This transcript has been edited for clarity.
Pam R. Taub, MD, FACC, FASPC: On behalf of the Medscape and American College of Cardiology Center for Excellence, I'm delighted to be here to present a dialogue on lipid management. I'm Pam Taub. I'm a cardiologist and professor of medicine at UC San Diego, and I'm delighted to be joined by my friend and colleague, Dr Steve Nissen.
Steven E. Nissen, MD, MACC: Thank you. I'm Dr Steve Nissen, and I am the chief academic officer of the Heart, Vascular, and Thoracic Institute at the Cleveland Clinic.
Eye-Opening Outcomes: Clinical Trial Results and Practice Recommendations
Taub: Steve, we have much to cover. There's been so much exciting data in the lipid management space, and you just presented the data from the CLEAR Outcomes study. Tell us the topline results and what excites you about CLEAR Outcomes.
Nissen: First, we were eager to do this study because, as I think most people know, there are a certain number of patients that get adverse effects, typically myalgias, from statins, and they're very difficult patients to treat and many of them are very high risk.
Bempedoic acid, the drug we studied, is a prodrug. It is only activated in the liver. It is not active in muscle or any other peripheral tissues. It was an ideal drug to try in patients who couldn't tolerate statins.
We recruited 14,000 patients. It was a global study, with over 1000 sites. They all had to have documented statin intolerance and they had to, in writing, state that they understood that statins were established for cardiovascular prevention, but that they would not and could not take a statin.
In the trial, we got modest lipid lowering with bempedoic acid — about a 22% reduction in low-density lipoprotein (LDL) cholesterol. We also got about the same amount, about a 22% reduction, in high-sensitivity C-reactive protein (CRP). We knew this drug had anti-inflammatory as well as lipid-lowering effects.
We didn't know whether it would reduce cardiovascular events, but in fact it did. The hazard ratio for a four-component major adverse cardiovascular event (MACE) endpoint was 0.87. That's death, stroke, myocardial infarction (MI), or coronary revascularization. For the harder, three-component endpoint of just death, stroke, and MI, the hazard ratio was 0.85 — a 15% reduction. There was a 23% reduction in MI, which was statistically significant, and there was a 19% reduction in coronary revascularization.
We concluded that bempedoic acid was an effective alternative in those patients who simply could not take a statin or would not take a statin. We were pleased with the results, and it was about what we expected based on the CTTC meta-analysis.
Taub: I also want to congratulate you for enrolling 48% women in the study. You've really set the new paradigm of what we should be doing in our lipid-lowering trials, and that we can't have that excuse that we just can't do it. You showed us that we could do it, even during the pandemic.
One of the most interesting aspects of that study, to me, is your paper that you published in JAMA on the high-risk primary prevention cohort. In my opinion, that group is so underappreciated. We focus so much on secondary prevention, and to me, when we get to secondary prevention, it represents a failure on our part. It represents everything that's wrong with US healthcare today. We focus all our resources on secondary prevention. The procedures that we do are very expensive, but the elegance and art of medicine are really in identifying those patients that are under that umbrella of high-risk primary prevention and coming up with evidence-based strategies for them. You demonstrated that so elegantly in your subanalysis. Tell us about that.
Nissen: First, you said that extraordinarily well, and I agree with everything you said. It's an underappreciated, undertreated group. Less than 50% of high-risk primary prevention patients are being treated, and remarkably, only a little more than half of patients with diabetes are getting the appropriate LDL-lowering therapy, typically statins.
In CLEAR Outcomes, we wanted to have evidence for both primary and secondary prevention. We took a chance and we enrolled 30% primary prevention patients. It was a very controversial and very difficult decision to do that. What happened was the primary prevention patients had a much larger treatment effect than the secondary prevention patients. For the four-component MACE, there was a 30% reduction that was highly significant. For the three-component MACE, there was a 36% reduction. For cardiovascular death, there was a 39% reduction, and for all-cause mortality, a 27% reduction.
Now, that should not surprise us. If you look back historically, there is a modest number of primary prevention studies that were done with statins. JUPITER comes to mind. It was stopped early for a 44% reduction in the primary endpoint. HOPE-3 had a very robust 20% reduction in the primary endpoint, all in primary prevention patients.
These patients have a more modifiable substrate. They probably have more lipid-laden plaque that can be reduced with LDL lowering. We showed that in some of our intravascular ultrasound studies as well. As you point out, they are a group in which we can prevent disease. Good doctors ought to prevent disease, not simply wait until the disease is highly evident. We were pleased with the result. We really wanted to make that point, and that's why we did the analysis.
That being said, there will always be criticisms of any subgroup analysis. This subgroup was large, with 4200 patients. It was statistically heterogeneous from the primary result that we saw. That was important. It was a prespecified subgroup. I think people should use this as a wakeup call that we need to identify people at risk before they have MI, a stroke, or a stent and try to treat them aggressively. I know you agree with that, as you said.
A Focus on Primary Prevention
Taub: I'm also very excited about the VICTORIAN-1 PREVENT trial that is currently ongoing, which is dedicated to high-risk primary prevention. We're looking at the impact of inclisiran in these patients. I think we're going to see more clinical trials in this high-risk primary prevention cohort, which hopefully will lead to many different therapies that we can offer these patients.
Nissen: I'm involved as well. I'm chairing the data monitoring committee for the trial. I know you're on the executive committee, so this will be a chance for us to work together for a while.
Taub: One of the things about high-risk primary prevention that I use clinically is coronary calcium scoring because it really identifies those patients with subclinical atherosclerosis. Do you use that in your practice?
Nissen: Only when I'm in a borderline situation. I try to be conservative about radiation exposure. I know the radiation exposure has been reduced substantially. If I have a patient that has a high LDL cholesterol level and risk factors, and by the clinical trials would qualify for treatment, I treat them. If they're clearly well below the threshold for treatment, I avoid treating them. If you're in that borderline group, that's where I think calcium scoring is useful.
I use two metrics: calcium scoring and high-sensitivity CRP. If you're in a borderline group and your CRP is 4, then based on JUPITER, you really ought to be treated. If you have a high calcium score, you ought to be treated as well.
Multiple Areas of Concern
Taub: I do the same. Let's switch gears for a minute and talk about obesity. Everybody has been mesmerized and dazzled by all the data that have been coming out on the GLP-1 receptor agonists and the dual agonists. One of the things that I'm concerned about is many people think that all you need to do is treat obesity. If you treat obesity, you don't really need to worry about treating lipids. We need to put some of this in context. I know you're involved in some of these clinical trials with tirzepatide. Tell us how you think about obesity, atherosclerotic cardiovascular disease (ASCVD), and treatment of hyperlipidemia.
Nissen: I think hyperlipidemia and obesity are independent risk factors. I think there is a large amount of evidence that they are. You can be thin and have a very high LDL. You can be obese and not have a high LDL. Many of these patients, in fact, have high triglycerides associated with obesity, as you well know. Yes, it's true that there is some improvement typically in triglycerides with weight loss, but there's not a huge reduction in LDL cholesterol.
I think the smart strategy is to address obesity, but not neglect the treatment of patients with high LDL. I think we're going to learn in the future that these are very independent risk factors. The opportunity to treat both gives us two opportunities to reduce morbidity and mortality from a disease that is the number-one cause of death in developed countries.
Taub: That's well said, because I think that sometimes when we are mesmerized by data, we kind of forget about the basics, just like sometimes we forget about our good old friend, the statin, because there are so many new therapies. We can't forget about the incredible data that we have with statins.
There are also many new drugs in the pipeline. For instance, there's the oral PCSK9 inhibitor that's in clinical trials. There are multiple drugs for lipoprotein(a) [Lp(a)] lowering that are in phase 3 trials. There's even an oral drug for Lp(a) lowering that was just presented at the European Society of Cardiology (ESC) meeting by Dr Steve Nicholls. There are many different things, including now gene editing.
What are you excited about? What are you cautious about, and what do you think the future is going to look like?
Shining a Light on Lp(a) and Emerging Targets
Nissen: Lp(a) is underappreciated. I published a study last year called the Lp(a)HERITAGE trial that included 48,000 patients, all of whom had a previous event, and only 13% of them had Lp(a) drawn.
My colleague, Leslie Cho, who heads up prevention here, has been obtaining Lp(a) values for about 15 years in every single patient that comes to our prevention clinic. We see this often. I am chairing, and Dr Cho is the principal investigator for the Lp(a)HORIZON trial studying pelacarsen, which is an antisense oligonucleotide. It was very effective at lowering Lp(a) in a phase 2 trial.
The phase 3 trial is 8300 patients, fully enrolled, ongoing, and probably just a couple of years from completion. We're going to get an answer. I think the answer is going to be that if we lower Lp(a), we will reduce cardiovascular events. I'm very excited about this target and there are other targets emerging as well.
Another very important emerging target is APOC3 . There are now short interfering RNA drugs targeting APOC3, and there's an antisense oligonucleotide as well. For Lp(a), we have the oral drug muvalaplin. I worked with Steve Nicholls on that manuscript. There are other short interfering RNA drugs in phase 2 and in phase 3 studies, so we have multiple shots on goal.
Statins are fantastic, but even if we lower LDL, we still have incident cardiovascular disease. We have to look beyond LDL. We cannot neglect treating LDL with statins, PCSK9 inhibitors, and bempedoic acid. We have very good tools, but they do not eliminate cardiovascular disease. We've got to look to the next generation.
Future Directions
Nissen: CRISPR is a fantastic opportunity to actually change the genome. Obviously, there are many regulatory hurdles to overcome, but we're looking now into the future and are seeing amazing opportunities for other targets to be treated with gene editing therapy.
Taub: Do you have any concerns about gene editing? Do you think there might be any off-target effects?
Nissen: That's of course the concern, and the regulators are going to be concerned about as well. What's good about antisense oligonucleotides and short interfering RNAs is they target one very specific messenger RNA. They don't seem to have off-target effects. They're very well targeted. They're connected to a sugar, GalNAc, that concentrates the therapy in the liver and not in other tissues. Again, it's very targeted. I think they are going to turn out to be safe.
CRISPR will have to meet the same high standard. The regulators need to be convinced. I'm optimistic that that can be accomplished with careful studies and with careful design of therapies.
Taub: The concept of "one and done," especially for our patients who have genetic syndromes like homozygous familial hypercholesterolemia, is very appealing. We're going to have so many different options ranging from the one-and-done strategy to once a month to every 6 months with some of the LDL-lowering agents. I think the future is bright, and we're going to have much to talk about over the next couple of years.
I want to thank you for your time and your insights on some of the new developments in lipid lowering.
Nissen: Thank you very much for having me. It's been a pleasure to converse with you.
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Cite this: Pam R. Taub, Steven E. Nissen. The Current State of Lipid Management: An Ever-Evolving Landscape - Medscape - Oct 20, 2023.
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