GLP-1 Drugs Cut Heart Attack Risk — And It Has Nothing to Do With Weight

SELECT trial explained: does semaglutide reduce cardiovascular risk because of weight loss, or is something else going on? In this video, I break down the SELECT trial and the follow-up analysis examining whether the cardiovascular benefit of semaglutide was directly mediated by weight loss. The answer matters, because the data suggest the reduction in major adverse cardiovascular events was not simply a function of people losing more weight.

I’m a board-certified vascular surgeon focused on cardiometabolic prevention, and in this video I walk through what the SELECT trial actually showed, what the subsequent analysis adds, and why this changes how we think about GLP-1 receptor agonists, obesity, heart disease, and prevention. If you’ve been wondering whether semaglutide’s heart protection is just about the number on the scale, this is where we separate mechanism from marketing.

In this video, I cover:
 • The SELECT trial design and main cardiovascular outcomes
 • How semaglutide affected heart attack, stroke, and cardiovascular death risk
 • The follow-up mediation analysis on weight loss
 • Why the cardiovascular benefit does not appear to be explained by weight loss alone
 • What this may mean for inflammation, metabolism, and vascular protection
 • How I think about semaglutide clinically in the bigger picture of cardiometabolic health

If you care about semaglutide, GLP-1 drugs, cardiovascular disease prevention, obesity medicine, insulin resistance, plaque, and the real mechanisms behind cardiometabolic risk reduction, you’re in the right place.

Question for you: when you think about semaglutide, do you mainly think “weight loss drug,” or has the cardiovascular data changed your view?


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___________________________
🧬 About Dr. Lily Johnston
  
Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

The most exciting thing about GLP1 drugs has almost nothing to do with weight loss. I know everyone talks about Ozempek and Wigovi like their weight loss miracles. And yes, of course they are. They do work for that. But a new analysis from the SELECT trial dropped in the Lancet recently, and it found something that should fundamentally change how we think about these drugs forever. And as a surgeon who has spent years operating on the consequences of heart disease and who now has a cardiometabolic prevention practice, this paper stopped me in my tracks, and I want to walk you through exactly why. Hi, if you're new here, I am Dr. Lily Johnston. I am a board-certified vascular surgeon, but I also specialize in cardiometabolic prevention. So hopefully you never need me as a surgeon. Let's get into the select trial. So I'm gonna start by walking you through the select trial itself, which was published in December of 2023 in the New England Journal of Medicine. And the premise of this trial was to ask the question: does semaglutide, a brand name Ozempic or Wagovi, improve cardiovascular outcomes in patients who have overweight or obesity, but do not have a diagnosis of diabetes? We already had seen some evidence that these GLP1 receptor agonists were helpful in patients with diabetes to reduce cardiovascular events. But the question was: does this work in patients who do not yet have diabetes or who just have obesity and overweight? So that's the purpose of the select trial. I'm gonna skip through the abstract here and we're gonna get right into the meat of it. We're gonna look at the trial population, which patients were included and excluded from the trial. Patients were eligible for enrollment if they were 45 years of age or older, had a BMI of 27 or greater, and had established cardiovascular disease. So the BMI of 27 is important because historically, when we're looking at the reasons that GLP1s are approved for the treatment of obesity, that starts at a BMI of 30. So this is more inclusive than just the treatment of obesity. Cardiovascular disease was defined as previous myocardial infarction, which is a heart attack, previous stroke, or symptomatic peripheral arterial disease. Now we also want to know who's excluded from the trial. Exclusion criteria were a previous diagnosis of diabetes, a hemoglobin A1C of 6.5 or higher at screening, treatment with any glucose-lowering medication or GLP1 receptor agonist in the last three months, New York Heart Association class 4 or the most severe class of heart failure, or end-stage kidney disease or dialysis. Those patients were excluded. Patients could not be enrolled within 60 days after a cardiovascular or neurologic event, or if they planned to undergo coronary, carotid, or peripheral revascularization. So when you're looking at a randomized controlled trial, it's always really important to understand who was and was not in that study so that you know whether those trial data might apply to you or to the patient sitting in front of you. So these patients were then randomly assigned to the drug or a placebo, and they were ramped up to the maximum dose of 2.4 milligrams of semaglutide weekly. And the study sites were allowed to adjust that as patients had side effects or were able to tolerate lower doses. That was all part and parcel. And then we have to look at what the outcome was. So the endpoints. Primary cardiovascular efficacy endpoint was a composite, meaning a combination of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke, assessed in a time-to-first event analysis, meaning it matters how long it takes to have that event. They have some secondary endpoints as well, and we can get into that. I'm not going to go through the statistics here. It's pretty standard for these time-to-event randomized control trials. Let's get into the results briefly, and then we'll talk about the second analysis that talks about why this is so important. So from October 2018 through March 2021, a total of 17,604 patients underwent randomization. Just stop for a minute and think about the power that's involved in this trial. That's a large number of patients. That's really respectable. We had about 8,800 assigned to each group, and we'll look at their baseline demographics here in a minute. Looking at that, the mean age of the patients was about 61.6 years, and 72% of the patient population was male. The average BMI was 33. And again, about 72% of the patients met the BMI criterion for obesity, meaning BMI over 30. And consequently, about 29% of the population was in that BMI 27 to 30 window. Mean A1C was 5.8. So patients were pre-diabetic but not diabetic by A1C criteria. Most of the cardiovascular disease in the trial was represented by a history of heart attacks. So that's three-quarters of the patient population. And most important, I want to bring your attention to the idea that all of these patients were already on what we would consider best medical therapy. So most patients, 90% were on lipid-lowering medications, so statins, repatha, enclycerin, bempadoic acid, drugs of that nature. And 86% were on platelet aggregation inhibitors. So this is like aspirin or plavix. 70% of the patients were taking beta blockers, 45% were taking angiotensin converting enzyme inhibitors, ACE inhibitors, which are blood pressure medicines. And about 30% were taking angiotensin receptor blockers, ARBS, also a blood pressure medicine. So most of these patients were already getting pretty significant medical therapy for their cardiovascular disease. Okay, we are going to skip and talk about the endpoints and the mean change in body weight over the 104 weeks after randomization, so two years, was about 9%, a little over 9% weight loss. So when you step back and think about the big picture of these GLP1 receptor agonists, semaglutide typically is thought to have about a 15% excess body or total body weight loss. The terzeptide, so the GLP1 GIP receptor agonists, is up to 20%. So this is a pretty modest weight loss actually for the semaglutide trials. And that's worth noting. We have the table here. So we're skipping back now to the baseline characteristics of the patient. I have highlighted here for you that they, on average, had a CRP or high sensitivity C-reactive protein of about 1.8. So in my practice, less than one is optimal. One to three is sort of that moderate range, and greater than three or is elevated and increased risk for cardiovascular events. Because 90% of these patients are on lipid lowering therapy, most of them have an uh HSCRP that's less than two. But we're going to see that this is important when we get to the next trial. You can see here baseline levels of LDL cholesterol of triglycerides, which are normal by most labs, but I would consider less than 100 optimal. So they're still a bit elevated. And even though most of these patients were on blood pressure medications, systolic blood pressure was still suboptimal at 130, 131 on average. This is the sort of big picture of the results trial. So in the upper left, we're looking at primary cardiovascular endpoints. So this is that combination of cardiovascular death, nonfatal heart attack, or stroke, and you can see a pretty clear separation even early. So these lines start separating before we get to six months. And that just goes to show you that this medication seems to be acting powerfully even early on when people begin receiving treatment. When we look at death from cardiovascular causes, uh, these lines are a bit more separate, but because that's a much smaller endpoint, they don't see any statistical significance here. And that means, based on how they pre-specified the statistics in this trial, that panels C and D, heart failure composite endpoint, and death from any cause are actually not hypothesis tested. They're showing you the data here, but they'll never show you whether these met statistical significance for a hypothesis test or not, because they weren't really allowed to test it based on how they designed their trial. So even though it looks like there is a reduction here in all-cause mortality, I'm not really allowed to say that there in fact was a reduction in all-cause mortality because we didn't test for it based on how the trial was designed. Okay. When we are looking at the changes that happened in these patients over this time frame in the study, what do we see? I already told you that the uh body weight reduction was about 9%. So the total loss in the semaglutide treatment arm was 9.39, but there was a small amount of weight loss in the placebo arm as well. And when we subtract that, what we get is 8.5% weight loss. And again, semaglutides typically 10 to 15% for all comers. So this is a modest weight loss effect in this particular study. We do see a significant decrease in waist circumference as well, uh, of seven and a half centimeters in the semaglutide group and one in the placebo group for a combined of minus six and a half. We see uh some reduction in systolic blood pressure in the treatment group versus placebo about 3.3 points, which is good. And here's what I think is really exciting the high sensitivity C reactive protein decreased by almost 40%, 37.8 when we look at the subtraction from treatment to placebo. This is very substantial. And we'll we'll see this again when we look at the um sub-analysis here. And the triglycerides also dropped as you would expect by about 15%. So I think that that's the most important thing to take away from the overall select trial. Let's now go to the next paper that came in Lancet that analyzed this outcome by the amount of weight patients lost. So this is the second paper, which is semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements, a pre-specified analysis of the select trial. And this came out in the Lancet in October of 2025. And the pre-specified analysis here is asking the question: does the cardiovascular protection just come from the weight loss? Because I think that that's a pretty intuitive thing. And early on when the GLP1 receptor agonists came out, people said, well, of course there's cardiovascular protection. People lost weight. That is intuitive and expected. Obviously, that happens. And the purpose of this analysis was to dig deeper into how much weight patients lost and whether or not that really accounted for what we see in terms of the cardiovascular protection. And the short answer is it's independent of the weight loss early in the administration of this drug. So let's go through this step by step and see how they come to that conclusion. I'm gonna skip through the abstract here for us. All right, so the select trial, which we just reviewed, has this 17,000 patients with cardiovascular disease. And we conducted a pre-specified analysis of the trial to address two issues. First, the association between baseline adiposity measures, including both total body mass and central fat distribution and mace or major adverse cardiac events. And second, the relationship between the magnitude and pattern of weight loss and subsequent cardiovascular benefit. So they're looking at does the starting weight or body composition of a patient impact their risk for adverse cardiac events? And does how much weight they lose impact any reduction in risk that we see? So I'm not going to go through the selection of the patients. We already talked about that. It's the same as the select trial. This is just another analysis of their data. And what they do here is break out these groups by BMI. So this table here, you're looking at the different categories. So in the leftmost column is a BMI less than 30. So these are patients 27 to 30. Then we have 30 to 35, 35 to 40, and BMI greater than 40. And they're showing you the different composition of patients by BMI here. The demographics are not that important, but I do think what is more important to look at are things that uh tell us a little bit about metabolic status with respect to BMI and the overall cardiovascular health and wellness. So if you're looking at the glycemic status here, you'll see that in the patients with the lowest BMI, only 37.7% of them have a BM, have an A1C, excuse me, less than 5.7. So that's about 40% of patients are less than pre the cutoff for pre-diabetes. This goes down as BMI goes up, which means more and more patients are pre-diabetic as body mass index goes up. Now, again, some people would say that's intuitive, but I do think it's important to point that out and show that in the data here. Obviously, uh the average BMI goes up, waist circumference goes up, uh, systolic blood pressure does go up a bit. And um we do see a bit of a trend in the triglycerides. Now, none of this was tested for statistical significance, so I'm eyeballing it here, but I do think it's important to show you those trends. And what I really wanted to come back to was the increase in high sensitivity C reactive protein by a quartile of body mass index. So they split it here. We showed you the average in the select trial. Here we're looking at the breakdown of patients less than two or greater than two. And what I've highlighted for you here is that the number of patients in any given group with a high sensitivity C reactive protein greater than two goes up substantially as body mass index goes up. So it's 36% in the lowest BMI group and it's up to 72% in the BMI greater than 40 group. Now, I have been preaching for a long time that excess visceral adiposity, fat around our organs, is pro-inflammatory, and that when I see elevation and high sensitivity C reactive protein in my patients with overweight or obesity, that's the first explanation that I go to for why their CRP is elevated. But I'm not sure that that is as well accepted an explanation as maybe it should be. So this goes to show you that yes, indeed, high sensitivity C reactive protein measures of inflammation go up as body mass index goes up. And uh you'll see almost all these patients had a had diagnosis of hypercholesterolemia. And again, we have this breakdown of why they were included in the trial or what kind of cardiovascular disease they had far and away, heart attack is the most common. Okay, so going here through results, they have done a lot of different analyses, but I'm gonna go through and show you where I think we have the most important results. So at 20 weeks, this is about six months into the trial, they measure where patients are in terms of the weight loss and a waste circumference. So at 20 weeks, the changes in adiposity represent about 71% of the weight loss and about 68% of the decrease in waste circumference that were observed at 104 weeks. So that's two years in. And what they're telling you is you get most of the benefit in this first 20 weeks. So if you're gonna see an impact of weight loss, that's when we would expect to see that manifest. Now, when we look at the adverse cardiac events, of the total 127st mace, 142 or 11% had occurred within the first 20 weeks, 52 in the semaglutide group and 90 in the placebo group. And incidence rates between patients receiving semaglutide and placebo had already diverged. So even in the first 20 weeks, we see a pretty substantial difference in events between patients on treatment and on placebo. And I showed you that in the select trial. You see that those lines diverge very quickly and early. In the placebo group, there was no linear trend in mace risk by the amount of weight loss at week 20, but there actually was an effect driven by the higher incidence of mace in patients with 5% or greater weight loss. So wait, placebo group, there were patients who actually lost more than 5% of their body weight and they had increased rates of adverse cardiac events. What's that about? We'll get to that in the discussion. Probably this was uh reflects uh unintentional weight loss from another disease process, maybe cancer, maybe something else. And so if you are unintentionally losing weight and you have a diagnosis of overweight or obesity, that may be a sign that you should go get checked out because you may have an increased risk of mortality. But getting back to the point, in the semaglutide group, there was no linear or nonlinear trend in subsequent mace risk of weight loss at week 20. What does that mean? It means that it didn't matter how much weight you lost in the first 20 weeks. You still got cardiovascular protection if you lost any weight. Now let me show you this in the table format. I think it's a little easier to see here. So this is the sun glutide group here on the left, placebo group here on the right, and weight loss at 20 weeks is right here. What I've highlighted for you is that patients who lost more than 5% had an incidence rate of two. Patients who lost between 0 and 5% also had a weight loss, uh, I'm sorry, a cardiovascular incidence rate of two. So whether you lost more than 5%, 0 to 5%, incidence rate was the same. It was two. Um and it's 3.1 in placebo, 2.3 in uh those two different groups in the placebo group. So it doesn't matter how much weight you lose in the first 20 weeks, if you lose any, you get protection. This is a big deal. What does come into play though is waste circumference. Okay, let me show you that here. And um in this table, now we're seeing further down change in waste circumference at 20 weeks. So we've broken this down greater than eight centimeters decrease, four to eight, zero to four, or an increase. And you can see that this is a linear trend. So the more circumference you lose around the waist, which is a much better reflection of losing that visceral fat, the fat around our organs, the inflammatory fat, the better off you are in terms of reduction in risk for cardiac events. So the people who lost the most circumference went down to 1.8 incidence rate, then it was 1.9, then 2.2, and if you had an increase, you went up to 2.6. So it's not just about fat loss, it's really about the visceral adiposity, the fat around our organs. They do a bunch of additional statistical tests, which I'm not going to go through in excruciating detail. Um, but what I want to show you here is that even though we see this linear trend for waste circumference being important, they did some gymnastics to figure out, well, how important is that with respect to overall the reduction in cardiac risk? And here's what they find. In contrast, an early change in waste circumference was estimated to mediate or mark 33% of the semaglutide reduction in the later risk of mace with attenuation of the hazard ratio. So 33% of the effect is related to waste circumference. That means 66% of the effect of the drug on reducing cardiac events has nothing to do with either weight loss or waste circumference. So what's going on here? I think this is um really interesting. So I'm gonna move on to the discussion and tell you what the authors think. This is all speculation, but I do think it's an important thing to think about. And it means that the impact of this drug could be profound even in patients who don't achieve the ideal amount of fat loss. So we show that early intral weight loss was not related to cardiovascular benefit after 20 weeks. By contrast, there is a linear relationship between waste circumference, which is a measure of central adiposity, and the treatment effects of semaglutide. However, mediation analyses estimated that waste circumference reduction accounted for no more than 33% of the mace effect. These findings suggest that the cardioprotective effects of semaglutide extend beyond its impact on adiposity, with important implications for clinical practice. Now, again, I showed you that the reduction in high sensitivity C reactive protein was 37%, which is on the order of what you get with statin therapy from the Jupiter trial. But we know most of these patients, 90%, are already on lipid lowering therapy. So we get inflammation reduction above and beyond what we see with other medications. I have a Little idea that I'm going to do a whole new other video on inflammation and the other medications like colchicine that are available to reduce that. Let me know in the comments if you want to hear more about that. We'll talk about it another time, but I think it's a really interesting idea. Let's finish up with this paper because I want to talk about the ideas of what else might be going on here. So, you know, although some adverse effects are related directly to weight burden, such as sleep apnea or muscular skeletal complications, other effects are likely to be mediated through the effects of obesity on different pathways, including glycemic control, lipids, blood pressure, and inflammation. So we talked about that. In heart failure with preserved ejection fraction, which is causally related to obesity, the magnitude of weight loss has been shown to predict the extent of improvement in patient reported outcomes. So in heart failure patients, the amount of weight they lose is directly proportional to the amount of improvement they get in their symptoms and in their cardiac function. But that's not what we're seeing with the plaque-related diseases. So again, outcomes were similar among patients who did or did not lose at least 5% of their body weight. In the patients who gained weight, the semaglutide appeared to have less treatment effect on mace, although the extent to which this is non-responder versus non-compliant with drug therapy was unclear. Mace outcomes were more closely associated with waste circumference. We talked about that. Consistent with substantial evidence indicating that visceral fat, more adequately reflected by waste circumference, exerts greater adverse metabolic and inflammatory effects than peripheral fat. And the stronger correlation between changes in waste circumference and body weight in the semaglutide group compared with the placebo group suggests that weight loss induced by semglutide preferentially targets visceral adiposity. So it's this thing. When they looked at patients in the placebo group who lost weight, it was not very well correlated with any changes in waste circumference. So some people lost fat, some people uh had reduction in waste circumference, but there wasn't much correlation. But in the semaglutide treatment group, there actually is a better correlation between weight loss and waste circumference, meaning semaglutide, we think, we hope, preferentially targets that visceral fat. All right, so they talk now here about the fact that this only mediates 33% of what we're seeing. Several potential mechanisms might explain the cardiovascular benefits of semaglutide on mace beyond adiposity reduction. Direct effects on endothelial function and other atherosclerotic pathways have been demonstrated. Recent data suggest a role for GLP1 receptor signaling in the brain, which may modulate systemic inflammation as well as other downstream effects on inflammatory pathways. Effects of blood pressure control and lipid levels may also be important. These pleotrophic, meaning off-target effects of GLP1 receptor agonists on multiple organ systems, indicate a complex network of beneficial mechanisms that might be independent of adipose tissue reductions reflected by weight or waste circumference change. Furthermore, adipose tissue biology undoubtedly changes before the mass of adipose tissue is measurably reduced, and this may in part mediate the earliest effects of semaglutide on mace. The temporal dissociation between weight loss and mace reduction, meaning patients got protection before they lost a huge amount of weight, supports the hypothesis that these and other mechanisms may play a key role in vascular protection. So, all that to say, we don't know exactly what the semlutide is doing above and beyond the fat loss. We know the inflammation comes down, whether it's that, whether it is the GLP1 receptor agonists that we know are in the endothelium on the inside of the blood vessels. We're not sure yet, but it's pretty exciting. And I know that on this channel we are really focused on using nutrition and exercise and our lifestyle modification to get patients where we want to be. And I am willing to use every tool in our toolbox to try to get patients safe and you know protected from these terrible events like heart attack and stroke. So I think understanding what these medications can do and then figuring out how to use them in the most safe and appropriate way. If you want me to talk about how I use them in my practice, I'm happy to do that. I use them very differently than the papers have used them in the past, especially when I'm treating patients who do not have severe obesity. But that's another video for another day. I'd like to wrap it up here. I know you've been with me for a while. Thank you guys for your patience. Let me know what questions you have in the comments below. If you have a minute, please take a second and like this video. Subscribe to the channel if you haven't already. Share it with someone who needs to hear it. And we'll catch you next time. Until then, take really good care.