Good morning. My name is Sheldon Litwin. I'm the Alicia Spalding Pelosi Professor of Cardiology at the Medical University of South Carolina. And I'll be speaking today about the new developments in the use of anti-obesity medications with a focus on their use by cardiologists. So I think as we all know, the prevalence of obesity continues to increase. It's a major risk factor for various forms of cardiovascular disease, especially heart failure and heart failure with preserved ejection fraction. Weight loss can be achieved through a variety of different mechanisms. Bariatric surgery is the most effective but has limited availability. Lifestyle is of course applicable to everybody, but typically there are modest amounts of weight loss that are difficult to sustain over time. And what I want to focus on today is the pharmacological approach that bridges the gap between those two things, because it's clearly more effective than lifestyle. It's more sustainable. There's cardiovascular safety and it's applicable to more patients than bariatric surgery. So again, here's the fundamental problem that we as cardiovascular providers face. And that is we all recognize that obesity is a major issue, that it affects a large proportion of the patients that we see, that it's a confounder for both diagnosis and treatment of many cardiovascular problems. And yet our response to the problem has been, it's not my problem, somebody else needs to deal with this. This is a societal problem. It's a primary care problem. It's an endocrine problem. And I think we as a cardiovascular community have failed to embrace our obligation really to both diagnose this, to talk to patients about it, and most importantly, to treat it. So I'm going to start off by just showing you that weight management actually is effective for important forms of cardiovascular disease. So this was one simple, very nice trial in patients with atrial fibrillation. This was 355 patients who had paroxysmal or persistent AFib and a BMI greater than 27. They were given the opportunity to participate in a structured, motivational, goal-directed, lifestyle-based weight loss program that included face-to-face counseling. And for those who initially lost more than 3% body weight, they were then prescribed a very low-calorie meal replacement. They were prescribed low-intensity exercise, and the goal was to achieve a BMI less than 25. And the primary outcome was AFib burden. And what they saw was that in those who lost more than 10% of their body weight, there was a much greater degree of freedom from atrial fibrillation, both total atrial fibrillation or atrial fibrillation requiring additional treatment. And that was much, much better than those who lost lesser amounts of weight. So this shows that weight management is effective, actually highly effective, for a very, very common cardiovascular condition. Now, this was a lifestyle management trial. And of course, we all know that lifestyle approaches are very challenging because of the issue of weight regain. And so I think everybody knows the story of Oprah Winfrey, who lost more than 60 pounds through a lifestyle approach. And this was her on her show in 2005, showing what 60 pounds of fat actually looks like. And then this is her four years later with issues of weight regain. And so I often hear things like we can't achieve good weight loss because it's too expensive to eat healthy or I don't have access to a gym or so forth. Well, obviously, people like Oprah Winfrey have access to all the best foods, all the best trainers, everything, and yet it's still challenging to maintain weight loss. And that's because there's something called metabolic adaptation that tends to promote weight regain when only lifestyle mechanisms are used to achieve the weight loss. Now, let me talk just briefly about bariatric surgery, and then we'll turn to to pharmacology. So bariatric surgery is clearly effective. There have been multiple meta-analyses and review papers that combine large groups that had bariatric surgery and those that did not. This is one of the more recent publications on the topic. None of these are randomized trials. These are all cohort sort of matched or propensity match studies. And in this particular publication, we can see that those that had bariatric surgery had a large reduction in the primary outcome, which was a combined cardiovascular endpoint. There was substantially fewer ischemic events. There was a very large reduction in heart failure events. And overall, this trial and others have suggested somewhere between 40% and 60% reduction, particularly in heart failure, but also in total mortality. Now, the problem, as I mentioned, is that bariatric surgery is really only available to a relatively small segment of the population. It's expensive. It's not always covered by insurance, and it has potential complications. So let's now turn to pharmacologic weight loss strategies that I think really fill that important gap between lifestyle and bariatric surgery and have the advantages of both of those. So first off, medications are effective. We can achieve up to 13% body weight loss with fentramine topiramate and somewhere between 15% and 22% with the newer agents, typically the GLP-1 or combined GLP-1-GIP agonists that are currently available today. And I would just remind you that we think that somewhere between 7% and 10% body weight loss is enough to achieve significant improvements in cardiovascular health. And as I just showed in the AFib trial, 10% body weight loss was associated with marked reductions in recurrent AFib. So we can do better than that. These drugs are widely applicable. Every patient that we see typically takes some form of medication. The drugs are low risk and, in fact, may actually be beneficial. The effects are sustainable, and there's a very high rate of patient acceptance. So let me start off talking about an older combination. This is fentramine and topiramate, and these are results from the CONQR trial. So the notion with this combination of drugs is that we have multiple appetite regulatory pathways in our brain. And this is a survival mechanism because eating is necessary to survive. If we inhibit one appetite regulatory pathway, there are typically many others that can take over, and so the effectiveness of a weight loss agent is typically not that great, or a single agent. So the idea here is that if we inhibit two different appetite pathways with low doses of two different drugs, we can minimize side effects and perhaps achieve synergistic effects on weight loss. And this was actually borne out in this trial where we saw, as I mentioned, about 13% weight loss with a combination of low-dose fentramine topiramate. This is at a year, and then this was another subgroup that was sustained out to two years. So almost no lifestyle weight loss program has achieved sustained weight loss that persists past a year. Typically after six months, there's weight regain. So this is great. Associated with this weight loss, there were very beneficial effects on serum lipids, and in particular, a 25% reduction in triglycerides, but also a 10% improvement in HDL. Along with that, there was a reduction in systolic blood pressure of almost five millimeters of mercury, which is comparable to what we would get by adding at least one blood pressure medication. There was improvements in insulin sensitivity. There was reductions in inflammatory markers, and associated with these beneficial effects was a mere 1.7 beat per minute increase in heart rate, which is really important because everybody thinks that fentramine should not be used in patients with cardiovascular disease because it's a sympathetic stimulant. And in fact, this increase in heart rate is very small. It's comparable to what's seen with GLP-1 agonists. And importantly, there was no sudden deaths and no MACE in the fentramine topiramate group in this trial. So I'm a big fan of these drugs, and I'll tell you a little bit more about why I think that's so important. But before I do that, let's turn to the new agents that have garnered so much attention worldwide. And these are the GLP-1 and or GLP-1-GIP agonists. So GLP-1 stands for glucagon-like peptide one. And GIP is the glucose-dependent insulinotropic polypeptide used to be called gastric inhibitory peptide. And these drugs are called incretins. And the reason that they're called that is that they stimulate insulin secretion. So that's sort of the short of that in response to a meal and they inhibit glucagon. And it's been shown that oral glucose leads to a much higher insulin response than IV glucose. And that's because these hormones are released from the intestines in response to seeing glucose delivered to them. So native GLP-1 is very rapidly degraded by an enzyme called DPP-4. And we have drugs that block DPP-4, but it turns out that they're not nearly as effective, certainly not for weight loss, and also not as good for diabetes control as the GLP-1 agonists. So the short half-life of GLP-1 is an issue. So when they were developed pharmacologically, they found that adding a fatty acid side chain allowed binding of the compounds to albumin after subcutaneous injection. And this blocks degradation and prolongs the half-life and makes it so that these drugs can be given just once a week subcutaneously. And that's actually a big advantage. So these drugs induce weight loss mainly through central appetite suppression, but they also have other effects that some people think are important. They increase insulin sensitivity. They delay gastric emptying, which is thought to make people feel satiated for a longer period of time after ingesting a meal. They block glucagon release. And there may be other effects. So all of the mechanisms that induce the weight loss are not entirely clear. The potential concerns about these drugs are some possibility of increasing pancreatitis. And in early studies with laboratory animals, there seemed to be an increase in medullary thyroid carcinoma, which is a very rare form of thyroid cancer that's associated with a syndrome called multiple endocrine neoplasia 2. So anybody that has a history of these things, it's relatively contraindicated to use these drugs. Now, these are the initial data. Semaglutide was the first GLP-1 agonist that has made it to the market for weight loss. And there's been a large series of trials with this drug and the other one, trizepatide, that I'll show you shortly. In this trial, it was shown that use of semaglutide in mostly healthy young to middle-aged women was associated with approximately a 15% reduction in body weight that was sustained out past a year. GI side effects, particularly nausea, vomiting, to some extent constipation, and others are prevalent, but they are generally manageable with slow titration. And I think this is evidenced by low dropout rates in the trials. I would also point out that the injection of these drugs is very easy. The needles are extremely small. They're virtually painless. They come on preloaded syringes that make it really a relatively simple process to do the injection for almost any patient. And the newer drug, the so-called twincretin or trizepatide, it's called that because it affects both GLP-1 and GIP, has been associated with even larger reductions in weight. And in this trial called CERMOUT1, we actually saw up to 22% reduction in body weight that was sustained out, again, more than one year. Now, this is kind of interesting. So these drugs were initially developed as drugs to treat diabetes. And so we see that in this particular trial, the the step two trial, that the amount of weight loss achieved with semaglutide was actually lower in diabetic patients compared to those without diabetes. And we got about a 10% body weight reduction, which is still fantastic, but it is important to recognize that something about having diabetes seems to blunt a bit of the weight loss response. But despite that, we can see that when we look at reductions in A1c, that the results of these agents are phenomenal, where we can take A1c levels down from the mid-8s down to the mid-6s. So prior to the advent of these agents, it was really unusual to see many patients that achieved the goal A1c less than 7. So they're fantastic for diabetes. They work for weight loss, but not quite as well in that population. Now, this is a really interesting study. This is looking at terzepatide versus glargine insulin, and the study was called Surpass 5. And the goal of this trial was to either add terzepatide or increase glargine with the goal of reducing hemoglobin A1c. And what we saw in the trial was that with almost an 80% increase in the dose of glargine insulin, that we were able to achieve about a 1% absolute lowering in A1c levels. In contrast, by adding terzepatide, we were actually able to get about a 2.5% reduction in A1c levels, so two and a half times greater effect. And with that, we can see that especially at the highest dose of terzepatide, that there was actually a reduction in the insulin requirements. And here's what I think is most important about this trial. The group that received the glargine insulin had about a five-pound weight gain over the nine-month course of this study, whereas those who were treated with terzepatide had about a 25-pound weight loss. So obviously, when we're treating diseases that are caused by obesity, giving a drug that causes more weight gain that then causes more insulin resistance that then causes more need for insulin is problematic. So clearly using a GLP-1 agonist is preferable to trying to escalate doses of insulin. And I think that the concept of de-escalating insulin use is one that's really important because it can help interrupt that cycle of progressive weight gain. Now, it is important to know that these drugs only work while they're being given. So this has been looked at with semaglutide as well as other trials. And when the drugs are stopped, it's shown that people relatively rapidly regain most or all of the weight that was lost while they're receiving the medications. So this is a cardiovascular outcomes trial with semaglutide. It was called SUSTAIN-6. These are diabetic patients and looking at cardiovascular endpoints. And it was shown that there were significant reductions in coronary events or myocardial infarction, reductions in stroke, but no change in overall cardiovascular death. And it's been shown in And it's been shown in other trials as well that there are renal protective effects of these drugs. They may be indirect effects due to improvement in diabetes, weight reduction, et cetera. And there may also be direct effects of these drugs on the kidneys. But regardless, they don't hurt kidney function like many other drugs do. And they seem to be protective. And importantly, they can be used down to an EGFR of 15 and maybe even lower than that. So again, this is important because there are many, many drugs that we have to either dose adjust or not use at all in patients with significant kidney dysfunction. Now, I just showed you the cardiovascular outcomes from this trial where there was reductions in stroke and myocardial infarction. But interestingly, in this particular trial, hospitalizations for heart failure were not reduced. And there was actually a numerical increase above one with heart failure risk. And there have been a couple of other heart failure trials with GLP-1 agonists that thus far have failed to show a significant benefit. Now, this is interesting and important. I will note that the trials done to date really were not geared toward heart failure populations and may not have been adequately powered to pick up reductions. But at this point in time, we don't know if these drugs actually improve heart failure outcomes. So the current status of the GLP-1 agonists, loraglitide or Saxenda is still available. This is a drug that requires daily injections. It's not nearly as effective for weight loss as the other two that are shown here. Somaglitide, or the brand name Wogovi, which is the weight loss version of somaglitide, given by weekly injections, and trizepatide or Monjaro, also given by weekly injections. Currently under FDA review for weight loss, it's expected that in the very near future, it will receive approval for this indication. Now, we know that these weight loss medications are underused in the United States. That is changing somewhat in the current era because of the very public knowledge about the effect of somaglitide and trizepatide. But until recently, less than 2% of eligible patients in the US actually got any weight loss prescriptions. And many of those were for drugs that really are not very effective, like oralistat. So as I mentioned, the uptake is clearly changing, but cardiologists still rarely prescribe these agents. And this is something that I feel needs to change. So why do we not use them? There's a lot of reasons. One is that there's lack of familiarity and knowledge. People feel like they don't have enough time. There's competing demands. There's perception that patients are not motivated, low confidence in ability to treat and change patient behaviors, futility. And I think there's still a stigma that obesity is not a disease, but rather it's just a failure of the patients to do what they need to do. And that is something that also needs to change because we can help people lose weight and it will help them certainly in terms of ischemic heart disease and stroke, and hopefully with heart failure. So this belief that obesity is a personal failure is a major problem. And it's something that we as a healthcare community still need to do much better at. So I would just point out that obesity is our problem as cardiologists, because so many of our patients suffer from this problem. And we need to take ownership of it. And in general, cardiologists are really a bold group. I mean, we do all kinds of crazy things. My interventional EP structural colleagues are putting ECMO and impellas and epicardial VT ablations and valve-in-valve procedures and all kinds of stuff that most people think would be very scary. So why is it that we would be afraid of prescribing weight loss medications? And I had an astute primary care colleague that said to me, cardiologists will do anything except prescribe medications they're not comfortable with. So again, the key is to just get comfortable with these. They're not difficult and they really don't need to be scary. Cost issues are the current big barrier to the use of most of these agents. They are still not covered by insurance in most cases. No one wants to deal with preauthorization. There's exclusions from Medicare. And the out-of-pocket costs for the GLP-1 agonists, for semaglutide and trisepatide is about $1,300 a month at the present time. Now, I will point out that for fentramine topiramate, these are both very old drugs. Fentramine's actually been on the market for more than 50 years. There are generic equivalents that are available. And these drugs can be obtained for 25 to 30 cents a day without any insurance coverage. And so we don't have to deal with preauthorizations. We can just write a prescription for these medications. They can take it to their pharmacy of choice or look up the cheapest place on GoodRx and get them for $10 a month. And although they're not quite as effective as the GLP-1 agonists, and there are some concerns about cardiovascular safety, I think those concerns are overblown. And when we talk about a 13% potential weight reduction with fentramine topiramate, that's something that's still very significant and important to many of our patients. So another word on fentramine, it's a controlled substance because it's related to amphetamines, but it's known to have very low or no addiction or abuse potential. The side effect profile is actually quite low and probably lower than that of the GLP-1 agonists that cause very frequent nausea. Although there's concerns that it causes sympathetic activation, it actually lowers blood pressure quite effectively. And as I mentioned, heart rate only goes up by one to two beats per minute. So I think the fears about cardiovascular safety of this drug are unfounded. So a couple of practical tips, particularly about GLP-1s. So we need to help patients overcome the fear of injectable agents, which is a big issue for some patients. We can show them the injector system. Sometimes they can get a first injection in clinic. And when they see how simple it is and how painless it is, that may help. By starting at a low dose and escalating slowly, we can help minimize the GI side effects. Adjustments to diet, especially in the day or two after people take their dosing of these agents, can help reduce nausea or vomiting. And we can eliminate other diabetes medications that have no cardiovascular benefits. So people love to get off of medications. So sulfonylureas in particular, and as I mentioned, particularly de-escalating insulin. So taking a once a week injection and then getting rid of a daily pill or other daily shots is something that's very desirable for most patients. And I would just say prescribe these yourselves. Don't count on primary care or someone else to do it for us. So there are ongoing trials of anti-obesity medications, particularly in heart failure. So the summit trial is looking at truzepatide in patients with heart failure preserved ejection fraction. Enrollment will be ending in the next month or two. And then we will have outcomes data within a year or two after that. There are two trials looking at semaglutide in HEF-HEF, one in diabetic patients, one in non-diabetic. Enrollment has been completed in these trials. And again, we are waiting for outcome data in the next one to two years. There are renal outcome studies in diabetic kidney disease, ongoing with semaglutide, and many trials in NASH or a variety of other diseases, sleep apnea, arthritis, et cetera, that are being performed with these medications. There are also an exciting pipeline of new drugs in development. There are other incretins that are being targeted. So GLP-1, GIP, glucagon, various combinations of these things, isolated GIP, agonists. There are drugs that are being called controlled metabolic accelerators, like this drug HU6 made by a company called Revus that actually causes mitochondrial uncoupling. And rather than being appetite suppressant, is actually targeting fat directly and potentially causing fat loss without changes in food consumption. There are other mitochondrial uncouplers. And then a variety of other novel approaches that are using very different strategies, but there are many, many new things in development that are exciting that we will undoubtedly see more of in upcoming years. So in conclusion, weight loss reduces the risk of atrial fibrillation, heart failure, MI, stroke, and survival. Most of the data thus far on these things is with bariatric surgery, but some of the data, especially for MI and stroke is with GLP-1 agonists. Lifestyle is great. It's important adjunct to pharmacotherapy or bariatric surgery, but it's rarely effective by itself in the longterm. Bariatric surgery works really well, but has limited applicability at the population level. And medications, particularly the GLP-1, GIP agonists are highly effective. They have proven cardiovascular benefits, but I would encourage you to consider the older medications, fentamethylpyramide for those who, for whatever reason, don't have access to the newer drugs. And there are many more novel agents on the way. So stay tuned. This is an exciting field. It's an exciting time. And I hope, again, that we as cardiovascular providers will embrace the use of these medications and help our patients get access to them so that they can achieve a healthier life. And I thank you very much.

anti-obesity medications

cardiologists

obesity

weight loss

cardiovascular diseases

pharmacological interventions