Dyslipidemia Podcast

Recent Clinical Advances in Reducing Risk for Dyslipidemia

Laurence Sperling, MD; Peter Toth, MD, PhD; Erin D. Michos, MD, MHS

Disclosures

February 15, 2022

This transcript has been edited for clarity.

Laurence Sperling, MD: Welcome to Medscape InDiscussion. We have two national and world experts with us here today, and I'm excited about our discussion.

This morning, we'll start off with a case and then introduce our experts and get down to a vibrant discussion. Mr L is 42 years old. He has genetically confirmed heterozygous familial hypercholesterolemia (FH) and coincident metabolic dyslipidemia. He also has an elevated lipoprotein(a) [Lp(a)] and has a history of an anterior myocardial infarction with a left anterior descending artery (LAD) stent at the age of 36 years. Despite a high-intensity statin and ezetimibe, his low-density lipoprotein (LDL) cholesterol is 160 mg/dL, his high-density lipoprotein (HDL) cholesterol is 32 mg/dL, and triglycerides are 190 mg/dL. This was a fasting lipid profile. His Lp(a) is elevated, at greater than 95 mg/dL, with a reference range of normal being less than 30 mg/dL.

Mr L is seeking your advice on optimizing his approaches to risk reduction. He's heard about several new cholesterol medications that may be of benefit, and his cousin is being treated with LDL apheresis. We'll come back to this case later on and ask our experts about their advice and opinions. But for our listeners, how would you manage a case like this?

This morning, as I said, we have two national and global experts on frontiers in lipid management. We have Dr Erin Michos, who's the associate director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and the coeditor of the American Journal of Preventive Cardiology. Dr Peter Toth is director of preventive cardiology at the CGH Medical Center, professor of family and community medicine at the University of Illinois College of Medicine, and the current president of the American Society for Preventive Cardiology. Good morning, Dr Michos and Dr Toth.

Peter Toth, MD, PhD: Good morning, Larry.

Erin Michos, MD, MHS: Good morning. Thanks for having me on your program today.

Sperling: Thank you both for joining. And as I said, what an important topic. What an exciting topic. Before we leap into medicine and science, we want to learn more about our experts here this morning. Erin, share with us a fun fact that others may not be aware of regarding you.

Michos: Well, Larry, you and I are both lifestyle enthusiasts, and I like to run, although I'm terribly slow at it, and I also like to travel. So prior to COVID, I had a goal of running a marathon in all 50 states, and I got up to 38 states. Most of the marathons got canceled last year due to COVID, but I hope to get back to it and finish the last 12 states.

Sperling: I have confidence you're going to make those 50 states. But you know, there are still those international marathons, so once you get past the United States, you'll start ticking off some other boxes. Peter, tell us a fun fact about you.

Toth: I'm a professional landscape photographer on the side, and I'm US Masters Swimmer. So those would be the two most important fun facts for me.

Sperling: Wonderful. I'd love to see some of your photos someday. I don't think I'd be able to compete with you in the water. But I'm looking forward to running with Erin someday.

We're going to start off here talking about some new frontiers, I'm going to start off with Erin: Provide us some guidance about a better understanding of the currently available lipid treatments beyond statins. What are some of the options we have in our toolbox?

Michos: It's an exciting time because we have new tools in our toolbox. Of course, statins are the first-line therapy that can reduce mortality by 10% and cardiovascular events by 22% for every 39-mg/dL lowering. Then we have ezetimibe, which blocks the Niemann-Pick C1-like 1 (NPC1L1) cholesterol transfer protein; this inhibits absorption of cholesterol from the intestine. This can modestly reduce LDL cholesterol by about 10%-18%. The IMPROVE-IT trial, which looked at ezetimibe on top of a moderate-intensity statin in high-risk patients after acute coronary syndromes, showed about a 6% relative reduction in major adverse cardiovascular events (MACE), but given their high risk, a number needed to treat of only 50.

Now we have our proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. These are very highly efficacious lipid-lowering drugs. These are monoclonal antibodies targeting the PCSK9 protein. You can achieve an LDL cholesterol reduction in the range of 50%-60%. We have two large outcome trials. The FOURIER and ODYSSEY trials showed about a 15% relative risk reduction and a 2% absolute risk reduction in MACE. The trials were short, with follow-up at about 2 years, and the curves are widening; we would probably see even greater benefit the longer we'd go. PCSK9 inhibitors can also reduce Lp(a) by about 25%, which is probably going to be important for this patient.

Then there are some new things coming on the horizon soon. Closer in is a new PCSK9 inhibitor, inclisiran. It works by a first-in-class mechanism of small interfering RNA that blocks the synthesis of PCSK9 and can achieve about a 50% reduction in LDL cholesterol, with some modest Lp(a) lowering. We are still awaiting results of the outcome trial ORION-4, but this drug is approved in Europe and is pending US Food and Drug Administration (FDA) approval in the United States. This is pretty exciting too, because it's only dosed twice a year, which would really help to improve patient adherence.

Now, recently FDA-approved, we have bempedoic acid, an oral medication that blocks ATP citrate lyase, which is an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. So it works in the same pathway that statins work, but upstream of it. It can lower LDL cholesterol in the range of 15%-20%, similar to ezetimibe (Agarwala and colleagues; Goldberg and colleagues). But when combined with ezetimibe, it can reduce LDL cholesterol by about 38% (Ballantyne and colleagues; Khan and Michos). This was FDA-approved last year, in February 2020. It can also lower C-reactive protein, which may be promising. We're still waiting for the CLEAR Outcomes trial, but we anticipate that bempedoic acid will reduce cardiovascular events as it lowers LDL cholesterol. This is FDA-approved for patients with heterozygous FH or atherosclerotic cardiovascular disease (ASCVD) who need additional LDL lowering.

Other things that are coming up include pelacarsen, a novel antisense oligonucleotide against Lp(a) that can reduce Lp(a) up to 80% and is being tested in outcome trials right now. So lots of exciting choices are currently available or on the horizon that could potentially help this patient.

Sperling: Yeah, there are lots of options. And really, these frontiers will pave the way to the future of cardiovascular disease prevention.

Peter, you're somebody I look at as a leading researcher and a leading educator. Hopefully our listeners have started to develop a comfort level with PCSK9 inhibitors. They have now been available to our patients for a number of years. How can we better predict who will benefit from a PCSK9 inhibitor? We'll talk about the case a little bit more. What would you think about a PCSK9 inhibitor in this gentleman?

Toth: Oh, I certainly would add a PCSK9 inhibitor, with an LDL cholesterol level that's still 160 mg/dL on a combination of a statin and ezetimibe and an Lp(a) that is greater than 95 mg/dL. I don't think you have a choice apart from considering LDL apheresis, which would remove both the LDL and the Lp(a). But a PCSK9 inhibitor would be my next choice because as you know, getting someone set up for LDL apheresis is an ordeal. First of all, it has very limited availability. Second, they're going to have to have an appropriate insertion site because it does have to be done every 2 weeks. It's a tremendous time commitment. And for a lot of people, it just doesn't work. So there are many considerations there. But a PCSK9 inhibitor would certainly help get this patient's LDL cholesterol well below 100 mg/dL. Given his personal and family history, that is exactly what you want.

Erin already alluded to the fact that the PCSK9 inhibitors also provide incremental reductions in Lp(a), and that's about a 25%-30% incremental reduction. Statins actually raise Lp(a). We know from analysis of both FOURIER and ODYSSEY Outcomes that the reduction you observed in Lp(a) when comparing the fourth with the first quartile actually contributes to overall risk reduction. This was shown for both studies, and hence, I think the next step of using the PCSK9 inhibitor is quite appropriate.

Sperling: Thank you. Let's say we do start a PCSK9 inhibitor; the patient's LDL cholesterol is under 100 mg/dL and we're starting to achieve that. Hopefully lower is better for this high-risk individual along the lines of the 2018 cholesterol guidelines, in terms of a threshold for starting nonstatins. But he's left with this metabolic dyslipidemia. Other than counsel about lifestyle and behavioral approaches, Erin, do we have any tools in our toolbox here for a high-risk individual with a metabolic dyslipidemia state that might improve his outcome?

Michos: It's important to note that elevated triglycerides do predict risk even in individuals who are well treated with a statin, who get to an LDL cholesterol level less than 70 mg/dL. Triglycerides independently predict risk. I can't emphasize lifestyle enough: weight loss, calorie reduction, physical activity, reducing intake of simple carbs and simple sugars, increasing intake of foods rich in fish oil, reducing alcohol intake, and reducing excessive body weight. Even a small amount of weight loss, 5%-10% of weight, can lower triglycerides. So it's really important that we have this conversation and refer the patient to a nutritionist or a dietitian as well.

I do want to emphasize not to use dietary supplements. There's no over-the-counter omega-3 product that would be FDA-regulated.

Sperling: Thanks, Erin. So we're pushing the envelope, we're hitting this gentleman hard with those new frontiers in cardiovascular risk reduction, and of course, the lifestyle and behavioral piece, as you said, is critically important as well. I'm going to ask both of you: Those PCSK9 inhibitors, we've had them in our toolbox for some time. Unfortunately, there's some hurdles, some barriers to prescribing these and getting these to the patients in need. For our listeners, could you provide some tricks or words of wisdom about how clinicians and health systems can overcome these access hurdles? Starting off with you, Peter.

Toth: First of all, the penetration of the PCSK9 inhibitors in terms of use across all 50 states averages between 0.5% and 0.9%. That is dreadfully low for such efficacious drugs. PCSK9 inhibitors can provide you with 10-12 titration steps' worth of LDL reduction compared with a statin. We know that there's no other drug that can give you 10-12 titration steps' worth of statin LDL reduction, only the PCSK9 inhibitors. So they are dramatically underused.

A lot of it has to do with the fact that people have burnt out on the prior authorization forms. But I have to say, it's gotten a whole lot easier in the past 2 years, ever since they dropped the price of these drugs by 60%. And quite frankly, in the past year and a half, I can't think of an instance, when the forms were filled out properly, that I had a rejection. Managed care is much more open to having us prescribe these drugs now, and as long as the patient meets the criteria for the indications of the drug, they are approving it. So I would say, guys, gals, get back in the arena, take another stab at it, because if you're burnt out and tired of having to deal with prior authorizations, you will not have the same difficulty as you did before.

Sperling: That's wonderful, thanks. And Erin, maybe just one point that you want to make — a hurdle or a barrier to overcome and some guidance for our listeners.

Michos: This patient would have an indication for both a PCSK9 inhibitor and probably icosapent ethyl as well. It's important to note that most drugs are covered by insurance; there are some additional hurdles, but they are covered. So the key point is, make sure your patient information and your documentation clearly indicate the FDA criteria and that they meet the FDA approval criteria and the guideline recommendations, and don't take no for an answer.

Sperling: Don't give up. I like that advice, and we, of course, want to be advocates for our patients and advocates for science, for the evidence. That's wonderful advice from both of you. Thank you.

Now we're really going to move into this frontier. I'm not going to say uncharted waters, but we're moving into some spaces that we're not used to: very, very low LDL cholesterol with these new agents. We published a paper recently in the European Heart Journal. It was titled "How Low Is Safe?" Dr Eugene Braunwald recently published a commentary in the European Heart Journal, titled "Cholesterol: The Race to the Bottom." I'm going to ask Peter: Are there risks or concerns about achieving very low LDL cholesterol — less than 30 mg/dL in these very high-risk patients?

Toth: A hazard ratio of 1.0, meaning no excess risk, occurs at an LDL cholesterol level of 38 mg/dL. The average LDL cholesterol that an infant is born with is somewhere between 30 and 45 mg/dL. When you look at hunter-gatherer populations from around the world, typically their LDL cholesterol is between 30 and 50 mg/dL. We were never meant to have the LDL cholesterol that we currently harbor, which is why ASCVD is a worldwide epidemic.

Should we be afraid of lowering LDL cholesterol too much? The answer is no. Let's take it point by point. There is a lot of phony baloney out there about how you're going to induce cognitive impairment or dementia, and you ask people, where did you get this from? Well, I heard it from so-and-so or I read it someplace, but they can't ever cite a source. And I mean, they cannot ever cite a source.

Now, cognitive impairment. Your brain could care less what a lipid-lowering drug is doing to your liver because your brain, your oligodendrocytes, your astrocytes produce all the cholesterol that they need. Look at it this way: If the brain really was adversely affected by aggressive cholesterol-lowering, it would wreak havoc. Because if you're breaking down myelin sheaths just to provide the brain with more cholesterol or you are setting off astrocytes to produce cholesterol rather than a balance of a variety of molecules involved in intermediary metabolism, that could lead to serious intracranial havoc. You do not observe it. And of course, the EBBINGHAUS trial showed no evidence of any risk for cognitive impairment. What is more important is when you look at the subsequent analysis of patients' self-assessment published in the Journal of the American College of Cardiology (JACC), even patients didn't think that there was any change in their neurocognitive capacity across the board, looking at five executive functions. This echoes the data from the Heart Protection Study as well as the PROSPER trial.

PROSPER was important because they actually had patients by the end of the trial up to age 80. And Erin published an extremely well-done editorial in Circulation on the whole issue of hemorrhagic stroke with aggressive lipid-lowering. That's a must-read, I think, for everybody, because she along with Seth Martin laid out all the data that do not support a role for aggressive lipid-lowering in augmenting the risk for hemorrhagic stroke. There is no increased risk for cancer, no increased risk for any type of hepatic or muscle injury.

The bottom line is that people need to start viewing LDL cholesterol as spent garbage lipid. All the data, all the mendelian inheritance study data, all of the genetic polymorphism data, every bit of evidence points to the fact that lower is better and lowest is best. The other thing is, all of your somatic cells can produce all the cholesterol they need. If you also look at hormones, aggressive LDL lowering does not lead to any significant change in steroid hormones. Why? Because all of your steroidogenic tissues produce their own cholesterol and the primary plasma reservoir of cholesterol for steroidogenic tissues is HDL, not LDL.

Sperling: Well, we've heard about some really amazing new frontiers. We'll come back to our case here. We've already heard from our experts that, of course, we should consider a PCSK9 inhibitor in this gentleman. So Mr L was treated with a PCSK9 inhibitor, with a resultant LDL cholesterol of 76 mg/dL. His triglycerides were addressed appropriately through lifestyle and behavioral approaches and medical therapy as well. The next steps included a discussion about a phase 3 randomized controlled clinical trial related to Lp(a) antisense therapy, and there was some discussion about consideration for LDL apheresis. When needed, this therapy has been available now for several decades. At Emory, we started the first and only LDL apheresis center in the state of Georgia. For those who need it, certainly it is a very viable treatment option.

As we begin to close here today with our two experts, Dr Erin Michos and Dr Peter Toth, I'm going to ask you to give a brief thought about a prediction for the future. These are leading preventive cardiologists in our country. They are leading the charge and leading the way. So, Erin, what's your prediction of the future? Will we be able to conquer ASCVD?

Michos: I think the most important thing is we need to start way earlier. You know, this patient had an MI at 36, and this goes to show that FH is underrecognized and undertreated. There is an acceleration of 30 years earlier onset. There are studies showing that in patients who have FH and began receiving statin therapy in childhood compared with their affected parents, you could really alter the whole trajectory if you start treatment earlier in life. If you treat early, even in children, you can slow the progression of plaque and they don't develop these outcomes that their parents did. This patient, I should mention, also needs cascade testing of all his first-degree family members. It seems like the patient had a missed opportunity to prevent ASCVD. I think for future patients, we need to start earlier. The risk is due not only to the magnitude of elevation but also the duration of elevation. So treat earlier.

Sperling: We don't want to miss those opportunities. Peter, you know, as we're coming to a close here. What's your prediction about the future?

Toth: We have multiple challenges. Yes, the toolbox is extraordinary. It's innovative, and it is exciting. The problem is that the rate at which our clinicians are taking up these tools is very slow. There are barriers to the use of new drugs, but we all have to learn to overcome these.

Second, we have long-term adherence issues. Can we conquer atherosclerotic disease? The answer is yes. We have the capacity. We have the capability. But when you have 5-year adherence rates of 20% just for a statin, we have a real problem. We have to help our patients understand what these drugs are doing, why they're important, and what the long-term consequences are of not taking them as prescribed. So I have both optimism and a sense of pessimism because yes, these drugs empower us to do amazing things. But unless we're using them and unless patients are taking them, they don't do us much good.

Sperling: I'm going to close with a quote that I've used from a former Surgeon General, C. Everett Koop. He said, "Drugs don't work in patients who don't take them." So if we don't understand and recognize the evidence, then we don't prescribe, and then we don't have that important clinician-patient risk discussion and partnership, focusing on the fact that these drugs often are more than drugs that lower cholesterol — these are drugs that favorably affect cardiovascular risk and can extend quality of life.

With that, I want to thank Dr Erin Michos and Dr Peter Toth for joining us today. This is Dr Laurence Sperling, from Medscape InDiscussion.

Resources

Cholesterol Treatment Trial: Efficacy and Safety of More Intensive Lowering of LDL Cholesterol: A Meta-analysis Of Data From 170,000 Participants in 26 Randomised Trials

IMPROVE-IT: Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes

ODYSSEY: Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

FOURIER: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk -- FOURIER

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk

ORION: Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

CLEAR Wisdom: Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial

Bempedoic Acid and Ezetimibe -- Better Together

REDUCE-IT: Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

STRENGTH: Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia -- STRENGTH

JELIS: Effects of Eicosapentaenoic Acid on Major Coronary Events in Hypercholesterolaemic Patients (JELIS): A Randomised Open-Label, Blinded Endpoint Analysis

PROMINENT: Rationale and Design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) Study

How Low Is Safe? The Frontier of Very Low (< 30 mg/dL) LDL Cholesterol

Cholesterol: The Race to the Bottom

SPARCL: High-Dose Atorvastatin After Stroke or Transient Ischemic Attack

EBBINGHAUS: Cognitive Function in a Randomized Trial of Evolocumab

PROSPER: Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER): A Randomized Controlled Trial

Achievement of Very Low Low-Density Lipoprotein Cholesterol Levels

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