Dr Micheal Tadros on GLP-1 Agonists in Gastroenterology

Dr Brian Lacy hosts Dr Micheal Tadros in a discussion of the increasing use of glucagon-like receptor 1 agonists and how use of these drugs can affect the gastro intestinal system for positively and negatively.

Brian Lacy, MD, is a professor of medicine at Mayo Clinic-Florida in Jacksonville, Florida. Micheal Tadros, MD, is a gastroenterologist at Albany Med Health System in Albany, New York.

TRANSCRIPT:

Welcome to Gut Check, a podcast from the Gastroenterology Learning network. My name

is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today to Dr. Michael Tadros, a gastroenterologist at Albany Med Health System in Albany, New York. Our topic today is one that is of great interest to providers of every specialty and to patients as well: GLP -1 agonists, and how they affect gastroenterology practice.

Dr. Tadros, thank you for joining this podcast today. Let's begin simply in order to set the stage for our listeners. What are GLP -1 agonists and how do they work? And before you launch into that, for some of our listeners who may not be aware of all the GLP -1 agonists available, includes semaglutide, which is oftentimes called Ozempic or Wegovy; exenatide, which is called Byetta; dulaglutide, called Trulicity; liraglutide, called Victoza; and tirzepatide, called Mounjaro.

Dr Tadros; First, thank you so much for having me. It's a great honor to be with you and to be invited for this podcast. So this is a very hot topic. A lot of people are taking this medicine right now for weight loss or diabetes and as providers we see a lot of patients on those drugs and they come to us for endoscopy or colonoscopy or various other reasons, so we need to be familiar with those drugs.

They are on the rise, you hear about them on commercials everywhere. It's a very beneficial drug for certain group of patients, so they are around and I get the feeling that their use is going to increase over the next decades. So we need to be very familiar with them because we either might be prescribing them or managing the side effects of them, or we're going to have to do endoscopy or colonoscopy or various other procedures for those patients.

This is a hot topic. And if you look at the application in just the GI literature, it has been expanding or exploding in the last year with lots of articles, lots of meta-analyses coming out. I hope today I can give a little bit of education to our listeners and get them familiar with those drugs.

Dr Lacy: Wonderful. And I like your point that in terms of scientific citations and references, the field is exploding. And kind of following up on that, there's a lot of new information about these agents and there's a lot of excitement and discussion. But are these agents really new, right? Haven't they been around awhile? When were they first approved?

Dr Tadros: So they are not new. They have been used for diabetes since 2005. So the drugs have been around for 20 years. But their use start for weight loss is what makes them very popular. And that started in the 2015, the first study about their use on weight loss in the SCALE study. But what really made them become more popular with a study that came out called the STEP study for semaglutide and I just checked and I think more than 10 articles in the step—step one, step two, step three—for their use.

So their use is expanding. But what that article found is about once a weekly dose of semaglutide can cause up to 14.9 or 15% weight loss, which is great. And that added a lot of healthy benefit from them. Not only use in diabetes, but for weight loss and any obesity related complication, they have been used. The biggest hurdle in expansion of their use is the insurance coverage for those medications, but their use is expanding. And I think they benefit a lot of patients. If you look at those studies, they have cardioprotective benefits; you know, you lower the blood pressure, they improve the lipid profile. And just last week, another study that came out for their use in fatty liver, which was a big deal because it actually resolves or reduces steatohepatitis in patients with stage 2 or stage 3 fibrosis. So their use is really expanding.

A couple of years ago, there was the SURMOUNT study for another class of the drugs like Zepbound and that also showed great benefit in weight loss up to 20% and there's had to have the studies trying to compare both drugs which you want work better but their use is exploding and we're going to end their benefit also they are very superficial. I just had this discussion with another doctor, “well, we don't know about the long-term side effects of those drugs,” but my point with this was with my colleague I was discussing with him was what is the benefit if you prevent a diabetes, if someone has hypertension for long term.

So although we don't have long-term data for their use, especially in weight loss, but it's always risk and benefit. We didn't have any option for steatohepatitis for our patients except try to lose weight, which we know is very hard for people to lose weight on their own. So now we can actually have a drug to reverse the side effects or the disease complication is really great. So we're going to see them and we're probably going to be prescribing them as a gastroenterologist as well.

Dr Lacy: Wonderful, wow. You hit on so many amazing teaching points. I'm just going to kind of encapsulate that and recap that a little bit. It's one, you know, we try to stick to the rules and use medications approved for the FDA indications. And you mentioned that's

for diabetes and also for obesity. And then you mentioned the STEP study and also other studies including the SCALE and SURMOUNT studies showing that weight loss is much better than diet and exercise in prior studies at 15 to 20%, which is really remarkable. And then you kind of touched on the topic of using these medications for other indications other than diabetes and obesity and I'm going to come back to that in a little bit.

Let's focus right now on GI issues related to these GLP1 agonists. What are some of the most common side effects of these agents?

Dr Tadros: So these agents cause significant amount of side effect because how do you work? So basically my first experience with these when the drug started to be used and I started to get referral from patients with various GI complaints— worsening reflux, dyspepsia, nausea, vomiting, diarrhea.

Their side effect profile in term of the GI system can be up to 5 to 20% and about 10% of patient might stop the medication because of the GI side effects. GLP-1 receptor agonists basically cause in the stomach some degree of gastroparesis or lazy stomach. So that will cause worsening reflux or the nausea or the bloating and those side effects are usually at higher doses of the weekly injection or also during the escalation phase, like those drugs you don't give the maximum dose immediately you have to build your way in the dose so as the more dose goes up, the side effects will go up. Some patients cannot tolerate the higher dose and we have as we are going to see some of this referral to us for the GI side effect because their benefit — we don't really want to stop the medication that has so much benefit if we can effectively manage those side effects.

Dr Lacy: So those are great teaching points. So one, for listeners today, we're all comfortable with the term of GLP1 agonist, but that GLP stands for glucagon-like peptide, although everybody just says GLP1 agonist. And then you've mentioned these side effects of nausea and vomiting and dyspepsia and worsening reflux and constipation and diarrhea. You also mentioned this kind of the risk-benefit that people may have these side effects, but they may benefit. So, how do you get through that in clinic? Do you just say, "Gosh, Mrs. Jones, you're having nausea and vomiting, just stop the drug?" Or do you say, "Boy, you're having these side effects, but you've lost weight or your diabetes is better controlled. Let's work around that.” What's your strategy?

Dr Tadros: I forgot to mention one thing—some other GI side effects because of the weight loss or rapid weight loss or some degree of malabsorption. So they also can cause gall bladder sludge or cholecystitis. They can also cause pancreatitis. Some of the drugs can also cause ileus. So when we see these patients, we have to see if this is more symptom management or a significant side effect that we have to look for, like someone developed gall stones or some salisette. So we have to look at those patients and actually if you look at some of the studies for weight loss, when those drugs were doing some people were doing elective cholecystectomy before starting those patients on the on the medication. So there's a lot of things that you have to learn about those drugs.

But in general, I liked one of the articles which say the 3E approach: first is education, then escalation, and effective management. So I can tell you one experience of one of my patients who's taking these drugs and was having severe symptoms so I went through what his diet is, so he's still eating his cheeseburger, his hot dogs, all of this heavy fatty meal, so I said I wonder why you have side effects. So my first step was to educate those patients it's still like diet and exercise is important, portion control, avoid heavy fatty meals. And once patient do this stuff, they can get better.

And another factor that's very important is hydration. Drinking a lot of water while taking those drugs. Some people advocate for high protein diet when you are on those medications just to try to avoid the fat. So, and a lot of insurance company actually requires a patient to be in a weight loss program. You know, not only to depend on the drug, but to be on a weight loss program.

So first step is education. Explain to the patient that this is going to cause some degree of lazy stomach, so you can't really have these fatty meals and if you might have gallstones, also avoid fatty meals, so all of this education is one of the most important steps.

Second is dose escalation. You can go up, but the patient cannot tolerate it from the side effect. Some providers will cut down the dose a little bit, it gives the patient some time to adapt to the drug. So it is not one dose fits all or escalation program but you follow up the patients like those drugs really requires that you follow up before the escalation of the drug especially in the higher dose when you are near the maximum dose of the drug. You really have to take the escalation carefully.

And the last step is effective management. Some patients might require an increase indication for reflux or antiemetic or fiber intake or management of the underlying constipation with whatever regimen you would like to do.

But also it's important to look at what other differential diagnosis. Maybe we're missing a pancreatitis; there are some animal studies that shows that those drugs cause pancreatitis. The incidence is low, but it's still part of the differential diagnosis, you know. The drugs are very useful for certain patients, so we hope and try to manage those side effects.

Dr Lacy: Great. I love your 3E approach. Maybe we could even make a 4E and add the concept of expectation, so if patients know that they might encounter some of these side effects at low doses, then they're prepared for it. Usually, they do better. That's great.

You mentioned at start that you know how these GLP -1 agonists affect the GI tract and let's think about our patients coming to the endoscopy suite. What's the impact of GLP -1 agonists on upper endoscopy?

Dr Tadros: So the studies are variables and the biggest risk we as a GI doctor with concern is some sort of delayed digastric emptying and is there going to be food in the stomach and if the patient is going to have an aspiration event or I have to be rushed just through the scope or I end up terminating the upper endoscopy. So that's the biggest risk.

So just in February a few months ago there were multiple meta-analyses that were published and they all had the same finding. It increases the risk of retained gastric content by older show from 5 to 15; it's variable but it's significant number that you have increased the gastric residual.

So that's something you might be expecting and you have to manage and we are the GI doctors, we are trained and know how to go to manage when someone has food in the stomach. We deal with a lot of gastroparesis. In term of aspiration event the meta-analysis didn't find increased risk of aspiration but there are some individual studies that show there is some aspiration event and if it's you and you have one patient who ended up with aspiration event it's going to be a big event for you and your patient. So this is something that we have to be aware of, that there is delay, there is delay in the gastric emptying. There is retained gastric content. We may have to terminate the procedure, and in some cases, even meta-analysis didn't show it, there is still risk of aspiration, and we have to be ready for it.

Dr Lacy: That's wonderful. Let's shift gears a little bit and think about screening colonoscopies. GI providers do a lot of colonoscopies for either diagnostic reasons or therapeutic reasons. What do you do about that patient with the GLP -1 agonist and how does it affect the colonoscopy?

Dr Tadros: So again, multiple meta-analysis came, there’s two of them published in the last few months. One did not show that there is increased risk of inadequate bowel prep, but another one showed. I think the number of studies and post meta-analysis was small, like about 6 studies, so I think we have like—if you go to all of the conferences there's multiple studies coming out so we're going to have a larger pool of studies and we can get better answer but as for now there's some new studies that just came out and they show like the rate of incomplete colonoscopy or inadequate colonoscopy or the need to repeat colonoscopy is slightly or modestly high. So we have to be aware of those side effects. And even after adjusting for comorbidities like for diabetes, constipation, or adjusting for the other variables, they still can cause a higher rate of inadequate bowel prep. So the least you can do is educate this patient. You need to be strict in the bowel prep. You need to follow the bowel prep instructions. And if you're concerned about your patient, whatever your practice does for effective bowel regimen, use extra medication or extra clear liquid diet.

I would like to point out to one of the meta -analysis findings— that they find when you do endoscopy and colonoscopy together, because you put the patient on liquid diet, there was less risk of retained gastric content in those patients. So the fact that you put this patient on liquid diet might be helpful for endoscopy and the colonoscopy. So you might consider putting your patient on a 2-day liquid diet if they can tolerate it. So the fact, like if I'm doing an upper endoscopy on this patient, I will probably do it during the same time as colonoscopy because there is less risk of aspiration in that case based on one of the meta -analysis that was published recently.

Dr Lacy: You highlighted this controversial area so very nicely and we all understand that the patients coming to see us are different, some have diabetes, some don't. Some have comorbid disorders. Some may even be on opioids. And we know that we have a variety of different medications being used, these GLP -1 agonists, and at different doses. And so you could imagine how these study results could all be different. So this is a hard question because, you know, we all like black and white answers and we know the world isn't like that. But when you think about your patients coming in now, are you making a specific recommendation for colonoscopy, as an example, like all of your patients should go on clear liquids and stop their medicine a day in advance or a week in advance, or what do you recommend?

Dr Tadros: So I would tell you first what the society says and what the recent article said. So that the American Anesthesiology association was very blunt. You need to stop those drugs. You know, if It's a weekly dose, you have to stop it for a week or two. If it's a daily dose, you just have to stop it. In a combined statement in 2023, the GI societies in general said there's not enough evidence to make us stop those medications, okay? We obviously work with our anesthesiologist colleague and usually it's a team approach or individual approach.

So I really like this article that came in Clinical Gastroenterology and Hematology last year and which you say it should be more individual approach—you know, look at the risk of this patient of having an aspiration event so if the patient is still in escalation phase or he's on the higher dose or he is on the weekly dose or—I think this is more important—if you're having symptoms of nausea and vomiting, especially if they're vomiting food, then they're likely to have retained gastric content. These are the patients that are higher, and obviously, if you have other comorbidities like diabetes or something else that makes them at risk of aspiration, then these are the patients that are higher risk for an aspiration event.

So I would recommend for this patient to stop the drug and hold the drug before the procedure. If they are a daily dose, at least a day on their weekly dose, I try to schedule them towards the end of the of the last dose. So that's easier for them to because some patients forget to stop it. So at least I tell them, skip one dose and come for the procedure. That's my approach to easier for them.

But if the patient is it doesn't have GI symptoms and he's a low doze and he's stable and he's doing fine, then you might not need to stop them. But in reality those patients end up in our endoscopy suite whether through open access or they might have started the drug between the time we have seen them and they come to us for the endoscopy.

So you have to you have to work with your anesthesiologist when they come to you, you know. If they are really high risk of aspiration. Some option is to do a gastric ultrasound and look if there is stomach content, and the more urgent procedures then you probably need to do the endoscopy with full aspiration or full stomach precautions. So there is no really right answer. But individualized approach working with your anesthesia, understanding the risk of aspiration, I think that's more important for us.

And although there's no good evidence for it, but we have our medications as old friends, the regulars, if we need to use it, to decrease the risk of nausea or aspiration before the procedure. So we have tools and we know how to manage it. And we as GI doctors, we are efficient, and we know how to manage people with gastroparesis, so we'll consider them as if they have gastroparesis, and if we proceed, we proceed with caution.

Dr Lacy: Wonderful. Your patients are lucky to have you. Like a lot of things in life, one size does not fit all. Let's take the whole patient, take a holistic approach, and really personalize things.

So let's go back a little bit to the beginning again, because you raise some intriguing thoughts and we'll shift gears a little bit and let's think about the use of GLP -1 agonist for other diseases and other disease states. And as a matter of fact you mentioned you know treating fatty liver disease. What are your thoughts?

Dr Tadros: So I think there were a lot of retrospective studies, small studies looking at patients that had fatty liver while treating them for weight loss and there were multiple studies and they found it is beneficial. But last week or last 10 days there was a study published in the New England Journal of Medicine specifically about their use in in fatty liver. So patients who have a steatohepatitis stage 2 or 3, fibrosis F2 or F3, they found about 69 % resolution, improvement of the steatohepatitis by liver biopsies. And another good percentage, 30% where there is reduction in the steatohepatitis or the markers of inflammation and fibrosis. So this is really significant because we didn't really have effective drugs. We have been at a decade or maybe 2 or 3 decades trying to find an effective treatment. And as a patient if you lose 5 to 10%  you can make a big difference Well now we can have a drug that we can patient might lose 10,15, 20% of their body weight. And the drug might have also a beneficial effect on the liver itself directly. So it's a great drug so and I know a little bit about the insurance company because I had few patients and now insurance company most of the time will approve this drug if you have certain BMI and you have 1 or 2 obesity-related complication, that's usually how they approve this drugs because the demand is high and the supply is still limite. So if you have 1 or 2 complications from being obese or overweight, then it's likely for the drug to be approved.

I was speaking to one of my colleagues as well in pulmonary and one of those drugs like Zepbound has been approved for obstructive sleep apnea as well. So who's going to be prescribing them? Is it us or the primary? I think we're going to enter that field as a GI doctor. And there is already, I know some GI doctors in our community who are already prescribing those medications as part of nutrition clinic or obesity clinic. So some GI doctors out there are already prescribing them and others will prescribe them later on down the line.

Dr Lacy: It's amazing how quickly the field can change. And it also explains why 1 in 8 of all Americans have now been treated for whatever condition with one of the GLP -1 agonists.

Micheal, this has been a wonderful discussion. Thank you so much. Any last comments for our listeners?

Dr Tadros: I think there will be a lot of studies coming up. Stay tuned. It's a large topic. There will be a lot of publication coming up. I think there's one study that looked in a capsule study, they found that the capsules get retained in the stomach or there's a higher rate of incomplete emptying. So, we're going to see it in every field or every aspect of GI. So, we have to be familiar with those drugs.

Dr Lacy: Wonderful. So, thank you so much for lending your expertise on this important topic.

To our listeners on Apple, Spotify, and other streaming networks, I'm Brian Lacy, a professor of medicine at the Mayo Clinic in Jacksonville, Florida. You've been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Micheal Tadros from the Albany Med Health System in Albany, New York. I hope you found this just as enjoyable as I did, and I look forward to having you join us for future Gut Check podcasts. Stay well.