The New Obesity Drugs: What Cardiac Practitioners Need to Know

Please join our special guest Dr. Ian Neeland from University Hospitals in Cleveland, to discuss the intersection of obesity and cardiovascular disease, and specifically the roles of the new agents semaglutide and tirzepatide. We discuss the recent data on cardiovascular outcomes with these agents, assessing patient candidacy, and tips for initiating and monitoring therapy.  We also reviewed the complementary role of bariatric surgery and pharmacotherapy to improve cardiac outcomes.

For more information, see the SELECT study.
For more information about the UH CINEMA program, click on this link.

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Transcript

Kanny: 0:12

So welcome back everyone to the CardioHop podcast. We're excited today to have a discussion about metabolic aspects of, of obesity and the intersection with heart disease. And we're going to talk a little bit about some new agents that have been very popular in the cardiac world and the general medical world as well, as well as with the lay public in the management of overweight and obesity. I want to start first by introducing as my cohost familiar Voice to many of you Dr. Alan Sabic, who's a cardiac imaging specialist at University Hospital. Alan, thanks for joining us today.

Ellen: 0:54

Well, thank you I actually am really pleased and honored to introduce Dr. Ian Neeland, who is our discussant today, who is a colleague of mine here up in Cleveland. He is the director of University Hospital's Center for Cardiovascular Prevention. As well as the co director for University Hospital's CINEMA program, which is a multidisciplinary cardiometabolic program here within the cardiology department. In addition to that, he is part of the American Heart Association's multidisciplinary task force and writing committee on cardiovascular, kidney, and metabolic syndrome. But first, I wanted to ask Ian, could you tell us a little bit about your career path as a cardiologist who now is really focusing on obesity and diabetes and intersection of that with cardiovascular

Ian: 1:42

disease? Sure. Well, thanks for having me. It's a pleasure to be on the, on the podcast with you all. I, I first got interested in cardiometabolic disease, the nexus between cardiovascular disease, diabetes, and obesity when I was a fellow. I went to University of Texas Southwestern Medical Center for fellowship and had phenomenal mentors, including James Delimas and Amit Khera. And when I went there, I started actually at a T32 where I would do 2 years of research up front and then 2 years of clinical work and I plan to go and do work in biomarkers. At the time Dallas Heart Study was ongoing and there were lots of different biomarkers to look at. And the kind of the biomarker craze was at its peak. And so when I got there, it turned out that I wasn't able to study biomarkers in the way that I, I had planned and so I had to pivot pretty early on in my training and figure something out of what to do next. So my mentor James DeLimas, he recommended considering looking at what's called adiposopathy. There was a an article that was in Jack called adiposopathy or sick fat by a researcher named Harold Bayes. And the concept of sick fat was such that body fat or adipose tissue was actually an active endocrine organ. Not some inert storage center where you just stuck triglycerides and and went on your day. And there was an idea that there was heterogeneity in patients living with obesity, how it manifested, some people get diabetes and heart disease. who have obesity and others do not. And and what underlies that question and that observation is that some fat is sick fat and some fat is quote unquote healthy fat in the sense that it doesn't exert the same adverse metabolic effects as as other fat. And my research then was really focused on trying to understand the concept of sick fat, Why and where and led me to researching body fat distribution as a key driver of the cardio metabolic consequences of obesity and led me to the path to look at visceral and ectopic fat that is fat that's in around the internal organs as well as fat that's in places where it shouldn't be such as the liver, the heart, the kidneys and such. And that led me then to be more interested in therapies, novel therapies that impact body fat and especially by fat distribution and led me to looking into medications such as SHLT2 inhibitors and agonists. And then, that, that kind of broadened from there when these medications. For the first time became not only anti hyperglycemic medications for diabetes, but also for obesity and cardiovascular disease and kidney disease. And so it's really been a an amazing kind of run since I started as a fellow looking into these concepts and really it's still, still going. I don't think we've reached a peak in any, any, any sense of the word for the, these compounds that are coming out and new therapies and novel things where the intersection between cardiovascular disease, diabetes, and obesity has never been as great as it has is today. So it's really fun to be in the field right now.

Kanny: 5:19

Well, thanks, Ian. That sounds like quite a journey to where we are now, we have an audience today of, cardiac practitioners, including cardiologists. Cardiac practitioners as well. many of us work on the front lines of kind of bread and butter heart disease. And of course, we see the contributing effects of obesity every day, in our clinical experience. But how do you frame, like, the relationship between weight metabolic dysfunction, and heart disease in terms of, contributing effects versus causative effects?

Ian: 5:50

So I mentioned visceral and ectopic fat as a as the driver for most of the cardiometabolic complications of obesity. And I really do believe that there's a, a single central pathophysiology that that drives That's a lot of the downstream consequences and essentially it comes from, excess body fat, but that body fat, depending upon where you're, you store it as an individual may impact down the line other surrogate intermediate risk factors such as hypertension, diabetes. dyslipidemia, obstructive sleep apnea, chronic kidney disease, all the different risk factors that we we know as intermediate upstream of, of cardiac consequences. And so I think the, the best way to think about it and frame it is, is when you have a patient who let's say has excess body fat is maybe living with overweight or obesity is to ask yourself, how has that manifested in terms of risk factors And if it has manifested often as a metabolic syndrome, then that patients at three to five times increased risk for coronary artery disease, and probably even higher risk for heart failure, often with half path over half ref. And and that's a patient that really requires aggressive risk factor modification, not necessarily in the sense that we, picking off the individual risk factors, but really focusing on the, on the driver, focusing on the underlying pathophysiology. And often cases when you can treat the visceral obesity with either lifestyle plus pharmacologic therapy, potentially with surgery, then actually you mitigate a lot of those intermediate risk factors, cure their hypertension, cure their diabetes, resolve their dyslipidemia, reduce their cardiovascular risk substantially. And so I think a lot of cardiologists myself included before I was in this field felt like, there's so many risk factors to, to, to look at and think about, that's really should be the domain of of the private primary practice doctor or the family doctor endocrinologist. But but no longer really is the domain of the cardiologist and having a good sense of how you can impact that central pathophysiology can really go a long way for not just primary prevention for your patients, but secondary prevention as well. So I think thinking in that framework is very helpful.

Ellen: 8:30

So, Ian, I know that you have done an awful lot with our cinema program here, this multidisciplinary program. Can you explain to our audience a little bit about how that is set up, how it works? And also, I know you've got some data on at least two year outcomes and sort of explain the benefits of a type of program

Ian: 8:48

like this. Sure. I mean the cinema program really does try to address the issue that I that I just mentioned is trying to attack that central pathophysiology and reduce cardiovascular risk through treatment of my cardiometabolic syndrome. The cinema program is one of a growing number of programs in the country. There's, there's only a handful out there. And we're one of the first actually with founding members of the cardiometabolic care Alliance, along with. St. Luke's Mid America in Kansas City, where we wanted to come up with a paradigm and a care model that was different than the usual siloed individual specialist care model where a patient would go from specialist to specialist to take care of this organ system and that organ system and without any real, understanding of the interplay and complexity between these things, like, the patient has an endocrinologist, a primary doctor, a cardiologist, a nephrologist. Well, really, a lot of these physiologies are interconnected and linked. And so we really wanted to change the model and, be a disrupter in that field. And create a situation where, where we would provide multidisciplinary comprehensive care to patients with type two diabetes or prediabetes and elevated cardiovascular risk. And we would then be very aggressive with evidence based therapies. Be very aggressive with lifestyle modification and use full support of our team, including a nurse navigator, a certified diabetes educator specialist, a dietitian, a pharmacist champion as well as a significant amount of educational resources, including zoom calls and support groups and and online education. And so the goal really was to improve reduce cardiovascular events. Through improvement in the patient's overall metabolic, cardiometabolic health. And so we started the program in May 2020 and we've now, we're now into our third and fourth years, almost four years into our fourth year. And so we published our one year debt data and a journal American Heart Association and our two year data in the journal of the American Preventive Cardiology Journal. And we've seen that even in patients are in our program on a median, let's say about six, seven months that they have substantial reductions in weight. blood pressure, LDL cholesterol, triglycerides urinaldehyde claritinine ratio A1c, hemoglobin A1c. They and they get on evidence based therapies like SHLT2 agonists three, three fold more than they would when they came in. And these are patients who have seen endocrinology for years, have primary care physicians who are managing them. And the, the issue is that people, most people don't have the time or resources to spend with patients to be very aggressive and, and the follow up that's needed to help people maintain, very very high level lifestyle modification care and, and, and get the access to the medications, these life saving medications that we have. And so we're very proud of our program. We're expanding substantially. We have. Currently four sites, we're going to six sites actually is coming here adding additional personnel, including advanced practice provider and a couple of their MDs. And and so, this is really the new model. This is the model that the HA has has said is the, is the future so I encourage people if they're interested to, to read the papers and, see how the model works. And it's definitely, implementable. In health care systems. I've talked to lots of different doctors, not just in Ohio, but in other states as well about how to implement care models such as ours in cinema and people are doing it and they're joined the alliance and getting on board with, standardized algorithmic care. And there's studies that are being presented and published to look at these. So I think it really is the future of cardiovascular care. Yeah, I

Ellen: 13:05

think we've shared several patients and I think this multi disciplinary aspect is really quite crucial because, individual practitioners don't usually have time for the degree of education that is needed for the pharmacologic support, both getting prior authorizations and also, Holding the patient's hands, going through certain side effects and stepping up doses. So what your group has really accomplished is, is, has been really quite incredible.

Kanny: 13:33

Yeah, thanks. And I would second that as well. I know how hard it is to get a multidisciplinary program, off the ground and functional, especially, since some of these lifestyle. And other modifications don't get, the same attention that, that other therapies do in terms of reimbursement and so forth. So congratulations on that and we will put some links, to your program in our notes as well. I do want to make sure we have some time to talk about, some of the newer therapies that you've put out. Do offering your clinic and that, of course, we've all been hearing about in and both the medical literature and in the lay media as well. I know, GLP one Agnes have been around many years. There have been studies documenting their efficacy and diabetic patients. Why do you think some of the new data such as a select study is so relevant to cardiologists in terms of how this can be a direct benefit to our cardiac patients.

Ian: 14:30

Sure. So GLP ones are fascinating. The they started out much like SGLT2 inhibitors as medications for diabetes. improving glycemia focus on A1C reduction. And it was only because they have, quote unquote side effects or additional effects such as weight loss that people became, become interested in them. And when the LEADER trial came out, which is a trial that was done on the araglutide, which is one staley araglutide or Victoza given to patients with type two diabetes. It was it was the first GLP receptor agonist trial to show cardiovascular benefit to reduce, cardiovascular events and and that came around the same time as some of the issues of two inhibitor trials and cardiovascular outcomes. And, this just blew up the field. And so since that time, there have been several agonists that have shown cardiovascular benefit in diabetes patients and once kind of that was accomplished the field moved on to what about patients just with obesity? Without diabetes, understanding the essential, major risk factor of obesity for cardiovascular disease can candy. Candy medications independent of glycemic control impact cardiovascular disease through vis a vis through weight loss. And this, this could be born out of look ahead trial, which was a trial and type two diabetes and lifestyle modification to reduce body weight where they were able to get about 8 percent body weight loss after the first year. These patients and improve intermediate risk for risk factors, but actually there was no difference cardiovascular events. And so the big question, the field was, just do you need more weight loss to impact cardiovascular outcomes, or is it how you lose the weight, through through a glp one receptor agonist, for example, to impact it. And so the select trial was designed to, to actually answer this question, patients living with overweight or obesity with established cardiovascular disease could giving the GLP 1 receptor agonist semaglutide with a 2. 4 milligram dose once weekly really reduce cardio, hard cardiovascular outcomes, right? Major adverse cardiovascular events, MACE. And indeed, even despite a relatively modest weight loss of about 9%, there was a 20 percent reduction in MACE events. And so No, this became the first trial ever to show that treating patients with obesity without diabetes with a medication to lower body weight reduced cardiovascular events. And in fact, on Friday, just a few days ago the FDA added and approved the label indication for semaglutide. to reduce the risk of major adverse cardiovascular events. And to my knowledge, it's the first drug ever to have that indication in, in a patient population without diabetes. So that's just the first though of, of ones that are, that are coming down the pike. There is the Trezepatide trial. Trezepatide is interesting. It's a dual agonist, GLP 1 and GIP. And that's going to be looked at and surmount MMO. That's a trial for cardiovascular outcomes. And and then there's now a triple agonist out there that's being developed not on the market yet, which is a receptor agonist for GLP, GIP and glucagon receptor. And then there are several others that are in development as well with the dual agonism. So the field is really expanded significantly of trying to harness the power of a creatine based therapy and, and, and the bodies on metabolism to to see if it can actually improve not just the metabolic pathways, but cardiovascular events. And, and so that's the reason why it's so important for, for cardiovascular practitioners and specialists is that just like you give a patient a statin to reduce their cardiovascular risk, not necessarily just treat their cholesterol, just like you give them, anti platelet therapy to reduce risk for another M. I. Not just to thin the blood. So to you would give them a G. L. P. One receptor agonist to reduce risk for mace, not just to treat their obesity. And that's why it really is important to to understand that the medications and not just treating obesity, but you're treating cardiovascular disease. And just as you would give life saving therapies to prevent, the next MI, the next stroke you would do the same here even though it's also for weight loss. So I think it's a, it's a frame shift that people have to have in the cardiovascular field, understanding that it's, it's, it's upon us as cardiovascular practitioners to take up the mantle and, and treat patients with these evidence based therapies that have, clear benefits and indications. So Ian,

Ellen: 19:22

one other question is, as far as we know, so many of our obese patients have issues with, Heart failure with preserved ejection fraction, not reduced ejection fraction. Can you touch base and give us a few lessons learned from the STEP HF trial? Using these medications to improve HF preserved EF.

Ian: 19:42

Yes. Yeah, sure. No half path, right? Heart failure, preserved ejection fraction is, is the next, kind of frontier of cardiovascular care. No, for many years we've had therapies that improve mortality, morbidity, and have ref part failure for the juice dissection fraction. And we never had anything beyond blood pressure control and diuretics for half path. And then the issue to two inhibitors came out. As showing benefit and have path and for heart failure hospitalizations and cardiovascular death. And and now we actually had a disease modifying therapy. Well, it makes a lot of sense that patients with half path who have a lot of comorbidities such as obesity, chronic kidney disease. hypertension and those patients could derive benefit potentially from something like a GLP 1 receptor agonist. So the STEP HF PEF trial was performed in patients without diabetes. There's actually one called STEP HF PEF DM that I'll be reporting out soon for diabetes, but this one was done in HEF PEF patients without diabetes to see if it actually improved symptoms using the Kansas City questionnaire KCCQ score. And indeed as you might expect improving body weight in patients with overweight and obesity and HEF PEF did improve symptoms to a substantial degree. And and so We don't currently have outcomes trials with heart failure hospitalizations, for example, or, or cardiovascular mortality with, with these agents, but those will be coming. And I, and I could envision a world where HEF PEF in the future could be treated with an H22 inhibitor and agonist. And and, and you'd have patients with diabetes who are treated the same patient with cardiovascular, atherosclerotic cardiovascular disease treated the same. And now. patients with heart failure are treated the same. So, despite the fact that we have so many different, pathophysiologic mechanisms underlying all these diseases, it's coming down to a final common pathway of a few, a few classes of medications that have a pluripotent benefit for cardiovascular and related diseases. So it's really, it's fascinating. Fascinating stuff. So keep an eye out for the STEP PEF PEF DM trial that I think is going to be discussed at ACC, if I'm not mistaken, or at ADA.

Kanny: 22:06

Yeah, that sounds really exciting. And all of us who've been struggling with these patients for so many years, it's great to see more options with proven. benefits coming down the pike. Do you have any tips for our cardiac practitioners? clearly as you've outlined, there's a benefit here in many of our patients, even the non diabetic or at least the pre diabetic patients. Do you anticipate that, even if we see a patient who seems to be a good candidate for either semi glutide or trizepatide, that it could be initiated in a cardiac operation? Practice or would you, do you see a more going through a multi disciplinary clinic like the one you've created, given that there's issues like cost and access to the medications and the fact that they're given, non orally as

Ian: 22:55

well. Well, I think it's, it's contextual just like anything else. I mean, if, if a cardiovascular practitioner is is comfortable with the medication, understanding how to use it, when to use it, potential side effects, dose escalation, just like you would, for example, with other injectables like PCSK9 inhibitors or other titratable medications like Contresto, then I think for sure, that Doctors should try to get an understanding of it and try to use it. it's, it's, it's not that difficult once you get the hang of it. there, the side effect profile is very is very easy to kind of learn about and, and, and, and consistent. There's no usual surprises most of it's GI side effects and getting just understanding how to, how to manage those really is 90 percent of the battle. And then just kind of figure out. kind of the nuances of between each of the, of the drugs in the class, but I, I definitely think that cardiovascular docs and providers should get familiar with, with these, try to, try to use them in their clinic. They'll, as more, more competition comes out, more trials come out and the drug company, the pharmaceutical companies are able to get better pricing and such. It's going to be a bit easier, I think, and more acceptable to get folks on therapies. And so I would say, don't wait, to have someone go to a multidisciplinary clinic like ours. There are only a few across the country and, it's not, it, it, it, patients could be waiting in long lines. And the other thing I would say is that, patients are going to go where they can get the therapies, they know these things work. And so there's pop up shops. That are really unregulated and getting medications, not necessarily from the manufacturer from, other places or trying to, third party places and selling it for, for cash for, for, for low amounts of money. So patients will get these. We'll get these drugs. And I think that if, if we can provide them as, in a safe monitored environment as as, as, licensed practitioners, that that's going to be safer for the patients and better for everybody. So I would encourage people to read about it, to learn about it. just like anything else, once you get a hold of of potential side effects and know how to manage them, it's, it's it becomes routine. So one quick

Ellen: 25:22

question. Are there any particular tricks and tips to initiate, well, two questions. One is getting approval through the insurance companies. I know they used to be better about pre diabetics approving them and now they're getting very strict about just diabetics. Do you think the fact that now that's been approved for with the FDA for cardiovascular, do you think that will? broaden the approvals through insurance.

Ian: 25:49

I do. I think I think eventually it will happen. I think there'll be a lag. Part of the problem is that CMS currently doesn't view obesity as a chronic disease. It's a behavioral condition. And so there's a lot of political clout trying to trying to convince the government that obesity is a chronic disease and needs to be managed like any other chronic disease, like diabetes or hypertension. And so coverage for the medications, especially now that there's a, an FDA approved indication for cardiovascular disease really should be the next step. And I don't know when that will happen, but certainly if it does, I think, I think to some degree payers will, will follow in line right now. it's, it's pretty much universally covered with or without a prior authorization for patients with type two diabetes. And you're right. It used to be pre diabetes was kind of, you can get it in there, but they become more strict and there are many patients who have pre diabetes or, or even just, just with, with obesity without pre diabetes. Who would be good candidates for this medication and cannot get it covered by their insurance companies. paying out of pocket for these can be somewhere between 500 to a thousand dollars a month. It'd be very expensive. And there's a lot of patients, unfortunately that we, we, we can't provide therapy to because they just can't afford it. Especially, patients, for example, Medicaid, Medicare patients who are in the donut hole becomes a real, a real problem. And these medications, they only work if you're taking them. There's a, there's not really a legacy effect. I mean, once patient stops the medication, there, there will be weight regain not necessarily all the way to the pre pre medication weight, but there is weight regain and and also. It's, you can't really switch between drugs in the class. So there's a big shortage now about, for certain medications used to be a big shortage for semaglutide, then it switched to Tirzepatide and back and forth. And so, patients sometimes can't even get the medications from the pharmacy even if they could afford it. So it's still, still a lot to be worked out. And at the, the, the rapidity of growth of the, of the data sometimes outstrips. It outpaces the the, the ability of society to keep up with providing medications in an affordable way. So I think time will tell.

Kanny: 28:14

Question I have for you, Alan, actually, I know you follow the literature pretty closely for heart disease and women and you have a practice often, skewed towards that as well. I know in this. In this particular select study, one kind of potential criticism was that only over 70 percent of the participants were men. And of course, coronary disease does present differently in men and women. So, Ellen, do you think, like, eventually we could apply this more broadly to, women as well? Or would, do you think the event reduction would be similar? Or is it just a matter of studying it more broadly in larger groups to, to see the benefits? Well,

Ellen: 28:51

I, I think that we, we probably need to do a broader study because I think for most cardiovascular studies now we really need to try and specifically look at women. However, I do think, with all the mechanisms that Ian has explained, I think it would make an awful lot of sense that we should probably see similar outcomes as far as improvement in MACE. So, I think, yes, we should study it more, but I think, would I hold back on my women patients just because, well, we don't have enough data? No, absolutely not. Because I, I do expect, I don't know if the exact magnitudes would be the same, but I do expect similar outcomes. So I, I think there's a lot more studying that can be done, but boy, these are really exciting medications with, broader and broader applications as we're seeing. So, hopefully industry can keep up and provide the amount of product that is needed.

Kanny: 29:46

Yeah, that makes sense to me too. Well, we only have about five minutes or so left. So, Ian one other question I have for you is, we obviously have had access to another very effective therapy for obesity for several years, which is bariatric surgery. How do you see these new agents Working either in collaboration or in conjunction with bariatrics and certain patients. Do you think certain patients would be candidates for one or the other? Or do you see them both being used and various patient populations to improve outcomes?

Ian: 30:22

Yes, I think it depends on the amount of weight loss desired and needed for health outcomes. And in terms of choosing what the best method would be, the, the GLP one receptor agonist and related therapies. Are really knocking on the door of bariatric surgery related to weight loss amounts. we were talking about upwards of 22 percent body weight loss, whereas bariatric surgery is, usually between 30 to 40 percent initially body weight loss at the, at the maximal end. So I think that if a patient, requires more than 20, 25% body weight loss for whatever the health reason would be. For example they're already on a GLP 1 plus other antihyperglycemic medications and their diabetes is still not well controlled, then bariatric surgery usually is recommended to reduce diabetes remission. Sometimes it's the only thing that can do it when someone's maxed out, so to speak, on medications or can't take certain medications and they have, severe, moderate severe obesity. But whereas, patients who, who really kind of end up The mild to moderate obesity range and they really tend to 15 to 20 percent of body weight loss would be completely sufficient to improve their health status. Then I think pharmacologic therapy would definitely be indicated. I've seen situations of collaborative therapy, like you mentioned, where. A patient will go on a GLP 1 to lose weight and show that they can lose and maintain to a certain degree before undergoing bariatric surgery as a next step. I've also seen situations where a patient will have surgery and then may gain some of the weight back. And for maintenance therapy, go on a GLP 1 agonist. So, I think there's a lot of ways to do it. Obviously the GI side effects have to be monitored very closely when it's given in conjunction with breccic surgery. And also nutrition is a really important key. To make sure there's no nutritional deficiencies, vitamin deficiencies that can often be seen with bariatric surgery and and, to some degree, potentially GLP 1s if the patient's not eating appropriate, food intake, any appropriate nutrition. So yeah, I think, there's lots of modalities out there now and very effective modalities and I think as, as the procedural complications are even lower metric surgery than it had been 10, 20 years ago. And we get more of the GLP ones in the market. I think you're going to see a competition between the two. And what I'd like to see ultimately would be a trial, a head to head trial. in cardiovascular outcomes. For the two, you don't have any cardiovascular outcomes trials for batch of surgery in a randomized fashion. That's all observational data. I think that's also really important and really needed. So there's a lot more work to do for sure. As when it goes to Patrick

Kanny: 33:16

surgery. Well, yeah, it sounds like there's just a lot of exciting directions that this field is going. And I think I think all of us and, and who deal with, cardiac, cardiac patients every day are, are very appreciative to have more and more options common. I know we could talk quite a bit about even more aspects of these agents, but I think we are up against our time. It sounds like, there's quite a few trials in progress, so I look forward to maybe having you back in the future so you can update us a little bit as this field evolves. In the meantime, we will put some links to the select study as well as to some of Dr. Nealon's publications. Addressing his program as well in our show notes, but I do want to thank you both for joining us and taking the time to educate us a little bit about these agents.

Ian: 34:09

Yeah, my pleasure. It's a it's been a real real fun and happy to do it again. Great. Thank

Kanny: 34:16

you. Kenny. Yep. Thank you both.

34:20

Thank you for joining today's podcast. For more information about the speakers or the topics, please go to Ohio acc.org,