==== Dr. Kenneth Cusi (00:09):

Welcome to this educational program. I am Dr. Kenneth Cusi. I'm the chair of the division of endocrinology, diabetes, and metabolism at the University of Florida at Gainesville. It's been my pleasure to have this opportunity to share with you a summary of a symposium that was presented at the American Association of Clinical Endocrinologists on May 12th, where we discussed some very cutting edge information on how to implement the best practices for fatty liver disease. So follow me in the next 25 to 30 minutes, where we're going to discuss key findings that will truly impact your care of patients with diabetes, obesity, and fatty liver disease. Without further delay, we're going to dive into some very new information on the magnitude of the problem. So our first few slides are going to try to put into the context of your clinical practice why it is important for you to understand what is the role of fatty liver disease, and what you can do about it. Slide 2 So we recently put together this worldwide, very updated work on the prevalence of non-alcoholic fatty liver disease.

Dr. Kenneth Cusi (01:33):

And just for those who are not so familiar with that nomenclature, non-alcoholic fatty liver disease covers the full spectrum of the disease in someone who has steatosis, when secondary causes of medications or some other diseases have been ruled out. And we're going to have simple steatosis when there's no inflammation or fibrosis, all the way down to NASH with severe steatohepatitis, and which, as you know, may progress to cirrhosis, and even hepatocellular carcinoma. But why is it important for us as endocrinologists? Well, the two main drivers of fatty liver disease, but it's more progressive way with steatohepatitis or NASH and liver fibrosis, are diabetes, type two diabetes when we talk about diabetes today, and obesity. In this slide, which is built upon prior work by Dr. Yanuzi, in terms of the worldwide prevalence of fatty liver disease, we focused on people with diabetes. And you see at the bottom, the more red the color, the redder, the higher the prevalence of type two diabetes. Notice that the countries that have a worse or a higher prevalence of type two diabetes also have the highest rate of non-alcoholic fatty liver disease.

Dr. Kenneth Cusi (03:07):

So if we focus on United States, where most of our audience were, that attended the meeting we were working at, in the United States, the overall prevalence of diabetes, of type two diabetes, almost 11%. But if you take people above 50, it's probably double that number. We have up to 70% of people with type two diabetes having non-alcoholic fatty liver disease. Among those, we think that at least 40% have NASH, which is this progressive necrosis and inflammation that promotes fibrosis, but the same is happening all over the world. And moreover, the real number I want you to remember is the one that's at the top corner. That 12 to 20% of patients you are seeing in your clinic with diabetes, and most of them with obesity, are going to have moderate to advanced fibrosis. So moderate fibrosis is labeled by liver biopsy, by histology, as F2. And then you have F3, which you could simplistically label as pre-cirrhosis, and then F4 is cirrhosis.

Dr. Kenneth Cusi (04:21):

If you think about this number, you have almost one in five to six patients in your clinic with advanced fibrosis, and this is something that you and me as endocrinologists can truly prevent with an early diagnosis. So keep this in mind. Slide 3 And other numbers that are important for us to understand is what is the wait list for liver transplant from the compensated cirrhosis? So as you may have heard, hepatitis C is coming down as there's been a major success in the treatment of the infection, and the two conditions that are going up continue to be alcohol and NASH. NASH is driven, again by the epidemic of obesity and type two diabetes, and will continue to grow as both epidemics worsen over time. Very soon, it is going to be the number one cause of liver transplantation. 4 Now, another important thing that you need to remember is that NASH comes associated with hepatocellular carcinoma. And again, many of you may say, "Well, I didn't see any of my patients developing hepatocellular carcinoma, or maybe you did have a personal experience.

Dr. Kenneth Cusi (05:47):

I had a patient of mine with severe NASH and early cirrhosis develop cancer, liver cancer, just about two months ago. And it's a very crude reminder that this is something real. So again, this is truly important because not only you have the ability to prevent cirrhosis, but you're also working to prevent cancer. So these are aspects that, as endocrinologists, we are not so familiar with. We are more used to endocrine cancers, but this is something that we're going to see more and more, as we continue to see more and more people have NASH. Now, what can we do? We're now boiling down to the practical aspects of this. We need to think about NASH, particularly in those who have features of greater risk. So we think older age might be a risk factor because there's a longer time to cause liver damage. Male gender has been an observation shown in many studies to be a risk factor. Metabolic syndrome and obesity, type two diabetes, and even family history has been shown, of type two diabetes, to be a risk factor.

Dr. Kenneth Cusi (07:15):

Low platelets is an indicator of portal hypertension and hypersplenism. So as a practical tip, look in your patient with diabetes at the platelets. If the platelets are approaching 150,000 or lower, that's a sign of cirrhosis. You need to do something. We're going to get back to a marker that uses platelets called FIB-4, but that's a term that you should probably memorize moving forward. Then a couple of things to remember, there's some genetic SNPs, genetic markers, that suggest worse prognosis, both NASH and liver cancer. Still not ready for prime time, but I'm sure this will change very soon. Ethnicity. People of Hispanic ancestry tend to have more steatosis, but when you match for obesity, it's not that much higher, and when you match also for diabetes, it's not that much higher than Caucasians. So again, ethnicity is something that should be kept in mind also. And smoking, there is some data in that regard.

Dr. Kenneth Cusi (08:26):

Again, these are the histological terms that we're going to be talking about. Fibrosis going from moderate F2 to advanced fibrosis F4, or cirrhosis. And then we're going to talk about just remember inflammation, and the ballooning is when the liver cell is swollen, and basically in the process of dying off. That's necrosis. So necroinflammation is another feature that the pathologists are going to look to decide whether the patient meets the criteria for NASH or not. Slide 6 So steatohepatitis drives fibrosis, and again, this is pretty much what we can treat today, even as we don't have any FDA approved medications. So in a nutshell, this is something you need to remember. Number one, from a normal liver, you can have a liver with just fat in the liver. Again about 50 or 60% of people who are obese may have a fatty liver.

Dr. Kenneth Cusi (09:35):

Then you progress to steatohepatitis, and then as I highlighted with this box, to fibrosis. So one very important concept is that despite the fact that we have ways to diagnose fat in the liver, our target is liver fibrosis, okay? So we're not going to do a lot of biopsies to diagnose that, but what we are going to learn as clinicians and endocrinologists is to measure FIB-4. There are also some commercial biomarkers like ELF, very important, and NIS4, more recent one, that is still not as evaluated as ELF, which has been broadly used in Europe and the rest of the world, and just approved recently for use in the United States, as the biomarkers to diagnose NASH. And then imaging, which we're going to talk about transient elastography. And then the gold standard is magnetic resonance elastography, but we're going to probably leave that to our hepatologist.

Dr. Kenneth Cusi (10:48):

NASH, steatohepatitis is something that we cannot diagnose noninvasively. This means without a liver biopsy. There are a number of biomarkers that may help, that are good, but need greater validation. And then there's a magnetic resonance liver multi scan that gives you some idea of inflammation, and it's beginning to make it into the clinic. So stay tuned with that. But still it is the liver biopsy which is going to be the gold standard. So how do we put all these tests together? Slide 7 So that's what we did with the clinical practice guidelines for fatty liver disease that we presented in a symposium on May 12th. Dr. Scott Isaacs was the co-chair with me. We put together a group of very dedicated and prestigious endocrinologists, and I want to thank particularly the American Association for the Study of Liver Disease, Dr. Rinella and Dr. Yonuzi, whom we work very closely in our conference calls, and in the development of the document, to make it consistent with liver guidelines and answer the questions that endocrinologists have in the management of our patients in the clinic.

Dr. Kenneth Cusi (12:20):

Slide 8 So let me dive into that, and with this, grasp what are the key concepts to keep in mind for our day to day practice. On the left, we have the high risk groups. This is key for you. People with type two diabetes, or with prediabetes. The patient you see with a fasting glucose of 105, 115, or with an A1C in the range of prediabetes. These individuals are very insulin resistant, same as those with two type two diabetes, and at risk of fatty liver disease. As we mentioned, the second group are those with obesity and two or more cardiovascular risk factors, as we observed in metabolic syndrome. And the last group are those who already have hepatic steatosis, on an ultrasound or a CT scan done for something else, or have elevated liver enzymes. So this is the catch. We are used to using a cutoff of 40 for the ALT or AST, but what we know now from epidemiological studies is that a value above 30 is associated with increased mortality in the general population, and most likely it is because most of those individuals have NASH.

Dr. Kenneth Cusi (13:44):

So 30 is a number that should be a red flag for you. So once you have one of these individuals, and as endocrinologists, we have a large group of people that fit in one of these groups or in all of them, we would do two things. Number one, prevention of cardiovascular disease. You are pretty good at doing that. But remember now that if you have a fatty liver, this is a high risk person, and I'm going to go over these four intervention pathways. What we're not so good, or pretty bad, I would say, is at thinking of cirrhosis, of preventing cirrhosis. But I know that this is rapidly changing. So we are going to think if this person can be at risk of cirrhosis, and after one or two steps, which I'll share with you, we're going to be able to say the risk is low, high, or somewhere in between, and put our patients in these three buckets. Slide 9 This is the risk stratification strategy. We have our three groups. We rule out secondary causes with a good history and a physical exam. And we use the FIB-4 index.

Dr. Kenneth Cusi (14:57):

The F4 is an index, very easy to calculate on a web browser, or your own electronic medical record can have it incorporated as doc, FIB-4 in your notes. We have it at the University of Florida incorporated like that, a simple phrase in our notes, or a calculator is the other way, and you divide it into low risk or high risk. And remember just two numbers less than 1.3, low risk. Greater than 2.6, and what I do to remember is 1.3 times two is 2.6, high risk, and then people fall in the middle. Now with that, we reduce by 50 or 60% of people who we consider need additional workup. About 10% fall in the high risk where their FIB-4 is greater than 2.67, but sometimes we have a lot of people in the middle. And these people in the middle, there are two practical approaches. Number one is to do an elastography test. We call it also vibration control transit elastography by FibroScan. Your liver doctor has this device and always measures that in your patients with liver disease.

Dr. Kenneth Cusi (16:25):

And again, easy number to remember. A number greater than eight should be a reason for referring the patient to a hepatology. If you don't have access to one, the next approach would be to do an ELF blood test. This test, what it does, it helps you discriminate whether the risk of fibrosis is higher or lower. And you have the cutoffs that you can see there in the middle. And a number of 9.8 or greater is pretty concerning, and numbers in between should also probably prompt the patient to be seen by hepatology, who can run additional imaging and biomarkers to get to a diagnosis, or sometimes need a liver biopsy. But if you have this, this is truly important, because I cannot tell you the number of patients that I have in these past 10 years identified with unsuspected liver disease, and really believe that we were able to prevent them from developing cirrhosis or liver cancer. Now, let's dive a little bit deeper into this, and what can we do for these people?

Dr. Kenneth Cusi (17:48):

10 Because what I get from many of my peers say, "Well, very nice Dr. Cusi, but we don't have any FDA approved drugs." And what I say, you're absolutely correct, but weight loss by any means, either simply lifestyle, or with pharmacological agents have induced weight loss, or bariatric surgery, you can completely reverse steatohepatitis and halt the progression of fibrosis, even reverse it to some degree. So let me show you quickly, in a nutshell, some of the evidence. There are many, many studies on lifestyle. This is one that is frequently cited. The reason is it was at least a one year study, it had a fairly large number of people, I think about 280, and they just told them lose weight. It was in a randomized trial, but what was nice about this study is that it allowed to see what the benefit of 5% weight loss was, 7%, or 10% weight loss. So resolution of NASH, and again, for those who are not so familiar, what it means is the pathologist looks before and says, you have a high score, and you have significant inflammation and necrosis of liver cells.

Dr. Kenneth Cusi (19:15):

If left alone, your liver is probably going to drift into end stage liver disease. And then after the intervention, in this case lifestyle, they say, well, there's minimal or no inflammation going on. So this is really important because what we think is that inflammation is what's driving the scarring, the fibrosis in the liver, that causes both cirrhosis and hepatocellular carcinoma. So if you look at this in the placebo arm or those who didn't lose weight, about 10% improved, probably they ate better, less saturated fats, whatever. But as you lost 5%, 26% improved, 7% two thirds. By the time you lost 10% of body weight, 90% didn't have active NASH. And the other factor that's important is fibrosis regression. Same pattern, again, a little bit more difficult to improve, but again, liver fat improved in all patients once they lost 10% of body weight.

Dr. Kenneth Cusi (20:24):

Of course only 10% achieved 10% of body weight loss, but so it's difficult, we know that, but it works. Again, I get also asked, what about other approaches? The regular healthy hypocaloric diet is nice, hard to follow. I would love to do intermittent fasting. Take home message is that it works too. So what they did, they just very briefly they did a low caloric diet, the standard one, they did the intermittent fast, and then the control group. And both, you can see that about 50% of the people achieved an improvement in their liver fat. So it didn't matter if it was intermittent fasting or just a standard hypocaloric diet, whatever works for your patient and leads them to a hypocaloric diet is acceptable and works. Finally, don't forget about bariatric surgery. That surgery works. And again, in this study, they looked at the number of people who had, again, that resolution of NASH I mentioned to you before.

Dr. Kenneth Cusi (21:47):

Again, these are severely obese individuals with BMIs above 40 in many of them. And you see as you get a greater reduction in your body mass index, almost everybody responds, improving the inflammatory component. And then when you look at fibrosis, just focus on the white portion, people without fibrosis after five years, basically about 60%. And so clearly NASH can be treated with weight loss by any means, or bariatric surgery. 11 Now we talked about this and these are the different stages in the life cycle of the liver, from healthy to having fat, to having inflammation and fibrosis, to having cirrhosis. What we want to do is prevent this. And we talked about lifestyle and bariatric surgery, we're going to talk about GLP1 receptor agonist.

Dr. Kenneth Cusi (22:46):

Again, the ones that have proven in the field of NASH to be beneficial are both liraglutide, although it was used at a lower dose in the LEAN trial, and semaglutide, which was used where they use a slightly different formulation, but that we believe that is biologically equivalent to this 2.4 mg a week. These are the two doses approved in the United States to treat obesity. And then these are the doses for type two diabetes. And now semaglutide has been approved up to two mg per week, and then pioglitazone, ranging from 15 to 45 mg. So again, one question that I get is what about vitamin E? So vitamin E has shown, and the best study has been the study by the Clinical Research Network and Dr. Sanyon. Also compared to pioglitazone, vitamin E and pioglitazone, both arms showed an improvement in liver fat, inflammation, and ballooning at the 30 mg dose. So if you don't have diabetes, it may work.

Dr. Kenneth Cusi (24:03):

In this study, nobody had diabetes, but again, in people with diabetes, we prefer pioglitazone. I'll get to that in a second. Before I do that, I just wanted to highlight that others have tried Metformin. This was in a pediatric population, with no significant benefit. And again, others have tried in a small study by Dr. Harrison, showed no benefit, or a modest benefit. But again, vitamin E has been linked to an increase in cardiovascular disease in some meta analysis, and some fear about increasing the chance of prostate cancer. One word about pioglitazone, our research group did a lot of work here. We published the first randomized trial in 2006 in the New England, we did a long term three year follow up study in 100 patients, 101 patients. And again, you see that the majority, two thirds of people, have an improvement in their liver histology in terms of steatohepatitis, and even there's an improvement in not only steatosis, but some degree of fibrosis regression as well.

Dr. Kenneth Cusi (25:19):

So pioglitazone, it's fairly cheap, and in doses of 15 mg caused minimum weight gain of about 1%. Could be a great option for your patients with prediabetes or diabetes. By the way, as I said, our opinion is it also worked in people without diabetes, but doesn't have an indication for the management of obesity. So only give it to people under the indication of treating their diabetes. Very good. And we're going to move on. I want to share three additional slides before I get into the guidelines, as a take home message. You may have seen the paper published last year in October in the New England Journal of Medicine of the pan-PPAR Lanifibranor. This is a PPAR gamma, alpha, and delta. So pioglitazone is predominantly a PPAR gamma, with some PPAR alpha activity. This compound also has PPAR delta activity. We think that that may help with the inflammation in the liver.

Dr. Kenneth Cusi (26:33):

So the very simple design, three arms, 81 patients with placebo, and then the two doses of Lanifibranor. And the take home message is here. And again, there was a significant improvement in the resolution of NASH with no worsening of fibrosis. This is a standardized FDA endpoint. Almost half of the people, if you looked at improvement of fibrosis, by at least one stage and no worsening of NASH. I know it's a cumbersome endpoint for endocrinologists, but there are reasons for this, in terms that you improve fibrosis and don't make worse the inflammation. Again, about 50% of the people and improving both. This is the first time a NASH drug has improved both endpoints with a third improving compared to 7% of placebo. So very exciting results, which support the use of PPAR gamma agonists in NASH. 14 And the other drug that was also in the news in 2021 was semaglutide. A study design, again, three arms titrated of a daily semaglutide formulation. And as you see here, there was a resolution of NASH happening more with semaglutide.

Dr. Kenneth Cusi (27:59):

Again, in the solid columns, patients who had moderate or advanced fibrosis, phase two and three. The other would be... Sorry. All the people, there were about a third that had a mild fibrosis. So almost 60% compared to 17 or 20% in placebo. So very exciting results. And then what about, did this reverse fibrosis? So if you look between 40 to 49% of people who received had an improvement in fibrosis, but again, 30 to 32% on placebo. So people are wondering, is this a result of difficulties in reading the biopsies, or we just needed more time than 72 weeks to improve fibrosis? 15 So now both drugs, Lanifibranor and semaglutide are in large phase three studies, and this is a little bit what the map of drugs that are being tested in NASH looks like. We talked about semaglutide and Lanifibranor, still until 2027 will have to wait. Obeticholic acid having some more questions from the FDA, and again aramchol, which again, uncertain if it's going to be approved. And Resmetirom, which is a thyroid hormone receptor agonist, having some readings this year and the part one as surrogate import endpoints next year.

Dr. Kenneth Cusi (29:42):

16 Okay. So in the last few minutes, if you still want to know what to do in the clinic, I'm going to review a little bit of this. Once again, how we can prevent cirrhosis, and tell you in the next five minutes, go into a little bit more detail on what to do for treating the different aspects of NASH in your high risk patients. So we have three high risk groups. We have a FIB-4, again, to try to learn more. If the person needs to be seen by a liver doctor, we do elastography or we do an ELF test. Remember the ELF test is a blood test that measures three aspects of fibrosis biology in humans, and has been extensively validated for many, many studies as being of significant value to know you have liver fibrosis. So this is something that we're going to learn more, but again, if you do the FIB-4, and either of these two tests, you're going to really have helped your hepatologist on his further risk stratification and management.

Dr. Kenneth Cusi (31:07):

So once we've done that, I mean, as endocrinologists, 16 how do we manage the diabetes differently if you have low risk of fibrosis, indeterminate risk, or high risk? The way to do that is as follows. Number one, the general goals of optimal glycemic control remain the same, preferring to prevent cardiovascular disease, GLP1 receptor agonists and SGLT2 inhibitors. We also will prefer an SGLT2 inhibitor for chronic kidney disease or heart failure. I'm not going to tell this educated audience about the diet, just focus on a major diet and anything to which the patient can adhere. The target doesn't change. The only thing is, be careful being too aggressive if your person has cirrhosis, because they're very prone to hypoglycemia and you probably do not want to use sulfonylureas, and you got to be careful with insulin because of the risk of hypoglycemia. They have less hepatocytes that make glucose from glucogenesis and release glycogen as needed.

Dr. Kenneth Cusi (32:28):

The pharmacological therapy of diabetes changes. So if you only have steatosis, it doesn't matter that much, but of course, with pioglitazone or a GLP1 receptor agonist, you're going to reduce that liver fat. Some evidence also there for SGLT2 inhibitors, but as you move along the risk pathway of indeterminate risk or high risk, I would recommend more strongly using diabetes medications with a dual purpose of treating the diabetes, treating the obesity in the case of a [inaudible 00:33:06], and treating their liver. Remember that most of your patients with NASH are going to die of cardiovascular disease, and both pioglitazone and GLP1 receptor agonists reduce cardiovascular risk. Finally, what do we do with the other diabetes medications? Well, we keep them to try to treat their diabetes, but remember that if you have cirrhosis, you've got to be careful and you're kindly restricted to insulin, as we don't have really trials on GLP1 receptor agonists and cirrhosis, and we should not be using pioglitazone in people with cirrhosis because it's metabolized by liver cells, and it can lead to some decreased clearance and toxicity. So remember, choose your diabetes drugs with wisdom.

Dr. Kenneth Cusi (34:11):

Before I finish, a word about weight management in people with NASH, obesity being a big driver of disease. You know that you need to encourage exercise, reduce saturated fat and simple sugars. But again, be careful in cirrhosis as they usually are malnourished and need unique nutritional guidelines, and the work of a dietician. I'm not going to talk much about alcohol intake, always controversial, but you want to minimize with more advanced liver disease. And remember, the greater the weight loss, the greater the liver benefit, and also the cardiometabolic benefit. To finish the obesity part I think we don't use enough our nutritionists and the weight management teams, more structured weight loss programs. So remember doing that, we talked that GLP1 receptor agonists are the preferred weight loss agents that have the strongest evidence, and bariatric surgery, please consider this more often, but again cannot be used in people with decompensated cirrhosis.

Dr. Kenneth Cusi (35:34):

Two words about hypertension and dyslipidemia. The only thing that we'll do differently in hypertension is be more cautious in people with decompensated cirrhosis on the selection of our diuretics and blood pressure medications. And about lipid lowering, the only thing I want to remind you is that in addition to what we are already doing for people with increasing cardiovascular risk, which are people with fatty liver disease do have this increased risk, is to continue using the statins. Statins have a number of beneficial effects on the liver, and they should not be discontinuing these people at high risk. Start at lower doses, and then titrate as needed. And be aggressive in getting that LDL to the target. Usually in people with type two diabetes, we want to be below 70, and if you had cardiovascular disease, below 55 would be beneficial.

Dr. Kenneth Cusi (36:40):

So with this, I'm going to finish. It's been a lot of information, and remember, your patients with NASH are in your clinic today. If you've not diagnosed them, I'm sure you will tomorrow. And again, once we know that, we need to divide and manage it between cardiovascular risk management and prevention of cirrhosis. So with that, thank you for your time, and look forward to sharing another session with you.