MJM MedTalks
MJM MedTalks (S02E03): Beyond the Hype - GLP-1 Agonists Redefining Glycemic Control

S02E03

Susan Joanne Wang1, Vanessa Tardio1, Michael Tsoukas1, Katherine Lan1, Vanessa Ross1, Samy Amghar1, Jan Pack1, Masha (Maryia) Samuel1, Samy Amghar1, Vanessa Ross1, Jan Pack1, Renée-Claude Bider1, Khiran Arumugam1, Meryem K. Talbo1, Predrag Jovanovic1 for the McGill Journal of Medicine
Published online: May 27, 2023

1McGill University
mjm.med@mcgill.ca

Abstract

McGill Journal of Medicine (MJM) MedTalks is a Podcast series where members of the medical and health science communities from McGill and beyond are interviewed on topics related to career, research, advocacy and more. The aim of MedTalks is to open a space where experienced professionals and researchers can share information and advice for trainees in healthcare and medical sciences. In this episode, Susan Wang, MJM Podcast Team Co-Lead and first year Internal Medicine Resident at McGill University interviews guest-experts and endocrinologists Dr. Michael Tsoukas, Assistant Professor in the Department of Medicine at McGill University, and Dr. Vanessa Tardio, Assistant Professor in the Department of Medicine and Program Director of the Endocrinology and Metabolism Residency Training Program at McGill University. This conversation covers GLP-1 agonists, what they are, their uses, the media hype, new and exciting research, and some advice for trainees. The show notes include a glossary of terms, links to publications referenced in the episode, and a full transcript of our conversation.

     

Content overview

Glossary

Links and papers

Studies:

News articles:

Guidelines:

Transcript

00:08 Susan Wang (SW): Hello and welcome to McGill Journal of Medicine (MJM) MedTalks. MJM MedTalks is a podcast series where members of the medical and health sciences communities, from McGill and beyond, are interviewed on topics related to career, research, advocacy, and more. The aim of MedTalks is to open a space where experienced professionals and researchers can share information and advice for trainees in the healthcare and medical science fields. My name is Susan Wang and I’m a first-year Internal Medicine Resident at McGill University and MJM Social Media and Podcast Team Co-lead. I’m joined here today by two expert guests, Dr. Michael Tsoukas and Dr. Vanessa Tardio, who are both endocrinologists and specialists in obesity medicine, as well as Assistant Professors in the Department of Medicine at McGill University. In this conversation, we will be discussing GLP-1 agonists, such as Ozempic—what they are, their uses, the latest controversies and studies, as well as general advice for trainees pursuing medical and health sciences. Our show notes, available on our website at mjm.mcgill.ca, include a glossary of terms, links to publications referenced in the episode, and a full transcript of our conversation. Of note, this was an event recorded in front of a live audience on February 7th, 2024. Disclaimer: The contents of this episode are intended for educational purposes only and are not meant to be used as medical advice.

01:56: Before we start diving into today’s topic, I want to invite our guests to introduce themselves and tell us a little bit about their training.

02:06 Dr. Michael Tsoukas (MT): So I’m Michael Tsoukas, I'm an Associate Professor in the Division of Endocrinology. I did most of my training outside of McGill, I was actually in the US for many years–I lived there for six years. I went to Internal Medicine at Tufts University, and then I decided “okay, I want to come back to Canada,” so I did my Endocrinology here at McGill and then actually went back to Boston, to Harvard University Beth Israel Deaconess, to actually do a specialty, obesity and diabetes fellowship. And actually, my main focus was on GLP-1 pharmacology and GLP-1 effects when they first came out on the market. This is, you know, about almost nine-ten years ago.

SW: Okay wow, so you’re a real pioneer in this field.

MT: Yes.

SW: It’s an honor to have you.

02:46 Dr. Vanessa Tardio (VT): Thanks Susan for having us here today. Quite excited to be talking about this, this new interesting topic. So I'm Vanessa Tardio, I’m from Montreal. I have a bachelor of nutrition—I did it at McGill University—and actually did my medical school and my Internal Medicine in Quebec City at Laval University. I came back to McGill to do Endocrinology. And then, with my Bachelor of Nutrition, I did actually a fellowship with the bariatric surgery team in Quebec City. So my fellowship is in bariatric medicine, obesity and bone health, and then I’m back here now as Assistant Professor and Program Director for Endocrinology.

03:28 SW: So both very decorated and very interesting career paths. So how did you come into your field of practice? What specifically about obesity medicine, and I guess also endocrinology, interested you in particular?

03:43 MT: So I found that it's such a high prevalence of metabolic diseases in the world, and if you look at the numbers, diabetes is only getting bigger and bigger in terms of disease process. What I find–, I really like the interplay with diabetes, obesity, and cardiometabolic disease all as a whole, because really they're related. If you lose weight, it improves all outcomes, if you get improved sugars or improve cardiac health, it actually improves all outcomes. So, I really found it very very interesting. And obesity only really got classified a “disease” during my fellowship in 2015. So that's actually when it became- classified a disease and actually became very interesting to actually study this. So I–, I'm still very interested in cardiometabolic complications: like how can you reduce MIs by losing weight?, obesity and how you actually maximize prevention of diabetes, for example, or even pre-diabetes. And this is kind of an area I'm really interested in.

04:38 VT: My interest actually started in my Bachelor of Nutrition. So we started to see, there, all metabolic problems, nutritional disorders, and obesity. What I actually find fascinating about the topic is that you can actually help people through prevention of the problem, but also in the treatment of the obesity, as well as all the comorbidities that come with it, which we see in our practice. So that, for me, was really interesting. And now, with new pharmacotherapies and medical management, it’s making it more exciting, and we'll talk about that in another question. So that's, for me, it was really the preventive aspect but also treating all the complications, like Dr. Tsoukas said.

05:21 SW: Honestly, I love that, and as someone who is interested in endocrinology and potentially obesity medicine as well, what’s really sparked my interest was actually being in the obesity medicine clinic with Dr. Tsoukas as a 4th year medical student. And the most satisfying part, I think, was the deprescription. Like, after people had gotten their bariatric surgeries, they come back with like 100+ pounds weight loss, and they would no longer have hypertension and no longer have diabetes. And I thought that was super satisfying and really ties in with that whole cardiometabolic aspect of obesity.

05:56 MT: It’s really interesting when you see, I’ll just throw some rates out for the audience here, when you see diabetes resolution 85% of cases—that's really, like, incredible. When we mean resolution, we mean having an A1C less than 6.5 with being on no meds. These people are on insulin, they (were) on like four or five other oral medications, off everything, and they have really well-controlled sugars. That's another sub-aspect that bariatric endocrinology, which we have a dedicated clinic at the Montreal General Hospital, but obesity as a whole, even as obesity medicine and pharmacotherapies is really interesting as well.

06:26 VT: And I think to add to that, we talk about comorbidities and treatment but really it’s seeing the patients’ quality of life improve after that. When they lose the weight, when we remove the medication, we really see the change in their quality of life.

06:43 MT: You remember, Susan, what we called that clinic? It was the “Happy Clinic”, ‘cause patients really, they come in actually were prescribed or getting them off medications, they come–, they're really happy after they lost weight and they're actually very happy. So it changes your quality of life and psyche a lot.

SW: Yeah, that was a really inspiring clinic for me, and definitely my favorite in all of medical school actually.

07:02 SW: Okay, great. So GLP-1 agonists have stirred up quite some attention in both the medical and lay community… To get everyone starting on the same page, do mind explaining what exactly are GLP-1 agonists and how do they work, and what are their indicated uses?

07:19 VT: GLP-1 agonists are a group of medications used to treat diabetes, and in certain instances, obesity. So GLP-1 is glucagon-like peptide 1. It’s a group of incretin hormones, so peptides that are secreted by the intestines, so the L-cells of the intestine. And their main action is on insulin secretion. So they cause insulin secretion in a glucose-dependent manner after a large meal. They can reduce inappropriate glucagon secretion. They act, also, to slow down gastric emptying, and they can also act for–, on appetite suppression and satiety. Their indications are in type 2 diabetes, type 2 diabetes with cardiovascular disease, as well as obesity.

08:10 MT: If I can add, there, to what Dr. Tardio said, these are completely physiological molecules. We all produce it. If you’re having a snack right now, or a sip of something, or have a big meal, you’ve produced a lot of GLP-1s. So these agonists are just giving it at really supraphysiological doses, that’s all that it is.

08:28 SW: Have you personally used GLP-1 agonists in your practice? If so, for what indications?

VT: Yes, we use them quite often.

MT: Like all the time.

VT: So, for what they’re indicated in, we both do metabolic, you know, diabetes clinic, obesity, post-bariatric, so we use them in Type 2 diabetes patients. We use them in patients with cardiovascular disease. So diabetes as well as in our obesity clinics.

08:54 SW: And what are some side effects to know when prescribing GLP-1 agonists? And how do you address them in your practice?

VT: The most common side effects with this group of drugs is, basically, gastrointestinal symptoms. So we advise the patients, we inform them that they can have nausea, vomiting in certain instances, diarrhea, constipation. The other side effects that can come that are less common, but we do mention them, are pancreatitis, gallstones, and now ileus.

09:28 SW: On the topic of ileus, I guess, we heard earlier this year that there was a class action lawsuit filed in the BC Supreme Court against the manufacturer of Ozempic on behalf of Canadians who claimed that they didn't– they experienced severe complications and they didn't believe that they were told of the risk of these complications. One of these such complications was stomach paralysis. So is that, like, what is Ileus, stomach paralysis, GI dysmotility? Is this a common side effect that you see when prescribing GLP-1 agonists and are there other serious side effects that patients should be made aware of?

10:10 VT: So one of the mechanisms of action of GLP-1 receptor agonists is the slow gastric motility. So yes, something that can happen, and we're seeing it more now, is gastric dysmotility. What that is is basically slowing down of the motility for the stomach and the intestine. Ileus is actually a non-mechanical obstruction that presents with nausea, vomiting, abdominal pain, and clinical signs of obstruction. So a patient will present nausea, vomiting, with abdominal pain. And usually, what we can see is that they've been constipated for a few days or longer prior to that to signal the obstruction. On x-ray, you can see signs of, actually, air in the intestine. So there's different signs to tell us the difference between, for instance, gastroparesis, which is gastric dysmotility, slowing down the stomach and intestine, and ileus. Ileus is more dangerous because you can have a complete obstruction, and that could lead to increased morbidity and mortality.

11:20 MT: The lawsuit, though, is completely unfounded. The lawsuit you mentioned about the BC Supreme, just to give you my opinion, when you give a medication and know its mode of action and know that it will actually reduce gastric motility, it’s kind of– it makes no sense that– you know, perhaps it wasn't explained properly to the patient, but it makes no sense that the BC Supreme Court would actually do a class action lawsuit on the way a molecule is supposed to be acting on. One of the four ways that Dr. Tardio mentioned is reducing gastric motility, so we kind of expect it. It will cause this. So it’s just something to know and explain to the patients. We always have to counsel the patients. I think it's more of a lack of counseling and just prescribing something without explaining it. And I don't think they– the actual lawsuit would actually bear any fruit.

VT: And the cases of ileus started with patients presenting with this, actually, the case reports and anecdotal evidence. And then there was a study that was published by the BC group in JAMA that actually used insurance claim data of millions of patients. And that actually presented– they were obese and non-diabetic on either Semaglutide or Liraglutide that presented with different complications, one being ileus. And they were compared, there was a comparator in that group which was Contrave. So they saw that the group with the GLPs had higher incidents of these problems. That's where all of this came from. So I think that we still– the FDA put a warning, now, on these medications. So we actually do– we do need to speak to the patients. And I agree with Dr. Tsoukas, counseling is extremely important, especially ‘cause the mechanism of action, you know, it states it in the mechanism of action, so it's really important what you say to your patients. And then, when you have a discussion with your patient, they can decide, also, the risks versus the benefits together.

13:16 SW: And how often is it, do you see ileus? Specifically in your practice, like with prescribing GLPs. Is it something that's more like inpatient, because they're you know, they’re super sick and admitted-

MT: I've never seen it.

SW: You’ve never seen it? Oh wow.

VT: I've seen it.

SW: Okay.

MT: And I have over 600 prescriptions per year, and I've never seen it, so just–

SW: Interesting.

13:44 SW: So I guess now we can dive into the media craze, ‘cause we talked a bit about like news and I guess like law with GLP-1 agonists. But recently, I guess dating back to May 2022 approximately, celebrities have been accused of using Ozempic. And I say May 2022 because that’s approximately when Kim Kardashian famously dropped 16 points in three weeks to– in order to fit into the Marylin Monroe dress for the Met Gala. And since then, the news cycles have been abuzz with accusations, and even admissions, from celebrities of Ozempic use, specifically for weight loss. There was even a time when there was– there were allegedly Semaglutide or Ozempic shortages for people who actually do have diabetes. And this was in the States, I'm not sure if that was true here as well?

MT: It's still ongoing.

SW: It’s still ongoing? Wow, okay. Yeah, like now if Google, like celebrities Ozempic, it comes up with a bunch of profiles as if you're looking at the cast of a movie, like it's very interesting. So it's a– it's a real thing and people know about it. How do you feel about this kind of media attention towards these life altering pharmaceuticals? Is it harmful? Has it impacted your practice at all?

15:07 MT: I'll start off by saying, GLP-1s have been marketed since 2013, guys. It's not new. It's 10 years or more. 11 years now, they've been on the market. But you know, there was very slow growth in terms of their use. And even though we were advocating to use Liraglutide, Semaglutide, Ozempic has been out since 2018. But it’s really only the media celebrities that really changed this, and I agree with what you're saying, it was completely altering for the company because you had two main tweets that really did it. It was Elon Musk, when he posted. He has like how many? Like 500 million followers or something? And Kim Kardashian. And those two tweets really triggered just awareness of the product so that people were then– were going to asking their family doctors or other specialists for this product.

Ozempic is not indicated for weight loss, right? Ozempic is indicated for type 2 diabetes. Semaglutide, in a higher dosage form, is indicated for weight loss. It's not yet available in Canada, but it is available in the US. So it's completely off-label use of Twitter then, and Instagram, that really led to it. So I think it really did impact everything. Sales went off the roof for the company that actually owns these products. There's currently a worldwide shortage of seven months delay for Ozempic. They're catching up– the company is slowly catching up of manufacturing and it has to do with these kinds of things. So it has impacted a number of patients that actually benefit from it, but you need to know that if it's not well explained, it can be harmful. It can be detrimental. And if it's not indicated or monitored closely, it can be dangerous. And you know, my opinion is that these are mostly social media crazes that are transient. So you'll hear a lot about Ozempic but it'll be another product, you know, next year. It will pass with time, especially the negative publicity like gastric paralysis or Ozempic face or whatever else you may hear in the media. This is all transient and will probably go away. But it has benefits in terms of actually putting it out there as a molecule that does– is really well.

17:04 VT: I think that's what any medication, there's benefits and risk, but I do agree with what Dr. Tsoukas said that when a patient comes in wanting, already, a medication because they heard about it through, especially social media, where you don't have all the information, you don't know if it's well indicated, you don't know either if the doctors are comfortable or the people know how to monitor. So I think what's important is that the doctors familiar with it, that we do a lot of teaching around it and that we're comfortable speaking to the patients about like the risks of it, with any medication. And also that it's indicated when you have, you know, certain people coming in with BMIs that are much lower that want the medication just to lose weight for a certain event, we really have to assess if that's necessary and also look at the patient.

SW: Yeah, that makes a lot of sense. I had– I didn't know that it was still an ongoing issue, like the shortage.

MT: Oh, so ongoing. Yeah. There's a rupture de stock everywhere in Quebec, and in Canada, and worldwide. And there’s actually emergency shipments from Copenhagen, Denmark, of Ozempic coming to Canada because they didn’t have enough supply. So they– it's like transiting over the Atlantic Ocean as we speak.

SW: Well, I guess, good for the pharmaceutical companies.

MT: Yeah, I mean they're making a killing, but you know, it's– it's– it's the appropriateness of indications as Dr. Tardio was saying.

18:25 SW: Yeah, for sure. Okay, moving on. How important are lifestyle modifications and changes, along with prescription of medications like GLP-1 agonists? And how do you emphasize this in your practice to your patients?

VT: I would say that lifestyle changes are extremely important. Whenever we meet a patient for the first time, we actually emphasize that that’s the basis of management of their diabetes, weight management as well, so we really do emphasize that. Why? Because taking medication is one thing, but delving into the environmental aspects, the behavioral, the psychological, and trying to change lifestyle can sometimes be quite difficult. So, we really– we really try to emphasize that, in order to have a treatment work and to maintain the positive effects of the treatment, we really need to make sure that the lifestyle was taken care of. So we look at nutrition, physical activity, and behavioral, as well.

MT: And if you want to take a purist approach, every weight loss study using this, every diabetes study and also every cardiovascular study, had an intensive lifestyle-behavioral component to it. So everyone saw a dietitian, you know, once every two weeks. They had strict diets. You couldn't just– you couldn't be in the study and lose all this weight if you weren't part of that, so it is the cornerstone.

VT: And we also look at the success of treatment comes with the motivation of the patient, but also their environment and their lifestyle, so that's why we tend to see patients more often to monitor them but to encourage them.

21:13 SW: And then, you mentioned seeing a dietitian. Are there other members of a multidisciplinary team that you would involve? Like a physical trainer, psychology, psychiatry, like who are the other people that are involved? Or is it mostly you doing the motivational interviewing?

MT: In reality or ideally?

SW: Both.

MT: I’ll let– I’ll let Dr. Tardio talk about ideally– reality, what’s happening. Ideally, the– it should be a multidisciplinary team. It should be an obesity specialist with a psychologist, a food psychologist specifically, a kinesiologist for exercising, and a dietitian-nutritionist. But in reality, I'll let Dr. Tradio say what we're actually doing ourselves.

VT: In reality, we’re quite important in the process.

MT: There's no one else.

SW: No dietitian?

VT: The truth is that the resources are limited and in our obesity clinic, because of limited resources, we actually do tend to speak about the importance of nutrition and going to the details of it, the physical activity, and we delve into the behavioral as well. Contemplation, where they're at in the process. So we do do that. We do it all with them. But I agree with Dr. Tsoukas that, ideally, it takes a multidisciplinary approach with the nutritionists, psychologists, nurse.

MT: Yeah. It's kind of sad that the funding of certain institutions, especially MUHC, we don't have a dietitian for an obesity clinic. That's at a quaternary treatment center, academic center, we have no dietitians. So it's something we're trying to advocate for at least. And it's not– shouldn't just fall on the backs of just one doctor doing everything, you know.

21:55 SW: And out of curiosity, like, do either of you have– I know you have a degree in nutrition, but specialty training in like motivational interviewing or like more the psychosocial aspect, or even kinesiology? Like to be able to, you know, counsel people through the things that normally you would have another professional doing? And also do you get paid extra? Because you’re doing like four jobs.

MT: No.

VT: So in nutrition, and actually in medicine, we do interviewing- motivational interviewing practice with speaking to patients and about the patient-doctor relationship, how to approach it, as well as we see with certain patients and people how to increase compliance to taking medications or having them follow certain treatment plans. There is a way of speaking to them.

MT: The guidelines I use are the Obesity Society. I was never formally trained in this, you don’t take a course on motivational speaking to patients with obesity right? But the Obesity Society, which is the largest obesity association worldwide, they actually put out specific guidelines. And even the Canadian obesity guidelines now have– approaches on how to speak to patients. So, for example, never call– you actually never use obesity as an adjective. You should never be saying “my obese patient”. That's so wrong. You say “my patient with obesity”. That's a first thing, number one. You have to do passive forms of acknowledgment. For example, the seats we’re sitting in are not bariatric chairs—a 400 pound person will not be able to sit in them. So you have to have that accommodation in your clinics as well. And it also, how to speak to people that you let them have power, so by empowering a patient by saying “What are your goals? What do you want to do out of this? What are your goals in terms?” You don't say “I think you should lose weight.” That's not the right approach. It's what the patient wants, and you kind of work on those goals together.

23:53 SW: So now shifting gears a little bit, we’ll talk a bit more about kind of like, I guess the up-and-coming research on GLP-1 agonists. Recently, I– my partner actually saw a Rybelsus, Rybelsus I’m not sure if I’m saying that correctly, ad on the metro or something like that. So what is Rybelsus? Have you prescribed it before? Why or why not? And are there other new formulations that are coming to the market?

MT: So Rybelsus is the brand name. It’s actually oral Semaglutide, so it’s as simple as an oral form of Ozempic. It’s indicated for type– the treatment of type 2 diabetes only, not for obesity. It’s– it was launched in March of 2020, so it was right during the start of the– of the Covid pandemic, so they never actually had an appropriate launch program. And you may not have heard about it, but it's been available almost for four years right now. It's an oral form of Semaglutide, so you take it every day instead of doing a weekly injection, it’s a daily medication. However, it's not really commonly prescribed as much as injectable forms because it's a daily use. There’s actually special instructions on how to take it, very similar to oral bisphosphonate use, so stand upright, 30 minutes, don't eat any other food, empty stomach use only, half a cup of water and not any more. Very specific instructions. It's slightly less efficacious than Ozempic. Not bad, but it's not as good as injectable form of Ozempic. And also, it's not covered by the RAMQ or other public formularies. So it's private insurance. So all those reasons: daily pill, a bit more difficult to take as a daily pill, and insurances, limits the use of Rybelsus.

VT: I agree. I think, like Dr. Tsoukas said, mode of administration: very important. Like we said, compliance is everything for patients. So, the injectables that are once a week, patients actually tell us they prefer that. As well as the cost. Cost and coverage here is a big, a big thing, actually, that we have to look at.

25:59 SW: Are there other formulations that you're aware of that you think might make an impact in this field?

MT: So in terms of oral GLP-1s, it's the only- it's the first and only in its class, the oral Semaglutide, Rybelsus. There are other Phase 2 and even Phase 3 studies of new molecules by three or four different other Pharma companies, but I mean, we can't talk about them. They're pre-launch and they're only Phase 2 and Phase 3. There are certain combination agonists as well, where it's not just GLP-1, it’s GLP-1 plus other enteric hormones that are now included in pill forms.

26:33 SW: So, um, recently the GLP-1 agonist, Semaglutide, has been shown to have cardiovascular benefits in people with obesity but without diabetes, the SELECT Trial, of which you are both investigators. How might this change the landscape of prescribing GLP-1s for patients with obesity?

MT: So what's really cool about these studies were that these, some of the more newer studies, use non-diabetic populations. So they use subpopulations that didn't have type 2 diabetes. They were– had completely normal sugars, but were still given injectable Semaglutide, so Ozempic. And the SELECT study was actually probably the most groundbreaking one. It was actually presented at the American Heart Association, it wasn’t even a diabetic study per se, because they didn't have a lot of diabetes in there. It was just Ozempic for patients that already had an MI or any other ASCVD. So if they had a stroke, an MI, peripheral vascular disease, they were given Ozempic. And they were actually great reductions in actually having other MIs. Even if you don't have diabetes. So, already, this medication had diabetic effects for heart and heart improvement, but now we know even if you don't have diabetes, it can actually help prevent heart attacks, strokes, etc. So I think it made a big impact. There's other studies that came out as well during the same time last year in 2023, one’s called the STEP-HFpEF, where Ozempic helps with heart failure, of all things, in non-diabetic patients. Non-diabetes patients that had heart failure were given Ozempic and they got better. Probably from weight loss mechanisms and inflammation, but still very interesting. And then finally SOUL study, which we’re also participants in, is for nephropathy improvements. So if you have CKD and your eGFR is decreased, or you have microalbuminuria, given Ozempic helps that as well. Even in non-diabetic populations. So it’s very interesting to see non-diabetes uses for these and it's actually changing a lot for the landscape.

VT: If we go back to all the actions of GLP, we listed three or four, but actually in studies, they’re seeing that it has different actions on many things. So improving endothelial function, contractility, inflammation, reducing inflammation, even neuroprotection. So we’re seeing like certain things come out and I think it– we’ll talk about it in the other questions, but that’s– that all ties in in non-diabetics.

28:54 SW: And specifically for the SOUL study, how– what do you– like is–

MT: It’s an ongoing study; hasn’t finished yet. It’s actually, I actually met with monitors today. It’s actually going to probably finish in August 2024, so it’s still ongoing. We can’t reveal data. I don’t even have access to the full data, but it is at least a 20% reduction in nephropathy outcomes by giving Ozempic. So it’s very interesting.

SW: Do we know the mechanism by which this is happening? Is it well-studied?

MT: It’s– it’s not– so it’s probably, again these are postulated mechanisms, it’s probably anti-inflammatory. Anti-inflammation in the actual nephrons that are helping nephropathy outcomes. Yep. And in SOUL, particularly, there's a cardiovascular component as well, where you were actually giving medication to actually prevent cardiovascular outcomes as well.

VT: And the cardiovascular outcomes, the mechanisms too, can go with endothelial function, inflammation, lowering lipids, so many, many different actions for these medications.

MT: And just to clarify, Susan, SOUL is Rybelsus cardiovascular outcome.

SW: Oh!

MT: It’s Rybelsus, oral Semaglutide, just to clarify that. FLOW is the nephropathy Ozempic study that’s, so we don’t have the outcomes, they haven’t been published yet, so I can’t talk about them. But– but there– everything’s being examined right now.

30:23 SW: Okay, wow. That’s incredible. While we’re talking about studies, and I looked through some of these studies that we’re talking about, the SELECT Trial, the STEP-HFpEF, as well as some of the like the Phase 2 trials for the new oral formulations, they’re pretty much all funded by the drug companies. So I just wanted to know, how, as investigators, do you mitigate that bias or like what’s your perspective on this?

VT: I think that we use, you know, using when our– if we look at the relationship with drug companies we use, they give us the tools to do the studies and to get the information, but we also learn from our perspective as well. So it's really a relationship that we have with them, where we basically, with our knowledge, are able to like as much as possible, be objective and you know, appreciate the advancement with what they can give us as tools to do this.

MT: As long as you’re objective, and you just like, look at things critically, there’s no problem working with any of this. A lot of the studies that you’re mentioning, the products haven’t been launched yet. They, the companies, have to provide cardiovascular safety, They have to provide placebo versus efficacy studies, so they have to publish them. And as long as you study, critically analyze the way it was actually done, they’re great. You know, no one’s– no one’s, no one’s doubting that Ozempic causes weight loss and the weight loss that were done by the pharma company. So it’s just that we have to be critically and appraise them properly.

31:53 SW: Next question is: what are your predictions for GLP-1 agonists and their future uses?

MT: So there's going to be huge amount of changes with GLP-1 and their indications very soon. Cardiologists are really going to grab on board, start giving it for heart failure, for MIs, for stroke prevention. Neurologists are already prescribing Ozempic right now for first stroke prevention. I think the main areas are going to be new metabolic-associated disorders. So MASH, which formerly known as NASH or MAFLD. I think, you know, the fatty liver spectrum really would benefit from GLP-1s and there’s ongoing studies for that. There's ongoing studies for PCOS and GLP-1s due to the weight loss indication, insulin sensitivity that's– that's actually needed for PCOS. There's a lot of European work on Alzheimer's dementia, dementia with GLP-1s because it helps with the neural– neuro tangles in the brain for Alzheimer's. It actually reduces the inflammation of that. So there's a lot of ongoing stuff. Even Dr. Tardio and I are now doing a type 1 diabetic study to see with type 1 diabetes what the effects of Ozempic are. So there’s gonna be a lot of new things coming out.

VT: We know that there's GLP-1 receptors like in many many areas of the body. So because of that, these agents can target many different things and, from that, a lot of studies. So I think it's gonna be pretty exciting to see.

33:23 SW: And do you think that these medications will be indicated for people with these conditions that you’re talking about? And with obesity? Like would that have– you think that like the effect is mainly through the metabolic pathways, right? Or would you think it could be like prescribed for example someone with CKD who doesn’t have diabetes?

MT: So unless there's a dedicated study on PCOS or on MAFLD, you can't actually get a license to actually give it on-label for it. Do people give it off-label? Yes. Even here at the MUHC, hepatology and myself, we give Semaglutide for people that don't have diabetes but that have fatty liver disease. So that’s just off-label use. But for indications, you need a dedicated study.

VT: And off-label use, just to add that as a point, you really need to– we were talking about the side effects and complications that can arise from any medication, you really need to discuss that with the patient, any off-label use, even for obesity.

34:27 SW: Shifting our focus a bit, what do you find the most exciting or interesting aspect of the future of obesity medicine, broadly? Not just the pharmaceutical part.

VT: I think what's fascinating about obesity medicine now is we're getting the tools to help the patients. So we have– we have the medical treatments now to discuss, we have a few agents in Canada, and so patients with that, they’re excited to see what they could try. A lot of it is based on prevention, but if we actually have options to provide to them, then that's great. We were also mentioning, you know, we're talking about GLP-1 receptor agonists but there's other agents now coming out like the dual agonists, Tirzepatide is one of them, for diabetes and approved in the United States for obesity. So I think that we're gonna see a lot more of these different options for our patients.

MT: I think what's interesting is that obesity is now recognized as a disease. It's the most common disease worldwide, okay, so it's not hypertension, it’s not arthritis, it’s actually obesity. It is number one by far the most common disease worldwide and the fact that governments are now recognizing, finally, it will be helping out giving these tools as Dr. Tardio said. Because as you probably know, you know, all the anti-obesity medications are not covered by governments, right? If you have your Medicare card, you can’t just go get free Ozempic. You have to pay out of pocket. But with obesity now being recognized as a disease, hopefully that opens up some doors and will be covered in some part to help prevention of other disorders.

VT: And recognizing obesity as a chronic disease, something that is not only treated for a few months but actually has to be maintained and monitored is something that’s important too, especially for our governments. That’ll help, you know, with cost and coverage and the importance of recognizing and treating the disease. And also, we know from a cost perspective, the comorbidities that come with obesity. You know, that's important to look at as well. If we can help prevent the problem, prevent and help and treat the comorbidities, and that could have a huge impact on cost.

MT: In the US, there was a study that came out a few years ago that demonstrated that per capita, so per person in the US, pays about $14,000 annually out of their health fund just to help people with obesity manage their complications. So it could be, you know, getting a CPAP machine. It could be missed work because I can't climb the stairs because my knees hurt, all these come out to $14,000 per person. That's a lot of money spent. It comes out to billions of dollars, it’s actually more than smoking and alcoholism combined is spent on obesity in the US alone. So that just gives you an idea that it's totally chronic and if you can prevent it and not have these, you won't spend as much and you have money for other things.

VT: And look at what we're doing as well, we’re referring patients for surgery like bariatric surgery to treat the obesity. So if we could get this rolling earlier in prevention and then treatment, and by changing like emphasizing lifestyle, then that could help as well.

SW: There's that saying “an ounce of prevention is worth a pound of a cure” or something like that.

MT: I’ve never heard of that.

SW: Has anyone else heard of this? Or am I the only one? Okay. I think that’s very topical to what we’re discussing now.

37:58 SW: I guess now that brings us to our conclusion. So, as a part of the MedTalks series, we always have a little section about advice for trainees, either those who are interested in your field in particular or maybe not in your field but may take some, you know, tangible advice from our conversation today. So do you have any words of advice for the audience?

VT: I guess one of the most important things is to choose something that you're very passionate about, that's with anything in life, and to work hard at it. When you're passionate and you love something, you don't, you know, I know that this could be cheesy to say, but you don't feel like it's work when you're doing it. So that's the first thing: choose something you're passionate about, work hard at it. Find a mentor, someone that you look up to that you can aspire to and that can actually guide you through the process for all of this. We were saying actually, how important wellness is as well. So yes, focusing on your work, but also on what you enjoy doing in life and balance– maintaining balance in your life is important.

MT: Dr. Tardio took all my answers. So yeah, you have to do what you like. If you don't like it, there's no point doing it and that gets people in trouble later on when they choose an area and then they don't they're not really passionate about it and they don't have that drive. So you have to really like it. But what I tell all trainees in various fields, whether you're a student or a resident, is think about the future and how you want your work-life balance. If you're a go-getter and you love the CCU and you want to intubate people, I mean, this might not be for you. And if you– if, conversely, if you don't like that, if you like, you know, establishing good rapport with patients, having chronic disease management, and seeing good benefits, you might like this kind of field more so. And see what you like. Like if you want to be super intense or you want to really go home to your family at night or go out for the weekends, you really need to know. It’s very important to have the work-life balance. I think that's something that physicians don't think about much because they’re just focused on the work. And if you're passionate about it, it doesn't seem like you're at work as Dr. Tardio said.

VT: Also to set realistic goals and expectations with yourself in your personal life, what your goals are and then you can work towards that. Always work towards something.

SW: Thank you, those are great words of wisdom. Did you have something else to say?

MT: I want to thank you for our invitation here.

VT: Thank you very much.

SW: Of course, and thank you to the audience, as well, for joining us today on our first live podcast event and, specifically, of course, thank you Dr. Tardio, Dr. Tsoukas, for your expertise and sharing your knowledge as well as your great advice. I think it's very tangible for most of the people in the room.

40:59 SW: Thank you so much Dr. Tardio & Dr. Tsoukas for joining us today, and to all those joining us from their podcast app of choice. We will be including relevant glossary terms and papers we have discussed in the show notes for this episode. This podcast was edited and produced by Susan Wang, along with feedback from the entire MJM Podcast Team. Feel free to reach out to us on Twitter or Instagram @mcgilljmed or by email at mcgilljmed.podcasts@gmail.com. We would love to have your feedback! We look forward to having you join us for our next episode, or in-person at our next live event. Stay tuned on our social media for more information. We hope to see you there.



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