In this presentation, Ian Neeland, MD, discusses the use of GLP-1 agonists to reduce cardiovascular disease.
Thank you dr link for that really insightful discussion about SQL T two inhibitors. Um It was really fantastic and I'd like to continue the discussion now by discussing GLP one receptor agonists. And we're going to talk about how they reduce cardiovascular disease risk and really focus on the how when in which to choose for your practice. You're very practical with the data and talk about future options as well. You're my disclosures. So the objectives today our discussion will be having is one to identify which GLP one receptor agonists demonstrated improved cardiovascular outcomes in clinical trials. I'd like to then compare and contrast the individual advantages and limitations for specific GLP one receptor agonists and ultimately identify new agents in development with high potential for cardiovascular impact that we can expect the next 5 to 10 years to have a really big impact on our practice. Um and in a big uptake in the cardiovascular community. We all know that the last several years with S. 32 inhibitors and GOP receptor agonists is really a new paradigm for cardiovascular prevention. GLP ones are endorsed by international society guidelines for patients with Type two diabetes with or at increased risk for atherosclerotic cardiovascular disease. These medications are really a paradigm shift because they focus on many different aspects of metabolic care and the metabolic system to really work synergistically and integrated lee to help improve diabetes and cardiovascular risk. The multi system effects include effects on the pancreas such as increasing insulin stimulation and secretion effects on the cns and hypothalamus have decreased appetite and induce satiety. There's surely cardiovascular impacts and adipose tissue destry distribution or decrease in visceral and a topic. Fat is a big component in my opinion of their action and we also know they reduce inflammation such as c reactive protein and other inflammatory markers. Now these medications are so important because there are no data out there that show that they reduced risk for cardiovascular events and in some cases cardiovascular debt. And for this reason, publications of GLP one initial T two's over time have increased exponentially from their initial show up in the market in 2000 and 10 now through 2000 and 20. Um and in many cases cardiology is coming on board and many cardiology journals will be seeing more and more reports about these medications. Yeah, the impact of GLP one receptor agonists on diabetes and cardiovascular outcomes is so important because they really are at the forefront of efficacy for both conditions. This graph is from a recent review article in circulation that shows on the left the hemoglobin a one C reduction versus placebo for select antihypertensive medications. And as you can see GLP one receptor agonists are at the head of the pack with regard to a one c reduction with a mean reduction about 1.4%. Now the graph on the right shows the cardiovascular death relative risk reduction versus placebo compared with both diabetes medications as well as medications for heart disease such as statins, um anti platelets and anticoagulants and as you can see that laura got tied the GLP one receptor agonists listed here is number three in terms of cardiovascular death, risk reduction and beating out statins to caligula, your pCS, canine inhibitors and other medications. So really these medications are super important and really a key to our cardiovascular practice, both for patients with diabetes. Um and obesity. As I'll discuss now, as I mentioned, the systemic effects of GLP one receptor agonists are multiple and they really hit on every system in the body uh with metabolic inputs. So just to kind of discuss briefly some of the systems organ systems that they impact. Um we'll start first with the brain. So, GLP one is shown to decrease appetite and increase society uh and therefore in many cases increase energy expenditure now with regard to the heart, they have been shown to decrease blood pressure. There are receptors on the heart for GLP ones. So heart rate does go up slightly, although in many trials it's not more than a few beats per minute. Uh And in some pre clinical studies, it showed improvements in myocardial contract, ill itty and cardio protection. Obviously cardiovascular outcomes trials just Sheltie Two inhibitors benefit the kidney GLP ones have also been shown to have kidney improved outcomes, as I mentioned later. Um and some people think that this is through natural recess or other metabolic impacts. Certainly peripheral insulin resistance is impacted by GLP ones. So at the level of the muscle glycogen synthesis increases in glucose oxidation goes up to make insulin efficiency better and improving insulin sensitivity. Uh Near and dear to my heart is adipose tissue GLP one is increased by policies and free fatty acid synthesis and glucose uptake. And what happens essentially is with increasing like policies in the very dynamic fat depots in the body is that they can actually melt away visceral fat and a topic facts such as that deliver to improve the metabolic milieu and they work part and parcel with delivered to do peace at a glucose production and improve insulin sensitivity. The pancreas is a major organ of impact for GLP. One is certainly the increase insulin secretion and decreased glucose and secretion so that that yin and yang bounds between insulin and glucose gun is favorable with this medication. Um and they increased vessel survival and proliferation. So decreasing risk for progression of diabetes and pancreatic insufficiency of the great debate of cells. And then finally one of the big actions for obesity uh specifically is decreasing gastric emptying and G. I. Motility. So uh food moves to the gut slower and appetite is decreased and early society is gained to decrease uh intake of food and improve weight loss and obesity. Now, as I mentioned before, I think reduction invisible capacity is one of the keys to see the outcomes data which I'll discuss. Um And before I get into the nitty gritty of the cardiovascular outcomes trials, I did want to discuss briefly um the impact of GLP ones in this case florida tied On visceral animosity. Now we know for many years now and data that I published back in 2015 showing that individuals with excess visceral adipose tissue that's fat in and around the abdominal organs have an elevated risk for cardiovascular disease. So in the Dallas heart study, for example, individuals in the fourth quintile Uh starting fourth quartile of this role, adequate tissue had over 10% cumulative incidence of cardiovascular disease compared with those in the first quartile, which was less than 5%. So certainly there is a gradation of risk with visceral adipose station. And the good news is is that we know from a trial that we recently published and Lancet diabetes endocrinology is that laura got I can directly reduce visceral adipose tissue Compared with placebo mean change on the background of diet and physical activity. The participants in the study we recently published showed a 1.63% reduction in visceral fat. But people on the radio tied who are randomized that drug showed it over 12% reduction in visceral adipose tissue. As you can see here in this waterfall plot. Almost everybody assigned to their adult side had a decrease in their visceral adipose tissue. Whereas about half assigned the placebo had a decrease in the other half actually increased throughout the trial despite diet and physical activity recommendations. Now let's talk more about the cardiovascular outcomes trials of GLP one receptor agonists. There have now been um eight trials in G. L. P. S. Uh with regard to cardiovascular outcomes. Now in general they've all included patients with type two diabetes and at least established or high risk for atherosclerotic cardiovascular disease. They range from follow up of only a couple of years up to five years. For example, in the rewind trial um and they have very populations, you know, many of them have patients with exclusively established CVD Um such as the Alexa trial and harmony outcomes trial. Whereas other trials have a more of a mixed population between primary and secondary prevention. Such as rewind which only included 32% of patients with established CPD. Okay, what's similar to all of them is that they all included patients with type two diabetes and the mean baseline A one C was about 87 to 8% in general. Um And the difference between an A one C between groups the end of treatment showed an effect obviously as we would expect unlicensed control between 10.32, a little over 1%. Which is what we expect with GLP once. Yeah. Now where it gets interesting is that many of the trials. Okay. The one specifically that I've starred here all hit their primary outcomes of three point major adverse cardiac events or mace and in general the point estimates were relatively similar between all trials. Somewhere between, You know, about a 20-plus point relative risk reduction to about a 13% relative risk reduction. Now, all of the trials here that are starved had a three point base outcome that was positive. And if you break it down into components in general, many of them were consistent, I'll beat with some variation and widening of the confidence intervals with reducing my stroke, heart failure, hospitalization all cause mortality and worsening of apathy. Now, it's important to point out that a only the leader trial showed a reduction in cardiovascular death as one of the component endpoints whereas the others, although it should um some some improvement. There was not statistically significant. It's also important to point out here that the uh Alexa and Excel which are GLP ones that are eggs ending based as opposed to human molecule base did not actually hit their primary outcome for four point base in Alexa and three point base in Excel. Um And also it's important to point out that Pioneer six, which tested semi tied, oral versus placebo. Three point mace was positive. Not significant, but cardiovascular death was highly significant as it was all cars mortality. So in general, I would say that the outcomes are relatively similar across the classes with human molecules being appearing to be more effective potentially than examine based molecules. Um and you know whether it be delayed, blue tide, semi tied, lyric, blue tide alba gu tied. uh, peg leg tied. They all hit. There are three point mason primary outcomes. Um, and so you know, this is important to uh to utilize for cardiovascular risk reduction because you know, we're talking about risk reduction on the same level two inhibitors that in many cases improving that from statins or other medications for exist for example, it pays you are high risk. So in order to understand the class effect on the overall risk of the medications. There was a really impactful meta analysis that was just published online this last month in the Lancet diabetes endocrinology from novice to our colleagues out of Britain. And what they were able to do was to include all of the major cardiovascular outcomes trials for GLP one receptor agonists In a meta analysis and systematic review to show really what are the class based effects on important cardiovascular and renal outcomes. And what they showed was that when you pull all the data together, indeed, there is a significant impact for these medications across the board. Uh and these arrows are pointing to these summary statistics for hazard ratio and risk reduction. You know, for the class. So for example, of three point mace. Uh, there was a 14% relative risk reduction that was highly significant. And this reduction was consistent both for cardiovascular death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke. And then on the right side of the screen, The effect was consistent through all cause mortality, hospital admission for heart failure, which is something that wasn't previously recognized for this GLP one receptor class and was thought to be just as guilty. Two inhibitors. Um, and indeed, a composite Kidney outcome, including macro urban area, was reduced again, something that was thought to be due just improvement, just industrial T2 inhibitors. But now it seems, the GLP ones and similarly worsening kidney function uh, was borderline significant. So, as you can see when you pull all the data together from all the trials, you have a significant reduction in cardiovascular risk, both for atherosclerotic and non atherosclerotic endpoints, including cardiovascular death and all cause mortality. So clearly, these medications are consistent and have a major impact on risk reduction in high risk patients that we see on a daily basis. Now, when you ask about subgroups and see which, you know, which patients would benefit to a greater degree than others. The truth is that the effects were consistent across subgroups which included those with or without established cardiovascular disease. Uh, those who had a high baseline humiliated and see, or a low hemoglobin, a one c those whose duration of follow up was longer short of three years. Um and it didn't matter with regard to the B. M. I was at baseline with the age was at baseline, or even the baseline G fr the effect was consistent across these subgroups without any significant interaction p values. So it's it's very encouraging to show that the point estimates were consistent because that means it's broadly applicable across a wide variety of patients that we see every day. I want to talk about some important points that came out of this meta analysis to really understand GLP one in the correct context. So, first of all, we saw, as I mentioned, that cardiovascular benefits may be restricted to you and based rather than examine based DLP once, although in the meta analysis certainly uh came out there was a class effect, but as you know, only two of the trials that were included um and all those trials were examined based. So it's possible that we should stick to the human based ones as opposed to uh, you know, like said it tied or executives. Um there is a probable class effect and there was no statistical heterogeneity of cardiovascular Vixie across human based molecules. Um and the previous differences that we saw in individual trials was likely due to differences in the population study. Um Indeed, when you pull up together, it's relatively consistent. Now, as I mentioned before, some things that came out of this were interesting because there was a modest but significant class benefit to reduce heart failure hospitalization by about 11%. Um Now that was seen specifically in the two trials testing our big low tide and FP Glenna tied and unfortunately are not clinically available at this time. So it's possible that the finding of heart failure, hospitalization reduction may not be extrapolated to other agents and indeed to trials of laura's all tied and have ref did not show a benefit. So the data are unclear and the jury still out for that despite the meta analysis finding they also found though, was that there was a modest and significant class benefit to reduce stroke by 17% which was seen prior with glue tied. Um and indeed very encouraging because yesterday two inhibitors are not known to influence stroke actually. So this class may be significant in of itself for that. Now. Obviously, there's limited data for cardiovascular efficacy and primary prevention populations as most of the trial studied included only those with preexisting cardiovascular disease and prior events. Um but certainly although the absolute risk maybe lower the relative risk may be preserved. So it may be potentially you utilize double in those populations. And then also we know that there is a multifactorial mechanism of action for cardiovascular benefit has to be because the benefits are independent of a one c lowering and therefore not linked specifically to glycemic control. What all this means is that we really have a big task and a big responsibility of the cardiovascular community here. You know what this could be is are we missing an opportunity for cardiovascular risk reduction. Um This graph shows the prescribing habits by clinician type Uh for patients with diabetes, cardiovascular disease across family internal medicine in purple and the chronology and blue cardiology and red and others in gray. And although cardiology outpatient encounters outnumber those within the chronology in the community by a ratio of 4-1. The prescribing rates in cardiology are woefully dismal. But you know, for 1.4% for GLP ones and 6% fresh guilty tubes. And really, what this means is that we have a call to action to the cardiology community to increase uptake and increase utilization of these medications that are evidence based, reducing cardiovascular risk and very robust for risk reduction and care for our patients. Now, obviously the limitations to such a huge uptake of this medication on a grand scale has a lot to do with costs. And it's known that GLP ones are probably one of the most expensive medications that are currently on the market, especially because many insurances do not cover these medications on a routine basis. Um, as you can see here, the median national average drug acquisition costs, which is what it costs the pharmacy to obtain the drug ranges between the $700 to almost $1000 range. And certainly when you're talking about wholesale pricing toward the consumer, there's a mark up there. And so it's not on Heard of that patients would pay over $1,000 a month out of pocket for these medications. So it's really important as time goes on, that payers reassess and hopefully we can get better insurance coverage for these life saving and sustaining medications in the future. So the question is coming down to brass tacks and practicality, which GLP one receptor agonists should you choose. So I mentioned that first of all, Albarghouti f Pagani tied are not clinically available. So those are unlikely to be used. I also mentioned that the human molecules are probably better than the existing based molecules based on the limited data that we have. And so if you were to ask me, I would recommend going with either the regular tide, which is Victoza doula, Blue tide, which is treeless City or semi tied, which is exempt Colorado tied was the 1st 1. Um it's the only GOP voters after agonists itself with both three point mace and cardiovascular death reduction benefit in this trial itself. Um the downside is it's once daily and it is the most expensive. Now, the upside is that it is available in a dose for obesity which is a 3.5 mg dose given day on a daily basis. Um and so there that's called sex agenda. And so that is available for an obesity medication. Do go tighter. Treeless city is a once weekly medication. Um and it's nice because as multiple doses starting from .575 weekly, all up to 4.5. And so it's, you know, it can be used for more tight tradable effect because the multiple doses. Unfortunately there is no available formulations for obesity currently on the market for this drug. Similarly tied or as epic is a hot one because it's also once weekly there are both subcutaneous and oral formulations which can be helpful in patients who do not want to take a subcutaneous injection. And it's also available in an obesity dose at 2.4 mg called Blagov, which in and of itself is going undergoing cardiovascular outcomes trial as I mentioned in the bed. So those are the three that I would probably recommend. And it ultimately comes down to patient preference uh ease of dozing. Um and the specific patient circumstance that you want to obtain. Now, as I mentioned, there are some new GLP ones on the market coming soon. First of all, the higher doses of MaGA tied called Mago V is now out for weight loss indication in patients without diabetes. Um and there's a cbot ongoing in these patients Called the select trial. And those data should be coming out in 2024 or so. And in this step trial which looked at weight loss here published New England journalists past year, we see that the weight loss effect is huge. I mean almost rivals that of bariatric surgery in some instances. And about a third of participants assigned to this magnitude high dose were able to obtain over 20% body weight loss in the trial. There's also a new molecule uh coming out called her Zepa tight and it's 15 mg once a week. It's interesting because it's a dual G. I. P. GLP one receptor agonist uh molecule. So it has both actions of the glucose dependent insulin trumpet poly peptide plus the GLP one receptor agonists and surpassed to trial in patients with diabetes compared with an active control semi tied. It showed that both people have anyone see reduction and weight reduction were superior to semi tied one mg or the olympic dose. Um and fortunately there is a cbot ongoing and diabetes and obesity and these patients called surpassed cbot. Um and those data should be out Also in 2024 or so. So in summary. Um I hope that, you know, we've had a good discussion today to show that GLP one receptor agonists certainly are indicated for patients with type two diabetes with or increased risk for atherosclerotic cardiovascular disease. The men analysis has shown benefit for three point mace am I stroke all cause mortality and see the specific mortality, heart failure, hospitalization and ckd outcomes. So abroad cardio metabolic profile and efficacy, the benefits were consistent across multiple subgroups and a multi factor mechanism of action is very likely And practically as we discuss, I would choose between lori liu tied tied and semi tied for my patients and obviously costs and lack of insurance coverage is a major barrier. But hopefully that will be continually worked out in the future and something to look forward to new formulations on the horizon with ongoing cardiovascular outcomes trials to further provide evidence and data for benefit in our patient populations. Thank you very much, and it's been a pleasure speaking with you today.
