 have significant fibrosis, this degree of fibrosis that puts you on a path to cirrhosis.

Very important to identify these individuals, 1 in 5, every fifth person that you see with diabetes. If you have not detected anyone in the last week, you may have missed a few.

Now, in a nutshell, we wrote this review with Amalia Gastaldelli, who works in Pisa, Italy, just to try to conceptualize why obesity is bad. It is not that you have more adipose tissue. It is that that adipose tissue, for reasons not fully understood, become sick. It stops responding to insulin. It becomes insulin resistant. You see in the left panel that the decrease in the response to insulin makes that you will release more fatty acids in the blood. Fatty acids come from the breakdown of the triglycerides that are in the adipocytes.

Now, this would seem not to be too bad. But what happens, these fatty acids go into the hepatocytes, create metabolic havoc, affect mitochondrial function, cause ER stress, and trigger the cascade of events of inflammation, and activate some cells called stellate cells that begin to lay collagen.

Of course, it is pretty complex. There are other biologies in place. But for what we can do in the clinic, that is target adipose tissue with weight loss or changing the biology of fat with pioglitazone or others, this is really important.

On the other hand, you also secrete a number of cytokines when you become overweight or obese that also promote insulin resistance and metabolic dysfunction. Very important to reverse that metabolic dysfunction and insulin resistance in your patients.

Now, this is the latest standard of care. This is also going to be coming out in a consensus statement with the ADA that Dr. Shubrook has been a main player. You see on the left, all the lifestyle changes, weight loss, optimal diabetes management, cardiovascular risk reduction, or bariatric surgery. But then we divided on the right your management based on what degree of liver fibrosis that you have. So our screening centered on FIB-4, which comes from equation that you can just put FIB-4 calculator in any website. It will give you the numbers of combining age, liver enzymes and platelets, will tell you very likely if the patient has or not significant fibrosis.

So if you do not have a lot of fibrosis, say, F0 means no fibrosis; F1, mild; F2, moderate; F3, pre-cirrhosis; and then F4 is cirrhosis. If you have a degree that is FIB-4 or below 1.3, just say in general, you should manage the cardiometabolic risk factors, including diabetes. You do not need any specific MASH pharmacotherapy.

Now, if you identify that your patient has moderate to advanced fibrosis, where I mentioned at-risk of cirrhosis MASH, you will also emphasize the cardiometabolic management. We are going to talk about GLP-1s and pioglitazone. But there is an option now called resmetirom that will, if approved specifically for people with F2, F3, and Mazen is going to tell us more about that.

Now, it is important that you work in an interprofessional team, where you have a hepatologist, because this drug has not been approved for cirrhosis, and we are not sure what the outcome of treatment is yet. There are ongoing studies. If you have cirrhosis, you do not have any specific approved pharmacotherapy, but you can continue in early stages of cirrhosis with the same approach that we did for people with earlier disease, GLP-1-centered or pioglitazone plus lifestyle.

In decompensated cirrhosis, again, we do not know the long-term efficacy of GLP-1s, and probably not a great idea. They also have severe sarcopenia. So insulin is the only pharmacotherapy that we would like to use.

Moving on, I am not going to flood you with this last slide, but just 2 things to remember. On the upper left, the effects on the central nervous system to control satiety are essential, very important. All of us have experienced, when you stop it after a week, these cravings sometimes or often come back. On the right, we know that these drugs enhance insulin secretion, which also explains why these drugs are first approved for the management of type 2 diabetes.

Emerging therapies

With that, let us dive into emerging therapies. I am just going to talk about the most recent data, which is the purpose of this as an update. You have learned from the paper published in the New England that we published Dr. Newsome and many others, that the phase II trial had shown improvement in steatohepatitis and less progression of fibrosis. But being a study in only 320 patients, did not reach statistical significance for fibrosis. This is the follow-up phase III study with a classic dose escalation that many of you are familiar with. Key standard inclusion and exclusion criteria as said in the left.

What was reported at The Liver Meeting in November were these results, and these 800 patients after 72 weeks and the effect of semaglutide at 2.4 milligrams after 72 weeks. You can see on the left side the effect on resolution of steatohepatitis. These are the 2 classic FDA endpoints. Hepatologists would be very familiar with them, nonhepatologists, less. But again, it is basically how much you improve steatohepatitis, of course, without fibrosis getting worse. This was very significant, almost twice as many people compared to placebo.

If you wonder how so many people in placebo did better? Well, they are getting in a study where they want to lose weight and they get dietary advice. You can see that that works in at least a third of the patients.

The right panel is the liver fibrosis endpoint, of course, with steatohepatitis not getting worse. Again, here we see a 14% delta, basically a third of the patients compared to 20% who follow dietary advice. This was a significant also impact. This larger study showed pretty much the effect that was shown in the phase II, but with 3 times more patients and making it statistically significant.

Last word, significant weight loss, as you can see, of 10% compared to 2% in placebo. If you take both endpoints, inflammation and fibrosis effects, also significant. Again, bodily pain, SF-36 is a well-known validated score of quality of life and also improved.

With that, I am not going to spend another second and let Mazen go ahead and tell us all the other drugs that are in development and a very exciting time for our patients.

Dr. Mazen Noureddin (Houston Research Institute): Thank you, Ken. Again, it is a great privilege to be here. Ken, I really like the ADA algorithm. It is very colorful and easy to follow and easy to read. Kudos to you guys simplifying.

Dr. Kenneth Cusi: That is what we try to do. Keep it as simple as possible. Thank you.

Dr. Noureddin: Yeah. It is like one shot you can read it all. Let me tell you what Ken was mentioning. I guess the liver doctor got excited this year. We have a new treatment for NASH with significant advanced fibrosis, which translate into stage F2 and F3, which is, you can call it also moderate to significant fibrosis. For disclosure, we are treating patients nowadays without a liver biopsy. We just have to be careful not to mix them with the cirrhotics because resmetirom is not approved for cirrhotics.

Interestingly, resmetirom is a thyroid hormone receptor beta which exists in the liver. When I was in medical school, I did not know there are thyroid hormone receptors in the liver. I do not think maybe I was studying hard enough. But anyways, I learned later on that the receptors are there. Guess who kind of played with this field is actually the endocrinologist. They knew about it. They found that such a mechanism decreased lipid panel in the blood, and eventually, what was found that it also decreases the fat in the liver. Through other studies and mechanistic study, the thyroid hormone beta receptors, you want to consider the NASH or MASH patients with the hypothyroid liver within the liver and replacing or like giving thyroid hormone receptors pathway lead to decreased triglyceride within the liver, possibly increase the fatty oxidation. Studies show it decreases steatohepatitis as well as fibrosis. We have done multiple studies in humans, which finally led to the phase III study.

We finally ended up with the resmetirom approval earlier this year in 2024. Again, this is an oral drug that is given once daily. We did the biopsy study, which I will show in a second. But because this treatment actually is recommended for NASH patients with advanced fibrosis, it was impossible just to go biopsy everyone and start treatment.

Here are some recommendations that came from the American Association for the Study of Liver Disease.

We also wrote a consensus paper on who to start resmetirom therapy and who does not. I am going to start backward. So people make sure we do not treat these cirrhotics. The way our Liver society define these cirrhotics as patients that they have noninvasive blood tests or noninvasive imaging tests that rule out cirrhosis. Some of those are VCTE or you heard about it commercially, FibroScan, and there are others. A cut off of a 20 or higher, this is the most used one and this is the one that we do not treat. There are mole elastography technique and stuff like that.

In addition, we also have to make sure patients are not drinking and they do not have active thyroid disease, and those are the patients that the guidelines are not recommended to treat.

In the middle, what you see is the range per the AASLD guidelines where you want to start therapy. It is basically what it is recommended, 8 to 15 on transient elastography, and their mole elastography numbers are here. Sometimes you can stretch it all the way between 15 and 20. However, you have to make sure the patients, they do not have cirrhotics beyond the 15 point of view. A lot of excitement around there. We already have that in clinic and we are treating our patients.

Let me tell you how we got there. This was the MAESTRO-NASH trial, which we published earlier this year in the New England Journal. This is a randomized, double-blinded, placebo-controlled trial which is multicenter, done in the US and internationally. I am not going to go into the criteria and details, but basically, there was resmetirom 80 milligrams, resmetirom 100 milligram arm and placebo.

You see this is a very well-powered study. Almost 1,000 patients. The patient had to have metabolic risk factors, had to have a liver biopsy, which is usually the primary endpoint in our MASH approval studies, which we call it subpart H approval, which is conditional until they prove outcomes. But they can have FDA approval of the approved biopsy improve and heading the right direction.

Biopsy at baseline

Again biopsy at baseline. Biopsy at week 52, which is almost a year. The primary endpoint was improvement either fibrosis stage by 1, meaning F3 patients go to F2, F2 go to F1, or improving in steatohepatitis score.

Those are the results. On the left, I show you this improvement in the steatohepatitis score which we call MASH resolution. It is a combination between fat in the liver inflammation and the cell injury. That showed statistically significant difference. You really needed to hit one of them, either improvement steatohepatitis or improvement on fibrosis. In this study, we had both on intention to treat analysis.

The fibrosis improvement, here you see it, it was about 11% or so, and was statistically significant in this patient population after 1 year.

To summarize it, both steatohepatitis as well as fibrosis improvement have been found after 1 year based on biopsy that led to the subpart H and the treatment recommendation that we started to. We do not use biopsy in clinical practice, but the regulators require us to use the biopsy for the approval. Beyond that, we go with noninvasive testing.

They were also in the trial multiple secondary endpoints, which confirmed our trust in the medication, such as improvement in liver enzymes, improvement in lipid MR, fat fraction improved. The transient elastography that I told you, now we use it widely to treat these patients has also improved in this study. That is all there.

I also want to mention other medications in the pipeline. The most exciting news this year was what Dr. Cusi presented earlier about semaglutide, which is about to come in publication, the semaglutide. The second one is what presented before that with resmetirom, and eventually to the FDA drug approval. Now we have options for our patients.

In addition, there are multiple medications in the pipeline. They are actually very promising. I want you to stay with me because I have really good news about one of them from their phase II study.

Lenifibrinol is a medication that is oral, that is pan-PPAR agonist. The study is ongoing in phase III. I will go to it in a second. Resmetirom we talked about. Those pegozafermin and efruxifermin, I really want you to know them. I need you to keep an eye on them. The mechanism is FGF21, which is a receptor in the body that plays a role in the liver or intestines, regulate glucose and lipid metabolism and improve the fat in the liver, inflammation in the liver, as well as lipid. We will go through these results. Both these medications are injectable and they are in phase III.

Survodutide is a GLP-1 and glucagon agonist. It is dual. We believe that the glucagon affect the liver directly, and this is why it is very attractive to us. It is an injectable drug, and of course it leads to weight loss, and semaglutide, Dr. Cusi already mentioned it.

Lenifibrinol

Let us look at lenifibrinol. Here, what we are showing you is not the lenifibrinol phase II data. The phase II data showed improvement on histology in both steatohepatitis as well as fibrosis. It is a very promising drug, pan-PPAR.

Here, I am showing you the most recent publication, showing that the effect on liver and metabolic health, such as improvement in A1C. You see it here. It is expected. It is PPARs, one of the best mechanisms in metabolic effects. You also see improvement in HOMA-IR triglyceride, ALT and AST and some noninvasive markers of the liver.

Survodutide

Now, let us look at the survodutide, which we also published this year in the New England Journal. This is a 48-week trial. Again, survodutide is a dual, GLP-1 and glucagon. GLP-1 has systemic effect. Glucagon, we think it has a liver-directed effect. That is why the titration as all medications in the same class 2.4, 4.86 milligram placebo.

They did, or we did biopsy before and after. We looked at multiple secondary endpoint. The result here I will show it to you in a second, showing on the left, and this is 2-points improvement, which is like a lower bar, if you want to say, in the steatohepatitis, showed improvement in steatohepatitis. We also here showed improvement in fibrosis again in this phase II study.

FGF21

Moving on. Now, I am going to talk about the FGF21s. This is actually one of the most potent drugs that we are doing trial. This is called efruxifermin, which is FGF21. I mentioned it to you. In this study that is one of the longest, 96 weeks, we had a serial biopsy at baseline week 24 and week 96. We had 2 doses, 28 milligram, 50 milligram, and the placebo. Again, the primary endpoint of this phase II study. Now we are in phase III, we do not have results yet. This phase II study was histology. And look here.

On a paired analysis, I want you to look at the 50 milligram on the left. 75% of the patients with F2 and F3 had improvement on fibrosis. This is paired biopsy analysis. This is unprecedented. This is quite improvement. You see improvement from the week 24 histology. With the first histology biopsy, there was improvement. By week 96, there was further improvement. It also had statistical significance with intention to treat.

On the right, I show you more detailed histological analysis. When we really look under the microscope using AI, it showed also better improvement there.

In other things, like we went beyond looking at improvement for F3 and F2 or F2 to F1. Here we look at improvement by 2 stages, F3 all the way to F1. We saw that and we saw multiple additional histological effect, as well as noninvasive testing, speaking of the strengths of this trial, of this efruxifermin.

There are many, many medications in the pipeline. I do not want to go to all of them, but on the right, I want to point out that there are many GLP-1s and duals in the pipeline. Actually, there are also triple that are being considered. There are drugs that affect the making of the fat in the liver de novo lipogenesis. There is another FGF21 here. This is very promising. All these data are out there. Let us switch to unmet need.

Unmet need

Here I have some good news for you guys that just came out fresh off the oven this week. Resmetirom has a trial, this is approved for F2, F3, not for cirrhosis. We have a trial ongoing for cirrhosis. We are going to see if resmetirom prevent outcome. Efruxifermin and pegozafermin, again, those are the FGF21, and survodutide is GLP-1 dual. We are studying it in cirrhotics.

However, this efruxifermin has started the study in phase III. Just this Monday, they announced their phase II study results on patients with cirrhosis, with biopsy. For the first time in the history of MASH, a drug has been able to reverse cirrhosis in a 96-week study on a biopsy, which was a huge win for the field of the patients. We are making progress, guys, the hepatologist. We have been silent for 10 or 15 years, maybe longer. But we finally are here.

In conclusion, we have the first drug approval for MASH, many coming in the pipeline. There are multiple drugs in phase III, THR beta, GLP-1s and dual PPARs. Keep an eye on the FGF21s, as well as the others. Options are currently limited for patients with cirrhosis when we wrote this slide, but now I have also further kind of new news fresh off the oven and I am really excited about it, excited about it for our patients, and it is just going to get better from here.

I think I will pass it back to Jay and we will go from there.

Dr. Shubrook: Yeah. Thank you both. And I think this is really exciting news. For many of you that are new to this space, I hope that you took from these presentations, that, one, there are evidence-based guidelines in the diabetes and the MASLD space for you to utilize as you look to evaluate and treat your patients with MASLD and MASH. We have diabetes treatments that have worked for this condition.

We have our first FDA-approved drug for this condition, and we have the ability now to even offer treatment without a liver biopsy. But that does require us to properly identify where someone is in that spectrum, and certainly make sure you take a team-based approach. I think you have really highlighted a lot of things. It sounds like, truly, the future is even getting brighter.

We are going to move now to case studies. I think these case studies are real important because we want you to take this conceptual and work it into patients you might be seeing in your clinic. So there are meant to be discussion points. We are going to talk about them. I see some questions coming in. I invite you to keep submitting your questions. We do want to hear what your questions are. All right.

Case Study 1

Gentlemen, our first case is a patient I was seeing. Her name is Joan. She is 59 years old, and she presented just for a routine physical. There really was no complaint. She does have a past medical history of excessive adiposity in the obesity range. She does have hypertension, and she does have dyslipidemia.

I ordered routine labs, and you can see that she has got some elevation in her transaminases, and she has got platelets of 184. So for those that are new for this, some of those should be actually alarming to you. But we will talk a little bit more about this case.

Gentlemen, when you look at this patient, she is not having any complaints. Her labs may just look a little off. What is your sense? Is she at risk for cirrhosis and other problems?

Dr. Cusi: Well, Jay, great question. I am going to give you the endocrine perspective and Mazen will be the counterpart on the liver side just in 30s because we have a couple of other cases.

Number one, for endocrinologists, primary care or others that are nonhepatologist, anybody with obesity and cardiometabolic risk factors, they are at risk. You have to do a FIB-4.

Again, that comes from a calculator on the website or in your own electronic medical record. We have Epic at UF in University of Florida, and it is there. You put that FIB-4 and it calculates and tells you what to do.

Yes, this person is at risk. The FIB-4 will answer the second question. I mean, what else do you have to do? The FIB-4 is just a starting point, low sensitivity. But if it is below 1.3, most times you will not have advanced fibrosis.

Now, when do you want to see these patients, Mazen?

Dr. Noureddin: Yeah. I mean, I want to make sure they have significant advanced fibrosis or, God forbid, in cirrhosis because we have now therapies for them. I do not want you to send it to me, Jay. I know how to do it. But as Ken said, I would love to see what is the FIB-4, if it is less than 1.3 or not.

Dr. Cusi: I calculated while we were waiting. It is 1.6. it is Higher than 1.3.

Dr. Noureddin: Higher than 1.3, but not too high.

Dr. Cusi: Not too high. Dr. Cusi: What we would do, we would do a transient elastography test, FibroScan.

Dr. Noureddin: Same here.

Dr. Cusi: Would you like to see them as one of those before we send them to you?

Dr. Noureddin: Sure.

Dr. Shubrook: Yeah. I think this brings up a really important point. Those of you in primary care, you should not think that everything is hunky-dory. I think there are some alarms there. I think that we need more tests. We do not send every person with elevated liver enzymes to the hepatologist. We need to actually make sure, one, they are not drinking, make sure they do not have other things. Then we do that FIB-4, and that is going to help us, right?

We did the FIB-4, and it was 1.6. Based on the ADA guidance and the guidance from essentially every organization, this person is at higher risk and needs a further evaluation. You heard, I think, Ken, say that VCTE or a FibroScan would be the next appropriate test to look at not only the fat in the liver, but the stiffness of the liver. That is going to help us to know whether we manage them in-house or we get extra help from hepatology. Yeah. Mazen, please.

Dr. Noureddin: Yeah. If you do not mind me. A lot of people hear, and they say, "That sounds like multi steps, and I do not have that machine in my office. Are you guys going to give us all that much work?" What I tell my friends, primary care friends, Jay is one of them, Jay has it all. But if it is more than 1.3 and you do not have a transient elastography, there are multiple ways to go about this.

There is ultrasound elastography with the radiologist that they have it, and there is also a blood test that has been recommended by American Gastroenterological Association, American Society for Liver Disease, called the ELF test that is available. That also gives you a reflection of that.

Honestly, if you do not have any of those, if you have 50 patients a day, I do not really want you to do that, just send patient immediately. But if you are busy and it is more than 1.3, that is fine. I will see the patient, preferably after a second test, but if you cannot, send the patient and we will send him back to you if it is not that high.

Dr. Cusi: Two little tips. A, if your AST is above 35, that is a red flag. If your platelets are below 200,000, another red flag. Think about that if you do not have time, and we will learn more about it in these 2 other cases. Go ahead, Jay.

Dr. Shubrook: Yeah, I love it. But this is really good guidance. There is a pathway for no matter what your resources are, and that FIB-4, especially if it is persistently high, if you do not have the other tests, get your team involved.

Case Study 2

Okay. The second case is Mike. He is 55 year old. He came over for diabetes management. He has got long standing type 2 diabetes. A1C is 7.9. Again, has obesity, hypertension, dyslipidemia. We call that the metabolic triad. He has done a fair amount of manages. He has trying to do lifestyle changes. He has on metformin, he is on a RAS agent. He is on a high-potency statin. Despite that, he has got the following. He has got an AST of 45, an ALT of 21, and a platelet of 193. Hopefully, all of you out there, you are calculating your FIB-4, you can do that even with MDCalc or the AJA[?] app. We get 2.8. Because our group has the luxury of FibroScan, we did a FibroScan and it showed not only steatosis, but F3 fibrosis.

So we have got some stiffness there. so I called Mazen and he did a liver biopsy, which often we do not even have to do, and it is got a NAS score of 6 and fibrosis stage F3.

First of all, how long is this going to take, Mazen, to have all this done, so patients and clinicians have a perspective of this process?

Dr. Noureddin: Yeah. I mean, it should be done really quick. I do not know if I needed to do liver biopsy, Jay. I think the transient elastography now AASLD guidance as well as expert opinions paper is probably sufficient. But maybe the patient wanted it, and it confirmed what we have seen. But also I want to reemphasize what Ken said. There is a lot of red flags here. A1C, uncontrolled diabetes, multiple metabolic risk factors, BMI. This is like the typical patients that walk in our office pre-cirrhotic like this patient.

AST flipped more than the ALT, more than 35, as Ken said. The platelet is less than 200. They all look normal in real life, like the platelet. The AST/ALT is slightly elevated, 1 upper normal of limit. Usually, back in the days, people do not pay attention to it. But look, this is like a typical patient for me, NASH with F3, or MASH with F3.

Dr. Shubrook: Yeah. Please.

Dr. Cusi: No, no. I would just comment that endocrinology are not used to looking at platelets, but it is something we should start doing in people with cardiometabolic risk factors. The other clarification is the FIB-4 is best validated between ages, say, 45 to 65, but definitely do not use it below 35. Above 65, you have to have caution. So do not do it in somebody who is 85 because the age will tilt it to be falsely positive. Liver enzymes, just around number, anything above 30 begin worrying, okay?

Dr. Shubrook: Yeah. Ken, staying with you, what are some of the pharmacotherapeutic options you would recommend that will address both diabetes and MASH in this patient?

Dr. Cusi: Well, one thing is metformin. Our normal metformin more than 50 years with us is great for type 2 diabetes, but many studies show now it does not improve the steatohepatitis or the fibrosis. I do not know if we have a table with this, that we have the effects on. Was it the next slide?

Dr. Shubrook: It is coming. Yeah.

Dr. Cusi: Okay. You want to go over it? I mean, I will just talk briefly. Pioglitazone is a drug that I have studied in clinical trials and used in hundreds of patients. It improves steatohepatitis, modest effect on fibrosis, although occasionally, it has had in studies an effect placebo-subtracted of 9% to 20%. If you ever would have had a phase III study, maybe it would have been an antifibrotic. But the beauty of it is that it lowers glucose by about A1C 1%.

Studies have shown some benefit in cardiovascular disease. If you start low at 15 milligrams, it is basically associated with minimal 1% weight gain. Then you see with 30 milligrams, you reach most of the benefit. One highlight is, again, the long-term effects on bone. You may want to do a bone density in people at risk. Do not give it to people with heart failure or a history of bladder cancer. Again, edema happens, as you say, 5% or 8%. Jay, do you want to comment on the GLP-1s?

Dr. Shubrook: Sure. Again, we have multiple agents that are beneficial for diabetes that appear to have benefit, as you heard today, for MASLD and MASH. Certainly, you have heard about the GLP-1 receptor agonists. We have evidence for dual agonists. Currently, tirzepatide is the only one. But there are more coming. These appear not only to reduce glucose, reduce weight, but they also reduce reduced steatosis. We are now getting evidence that they also reduce the progression of fibrosis, which is so important. Again, this is a twofer for our patients because they are going to get benefit for diabetes, they are going to get benefit for their weight, they are getting a reduction in cardiovascular risk. Now I guess that is more than a twofer.

Now they are getting benefit for their liver as well. I do think it is important for us to say, while those are not FDA indications, they are very appropriate for our patients with early MASLD to moderate MASLD and MASH because they have the benefit of those both things.

Now, Mazen, how about the hepatologist?, Are you going to use diabetes agents? What are you going to use for this patient?

Dr. Noureddin: I mean, Jay, you guys are way more familiar and savvy with these medication. However, we have been doing clinical trials with these medications for some time, so we started getting experience. We are also on the footstep of probably potential approval of semaglutide in NASH patients. We should have to familiarize ourselves with prescribing these medication. I am one of those that when I get NASH patients with significant advanced fibrosis, I follow what the FDA approved, which is resmetirom.

However, if they need a GLP-1 for weight loss or diabetes management, especially for the weight loss, I try not to interfere with diabetes management. I am more than happy that prescribe the medication, especially after I started the liver-directed therapy and titrated, sometimes I refer them back to you, Jay. I get a little bit nervous when they are on insulin. This is not my strength though. This is when I call on you guys and say, can you help me? I do not want to mess around with GLP-1 and insulin. A lot of times we need to call you anyways. That is the good medicine, right? Communication. The same note and multidisciplinary management. This is a holistic approach for metabolic features.

Dr. Shubrook: Yeah. We need to work as a team, right? Absolutely, we should be talking to each other. These are therapies that we have used together. No matter what you are doing with your patient with MASH, weight loss is part of the central part of that treatment. Whether that is lifestyle, medication-induced, surgery-induced, plus liver-directed therapy.

Okay. Last case. Then we have lots of questions coming in. And I am excited to ask you gentlemen about this.

Case Study 3

James is a 58-year old gentleman who presents to a hepatology clinic. He complains of fatigue, mild abdominal discomfort and lower extremity edema over the last 3 months. This does not sound good. He has got an A1C of 8.1. He has got hypertension. He is on metformin, lisinopril and high-dose atorvastatin. You can see that his exam shows a mild elevation of blood pressure. His BMI is only 25.7, so in the overweight category. He does have some abnormalities in his abdomen where he has got hepatomegaly, but no palpated ascites.

He has got mild bilateral pitting edema. You do not see any jaundice or spider angiomas. His transaminases are a bit higher. He has got elevated total bilirubin, albumin is a bit low, platelets are quite low at 110, and his INR is 1.2. Where do we go with this gentleman? You got an ultrasound in the hepatology clinic, and you have got a FibroScan that shows consistent with cirrhosis. All right. What do we do? Or what are you going to do? And what should I expect when you send them back?

Dr. Cusi: This is getting straight to your clinic, I think.

Dr. Shubrook: Yeah.

Dr. Cusi: I know. That is what we spend our careers trying to do. Like, find treatment and discover those earlier and spread the message. At this point, unfortunately, James has not a lot of options. We talked about clinical trials that they started showing maybe some evidence. Other than that, and to see if we can do anything, it is clinical trial. But in my clinic now, I do have to do the health maintenance of cirrhotics. One, screening for HCC; 2, looking for varices. A lot of doctors will ask me about the metformin and atorvastatin.

Atorvastatin, we did not take it immediately from the child ACE cirrhotics. We can debate that. There are some data that it is anticancerous HCC. I lower the dose usually and I keep them on the radar, hopefully that I reverse the disease with clinical trial, but eventually if that HCC screening needs to continue and if they decompensate, I will take James to my transplant center.

Dr. Shubrook: Yeah. This is a patient where we have missed the opportunity for that early intervention. Now we are really doing cirrhosis management and hepatocellular screening.

Okay. We have got some questions that have come in. I believe that is my next step. I guess we better do the posttest so we make sure we get it done.

Posttest

We have a 58-year-old person with a BMI of 34 on a GLP-1 for 2 years, dyslipidemia with fatigue and elevated LFTs. You saw that the liver biopsy, which we might be doing less often now, showed steatohepatitis with active disease, a NAS score of 6, and F3 fibrosis. The person is eager to start treatment. Which of the following medications would you use?

1. Metformin;
2. Pioglitazone;
3. Resmetirom; or
4. Vitamin E.

Please vote. All right. Comments, gentlemen?

Dr. Cusi: I would just say briefly that obviously this person, there is the rationale explained there. I mean, this person has advanced liver fibrosis, and the approved drug for F2, F3 to reverse fibrosis would be in this case resmetirom. Some mentioned pioglitazone. I mean, I love pioglitazone, and I would use it too because it costs $5 a month compared to resmetirom, $47,000 a year, but it does not have an approval for people without diabetes and it is not really a medication with proven antifibrotic effects.

Resmetirom would be based on the evidence and independent of the cost. The better choice for this person. But again, I would do it working with your hepatologist who would have extensive experience on how to make sure it is an F2, F3, how to monitor the patient, when to stop it if after a year there is no indication of improvement. Vitamin E, again, does not have FDA approval for MASH and fibrosis, and it is very mild, if any antifibrotic.

Dr. Shubrook: Mazen, are you comfortable with me saying that if you have F2 or F3, no matter what the treatment is, you should be doing that in concert with your hepatologist?

Mazen Noureddin: I mean, Ken has been doing this for a long time, so he can do it a lot. Some people can do it, but yes, I would love them to call them.

Dr. Shubrook: More than anything, it is a safety that you do not give it to somebody who does not need it and F1 or somebody with cirrhosis.

Dr. Cusi: Absolutely. Call us. I want to stay employed.

Dr. Shubrook: Okay.

Dr. Noureddin: We will keep you very busy. Do not worry.

Posttest

Dr. Shubrook: Posttest is the 67-year-old with type 2 diabetes, controlled with metformin, with HFrEF with an ejection fraction of 30%, presented elevated LFTs and known steatosis. The diagnosis is MASH with F3 fibrosis. They are obese. Which of the following would you recommend?

1. Add vitamin E to improve fibrosis;
2. Continue metformin and start pioglitazone;
3. Discontinue metformin and start semaglutide; or
4. Recommend lifestyles with a target of 3% to 5% weight loss.

Please vote. Okay. We do have a predominance of people that said discontinue metformin and start semaglutide. What do you think? We are all in agreement?

Dr. Cusi: Well, the explanation is right there. I do not want to repeat it, but again, do not use pioglitazone if you have heart failure. Even metformin should not be used, not because it worsens it, but because you are at risk of acute renal failure and a decompensation and getting into trouble. The lifestyle to reverse fibrosis will need to be 8% or 10%, and vitamin E will not do a whole lot. That is the summary.

Dr. Shubrook: Yeah. And I agree that, really, lifestyle is a critical part of this. But we need more weight loss to get sizable changes.

Dr. Cusi: Yeah. Jay, the other point is that if you think about it, there is no indication for GLP-1s or pioglitazone because they are not FDA-approved. But the treatment with the GLP-1 for MASH is really free because you are using it for obesity and you are using it for diabetes in contrast to spending $47,000 with resmetirom, which would be valuable, but in selected patients, working with your hepatologist.

Dr. Shubrook: With the right stage. Yeah. All right. Last question and then we get to yours. How often do you do you prescribe GLP-1s to individuals in your practice with MASH and obesity?

1. Never;
2. Rarely;
3. Sometimes;
4. Frequently; and
5. Always.

Actually, I assume the answer is going to be the same as you did before because we probably have not seen any patients since this webinar started.

Dr. Cusi: I hope you have not seen any patients in this hour, right?

Dr. Shubrook: Yeah. Please vote and we will get to your questions. Okay. Excellent. All right. There are lots of great questions here I am going to start from kind of the collection. First of all, maybe we start with if someone has F2, F3 liver fibrosis, can it be reversed with lifestyle alone? Mazen, you want to take that first?

Dr. Noureddin: There are data showing that lifestyle intervention fibrosis has improved. If you lose weight by 7%, reverse steatohepatitis 10% for fibrosis. However, the data showing that less than 10% achieve less than 10% weight loss. A lot of failures. If I have this F3 in front of me, I will be worried about waiting just like [inaudible]. And by the way, all medications, including resmetirom recommend lifestyle intervention at the same time. We are trying to avoid this cirrhosis, act early act fast. But at the same time, do not forget the weight loss and exercise.

Dr. Shubrook: Excellent. There is 2 other questions that I am going to loop together. This same patient who is F2, F3, if they get rid of the insults and if they get rid of their metabolic risk, do we expect fibrosis to continue to move forward regardless, or can you change the needle, I guess is what is being asked, if you take out some of the underlying problems?

Dr. Noureddin: Ken, do you want to do that? You have done a lot of studies on that.

Dr. Cusi: Well, the question is, again, specifically, what is the specific point to make you think?

Dr. Shubrook: Let us say they lose weight, they get control of their diabetes, they are not drinking.

Dr. Cusi: I think that from the experience with hepatitis C, that you remove the virus over time, fibrosis would get better in most patients. I think you can achieve that with lifestyle alone. This magic number has a lot of variability, but at least 10% and maintain it, which is difficult, in that sense, GLP-1s to help you induce and maintain the weight. But one thing is, as you know, if you stop the GLP-1, many regain weight. That is because we do not do a concomitant lifestyle education and change the wiring that many of us have to choose cake over broccoli.

Dr. Shubrook: Fair enough. There is one in there that I think Ken's typing. But I will also say if you do your FIB-4, which we recommend you do for all your patients at high-risk, and it is less than 1.3, they stay in your practice and you do cardiovascular risk reduction and weight loss.

Dr. Cusi: Great question. Again, these are guidelines. There will be some people with F2 or a moderate advanced within 1 to 1.3. But the majority will be fine. You just keep them in their practice. Do not send them to their pathologist. Steatosis is not an indication to send them to the liver doctor. It is the FIB-4, and do all the things that you usually do. Optimize diabetes and promote weight loss.

Dr. Shubrook: Love it. There was a comment.

Dr. Noureddin: Well said.

Dr. Shubrook: Go ahead, Mazen. Do you want to add something?

Dr. Noureddin: I said, well said.

Dr. Shubrook: Okay. Does the diagnosis of metabolic syndrome automatically trigger the need for a liver biopsy? The answer should that be no? We just kind of said, highlighted that we do have noninvasive tests, including FIB-4 and the elastography that will be real important as we move forward. The liver biopsy is going to go down, but if you are above F2, work with your hepatologist.

All right. So the last question before Dr. Noureddin jumps off is, how long do we wait for adding combination therapy if we think they benefit from a GLP-1 and resmetirom?

Dr. Noureddin: As of today, the FDA-approved drug for liver-directed therapy is resmetirom. I add GLP-1 later on for weight loss. It is expected that we are going to have a GLP-1 approved in the near future. I think it will have to do a lot with the comorbidities and weight and all this, but stay tuned. We will update the guidance then.

Dr. Shubrook: Excellent. Ken, any thoughts there?

Dr. Cusi: Well, I have an endocrine angle because I see so much obesity and diabetes. I would always choose a GLP-1 because, as a first step, if they can afford it because it will treat the obesity and the diabetes, which may improve NASH and the treatment of NASH will be free in that setting. But as you know, many patients still have significant NASH and will develop cirrhosis on GLP-1s. That is when I think you need to add a combination therapy with resmetirom.

I think the combination would be the way of the future. I think that is where the field is going, not one or the other, but smartly use it sequentially.

Dr. Shubrook: Ken, this one is for you. I know that there is going to be guidance coming out almost momentarily. If someone is having a FibroScan, do you have a FibroScan level for which you would recommend hepatology for hepatocellular carcinoma surveillance?

Dr. Cusi: That is a tough question. A number of things, and we need to go actually. Number one is FibroScan is a good test, but has an error under the curve of 0.8, means that there is a lot of variability. But if you have somebody with low platelets below 150,000 plus a value of greater than 15, that person is at risk of cirrhosis. That would be a level where definitely you would want to have a liver biopsy. But more than anything, send it to your hepatologist.