From GLP-1 to Triple Agonists: Transforming Cardiometabolic Care

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Daniel Simon, MD: Thank you for listening to another episode.  Today, I am happy to be joined by our guest, Dr. Ian Neeland. Ian is the Director of Cardiovascular Prevention, the Co-Director of the Center for Integrated Novel Approaches in Vascular Metabolic Disease, and he is the McCamon Family Chair in Cardiovascular Excellence in the University Hospital's Harrington Heart & Vascular Institute. He is also an Associate Professor of Medicine at Case Western Reserve University.

Welcome back, Ian.

Ian Neeland, MD: Thank you very much. Great to be here.

Daniel Simon, MD: It's so great to have you back. You were with us back in 2023 and the pace of change in this field is really staggering. I'm really excited to be able to sit down with you and review some of these big changes. Perhaps you could give us just a very brief update on - really - some of the explosion of new therapies. We've gone from single peptide drugs to multi-peptide in combinations. Just give us a little bit of an overview.

Ian Neeland, MD: Sure. There has been really, an explosion of research and development into new GLP-1 and related therapies. You know, we now refer to them as in incretin-based therapies because it's not just the GLP-1 receptor that they're being targeted. It’s now multiple different receptors in various combinations in various medications.

Just some things that have changed since 2023, there are now dual agonists out there, including both GLP-1 and GIP as well as GLP-1 and glucagon receptor agonist, two different medications. As well as an antagonist, where it's a GLP-1 receptor agonist and an antagonist of GIP.

There’s also a medication, under development, which is a triple agonist, both GLP-1, GIP Glucagon, that's called Retatrutide, and in clinical trials participants on the highest dose of that medication, 12 milligrams, actually lost an average of about 24% of their body weight at 48 weeks. It is the most effective medication for body weight loss that we've seen to date.

And then, another shift in, this whole field has been the development of oral GLP-1s where, you know, it can be more convenient for several people, it's a small molecule, doesn't require injection or refrigeration, and it's given once a day, and there are two oral medications right now under development; one still in a research phase, and one is actually available from the FDA. One is Orforglipron and that has shown significant weight loss in clinical trials, usually about 11% reduction versus placebo, as well as improvement in glycemic control for patients with type two diabetes and various cardio metabolic health markers. 

And then what’s been really exciting and really is hot off the presses in the last month is oral Semaglutide or oral Wegovy, which is now available for weight loss. Oral Semaglutide has been available for diabetes for several years, and here the company's offering it lower out of pocket cost and other approved weight loss medications for those individuals whose insurance doesn't cover medical weight loss. Additionally, there is a shift to trying to compound GLP-1s with other medications in different classes such as CagriSema, which is a fixed dose combination of 2.4 milligrams of semaglutide, which is the active ingredient in Wegovy and Ozempic and also with Cagrilintide, which is a long-acting amylin analog.

There's also Bimagrumab plus Tirzepatide. Here is very interesting, Bimagrumab is actually a blocking antibody of the active in type two receptor, which stimulates skeletal muscle growth, and adding that to a GLP-1 GIP receptor agonist can both improve weight loss but also preserve muscle mass potentially. Those are currently under development.

Also, the field has seen new data come out with regard to cardiovascular outcomes trials. So, we have the SELECT trial and semaglutide showing cardiovascular benefit as well as the SURPASS-CVOT trial, which showed cardiovascular benefit with tirzepatide in patients with established cardiovascular disease in diabetes and there are others, you know, coming down the pipe as well. We've also seen a lot of additional indications for these medications beyond diabetes and beyond obesity. So, obstructed sleep apnea is one that now tirzepatide is approved for to reduce hypopnea index and obstructed sleep apnea patients. It's also, the field of metabolic associated steatotic liver disease or metabolic dysfunction, used to be called NAFLD or NASH. It's a whole field where these medications are making headway, as well as chronic kidney disease.

And interestingly enough, you know, cardiometabolic conditions are also being investigated such as do GLP-1's improve arthritis for patients with obesity and arthritis? Do they impact dementia?

So, these are all, you know, various conditions that are being investigated with GLPs. And then finally I would say the, you know, the side effect profile has become much clearer in the past several years. And so now, there's a focus on muscle loss and preserving muscle mass in patients with, you know, on these medications, where developing significant weight loss, and that's one area that I've been very interested in and in working some in. As well as gastrointestinal side effects…how to mitigate those and, and fatigue. A lot of people have been developing fatigue, probably a combination of fact that they're not eating as much and getting enough fuel, as well as, you know, some of the impact on, on lean mass. So, you know, we continue to find out and look for, you know, how to address new side effects and, and how to help people get the maximum benefit for the medications with the least side effects and increase safety, and really, you know, to help people improve their cardio metabolic health.

Daniel Simon, MD: So obviously tremendous progress and I think the most exciting part are the expanded indications, as you indicated for sleep apnea, for liver disease, and even potentially heart failure with preserved ejection fraction as well as coronary artery disease.

I guess one of the questions that, you know, we all have is that - we know all the success stories, people losing 25 to 50 pounds, changing their life, but then there is the sustainability issue, whether it's economic due to the cost of the drugs, whether it's… I guess you would say fatigue from injecting continuously. Tell us a little bit about what you can anticipate if you stop the drug completely?

What is the weight regain, on average, and are there efforts to either reduce dose, microdose, change, frequency of dosing, maybe turning to pill forms now that could maintain weight loss and benefits without potentially needing the same level of treatment that you use to get to weight loss.

Ian Neeland, MD: Yeah, so this is a very important area, obviously important for patients, for long-term success and unfortunately, we don't have a lot of good hard evidence showing what the best approach is to maintain weight loss over time with these medications.

Certainly, clinical trials have shown that there is weight regain, often, close to the starting weight for patients, although not always. Usually there's a 5% difference, or so in, what a patient may start at and what they may, might regain. But the regain happens essentially once there's discontinuation. It's consistent across several clinical trials. And so how to maintain it continues to be an issue.  

I've seen multiple different approaches that have worked for various patients. These span anywhere from maintaining the lowest dose possible over time or spreading out the dose. So, kind of what we call microdosing, where a patient may be on, a dose this week of medication, maybe wait a week or two, and then do it again. So, kind of spreading out the medication. I've seen switching to pill form, as well, although pill form purportedly has similar efficacy. So, you know, you could decrease the dose again of the pill form by the same similar dose that you can get is going to be the same thing.

I also think it's important to, for maintenance, to address other areas. So, for example, resistance training and protein implementation to maintain muscle mass that can help people maintain long-term weight loss in the, you know, face of medication treatment, when going down on the dose of those medications. It can be very important to, you know, replace fat with muscle. So, gaining muscle rather than fat is a great approach.

And I think that doing additional lifestyle management, things like exercise is important, aerobic exercise. Another thing that's come out about these medications interestingly is that beyond the weight loss per se, there is evidence that it changes one's interest in food and what food somebody eats. So, there's a really interesting study that shows that food choices change on the medications to healthier choices. And so, maintaining those healthy choices, even when stopping or reducing the dose of medication for long-term success is incredibly important, right? Going from a poor, you know, poor diet to a really healthy diet, one doesn't want to go backtrack, once stopping the medication or reducing the dose toward a less healthy diet. So that's, those are all, you know, important factors when considering, reducing the dose or stopping or spreading out the dose over time for maintenance.

Daniel Simon, MD: One of the questions that's looming for a lot of people is, what exactly is the mechanism of benefit? We understand in diabetes that weight loss improves insulin resistance; hemoglobin A1C goes down, and I think we understand that. We understand in sleep apnea, we understand in arthritis you're reducing weight in visceral fat that impairs either the airway or the weight ratio, 3:4:1 on the knee joint, compared to not losing weight.

But there's this notion that these agents, these incretins are anti-inflammatory, that they have additional actions that explain the benefit, for example, in coronary artery disease. Can you talk a little bit about that? I know that you're investigating that. So, what are some of the benefits that we potentially realize that these receptors are more widespread than we think?

Ian Neeland, MD: Yeah, so as you said, these medications impact multiple different organ systems throughout the body. These receptors are present on adipose tissue. They're present on the heart. They're present in endothelium, so there's a lot that these compounds can impact.

I think that there are several reasons why they have cardiovascular benefit that really kind of all work together. Primarily I think that these medications address the crux of what we call cardiovascular kidney metabolic syndrome, which is a syndrome that really stems from dysfunctional and excess adiposity at its very core. And these medications can actually modify and modulate dysfunctional excess adiposity, such as visceral fat, for example, liver fat. So, these issues the source of downstream cardiovascular kidney metabolic complications, and so for the first time we have medication that can actually get to the crux of the matter, the source of the matter.

I do think inflammation plays a very important role. There was a very interesting study that came out of the STEP program with semaglutide in patients with overweight and obesity that showed that inflammation measured by C-reactive protein was reduced and it was associated with weight loss, but weight loss could not explain all the reduction in CRP. So, I do think there is an anti-inflammatory effect of these medications that goes apart, you know, along with that is beyond just the weight loss benefit and partially explain the cardiovascular benefits.

I think the biggest, you know, example of that is the SELECT trial where patients lost about 8 to 9% of body weight, and yet there was a 20% reduction in the cardiovascular outcome. And so, if you look at other weight loss trials in other areas such as lifestyle, for example, the Look AHEAD trial, there was also about 8 to 9% weight loss over one-year in that trial. And yet that trial was null with regard to cardiovascular benefit, in patients actually with higher risks with diabetes. So, I do think that the cardiovascular benefits are not just because of weight loss. I think there are multiple factors, at play including inflammation, including modulation of visceral and ectopic fat, which are primary jars of CTM syndrome, as well as potential impacts on endothelial function. For example, in renal vascular space, it becomes very important modulating fat in the liver, which impacts liver disease, obviously. And I think that we're also doing work looking at sleep apnea because sleep apnea has two components. Sleep apnea has a component of anatomic change, right? Fat cumulation in the neck and the jaw, the mandible and that can impair, you know, anatomically, the airway.

There's also recognition of what we call non anatomic traits or non-anatomic physiological traits. And these are things like loop gain, increased muscle responsiveness or lack thereof…these things are not necessarily body fat related, and so we're looking to see if these medications and other things like SGLT2 inhibitors can modulate the physiology of that as well.

So, there's a lot of very interesting things going on mechanistically with regard to these medications and the general cardiometabolic space and beyond.

Daniel Simon, MD: So, you know, there are some real-world challenges, Ian, in these medications and obviously far and away number one is cost. Now the good news is Novo Nordisk is facing a generic competition starting next year. So that drug is going generic, so the price will come down. We have direct to consumer options now with Lilly Direct and others that are bringing the prices down as low as $250 a month. You mentioned that oral pills will be even lower than that. Do you think that cost will go away shortly with generics?

Ian Neeland, MD: I definitely hope so. I think that the people going into the third-party compounding pharmacy market, which we saw when there were injectables alone were available, shows the market pressure. People want cheaper alternatives and are willing to pay for cheaper alternatives. And I think that the other thing that you have seen in the past several years, the price differences. The prices have gone down substantially from what I started looking into and researching this space. Right now, the oral Wegovy, you can get it for $5 a day. So that is probably the best price that I've seen yet, and it's really because of market forces and competition between the various companies and trying to help people obtain the medication, which is very important for them where insurance has been a big gap.

Unfortunately, you know, Medicare/Medicaid still does not recognize obesity as a chronic disease, and therefore the vast majority of programs, both commercial and non-commercial, don't cover medical weight loss. And so many patients are not able to access these medications for weight alone. So, we've been looking at trying to, you know do some sleep apnea screening to diagnose sleep apnea, maybe they can get it covered like that or doing these direct pay, you know, a direct for manufacturer of pharmacies, which are, have been, I think is, panacea because without that, market forces would not push the cost down. So, I do think with generic coming out, and with the, you know, competition, I think it's a great opportunity for costs to, you know, meet the more appropriate levels that you know, where people can get greater access to them. And so, you know, these medications have great, you know, short and long-term effects, great upside. And so, I think that once the costs come down, people will be, you know, able to access them greater.  

On the other side, it's important to understand that if one were to extrapolate out how many people could potentially have an indication for these medications, be it for obesity or any other, you know, diseases, the total costs, you know, as of today's dollars - would exceed potentially the cost of every other medication out there. So, you know, there's, there's a lot of potential, but also, we need to kind of be cognizant and be good stewards of health resources in this, in this area.

Daniel Simon, MD: Yeah, I think you know, the sobering fact though is that about 40% of the population in Cleveland is obese. And if you look in the United States as a whole, the US is ranked 20th in OECD countries for life expectancy both in men and women. So, we spend four times as much on healthcare - our outcomes are not there - and we have some of the highest rates of obesity. So, this needs obviously, to be sorted out.

Now the final question I have for you is… we have all these new combinations. Side effect profile is a big part of why people stop. So still GI upset is a problem. Are there reduced side effects in the two and three peptide drugs because they're more potent? You can potentially use lower doses for improved weight loss, are some of the combinations with other incretins helping in this space? I mean, clearly people want to continue, but you know, it's the, one to two days after injection that they're still feeling a little bit of this GI upset. What's your experience in that?

Ian Neeland, MD: Yeah, so, generally anecdotally, my experience has been that the dual peptides like Tirzepatide, have been a little bit better to handle for GI upset than the single peptides and whether the GIP component of that modulates some of the GI effects. It's not quite known, but I have seen that.

I've also seen that certain GI side effects can be seen with certain medications. So for example, it turns out that constipation tends to be more common with semaglutide and diarrhea tends to be more common with Tirzepatide and so, you know, understanding a patient's kind of baseline, many patients have issues with constipation chronically, so tirzepatide would be a good choice and, you know, vice versa. So those are, you know, those are important.

I think that counseling patient's and giving them a heads up on how to manage the side effects, what to expect, and that these are normal situations how the medication works and part of the physiology and that it, you know, over time it will get better and people can, you know, work through it. Some people cannot, but the vast majority of people can tolerate these medications at some, you know, dose. And I think that the more potent dosing will allow, you know, a little more flexibility and, you know, how much weight a person really needs to lose and wants to lose and, and how to manage that and you know, how to mitigate that with side effects and come to a nice sweet spot. So, I do think that's really important.

I also am interested to see if the pills are generally better tolerated. In the real-world practice than the injections. Obviously, the pill is absorbed through the GI tract and so there's some breakdown of peptide there, which is why they usually have to give a larger dose. But whether or not that has a better GI side effect profile remains to be seen.  In the trials, it was similar in terms of GI effects, but I think in real-world practice, I'm excited to see how the pills work and what people's experience is on those pills.

Daniel Simon, MD: Well, thank you so much for joining us again today. You know, the progress in the past three years has been breathtaking. I can't think of a class of drugs that has more and more indications, you know, beyond its original, diabetes and weight loss to now as we talked about sleep apnea, liver disease, coronary artery disease, heart failure, and others, the list keeps, growing.

We look forward to having you back, hopefully before three years to learn about some of the new indications in progress and hopefully the fact that these will be covered and be much more affordable for our patients.

Thank you for taking time to speak to us today, Dr. Neeland. To learn more about research at University Hospitals, please visit UHhospitals.org/UHResearch. Thank you.

Dr. Neeland is a consultant for Boehringer Ingelheim, Eli Lilly, and Bayer.

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