Beef to Biologics_Final ===

Hello again from the University of Michigan Department of Vascular Surgery. I'm Luciano Del Bono and I'm joined by my co-resident, Andrew Huang as well as our program director Dr. Bobby eu. Howdy. Alright man. What do we got on the docket for today? Okay, so today we're gonna flip the script. We should start off by recognizing that this is a surgical podcast and most of this conversation is going to be about avoiding surgery. That said, today's discussion should hit on some really high yield hot topics. That everyone should be aware of. Now, most listeners will already be aware of PAD and its impact affecting millions limiting mobility, and quietly raising the risk of heart attack, stroke, and limb loss. For decades, medical management has relied solely on aspirin and statin therapy. But today the landscape is changing from PCSK nine inhibitors that drive cholesterol to record lows to GLP one agonists like semaglutide, improving walking distance. To novel Antithrombotic strategies, PAD Care

is entering a new era. And perhaps more importantly, these are therapies that are being advertised to your patients already. So they're coming to clinic, asking about them. They're countless Insta posts, commercials, and even influencers discussing the use of these medications for other purposes. So today, we'll explore the breakthroughs, the evidence behind them and what they mean for patients who just want to keep moving forward, managing their PAD with a prescription pad instead of a scalpel. So to kick us off. Andrew, can you please give us a brief overview of the major tenets of cholesterol management and why it's so important for our patients? For sure. Dander medical management, PAD, typically focuses on smoking cessation, blood pressure management sugar management, and lip controls. Major medical societies from the a HA to the SVS consistently emphasized reducing saturated fat intake. Recommending that you make up less than six to 10% of your daily calories depending on individual risks. That's because saturated fat typically raises LDL, the so-called bad cholesterol promoting atherosclerosis and worsening vascular disease.

This, it does this by disrupting liver cholesterol processing and downregulating LDL receptors, which means more LDL stays in the bloodstream contributing to plaque formation. Meanwhile, unsaturated pets do the opposite. They help clear LDL from circulation by upregulating these receptors. However, LDL is not the whole story. There is emerging evidence that measures other lipoproteins, such as a lipoprotein B levels that correlate with cardiovascular outcomes even more tightly. That said, one thing we have consistently seen is that the lower the LDL levels. That lower the risk of cardiovascular outcomes. And this has led to the SVS recommendation of treating all symptomatic PAD patients with statins. Yeah, Andrew, this is actually pretty interesting 'cause I have a number of patients that come into clinic now and they have these markers. That have been got from either doing blood tests on their own through some commercial company or from their cardiologist, and they actually want to

know what the interpretation of their LDL and A POB levels are. So I really hope we can dive into some of what we should be doing for these patients. Yeah, and that's what we will talk about for the next 30 minutes here. I know it can be pretty tough for them to connect the dots and talk about maybe our recent landscape of what they, this may be more difficult, especially with the recent landscape, with a lot of confusing comments such about man fats, beef tallow, and other dietary changes. This is really important time for physicians to make sure that there's a good understanding of what data is actually available so that we can properly communicate it to our patients. We're often the ones that have to have this face-to-face conversation with patients, especially vascular surgeons, who may sometimes see these patients more often than their primary care providers. Okay, so just let's break this down really quickly between beef tallow. What is it? What's it made of and why has it become such a controversial topic in the nutrition world? Oh man. Are you targeting out the vegetarian in the group? All right, man. Well, beef Callow, I mean, let's just first of all say this,

it's gonna be impossible to address many of the claims that exist out in the ethisphere about some of the dietary changes you can make. So let's just focus this a little bit on. What we know about how they can affect your cholesterol levels and how that may lead to different cardiovascular risk. And, and we'll kind of tie it in with the PAD aspect of it too. So beef towel is the rendered frat fat from cattle. It hurts me just to say it, and it's commonly used in cooking and frying. What makes it nutritionally significant is its fat composition. So it's made up about 50% saturated fat, and I think most people are. Pretty intuitively taken aback when they hear that number because we know when we've been ingrained with these USDA guidelines that saturated fat should make up less than 10% of your daily calories, and that's from a young age onwards. Alright, so one of the key arguments that people often make in favor of beef tallow is that it contains a fatty acid called

conjugated linoleic acid, or CLA. Some early animal studies like one by Hubbard et al, that we'll link to in the show note. Suggested that CLA might improve insulin sensitivity or even reduce cancer metastases in mice. I haven't treated very many mice, and so here's where the problem lies. These findings haven't been replicated in humans and the amount of CLA used in those studies were much higher than you'd ever realistically get from eating beef towel. You'd need to consume around 11 tablespoons of beef towel daily. Just to match the CLA dose used in those mice and even then the health be benefits remain unproven. Meanwhile, what is very well established is the health risk associated with saturated fat. We outlined the link previously, but basically saturated fat impairs uptake of LDL from the bloodstream by the liver. As a result, you have higher levels of circulating LDL and these can contribute to atherosclerotic plaque development. Another thing

I hear a lot about is. Beef towel kind of being a more natural food. I'm sure y'all have heard this. It's kind of like the push we're all making to eat more naturally right now, and the thought is that by being less processed than other quote unquote seed oils, that may make it intuitively healthier and that it's more stable at high heat and doesn't oxidize as easily when frying. Well, what we've seen is that doesn't necessarily translate to health benefits. It's also been shown that plant oils like. Olive oil and canola oil actually remain relatively stable when you heat them up once or even twice. It's these repetitive cycles of heating that seem to destabilize these and lead to the oxidation, these plant oils like olive oil and canola oil, and. Flax seeded oil are actually rich in the unsaturated fats that we talked about before, which may have a role in reducing LDL levels by upregulating, the liver's processing of them. They also have fatty

acids like alpha linoleic acid or a LA. This is found in things like flax seed, GIA, and walnuts, and has been shown to lower LDL levels and reduce cardiovascular risk. So overall beef TA is not a health food. Yes, it's stable for for frying and contains a few minor fatty acids with theoretical benefits, but none of those benefits have been demonstrated in humans and none of them seem to outweigh the well-documented cardiovascular risk. Of saturated fat. We've also seen a lot of villainization of the so-called seed oils, but to be honest, the data don't really support the risks that are discussed. If anything, there's an overall net benefit from the use of these oils like olive oil, which has been shown to improve endothelial. Function and nitrous IDE release, and even canola oil, which has had mixed results, but has not shown an adverse effect, especially when you consider using these oils at so-called normal levels or to replace other foods that would've had higher saturated fat

content. So if you're looking into what fats help to support your health, I think the data pretty consistently point more towards the seed oils than they do towards beef towel. Yeah. Thanks Bobby. So let's try to bring this back to PAD. Specifically, I wanna look at some of the effective cholesterol on measurable cardiovascular outcomes. And want to get more towards some of the trials that have come out recently and influenced our decision such as the four year trial. So when we think about cholesterol management in patients with acro atherosclerotic disease, the four year trial is one of the landmark studies that has changed our approach. And it was published in 2017 by 17 and colleagues, so this was a large, randomized double-blind placebo controlled trial that enrolled over 27,000 patients with established atherosclerotic cardiovascular disease, IE people who had prior heart attacks, strokes or symptomatic PAD, all of whom were already on statin therapy. And

their question was simple but profound if we lower their LDL cholesterol even further. Can we reduce the cardiovascular events even more? But I thought like statins were kind of our best line therapy right now to help lower cholesterol levels. What did they look at to get this done? Yeah, so to test this, patients were assigned to either receive. Evolocumab, a monoclonal antibody that inhibits the PCSK nine enzyme or placebo, both on top of their background. Statin. PCSK nine normally inhibits the LDL receptor in the liver, marking them for destruction by blocking. PCSK nine. Evolocumab effectively rescues these receptors, allowing the liver to clear much more LDL cholesterol from the bloodstream that ends up resulting in LDL levels plummeting by about 60% from around 92 milligrams, down to an astonishing 30 on average. Importantly, this degree of LDL

lowering was achieved safely. Nearly 90% of patients got their LDL levels below 70 and two thirds even dropped below 40 without an increase in neurocognitive issues or hemorrhagic strokes. The relationship between LDL and cardiovascular risk was striking. Strikingly linear meaning the lower the LDL, the lower the risk. Wait, so how low can you go? Can I have an LDL of 10 and look forever or, well, we really haven't bottomed out at this point, so we don't know what the lower limit is. When it came to outcomes, evolocumab made a real difference. The primary composite endpoint, including cardiovascular death, mi stroke, hospitalization for unstable angina or coronary reask. Was reduced by 15% compared to placebo. The secondary endpoint of cardiovascular death, mi, or stroke, was reduced by 20. These benefits grew over time, suggesting that the longer patients stayed on the therapy, the greater the protection, the effects were consistent across all subgroups, meaning those also with

PAD, diabetes and even. Patients whose LDL were already relatively low at baseline In PAD specifically, this translates to fewer heart attacks, strokes, and likely a slower progression of limb, ischemia and vascular events. So essentially, to summarize, the four year trial confirmed that high risk patients, particularly those with PAD or other manifestations of cardiovascular disease, by adding a PCSK nine inhibitor like evolocumab to maximally. Tolerate statin therapy, you can deliver substantial reductions in their cardiovascular risk. It also reinforced the principle that lower is better when it comes to LDL and we really haven't established a lower limit. Achieving those levels once thought to be dangerously low can in fact both be safe and profoundly profe protective. So for our patients with PAD already at the highest risk for cardiovascular events. The four year trial tells us that aggressive LDL lowering with statins

plus PCSK nine inhibition isn't just safe. It saves lives and limbs. Yeah, and I mean, I think we need to temper that trial just a little bit with some of the cost data that these are real expensive therapies with estimated yearly costs of over $14,000 and depending on how you look at the outcomes is gonna in impact whether or not you think this is a cost effective therapy. We actually have two big trials that have looked at this, and one looking just at the cost of the therapy has said, this is probably a little expensive. It needs to get closer to $9,600 mark a year to be a cost effective strategy for our patients. While others have looked at the impact that either limb loss or a cardiovascular event has on a patient's ability to generate an income and the quality life years lost. And say, Hey, this is an effective strategy that is both medically effective and cost effective. So I don't know that the jury are out on what's gonna necessarily be the right number, but I'd say in a lot of

patients, this is a good strategy that makes both economic and as you've pointed out, medical sense. So I think this would be a good time to talk about another class of medications that's in our vascular medical toolbox here. And that's gonna be the GLP one, agonists in particular. We're gonna take a look at the Stride trial, which is a recent trial from 2025. This incorporated GLP one agonists. Think of Wegovy or O oh oh ozempic into our daily or medical regimen here. This was a phase three B double-blinded randomized trial of nearly 800 patients with intermittent claudication, and for some of the listeners here, these are patients who could still walk but are limited in their walking distance by leg pain. These patients received either semaglutide, which is a GLP one agonist, or placebo for 52 weeks. Yeah, and I think Andrew, it's probably important to butt in here and just talk a little bit about the motivations behind this trial. So I would be surprised if any listener of this podcast hadn't heard of either Wegovy or Ozempic or Manjaro.

And that's because these GLP one agonists have become such important medications to help both diabetic patients and those without diabetes for weight loss. But mechanistically, it actually does a lot more than that. So GLP one is an incretin hormone. It enhances glucose dependent insulin secretion, reduces glucagon release from the liver, slows gastric emptying, and that's how it mitigates a lot of its effect with with weight loss. And it even acts in the brain to reduce appetite. Kind of the two hit hypothesis that allows for it to be so effective in weight loss. But beyond glucose control, it's thought to improve endothelial function, reduce oxidative stress, and promote vascular health. And so for a while, there's a few factors with GLP one that seem to be pointing towards its effectiveness in this high risk patient population that we're talking about. Those with PAD. Yeah. And that's what the Stride trial found as well, that patients on glide with intermittent claudication were able to walk further and

longer without pain compared to those patients who were getting the placebo. Their quality of life scores increased. They had fewer needed rescue therapies with medications as, as ol or oxic filing, and fewer of them require went on to require revascularization, which not all the vascular surgeons might be excited to hear. This study wasn't though powered for major limb or mortality outcomes, and all the trends leaned in favor of some semaglutide. Importantly, it was well tolerated and only mild GI side effects were slightly more common in these patients. In context. In earlier PAD trials, ELA isol was able to improve walking distance by about 43 meters and semaglutide in the Stride. Trial was able to achieve a similar magnitude improvement, but with much broader metabolic and vascular benefits in comparison. In fact, this impact was significant enough that the European Medical Agency recently updated his em. Label to include data from the strike. Trial for use in the PAD and the

us. FDA decision is suspected later this year on this topic. Clinically, the strike trial represents a major step forward. It's the first trial to show that therapy can improve walking, performance and quality of life In diabetic PAD, which suggests that a GLP one receptor agonist may protect the bath suture in ways that go well beyond glucose or weight management. The initial targets. For this medication. So together trial sessions, the four year and Stride trial are really redefining what medical therapy has classically meant in PAD, not just slowing disease, but actually helping patients live better and walk further. Okay, so mechanistically, we understand that decreasing saturated fats also helps decrease your LDLs, which improves your cardiovascular. Function. So Bobby, what do you do clinically? Yeah, I mean, I think one of the most exciting things about this is there's a lot more tools to be able to treat our patients before we ever get 'em to the operating room. So when I see a patient in clinic who's got PAD, which the SES.

Currently defines as an A BI less than 0.9 in symptoms like intermittent claudication or rest pain. There's a pretty easy checklist to go down to make sure that you've maximized the medical therapy first. So these patients should be on a statin therapy, sort of hitting that LDL lowering goal that we just talked about, and we'll get back to just what I do in a second if that's not effective. But there's a couple other easy ones. If they have other indications for being on a beta blocker, I'll make sure that they're on that. They should be on a aspirin 81 milligram monotherapy. Or if they've had difficulty tolerating aspirin, we can switch to a Plavix monotherapy. I won't do some things like start Sasol right away because those patients should be confirmed. They don't have congestive heart failure as there's a black box warning for the use of OL in patients with congestive heart failure. But there's a couple easy things to just go through, like we just talked about now, once we've had that initial conversation. And so we've touched on the topics like what their dietary habits are

like. Are they smoking? Can they stop smoking? And whether or not they have good blood pressure control, I wanna see how far they're walking typically. And that walking distance can be something they subjectively report, or it can be something where they've undergone supervised exercise therapy and we have a report on how far they're walking. But you wanna get an idea of where they stand baseline. It's at this point that you can really start talking to 'em about some of these other therapies to help improve their walking distance, like the semaglutide or ozempic. Or you can start talking to them about. Whether or not they need to go on something to buffer the effect of that statin and allow their LDL levels to be even lower, and that's where the umab comes into the conversation. Bobby, do you typically order labs such as LDL or other biomarkers like that regularly in clinic, or do you do a elective on patients? I mean, it's kind of hit or miss. I feel like if there's a patient that you have a good relationship with. The surgeon is in a really unique spot to be

able to sort of catalyze that change. You're often even saying, Hey, listen, you've gotta undergo a major surgery in which we either do some sort of endovascular therapy or an open bypass, or we can start with these medications and I need to get the information appropriate. To be able to know what medications are right for you. And given that choice, a lot of people would just kind of choose the easier side up upfront. I mean, I'd probably do the same thing. Yeah. And do you have a typical algorithm that you kind of work through in how you prescribe some of these cholesterol lowering medications and even taking into consideration whether or not they have intolerance to them? Yeah, that's a really good question. So. In clinic, I have no problem prescribing statins, and I think most surgeons should be empowered to prescribe statins. The rates of myalgia are quite low, and what we initially thought were high rates of liver dysfunction manifest by liver enzyme rises on a check that's typically done at three months. They just don't

seem to be as high of a risk anymore. And so often what I'll do is I'll start them on a high intensity statin, and the a HA actually has pretty clear definitions on what a high intensity statin is. That's a Atorvastatin or Lipitor is its straight name at 80 milligrams for patients that are 75 or younger. And then once they're over 75, that high intensity dose becomes 40 milligrams. And then by the same metric, it's Crestor 40 or or 20. And Crestor is Rosuvastatin. What if patients don't tolerate either of those? Is there good data on any of the other statins or should we just move on? Yeah, I mean, the key thing to do is you can often find something within the class of statins that they'll tolerate. The bigger wall you'll often run into is patients have tried a couple statins, and that's kind of it. They don't want to try another one because of either myalgias or they did have that rare liver enzyme rise in. Those are the ones who you're thinking, you know, ezetimibe may be, start 'em on some Zetia and see if maybe you can help to reduce their cholesterol that way, and

or if you want to go down the evolocumab route. Now, I'll be honest with you, I'll often work with their PCP or their endocrinologist in order to start working on some of these. And that's not necessarily because it's a big hassle anymore, which it, it kind of used to be to get these approved through the insurance. But now that, that's quite easy, it's because, you know, you really want to make sure that you're doing this in conjunction with excellent blood pressure control discussions about changes in their diet, good blood glucose control, and whether or not you wanna add on something like the semaglutide that we talked about. And so these are conversations that should exist. Outside of just the bubble of surgery and really expand to their whole health landscape. Yeah, it really does reinforce the fact that these patients are complex patients with complex medical care and really need a village in order to make sure that they stay healthy and progress well through all their other medical problems. Yeah, you're absolutely right and I mean, I think. This should really empower the surgeons listening amongst this to take hold of the reins because we can really

help to drive better outcomes. For a lot of these patients who are referred to us, oftentimes if you're a vascular surgeon, they're referred to you with the idea of you're gonna revascularize this patient, and I can't tell you how many are actually happy when they know that there's. Some medical therapy options that can keep them from having to go to the operating room. Mm-hmm. Okay. So it sounds like we have a pretty comprehensive plan on how to treat these patients, walking through different algorithms of statins biologics and even including not just the surgeon, but also the primary care physicians. So just wanna say, dominate the beef tallow. I mean, what? Come on man. Sorry. Dominate the day and go blue.