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Okay, welcome everybody. If we can just make sure everybody's on mute, so we can hear the speakers, nice and clearly, that would be great. So to today's topic, I will go through the speakers, but just a quick housekeeping from Cherie before we start, just to make sure we're promoting online as well while the event is taking place today.
Absolutely. Welcome everyone. Thanks so much for joining.
If you are using Twitter, if you would connect with at EASOobesity using the hashtag, hashtag EASOComms, you'll see a post that I've just put up on the Twitter handle. And if you would also keep yourselves on mute if you're not speaking, and please feel free to use the chat to communicate amongst yourselves and with everyone on the panel. Thanks so much, Katie.
Thank you. And yeah, please do also feel free to let me know if you would like to speak at a future event or if your centre is interested in presenting, you can contact me, I will drop my email in the chat as well. But I'd like to welcome our first two speakers who are going to be opening the floor for us today.
We have Juan and Andrea. So Juan is a Doctor of Medicine. He is Team Leader of the Liver Metabolism and Infection Study Group and is also PI of NASH at the liver unit of De Waal-de-Bron University Hospital.
And Andrea will be presenting with him. She's an endocrinologist. She is the coordinator of the obesity unit, so their comm centre, also at De Waal-de-Bron University.
She is an Associate Professor of Human Physiology in Barcelona and is also a member of the Executive Board and Coordinator of the Spanish Society of Obesity. So I hope I have that right. And I will pass the floor to both of you now.
Thank you very much. Thank you, Katie. I think that we should start with the first presentation.
Right, Juan, are you here? Indeed. So I go straight ahead. OK, thank you.
Thank you, Katie, for your warm introduction. Thank you, everyone, for the invitation. It's very exciting for me to be in this multidisciplinary setting.
So I'm just going to start by laying out some basics of what is now called, or increasingly called, MAFLD, which is actually the metabolic dysfunction associated with fatty liver disease. And it's, as you know, very strongly associated with obesity. And well, first, let me state the obvious, which is that MAFLD and now MAFLD is the paradigm of the iceberg in public health medical.
When we eventually diagnose someone with MAFLD, he or she has usually passed through several doctors over the years. And it's normally referred by one endocrinologist or GP or other doctor after one of the metabolic or several of the metabolic factors have gone astray. So it's usually diagnosed late and we are still not being able to diagnose on time.
Most of the patients and health systems are not prepared for the tsunami that goes hand in hand with obesity and diabetic epidemics. So the overall prevalence... Juan, sorry, could you please put the slide in the presentation mode so that we can see a larger view? I thought it was in the presentation mode. No, no, I see it.
Just let me know now. I see it as presented, so I see full screen. It's now being shared as full screen? No, unfortunately not.
Okay, let me try something different. Okay, now it's working. Okay, I'm sorry.
I wasn't aware. Sorry about that. So the global prevalence of MAFLD is estimated on 25% of the global population.
Of course, this does not mean that everyone has a liver disease, but at least a condition that may predispose to further progression to cirrhosis or vascular carcinoma or cardiovascular complications. And as you can see in the slide, although the information we have been able to gather in several geographical settings is not so good, there are concerning prevalences all across Western countries. And the forecasting is not much good.
You can see here the rates of incident cirrhosis, hepatocellular carcinoma, or liver-related deaths, namely the final stage of liver disease is estimated to increase almost exponentially in many, many countries where we have more granular data, including several European countries such as Spain, Germany, Italy, or the UK, France, China, Japan, and the US. And well, for the natural history of NASH, being very straightforward, we can say, well, we may have fat steatosis, and this is defined as more than 5% of hepatocytes having fat within them, to cirrhosis. And this is a two-way pathway from non-diseased natural fatty liver that may become inflamed and then start having some cirrhosis of valonin and fibrosis.
Fibrosis is the mainstay of what we as hepatologists consider the foremost progressive indicator in this disease, to cirrhosis. It usually takes 20 to 30 years, but of course there are different phenotypes, there are progressors, there are lean NAFLD, and there are…this is just to be taken as a rule of thumb for those people that have not yet been diagnosed, but we cannot just sit quietly expecting them to progress, because some of them may progress very quickly. And just…there's a detail in that NAFLD is the only chronic liver disease that has been described to be able to progress to hepatocellular carcinoma without going through the cirrhosis stage, which is a very worrying landmark.
However, this is not being described so strongly in European countries, at least in non-Anglo-Saxon countries, and Southern Europe, for instance, Greece and Spain and Italy and France, is not so common, but in the States and the United Kingdom, it's almost 20 to 30% of cases of hepatocellular carcinoma occur in patients without cirrhosis. And last year…well, in 2020, when the pandemic was outbreaking, a group of experts proposed this definition, the new definition called metabolic dysfunction of cirrhospiratory liver disease, and the reason was that, okay, do we really need to use a liver biopsy to diagnose all these patients in such a prevalent disease? And the other thing is, we are diagnosing negatively this disease. Okay, non-alcoholic, this is part of the definition, but there are a lot of patients that do drink a little bit more than what we consider the harm from threshold, or people that have been drinking for several years before being diagnosed with NAFLD, and this is very common indeed.
Obese patients that also drink, let's say, a bottle of wine a day, so it's not enough alcohol to create a liver disease condition by itself, but the combination is very common, and for people that have been cured for hepatitis C, chronic hepatitis C, and then develop NAFLD, they also have metabolic dysfunction associated with liver disease, but have not a clear NAFLD. So they try to be more clinically comprehensive by proposing this disease, and this is the algorithm they propose. So if you are either overweight or obese, or have type 2 diabetes, and either have an ultrasound or a CT scan or alteration transaminase, or you have a biopsy, and therefore have a diagnosis of steatitis, you already might be considered to have a NAFLD.
And if you are lean or normal weight, you need to fulfill at least two of these criteria. As you can see, waist circumference, blood pressure, triglycerides, cholesterol, HIV, prediabetes, defined as either as post-load with both levels, or glycosylate, hemoglobin, coma, and high sensitivity to seroreactive protein. But this is not without constraints, it's not without controversy, and there's been a lot of discussion around this issue.
And in particular, there's, I think, two main barriers or two main criticisms that were reflecting. First of all, the drug pipeline for NAFLD has been defined with the NAFLD definition, so most all trials have been done with liver, biopsy, and NASH definition. And the second one, which is, I think, more interesting, is that we don't know the pathophysiology of NAFLD, meaning what happens if you mix two potential etiologies.
Is the natural history the same thing? Is the response to drug therapy or to lifestyle intervention the same thing? So this is still a work in progress. Let me just mention this study, which was the same using the Nankhain's code, that tried to see what is the overlap between the NAFLD and the MAFLD definitions, and whether the outcomes are the same thing for both. I suppose you know this code.
This is not very rich in liver data, so most of them do not have a Fibroscan or transient astrography, so it's not intended to study this specific disease, but it's been very commonly used to define NAFLD epidemiology. But what is interesting is that only 23.5% of cases did fulfill both MAFLD and NAFLD definitions, where only a part of the estiator is a big proportion of them. So it's not exactly the same, and as you can see, there's a lot of patients that do not fulfill just the NAFLD definition.
And what is more important is when you compare the outcomes, for instance, all-cause mortality, whereas when you did not fulfill the MAFLD definition, this was not associated to an increased risk of overall mortality. If you fulfill the MAFLD definition, this was statistically associated with death, both when it was without NAFLD or with NAFLD. So this is very preliminary data that was also validated for the degree of fibrosis in case of MAFLD.
And just let me say two words about fibrosis. This is the main predictor of poor outcomes in NASH, and this is because there's been one study after the other since 10 years to date that have proved by liver biopsy and noninvasive tests that those patients presenting more advanced liver fibrosis, and that normally means at least from stage two to stage four, which is considered cirrhosis, do present more complications. And this study by St. Allen College was published in New England late last year, and it in brief shows that both F3 and F4 stages are associated with all-cause mortality, hepatitis compensation, and hepatocellular risk.
So I mentioned noninvasive tests, so not only liver biopsy, and there's been a huge effort in order to, at least in the clinical setting, replace liver biopsy in order to identify a staging and treating this patient. And the most used tool is what we call FibroScan because it's the commercial name of the trans-enlistography for the liver, but it's also used in the spleen. And this can provide us both with the liver stiffness, meaning fibrosis, or the CAB, the control attenuation parameter, that provides an overall assessment of the degree of steatosis and how it's distributed through the liver.
And there are a bunch of different noninvasive serum-based scores, which are mostly used not to a stage, but to a screen at the primary care level. And this is the same thing. The FibroScan was mostly developed during the hepatitis C treatment era, and the metabolic scoring system was the equivalencies between the degree of fibrosis and the kilopascals that were found in the trans-enlistography, but it's not exactly the same in the case of NASH.
We might need to remember that if you find a patient with at least 8 kilopascals, you should rule out advanced fibrosis. Not let them go. Please talk to a liver specialist or continue the study.
So, Andrea, it's your turn. Thank you. Thank you.
Thank you very much. It might seem a little bit odd that we have mixed presentations, but we wanted to reflect the idea of collaboration and multidisciplinary approach by doing this. So now it's my turn in this first topic, and to speak about obesity and NAFLD.
Here you have just a picture of the link between the adipose tissue and the NAFLD, because we have a high amount of free fatty acids that will go directly to the liver and promote NAFLD, lipid accumulation in the liver. Then I'll explain in the next slide more the physiological mechanism, but I would like to reflect the link between the adipose tissue, the liver, and the glucose metabolism, because here in this very beautiful review, we see that NAFLD is a continuum from obesity to metabolic syndrome and diabetes. And in the next slide, we'll see the physiological mechanisms.
So please, on the next. This one has a lot of animation, so you'll just keep pressing the button. No, no, no.
Go back. Okay. So we have the environment, the genetic factors.
Then we'll have the increase in the adipose tissue that has a limited expandability. And then we have an increase in the free fatty acids. Oh, please.
Next. Then we'll have a dysfunctional adipose tissue, and the consequences of this dysfunctional adipose tissue will be an increase in the free fatty acids that will go to the liver and promote NAFLD. On the other hand, this dysfunctional adipose tissue will promote adipose tissue insulin resistance, ectopic fat, supplementary increase in free fatty acids, an increase in the visceral adipose tissue, decreased adiponectin, and increase in pro-inflammatory adipokines.
Then if we keep going, this NAFLD and this dysfunctional liver will promote an increase in the atherogenic dyslipidemia. Then if we keep going with the physiopathological mechanism, we'll reach to this fatty liver. Then we'll have a hepatic glucagon resistance that will have an impact on the amino acids metabolism.
Then we'll have the pancreas islet will detect this hepatic glucagon resistance and will increase the glucagon levels, supplementary. Then we'll have a hepatic insulin resistance with increasing glucose and gluconeogenesis. Next.
Then we'll have an impact on the beta cell function with endogenous hyperinsulinism, and this is how type 2 diabetes is promoted. Then the increase in the insulin levels will provoke an increase in sodium reabsorption and sympathetic nervous system activity, promoting hypertension. Then the increase in the visceral adipose tissue will promote central obesity.
And then we have settled the metabolic syndrome related to obesity and NAFLD. This is a brief summary. Then the point is that we have very clear when and whom to screen for complications if type 2 diabetes is present.
Now we screen for type 2 diabetes complications at the time of the diagnosis and annually after the first evaluation. Here you can see in these pictures that since 2019 we recommended to screen for NAFLD. I don't know if you agree with this, but the recommendation of the guidelines for diabetes management is that we should screen for NAFLD in patients with type 2 diabetes or prediabetes with elevated liver enzymes or fatty liver or ultrasound.
We have very clear when to screen for NAFLD if type 2 diabetes is associated, but if you can go to the next slide. Here you can see the clinical practice guidelines from the European Society of Liver, European Society of Diabetes and Obesity. Then I'll explain a little bit later in the third topic.
It seems that it is mandatory to screen for NAFLD in obesity, at least when we have insulin resistance associated. I think that it's time for action and to define more clearly the criteria and whom and how to screen for fatty liver disease. I think that's all for this topic.
We made short presentations just to give time for the discussion with everybody. I don't know, we will have the discussion in the end, after all the presentations or after each topic? What do you think? I would suggest after each topic. We have time to do them now.
If anybody would like to raise their hand, we can ask questions or you can pop them in the chat. I don't think I can see any questions in the chat just yet. If anybody does have any, please raise your hand or feel free to ask away.
So perhaps I can say something about your question. We actually do not screen for NAFLD when there's only either diabetes or obesity and abnormalities in the blood analysis. If you have any other metabolic risk factor and you have persistent or long-term adenine or transaminase or adenine transferase alterations, this may be worth a try to see whether there's any type of stiffness or at least inflammation in the liver, even if you are not obese.
First, because you can have a lean NAFLD. That's one possibility. It's not the majority of them, of course.
And the other thing is that there are NAFLD that are associated to drugs, for instance, methotrexate or other drugs for HIV or other. So, of course, if you have both diabetes and obesity, the risk to have a fatty liver that is at some point inflamed and may progress to NASH and cirrhosis increases exponentially. And the prevalence in the community of when both risk factors are present to have a fatty liver is at least 60%.
So, of course, both things. But I wouldn't say that this only needs to be done when you already have abnormalities in the liver test. Any other questions before we move on to the second speaker? Maybe one short question.
There are wonderful talks, both of you, I think, very relevant topic. I'm happy that you shared all your information. For the clinical practice, it's always very hard who is green and who is not.
Do you make use of these known algorithms? There are several algorithms making use, for example, of thrombocytes, also including the liver enzymes, but there are more algorithms. Do you use them in clinical practice and which would you recommend? Shall I answer, André? Yeah. Yeah.
So, yeah, in practical terms, although there's a lot of research being done, including us, what we do is use PIP4 in the primary care setting to screen as the first wave of screen when there are metabolic risk factors or when something is going wrong. Either you find steatosis in the liver through imaging and also have blood test abnormalities. So PIP4 is the first step.
You know that when, especially in diabetic patients, when you are in the grey zone between 1.3 and 2.7, 2.767, sorry, and particularly if you are over 65 years, this is not very accurate. So my recommendation would be, even if you have a PIP4 that is not normal, if it's in the grey zone and it's a diabetic patient, please refer them to a specialist or never to rule out liver fibrosis. But yeah, we use PIP4 ELF, FLI, Epameth score, Nafld, fibrosis score and others are there, but we don't usually use it so commonly in our communication with the primary care.
Yeah, thank you. That was what I meant. We have to choose between the FLI, the steatotest, Nafld, LFS to choose for research, to choose for clinical practice, they all have pros and cons.
So I was wondering what you were using for practice and for research. There's no optimal choice, you need the gold standard still. Okay, thank you.
Thank you. And we've got, Bridges raised his hand, so would you like to ask your question? Yeah, so my question is, how does changing the terminology from Nafld to Mafld make any difference in the understanding of this disease or in the clinical implications in terms of management? Do you want to go, Andrea? Yeah, no, no, no, it's your field of expertise. No, I mean, in the outpatient clinics, there's currently no difference, unless you need to make the patient to also remove other etiologies, either because they have an Epsi not treated, but then you are not talking so much about a pure Mafld, because probably the inflammation due to hepatitis is more important than the one induced by metabolic factors, but alcohol consumption should be discontinued, of course, and then lifestyle changes.
But what is important is that these patients, if sometime soon we have some approved drugs for NASH, might not be treated with these drugs if they do not fulfill the standard non-alcoholic definition. So that's what concerns us as liver specialists, because there's probably the combination of both risk factors, alcohol and metabolic risk factors, is the most common phenotype we find in the clinical practice. So a huge proportion of the patient might be out of indication for drugs, because we use drugs indicated for diabetes or weight loss, such as GLPA1 agonist, SGLT2 in collaboration with Andrea's group, they are the ones mostly prescribed on them.
But when you need to put someone in a clinical trial, you are not allowed, at least for a while. So that's the reality now. We can do something for them, but I hope we can change definitions to include them in clinical trials so the drugs are approved for them as well in the near future.
I hope I have answered your question properly. Yeah, I think there is still a lot of overlap, you know, despite we considering alcohol intake, not exactly to what level a person is taking. A lot of people who take only maybe twice a week, would you consider them as alcoholic liver disease or would you consider them as metabolic associated? No, metabolic associated, of course.
So ultimately, the clinical management moves in the same direction, whether we put this as non-alcoholic fatty liver disease or as metabolic associated fatty liver disease. And as you mentioned, you know, we have to work more with the clinical judgment rather than biopsy and further interventions. So most of the people just finding fat in the liver would be, you know, good enough to manage them on the lines of MAFLD or NAFLD, whatever you label it.
I agree. Thank you. So, guys, is the definition now, is that now official through the EASL? Is that the transition now from M to M? No, actually not, because the most recent guidelines, which are the ones providing guidance on the use of non-invasive tests to diagnose several chronic liver disease, did not use MAFLD as the category, but NAFLD still.
So even though there's been an advancement, a recent advancement, because it was published in National Anthropology, a joint consensus by the American Association for the Study of the Liver and EASL, the European Association, it's not yet widely used. No, it's not official. OK, great, thank you.
We'll be coming back to you two after the second speaker. So any other questions that we have, we can, you know, we can pick up with those at the end. So I'd now like to pass the floor to our second speaker, Paolo.
Thank you very much for joining us. So Paolo is a Doctor of Medicine, PhD professor at the Internal Medicine at the University of Rome. He is the chief of the comm centre there, and he is also serving as president of the Italian Federation of Endocrinology, Diabetology, Andrology, Metabolism and Obesity.
And he's also treasurer of the EASL Executive Committee. So welcome, the floor is yours. If I've missed anything off your title, please let me know.
No, not at all, Cathy, and it is also too much. So good afternoon to everybody. It's a pleasure to share with you some of the data I will present in my talk.
And also, I'd like to say that as a smooth transition from pathogenesis and definition and treatment, I just provocatively present some very few slides, again, on the NAFLD versus MAFLD. One thing I don't like, but I think nobody likes, is the N, the negation. That is, that you need to use it when you really don't know what this is, and you know only what it is not.
So you will remember the old definition of type 2 diabetes, non-insulin dependent diabetes, mellitus, and of course, the one we are talking about right now. I think they share a lot, and the transition from NIDDM to type 2 really did not solve the conundrum of the pathogenesis that I think, however, is now quite clear. This is an obvious slide, and as a matter of fact, you really can understand that both obesity and type 2 diabetes, they share a lot metabolically, have an extremely high prevalence of NAFLD.
And it is now clear that, as Andrea already pointed out very well, that the surplus energy calories that enter the portal vein, especially fructose, free fatty acids, especially saturated fats, undergoes all the metabolic pathway that end up with the accumulation of extra fat. And this is something that characterizes steatosis. And somehow, exceptionally, I would say, compared to the high number of the obesity-related steatosis, are due to this.
And this is the reason why, at a certain point, the N has been proposed to be changing N. I would personally like, but this is too much, I know, to go into an all-obesity-associated fatty liver disease, because I'm pretty much convinced that this is the real cause, a chronic positive energy balance. And this is the same reason why I would talk, instead of type 2 diabetes, of adiposity-based diabetes. 90% or more of the vast majority are based on chronic positive energy balance.
And also, as we saw for the NAFLD, there is an exception of truly lean individuals, that has MODY, LADA, pancreatopathies, and etc. Now, let's turn on treatment, but the first thing that is important to underscore is the fact that currently there are no approved therapies for NAFLD. However, there are emerging therapies, and the pipelines are quite rich.
I took this table for a recently published review, and I would like, not extensively, to show some data related to the major targets here, that are the fibroblast growth factor, the farnesoid receptor, the PPR, and the thyroid hormone receptor agonist. In the first part, I will show some data, just to have a view of what these therapies can do in terms of efficacy. Then, in the second part or so of my talk, I will talk about weight loss, and in this regard, also of drugs that act by inducing weight loss, and possibly acting also with weight loss-independent mechanisms.
Let's see the first treatment that I'm going to show. This is a PEG-related FGF21 analog, the PEG-belfermin, that has been shown to reduce, in a nice fashion, the hepatic fat content. You can see this is a representative patient, and also you can see the placebo in the bars right here, and the percentage of reduction in terms of fat.
In the next slides, you'll see that some trials have, as primary outcome, the reduction of liver fat. But other trials, instead, are more powerful because they perform liver biopsy, and therefore the outcomes are those related to the combined improvement of mesh without worsening of fibrosis, or improvement in fibrosis without worsening of mesh. Obetic folic acid is a very interesting agent.
It is an FXR agonist. These are data of a phase three study, and it is exactly what I was saying. You'll see on top the improvement in fibrosis obtained by the two doses of obetic folic acid, 10 and 25 mg, and you'll see that there is a nice increase in percentage of patients that reach the improvement in fibrosis without the worsening in mesh.
These are data related to the intention to treat population versus the protocol population that is more related to the on-treatment patients, and so you'll see that the panel on the right have higher numbers here, 28% versus 23%. It is more tough to have mesh resolution with no worsening of fibrosis, but in any case, 14% of patients is not a bad number. Chilofexor is a non-steroidal FXR agonist, and this is a phase two study.
All these data, as you see, are quite recently published, and this, again, is the measurement of the reduction in liver fat. These are the percentage of patients that reach a percentage of reduction of more than 30%, so one third of patients obtain one third of reduction in liver fat at week 12, and these numbers increase a little bit further after doubling of the period of study. Certainly, another very interesting target is paroxysm proliferator activated receptor.
We all remember the data about pioglitazone. Lanifibranor is a PAM PPR, and as a matter of fact, it also shares some of the side effects that we now know very well about pioglitazone, and this is also a trial with histology, therefore with liver biopsy, and you'll see that the primary endpoint, that is, the reduction of more than two points of the SAF score that measured the fibrosis in the arms treated with a higher dose of lanifibranor is better, significantly better. And then the various secondary endpoints that are always related by the interrelation of improvement in NASH without worsening in fibrosis are certainly of interest.
And then the data related to resmetiron, that is a thyroid hormone receptor beta agonist. So we don't need to underscore the mechanism of action, that is, that related to a drug which do not interact with the typical pathways that gives, you know, upper thyroid symptoms. This is a representation of one of the patients in which there was a progressive clearance of the liver steatosis by week 36, and in the top panel, you see the relative reduction of fat, and certainly the reduction are definitely quite interesting.
Well, let's turn now on weight loss intervention. If we agree that the vast majority of patients develop MAFLD because of chronic positive energy balance, and I would like also to underscore the fact that in the slide that has been presented by Juan, in which, in the recent guidelines, there is the lean individuals that are those with BMI below 25, but those are not truly lean, because in fact, true lean individuals with an increased waist circumference, or other metabolically altered values that are typical of the metabolic syndrome of person that are in positive chronic energy balance. These are data of the group of Sam Klein at the Washington University in St. Louis, published a couple of years ago, is a very clean and elegant study.
You see here the contribution of the novel lipogenesis, which is the key pathway that determines the steatosis, and you see that the contribution is proportionally higher when you move from lean obese and obese with MAFLD. And again, these black circles contribute linearly with a significant correlation between the intrahepatic triglyceride content and the novel lipogenesis. Well, if you induce a weight loss in these patients, there was a significant reduction in both the percentage of triglyceride-rich lipoprotein TG palmitate that contributed to the novel lipogenesis and the intrahepatic triglyceride.
So, with metabolic data, elegant metabolic data, it is clear that weight loss translates in an improvement as weight gain determines a worsening of the hepatic steatosis. This is an interesting study, a little bit old, published in Gastroenterology. Liver biopsies were performed.
And this slide tells us that in order to gain the most of improvement, you need to go to weight loss that are greater than 10%. In fact, in those who reach a weight loss greater than 10%, there was 81% of patients in which the liver fibrosis regressed and a small percentage in which stabilized and there was no worsening whatsoever. So, I think this is very indicative data.
And certainly, having said that, if we look at the data of patients who underwent bariatric surgery, the data are really impressive. If you look at those patients then that reduced the BMI of 10 points, so going from 45 to 35, for example, well, the resolution of NASH was of 90%. And the evolution of fibrosis, if you look at the white part of the bars, that is zero fibrosis increase over a period of five years.
So, again, if MFLD is due to obesity or even to a normal weight according to BMI, but with increased waist circumference, these of course are bariatric surgery, so we are talking about obesity or severe obesity patients. But in any case, the indications are clear that you are able to reverse the situation at the level of the liver. And as a matter of fact, if you look at the prospective data and therefore the cumulative incidence of adverse liver outcomes, you'll see that those patients who underwent bariatric surgery had a reduction of about 90% of esophageal viruses, ascites, hepatic encephalopathy, or histological cirrhosis, hepatocellular carcinoma, liver transplantation, and so on.
GLP-1 receptor agonist. This, of course, is a field of extreme interest because we have drugs and we expect others to come that act in this way, improving type 2 diabetes, reducing body weight. And as you will see, acting at the liver level.
These are data related to this trial called LEAN published seven years ago, so this is an old study. In this study, liver biopsies were performed. This slide showed the values of transaminases, and you see that in blue are the liraglutide R, in which there was quite, not huge, but quite enough difference in terms of reduction of transaminases.
And if we look at the data, this is not a huge score, and it's also important to remember that the LEAN trial was done at 1.8 mg of liraglutide daily and not 3 mg, that is the dosage used for weight, for obesity. And you'll see that in terms of hepatocyte ballooning score and steatosis, there was a change from baseline that was significantly higher in the arms with liraglutide. These are data with dulaglutide, and this is just liver fat, there is a small reduction in type 2 diabetes, however, and it is also related to patients in which lifestyle were added.
Let's turn now to semaglutide. These were data recently published. This is a trial which included liver biopsies.
These are the data of transaminases that now, I would say, are much, much, much more interesting in terms of the progressive reduction during the 72 weeks of the trial, especially at the 0.4 mg per day, that is, somehow, we can match it with the 2.4 mg per week, more or less. And these are the data of the liver biopsy that enable to show the numbers related to the primary outcomes that are resolution of NASH with no worsening of liver fibrosis. And you'll see that almost 60% of patients at the higher doses of SEMA obtained the resolution of NASH.
A little bit less powerful is the improvement in liver fibrosis with no worsening of NASH, and at the higher dosage, there were 43% that, however, were not terribly, although significantly different from the placebo that I have to remember, in any case, underwent the lifestyle changes. Very recently, on hepatology, it was published this big meta-analysis review, which included GLP-1, which include PPR agonist, GLP-1 receptor agonist, SGLT2 inhibitor for treatment of NAFLD, and you'll see that pyroglutazole, anifibranol, GLP-1 receptor agonist, mostly Lira and SEMA, improved individual histological feature of NASH or achieved resolution of NASH without worsening of fibrosis, SGLT2 inhibitor, mostly empagliflozin and apagliflozin, reduced liver fat content as assessed by magnetic resonance-based techniques. Yes, this is probably the last slide, just to recall that certainly microbiota might have a role in all this hepatic scenario, also interacting with the immune system that modulates the immune response.
So, this is the inflammation that characterized NASH, and therefore there is space for probiotics to see whether they would be able to act efficaciously in reversing steatosis. Well, so let's go through the take-home message. Number one, I think it's useless to mention, you are all well aware of these tremendous numbers.
Weight loss, it is really the key. When it's higher than 10%, it is able to induce fibrosis regression, and this I think is very, very important. There are no approved therapies for NASH.
FGF19 and 21, FXR, PPR, thyroid hormone receptor agonist, gut microbiota, and some others are promising targets for effective treatment of NASH. Post-bariatric with more than 10 points reduction of BMI is able to induce greater than 90% resolution of NASH with a long-term regression of fibrosis, and SEMA at a higher dosage leads to NASH resolution in up to 60% of patients. And thank you for your attention.
Fabulous. Very interesting. Thank you very much.
Are there any questions before we press on for the last presentation? Anybody like to ask anything to Paolo there? I see many faces, but I want to say hi to Ada. Hello, my friend. Nice to meet you.
Hello, Ada. Yes. Nice to see you.
Great talk. I hope to see you. When I look at me in the queue, it seems that I am your grandfather.
No, absolutely not. My great friend. I want to see you very soon.
I really hope that we can see somehow. Yeah, I hope so. Thank you, Paolo.
Thank you, Ada. Andrea, I can see you've raised your hand. Would you like to go ahead with your question? Yes, I would like to make a comment and to ask a question.
You talked about the beneficial effect of the weight loss and the bariatric surgery and significant weight loss on the NASH outcomes. But do you have experience or do you know any data on what happens with the patients that lose weight and then significantly regain weight and had previous NASH? You know, because in the NASH development, now we are speaking about the two hit theory. Could the weight regain be the third hit and provoke a worsening of the regression of NASH? This is a very important issue, very delicate issue, because we all have to remember, as Juan probably mentioned, that NAFLD or MAFLD is characterized by the tremendous possibility to develop a protocellular carcinoma in the early stages as compared to hepatitis C, cirrhosis, etc.
And therefore, yes, I think we should really look at this data. I'm not aware of strong data that can tell this, but I have a bit of experience of those that after bariatric surgery regain weight and certainly the steatosis return. But I have the impression that, in fact, in terms of clinical indicators, have not performed any biopsies, that they did worse than before.
But at the moment, I'm not aware of strong data that can tell us that this might be a third hit. Thank you. You confirmed our impression also in the clinic that when they have NASH once again after the gaining weight, it's worse than before.
Probably. It's mandatory to run a trial to look carefully at these possibilities. Yeah.
Great. Thank you. And Brij, your question? Yes.
Paolo, wonderful presentation. Just wanted to make a comment and have your view also on that. Recently, we saw wonderful data on weight loss with lifestyle interventions in the direct trial from Roy Taylor from Scotland.
And that trial also showed that once people were losing about 15% weight, then these MR spectroscopy studies showed that there was decongestion of fat from liver as well as pancreas. And possibly that led to reversal of the whole cycle and remission of diabetes. So normally, you know, we talk about lifestyle interventions, but the focus on that is limited.
What is your take on this? Well, thank you, Brij. Well, I am a fan of Roy Taylor. So am I. Yeah, yeah, yeah.
He did impressive, truly elegant observational studies before running the direct. And I think that these are really, you know, very, very important data. Yes, he also published a beautiful paper on cell metabolism after the direct in order to look at the outcomes in the responders versus the non-responders, because certainly there was a part of the cohort that did not really reach the same weight loss of the good responders.
But again, I found that everything goes in line to what I believe and what I taught during my first part of the presentation, that most of the metabolic abnormalities are driven by the surplus of energy that goes ectopically in many parts, pancreas and liver. And therefore, again, I think this is important. Now, if we want to couple these considerations to what Andrea asked before, and so if even in lifestyle weight loss with very low calorie diet, and unfortunately with the regain, this can have a third hit, I really do not know.
But again, I think that the direct data give us more information and more proof of principle that the NAP will be as strong metabolic and food and yes. So another important thing you highlighted was that there are people who have normal BMI, but excess body fats are the typical profile which is labeled as metabolically unhealthy normal weight individuals. There, you know, always a question that weight loss is important or no.
So just wanted to add my personal observations because we do a decent number of obese individuals management. And in India, the typical population is of the metabolically obese normal weight phenotype. The cutoff for Indian obesity, the normal BMI is considered less than 23, 23 to 25 we take as overweight and more than 25 we take as obese.
And I have quite a few persons who had BMI less than 25, developed type 2 diabetes. We didn't go for the MRI for them, but on ultrasound, these people had fat in the liver. We put them on aggressive lifestyle intervention.
So even with 5-7% weight loss, these people went into remission. Sure, this is this is another topic of great interest. I would like just to underscore another concept that in which I believe somehow, then those male, especially individuals that you are describing very often have a sort clinically and might be who knows genetically, have a sort of lipodystrophy of the subcutaneous tissue, they tend to have, you know, thin legs and arm, and they are at increased risk of developing type 2 diabetes early compared to some with higher BMI that has a good subcutaneous tissue.
So we label this as one of the variants of sarcopenic obesity also. Yes. Thank you.
Thank you very much. Lovely. Right.
Well, if there aren't any further questions, then we'll move on to the final presentation. We're going back to Andrea and Juan. But if anybody does think of anything in the meantime, please feel free to use the chat function and we can pick up any further questions at the end.
So back to you, Andrea. Thank you. So, we have a short presentation based on the implications of nutritional and clinical practice.
And we have two clinical cases to discuss that we thought that are interesting. Can you see the presentation in full screen? Okay, so we have presented ourselves before. And I spoke before about these clinical practice guidelines.
And just here with this slide, I want to highlight that, as was mentioned before, unhealthy lifestyles play a role in the development and progression of NAFLD and is mandatory to assess the dietary and physical activity habits as part of comprehensive NAFLD screening. We saw whom we have to screen for NAFLD in people with obesity. And these clinical practice guidelines also make a recommendation for a lifestyle changes approach for the treatment of NAFLD.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food. So, for example, if you have a diet that is not healthy for you, then you have to eat healthy food.
Thank you. So, we presented two cases, one with a very, very good liver outcome after losing weight with a low-carb diet, and the second case that despite of a massive weight loss in six months did not improve significantly, especially the fibroids. I put here these pictures too much, too fast, won't last, because my next slide refers to another doubt that we have in the clinical practice, that losing weight too rapidly could have a negative impact on the NAFLD and NASH.
And here we have an example, it's true that it's a paper including females that underwent bariatric surgery, and they underwent jejunal bypass, which is highly malabsorptive, and now is contraindicated due to severe adverse effects, but these women presented rapid and significant weight loss and presented acute liver injury. The point is, and the question is, whether or not very rapid weight loss in a short period of time could have a negative impact on the fibrosis and histological changes in NASH. It seems that, according to this paper in the review, that you can have an acute liver injury and also functional changes at the sinusoid levels, and that could have an influence, and this might be one explanation of the reasons why our second case did not show the expected improvement in the liver parameters.
In conclusion, and this is the last slide, the management of NAFLD, we think that should be multidisciplinary. Yes, you have to lose weight, but not too quick and in a safe way, and the teamwork is needed and we are all pieces of the same mechanisms in this disease. So this is all from our side, and the floor is open for discussion and you can say whatever you like and discuss on the cases that we presented here.
Lovely. Thank you so much, Andrea and Juan. It looks like we go back to Paolo for the first question, please.
Well, thank you very much, Andrea and Juan, for these very interesting cases. I just want to comment on the very last cases and slide, because what I think is that irrespective of the likely possibility that a very low-calorie diet stimulates ketogenesis, but in any case stimulates lipolysis, and therefore you somehow go from a high FFA influx from a chronic positive energy balance, and then you go into an increased lipid flux from increased lipolysis, so probably this is the situation when you go from one extreme to the other one. I don't know, what do you think? Actually, we didn't recommend the ketogenic diet, but with 20% of carb content, which is low-carb, almost ketogenic diet, in order to avoid the negative effects at medium and long term of the ketogenic diet.
Great. Thank you. And Eiza has a question.
Yes. Thank you to all of you for the great presentation. Regarding to the clinical case I want to ask you, in the second patient, do you think that the race, because he was a Lyman from Ecuador, you mentioned, is it possible that some genetic factor will influence the worst response, in addition to the very rapid weight loss? I'll just leave the answer to the hepatologist, please.
I don't know why, because I'm sure you have a better answer than I do. I think it's likely. Actually, we performed the polymorphisms and were negative, but we did so with serum before the change.
Since PMPL3 is located in the surface of the lipid droplets, when a huge lipolysis is performed, it's been described that the test to detect the polymorphisms might be altered. So I don't know if he really carries any polymorphisms that might have predisposed to that. And of course, there's another limitation, that liver biopsy only goes through a slice of the liver, and the liver is heterogeneous in its inflammation and fibrosis.
But the point here is that if you lose a lot of fat, since he had a very high cap, you leave room for fibrosis as well. So when the inflammation changes very quickly, you might not achieve this point of trying to slow down fibrosis and even regress a little bit. And of course, there are a lot of different potential aspects that might have influenced this point, and genetic background is one of them.
But I think in this case, epigenetics that changed his life, he was very stressed, he really entered a catabolism situation, not sleeping well, a lot of family issues because he went from being a happy, fatty boy all day partying to a very strict, almost Spartan guy and having a lot of issues. So I think the inflammation did not improve so much at the end of the day. My question is because, do you have some data regarding the worst response in people from South America, independent of the treatment? I'm not sure if there is some data with drugs like GLP-1 agonist comparing the result between different people from different race or ethnicity.
I don't know if you have some information about that. That's a very good question. Giovanni Targer just published a review on the potential use of GLP-1 agonist and ISGL2 inhibitors in Nathalie, but trials are just underway.
And unfortunately, global trials do not usually include many patients from South America. There are some sites in Chile and some sites in Mexico, some sites in Argentina, but it's a very few, small part of the trial population. So some analysis are not very good.
There are some trials in Hong Kong, but it's not the same thing. We have a population selection bias, as in many other cases of clinical trials, but this is a very good question. Thanks.
Okay, great. Any final questions from anybody? Anything anybody would like to ask before we close today's session? No? Okay. Well, thank you so much to our three fabulous speakers.
It's been another great session. The next session will be on the 26th of April, and that's going to be on rare genetic obesities. And then the following session after that will be at the end of May, and we'll look at our energy balance and body weight.
So like I said before, if anybody would like to present or has anybody in their centre that would like to present at future webinars, please contact me. My details are in the chat. But if not, I will leave you all to a lovely evening.
And thanks again for joining us. And we look forward to much more collaboration with the comms going forward. So thank you very much and good evening.
Thank you very much to all. Thank you. Bye bye.