Identification and Risk Stratification

 

Dr Kenneth Cusi (University of Florida): Let us get started and let us see how we can identify and risk stratify our patients in an efficient way in our clinics.

 

[00:11:28]

 

Patient Case #1: 64-Yr-Old Female With Obesity and T2D

 

With that, we are going to start with patient case number 1. Again, 64-year-old female with obesity and type 2 diabetes. She had come for a regular follow-up. You are a very famous doctor in your area. To follow on type 2 diabetes and reports increased weight gain and fatigue. She want to know if her medications can be adjusted?

 

Past medical history, positive. As we said, type 2 diabetes, coronary disease, heart failure, and a BMI of 39.2.

 

The therapies you can see here:

 

• Empagliflozin;
• Metformin;
• Sacubitril;
• Valsartan twice a day;
• Carvedilol twice a day;
• Atorvastatin 40; and
• Baby aspirin.

 

Physical exam, central obesity.

 

These are the labs:

 

• A1C of 7.2%;
• Fasting glucose, 109 milligrams per deciliter; and
• eGFR creatinine clearance of 88;
• ALT is 39;
• AST is 32;
• Hematocrit, 42%;
• Platelets, 230.

 

Let us see here.

 

[00:12:44]

 

Small Group Discussion With Poll: Does this patient have any red flags for MASH?

 

What we are going to do now? We would like you to participate in small groups. We have Marc and Arun are going to mingle around your tables. I would like each table to resolve this case in small groups and try to answer if this patient has any red flags for MASH?

 

1. No;
2. Yes; or
3. Not sure.

 

That is what you are going to have to answer. Can we get back to the screen? I cannot do that. Can you go back? There we go. Thank you. You have 1.5 minute to crack this case, guys. I know you can do it. How is my Dominican Republic table? Doing good. We have some experts here. You guys are in another league now.

 

Okay. You have 10 seconds here to vote. Decision time.

 

[00:15:23]

 

Small Group Discussion With Poll: What additional questions or lab tests do you recommend? Select all that apply.

 

Now, what additional questions or lab tests do you recommend for this person? You have a laundry list there. You can select all answers that apply.

 

1. Lipid panel;
2. Liver ultrasound;
3. MRI;
4. Viral hepatitis panel;
5. Iron studies;
6. Autoimmune liver markers; also
7. Alcohol intake history; and
8. Assessment of sleep apnea.

 

Okay. The option that it says MRI-PDFF is an MRI, a measurement of liver fat by magnetic resonance. It is a measurement of liver fat by MRI. You have to keep the cost low here. Be careful.

 

[00:17:54]

 

ADA 2025 Diagnostic Algorithm for Risk Stratification and the Prevention of Cirrhosis in Individuals With MASLD

 

Well, I am going to move a little bit forward here and give you some ideas. Are we okay there? Have we cracked the case on the left, Arun? They all got it right. Yeah. We are in trouble because you already know all this stuff.

 

Just to make it easy, the American Diabetes Association with other associations have made the diagnosis simple. If you go to the website of the ADA, you can download slides of all of this. Also on the website, we will have this information available for you too.

 

Three big groups. The highest risk of having fibrosis stage II or higher are people with type 2 diabetes, especially if they have obesity. Next would be people with prediabetes, especially if they have obesity, much less if they do not have obesity. Then not all obesity is the same. But the more cardiometabolic risk factors, the greater the chance that you have a liver problem.

 

The key thing is to think of the FIB-4, which if it is equal or greater than 1.3 has been associated with negative liver outcomes. This is an important thing to know and now several studies show a correlation with cirrhosis in the future.

 

Now, if you are, as you see in the top that it is below 1.3, it does not mean that it is a perfect test or that you do not have to worry anymore, but means that the person does not have a degree of fibrosis that is worrisome today, but can develop it tomorrow. You have in the meantime do a lot of cardiometabolic risk management, as I know you do with lipids, blood pressure, controlling diabetes and optimal weight.

 

But then you need to monitor this FIB-4, we say yearly. It is just easier to say every 2 years, but yearly. Because everybody, at least in the United States and in many countries, gets once a year a liver panel and a complete blood count.

 

Now, if FIB-4 is equal or higher, then you probably want to do another test. In the United States, you can easily order in your electronic medical record transient elastography test, also known as FibroScan, or there are other shear wave elastography tests that are not so well standardized, but can be helpful if you do not have access to it.

 

There is also a biomarker called ELF that you can order if it is higher than 9.8, but today it is still an expensive test. Then they will be managed by Arun. You send all your patients to Arun, and he will see them immediately for you.

 

[00:20:50]

 

Case Files

 

Now this person has a FIB-4 of 1.43 and it is higher than 1.3. This is a red flag. We do this transient elastography/FibroScan test that gives you information on the amount of liver fat that you see there as capped. So fat is capped. It stands for controlled attenuation parameter. It is just a technique that tells you how much fat the liver is.

 

It is relatively accurate. If it is equal or higher than 274, in this case, 310, this person clearly has steatosis.

 

Now the other test that is very important is if they have a significant amount of fibrosis. We worry when it is equal or greater than 8. In this case, it is just 2.8.

 

Prevalence of MASLD and MASH

 

In this case what we are having, if we have to plot this over time, our patient would be in the early stages where it says steatosis probably. We do not have any great tests in the clinic yet to measure inflammation steatohepatitis. But we assume that if there is a lot of scarring, there is active steatohepatitis.

 

In this case, our patient most likely has steatosis or some degree of steatohepatitis. But we would stop the liver assessment there and focus on the cardiometabolic risk factors to prevent progression of steatohepatitis and reverse steatosis.

 

[00:22:25]

 

Endocrine Factors Associated With MASLD

 

Now, the 2 risk factors that are most important is, as I said. As endocrinologists, there are many hormonal imbalances that can cause steatosis:

 

• Hypogonadism;
• PCOS through insulin resistance;
• Hypothyroidism;
• Even growth hormone deficiency.

 

But what has been well documented that can cause cirrhosis is having obesity and diabetes. Those 2 risk factors.

 

[00:22:56]

 

Guideline Recommendations: Who Is at Risk for MASH and Advanced Fibrosis?

 

These are the guidelines. At this time in the evening, I do not want to put you to sleep reading all of this. But in all honesty, all the guidelines say pretty much the same. What I showed you from the ADA is nothing new. It just packaged in a clear way for all of us.

 

The Liver Society, AASLD and AACE, the American Association of Clinical Endocrinologist both are saying use the FIB-4 followed by transient elastography.

 

[00:23:26]

 

Red Flags and High-Risk Populations

 

The red flags to look at our older age can be a factor in the sense that these metabolic factors chronically can cause more damage, type 2 diabetes. Some studies show first degree relatives of somebody who has MASH. Many times I have a patient that says, “My mom died of cirrhosis, but she never drank any alcohol. We do not know what happened.” That is probably undiagnosed MASH.

 

Risk factors, as you know, lack of physical activity, overweight or obesity, metabolic syndrome, and again, sleep apnea is frequently associated with these risk factors.

 

[00:24:05]

 

Panel Discussion

 

I want the panel here to work a little bit. We are going to be talking about a number of things. How often do you screen, Marc, people with MASH in your practice?

 

Dr Marc-André Cornier (Medical University of South Carolina): Well, I think now with these new guidelines, I am doing it in everyone with diabetes and obesity. Certainly in my practice as an endocrinologist, that is mainly who I am seeing or in the lipid clinic. I mean, it is an easy screening, right? We get the labs.

 

I think maybe a little different is that we did not used to always get a CBC as part of our labs.

 

Dr Cusi: That is true.

 

Dr Cornier: We are on Epic at my institution, and it is FIB-4, and it calculates it for me. Boom. It even gives me the parameters. There really is no reason to not screen as long as I have that platelet.

 

Dr Cusi: Again, the use of the electronic medical record. Epic is one of the most common electronic medical records. We have people from all over the world. I mean, try in your institutions to incorporate it in your electronic medical records, is the fastest and easiest way if you can. If you own your phone and go to any web browser and type in FIB-4 calculator, it will get it to you in a second. That is fairly easy.

 

Now, from a hepatology perspective, talking about diabetes as a risk factor, how often do hepatologist order a hemoglobin A1C in people without known – I am trying to get him in a sweater, but he is too relaxed here. We are going to try to get some adrenaline going here.

 

Dr Arun Jesudian (Weill Cornell Medicine): Yeah. What you do not know would not hurt you. So we never send it, which is not true. I think these patients come to different providers attention. It is not always a uniform, say, primary care endocrinologist then to the hepatologist. I think we do them a disservice by having some tunnel vision.

 

Even if we are not going to manage their diabetes necessarily, if I am seeing a MASLD or a MASH patient, I am thinking about their extrahepatic disease because oftentimes that might be what is most life-threatening to them. Even if I can then pass off their care to an endocrinologist, it is worthwhile sending while they are there in front of me and I can engage them.

 

Dr Cusi: Okay. Very good. Again, in your institution, how easy is it to get a FibroScan?

 

Dr Cornier: Well, at my institution it is very easy. But twofold. We have a weight management obesity clinic. One of my providers actually does elastography in the clinic, as he is talking to this patient. He does it in everybody. But that is not available to everybody. But I can easily order a FibroScan is what we have available through our radiology department. Very simple to do and generally well covered, at least in our area. That would be the test of choice for me and my practice.

 

Dr Cusi: One thing that I get a lot is sometimes there is some confusion. You are an obesity manager, why should I screen if I anyway tell them to lose weight or give them a GLP-1? I mean, what would our liver hepatologist answer?

 

Dr Jesudian: In terms of why get a non-invasive test?

 

Dr Cusi: Yeah. Why are you going to still tell them to lose weight? Why would you want to do a FIB? What are you trying to also discover incidentally?

 

Dr Jesudian: Yes, I think why this is important to know what their fibrosis stage is, is partly you can have a better informed discussion with the patient. If someone has F3 fibrosis, that is stage III out of IV, they are almost at cirrhosis. It becomes much more urgent to deal with their MASH and try and at least arrest the fibrosis progression. Or even now we have good data that you can cause some of that fibrosis to regress on the appropriate therapy, but also as you get into F3 and certainly F4 cirrhosis, those are patients who need to be screened for hepatocellular carcinoma. Might need to get an endoscopy for varices screening could decompensated. Knowing that puts them in the right care pathway. If you did not know that, then you might be surprised.

 

Dr Cornier: Well, I would also say it helps us guide our medical therapy potentially. Yeah, obesity management and weight management is going to be important. But we may also use other tools. I need to know when I need to send them to see.

 

Dr Cusi: Yeah. That is important. Just the take-home message is no matter what you are going to do with lifestyle or other, you are going to discover some patients with undiagnosed cirrhosis. Again, cirrhosis for non-hepatologist is something that you are just stuck and get worse. But it has some plasticity, means that it can go back in the early stages.

 

They need to find out if they have varices. They need to find out maybe they have early hepatocellular carcinoma and they can educate the patient. It is important to stratify everybody because it is not only a matter of jumping to treatment. That is important.

 

[00:29:25]

 

Commonly Used Noninvasive Tests

 

Now just for you to know, we are just recommending the FIB-4 on the left. There are other tests that can be checked. I hope you do not start dancing here. Okay. There are also the enhanced liver fibrosis, or ELF test. In the United States, it costs $300-plus. I would think that you would use that carefully only if you do not have a FibroScan.

 

There is an under review a NIS2+ and PRO C3 are the 2 proprietary tests. There is going to be a number of new tests to add as a second-line therapy.

 

Then imaging. We mentioned the measurement of liver fat. There was an MRI-PDFF. It is measuring by MRI liver fat. It is really something only hepatologist should do, what we do in research. There is also MRI, magnetic resonance elastography there. It is calculating the elastography by MRI also, more expensive.

 

Then there is corrected T1 or Liver MultiScan that is increasing its uses and penetrates the CPT code and might be helpful to identify disease activity and eventually fibrosis. But I think at the time those will be tools that I think the hepatologist should manage.

 

[00:30:47]

 

MASLD Fibrosis Score and FIB-4 Score: Online Calculators Easily Interpret Noninvasive Tests

 

This is the FIB-4 calculator that we mentioned that you can get anywhere if you go to any web browser. I am not going to advertise any web browser.

 

Again, this puts us back to where we were. The key thing is to develop these networks where you have a hepatologist. The hepatologist will not want you to send this patient to him, because 70% of the people with diabetes or with obesity already have steatosis. That is why we do not recommend using an ultrasound, because almost all your patients are going to be positive, and it does not tell us about fibrosis. You want to do the FIB-4. Again, based on that, decide what your strategy is.

 

With that, I am going to get Professor Cornier here to take it on to the more challenging part of the talk.

 

[00:31:41]

 

Significant Impact of Early Intervention and Treatment

 

Dr Cornier: All right. How is everybody? How was dinner? Was it good?

 

Dr Cusi: Yeah. I think they are recovering from dinner.

 

Dr Cornier: Yeah. The insulin levels are high. People are starting to get a little sleepy. The wine. Maybe we need to bring out the coffee. But first, before I get started, I want to thank again, Ken and the organizers for inviting me tonight. This is a lot of fun. We are going to talk about early intervention.

 

I would actually say that we are talking about way late intervention. We should be treating obesity first before any of this happens. I am sorry, I am wearing my Obesity Society President hat right now.

 

We put obesity as the last diagnosis on the problem list. It should be the very first one. It is the one that causes all these problems. Actually, in our charts, 40% of our type 2 patients with obesity did not have obesity listed as a problem. This is not an endocrine practice, right? It is embarrassing. We need to do a better job. We need to list obesity at the top. It will be reimbursed better and better. Sorry, I will get off my soapbox now.

 

Dr Cusi: You got it. Yes I know.

 

[00:32:48]

 

Patient Case #1: 64-Yr-Old Female With Obesity and T2D

 

Dr Cornier: Remember our patient. This is our 64-year-old woman with obesity and type 2 diabetes. Her elasticity or FibroScan value is 2.8, which shows low likelihood of fibrosis and low risk for cirrhosis.

 

Remember past medical history. New diagnosis of OSA confirmed recently after sleep study. Remember, do not forget to screen your patients for OSA. Additional cardiovascular risk factors include dyslipidemia. She is on a statin and she also has an elevated hsCRP.

 

[00:33:27]

 

Small Group Discussion With Poll: Would you refer to GI/Hepatology?

 

Small groups. Would you refer this patient to GI or hepatology? Who is going to send them to see Arun now? Are you going to do other things first?

 

Okay. Thank you. Again, what is your comfort level? I think that is important. Okay. Anybody, far tables over there, are you going to refer to GI yet? Anybody? No. You got this under control. That would be good.

 

You are ready for the next one? They would not let me go forward.

 

[00:35:00]

 

Small Group Discussion With Poll: What Interventions are appropriate at this time? Select all that apply.

 

Next question. What interventions are appropriate at this time?

 

1. Lifestyle change to promote weight loss;
2. Metabolic bariatric surgery;
3. Medications for MASLD; Or
4. I do not know. I am not sure. That is why I came to this program to learn something.

 

What do you think? Remember all of the above. Her BMI was in the 30s. Remember, metabolic bariatric surgery is now acceptable for BMIs over 30 with diabetes. Well, I mean, do we care what her weight is? Her BMI is in the 30s. Yes.

 

What do you think? Should we move on? I think 88% of you say weight loss with lifestyle. Almost 20% saying surgery. That is good. Surgery is an option. Then medications. I think we are going to talk more about that as well.

 

[00:36:53]

 

Panel Discussion

 

Let us ask the experts here. The first question is how are you managing people with intermediate risk?

 

Well, I think I am going to ask the endocrinologist that first. All right. How are you going to manage this intermediate risk individual? What is your practice?

 

Dr Cusi: Yes. What you need to do is, in general, the hepatologist we are going to get to them when we have more advanced fibrosis. Because one of the problems that happens is we need to screen and people do an ultrasound. They see fat and send all those people to the hepatologist. The hepatologist is really going to only act on those who have moderate to advanced fibrosis. Why? Because those are the ones who are like on a path to cirrhosis. Okay?

 

Left alone, and with diabetes and obesity, it is a matter of time. Some progress faster, others slower. What I am going to focus is on cardiovascular prevention.

 

One thing that I do not want to forget is that typically liver enzymes might be a little bit elevated. Many primary care doctors stop the statins.

 

Do not stop the statins. That is a very typical problem. I see it all the time. Because statins are relatively safe and you can start at lower doses and titrate up, but they have a lot of good biological effects on the liver. Hepatologist love them.

 

The other thing is the typical traditional risk factors. If you have obesity and you can afford them, probably a GLP-1 would be a great option. We are going to look at the evidence for that. If you have diabetes, also GLP-1. When I say GLP-1s, it is class. It is also dual agonists have shown to improve diabetes and also reverse the inflammation, the steatohepatitis and reverse the fibrosis.

 

Dr Cornier: You are jumping the gun, Dr Cusi. We are going to talk about all that. Just getting ahead.

 

Dr Cusi: I know. The bottom line, yes. Cardiovascular risk factors and optimal management of obesity and diabetes.

 

Dr Cornier: What if the patient gets sent straight to you? Because, I mean, not everybody is comfortable taking care of these patients.

 

Dr Jesudian: Yes, it happens. Certainly I see patients who sometimes just have steatosis, and I have a FibroScan in my office. I will do one and just see a high CAP score, but F0. Those lower risk patients, as long as I have good communication with whoever referred them to me, I might say it is okay to go back to your primary or your endocrinologist and focus on your obesity and your heart disease, and you do not necessarily need to keep seeing me.

 

If someone has maybe a suggestion of some fibrosis, this came up in the small groups. As long as you have it very accessible, we might do an annual FibroScan on that patient and see are they progressing over time? Are they getting to the point where their F2, F3 or I might consider more liver-directed therapy?

 

[00:40:06]

 

ADA 2025 MASLD Treatment Algorithm for Individuals With Prediabetes or Diabetes

 

Dr Cornier: That is great. Great. Okay, so as Dr Cusi earlier presented the ADA guidelines, we are proceeding with the algorithm. Look at the publication. Who is the lead author on that? This guy right here. He is the guy, right?

 

I think now we are talking about treatment algorithm. We have identified the patient. What are we going to do with them?

 

On the left side of the screen, I think is critical. We need to talk about healthy lifestyle. That is important. We need to talk about weight management, if indicated. We need to consider surgery. I mean, metabolic bariatric surgery is a very important tool in all of this as well.

 

But what are these patients going to die from? Probably, I mean, it could be liver disease, but ultimately it is going to be cardiovascular disease. We really need to be focused, as Dr Cusi was mentioning a minute ago, on that cardiovascular risk profile.

 

Then we move into actual direct treatment of the liver disease. It is based on the degree of fibrosis. On the far right, you will see there is like that those yellow, orange and blue columns. I am going to focus on the yellow and the orange. So patients with obesity without diabetes and orange patients with diabetes. Then we will let our hepatologist in a few minutes talk more about the patients with actual fibrosis and MASH.

 

If you have no fibrosis, there is a number of options in those without diabetes. A GLP-1 or GLP-1/GIP receptor agonist would be a great tool if we can get them approved. If they have some fibrosis, again, these are the same considerations that we would look at. If they have diabetes, we have a couple of other options. We are still thinking GLP1-based therapies, but we also can consider pioglitazone. We have some evidence there.

 

If there is no fibrosis, SGLT2 inhibitors. We just do not have data yet about the SGLT2 inhibitors in terms of fibrosis.

 

Now if they have F2, F3 fibrosis, then we take away the SGLT2 inhibitors for now, until we have more data, and we consider using a GLP-1 based therapy and/or pioglitazone at that point. That is the general direction we are looking at.

 

Now if they have end-stage decompensated cirrhosis, I am leaving it up to him to take care of him at this point. Yes, but if they have diabetes, I think the important thing to consider here is really we are going to be focusing on insulin therapy at that point as the best way to manage their diabetes.

 

[00:42:58]

 

American Diabetes Association 2025: Pharmacological Management of Type 2 Diabetes

 

We all know this right. This is the ADA: pharmacologic management of type 2 diabetes. Certainly for the last few years, there has been the deciding factor of if patients have ASCVD or risk factors for ASCVD or they have heart failure or CKD, we go down this side of the algorithm.

 

Newer is if there is weight management, we go down this side of the algorithm. But now even newer is now we have a liver component to it at the bottom. Patients at risk for MASLD or MASH, let us consider treatment.

 

This is so tiny, I cannot see it. I have this little bitty iPad here, and even with my glasses, I cannot see anything. We are going to focus in on this and make it maybe a little bit bigger so we can actually see it.

 

In patients with risk for MASLD or MASH, we are going to think about agents that have potential benefit in these patients. GLP-1 receptor agonist, GLP-1/GIP dual agonist, pioglitazone or a combination of a GLP-1 agonist with pioglitazone. There is some data there that is a pretty intriguing.

 

I really do think we underutilized pioglitazone, now a generic cheap drug that actually can be very effective in the right patients. Do not use the high doses, 15, maybe 30 milligrams. Do not go to 45 milligrams. In my opinion, I think a lot of patients do well with it. So something to consider.

 

Then obviously, we do not want to use these drugs in the setting of decompensated cirrhosis. This is new to algorithm of how we are going to decide what drugs to use in our patients with type 2 diabetes.

 

[00:44:49]

 

Role of GLP-1 in MASH

 

The role of GLP-1 in MASLD and MASH is multiple. We know how these drugs work, right? They work in the brain to make you full. GLP-1 is a satiety hormone. That leads to weight loss. That leads to reduced liver fat. We know that weight loss is probably the best treatment for liver fat, but there is probably some other direct and indirect effects of GLP-1 based therapies, certainly an effect on insulin secretion, which is usually a good thing for our patients with diabetes.

 

It impacts directly liver lipid as well. There may be some indirect effects on the bottom left of your screen with the increased insulin, reduced glucagon in terms of lipid metabolism and also chylomicron secretion as well at the intestinal level.

 

There is a number of mechanisms for these drugs to be effective at lowering liver fat and potential liver disease.

 

[00:45:58]

 

Treatments in MASH

 

This is a summary of a lot of data. Some of this is repetitive on this slide. I would not go through all of it. If we think of the 3 main categories of drugs that we are recommending here, we are talking:

 

• Pioglitazone;
• GLP-1 based therapy, which could be a dual agonist; and
• SGLT2 inhibitors.

 

What the data show is that steatosis improves with all 3 of these. You see improvement in steatohepatitis with pioglitazone and GLP-1 based therapy, but we do not know yet with SGLT2 inhibitors. Fibrosis improves with GLP-1 receptor agonists.

 

Then with all 3, we see benefits in cardiovascular disease. I mean, I think there is people out there who still think that pioglitazone is bad for the heart, but actually, there is a couple of studies that suggest positive, reduced cardiovascular outcomes in people with diabetes and people with prediabetes in terms of stroke outcomes.

 

There is a number of effects. Think about if they have fibrosis, that is right now we just do not have the data to support SGLT2. They may be good, right? They may turn out to be a good treatment for these patients. The reality is most of our patients end up being on multiple drugs anyways. It is like treating hypertension. You could talk all day about whether they should be on an ARB or a calcium channel. But the reality most of our patients need to be on all of those drugs to control their blood pressure. That is the reality.

 

[00:47:31]

 

Panel Discussion

 

Let us come back to our experts here. What are your treatment goals? What are we trying to do? Are we trying to reverse disease, or are we trying to reverse progression? Maybe I will go to the liver specialist.

 

Dr Cusi: You are a liver specialist?

 

Dr Jesudian: Yes. It depends on where they are starting. But at the very least you would want to stop their progression. Because although I am a transplant hepatologist and I am in the business of getting patients a liver transplant, I would love for no patient to need that. If they cannot get to F4 cirrhosis, then their liver is going to work perfectly well. If they could stay at F2 or F3, that would be great.

 

But again, we are seeing data now that we can regress fibrosis, which is really revolutionary, at least in the field of hepatology. We used to think that fibrosis regression either would not happen when you had compensated cirrhosis, or it would take 5 years or more, but the data in MASH are showing us that you can see that potentially within a year or so.

 

Dr Cusi: That is really good.

 

Dr Cornier: Great. How do you talk to your patients about weight loss for MASH?

 

Dr Cusi: I am embarrassed to talk in front of the President of the Obesity Society about this.

 

Dr Cornier: I am putting you on the spot.

 

Dr Cusi: Yeah. Well, okay. What can I say now? No, but the important thing is that there is a sense from many, many studies and any way that you try to lose weight, that the more weight loss is correlated with a greater reduction in liver fat that plateaus with the weight loss of about 20%. But for reasons we do not fully understand, that is also the reduction in the inflammation.

 

It is also somehow proportional to the weight loss. Also this fibrosis also in general. But there is a lot of variability. Now, even eating better and avoiding some foods like saturated fats or a lot of fructose in our sodas and things like that has shown without a major weight loss to improve. It is quality of the food and quantity.

 

What I like to do is when I suspect somebody might have a liver disease and the FIB-4 is elevated or the FibroScan is elevated, it is very motivating because the liver has this emotional connection and saying, it is really important that you lose weight because in addition to all the other things, your liver is screaming for help. It is really motivating. But again, a pep talk is not enough.

 

I mean, if you can, you need to get support by nutritionist, support by a diabetes educator. If you have a weight management program, I think that is really useful.

 

Then the GLP. I am going to throw the ball back to you for the next one. When do you add a GLP-1?

 

Dr Jesudian: What you are saying is important. I mean, if all we talk about is, you need to lose weight. That is not going to work, right? Our patient has to want to lose weight. They have to be motivated. They have to be in action phase. Now we are going to use some of these medications that is going to control their diet. I mean that is the reality. If I put someone on a GLP-1 or a dual agonist, they do not need to count calories anymore. The drug is going to do it for you.

 

Dr Cusi: Give us 3 tips. He is the master of weight loss. All these patients lose weight.

 

Dr Cornier: No. I think the first thing is if you diagnose them with liver disease, using that to educate the patient about their health and how it is impacting their health and using that as a potential motivator. But you cannot motivate a patient. They have to be self-motivated.

 

I am going to be aggressive with medical therapy because I am treating their diabetes too, which is really important. Yes, lifestyle is important. Diet is important. Exercise is important. End of the day, weight loss is going to be the most important.

 

In the last 30 seconds, we have, for this part, I am going to ask the hepatologist what do you think the role is for us endocrinologists and primary care providers out there?

 

Dr Jesudian: I think I am so glad that we are doing programs like this because I think one of the biggest roles is just being aware of this disease screening. You are in touch with all of the patients at risk or many of the patients within your practice. So knowing what to look for, how to risk stratify them, how to appropriately then refer them over to someone like myself if they truly do have advanced fibrosis or cirrhosis, or they need to be considered for a liver specific therapy. I think those are some of the big themes I would say are important from my perspective.

 

Dr Cornier: Yeah, I think raising awareness is a huge one. If we do not get our head in the sand, we are not going to take care of the patient.

 

Dr Cusi: Each one of you have to play this role wherever you work, because this just needs all hands on deck, as they say.

 

Dr Cornier: I think it needs to become in our standards of every year, you do albumin to creatinine ratio. You do an eye exam, you do a FIB-4, right. It has got to be part of our annual assessment for the patient.

 

Well, I think now we are going to turn it over to our liver specialist.

 

Dr Cusi: Let us put him to work.

 

[00:52:55]

 

Future Directions in MASH Management

 

Dr Jesudian: I am ready. Thank you for having me. I was just saying earlier, it is so surreal to be at a conference that is not your own specialty. Because we have conferences here at McCormick, and everything looks so familiar apart from I do not know anybody. I am glad to say I know all of you. At least I have 2 friends now. Thank you for welcoming me here.

 

[00:53:21]

 

Patient Case #2: 59-Yr-Old Male

 

We will focus a little bit more on the liver specific questions through a second case. This is now a 59-year-old man, who presents for weight management referral for obesity. In terms of history, 10-year history of type 2 diabetes, has dyslipidemia. Importantly to me, his liver enzymes are elevated, which is a little bit different from the earlier case.

 

He does have a father with liver disease. He is not sure what type of liver disease his father had. That is very common. Medication-wise, he is taking atorvastatin, metformin and empagliflozin. He has a 44-inch waist circumference. You examine his abdomen. If you do that and you find that he does have an enlarged liver that is palpable below the ribs, but it feels smooth. It is not necessarily lumpy, bumpy, nodular, or at least that is what you pick up on your exam.

 

His A1C is 8.5. His fasting glucose, 162. You see his lipid panel here. Liver enzyme wise his ALT is 57. That is certainly above normal. AST is 39. His FIB-4 is 2.1. You saw before the cutoff of 1.3. Some studies would tell you if you are below 1.45, your risk of having advanced fibrosis or cirrhosis is really low. If you are above 3.25, your risk of being in that category cirrhosis or advanced fibrosis is very high. He is in the middle. He is in this intermediate range.

 

[00:55:04]

 

Small Group Discussion With Poll: What additional recommendations would you make for this patient? Select all that apply.

 

The question for a small group question is what additional recommendations would you make for this patient? Select all that apply.

 

1. 1. Lifestyle changes to promote weight loss;
   2. Metabolic surgery;
   3. Medications for MASLD; or
   4. Not sure.

 

Same options as last time, different patient.

 

Our discussion time is up. Let us take a look here. Let me see if I can go back for a second. There we go.

 

Almost all of you said lifestyle changes to promote weight loss certainly would be important in this situation and many others. Just after that, medications for MASLD, and then about 30% saying metabolic surgery. I think you are recognizing that this is someone who could be at risk for some degree of liver fibrosis, but also has his other present risks of heart disease and obesity related complications.

 

It definitely makes sense to focus on lifestyle and think about medications or even potentially metabolic surgery.

 

[00:58:22]

 

Case Files

 

One thing that would be helpful, and we talked about this before his FIB-4 score is in the intermediate range. It would be great to have a more accurate test that tells us really what degree of fibrosis does this gentleman have. Can I say what his risk is for liver-related complications right now in terms of developing them over time.

 

You get a FibroScan. Remember, the CAP score is going to tell us about how much steatosis he has. The CAP score is 330. That range goes from 100 to 400. As you get above 320, you are in the severe steatosis range. Certainly he has quite a bit of steatosis.

 

Then in terms of how stiff is his liver. The VCTE is vibration controlled transient elastography and the LSM part is liver stiffness measurement. Basically, if you vibrate his liver and measure the sound wave across it, is it a very stiff liver or is it a very smooth liver without fibrosis? Or is it somewhere in the middle? His reading is 12 kilopascals. You see likely fibrosis of F2, stage II fibrosis or above if you are above 8.

 

He is certainly above that. He is not really as high as the range as I would be worried about cirrhosis or F4 necessarily. But he may well be in this F3 or advanced fibrosis range based on that kilopascal reading.

 

[00:59:49]

 

Small Group Discussion With Poll: Would you refer this patient to GI/Hepatology?

 

One more small group for you. Would you refer this patient to GI or hepatology?

 

1. Yes;
2. No;
3. Not sure.

 

Dr Cusi: How much time do we have? A minute.

 

Dr Jesudian: I think so. One minute. We would not come around and pester you this you.

 

Dr Cusi: We do not want to invade your privacy. We only have a minute by the time you get there. I think at this point, they know what they are going to do. I have faith in this.

 

Dr Jesudian: I have faith. Yes.

 

Dr Cusi: Michael is very confident. I see some security and fire in those eyes.

 

Dr Jesudian: Okay. Again, yes, vast majority say yes. I think it is a very appropriate patient to refer because you are worried he has stage III fibrosis. Again, this is someone who does not have cirrhosis but is well on 3 quarters of the way to being there. You would ideally be under the care of a gastroenterologist or a hepatologist and focus on at least stopping this fibrosis accumulation, or if we can get on a therapy that would allow for this fibrosis to potentially regress on therapy.

 

[01:01:07]

 

Case Files

 

Again we said severe steatosis, likely F3, stage III fibrosis based on this FibroScan, gets referred to a hepatologist and the hepatologist likes to spend money. Gets an MRI with the elastography. Not necessary, but it is nice to reassure yourself that this one fibrosis assessment is going to be backed up by other modalities.

 

The kilopascals and an MRE are different. They are apples and oranges. You cannot take a FibroScan number and compare it to MREs. 3.8 would be stage III fibrosis on an MRI with the elastography. The corrected T1. Remember, that was like the Liver MultiScan. This is a technique that can tell us about inflammation and fibrosis on an MRI. That is also consistent with this moderate to advanced fibrosis.

 

Stage I or F1 is mild. Stage II is moderate, III is advanced and IV is cirrhosis. That is saying II to III. A lot of our testing is pointing to III. This hepatologist really likes to get a lot of data, so I sent him for a liver biopsy.

 

Dr Cusi: Got the liver biopsy. Probably should not need it at this point.

 

Dr Jesudian: Exactly. The reason to potentially get a liver biopsy is if you had completely conflicting results. If your FibroScan is saying F3 and your MRI is saying F1 or something along those lines, or if in your workup, I am often sending, say, autoantibodies and I am saying could this person have autoimmune hepatitis and MASH and that would require its own treatment. Those would be reasons to get a biopsy. But just to confirm fibrosis staging, you really would not need to.

 

But if you get one, you are seeing here the NAFLD activity score. This is really mainly you will see it in trials because many of these trials require biopsy for inclusion. Then at whatever the outcome time point is. The pathologist is looking at how much fat there is, how much inflammation there is, how much hepatocyte damage there is, that score can go up to 8. He has quite a bit of active MASH. It is the old nomenclature NAFLD activity score.

 

Then also you are not just focusing on his liver, but he also has some risk for significant atherogenesis or cardiovascular disease when you look at his carotids.

 

Dr Cusi: But you should not order the CIMT.

 

Dr Jesudian: No.

 

Dr Cusi: If you are going to order something.

 

Dr Jesudian: Yes. Who was the hepatologist? You have to give us a little.

 

Dr Cornier: It was a hepatologist.

 

Dr Cusi: Yeah. He did not know what they were doing.

 

[01:03:46]

 

Small Group Discussion With Poll: What interventions are appropriate now after referral? Select all that apply. 

 

Dr Jesudian: We were just spending money. What interventions are appropriate now after this referral? Already been sent to the hepatologist. It could be:

 

1. Lifestyle changes;
2. Metabolic surgery;
3. Medications for MASLD;

 

Your same options.

 

Dr Cusi: We are going to go around. I think we have some time.

 

Dr Jesudian: Okay. We have a lot of choices across the board and almost everyone is saying again lifestyle changes and medications, particularly because we know this gentleman has like F3 or advanced fibrosis. Then also a consideration of metabolic surgery, which in the right context could certainly address some of his problems. As long as in terms of risk, he is okay.

 

[01:05:23]

 

Small Group Discussion With Poll: Should the statin be increased or stopped?

 

Then should his statin be increased or stopped? This is just a yes, no, not sure.

 

Dr Cornier: We should not have a discussion about this. Absolutely should not be stopped.

 

Dr Jesudian: I agree.

 

Dr Cornier: Remember, if it is not more than 3 times elevated, keep the statin.

 

Dr Jesudian: Completely.

 

Dr Cusi: What dose of statin was it, 10 milligrams of atorvastatin? Can you remind me?

 

Dr Jesudian: I think it was atorvastatin 10 or 20 milligrams.

 

Dr Cornier: He was not well controlled. His LDL was well over 100.

 

Dr Cusi: Okay.

 

Dr Cornier: If anything, we should double his statin.

 

Dr Jesudian: Okay. All right. The wording of the question might have led to this results. I think everyone is saying that you are not going to stop his statin, right? Because statins are very safe, remarkably safe in terms of the liver. Mild liver enzyme elevation, very common, but usually does not indicate any true hepatotoxicity. It is exceedingly rare for statins to cause true hepatic toxicity.

 

He clearly has reasons for his statin to be increased. Even I will tell you in cirrhosis, perfectly safe to use statins. There are good data within our cirrhotic population that statins can improve liver specific outcomes in a number of ways, so we are always comfortable with continuing it.

 

Dr Cornier: There is actually a couple studies that have shown that people who have elevated liver enzymes actually get more cardiovascular benefit.

 

Dr Jesudian: Yes.

 

Dr Cusi: The risk is also very high. Typically the absolute benefit is going to be larger too.

 

[01:07:45]

 

Patient Case #2: 59-Yr-Old Male

 

In this gentleman, consider GLP-1 receptor agonist therapy, be like semaglutide and it gives you some starting dose there for weight loss, for A1C reduction. Also we will go through the data, but certainly we will see that this can be associated with improvement in MASH itself. Increasing the atorvastatin for better lipid control because he was not at goal and we think it is completely safe to do so even though he has MASH with advanced fibrosis.

 

Then not to forget that he does need a multidisciplinary approach. He has a lot going on. An endocrinologist, diabetes education, a hepatologist because he has this advanced fibrosis nutrition counseling, this is all essential to tackle all the problems he has and give him the best chance for a good outcome.

 

[01:08:40]

 

Panel Discussion

 

In terms of the panel, and I will leave it open to either of you. But how do you approach targeted comorbidity management?

 

Dr Cornier: I think we need to do both. We need to treat the whole patient, the big picture which is weight management. Drug like a GLP-1 receptor is going to treat multiple things. We have one. The dual agonist actually treats sleep apnea, which he probably has as well. I think he has subclinical atherosclerosis. Again, semaglutide has been shown to reduce cardiovascular outcomes in people with clinical ASCVD.

 

I think treat the whole patient. But then I still target the lipids. I target the blood pressure independently. I think I do both at the same time. I do not know.

 

Dr Cusi: Yeah. I mean, again, it is a good point, but they are all integrated, right. Number 1, because we have these medications not just they live with injectable and do not get the lifetime modification. Also for starting GLP-1s, which would be very well indicated. It is very important that they change their life habits and begin doing physical activity, because that preserves muscle mass when you lose weight and you give a GLP-1.

 

I think it is very important. As Mark said, semaglutide is shown to reduce cardiovascular disease in people with or without type 2 diabetes, which is very important and has an indication in the United States for that. So very, very important. Take it all together.

 

Statins treat your target. I mean this person has a documented atherosclerosis, should have an LDL below 70.

 

Dr Jesudian: Yes. Thank you. The next one I will start with how do you use noninvasive imaging tests in treatment monitoring.

 

One take-home I would say from this is FIB-4 is good at screening. Who are you worried about in terms of liver fibrosis? Who are you not worried about? Who really potentially needs another test of FibroScan. But once you are there, you do not need to go back and you should not go back to FIB-4, which is not a perfect test. If you are following someone over time for how is their fibrosis either worsening if they have not been controlled in terms of their risk, or getting better on therapy, on lifestyle modification, then that same non-invasive testing, usually imaging based, elastography.

 

Potentially, if you could get it paid for an ELF test, enhanced liver fibrosis, the serum based test, although it is on the pricier side, could be followed sequentially over time. But FIB-4 just used for the screening part, not for the following treatment response or following fibrosis over time.

 

Then what do you think the role is of endocrinology and primary care in these patients who have clearly advanced MASLD/MASH?

 

Dr Cornier: I mean, I think we all need to get comfortable treating this disease because there is not enough GI or hepatologist out there. It is like there is not enough endocrinologist to take care of all the patients with type 2 diabetes, right? The primary care providers need to feel comfortable with that.

 

Certainly we can get involved when there is more complex patients. Then same with the liver disease. Once they get more complex, then I am going to refer them on to you. That is at least my approach.

 

Dr Cusi: Completely agree. Yeah. I am going to take just 1 second. There are a number of questions here from the virtual attendees who are not ignoring you, but we are going to go on. The only thing there was a question maybe you should answer. What is LSM? It is liver stiffness measure. Maybe explains briefly. It is what you tell before.

 

Dr Jesudian: Yes. Say you get a FibroScan, you will get a kilopascal number. That is, in this gentleman it was 12. That is a liver stiffness measurement. Basically livers without fibrosis or scar tissue, very low number. Low liver stiffness. As you develop scar tissue fibrosis, stiffer, higher number of kilopascals.

 

How do you get the number? From the FibroScan itself. The vibration happens during the FibroScan. A sound wave goes across the liver, comes back. The more fibrosis there is, the higher that number.

 

Yes. The question is some institutions do not have FibroScan, the proprietary FibroScan. Might be using something like shear wave elastography or a different type of elastography. What I would say is that within your individual institution, there will be cut offs with that report or provided to you. That is the most accurate way of seeing which patients on that particular study fall into which category. These numbers that we are throwing out usually will apply to FibroScan itself.

 

Dr Cornier: Is it like a DEXA for bone density where you cannot compare one machine to another machine?

 

Dr Jesudian: It can be a little variable. One thing not to overcomplicate it, a lot depends also on the operator. The accuracy of your FibroScan or your elastography has to do with how alike the measurements are when you take a number of measurements. You might need to interpret these with a grain of salt.

 

Dr Cusi: Yeah, that was a question here. Is that yours? Yeah. There was one question about age and FIB-4 below 35 and above 65.

 

Dr Jesudian: Yes. If you play around with FIB-4 calculator, what you will find is that patients above the age 65 almost always fall into the high risk category. My personal opinion on that is that a FIB-4 in isolation is not terribly useful in a patient above age 65. If you can get some other non-invasive testing, that will be much more helpful to you than to try and figure out.

 

Dr Cusi: In many places, only FIB-4 is available. What people can do is simply increase the cut-off from 1.3. A couple of studies that used 2, but it is common sense. It is not that at 64 it is 1.3 and 65, it is 2. There is common sense. You may increase it to 1.6, 1.7. Then you take the picture of somebody with diabetes, obesity and multiple risk factors and elevated liver enzymes. Probably you want to go to a second test.

 

Okay. We have got to move on.

 

[01:15:29]

 

American Diabetes Association 2025 MASLD Consensus Report: Lifestyle Intervention

 

Yes. Now let us just talk about therapy. This you will have available to you, so I would not go into it in detail. But lifestyle intervention, you see there are many components of that:

 

• Education;
• Nutrition;
• Weight loss;
• Physical activity;
• Alcohol not to be forgotten.

 

Many patients drink alcohol. There is an entity called MetALD, metabolic and alcohol-associated liver disease together. It is something to talk to your patients about and try and quantify what they are drinking and counsel them if they are drinking too much.

 

[01:16:02]

 

Estimated Impact of Weight Loss on MASLD

 

Weight loss. I like to use percentages with my patients because of figures like this, which are supported by data, which will show you that weight loss of 3% or more, you can address your steatosis. Then to get into the inflammation, you are looking at more like 5% resolution of MASH as you get to 7%-plus.

 

Fibrosis can respond if you are able to lose 10% or more. So that is just more motivation to the patient when you are counseling them.

 

[01:16:32]

 

Phase III ESSENCE: Semaglutide in Patients With MASH

 

Some therapies to talk about in terms of just top line data so you are available for them. This is phase III ESSENCE. This is semaglutide in patients with MASH. Multicenter, double-blind, placebo-controlled, randomized, phase III trial.

 

These are patients who had a biopsy and had confirmed MASH and fibrosis stage II or III and a NAFLD activity score of 4-plus. They were similar in terms of being diabetics, fibrosis stage, region where they came from, randomized to the semaglutide. You see the dosing there or placebo.

 

Then we got out to week 72, because when you are looking at fibrosis in the liver, you need to wait we think at least a year or so.

 

Looking at did the steatohepatitis part resolve without the fibrosis worsening. If the fibrosis improved with no worsening of the steatohepatitis and also being free from developing cirrhosis because none of them had cirrhosis, they were stage II or III, very common endpoints in this type of clinical trial.

 

[01:17:41]

 

Phase III ESSENCE: Change in Liver Enzymes in Patients With MASH With Semaglutide 2.4 mg/wk for 72 Wk

 

First, let us just see what happens to liver enzymes. Placebo group is in the red and the semaglutide in the blue. Clearly, their inflammation is improving because their liver enzymes drop precipitously very early on.

 

[01:17:55]

 

Phase III ESSENCE: Primary Endpoints Interim Analysis

 

Then what is really important is this is a paired biopsy trial. They get biopsy. They have MASH stage II or III. Then we are looking at a biopsy at 72 weeks.

 

The left side steatohepatitis resolution with no worsening of liver fibrosis. You see almost 63% in the semaglutide group are meeting that as opposed to 34% in the placebo group. All of these patients are instructed on lifestyle modification. It is not uncommon to see a pretty decent placebo response but significantly better response. You see that P value in the semaglutide vs placebo.

 

How about liver fibrosis reduction? This is really the holy grail in the world of hepatology. Can we get rid of some of this liver scarring or fibrosis? You see that that was significantly better in the semaglutide treated group at 72 weeks. Again this is biopsy proven. It is not just noninvasive, 36.8% vs 22.4% in placebo.

 

[01:19:04]

 

Phase III ESSENCE: Secondary Endpoints Interim Analysis

 

Secondary endpoints. The ELF score, the enhanced liver fibrosis score. This I would say is very similar to doing a FibroScan, if it was not available to you. It is a blood test. Unlike FIB-4, which is a good screening test, you can follow this over time.

 

You see in the semaglutide group that the ELF score improves considerably and then maintains that improvement over the course of the study compared to placebo, where we do not really see that much improvement.

 

Liver stiffness, transient elastography here or like FibroScan, also improves. The improvement continues up until week 72. This is interim analysis. It will be interesting to see what happens beyond that.

 

[01:19:46]

 

Phase III ESSENCE: Safety

 

Adverse events, pretty similar percentages between the 2: 86.2% in the treatment group vs just under 80% placebo. Serious adverse events around 13% both groups. Very uncommon to discontinue study medication because of adverse events, which is helpful to see. The most common ones, I am sure, no surprise to you being GI adverse events.

 

No new or liver specific safety concerns. Very important when you are taking patients with moderate to advanced fibrosis and testing them.

 

[01:20:22]

 

Phase III ESSENCE - Part 1: Conclusions

 

In conclusion, we see significant histological biopsy improvements in these patients with stage II to III MASH and higher rates of steatohepatitis resolution and fibrosis reduction in the semaglutide-treated patients. Also improved, as you would expect, cardiometabolic risk factors, obesity, type 2 diabetes. The adverse events or side effects seen was not different than what we know about real-world experience with the medication.

 

Certainly this is a very promising therapeutic option for these patients with MASH with this moderate to advanced fibrosis, because it can address their steatohepatitis, their fibrosis, but also the rest of their obesity picture or their cardiometabolic risks.

 

[01:21:09]

 

ADA 2025 MASLD Treatment Algorithm for Individuals With Prediabetes or Diabetes

 

We have seen this figure before, and we will just focus on the light blue side towards the end. But in terms of MASH pharmacotherapy. The patients who could certainly benefit from a GLP RA or potentially resmetirom, which we will mention in some subsequent slides, are these F2 to F3 patients based on the studies that have been done. Before that, you are really just focusing on lifestyle modification and their diabetes and their comorbidities.

 

As we get into cirrhosis, what I would say is that if you find an F4 patient, these are patients to refer to me, not to necessarily be treated with MASH specific therapeutics, because there can be some increased risk of adverse events. If they have decompensated cirrhosis, then we need to consider liver transplant and they have bigger fish to fry.

 

[01:22:00]

 

MAESTRO-NASH: Resmetirom (THR-β Agonist) in Patients With MASH and Fibrosis Stage F1b-3

 

MAESTRO-NASH. This is resmetirom. Resmetirom is FDA approved for this indication. It is a thyroid hormone receptor beta agonist. What that means? This was new to me as a hepatologist. But basically that activity of thyroid hormone in the liver will cause mobilization of fat. It can decrease liver fat. Along with that, can lead to improved steatohepatitis or inflammation and fibrosis.

 

This was a year-long trial. Very similar in design. You get a biopsy to get in the trial, you get a biopsy at the end of a year. You see they were studying 2 doses of resmetirom. But with either dose, you see MASH resolution without fibrosis happening much more frequently in the resmetirom treated patients vs placebo. The same goes for fibrosis improvement by 1 stage or more without the MASH worsening. That is why this was approved by the FDA. Do you have a question?

 

Speaker: Does it affect thyroid function?

 

Dr Jesudian: Does it affect thyroid function? The answer is no. It has been studied pretty robustly. Because it is beta specific and not alpha, it should not interfere either with patients who are U thyroid. It should not interfere with that, or patients taking thyroid hormone supplementation.

 

[01:23:15]

 

MAESTRO-NASH: Resmetirom (THR-β Agonist) Safety

 

Safety wise, GI side effects were the most common here as well. In my experience, many patients if they develop them, it will improve. So they potentially do not need to stop taking the medication. Stopping it because of these side effects is pretty rare.

 

[01:23:33]

 

SYNERGY-NASH: Tirzepatide for Patients With MASH and Moderate to Severe Fibrosis

 

Tirzepatide, you are also, I am sure very well aware of, has also been studied for this indication. These are all similarly designed trials. Again, MASH stage II to III fibrosis with or without type 2 diabetes. We are looking at those same histologic endpoints.

 

But here we see different doses of tirzepatide vs placebo. MASH resolution without worsening fibrosis in 62% of patients in tirzepatide vs 10% of patients in placebo. Fibrosis improvement of greater than or equal to 1 stage in up to 55% of tirzepatide vs 30% in placebo. You are getting the same theme. If we can address fat in the liver, that can resolve steatohepatitis without worsening fibrosis. That can also lead to regression of fibrosis without worsening of steatohepatitis. Gi symptoms again most common.

 

[01:24:31]

 

SYNERGY-NASH: Tirzepatide in MASH

 

Tirzepatide in MASH, just to see it in graphic representation. The different doses and the response rates that is MASH resolution on the left. That is fibrosis regression by 1 stage or more on the right vs the red placebo.

 

[01:24:46]

 

Survodutide (Dual GLP-1/Glucagon Agonist) in MASH

 

Finally, just the dual GLP-1/glucagon agonist in MASH. Here again, you see the different doses vs placebo in red. We are looking at same outcomes. These trials are again designed very similarly but promising results here, where you can see MASH improvement of up to 62% in the 4.8 milligram group. You can see the fibrosis regression of north of 30%, so 1 out of 3 or so vs 20% in placebo. Also seeing nice weight loss in this the dual agonist type therapy.

 

[01:25:28]

 

Summary

 

In summary, NAFLD highly prevalent in people with diabetes and obesity. It can progress to cirrhosis, F4, the need for liver transplant or the risk of hepatocellular carcinoma. We want to prevent patients from getting there, if at all possible.

 

How do you risk stratify them? You can use FIB-4 and then you can use FibroScan or elastography. That can help you identify most individuals with MASH-related clinically significant fibrosis, which is 2+. Those are patients who you certainly can consider sending to a hepatologist or a gastroenterologist.

 

Management of patients with type 2 diabetes warrant lifestyle modification. But also we went through a lot of nice clinical trial data. There are different agents available to you based on their risks.

 

I will hand the post-test over.

 

I believe that how many patients on resmetirom were taking GLP-1 in the trial? I think it was around 19%. Without getting into too many specifics, you can consider treatment with both classes in the right context.

 

Dr Cusi: There is not a lot of data, but one would suspect, given the different mechanism of action that could be additive. Yes.

 

Speaker: [Inaudible].

 

Dr Cusi: Okay. Number 1, in the trial, people were excluded if they have hypothyroidism, hyperthyroidism, or they were not allowed to get in the study if they were more than 75 micrograms of levothyroxine. T3/4 drops about 20%, a little bit more if you are on a thyroid hormone. Most patients did not have problems with that. But I think you need to make sure you do not have a hypothyroid patient that you can mention in the study.

 

I helped write the guidance for that via AASLD. It is all documented there. Get thyroid function test before and I think during the study during the treatment just to make sure it is very few people needed levothyroxine. It is something that it is good to know because 12% of the people in the United States have hypothyroidism. That was checked before getting into the study.

 

[01:28:10]

 

Posttest Assessment 

 

Okay. Now we are in the last few minutes, and I want to know how much you learn. We are going to get into this post program assessment.

 

[01:28:23]

 

Posttest 1

 

Okay. Here we are, post-test number 1. After this program, how often do you plan to screen patients who are at risk for MASLD and MASH?

 

1. 1. Never, hopefully not;
   2. Rarely;
   3. Sometimes;
   4. Frequently; or
   5. Always.

 

Come on, my liver health champions. Okay. Come on, guys keep going. Very good.

 

[01:29:01]

 

Posttest 2

 

Next. Now is your experience as gastro endocrinologist. A 54-year-old patient with type 2 diabetes, obesity and well-controlled hypertension and hyperlipidemia presents for follow-up screening for viral hepatitis is negative. The patient does not consume alcohol. According to current guidelines, what is the most appropriate next step in evaluating this patient?

 

1. Liver biopsy;
2. FIB-4;
3. Refer to Arun as a hepatologist for liver fat by MRI, biopsy; or
4. Vitamin E for inflammation.

 

Okay. Well, it is hard to improve 93%, but we got some additional adherence. So I am very proud of you. You should know that.

 

[01:30:00]

 

Posttest 2: Rationale  

 

This is the rationale. Basically you all paid very good attention during the meeting to what we said. Yes, FIB-4. It is an imperfect test, modulated by age. Again, these are guidances. If you have a high-risk patient and it is 1.2, just use your common sense, might need additional assessment.

 

[01:30:26]

 

Posttest 3

 

Posttest 3. Which statement best characterizes semaglutide’s therapeutic potential in the management of MASH in patients with cardiometabolic risk factors based on the phase III ESSENCE trial? You have the 4 options that I read to you before.

 

1. 1. Improve MASH and fibrosis;
   2. Significantly improve MASH, weight and glycemic, but not fibrosis;
   3. Despite improvements in steatosis, it did not have histological endpoints required for MASH; or
   4. Semaglutide metabolic effects overshadow its limited impact on liver histology, aligning it more with obesity than with MASH therapy.

 

Okay, I am very impressed. This is a really incredible audience. Hands for you.

 

[01:31:32]

 

Posttest 4

 

Okay. It is not over. You can spoil it on this one. Okay. A 61-year-old patient or person with type 2 diabetes, A1C 7.8. Obesity, coronary disease, treated with a GLP-1 and a statin after 18 months. The patient has lost 8% body weight, but liver enzymes remain mildly elevated. Liver biopsy confirms MASH with F2 stage fibrosis. Which of the following is the most appropriate next step in the pharmacological management of this person?

 

1. Wait another 3 months to see if fibrosis will improve with a GLP-1;
2. Add pioglitazone to optimize diabetes care and steatohepatitis, refer to GI for risk consideration;
3. Switch to a dual GLP-1/GIP receptor agonist to enhance metabolic and hepatic outcomes further; or
4. Add an SGLT2 inhibitor to lower A1C.

 

Okay. Very, very proud of you once again.

 

Okay. With this, there are also some questions here. Let us finish the questions here on the screen.

 

[01:32:40]

 

Poll 3

 

Poll 3. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No;
3. Uncertain.

 

Did I see 93%? Okay. Yes. Got an overwhelming support in that question, so do not worry.

 

[01:33:17]

 

Poll 4

 

Please take a moment to text in one key change that you plan to make in your clinical practice based on this education. We are going to cover a few questions for the virtual audience. Okay. That is something you can fill in.

 

[01:33:35]

 

Q&A

 

Dr Cusi: While you do that, I am going to cover some questions here. Number 1 is, some are related to pioglitazone. I do use GLP-1 for MASLD. When should I add pioglitazone?

 

That is a great question. The benefit of pioglitazone is very low cost. It is a generic. In the United States, it costs $5 a month. Its effect on steatohepatitis is pretty robust. It is not been well tested for fibrosis because the studies have been small, and in those studies most people did not have very advanced fibrosis. But typically what I would do, I would put them on a background of GLP-1 therapy, which I think is going to be like our metformin management of the future. On that background, you do not gain weight with pioglitazone and you have additional metabolic benefit.

 

Dr Cornier: Can I make a comment on the pioglitazone?

 

Dr Cusi: Yes.

 

Dr Cornier: The other thing is, in my lipid clinic I often use it for patients with difficult to treat hypertriglyceridemia in this metabolic setting with central obesity. So another place to consider.

 

Dr Cusi: It lowers triglycerides about 20%, 30%, depending on where they start, and increase HDL 20%. To be honest, also you can also lose weight if you add an SGLT2 or at least a weight neutral. That is an important thing. Yeah. Quick question.

 

Speaker: Is there any concern for bladder cancer?

 

Dr Cusi: Okay. Side effects. Weight gain is the number 1. You can prevent that by using 15 milligrams, which is the lowest dose. If you do lifestyle and 15 milligrams, you should not gain weight. Placebo controlled trials that do not do any weight management, you gain 1%.

 

Regarding bladder cancer, there have been 23 studies, 18 have been negative. In general, if there is a risk, it is very low. I would not give it to anybody with a history of bladder cancer or family history or smokers. That is a major risk factor.

 

About fractures. Yes, there could be bone loss. At the higher doses long term, so be careful to not give it to postmenopausal women without a baseline bone density.

 

There is another question here. This is for Dr Marc. Tell me one thing. There is a question about, I have some patients that do not lose much weight on tirzepatide or semaglutide. Is that your experience? If that happens, what do you do?

 

Dr Cornier: Well, we know with every medication that has ever been studied for weight loss that there is a variable response. Obesity is a complex, heterogeneous disease caused by different factors. Yes, there are people on tirzepatide. On average, the weight loss was about 20%, but some people gained weight on that drug. We see the same thing with semaglutide.

 

Typically, in a head to head trial, tirzepatide seem to be better in patients without diabetes. But we have all seen that. I recently had a patient who lost no weight on tirzepatide and then lost 20% of their body weight on semaglutide. We do not have a good predictor. We do not have a test to say you are going to respond to drug A or drug B. Unfortunately, we just have to go with the law of averages and say what is going to be the best for you based on averages, but then we have to test it.

 

So yes, some patients are not going to lose weight on these drugs. Our experience as well as the data would show that patients with type 2 diabetes tend to lose a little bit less weight than those without diabetes.

 

Dr Cusi: That is a great point. There is one last question. What about can we use fibrates or other lipid lowering in MASH? Yes, you can.