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Hello, I am Blanca Mayo, a transplant hepatologist and medical director of the Liver transplant Center at Mayo Clinic in Arizona. It is my great pleasure to be presenting today at the Mash Academy Advanced Care strategies for metabolic dysfunction, associated steatohepatitis. As we all know the nomenclature of what we used to know as non alcoholic, fatty liver disease has changed. Why did we change this? Well, the process took around two years and it were 56 countries and 275 panels were involved and it was at EO in 2023 in Austria where the new nomenclature was shown. When did we decided to change this nomenclature? We wanted a nomenclature that was affirmative and non stigmatizing. And we also wanted something that was simple, readily available and with the easily measurable pa parameters. As we know before nonalcoholic fatty liver disease used to be a diagnosis of exclusion as well. We now know that has well established cardiometabolic risk factors. And also we wanted to adapt this for our pediatric population, the exclusionary nature for the diagnosis, the lack of recognition, recognition for the root cause of the condition and the use of potentially stigmatizing terms were removed. With this new nomenclature. Before we jump into it, I want to introduce to you a clinical case. I, I'm presenting you a 54 year old female with past medical history of class one, obesity with a BMI of 31.2 and type two diabetes on insulin. And she asked you if she should be tested for fatty liver disease. You one reassure her as her liver enzymes are normal. Two, decide to calculate af for score three, refer her to a hepatologist for further evaluation or four, perform a liver biopsy. I wanna invite you to review some of the ASL D resources that are excellent and in different languages and will help you to understand the omination be better. And also it has a lot of resources for your patients to explain in a better way what muscle d steatotic liver disease is. And here it is published at the Annals of Hepatology in 2024. We have a new diagnostic umbrella of steatotic liver disease which we used to know as non alcoholic fatty liver disease. Under this. On the, on this side, we can see that what used to be known as non alcoholic fatty liver disease is not known known as metabolic dysfunction associated steatotic liver disease. Below that we can see that what used to know as NASH is now known as MSH metabolic dysfunction associated steatohepatitis. That as we know, reflects inflammation and we will talk more about that later. There's a new, a new terminology that is extremely important to recognize what when we have patients that have metabolic dysfunction, associated steatotic liver disease with significant alco alco alcohol consumption. These patients are now known as having met A LD. And what is significant alcohol consumption? A weekly intake of 140 to 350 g of alcohol in females or 210 to 420 g of alcohol in males with an average daily consumption of 20 to 50 g in females and 30 to 60 g. In males. On the other hand, the alcohol associated liver disease has not changed. We also have a specific etiologies of steatotic liver disease that as we know, there are many other causes where patients can develop liver steatosis, for example, drug induced liver injury because of methotrexate tamoxifen steroids in amongst others monogenic dis diseases and miscellaneous like celiac disease, hepatitis C genotype three that we still see malnutrition, rapid weight loss, human immuno immunodeficiency virus, et cetera and cryptogenic. So here it is MS muscle D and you can see which terminology has been updated as you know, steatotic liver disease used to be known as non alcoholic fatty liver disease. MSH is now MSH, na, NA is now M NAFLD is now D the new terminology me A LD and the rest stay the same. And we now know uh also identified cryptogenic. So, how do we diagnose muscle d we now know that a patient that has hepatic steatosis with one out of five cardiometabolic risk factors. Specifically, a BMI more than 25 meaning overweight or weight circumference of more than 94 inches in men and more than 80 inches in females. Uh, a glucose level of more than 100 fasting or two hour blood glucose of more than 100 and 40 or a hemoglobin of A1C hemoglobin A1C of more than 5.7% or a patient with type two diabetes or in treatment, BP, more than 100 and 30/85 or 85 or a patient that is on antihypertensive patients, triglycerides, more than 100 and 50 or a patient being on antilipid medications and lastly, an HDL be below than 40 in men and below than 50 in females. So, if your patient has hepatic steatosis on imaging, an ultrasound, a CT scan and MRI plus one of one of five cardiometabolic risk factors, your patient may qualify for mass. Now, it's very important to remember that alcohol use disorder is extremely prevalent and we saw a rapidly increasing incidence in patients after COVID and during COVID. So it's very important to dig in and this is where the treatment of muscle disease starts. The most important thing. And what I always focus on during my first visit is to establish a very good relationship with my patients where they trust me and they're, they're able to open up and tell me in reality how much alcohol they're drinking. Us, asking our patients how much do you drink? And them an answering socially. Well, how social are you, how many drinks do you have per day? Do you have a drink or you have a big drink? As you can see in this slide, we can, we can identify that in females, as we already mentioned, you know, heavy alcohol use considered as 20 to 50 g per day or 100 and 40 to 350 g per week. And here are the different sizes as uh explained in the United States or the, the different uh standard. What is uh uh standard drink is six fluid ounces or 14 g of pure alcohol. Now let's jump, let's jump to the muscle of the epidemiology. We know that this has dramatically changed in the last, in, in the last decade before we used to be treating Hepatitis C transplanting patients for viral hepatitis. Nowadays, we know that alcohol use disorder and muscle D or MSH are the number one causes for liver transplantation in the world. We know that by 2, 2030 muscle D is gonna be the number one cause for liver transplantation. Some of the most important factors for, for muscle d are male patients, Hispanic patients and the most important risk factors for this or drivers are obesity type two diabetes, hypercholesterolemia and hypertension. We also know that the glo the global fatty liver disease prevalence is around 25 to 30% in the United States is around 30% in Europe is around 23.7. This is based on Doctor Janus's uh paper and it's more common in men as I mentioned. However, we need to remember that we will see in the next slide how uh menopause affects women and how it interferes or affects uh the development of muscle D or MSH in women. Unfortunately, we're seeing it more and more commonly in kids with a prevalence of our own 7 to 10%. And as I mentioned is the second leading cause of liver transplantation. However, it is expected to become the number one cause by 2003, the leading cause of death in these patients is cardiovascular causes. So let's spend a couple of min minutes talking about the importance of menopause and muscle d or the premature menopause induced premature menopause. And why this is important? We know that women with hypoestrogenism, dysli men insulin resistance. All of this develops after menopause. These patients are at increased risk of mass progression. In a pilot analysis of 537 individuals with biopsy proven the prevalence of advanced fibrosis stage three or four was significantly higher in postmenopausal women of 36.1% compared to men, 17.7%. And premenopausal women of only 13.5%. So, in the moment that women lose that estrogenic protection, the risk of metabolic syndrome and muscle d increases significantly. We also know that women with heavy alcohol use also are more prone to faster progression to cirrhosis and liver related outcomes in the setting of alcohol use disorder and me LD. And this brings me to have the opportunity to talk to you about the importance of bariatric surgery and alcohol use disorder and the rapid progression to cirrhosis in our transplant center, we're seeing more and more patients that used to have obesity underwent bariatric surgery after it started consuming alcohol heavily and now have cirrhosis and had had a liver transplantation. Patients who undergo bariatric surgery are at increased risk of alcohol misuse problems in early years of following bariatric procedures. This is a fact we also know that is, this effect is more pronounced in women. Ho however, there's very pure, there's very few information and awareness about the the connection between bariatric surgery, alcohol use disorder and the develop development of cirrhosis postoperative substance use and alcohol misuse disorder rates ranging around 7 to 33%. Women are more susceptible to liver disease at lower doses of alcohol or poorly understood phenomenon that is likely related to differential distribution of hepatic alcohol dehydrogenase difference in in body composition or to hormonal differences between genders. More women than men undergo bariatric procedures as well. So we need to create awareness in our patients. And we need to inform them about the potential risk of developing cirrhosis in the setting of bariatric surgery and significant alcohol use. How do we diagnose muscle D and how do we screen these patients? So, let's go back to our question. So we know that our 54 year old female with past medical history of plus one obesity, type two diabetes uh should be tested for fatty liver disease. So, what do we do? First? The most important thing and the first thing that we need to do in this patient is based on the A LD guidelines is calculate A four which we will discuss and review a little bit later. So what's the difference between muscle D and MS? We briefly touch upon this. However, I wanna talk to you about a little bit more about this because it's very important the way that we explain this to our patients. And what I always emphasize to our patients is that if they do not have cirrhosis, this is reversible. So muscle D is known as more, more five or more percent of hepatic steatosis by imaging or histology or lack of secondary causes of hepatic fat accumulation. And on the other hand, mesh or metabolic dysfunction associated steatohepatitis is five or more percent of hepatic steatosis and inflammation with hepatocyte injury. What do we mean by secondary causes significant alcohol consumption? As we already talked long term use of steatotic medications steroids, methotrexate, amiodarone, tamoxifen, mo monogenic hereditary disorders and the other diseases that I already mentioned during the nomenclature, how do we identify hepatocyte injury through hepatocyte ballooning under the microscope? So, the new nomenclature just to review this one last time, we know that its muscle D mesh and the cardiometabolic risk factors where the patient apart from having hepatic steatosis needs to have one out of five cardiometabolic risk factors. I really like this slide because it tells you about the natural history of non alcoholic fatty liver disease are now known as muscle D. Currently, we know that in the United States, 60 to 80% of Americans have muscle D from this 15 to 20% have mesh or steatohepatitis. From this 20 to 30% over the next three years will progress to advanced fibrosis. And remember that advanced fibrosis is stage two or above and 20% that are in stage three over the next two years will progress to cirrhosis. Currently in the United States, 1 to 2 million uh patients have cirrhosis. We know that the risk to develop for development of hepatocellular carcinoma is around 1.5 to 2% per year. However, remember muscle d just like hepatitis B is one of those diseases where patients can develop hepatocellular carcinoma without having cirrhosis. And the most thing important thing here, remember that this disease is reversible. We can reverse this disease as long as the patient does not have cirrhosis and I will keep repeating this over and over again because many patients do not believe that until they start seeing changes in their fibro scans. Mr elastography or in their blood work, et cetera. Remember that liver fibrosis normally progresses at a rate of approximately one stage every 7 to 10 years. However, 20% of patients are fast progressors, meaning that they will develop cirrhosis within 10 years. So in summary, which patients should we suspect steatotic liver disease? Just like our patient from the case two or more cardiometabolic risk factors, central obesity, prediabetes, insulin resistance, hypertension, high triglycerides. All those patients with type two diabetes in those patients that have liver steatosis via ultrasound ct scan MRI or they have elevated aminotransferases for more than six months, six months in men, more than 40 in women, more than 30 all these patients should be screened for advanced fibrosis in the setting of muscle d. So what prediction test do we have? We have uh NAFLD fibrosis score. We have the A score as pertain amino transfer to platelet ratio, uh index. However, the most utilized and easily and readily available and cheap is the fifth four score. It's very easy to calculate the only things or markers that you need is the patient's age ast A LT and platelet count. As you can see on the right box, they are different cutoffs less than 1.45 which normally indicates F zero to F 21.45 to 3.25 which is indeterminate or more than 3.25. That is normally stage uh fibrosis three or stage four. What do we do with the in, in indeterminate uh cases? We will need to have another noninvasive test to really assess if the, if the patient has advanced fibrosis or not. This prediction test, their strength is in the ability to exclude advanced disease. Hence, good negative predictive value with somewhat poor uh positive predictive value ranging from 27 to 79%. It's poor to diagnose MS and fibrosis isolation. Another weakness is their poor accuracy in older patients and diabetics. However, now we have age adjusted cut offs. One of the limitations about NAFLD NAFLD DFS and F four is that some patients will be classified as indeterminate as we already mentioned. And these are the patients that we will need another noninvasive test to assess liver fibrosis. Fifth four was originally developed to predict advanced fibrosis in patients with HIV and hepatitis C coinfection. Then it was started in patients with muscle d specifically 541 patients and this uh tool or index was validated for patients with muscle D. So, after having or calculated fi four in those patients that have indeterminate, indeterminate uh classification, what we can do, what we can now use is something called a fiber scan or transient elastography to talking about imaging for the liver. There are different things that we can utilize. For example, on ultrasound, a ct of the abdomen that we will a this will be able to tell us if the patient has 30 or more percent steatosis in the liver. When we start seeing hepatic steatosis in the liver, these patients already have around 30% steatosis. However, an ultrasound, a CT scan and an MRI will not be able to assess the fibrosis. They will be able to give us um indirect markers or signs that the patient may have portal hypertension or advanced fibrosis by seeing recanalization of the umbilical vein or uh viruses in the, in the abdomen, et cetera, hypersplenism, for example, Trans Asy and the reason why I added a cheese there not to make you hungry was originally invented to assess cheese ripeness in France. And we stole the technology to now assess the ripeness of the liver in some way. So I wanna, I wanna bring your attention to the to the cut off. So 6.5 kg pascal excludes advanced fibrosis with a negative predictive value of 0.91 and a cut off of 12.1 excludes cirrhosis with a negative predictive value of 0.99. Always remember other factors that may influence the results, congestive hepatopathy, inflammation for patients with a active alcohol use, ascites, et cetera. So, elastography is the most widely used. It predicts risk of decompensation and it's accurate in detecting advanced fibrosis. However, emery or magnetic resonance elastography continues to be uh the gold standard for the diagnosis and quantification of hepatic atos. The limitations of course are point of care of access cost, metal implants, patient size and claustrophobia. An MRI an MRI has a sensitivity of 0.86 and a specificity of 0.91 a positive predicted value of 0.68 and a negative predicted value of 0.97. So, as you can see the results from this are excellent. And now I'm utilizing it more and more in my patients with steatotic liver disease, especially for those that have ABM I of 33 or above. So who do we, who should we be referring to gi or hepatology? Any patient that has inde indeterminate risk or high risk based on fibrosis risk stratification. As we already discussed, evidence of advanced liver disease of normal liver enzymes for more than six months screening. We need to continue screening these patients. Uh specifically the ones with pre diabetes or diabetes or two or more cardiometabolic risk factors with 1/5 for every 1 to 2 years. If the patient does not have type two diabetes or has less than two metabolic risk factors, the screening for advanced fibrosis should be every 2 to 3 years coming back to our case. So we calculated uh the fifth four on our patient and his score is 1.7. She's her score is 1.7 the best. Next step is refer to hepatology, order a fiber scan, reassure the patient that she doesn't have liver disease. Excuse me, where as four rules out advanced fibrosis, she should follow up with you in one year. Well, you have the cut offs here. Remember that a 1.7 falls under indeterminate. So the next step for this patient will be to order a fibro scan. What about muscle d treatment? And this is where the excitement starts. And um there they have been a lot of, of recent publications and we've done great strives in the treatment of muscle D. The treatment approach that I always recommend is a multidisciplinary personalized approach with lifestyle modifications as the base and then we can consider medications, bariatric surgery and the bariatrics amongst other. If we see muscle D just as a unique disease, we won't be able to succeed. We need to remember that muscle D is part of the metabolic syndrome. Therefore, it's extremely important to treat all the other diseases to be able to succeed. So, coming back to our case fro scan suggests that the patient actually has stage three fibrosis, which of the following therapeutic options has proven to be more beneficial for MS lifetime modifications, meaning diet and exercise, weight loss, medications, bariatric surgery or Vitamin E plus pioglitazone. Every time that I see a patient in the uh in the clinic. One of the most important things that I reviewed before meeting with a patient is their medication list. We know that there's a large amount of medications that can increase the risk for obesity including pioglitazone, for example. But on the, on the, on the, on the left side of your screen or maybe your, your right side, you can see the obesogenic medications. And the important thing is to identify these ones and if possible, switch them to a medication that will be weight neutral or will help the patient to lose weight. For example, what about last time modifications? As I mentioned, uh a couple of minutes ago, it's very important to teach the patient why eating better is important, why it's so important to exercise and develop muscle mass. We know that muscle D and MSH can be reverted with weight loss. We know that if our patient loses from 3 to 5% we'll be able to improve the steatosis. If the patient loses around 7% we'll be able to improve the histological characteristics of MSH. And if it loses 10 or more percent, the fibrosis can be reverted. Also, it's very important to tell your patients do not get obsessed with the scale. Many patients start exercising, building muscle mass won't see much change in the scale. However, their body composition will be significant. Don't focus just on the way. Very important to explain this to your patients because the scale is not only the one that is telling the story, the, the the body composition is a better way to assess to assess uh the progression of our patients and also the sizes, the clothes sizes, they also focus a lot on that where they start noticing that the clothes start feeling better and, and feeling better. So those are things that they should also focus. And it's a, a very good way to keep our patients motivated, motivated on their weight loss and treatment uh journey. What about diet? So normally we recommend calorie restriction from 500 to 1000 calorie per day. Uh meaning restricting around 500 to 1000 calorie per day from their daily diet limit, red meat, processed and high fructose foods. Uh And my favorite part of all of this is caffeinated coffee reduces the risk of liver fibrosis. And MSH, there's a lot of research and a lot of publications that have shown that coffee, black caffeinated coffee is very good three cups of coffee per day. As I always tell my patients keep the hepatologist away and of course, always avoid any herbal supplements or dietary teas. Uh The only substance that as I mentioned helps with the liver is black caffeinated coffee. Apart from that, we normally do not recommend anything else. Some recent studies have shown that coffee consumption may play also a role in prevention of type two diabetes, neurological disease, depression, cancer, hepatic injury and cardiovascular disease. Uh important also to remember that we need to vaccinate our patients uh against hepatitis A. We also need to keep a close eye in in the development of hepatocellular carcinoma. As I mentioned before, muscle D patients can develop cancer without having cirrhosis. However, based on our current guidelines, there's no specific recommendations to screen for these patients for ACC but I believe that uh soon we will be seeing some recommendations about this. And remember, as I told you in the beginning, fatty liver disease or muscle D is part of the metabolic syndrome. Therefore, it's very important to screen our patients as well for other cardiometabolic diseases, for example, sleep apnea. And normally what I utilize for this in my practice is the stop bound questionnaire. Let's talk a little bit more about the diet. So very important to remember if you have a patient with compensated cirrhosis with muscle D, you also recommend that you will also recommend for these patients to lose around 5 to 10% of their current weight. And it can be a hypocaloric diet. However, remember these patients as they are in a catabolic state need to eat more protein. So it's very important to remember that in a normal patient with cirrhosis, the calorie intake should be around 35 kg calories per kilo per day. And the protein consumption should be from 1.2 to 1.5 g per kilogram per day. It's a lot of protein in it. And it's very important to, to, to spell this out to our patients where they understand that they should be eating around 90 100 g of protein per day, which is a lot. And in those patients with, with obesity, they should be consuming around 15 to 20 kg calories per kilo per day. And the protein intake should be more than 1.5% in decompensated cirrhosis. You need to avoid prolonged fasting. Focus on improving nutrition and muscle mass, high protein diet is key and a nightly snack. Um high in protein and calories is also extremely important. What about diets? This is one of the most common questions that I get. Uh in clinic. We know that the Mediterranean diet is the one with the most cardiometabolic benefits. There are many diets out low carbohydrates, the keto diet, intermittent fasting plant based. And as we can see, the one that has shown the most benefits is the Mediterranean diet. However, what I always tell my patients, the best diet that you're gonna be able to do is the one that you're gonna be able to comply with. And of course, we always need to, to avoid the tea diet as I call it tacos tosta tamales, tequila, et cetera. Everything in moderation. Of course, in a patient that is cirrhotic or has advanced fibrosis or even has muscle D I normally do not recommend any alcohol. As we already seen me d is extremely prevalent. It, alcohol has a lot of calories and it directly affects the liver moving forward into exercise. Uh Normally what we recommend is 100 and 50 to 100 and 80 minutes of moderate intensity exercise per week or 75 to 100 and 50 minutes of intense exercise per week in 3 to 5 sessions, in decompensated cirrhosis exercise is not contraindicated. We just need to adjust the type of exercise based on their limitations. And remember just like the diet, the most important thing for this is teach your patient find an exercise that you enjoy. So you're gonna be able to comply with and be, uh, persistent and consistent with this type of exercise. Developing muscle mass in these patients losing um, uh, fat around the abdominal area is extremely important for our patients because they will, this will drive and it will decrease the insulin resistance and with time it will hurt, help and improve the metabolic syndrome and therefore also muscle. What about weight loss interventions? It's very important to remember that through last time modifications, patients normally lose around 5% of their weight. However, it's very easy to fall off the wagon and go back to our old habits. That's why we have other options now, which is excellent. But the base of all of this is changing the way, understand why eating better, why exercising regularly is so important if we impair that to oral medications or injectable medications or even bariatric surgery, and then the bariatrics, we will be able to succeed. As you can see, with oral medications, you can lose around 10% 10% of your weight with injectable medications that we have seen dramatic and amazing results where patients have lost up to 20 to 20 22% of their weight and bariatric surgery and end the bariatrics where the weight loss is even more significant based on the, um, FDA, these are the medications that have been approved for obesity. I wanna highlight this. These medications have been approved for obesity. Are we utilizing this type of medica medications on our metabolic liver clinic? Yes, we are using G LP ones which we will talk a little bit more. Uh moving forward. We're also using phentermine uh and le glutide as well and, and the semaglutide that are G LP ones. So these medications are excellent. Uh it's very important to have a good understanding of how they work and also teach our patients the potential side effects and look for any potential contraindications. And here's where the, the, the exciting stuff starts. So we now know that a there was a recent publication of a phase three randomized controlled trial of Remeron in, in patients with MS with liver fibrosis. This is the first drug that has been able to be published that has shown to revert fibrosis. However, this rapidly burst the bubble. Uh As more recently, Dr Lumba published uh an excellent study of sepa for metabolic dysfunction associated steatohepatitis with liver fibrosis. In those patients that had biopsy proven F two or F three mesh. They were randomized uh uh two ceide in different doses. As you can see in this slide from control and 5 mg 10 mg and 15 mg. And the results were amazing. These patients were able not just only reverse the, the, the fat but also reverse fibrosis, which is extremely exciting because I believe that these drugs will come later on and we will be able to, to utilize these drugs and then get them approved by insurance um for the use of our patients with muscle D with advanced fibrosis. So definitely very exci exci exciting times for in the world of muscle D, I would also like to emphasize that normally what I do in my clinic, I start the first clinic, the first clinic visit is to establish a good relationship with your patient. Get the trust from your patient where they're able to tell you why do they consume alcohol? If they do consume alcohol? How much are they really consuming? If they stress eat, if they have anything that is bothering or worrying them? Meaning are they depressed? Do they stress eat, et cetera? It's very important to understand this. And really, as I mentioned, educate them about why it's so important to treat all the other cardiometabolic risk factors later on after teaching them and showing them how to properly what we normally do, send them to a nutrition class that we created with our nutritionist here at Mayo Clinic in Arizona where they are taught how to eat in a better way, utilizing med Mediterranean diet. But also any things that they enjoy and making sure that they change, change macronutrients in a way that they're gonna be able to improve their, their limit, the insulin, the glucose spikes and, and the insulin spikes. Therefore, and, and that way, once it clicks, I had several patients that have been able to sustain their weight loss and not, and have not required medications, uh, for the use of their muscle d and have slowly been able to revert the steatosis and the fibrosis that they had. So it, it's all in there, right? How you establish, establish a relationship with your patients and how you educate your patients for this. So we know that these medications work, we know that, that the GOP ones and, and, and the ides and agt and all these medications really, really work. However, what happens when we stop these medications? Well, the next question you have on your mind is what happens if you, if suddenly your patient has been able to do a lot of, of progress and suddenly the, the patient stops the medication. We now have some, some publications about this, um, a publication from Jama in 2021 called Step Four where a total of 902 participants received once weekly subcutaneous semaglutide during running. And after 20 weeks, 16 weeks of dose escalation, four weeks of maintenance dose, 803 participants, meaning 89% who reached the 2.4 mg per week of semaglutide maintenance dose were randomized 2 to 1 to 48 weeks of continue subcutaneous semaglutide or switch to placebo plus lifestyle intervention in both groups. This was a trial to assess the change in weight after switching from semaglutide to placebo. What we found here is that the main outcomes and measures were the primary endpoint was percent change in body weight. Uh from week 20 to week 68 confirmatory secondary endpoints were changes in waist circumference, systolic BP and physical functioning assessed using the short form 36 version two health survey and acute version of sf 36. In the results, we saw that 803 people completed the 20 week run period. Then randomized, we continued semaglutide. The mean body weight change from week 20 to week, 68 was less than 7.9% versus more than 6.9% with a switch to placebo with a difference of 14.8%. Meaning that this was statistically significant. The weight conference was 9.7 centimeters uh compared to 10.9 to 8.5 with a systolic BP change of 3.9 millimeters of millimeters of mercury versus less than uh 5.8 to 2 millimeters of mercury. So as you can see, uh the difference were significant, same thing with the physical functioning score also improved with continuous of within a semaglutide versus placebo. So, in conclusion, and the relevance of this is among adults with overweight or obesity who completed a 20 week running uh period with subcutaneous semaglutide 2.4 mg, milligram once weekly maintenance dose uh compared to placebo uh resulted in continued weight loss over the following 48 weeks. So something to consider if the patient is tolerating this medication. Well, it's something we can definitely consider another important thing that I have not mentioned about. Um before I start prescribing these medications is education, we need to tell our patients that they will probably develop nausea. They will probably develop early society and many of them actually stop eating, which is extremely important to remind them that they need to keep eating. They need to be able to get an appropriate caloric intake because the weight loss achieved with these medications also includes loss of muscle mass. Very important in another study. The Step one trial Extension which was published in 2022 in diabetes, obesity and metabolism. So was officially titled Weight Regain and cardiometabolic effects after withdraw of semaglutide. Uh the Step one trial Extension uh analysis enrolled a total of 327 participants. And as, as you can see what they wanted to explore is the changes in body weight and cardiometabolic risk factors after treatment withdraw in the step one trial extension from that part from this participants, uh The intervention was to discontinue treatment. There was semaglutide uh and last time modifications at 68 weeks and the duration was 52 weeks. And what we found here is that from week zero to week, 68 the mean weight loss was 17.3% with semaglutide at 2%. and we was and, and um with placebo following treatment with draw semaglutide and placebo participants regained 11.6% and 1.9% points of loss uh of weight loss respectively by 820 resulting in net losses of 5.6%. Um and 0.1 respectively, cardiometabolic improvements, cardio metabolic improvement seen from week zero to week 68 with semaglutide reverted toward baseline at week 120 for most variables. So, in conclusion, as we can see here, one year after withdrawal of once weekly subcutaneous semaglutide of 2.5 mg and lifestyle modifications or intervention, participants regain two thirds of their prior weight loss with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvement in weight and health. As I tell my patients, obesity is like having high BP is like having alcohol use disorder. It's a chronic disease that never goes away and our bodies are very aware of uh of weight gain and we need to, to be very cognizant about this change from baseline in body weight by week uh for A and A two participants in the X SB participants in the se alu arm group by categorical weight loss from week zero to week 68 participants not using obesity pharmacotherapy during the extension. And the participants in the semaglutide arm for the full access and the subgroup with pre diabetes resolution at week 68. And the subsequent reversion by 320 participants who did not use obesity pharmacotherapies, investigator assessed uh during the extension phase. Participants who shifted from pre diabetes at baseline to normal glycemic and week 68 to prediabetes at week 120. The glycemic category was determined for hemo from hemoglobin A1C assessment as per the American Diabetes Association uh criteria. So I guess, I guess there's people who were still using some medications that might be considered drugs used for obesity. And so those were separately assessed differences between A and C as you can see here. So following up on the step one trial extension results. So this is the data for the cardiometabolic risk factors. As you can see on table A systolic BP, B, diastolic BP, cc, reactive protein and D hemoglobin A1C. By week, the data observed uh means and for the extension analysis set from the in trial period for c reactive protein. Standard error was calculated on the logarithmic logarithmic scale and back transform to the linear scale. The dashes vertical line at week 68 indicate the end of the main phase and start of the off treatment extension phases. Numbers shown in the lower panels are participants contributing to the main C RPC reactive protein. So can we use it long term? What happens if we do use these medications? Well, we'll see there's actually a trial, the step five trial uh that was published in Nature Medicine in August 2022. For previous studies in step trial program were limited to treatment duration of up to 68 weeks. The two step trial, step five study was conducted to evaluate the long term effect of once weekly subcutaneous semaglutide compared with placebo as an adjunct to behavioral interventions in the long term. Uh uh weight management. 12 step 5, 304 participants with obesity or overweight without type two diabetes were randomly assigned in a 1 to 1 manner to receive semaglutide 2.4 mg or placebo to assess uh weight loss over a two year period. So, as you can see here at week four, participants in the semaglutide group had achieved a mean weight loss of 15.2% from baseline. A difference of 12.6% points versus placebo plus behavioral intervention. This was similar in step one where they saw a total body weight loss of 14.9% weight loss of more than 5% seen in more than 75% and more than 10% in 61.8% and more than 33% of 20%. So, what they say in this study is that weight loss plateau after approximately week 60 was maintained for the remainder of the study. This is an, this is important for us to know that the weight loss is not infinite, but also that continuous is ok. They're not going to disappear, they're not gonna waste away. But we need to remind our patients importance of exercise and building muscle mass. Furthermore, a small proportion of participants experience weight gain. We do not know how weight would have changed in these participants had they not been received the drug as this proportion was less than in the placebo group safety. The safety profile of semaglutide of 2.5 mg in step five was consistent with that in other step programs trials and with the G LP one receptor agonist class in general gastrointestinal disorders were the most common adverse events with semaglutide, typically transient of mild to moderate severity severity occurring during dose escalation and infrequently leading to treatment discontinuation. However, as I already mentioned by good education to our patients and by letting them know what to expect with these medications are able to tolerate the the original side effects from these medications that we time up with this study. The authors concluded that that in addition to step four and the step one extension that is support to continued use of the medications. The strength of this study, the step five is to include the high rates of adherence uh to treatment uh and completion for the trial which contributed to consistency in findings between two estimates. The limitations include that the low proportion of non white participants and the preponderance of female participants. So just touching uh a little bit more about her Hepati as we know it's not approved product related um uh yet for the use of MS. Um However, this medication has been approved for the use in patients with obesity with ABM of 27 with cardiometabolic risk factors or with a BMI of more than 30. We know that it's a GLP one receptor agonist and a G IP I don't. So the root, the the root of of injection is subcutaneous. The doses go from 2.5 increase to 2.5 every four weeks with a max dose of 15 mg. And the effi the efficacy is excellent. Uh The weight loss is from 15 to 26%. As we already mentioned, the side effects are extremely important, nausea, vomiting, diarrhea, constipation, abdominal pain in some cases, pancreatitis. Um I recently read a paper regarding a patient that had vision loss, um injection, uh side pain, depression, suicidal ideation and hypoglycemia because remember these medications inhibit the reward area. So patients start not feeling hungry not having cravings and in some way, uh some patients just stop enjoying things that they used to contraindications. Uh Remember past family history of medullary thyro carcinoma men, two pancreatitis and severe DKA. You always need to ask this before you consider starting patients on these medications. So in conclusion, I can tell you that muscle D is the number one chronic liver disease in the world. We need to screen patients that we suspect that are at high risk. Stage. Two fibrosis is associated with liver related outcomes. This is the, the stage that we need to identify and aggressively treat. This is a treatable disease. Tell your patients this is reversible. We can do it but it's gonna be hard and the best approach is multidisciplinary and aggressive treatment. Thank you so much for having me today. I have enjoyed my talk and I look forward to, to your questions. Have a great day.