Cholesterol Breakthroughs and Lp(a): New Guidelines, Drug Updates, and What Actually Works

In the span of about the past two months, we got the first cholesterol-lowering PCSK9 drug, which you can take as a pill. Then we also got the first big answer on whether lowering lipoprotein prevents heart attacks or not. And the answer, a spoiler alert, was no, it didn't make any difference. So we've got a lot of sobering news and a very practical question. What do you do actually if your lipoprotein A is high and all the nuances in it? Just because a drug lowers a particular abnormal number, it does not mean a drug actually saves your life. It actually explains everything.

How are you doing? How's everything?

Oh, well, it's crazy. As you know, Layla, I'm kind of in both continents, uh United States and India, all at the same time. So I'm everything everywhere all at once. But I'm practicing in India. I'll still be visiting my hometown, Charleston. So I'll be everywhere.

It's definitely a lot going on and super busy. And just for those who may be tuning in for the first time, a little background on you, Dr. Moran has spent more than 25 years opening blocked arteries and who is frankly ready to maybe have less people need her. So I think that that's also what this conversation is gonna be about as well. And I think another thing with this episode is that it feels kind of like the rules have just changed. So let's kind of hop into it and dive right in. All right.

I mean, it's uh true. It's this is truly an episode where the rules have changed in the world. And in the span of about the past two months, we got the first cholesterol-lowering PCSK9 drug, which you can take as a pill. So that's great. Then we also got the first big answer on whether lowering lipoprotein little A prevents heart attacks or not. And uh, and the answer, uh spoiler alert, was no, it didn't make any difference. So we've got a lot of sobering news and a very practical question. What do you do actually if your lipoprotein little A is high and you know, all the nuances in it?

Perfect. So here's the roadmap of what we're gonna get into. First, the cholesterol drugs that have earned their place. Second, the LPA story, what just failed and why it's not the end. And then third, Dr. Moran's step-by-step plan for patients with high LPA, and then my favorite part, rapid fire.

All right, and one ground rule I uh always have on the show just because a drug lowers a number, it does not mean that drug is going to save lives. And, you know, we've been talking about that. So I would encourage the audience to keep that sentence in your head throughout this episode. Just because a drug lowers a particular abnormal number, it does not mean that drug actually saves your life.

So let's start with the basics for people who may have tuned out of biology class. So, what is LDL and why are cardiologists so obsessed with it? All right, great question.

LDL is low density lipoprotein. It is basically a particle that carries cholesterol through the blood. The problem is that these particles can slip into the walls of the artery and they get stuck. And once they are stuck, the body treats them like an invader. Inflammation starts, there's more buildup, and over the years that becomes pluck. What makes LDL extra special is that we have every kind of evidence against it: randomized controlled trials, retrospective trials, registry analysis, anecdotal stories, etc. The most important thing here is genetics. People born with low LDL have far fewer heart attacks. So uh if you lower the LDL, the plaque actually shrinks. And most importantly, dozens of randomized trials show that when you lower the LDL, events go down. So there you have it. And is that why the new guidelines got a little bit more aggressive, would you say? Absolutely. So in March 2026, the American College of Cardiology and the American Heart Association released a new dyslipidemia guidelines, and they brought back actual LDL goals. For people with established heart disease and those who are at very high risk for heart disease, the goal is below 55 milligrams per deciliter. For people with heart disease, but they're not at a high risk group. You know, they have heart disease, but they've never had a heart attack. That's not a high risk group, it's below 70. So the theme of the guideline essentially lower levels, get them sooner there and stay for a longer time in the low level. And the guideline also talks about APOB or APOB. We just call it ApoB, okay? It's an apolipoprotein B. And um it is basically uh a count of the dangerous particle rather than a measure of how much cholesterol uh you carry. It's especially useful in patients with diabetes, high triglyceride levels, or insulin resistance, where the LDL number can look deceptively reassuring. The new guidelines bring Epo B into the US recommendations for the very first time with goals that mirrors the LDL level. So keep it below 55 if you are very high risk, below 70 if you have heart disease but you're not high risk, or you can keep it below 90 in general, so depending upon your risk, the number of babies for each individual.

Okay, and so the winners start with the statins because I feel like they get a bad rap online. I feel like they're also something that are talked about more so than others. Absolutely.

I think statins, we have talked about statins. I think we have an actual full episode on statins. Uh, statin is truly it's a frenemy. Everybody loves to hate on statins, even though it's such a beautiful, wonderful drug. Statins are one of the most studied medications in history. They work mainly by telling your liver to pull more LDL out of the blood. Are there side effects? Yes, of course. In some people, the muscle aches are real and it's a small subset, but it's there and it's true. But in blinded trials, when patients do not know whether they were getting the actual drug or a placebo, many symptoms people attribute to statins also happen to the people who are not taking statins. So my approach isn't statins for everyone at any cost. It is if you have real risk, then statins are your foundation. And if you can truly cannot tolerate them, then we have excellent alternatives. That's the good news of the past decade. And then can you walk us through some of those alternatives? Okay. Think of it as a toolkit. Okay, you have the acetymabite, uh, which is an old inexpensive pill that blocks cholesterol absorption in the gut. It adds a modest LDL reduction on top of the statins and it has real outcomes data which backs it. Okay. Then you have PCSK9 antibodies, which is evolucumab and allurocumab. These are injections which are given two to four weeks. PCSK9 is a protein that destroys the LDL receptor in your liver. So the LDL is floating around and it needs to sit on a receptor. PCSK9 destroys the receptor, so LDL does not have a place to sit and it's just floating around aimlessly. So you block it, then your liver has more uh access to the LDLs and can destroy more of that. These drugs lower LDL by roughly half or more on top of a static, and both have proven reductions in heart attacks and stroke in patients with established disease. But to add to this beautiful cake, the cherry on top of this beautiful cake, is the important new chapter which came out last year, the Vesalius CV trial, which tried evolucu, which is Rapatha, in high-risk patients, but they've not had heart attacks or strokes at all. And it reduced major cardiovascular events. That matters because when in high-risk patients, when you push the uh LDL to even much lower earlier in the disease, you're getting much more benefits. Then there was this other drug, including, which is a very clever drug, I would say. Instead of blocking PCSK9, it's a small interfering RNA that tells the liver to stop making PCSK9. And after the first two doses, it's an injection twice a year, it lowers LDL by about half. Okay. But the caveat here is the large outcome trials are still underway. It has strong LDL data, but we are waiting on hard outcomes answered.

Wait, you mentioned twice a year, so it's only twice a year?

Yes, that's the advantage of it. Twice a year. And after the loading dose, it's given in the clinic. And this is basically for patients who have compliant issues, who don't want to be injecting themselves every two weeks, or don't want to be taking medications every day. It's almost like a vaccine. You take it every six months, and you can give it even when the patient is hospitalized after a heart attack or something like that. So you kind of prepare and prevent the second heart attack and things like that. The honest caveat, we know it lowers LDL powerfully. The big trials, whether it prevents heart attack, are still finishing up. So give it till 2027, the first quarter, we might have more information about it. And what about the pill that everyone's talking about? Oh yeah, everyone is talking about this. This is big news. Enleasetide, the brand name is Lipfendra. FDA approved it just in July 2026. It's the first PCSK9 inhibitor you can take as a once daily pill. Okay? This was a pretty hard chemistry problem, right? Because PCSK9 inhibitors have been large injected molecules. But this one is a macrocyclic peptide, essentially a ring-shaped protein fragment engineered to survive your gut. In the two-phase three trials, it lowered LDL by 56% compared with the placebo in the broader high-risk population, and 59% in patients with hypercholesterolemia. Side effects were very similar to that of the placebo, which, you know, um diarrhea, dizziness, etc., all of that. So this is great news. You don't have to get injected uh either once in two weeks or once every six months. Instead, you can just pop a pull. You don't need to go to a clinic, it makes life a little bit more easier. So is this the new statin, would you say? Oh no. Do you remember I said statin is the foundation? So this is not a replacement for the statin, but it is an addition. You want this at least a very low low dose statin, and then you give this medication, and then you see the LDL lowering. The outcome trials, you know, we are all waiting for it. Given everything we know about PCSK9 pathway, I'm very optimistic, but optimism isn't evidence-based medicine. Let's be very clear about that.

And then you mentioned bempadoic acid on past episodes. So can you talk a little bit about that?

Yes. Pampadoic acid is a pill that works in the same pathway as the statin, but it is activated in the liver and not in the muscle. That's why it's very attractive for people who get muscle symptoms with statins, then pempidoic acid is an alternative. The trial, the clear trial outcomes, it's an outcomes trial in statin, intolerant patient showed a meaningful reduction in cardiovascular events. The reduction is more than modest, and it's it's proven it does to uh give you great outcomes reduction, also.

And what about the one that's still kind of waiting in the wings, if you will?

Yes, a CTAP inhibitor called Obesetra Pib. They just come up with these names which you can never pronounce, but anyway, this one has a very dramatic backstory. Okay. CTAP inhibitors, these were supposed to be the big blockbusters of the 2000s. They raised HTL, high-density lipoprotein, which is a good cholesterol. The first one was torsi trapib. It raised HTL beautifully, but unfortunately, a lot of people died. So then came Dalcitrapib that also did not work. Then Ivasitrapib came, that also did not work. Then anasitrapib, which is a s uh had a small benefit, but it was never brought to market. So we learned a very painful lesson just because you raised the good cholesterol, you are not getting protective. Okay? Now the new drug, OBC trapib, it works in a different way that actually matters. It lowers LDL and UPOB substantially. In the phase three trials, it lowered LDL roughly by a third on top of existing therapy, and more when you combine it with uh Ezitamaby. The big outcome trials prevail in which there were about 9,500 patients. It's expected to finish by the end of this year. So uh I think we will know more, and the next year is going to be as exciting as 2026 was.

So LPA, can you explain it like I'm smart, but I'm not a doctor? Okay, it is LP little A.

Okay. It is an LDL-like protein or a particle with the extra protein attached called the A, little A. Okay. That extra piece makes it a little bit more stickier, more inflammatory, and more likely to promote clottic. Three things make LP little A unusual. First, it's mostly genetic. Your level is largely set at birth. Second, diet and exercise barely moves it. Third, and the most important, one in five people worldwide have an elevated level and they've never been tested. So imagine one in five people have this inherited risk. Diet and exercise does not fix it, and we've never checked it, even though it's a one simple blood test. So, and that's why when you hear people say my lipid panel, my cholesterol was fantastic, but I still had a heart attack. And why did I have a heart attack? More than likely this was the cause, and it was never, you know, it was not in our horizon for us to even look for it. And the guidelines finally caught up, it sounds like. Yes, finally is the right word because for the first time in the 2026 ACC AHA US guidelines, they recommend measuring uh lipoprotein little A at least once in all adults. It's a strong class one recommendation. The threshold they highlight is 125 nanomoles per liter, which is roughly 50 milligrams per deciliter. This is extremely important to know whether your LP little A is measured in nanomoles Nm per liter or milligrams per deciliter because the value changes. So about that, the risk rises meaningfully. That is, if you have high levels, it is you are at high risk. So if you have 300 to 400 nanomoles per liter, then it approaches the risk approaches what we see in patients with inherited familial hypercholesterolemia. So we have to be super, super, super aggressive about it. So we can find it, but can we treat it? Yes. That's you know, I think we were not checking for it earlier because we did not have uh meaningful ways to treat it. Okay, but now there are several drugs that were built specifically to shut down LP little A production in the liver. The first to finish a large outcomes trial was Pellacarsin from NoArtis and Ionis, which are monthly injections that lowers LP little A substantially. On September 4th, earlier this month, NoArtis announced the LP little A horizon trial did not meet its primary endpoint. More than 8,300 patients with established heart disease and LP little A of at least 70 milligrams per deciliter or were given uh pelicarcid. It lowered LP little A, but it did not significantly reduce the combination of cardiovascular death, heart attack, stroke, or the need for urgent revascularization compared with the placebo.

So let's kind of be honest with all that being said, does this mean that LP little A doesn't matter? No.

This is where I ask people to slow down. Unfortunately, the internet is not slowing down and all this information is being thrown around before we can actually process that. What does it mean? You know, the genetic evidence that LP little A causes heart disease is very strong. That's established. Okay. What this trial tells us is narrower. This drug in this population over this time frame didn't reduce events enough to show a benefit. And there are several possible, reasonable explanations, and we need the full data to sort it out. And uh, you know, we just don't know yet. These patients were very well treated uh and they noted an average LDL was around 66. When background risk is that well controlled, it is harder to show that an added benefit. Okay, that could be reason number one. Number two, absolute reduction may matter more than the percentage. Genetic studies suggest that you may need a large absolute drop in your LP little A to see a clinical effect. A 70% reduction from a very high level may still leave you with a substantial LP little A circulating. Third, the timing of it. LP little A has been working on your arteries since birth, and treating someone with established disease for a few years may be too late to change the story. The way you can't unage a bridge by repainting it. So, and number four, the end point. It included several types of events and some like stroke, maybe less tightly linked to LP little A than heart attack. Here is the key message. We only have a press release. Full results will be presented at a medical meeting. And until we see the subgroups, especially the patients with the highest LP little A levels, I will resist any sweeping conclusion that LP little A does not matter or decreasing LP little A does not matter. All those are hooks and uh, you know, done for virality within the internet realm rather than actual medicine.

And this came right after another big failure in cardiology, is that right?

That is correct. Last month we got the results of the ZUS trial of ZiltiVecimab, an anti-inflammatory drug targeting IL1. And that also came back negative. So it's been a humbling late summer, early fall for the new cardiovascular targets. And honestly, that's healthy. It means the system is working. We don't approve drugs because the biology sounds good. And honestly, this evidence of these two trials, I think people should look at it and think of all those unnecessary peptides, which has mechanistic possibilities and no actual evidence, and people are injecting them into their bodies and kind of take a page out of these trials that just because you lower a number with a drug does not mean the drug is going to save lives. The statement I made in the beginning. So, what do you think is still coming for LP little A? Uh, there are three major programs still in large outcomes trial. The number one is Alpaciran from AGEN. It's a SIRNA given every 12 weeks. In phase two, it lowered LP little A by more than 95% at the highest dose. Its outcomes trials has more than 7,000 patients. Results are expected around 2028. Okay. Then we have Lepodiciran from Lilly, also a SIRNA with LP little reductions around 94% at phase two, potentially dosed once or twice a year. Its trial acclaim LP Litle is large and importantly includes people who have not had a first event yet. That couldn't be dramatic. The results are expected around 2029. Then you have MUBALA. Also from Lily, an oral pill that blocks the LP little A particle from assembling it. It lowered uh LP little A by 86% in phase two, and it's now in phase three outcomes trial. The pelicarsin result raises the bar for all of them. But the deeper reductions and the inclusion of earlier stage patients mean that these are genuinely different experiments.

And I think that this is the part most people are going to want to screenshot. So someone gets their labs back and LP little eight is flagged as high. So what happens next?

Okay. Let's think of it as six steps. Okay. Number step one, confirm and understand the number. Okay. LP little A is usually a one-time test because it's mostly genetic. Check which unit your lab used. Nanomoles per liter is preferred or milligrams per deciliter, which is also common too, and you can convert them perfectly between the thing. So don't panic over a conversion you found online. A practical guide, 125 nanomoles per liter or 50 milligrams per deciliter, and anything above is where risk becomes clinically meaningful. Higher the number, higher the risk. Repeat testing usually isn't needed. The levels can shift with things like menopause, kidney disease, significant inflammation. So occasionally I will recheck. Step two, test the family. Okay. LP little A is an inherited in an autosomal dominant way. Each child of an affected parent has roughly a 50% chance of inheriting it. The guideline recommends cascade screen of the first degree relatives. And if I find a high LP little A in a 50-year-old, I want her siblings and her children to be tested. And it might be the most impactful thing we do in the entire visit. Okay. So if your LP Lickle A is high, there's a roughly 50-50% chance that your children have inherited too, and your siblings have inherited too. So talk to your family, talk to your children. Okay. Step three build the full risk picture. LP licklee is one piece of this giant jigsaw parcel, but you need to look at the whole parcel LDL, APOB, blood pressure, blood sugar, insulin resistance, kidney function, smoking, family history. For women, pregnancy history like pre-eclampsia, gestational diabetes, which phase of menopause are the patient is. The new guideline uses the PREMENT calculator to estimate 10-year and 30-year risk and treats high LP litholate as a risk enhancer. For people in the gray zone, borderline or intermediate risk, I often recommend a coronary calcium scan. The guideline supports selective use generally in men 40 or older, women 45 or older. If there is calcium, the plaque is already there and that changes how hard I push. Okay. And step four, lower what we can lower very aggressively. This is the meat of the whole thing. We can't meaningfully lower LP little A, and the drugs, you know, did not show any good important outcomes so far. So the guidelines approach for LP little A is to intensify overall lipid lowering and aggressively control all the other risk factors. In practice, for my patients with high LP little A, I am pushing for much lower LDL and APOB low levels compared to a patient who does not have. And you know, statins are the foundation. You can add ZIA, then you can add PCSK9 inhibitors or membadoic acid. Then of course, you're still targeting the foundation, which is blood pressure control, blood glucose control, maintaining a healthy BMI or a healthy fat composition and muscle mass, sleep and smoking. All of that together is what is going to reduce your risk of heart disease and stroke.

So do PCSK9 drugs really lower LP little A at all?

Modestly, the antibodies lower LP little A roughly by a quarter, but I don't prescribe them for LP little A reduction. I prescribe them to get the LDL where it needs to be. Any LP little A reduction is a bonus and I'll take it. Okay. And a word of caution on niacin. Niacin does lower LP little A somewhat, but in again, large outcome trials, it did not reduce the events at all. And when I say events, I'm talking about heart attacks and strokes and cardiovascular death. And it caused a lot of side effects. So niacin was flying very high, and it's an over-the-counter supplementation, but you know, the evidence is very clear, it has no benefit and only side effects. And another thing about LP little A, you need to remember is you can't run it down. You can't starve it out or any of that start. Okay, so remember all the things we've talked about. Lower your LDL, control your blood pressure, control your blood sugar, stop smoking, don't start smoking, stop vaping, don't start vaping, and you know, manage your sleep and stress, etc. And then step five, individualized decision. Aspirin and the aortic valve are the two conversations that are individual and not automatic. Okay. Aspirin, uh why aspirin? Why am I even bringing aspirin? LP little A has pro clotting properties. And some observational analysis suggests people with high LP little A may get more benefit from aspirin. But aspirin also causes bleeding. So for people who've had a heart attack or a stroke, aspirin is usually part of the treatment. But people without a known heart disease or stroke, a shared decision with your doctor, weighing your own individual bleeding risk is something which should be high. Okay. Now let's come on to the aortic valve. LP little A with high levels are linked to calcific aortic stenosis, narrowing of the heart's main blood valve. Okay, so literally all the blood in your heart gets pumped out of the heart to the rest of your body via the aortic valve. And if you have high LP little A levels, it can cause stenosis of that valve. So it's important that your doctor listens to your heart carefully. He listens and checks out if you have a murmur or not. And you know, have a low threshold to get that echocardiogram if there are any concerns. And step six, consider a clinical trial. A lot of LP little uh little A trials are still enrolling, and if your levels are high and you're motivated enough, talk to your cardiologist if their center has trials enrolling patients, and you can benefit the larger population. And that if someone remembers one thing from the segment, high LP little A is not a diagnosis of doom. It's not death sentence, it's information, it's one piece of the puzzle, and it's your doctor's job to put the whole, all the pieces of the puzzle put together and take a you know longer look than a closer look. Okay. It just tells me to start earlier, aim lower, and pay close attention. Plenty of my patients with high LP little A levels may never have a heart attack, you know. I so just keep that in mind as well.

And then, okay, so we mentioned rapid fire, so it's that time. So rapid fire, ready? Ready, ready. Okay. So should every adult get their LP little A checked? Yes. At least once.

The 2026 US guidelines recommend it.

Can diet lower LP little A?

Not meaningfully, mostly genetic.

So no. Does the pelicarcin failure mean you stop testing?

No. The risk is real. The drug just didn't prove it could fix it. So no. I will still keep testing for it.

Pill or injection for LDL, which is better?

Mmm, a tough one. The one you'll actually take consistently. So it might be injection for patient A and pill for patient B. Good answer. Okay. So is HDL good cholesterol? It's a marker, not a shield. Raising it with drugs has not helped it. So it's a good cholesterol, but don't worry about it. So next one. Statin side effects.

Real or exaggerated?

Absolutely real for some people. Blamed for more than what they cause. So the complications, the side effects are real. I mean, statin-induced myopathy. I've had patients who had to take other monoclonal antibodies because of intense myopathy. For that patient, it's real, but for most patients, it's not. So it saves more life than it comes. And then lowest LDL you'd worry about? Very low LDL from medications has looked so far in major trials so far, but I don't like single-digit LDL numbers. I keep them in the double digits range. Less than 50 double digits. And most underused test in cardiology? LP little A tied with Epobee.

Okay.

Most overhyped supplement for cholesterol. Anything claiming to be naturally lower LP little A, my answer is show me the trial, man. Show me the evidence. Okay. Red yeast rice. Uh red yeast rice contains a statin-like compound with unregulated dosing. If you need a statin, take a statin. Why are you taking a natural compound which has the statin? I mean, it doesn't make sense. It's measured. It needs to be, you know, people are now taking berberine uh instead of taking metformin. Berberine is metformin. It's just the raw material of the metformin. So take a statin if you need it. Coronary calcium score, worth it? In the right person uh in the gray zone, one of the most meaningful tests we have. But remember, there is also what is called the calcium paradox. There are very young patients who get a calcium score of zero, but they have a lot of non-calcified plaque. You know, this is why it's personalized medicine. It's not cookie cutter medicine. And each patient should be looked individually and with special lenses based on their needs.

And what is one thing that you would tell your 30-year-old self?

You know, know your numbers early and uh, you know, and take charge of your health. For example, I'm a cardiologist and I checked my LP little A just this past year, and it was through the roof. And now I'm on treatment, and I truthfully wish I had checked it in my 30s. So I would love to go back to my 30-year-old self and say, check your LP little A. Absolutely.

And what's the most exciting drug that you're watching?

The SIRNA LP little A drugs, Ulpaceran and Lepodisaran. We will talk about it in 2028.

And last one, hype or hope? The oral PC SK9 pill.

Oh, hope all the way with the outcomes trials uh still to come. I'm extremely hopeful. Absolutely.

And Dr. Moran, let's bring it home. Are there any other thoughts or anything that you want to touch on for this episode?

Yeah, let's uh let's summarize three things. Number one, LDL is still the target we trust the most. And we now have more ways to lower it than what we had. It could be a pill, it could be um injection. We have a lot of ways. Okay, that's number one. Number two, LP little A is real, it's inherited, it's common. Please get it checked. If it's high, please tell your family. Number three, the palacarsin result is a reminder that biology is humbling. Lowering a number is not the same as saving a life. And that's exactly why we wait for outcomes and why you should be skeptical of anyone selling you certainty. So keep that in mind when you're thinking of injecting yourself with random peptides.

Absolutely. Thank you so much, Dr. Roman. And this has been another great episode: infinite health, no fluff, no hype. And if this episode helped you, make sure that you share it with at least one person in your life who has normal cholesterol and a family history of heart disease. That person definitely needs this episode. And make sure you're following the show and your subscribes and sharing it with anyone else who may need it. And make sure that you're following Dr. Moran on Instagram as well at Doc Arassi Moran, D-O-C-A-R-A-S-I-M-A-R-A-N for clips and everything else and all her other great information that she's been posting. And again, subscribe wherever you're listening, whether it's Apple, Spotify, or YouTube. And Dr. Moran is always great to see you, as always. Anything else you want to say before we wrap up?

Well, I mean, this podcast is for educational purposes only, and it's not medical advice. So don't start, stop, or change any medication without talking to your own physician. Several drugs are discussed here, are investigational and not FDA approved. And we are waiting for the outcomes trial, etc. So this is more to stimulate your curiosity and dig for more information.

Absolutely, that's a great disclaimer. Thank you again. I can't wait to speak with you soon. And we'll talk later. Yes, thank you. Bye bye.