Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Great. I wanna um thank the organizers for inviting me to do this. I'm super excited um to be talking to you about some evidence based strategies for long term management of mash. Specifically, we're going to um focus on lifestyle and dietary modifications and see how we can provide sustainable health um lifestyle related um um counseling to our patients and then also apply the latest pharmacological treatments as per current guidelines um uh for, for appropriate uh patient outcomes. So to start off with Masso is a global epidemic, you've probably all seen this uh map before. Um And when we think about the global prevalence, we predict or estimate that it is about 30% or higher with the highest rates really found in the Middle East. And Latin America truly dictated by probably the genetic predisposition. Um And you can see this is not just a disease of the Western countries but truly a disease um that affects um uh a lot of our patients uh globally. What I'm showing you on the right of the screen is actually data that was shared from the Global Nash Council at EASL in 2024 and you can see over time, um the rates of um Massel d have increased over time uh from 25% in the 19 nineties uh to the early two thousands. And if you move to um in a clockwise fashion to where the light yellow is almost as high as 38% based on this data set. So when you think about um you know, the United States, you know, we think the global population, the the population is about 30% and that is really more than the population of California, Texas, New York and North Carolina combined together. So the prevalence is high um in the United States um and probably higher in our patients with type two diabetes um predicted to be as high as 70%. Um So this is, this is a problem and I'm excited to be talking about it. So we're gonna start off with a case. So this is a 38 year old uh with class to obesity, uh class to obesity with ABM I of 34 prediabetes who you see in clinic from S LD. She'd like to discuss what she can do to improve her underlying liver disease. She's not interested in medications and believes that she can truly do this on her own dietary history reveals that she eats most of her meals outside including breakfast. She has to be at work early. So she picks up breakfast, she drinks a diet ginger ale with lunch. She eats dinner at 6 p.m. and she's been trying to eat at home. She finds herself hungry at night. So she snacks and a couple of cookies and chips. Occasionally, she eats fruit. She has a gym membership that she doesn't really use and she'd like to start walking. She has no arthritis, um, involving the joints. So the first question really is to ask what lifestyle recommendations, can you suggest One meal planning and planning ahead for meals? Two, start walking, three, eliminate diet drinks, four, cut back on number of meals. She eats outside five set realistic weight loss goals. And we're gonna try to touch on all these aspects um and the rest of this presentation. So to start off with, we have multiple society guidelines um um that uh recommend that um that weight loss by adopting a healthy lifestyle, a hypocaloric disease. Um and exercise will improve not only fatty liver disease but also improve the metabolic diseases such as diabetes and cardiovascular disease that are very closely associated with mas LD. And this is not just endorsed by our liver guidelines, uh but also endorsed by um our cardiology guidelines and also our diabetes guidelines. And I'm gonna start off by kinda giving you that summary slide of what lifestyle changes should truly look like. I'm highlighting here then and we're, I'm highlighting the whole kind of the breath of lifestyle changes and we are gonna go into some of these um aspects in detail. Um One thing that I do just wanna point out here is that I think when we once get to really advanced fibrosis and cirrhosis, then in addition to lifestyle changes, I think we probably need another form of inter intervention, probably medical therapy to help reverse fibrosis. But in general, adopting a hypochloric or Isochor Mediterranean way of eating um involving in some form of physical activity. Um with um with the aim to lose anywhere between five to se uh 57 to 10% weight reduction will improve uh lifestyle and the quality of the food that we eat, which will then impact mascle the outcomes. So here I'm gonna start off by um reviewing some data on a meta analysis of randomized controlled trials, included intervention for weight loss. There were 22 studies with two tho over 2000 patients. Um and um of these, there are 15 studies that have two behavior modification. And as you can see here, um that um weight loss was achi when weight loss was achieved, we saw improvement in hepatic steatosis and we also improved, we saw improvement in our liver enzymes. And in the, in the, in the studies that had histological data, we also saw improvement in the NASS scores and the NAS score is a histological scoring system that we use to um define severity of liver disease as a result of mas LD. Things to note is that most of the these studies had a very me uh short median followup of about six months. Um and so appropriately, we did not see an impact on fibrosis. This is one of the best studies I think that we have that looks at the impact of weight loss on mash or NASH resolution. Um And this was a prospective study looking at um the impact of lifestyle changes on histological features of mash. There were 293 patients um um who had liver biopsies at baseline and then at 52 weeks after intervention and the intervention really involved a hypochloric diet and uh 2, 200 minutes of exercise per week. And you can see here that even with as little as uh 5% weight loss, you will see an improvement in steatosis and uh steatohepatitis. So those are those um NASH features and as you get more weight loss, 7% and 10% we will see a more dramatic impact on steatosis and NASH resolution. And of these, we also have the potential to reverse fibrosis if you achieve 10% weight loss. When they did a post hoc analysis of this data, we found that weight loss of 7 to 10% was associated with lower rates of NASH resolution. Um And the unfavorable um patient characteristics were w were women uh type two diabetes and having ABM I of 35. And really based on this type of data, um uh I typically recommend especially if you have diabetes at least 10% weight loss versus aiming for the 7% weight loss. But again, the message really here is weight loss will improve the histological features of mass um inflammation, which is steatohepatitis and have the potential to improve fibrosis as well. What's really impactful to tell our patients is that how uh is how does weight loss improve? Mail D? So you can tell your patients you can get improvement in your liver enzymes. You will have improvement in your metabolic parameters such as fasting, glucose and insulin sensitivity. We will see an improvement in fat in the liver and the liver is very forgiving. We can actually see um fat just dissolve uh from the liver and again, with 7% total body weight loss, we will see improvement in the static hepatitis features and improvement in 10% has a potential to improve uh the fibrosis or the scarring features in the liver. Now, let's talk a little bit more about the dietary composition. We know we need to lose calories to achieve weight reduction, but many of our patients fail. So we have to offer them other options. Besides weight loss, do diet quality matters here? We're not only referring to the macronutrient and micronutrient intake, but the way food is prepared and processed and these all have implications on metabolic health as I'm showing you here in addition to having implications on mass LD So here, what I'm showing you are examples of what an ultra processed food would look like and what an unprocessed food or minimally, minimally processed food would look like ultra processed foods are anything that has a lot of added sugar, high energy dense foods. Um, you know, um, sugar sweetened beverages, uh, and these are typically of low nutritional value. So, here on the top are ultra processed foods are things that we want to refrain from eating and at the bottom are unprocessed foods, uh, foods that we wanna encourage our patients to eat. So, a common question I get asked is how do you recognize an ultra processed food? And really what you want to look at are start reading labels. You want to look at the list of ingredients and you'll see that a lot of the ingredients in processed foods will be ones that you're often not able to recognize and you don't usually find them in your kitchen. You will see added quantities of high fructose corn syrup. So here I've highlighted it with a uh red rectangle, lots of flavors and coloring. Uh So juice concentrate here. Um and again, hydrogenated oils, some more saturated oils such as soybean and canola oil. So in, in, in uh theory, this would not be a cereal that I would be recommending to a patient of mine. These are actually results uh from a recent um meta now, a systematic review that assess that, that was assessing the association between um ultra processed foods and uh and uh and mass LD. Um and trying to define what the leading risk factors were. The, there were a total of 15 studies that were included with over 52,000 participants, of which one of them was actually a randomized controlled trial. Um And um in all the large prospective trials um that were study, uh both massy or metabolic syndrome demonstrated a positive association between uh between um massy and consumption of ultra processed foods. Um In contrast studies that did not demonstrate um significant associations were mostly cross sectional studies or small studies. Uh But there was definitely a good, strong evidence to show the association between insulin resistance um and um consumption of processed foods. Similar results have been shown in the in uh in this study. And this is a US based study which included consumption of red meat, processed meat and ultra processed meats. Um And found that there was an association between uh uh with consumption of these foods and mail d whether or not you had, whether or not you had cirrhosis. Well, the study also found that increased consumption of cholesterol was associated with mass D. And in fact, consumption of fibers were actually protective against the development of massel d here. What I'm showing you is an elegant study of a small populations. So third patients were overweight and again, overfeeding with saturated fats led to an increased amount of fat, liver fat, um even more than consumption of simple sugars um in the same um or iso chloric diet. So, here, what you're sh what I'm showing on the graph is that consumption of saturated fats, um sh uh was associated with increased fat that was um seen on imaging even compared to consumption of just simple sugars. Um switching gears to uh fructose. So fructose is found in a lot of our processed foods um in a lot of sugar, sweetened beverages. Um And here what I wanna illustrate to you are some results uh from a study that was conducted in Children looking to see the association uh between um fructose consumption and mass leaf. There were 202 171 obese Children uh who had liver biopsies uh that were included in the study. And uh basically fructose consumption was assessed uh by using questionnaires um and food diaries. Um And the study wanted to look at the associations, independent associations uh on massively and other metabolic outcomes. You can see here that high uric acid was high in these patients with uh mash compared to those without MS and uric acid and fructose consumption were in independently associated with mash. After adjusting for fou confounding variables, I think uric acid is a uh is a great marker to look at because it has been, it has been asso uh has been associated with um um metabolic disease and cardiovascular disease and could always serve as a surrogate marker. Um When you are thinking about noninvasive tests in terms of how to monitor uh patients. Uh when they're adopting lifestyle changes, soft drinks, switching to soft drinks. Uh, so soft drinks have been associated uh with the development of hepatocellular carcinoma and liver related mortality. Um, so just to give you context a approximately 65% of adults in the United States consume sugar sweetened beverages daily. And these are results from a prospective study in almost 100,000 women uh, who were enrolled in um, the Women's Health Initiative uh program from 1993 to 1998. And these patients were followed prospectively for over 20 years. And what the study found that was, was that even consumption of one or more su sugar sweetened beverage per day had a high incidence of liver cancer and death from chronic liver disease. And further studies, uh of course, need to be conducted to truly find um, the b the biological pathways that, um, um that explained this association. So, um, consumption of su sugar sweetened beverages is not only associated with an increased risk of developing liver cancer, but also associated with developing chronic liver disease and associated mortality, fructose. Um, just to touch on a little bit more on just fructose. So, fructose is not as tightly regulated as uh sucrose is it is almost entirely cleared in the liver. Um And basically what hepatic metabolism does. Um is it stimulates lipogenesis and the way it really does, this is uh when fructose comes into the liver, there's fructose phosphorylation that happens in the liver. So we have a um high consumption of AP and what ends up happening is you get this accumulation of ADP and this serves as a substrate for uric acid formation. And this in turn will then facilitate hepatic oxidative stress and damage and lipid peroxidation. Then again, affecting de novo lipogenesis and lipid deposition. Um and then uh causing mitochondrial toxicity and oxidative stress, which we believe are some of the driving factors of how fructose can be detrimental to the liver. Um and how it contributes to the development of Mail D. I think this is a great proof of concept study about how powerful um eliminating sugar can be in um in mail D. This is a, these are results from an open label eight week randomized trial of adolescent boys who had histological diagnosis of mail D and they were randomized to two arms, an intervention arm which is a low sugar diet and a usual diet. And you can see here very clearly that the amount of fat um at the end of the study in patients who were on a low sugar diet decreased dramatically. And this was quantified by an Mr by MRI uh PDF F. Um And so I think this is a great concept and something to share with our patients. Um It is a short study. Um The question just really becomes, is this going to be sustainable? Is it realistic? Um And is this something that patients can do long term? But a good proof of concept study to show the impact of low sugar diet on improving hepatic steatosis. So I'm gonna switch to what is a healthy diet. Um And I get asked this a lot. Uh a healthy diet was basically determined by reviewing the existing literature. And what you see here is an, basically an illustration of what is considered a the healthiest diets, not just for humans, but also for the environment. And um the in this study, uh what the um investigators were interested in doing was they uh they calculated uh prediction models um to show that if globally we adopted this diet, uh we would be able to approximately decrease about 20% of global deaths which basically clowns to about 11 million adult deaths a year. So what does this really look like? Um What this really looks like it, you want to make sure your diet is predominantly uh full of vegetables, fruits, um very little animal protein and close to zero unpr uh processed foods. Um The the recommendation is also to predominantly consume nonanimal protein sources. So such as legumes nuts, um a as a source of protein. And um in terms of animal protein, we're trying to limit it to um um a moderate portion uh from daily to weekly. So we can indeed improve the quality of our diet in people with mass ad, even without weight loss. Uh we do get a decreased amount of liver fat. Um and that has been shown in this prospective follow up study. Um but it has also been shown that we can decrease the incidence of new cases of mas LD. Um What was really interesting about this study is that um when you improve the quality of your diet in those that are also those who are susceptible, who have a genetic sus susceptibility to mail D. We will also be able to um modify the genetic risk and we will still be able to observe a decrease in liver fat. So here, what I'm trying to show you is that with an adoption of a healthy diet, you can prevent the development of MAS LD. Um and you can modify your genetic risk. So I think this is really powerful. Um I think this is really powerful for patients who have strong family histories of MAS LD or um ethnicities who are thought to have an increased um predisposition to mail D because of their gene genetic risk. I think it's really powerful to be able to tell them that if you did improve the quality of life, you are still able to modify your genetic risk. Um We know that we need to do this. Um And we've all been told um that we need to eat a healthier lifestyle, adopt healthier ways of living. And a lot of our patients have already been told this by the time they come see us in the liver clinic from a diabetes standpoint, from a hypertension standpoint, from a hyperlipidemia standpoint and other metabolic diseases that they have. But what I'm, what I'm showing you here really is that when you think about red meat consumption and processed meat and even sugar sweetened beverages, um majority of the countries, majority of the regions in the world um are really exceeding the, the, you know, the optimal levels that are recommended uh by a lot of our society guidelines. So we have a lot of work to do. Another factor to think about is the impact of low socioeconomic status uh or higher food insecurity and the prevalence of mail D. And I think this is really important food insecurity leads to greater consumption of ultra processed foods and junk food, which leads to poor metabolic health and massy D. The graph on the left illustrates results from a cross sectional study that included data from the NHS database which included over 2000 adults from low-income uh households from 2005 to 2014. And NAFLD um was diagnosed here using ultrasound. You can see that with very low food security, there was an association with an increased prevalence of mail D in advanced fibrosis, the Kaplan Meyer curves um on the right illustrate all uh results also from the enhance database including over 34,000 eligible patients of these about 4800 head mail. The um and 1600 head advanced fibrosis food insecurity was present in 28% and uh 21% respectively in these populations. Um Multivariant analysis has shown that food insecurity was independently associated with higher mortality among patients with uh mas LD. Um and also with advanced fibrosis. Now switching to exercise or physical activity, physical activity is is helpful even without weight reduction. And this is very important to mention to our patients. These are results from a meta analysis of randomized controlled trials to assess the impact of exercise on mass health d including over 1000 patients. And you can see with exercise, there was improvement in liver fat and liver enzymes as well. These are actually more recent uh results that show that that exercise in addition to having an independent impact on improving mail D without weight loss, that there may also be a signal for improvement um of fibrosis. And again, this can also be seen in um um patient patients that are gen uh genetically predisposed to developing mas LD. So here exercise led to an improvement in serum biomarkers of liver inflammation and also uh surrogate markers of fibrosis. Um And uh furthermore, a greater than 17 reduction in the A LT was observed in 53% of individuals in the exercise arm compared to the placebo arm, which is only 13%. Um and this correlated well with MRI findings um and presence or absent of the P NPL A three gen uh genetic mutation, the type of physical activity you do, I will recommend to your patients um, doesn't really matter. Um I think the general consensus and the guidance should be that you should move. It could be aerobic exercise, it could be anaerobic exercise, it could be resistance training or a combination. And uh and in my opinion, I think a combination of exercise or physical activity should be what we should be advising to our to, to our patients. Um Again, whether or not, um you know, exercise um improves liver fibrosis has not really been shown in our studies. But again, this is a study that shows some indirect markers of liver fibrosis improvement with the uptake of um um some form of physical activity. So you can see not just an improvement in liver steatosis, but liver stiffness as well. Um as well as uh the uh as well as a fast score, which is another uh noninvasive test which combines liver stiffness measurements and ast um um to, to show an improvement in fibrosis. So how do we implement an effective lifestyle intervention in mail? So it's very easy to tell a patient. Um Go ahead. Um You know, the recommendation is to lose weight to eat a little bit healthier, but the challenge really becomes in uh in implementation. Like how can we get our patients to actually do this and how can we make these changes sustainable? So one way to think about intervention might be an internet based uh model. Um And these are results from a internet internet ba internet based approach for lifestyle change. And basically, here in this study, patients were either um randomized or group based uh program which was an in person program or a web based uh program. And the primary outcome that we were that we're trying to rec um achieve was a weight loss of greater than 10%. And then looked at some secondary outcomes such as change in liver enzymes, surrogate markers of steatosis and fibrosis. And it was a good number of patients in the study, over 700 patients um with mass LD with a mean age of 52 years. Um And about a third of these patients had type two diabetes. At the end of the study, there were similar results achieved in both arms. So both the in-person arm and the web-based arm. Um and basically health, healthy lifestyle changes were observed in both groups uh with improvements in BM I. Um there was a 10% weight target that was reached um in the um in person uh in the in-person arm. Um sorry in the in the web based arm and there was a 15% weight reduction achieved in the in-person program. So I don't think it matters whether it's in person or web based. And I think you can adapt this based on the person's um life. Um But in having some form of accountability, some form of education around how to achieve lifestyle with support, um from, from col uh from others, uh from dieticians, from physicians or clinicians is helpful to achieve um weight loss goals. So, um the I wanna switch to something called a diabetes prevention program. Um and think about this as a possible way to achieve weight loss in mass these. So for those of you who are not familiar with this program, the diabetes prevention program has been existing in the United States and it is called, um there are similar programs uh in Europe. Um but basically, it's a program that was able to show um that with lifestyle changes, you will be able to prevent the development of diabetes in patients who have prediabetes with the primary goal of weight loss and behavior change. And in um in the original study, the diabetes prevention program was able to show um prevention of new cases of type two diabetes, uh prevent cases of new case prevent cases of type two diabetes by 50 per 58%. And this was even more pronounced in patients who are 60 years and older. So, what we did was we adapted the Lysol the diabetes prevention program and adapted it for a mass LV. And we had a group of patients who went through this program over a year, they were um a total of 16 course sessions which occurred over four months. And then the maintenance session for there was the remaining um eight months of the study um doing these during this program. Um There was a lifestyle coach that was present um du during the entirety of this program as well as a clinician. And this was a one year program and the outcomes we were interested in looking at was retention rates and other indicators of feasibility. And then again, looking at the impact of the DPP program on mass of the hepatic steatosis and uh coord and the other um second outcome, we were interested in looking to see how many patients were able to achieve weight loss goal of 7%. So you can see here the results um from uh from this study. Um And you can see very clearly that uh one, there was a 70 if one, in terms of the primary goal of the study, there was 79% return to that 12 months. And at the 12, at the end of the 12 months, there was just significant weight loss, observed many normalized their liver enzymes with significant improvements in other metabolic parameters. Um I think this is something to think about in patients who have mas D with prediabetes. Again, uh It's a limited study. It's a one year study. It's pilot data, we didn't have a lot of patients in the study, but it's something definitely need to consider. Um I think the big thing that it does is it provides patients with accountability um f uh knowledge about food um and also partnership with other people who have similar um um sim similar setbacks in how to improve uh the quality of your life uh of your food choices and lifestyle intervention. So in general, to implement an effective lifestyle change in our patients, it's really important to shift the focus. I think from a weight reduction centered approach to a sustainable healthy behavior centered approach. And this can be achieved several ways. I think it's really important to reiterate to our patients with mas LD that it is a reversible disease with changes in lifestyle, even with modest changes, even with a 5% weight reduction, dietary composition matters and making healthy dietary changes will impact your liver disease. Even small changes in physical activity are a win. And I think those need to be acknowledged. Um You, you need to reinforce your patients that these small changes are meaningful and this really allows you to empower your patients uh on how to make these changes. I think another really important thing to understand when you are implementing lifestyle intervention is that goal setting is really important, but you also need to make it realistic. So, breakdown weight loss goals in terms of number of pounds or kg per month versus telling them how much weight they need to lose over a year, which can be very daunting. It is very scary. And remember for these patients, they've tried all these things, they've tried diets, they've tried it all. Um, and have failed. Um So you wanna provide an approach that's, um, that's easy, that's adaptable and can change. Um, depending on the needs of your patient. Um, and involve your patient in that conversation about goal setting. One thing I think is really important that patients need to also learn about is a simple concept of my plate. And I put the reference here uh really thinking about your plate kind of dividing it up into half, half being fruits and vegetables, about a quarter being grains and about a quarter being protein. Um And this is how we should be thinking about our plate every time we eat um during breakfast, lunch and dinner and theoretically even when you snack. Um So these are simple tools that you can adopt um to help your patients uh when it comes to goal setting and how to um adopt healthy lifestyle changes. One of the things um as I as I talk about this, II also acknowledge that some of these um lifestyle interventions are not easy and there are several challenges and hopefully, I could provide you with some examples of how to um address some of these challenges. So I think one of the big things that we have realized um is cost and especially after the COVID years, uh the cost of food has just increased. So I think of, you know, some recommendations that I give or I think about uh buying fruit and vegetables in bags versus buying them individually. I think, you know, um, if you can't afford um, fresh fruit, think about a frozen fruit uh before you resort to a canned fruit and think seasonal that those tend to be cheaper. I think there's a lot of um knowledge and misconceptions about foods. It's really important to understand your patient's education level when it comes to food and knowing what the food groups are or what the macronutrients are. So I think it's really important that we empower them with that type of information. There are also some physical limitations, right? So you wanna focus on physical activity versus a type of activity and slowly encourage them to increase it to 100 and 15 minutes a week. Um There's some toxic environments, right? So we all know we need to do this, but also we live in environments where it makes it very easy for us to eat out um to, to consume al processed foods and sugar, sweetened beverages. So, an easy thing to do would be to shop in the surrounding aisles, um the outside of a grocery store versus down the aisles in the middle. Um And then there's socioeconomic risk factors which I think are astonishing and uh really, really sad to see that, you know, about 12.5% of us residents uh receive staff benefits of which 40 about 40% and and 40% of Coca Cola revenue really comes from food stamps. So it's super important again to educate our patients that uh though these things uh may be more affordable with the limited financial resources that they have, that they are truly detrimental, not just to S LD but overall metabolic health. So bring you back to that first slide that I showed you. Um So, you know, um along the spectrum of mass d all the way from a healthy liver to um developing cirrhosis in advanced liver disease, adoption of an hypochloric, a 500 hypochloric diet at least or Isochron diet um in adopting a Med Mediterranean way of living, um is helpful, doing some sort of physical activity is helpful. Um with the aim to achieve 100 and 50 minutes a week in terms of dietary composition, think about reducing fructose, adopting a Mediterranean diet, uh re reducing the consumption of processed foods. Think about increased consumption of fiber. Give you some data to suggest that fiber was protective. Uh think about lean proteins if you are someone who consumes animal proteins. So chicken, turkey fish definitely over red meats. Um and then of course, other modifiable risk factors that we aren't gonna be touching into are things like coffee. Coffee is good for the liver, uh no alcohol, especially if you have advanced liver disease or cirrhosis. Um and smoking, which is a true modifiable risk factor and independently associated with advanced liver disease. So now I'm gonna switch gears to talking about some of the medical interventions uh for people with uh mail d um guided around uh published guidelines. Also some exciting results uh for the first approved medication for massel D. Um And then in addition to that, think about some of the other uh pharmacological or medical therapies that we have uh present today that could actually be beneficial for patients with Massel D. So we have a 60 year old female with class to obesity, hypertension hyperlipidemia and a 15 year history of type two diabetes and abnormal um aminotransferase levels for many years. So, aminotransferase levels are an A LT and AST that are um in general, greater than 30 statins were stopped due to elevated liver tests. And currently she is on amLODIPine, enalapril, Metformin and omeprazole and recent evaluation of her blood tests. Um Laboratory tests are um here. So you can see um elevated liver enzymes with an A LD of 92 and ast of 80 bilirubin of 0.6 which is normal platelet count is normal at 210 thou um 210,000 A hemoglobin A1C of 7.6%. So, not the best controlled diabetes on the Metformin that she's on. And you see, there's an uh she also has elevated an LDL and an elevated tri uh triglyceride count. Um So anything greater than 150 is considered abnormal, you've ruled out other etiologies of liver disease. Here, you've done some noninvasive test to suggest that she has uh if not moderate to advanced fibrosis. And then ultimately, you did a liver biopsy which did show that she had histological features of steatohepatitis, which would be consistent with mesh and extensive bridging fibrosis. So, f three fibrosis and no evidence of cirrhosis. So the first question is you recommend lifestyle change and increased physical activity for weight loss and refer the patient to a dietitian for support. In addition to the above recommendations, which of the following is the best next step in treating mash one A G LP, one receptor agonist, two resmit, three start Vitamin E or four pioglitazone. And we'll talk about these over the next few slides. And the second question is which of the following agents has been shown to result in MS resolution and improved cardiovascular outcome. Uh One cacit two lyin, three pioglitazone and four Vitamin E. So now there's a, so here, what I'm trying to show you is that there's a growing consensus uh that the treatment of mass Aleve should be around management of cardiometabolic risk factors, addressing cardiovascular risk factors, treating type two diabetes, obesity and other chronic illnesses. One thing really to highlight is when we think about this uh po the population that is at risk for this disease. You wanna think about the patient with prediabetes or diabetes, people who have obesity with metabolic, with other metabolic risk factors and anyone who has hepatic steatosis with no other causes for hepatic steatosis, um or elevated liver enzymes. Um adding. So, um one of the things that we do know also is uh when you um treat massively, we will in turn prevent uh progression of cardiovascular disease and hopefully prevent um complications of cirrhosis and associated um complications. Um And just a, a quick note on um um uh lipids, adding or continuing statin therapy in mass. So these is actually safe and we'll talk about this over the next few slides. Um Just remember, you don't wanna use this in decompensated cirrhotics. Um And the recommendation is to actually use moderate to high intensity statins um in this patient population as it is a true cardiometabolic uh risk factor. This is an adaptation from our recent guidelines uh in mass. The approach to management, as you can see is a multidisciplinary approach with initial risk stratification, typically happening in the primary care or endocrine setting. The goals of treatment are identifying bar barriers too, but at the same time, creating sustainable ways to incorporate healthy lifestyle, which we talked about movement into our daily routines or physical activity, medical management of co morbidities. Um um medical man of comorbidities. Um And in addition to that thinking about liver directed therapies, access to clinical trial opportunities and then thinking about acc prevention and preventative health um in those with more advanced fibrosis um and cirrhosis. So when we look at our guidelines, especially when we look at the uh guidelines, the in terms of the liver guidelines, the ASL D guidelines, um the recommendations are to use drugs that have been approved to treat associated comorbidities with potential benefit in um in maso D Somali tide should be considered um in those with appropriate indications and think about pioglitazone as it can improve. Um the static hepatitis features um in the context of type two diabetes, I just wanna point um point this out um because this will be important um as we go through the results of some of the potential therapeutic agents um um in the next few slides um when uh drugs are approved, in terms of the FDA guidance really is to kind of look at two end points. So the first one is looking at nash resolution or mash resolution and this is really looking at the improvement in those histological features of steatohepatitis uh with no and and the key here is with no worsening of liver fibrosis. So the features of scarring in the liver and the second endpoint is fibrosis, improvement of at least one stage with no worsening of steatohepatitis. So you will see these endpoints as either being primary or co primary endpoints in many of our phase uh phase three trials. Um um So just, just keep that in mind. So here, I'm actually sharing with you uh results um from an ongoing phase three trial. Um This is a readout from 52 weeks and this is um some of the data to support uh the approval of the first ever pharmacological therapy for mash. It's called Resol. And um it is um commercially known as RES Dra and it has been approved for patients with uh mash with moderate to advanced fibrosis. So those with F two to F three fibrosis, so not indicated in those with cirrhosis at this time. In combination with lifestyle changes here, you can see um the the different outcomes of the study. Um So patients here were randomized to placebo arm or ResMed, 80 mg or 100 mg. And you can see when it comes to um fibrosis improvement of one stage uh or higher with no worsening of the scatter hepatitis features. This was observed in both treatment arms compared to placebo with a delta change of about 10%. And then when you look at NASH resolution on the right, you can see that um there was improvement in the standard hepatitis features with no worsening of NASH observed in both doses of ResMed of 80 mg and 100 mg compared with placebo with a delta change of about 20%. So, uh what is Risidon? Um and how does it really work? Really, this is a thyroid hormone receptor, uh beta agonist. And the thought is that it will affect hepatic um hepatic lipid metabolism and reduce LDL cholesterol. So it is selective for the beta subunit. So it can provide all the metabolic effects of thyroid hormone that are, that are, that are mediated by the liver but avoiding the unwanted systemic actions of axis um thyroid hormone on the, for instance, the heart and the bone that are really um driven by the alpha alpha subunit. So, thought really is uh with uh with uh risidon, we will see improvement in fatty acid oxidation, novo lipogenesis, uh mitochondrial biogenesis as well. Cholesterol me uh metabolism and has a direct antiinflammatory and antifibrotic effect. Uh which as I showed you has been observed in the ongoing phase three trial and I'm gonna switch gears to uh the GLP one receptor agnus. And here, what I'm gonna be showing you is uh the different multiple, the different mechanisms of actions and different organ systems uh that have been shown to be impacted by uh a GLP one receptor agonist. So, we know this to be an approved treatment for type two diabetes and obesity. And it does this by decreasing gastric emptying, it increases in insulin res um production and uh decreases glucagon. Uh But in addition to that, we have seen more and more data to show its cardioprotective and cardiorenal effects. Um So, um um I think it has a lot of uh promise specifically. Um in terms of the liver, the actions of the G LP one on the liver are primarily indirect. And the reason they're indirect is because we don't um express um a receptor for G LP one in our liver. And so what, what, what happens here is the G LP one reduces appetite and body weight and uh decreases postprandial lipoprotein secretion. And what this in turn does is it decreases systemic and tissue inflammation. Um And by this mechanism, it will increa increase insulin sensitivity because of its impact on the pancreas. Um and in turn, decrease de novo lipogenesis, um free fatty acid um influx into the liver. Um and, and, and lipolysis. And in turn, we will see an improvement in liver inflammation, hepatic steatosis. And also we'll see improvement in steatohepatitis. We have a number of studies that look to have looked at surrogate endpoints for G LP. One treatment in patients with mas LD. Um And in general, we are seeing about a 30% reduction in improvement in mas LD when it comes to hepatic steatosis. Um There are only two studies and I've highlighted them here that had histological outcomes and, and both of these studies had um positive results. Um and I will also share some results of a cirrhotic study um which actually showed the safety profile of this medication in a population that have uh cirrhosis as a result of mass relief. Here are results from a phase two B study that looked at the efficacy of semaglutide. So, semaglutide is a medication um is a G LP one receptor agonist. Uh that is currently being used um to treat type two diabetes and obesity. And these um and in this study, patients with uh histological diagnosis of MS were randomized um to different doses of semaglutide uh compared to placebo. And this was, these are results over 72 weeks. Uh patients had a biopsy at the beginning of the study. And at the end of the study, the mean age in this uh study was about 55 with ABM I A mean BM I of 35. So consistent, consistent with uh class two obesity um and a total of 320 patients uh were included. Um you can see here in this study um that when you look at resolution of NASH with no worsening of liver fibrosis, um this was achieved um at the semaglutide dose of 0.4 mg compared to placebo. Um And furthermore, when you look at the secondary outcome in terms of improvement in liver fibrosis with no worsening of NASH, um there may be a signal for an improvement, but this was not statistically significant. And then again, I think this is also due to the fact that this was a short study. So we are seeing improvement in um some histological features of scat or hepatitis. But we um in this study, we are not seeing improvement in liver fibrosis. This medication was well tolerate tolerated and had a similar safety profile. Um as that we've seen in our patient with type two diabetes. So with no safety concerns. And uh when you look at the histological data, at the end of the study, you can see that per again, there might be perhaps a signal for fibrosis improvement and this is really seen mostly in the patients on the 0.4 mg dose. Um Again, we should take these results with a grain of salt because there was about missing data in about 30% of this patient population. Um You know, the safety of um G LP ones is um always um discussed and thought of and I think it's really important um to know that we at this point have data on over 5000 patients who have participated in multiple um RCT S with this medication. Um and specifically um two RCT S in noncirrhotic patients with NASH. Um and they are generally considered safe with similar safety profiles. Um And just to share a fact with you, you know, the number needed to treat for weight loss is great uh for of greater than 5% is two. Well, some of the concerns with using a G LP one receptor agonist is thyroid cancer. The number treated a number needed to treat to harm from thyroid cancer has been estimated to be about uh 1400 or more. So, um I think it's a safe medication to consider in patients with MS who have an appropriate indication uh to receive a G LP one receptor agonist here. I'm sharing some results with you. Uh some uh results of semaglutide um in mesh with compensated cirrhosis. There was a phase two study looking at um um semaglutide 2.4 mg weekly in uh patients with histological diagnosis of mash um and compensated cirrhosis. And you can see here that uh the primary endpoint was improvement in liver fibrosis with no worsening of NASH. Um And you can see here that there was no difference observed in the placebo arm compared to the semaglutide arm. And similarly, there was no difference observed in the placebo arm, just some arm when it came to a resolution of NASH. So my conclusion from this has been while we were not able to achieve the primary endpoint or second endpoint of this study. Um And I think that's truly driven by the fact this was a short study and it does take time to improve fibrosis. We were able to show that it was safe and well tolerated in this patient population. Um And then other observations that were made is that it did reduce liver enzymes, hepatic fat and improved um the lipid profile um of um of, of our, of these patients, there are a plethora of side effects. Most of them are gi related uh gastrointestinal side effects that we get with this uh with this medication. I'm here, referencing a really great article that provides some practical guidance on how to manage common side effects experienced by our patients who aren't GLP one receptor agonists. And I strongly recommend that uh you look at it, I'm gonna switch gears to uh you know, combine creatin uh therapies such as ters appetite. Um So these are results from a phase two study that assessed the efficacy of ters appetite. A combination of G LP one and A G IP in patients with a histological diagnosis of mash with F two and F three fibrosis and they were randomized to 5 mg 10 mg 15 mg of s appetite compared to placebo. Um And you can see here that when it comes to resolution of mash with no worsening of fibrosis, this was observed in all the different doses of TPA compared to placebo and the highest of course change seen with the higher dose, uh the highest difference seen with the high dose of appetite. And when it came to uh decrease in uh one stage of fibrosis or worsening of fibrosis while we did not see a significant difference. Um Again, I think this is driven by the fact that um it's a short study. Um it um it is meaningful um and something for us to think about when we uh treat patients who have MS and other indications for a terse appetite again, the most common side effects were uh gastrointestinal events. Um and most of them were mild to moderate and these were just recently uh recently published other surrogate markers. Other studies have also uh looked at circuit markers of mass. So here, what I'm showing you is different doses of ters appetite compared to placebo. And you can see with uh there's appetite, there's an improvement in markers of liver inflammation and potentially also mark um improvement in surrogate markers of liver fibrosis. Now, we're gonna switch gears to the PNS and their role in um SD. So we truly believe the restoration of normal adipose, uh tissue biology will improve adipose tissue, insulin resistance and in and, and an increase in plasma adiponectin levels will play uh do play a key role in type two diabetes and potentially in um ash patients. So, um PR S, you know, there's um um three receptors that we think about. We think of alpha A gamma and delta and essentially depending on the uh pa that we use. It has different um impact um whether it's on the liver or adipose tissue. But the thought really is how do we um control the lipid influx which is driven by the alpha pathway. Um how do we improve insulin resistant, which is the, which is driven by the gamma um gamma pathway and then inhibition of lipogenesis which is um by um by the delta pathway. So, the um you know, the first, the 1st 1st 1 that was ever studied was pioglitazone. Um And this was a um Taiwanese study where, you know, there were about 90 patients who had liver histology that confirmed um uh mesh. And um they were, and they were randomized to either placebo or platelets and of 30 mg. And we did see an improvement um in steatohepatitis and the thought is uh prevention of fibrosis. And here, what I'm really highlighting for you is that there have been multiple, multiple RCT S of using PGLI in uh in MS. Essentially, we will see improvement of glucose and lipid metabolism, which is why it's indicated for people with type two diabetes and has also been shown to reduce cardiovascular disease as highlighted in these studies in this landmark. And II wanna share these results from a landmark I think three year study that looked at um the impact of pioglitazone in patients with MS. There were 100 and one patients with either prediabetes or diabetes who were either randomized to pioglitazone or placebo for 18 months and then followed for an additional eighteen-month extension or open label um arm where they uh received pioglitazone. All patients were prescribed a hypochloric diet and then were randomly assigned either to a 45 mg adult arm or placebo arm. And you can see here that there was improvement in all histological features of uh N A. So improvement in steatohepatitis inflammation and ballooning and while there was no signal here uh for fibrosis, they were, they, they, they, there appeared to be a trend of improvement in fibrosis here. This is, these are results from a pool meta analysis demonstrating that pioglitazone was better than placebo and achieving greater than 1.1% sorry, one point of fibrosis improvement. Um And you can see here um um highlighted by the um green uh diamond or rhomboid shape um that we um that we favor treatment with pioglitazone on its potential impact on liver fibrosis. And then here this whole concept of combination therapy that we think about when we think of patients with obesity or type two diabetes, you know, does this uh concept of combination therapy, uh could this be potentially helpful for patients with MS? So these are just results from a combo study looking at um uh pioglitazone, either with an SGL um SGL T two inhibitor or G LP one receptor agonist. Um And you can see here that there was a change in body weight uh with the addition of some Agli um or an SGL T two inhibitor. Um So these are some things and concepts to think about when we um think about combination therapy. But in addition to that both these medications, additional medications in addition to pioglitazone have been shown to improve myocardial uh function, uh decreased cardiovascular death, heart failure. Um and um, and stroke. Um one thing to just keep in mind, um, is the risk of fluid retention and uh, weight gain, um, that I think can be counteracted by the, um, addition of something like an SGL T two inhibitor. Um, so I think it's again, a combination to consider, um, in our patients who have mail d with other indications for these medications. So, going back to our patient, this is a 60 year old female with class two obesity hypertension hyperlipidemia and a 15 year history of type two diabetes and abnormal liver enzymes. Statin was stopped. And here on her medications, uh just to review again, she has elevated liver enzymes. She has dyslipidemia and not um the best controlled diabetes and she has histological evidence that she has uh steatohepatitis with bridging fibrosis. So, the first thing would be to consider Remidol, which is um which is um known as reser commercially known as Res Dia. Uh we know that ResMed is the first medication that has been impro uh has been indicated and approved for MS resolution and fibrosis improvement. Um Some caveats with Reifer to consider is that the statin dose needs to be dose adjusted. Um uh um So keep that in mind. Um other things to think about are if patients are on Plavix or clopidogrel, uh their doses need to be adjusted based on their weight. Um I think it's really important to monitor for hypertoxicity. So we see a rise of liver enzymes uh when patients are prescribed this medication. Um Other things that have been observed and been and guidance and we've received guidance on is um in the event you develop gallbladder disease such as cholelithiasis or cholecystitis, it's important to stop the medication, um treat the gallbladder disease and then resume appropriately like you would do with other chronic uh management. Um And again, this has not been approved for patients with cirrhosis or other coinfections. Um So there's still some work to be done in this space. But this is the first medication to be approved for a mash with moderate to advanced fibrosis. So it's very exciting. The other thing I wanted to again, highlight is semaglutide has been shown to achieve mash resolution with no versing or fibrosis. So again, these are results from the study that I showed you earlier. Um So something to think about if someone uh does require a G LP one receptor agonist or actually a combination therapy such as te if they have an appropriate indication. Remember, in addition to potentially improving um MSH features, we can improve metabolic features including weight, hemoglobin A1C S lipid profiles and similarly similar safety profiles. Um um As um as senior in our patients with type two diabetes and obesity, statins are safe in mass LD. So just remember, mass D is an inflammatory state with high oxidative stress and impaired endothelial function. So we think statins actually um by their pleiotropic effects, probably improve liver histology by decreasing the oxidative stress. Uh but also, in fact, may actually have an impact on fibrosis. Um So we actually encourage our patients who have MS and to, to remain on statin therapy. Um Truly, because um the biggest thing we worry about in patients who have non noncirrhotic MSH is that they are at risk for cardiovascular disease and uh poor cardiovascular outcome. So we uh we strongly recommend there are patients with MS should continue tens. Um even if they have slightly elevated liver enzymes. And again, these are um some results to support um that we f that we favor uh statin therapy in people with mas LD. Um And you know, the thought also is here that patients who have dyslipidemia um probably already have some fluctuating li uh fluctuating levels of liver enzymes, uh whether or not they're taking statin therapy. So, um y you know, really important um to continue it and if concerned uh please speak with a uh with, with a hepatologist. And just so, you know, there's an ongoing phase two trial that's actually looking at the impact on statins um on MSH and fibrosis. And then again, uh just wanna highlight some of uh the uh some of our oldest data are probably one of the first RCT S that was uh was performed in the space um back in 2010, looking at pioglitazone and Vitamin E in patients with MS or at that time, what was regarded as nash. And again, um in this study, um able to show that uh there was improvement in steatosis, observed um inflammatory feature, the inflammation that we typically observe in people who have um MS. Uh but there was no signal for fibrosis observed in this study. So take away messages. Uh lifestyle modification and weight loss remain. The foundation of treatment for MASL D. Resmit or Reser is a first approved treatment for MASL D with F two F three fibrosis. I think it's important for us to consider combination pharmacotherapies that for instance, have been approved for type two diabetes and obesity, but at the same time, have shown to reverse G hepatitis, halt fibrosis progression and reduce cardiovascular disease. Thank you.