Is Lower LDL Actually Better? New Research Has an Answer

Is lower LDL cholesterol actually better for your heart? In this video, I break down the brand-new results from the EZ-Pave study to answer the question that keeps my patients up at night: How low should your cholesterol really go? 

As a vascular surgeon, I see the end-stage results of heart disease every day. 

We’ve heard the "lower is better" mantra for decades, but new research is finally providing the hard evidence we need to settle the debate. 

Study link: https://www.nejm.org/doi/full/10.1056/NEJMoa2600283 

We’re looking at how LDL cholesterol levels impact actual cardiovascular events and whether adding medications like ezetimibe truly changes the outcome for your heart health.

If you’ve been skeptical about statins or confused by conflicting health trends, this breakdown of the latest science is for you. My mission is to put myself out of business by giving you the truth about prevention before you ever need to see me in the operating room. 

For educational purposes only. Not medical advice. Always consult your healthcare provider before changing any treatment plan. 

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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

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A paper just came out about intensive LDL cholesterol lowering therapy in patients with atherosclerotic cardiovascular disease. And it's one more piece of data in our whole compendium of does LDLC matter and is lower better? Let's take a deep dive into this paper published in the New England Journal of Medicine just last month. If you're new here, I am Dr. Lily Johnston. I'm a board-certified vascular surgeon who treats plaque in the arteries, but I also specialize in cardiometabolic prevention. So hopefully you will never need me as a surgeon. The paper is titled Intensive LDL Cholesterol Targeting an Atherosclerotic Cardiovascular Disease by Drs. Kim and colleagues for the EasyPave investigators. This is a group out of South Korea who published this paper. So I'll just read the background here in the abstract. Despite guideline recommendations, evidence from randomized trials evaluating the appropriate low-density lipoprotein cholesterol target for secondary prevention in patients with atherosclerotic cardiovascular disease remains limited. So already we know this is about patients who've had heart attack, stroke, or PAD peripheral arterial disease, and we're under trying to understand how aggressive we should be in lowering the LDLC or LDL cholesterol. Let's go through the methods here. Trial population. So what is, how are they defining ASCVD and who gets to be included in the trial? Patients were 19 to 80 years of age, and the definition of ASCVD was previous occurrence or presence of at least one of the following. Acute coronary syndrome, meaning myocardial infarction or unstable angina, stable angina with imaging or functional studies, coronary revascularization or other arterial revascularization, stroke or mini-stroke TIA, or peripheral arterial disease. They excluded patients who had an LDL cholesterol less than 70 milligrams per deciliter without statin therapy. This was a randomized, but it was an open label trial. So what does that mean? It means patients and providers or physicians knew which group the uh participants were assigned to. So even though they're randomized, everybody knows who's in which group. So the patients were randomized in a one-to-one fashion, and they were randomized to a group where the target, the goal, LDL cholesterol, was less than 55 milligrams per deciliter, and the other group was less than 70 milligrams per deciliter, which, if you've been paying attention, is sort of what we think of as the general target for most patients with secondary prevention these days, is less than 70. Many of us who are kind of lipid nerds will be more aggressive in patients with enhanced risk factors and drive that less than 55 milligrams per deciliter, but we don't have data about exactly which of those is better. So that was the whole point behind this trial. The patients were stratified based on acute coronary syndrome, presence or absence of diabetes, their baseline LDL cholesterol levels, and they also had random assignments to different treatment protocols. So patients were potentially on statin monotherapy or statin plus a zetomide. And if they were on statins, they could be on either Rosuvastatin or a Torvostatin. Those are the two that can be eligible for high-intensity statin therapy in our modern era. This gets complicated because they actually did have an option to escalate therapy in patients to PCS canine inhibitors or other agents. We'll talk about how often that really happened and whether I think that confounds these data, but it is a little bit messy in the sense that the treatment protocol was variable despite assignment, and the real goal was just to get the cholesterol level down to below the goal. And so what I've highlighted here, increasing the statinose and adding azetomide were recommended before consideration of PCS canine inhibitors. So they did recommend sort of a standard escalation in statin dose, then adding azetomide, then going to PCS canine inhibitors. They followed these patients for three years. Follow-up assessments were performed baseline, one month, one, two, and three years. And they used the national database to validate their survival outcomes. So they have a Korean national health insurance database, and they were able to adjudicate survival based on that. What was the endpoint of the trial? What were we actually measuring? This is another composite endpoint, meaning a combination of death from cardiovascular causes, nonfatal MI or heart attack, non-fatal stroke, any revascularization or hospitalization for unstable angina at three years after randomization. They had secondary endpoints, including efficacy and safety measures. And they also did multiple analyses of the different combinations of the endpoint. And I think we'll see that a little bit later in the results. Okay, so going down through their statistical analysis, they do go through their power calculation, meaning they looked at how many patients they would have to enroll. So they estimated enrollment of 3,448 patients would provide the trial 80% power to detect about a 25% lower relative risk of a primary endpoint in three years. Okay, I'm gonna scroll through this because the statistics are not that exciting, which is a good thing. All right, results. So patients were enrolled January 2021 through July 2022. They underwent randomization at 17 sites. This is a pretty broad-based trial, and I think that's helpful in terms of understanding the generalizability of the results. You know, if it has if it's only done at one place or two places, then you wonder, would it be the same if it were done in many, many places? Many, many places increases our variability, but it also, in my opinion, improves our generalizability of our trial results. So they achieved their enrollment targets and at baseline patients were pretty pretty well balanced. Mean age of the patients was about 65 years old, and only about 21% were women. So this is again, if you've heard me talk about the perils of cardiovascular research, uh, we know that women are generally underrepresented in these trials. We're this is an important point we're gonna come back to because the impact of intensive lipid lowering therapy was not actually significant in women. But uh I think that that's an underpowered issue rather than, well, we don't know, but let's just say that they did not have uh as much representation of women in the trial as you might like to see. Their median LDL cholesterol level at enrollment was 76 milligrams per deciliter. And just breaking down, you know, what were the general criteria for inclusion? Most of the patients were previous acute coronary syndrome, about half had stable angina, many had had revascularization, 67%, 3.8% had a stroke or TIA, and less than 10% had peripheral arterial disease. So they go through at the different time points, sort of what was the degree of patient, like the number of patients who were on high-intensity statin therapy versus other things. What I want to highlight down here is the number of patients who ended up on PCS-K9 inhibitors was ultimately really quite small. Uh, PCS-K9 inhibitors were in use by 0.2% of the patients in the intensive targeting group at one month, and by 0.8%, 1.4%, 2.3% at 1, 2, and 3 years, respectively. And in the conventional targeting group, it was less than 1% at three years. So it was 2.3% in the intensive group, about 1% in the conventional group. Overall, PCS canine inhibitors were pretty small contributor to the treatment strategy in this trial. Okay. How many patients stopped taking their medications or were uh limited by side effects? A total of 110 patients, 62 in the intensive group and 48 in the conventional group, discontinued LDL cholesterol-lowering therapy or underwent a downward adjustment in the intensity of therapy despite not reaching the target LDL cholesterol levels, with the primary reason being an adverse event in 85 patients and um 50 in the intensive group and 35 in the conventional targeting group. Okay, so these are the baseline characteristics here in this table. Mostly these are going to be pretty well balanced. Again, as a randomized controlled trial, we would expect that to be true. I'm not going to belabor this point just as a general observation. About 70 to 75% of the patients have high blood pressure, about 40% have a diagnosis of diabetes. 23 to 25% are current smokers. And at time of enrollment, they are generally on moderate intensity statin therapy, 67 to 68%. Only 22 to 23% are in high-intensity statin therapy, and about less than a third, 28 to 29%, are on azetomib at baseline. Okay. So looking at the figures here, and I have not actually gone through these results in detail yet, so we're gonna do a little uh bit of Discovery Journal Club here together. LDL cholesterol levels. So they are pointing out to you here with this graph what has happened as at their follow-up time, right? So they did this one-month follow-up, 12 months, 24 months, and 36 months. They're showing you that indeed there was a significant difference between the LDL cholesterol levels in the conventional targeting group and the intensive targeting group. So they did what they intended to do, which was really drop that level much lower in the intensive targeting group. And now they're gonna show us the Kaplan-Meyer curve of the primary endpoint events. Again, this is that combination of revascularization, cardiovascular-related death, or non-fatal cardiac events. And what you'll see here is that the lower line, meaning reduced levels of events, was seen in the intensive targeting group. And we start to see separation really even at six months. Now, I don't know whether that would be statistically significant, but uh just visually you can see that that does begin to separate even well before the one-year mark. All right. What else do we have here in our tables? Primary endpoint. So we had this composite event in 100 patients in the intensive targeting group. So that's 6.6% of the patients versus 147 or 9.7% of the patients in the conventional targeting group. And that is a difference of an absolute difference of 3.1 percentage points, and that is statistically significant. If you come down here, we can now look at the individual endpoints and see what really drove that composite event. So when other people have looked at this paper, there was mention that in fact what really drove the outcomes here was revascularization. And in an open label trial, that's a little bit concerning because that's sort of one of the things that is most likely for people to be able to impact, right? A doctor can make a decision whether a patient needs to be revascularized or not, and perhaps that is related to bias in the trial versus death, which is really not something that the investigators or the people on the care team could impact. So if you look at death from cardiovascular causes, we don't really see a significant difference here. Uh, one versus 1.2%, and that is not statistically significant. I will point out that in a three-year study, death from cardiovascular causes is going to be sort of the least likely thing to happen. And so I'm not surprised that we don't see a huge difference just in cardiovascular mortality at a three-year, in a three-year time frame. But if we kept following these patients out longer and longer, eventually I would potentially expect to see this be a significant finding if we gave it enough time. In terms of non-fatal myocardial infarction, this is significant. We see that it happens in 0.8% of the intensive group versus 1.7% in the conventional group. And looking at our hazard ratio here, that's uh 0.46 with a confidence interval of 0.23 to 0.91. Nonfatal stroke was not significantly different. Any revascularization, this was much different. Again, 4.8% in the intensive lowering group, 7.5% in the conventional group, uh, again, about a 40% reduction here, and driven, of course, mostly by coronary interventions. But if you take the composite and you take revascularization out of it, do you still see a significant effect? So now we're just looking at death, heart attack, stroke. And if you do that, yes, in fact, we still we still see a significant impact. So 2.3% in the intensive group versus 3.6%. That's a difference of 1.3%. And that remains statistically significant with about a 40% reduction. So we do see, even without revascularization, that this is statistically significant even in just a three-year timeframe. Let's see what they say about safety here. The incidence of new onset diabetes, worsening of glycemic control, statin-associated muscle symptoms leading to changes in therapy dose or regimen, cancer diagnosis, cataract surgery, elevation of liver function tests, or creatine kinase levels did not differ substantially between the two trial groups. However, incidence of elevated creatinine was lower. So higher creatinine is worse. You would prefer it to be lower. So this was actually a positive benefit in the intensive targeting group versus conventional targeting group. Okay. That is the summary of their results. Let's think about well, let's see what they say in their discussion. Trial showed significantly lower three-year risk of the composite of death, non-fatal myocardial infarction, non-fatal stroke, revascularization, or hospitalization. No substantial between group differences in the incidence of safety endpoints were observed. All right, and here is a forest plot. Right. So here is what I mentioned earlier in terms of the breakdown by gender. When you're looking at these forest plots, you want the little TIE fighter or the little box to be left of the dotted line. That dotted line is a hazard ratio of one. And what that means is that the results are basically null. They are not any different than the conventional group. So in the male group, you see that the intensive targeting was 6.5% had the composite event versus 10.8% in the conventional group. And this is squarely below the one line, meaning that was a statistically significant effect. And you see that here with the confidence interval 0.45 to 0.79. In the female group, you see that there was a 7% event rate in the intensive targeting group versus 5.7% in the conventional targeting group. That's actually even a little higher than one, and a very wide confidence interval that includes the null or includes one. You can argue that this means women did not benefit from intensive lowering therapies. You could also argue that women are not powered in this trial to detect a difference because they only represent about 20% of the study population. We also know the average age in the trial was 65. Women don't really start to catch up to men in terms of cardiovascular risk of events until about 70. So again, that's the loss of protection from estrogen through the menopausal transition. And eventually, in women, especially who are not replaced, that signal starts really showing up late 60s, early 70s. So it's possible that we just don't have an old enough population of women to see the equivalent risk. But we have to acknowledge that one possibility, one possible explanation is that women do not achieve as much benefit from intensive lipid lowering as men. That is something that I don't think we can say one way or the other from these data, but we we must acknowledge. Seemed to show a little more benefit than greater than 25. Again, I would argue that these are both in the same direction. We just have uh less confidence across this particular finding here. And patients with diabetes seem to have a little bit more benefit from the intensive lipid lowering than patients who did not have a diagnosis of diabetes, so uh 6.5% versus 12.1%, um, which again, given that we know statins do worsen glycemic control, this has always been a question. You know, is it appropriate for us to be using this when we know metabolic status is really important in risk for cardiovascular events? I would say this particular situation would argue for yes, intensive lipid lowering therapy does provide benefit, even if you're incurring some worsening of metabolic status or glycemic status, which we don't test for in this particular study, but is certainly a possibility and something we have seen in other investigations. Patients with chronic kidney disease were a little less likely to benefit. That's an interesting finding. And some signal for patients who had a lower baseline LDL cholesterol receiving more benefit, whether that's because those patients were able to get even better control or not, unclear to me. So these are some subgroup analyses that provide interesting hypothesis generation for future studies, but I would say nothing in this secondary analysis should be taken as proof positive of a subgroup event rate by itself. All right, here are the data for their safety analysis. Again, we mentioned that there really wasn't much significant difference except that patients uh were less likely to have creatinine elevation in the intensive group versus the conventional group. Okay, so the discussion continues here, and they are reminding us that the European guidelines have introduced this target of less than 55 milligrams per deciliter for patients with ASCVD. And that recommendation has been supported by an expert consensus by the American College of Cardiology for patients at quote unquote very high risk for cardiovascular events, but most trials still haven't shown that. So most of these previous trials have evaluated primarily the effects of these therapies themselves rather than the strategies defined by the specific targets. So again, are we testing the drug or are we testing the targets? This paper is interesting because we're actually just testing the target, not how we got there. Meaning, whether it was high intensity statin, whether it was moderate intensity statin plus a zetamide, whether it was moderate intensity statin plus PCS K9 inhibitors, we actually don't care. We're just looking at the LDL target. TST trial. Evidence from randomized trials comparing an LDL cholesterol target of less than 55 milligrams per deciliter with a target of less than 70 milligrams per deciliter in patients with ASCBD has been limited. The present trial addresses this gap in evidence, and the results suggest that intensive targeting confers a greater cardiovascular benefit for secondary prevention. Again, we are not talking about primary prevention here. These are only patients with known disease. They're going to talk about the approach to achieving the target warrants strategic consideration. In the present trial, the most potent statins were used. 50% of the patients were assigned to receive a zetamib and PCS K9 inhibitors were permitted. At three years, 60% of the patients in the intensive targeting group had an LDL cholesterol of less than 55 milligrams per deciliter, and 85% had a level of less than 70. 48% of the patients in the intensive targeting group were receiving high intensity statins at three years. These percentages were substantially. Higher than those in the conventional targeting group. And these findings may help explain the cardiovascular benefit of intensive targeting of LDL cholesterol. I think I'm going to leave the rest of that discussion for you to read if you wish. We can also talk about it in the comments if you have additional questions about it. So let's think about the big picture here. This is a very specific population. So it's a group of South Korean patients. So does that apply to patients here in the United States or Canada or the UK, wherever you may be watching from? No offense to any South Koreans. I think my South Korean audience is pretty limited, but in any case, it's a specific population. So may it maybe it doesn't generalize to wherever you may be watching from. And it may or may not generalize to the patients that I treat every day in my clinic here in sunny Southern California. We have the issue of women may not have as much benefit as men. We also wonder about which drugs were doing the thing. Now, again, the strength of the trial is that they actually didn't care. And most of this was achieved with statin therapy and acetamib. Very few people on PCS canine inhibitors. So that means if those PCS canine drugs are not accessible to you for any particular reason, you can still gain a lot of benefit through the use of statins and acetomib. And perhaps if you are not doing well in high-intensity statin therapy, you can be on moderate intensity statin therapy at azetomybe and actually get to that target. Let me know what other questions you have about this study in the comments below. It's going to generate a lot of controversy here on the channel. I know it will, but let me know. Let's have it. Until next time, guys, take really good care.