® presentation, which is titled “Advances in the Management of Hypercholesterolemia.” I’m Howard Weintraub. I’m a cardiologist. I am a clinical professor of medicine at the NYU Grossman School of Medicine and I’m the clinical director of the NYU Center for the Prevention of Cardiovascular Disease. It is my pleasure to be joined by Dr Alan Brown, who is the director of the division of cardiology at the Advocate Lutheran General Hospital in Park Ridge, Illinois. We’ll be discussing hypercholesterolemia and its management in a variety of patient populations, including consideration of the use of the newer PCSK9 monoclonal antibodies.

Alan, what would you consider to be causes leading to hypercholesterolemia and resulting effects on peoples’ health, namely genetic and environmental?

I’m going to steal a line from an old friend of mine, Gregg Fonarow, who says that genetics load the gun and environment pulls the trigger. Most people with dyslipidemia have some underlying genetic predisposition. There are groups where it’s a very clear, single gene as in familial hypercholesterolemia. The majority of the population has more minor genetic abnormalities that lead to elevated cholesterol. As they gain weight or they eat a diet high in saturated fat or cholesterol, you start to see the numbers go up, often after adolescence. Both genetic and environmental factors contribute to dyslipidemia, and we know that leads to the potential for cardiovascular disease, whether it is cerebrovascular coronary disease or peripheral vascular disease.

Consequences of Hypercholesterolemia

Howard, I know you have spent a lot of your career dealing with multiple risks for cardiovascular disease—not just lipids but hypertension, cigarette smoking, and other things—as a former board member of the American Society for Preventive Cardiology. I’ve had the pleasure of serving with you on that. Do you want to talk about all the different risk factors that contribute to cardiovascular disease, beyond lipids, and why we need to have a multidisciplinary approach?

That’s a very good question, Alan. It’s fairly obvious that if all you do is focus on 1 risk factor and ignore the blood pressure, diabetes, smoking, obesity, inactivity, and the increasingly important issues of genetics, as you just pointed out, you’re going to have a woefully inadequate response. One of the things that separates us as the preventive cardiologists is that we have to keep our eyes open on the whole horizon and call attention to everything. Those efforts, in my experience, have led to very gratifying results in reducing the severity of atherosclerosis and made a real impact on the likelihood of stroke, MI [myocardial infarction], or severe peripheral vascular disease. You already brought up in our discussion before the meeting that the younger generation may potentially not have as good of a health outlook as their parents. This is related to obesity and the pursuing effects of insulin resistance, metabolic syndrome, and prediabetes, which some people are now talking about. We’re really getting in on this feature. You can’t underestimate the role of multifactor evaluation and really diligent attention. Making it well into your eighth and ninth decades of life without having had stents in your body, stitches on your sternum, or balloons being putting into your femoral artery has a certain degree of merit.

Cardiovascular Disease Risk Factors

There are certain issues that I know that you’ve discussed and that we all have to deal with certainly on a day-to-day basis. Those are namely the effects of things that are not in our control, such as age and gender. These are things that we now know have very significant impact. The coronavirus pandemic has shown us that ethnicity, demographics, and socioeconomic status can also have a very big impact on health. The ways people get health care and use health care also ultimately impact whether individuals end up being beneficiaries of this or suffering with it. Please let us know your thoughts.

Yes, I certainly agree. Obviously, age is the single biggest risk factor for developing cardiovascular disease. There’s not a lot we can do about it, even though many of us attempt to act younger than we are, much to the dismay of our spouses, in many cases.

What we know is that cardiovascular disease is still the No. 1 killer out of all causes of mortality in the United States. That’s true for both men and women. Years ago, we thought women had a lesser incidence of cardiovascular disease, but we know better than that now. They often have it 10 years later than men. The theory is that they possibly may have some protection from estrogen during their premenopausal period, but they clearly have an equal incidence of cardiovascular disease. It’s still the No. 1 cause of death—more than all the cancers combined.

We’ve spent the past decade educating ourselves and others about the importance of identifying cardiovascular disease in both men and women, and also about some of the gender differences. Women present with different types of symptoms and different risks for procedures. A lot has been done in that arena. As far as the ethnicities go, we know that particularly for hypercholesterolemia, certain ethnic groups have a higher incidence. French Canadians have a higher incidence of familial hypercholesterolemia [FH]. We see that in Lebanese patients and Dutch patients. In fact, FH was first described in South Africa in the Dutch Afrikaners. There are populations—especially those who tend to cluster together and have a founder effect because they live in similar communities—where we see higher incidences of hypercholesterolemia. We know that lower socioeconomic groups, partly because of ethnicity and partly because of status and lifestyle, tend to have a higher conglomeration of risk factors, including hypertension, obesity, and diabetes. Some of that is probably related to ethnicity, but in the lower socioeconomic groups—it’s unfortunate, but the least expensive food, for example, is often the food that’s highest in saturated fat. In many cases, there are what we call food deserts in those localities where they really can’t find a place to get fresh produce or other healthy food, but there’s a McDonald’s right down the street. It becomes less expensive to feed the family and more satisfying to eat a high-fat meal that suppresses your hunger. The amounts of sodium and fat all lead to health issues.

All these things work together. We have to be aware of all of them. When we talk about diversity and inclusion, we mostly think about ethnicity or language, but there are many dimensions of diversity, including socioeconomic group, gender, and age. As we move forward in health care, we’re going to have to consider all those things if we want to be good stewards of the health of our communities.

I agree with you. Actually, the 2018 ACC/AHA [[American College of Cardiology/American Heart Association] guidelines identify Southeast Asians as a group at considerable cardiovascular risk. We at NYU have seen a lot of patients from Central America, South America, and the islands with a particular virial inversion of mixed lipid abnormalities. Many of them have very elevated triglycerides. There is this ethnic predisposition toward certain dyslipidemias. Our cardiology fellows are constantly astounded when they see a small, thin, Indian woman who’s 35 years of age, nondiabetic, and a nonsmoker who comes in with a proximal LAD [left anterior descending coronary artery] infarction. They go, “Wait a minute. This isn’t supposed to happen.”

I’m glad you brought that up, Howard. You mean “South Asian,” rather than “Southeast Asian.”

We actually have a South Asian Cardiovascular Center at Advocate Lutheran General Hospital because we have such a high population of Indian and Pakistani individuals in the Chicago area. You’re absolutely right. They have 3 to 4 times the risk. There’s a lot of theory as to why that is. They tend to have insulin resistance, as well as high incidence of elevated LP(a) [lipoprotein (a)]. The National Lipid Association is about to publish a very comprehensive discussion of that. I’m sorry I left that out. I’m glad you brought that up. That’s very important. It’s important for all physicians to be aware of the high incidence of early heart disease in South Asian patients, so thank you for that.

It’s something that used to be an issue only in urban areas like New York or Chicago, but now as people spread out and there are communities growing in multiple parts of the country, doctors need to recognize where this is from and how it all works. As you pointed out, you have these issues in Chicago. We’ve been seeing them at Bellevue Hospital for years. Jamie Underberg, who I’m sure you know well and is part of our convention center, runs the lipid clinic at Bellevue. We also have a dedicated prevention fellow. He and the fellow are constantly amazed by some of the genetic lipid disorders that come in and those that are there in an ethnicity where there is significant cardiovascular risk. That used to be attributed only to long-standing type 1 diabetes, renal disease, and smoking. This is very important. It’s something that we’re going to need to pay more attention to, particularly with attention drawn to disparities between different socioeconomic groups and demographics. This is something our trainees need to know about, and our colleagues need to be very well educated about this as well.

That’s very well said. As you pointed out, the COVID-19 [coronavirus disease 2019] crisis has really emphasized the importance of understanding the effects of disease and health care systems on diverse populations. My suspicion is that all our health care systems are going to change forever based on those experiences. This pandemic really affected certain ethnic and socioeconomic groups with such vigor compared with others.

Socioeconomic Status and Hypercholesterolemia

 The next thing I’d like to mention, as you’ve brought this up, is this rising concern about worsened cardiovascular outcomes. It turns out, interestingly, that this has been directed toward younger groups. You have people—and oddly enough, women particularly—entering the cardiac care group at an age that is much lower than anticipated by the people who make models for budgets. You get people who are now having very costly cardiac ailments and even more costly cardiac interventions. As a consequence, stresses are placed on society, on the budget, and more important, on these individuals’ lives.

One of the problems with stroke is that it is frequently not a mortal event, but it can be something that changes someone’s quality of life forever. You can’t underestimate the role of genetics and then obesity in even moderate degrees, along with the genetic predisposition toward more glucose intolerance. Now, we’re finding an even newer player, which is steatosis or the condition of NASH—nonalcoholic steatohepatitis. This all becomes involved with glucose intolerance and diabetes, dyslipidemia, and cardiovascular disease. We’re paying the price as this tornado begins to roll even more, flattening a lot of the expectations in health care. People are becoming consumers of health care, but economically, we’re hoping they’d simply be paying premiums and not actually using many of these dollars. I’m sure you guys have had a problem with this in Chicago as well.

Cardiovascular Disease in Younger Populations

At this point, we’re going to look at guidelines. When doctors think about what they’re going to do, they have historically enjoyed or looked for guidelines. You and I could talk for hours about our affections and disaffections toward some of the guidelines and what each of them have done over the last several decades to either make people more enthusiastic or, in some cases, to disenfranchise. There were guidelines from the ACC [American College of Cardiology] and AHA [American Heart Association] in November 2018, which were followed about 10 months later by European guidelines. This is very important when it comes down to how decisions are made, because a lot of doctors find that this is their blueprint or their recipe for how they want to treat their patients. One of the things that’s important has been consent of shared decision-making. I’m sure when doctors started telling patients about their condition, a lot of the time it wasn’t, “So tell me what you want to do. Do you want to take a drug? Do you not want to take a drug?” Then the patient swears on several Bibles that they’re going to do the very best they can. Depending on the follow-up or absence thereof, people can get lost in the shuffle. Discussion with the patient is so important. I’d love to hear your take on this, because I’ve thought a lot about this myself in the way I treat my patients. How do you get your patients to consider what would be optimal based on your interpretation of guidelines? In addition, we all know that every medicine that’s ever been developed is said to be an adjunct to lifestyle modification, namely diet and exercise. How do you work these things out and what kind of success have you had?

Let me start with the lifestyle because that will be a shorter answer. First, many of my patients want to be natural. They often say, “Why do I have to go on medication? How come I can’t be natural?” I explain to them that 100 years ago, everybody was natural, and they lived until about 38 years old, on average. So natural is not all it’s cracked up to be. That’s No. 1. No. 2, we do have some data about the importance of lifestyle modification. We have a lot of data that show you can lower your LDL [low-density lipoprotein] approximately 10% but lower your risk of an event even more than that. That’s true even in patients who are being placed on statin, for example. David Blankenhorn showed that 25 years ago via angiograms in people who were on statin plus niacin vs placebo. The folks on medication had less progression of atherosclerosis on follow-up angiogram. That goes without saying. But when you look at the people who were on medication—those who did well and those who didn’t seem to get the benefit of the medicine—the only differentiator between the 2 groups was the percentage of saturated fat and the diet. When patients say to me, “I’m taking my statin and my numbers are good. Can I go eat pizza?” The answer is no. There is good evidence that you’re going to get the best outcomes when you combine lifestyle modification plus the medication, if the medication is appropriate for you.

As far as the shared decision-making, I’m interested in taking a second on that. They say the most important part of caring for patients is caring for the patient. That is, to really care about them and let them know you care about them. Probably the most important thing that anyone ever said to me in my career is to consider how you influence people. This is not about how you make friends or how you keep your spouse but about how you become influential. The way you influence others has absolutely nothing to do with what they think about you. It has everything to do with how they feel about themselves when they’re in your presence. The first part of the shared decision-making piece is for that patient to understand that you truly care about them and to believe that you have their best interest at heart, which means taking a few minutes to make them feel good about themselves when they’re in your presence. This is true whether we’re dealing with colleagues at a committee or a medical organization or whether we’re dealing with other people. I have found over the years that the biggest impact that leads to a really valuable shared decision-making discussion is to make sure the patient understands that you care about them as a person. After that, it is really important for them to feel as if they were part of the decision of what’s going to happen going forward. Our job is to arm them with the data, explain how much we care about them, give them what we think is reasonable for them, and see if they agree once they have the data in hand. That is really important. It’s important in everything we do. It enhances compliance with our treatment and also reduces conflicts with patients and colleagues.

Lifestyle Modifications to Manage Hypercholesterolemia

I couldn’t agree more with what you’ve said. I’m going to go 1 step further. Along with caring, it’s also listening. I’ve seen a lot of individuals in their 30s and early 40s who were summarily told by their primary care doctor, “Your LDL [low-density lipoprotein] is X, and you need a statin.” Many of these people, as you already pointed out, want to be “natural,” so they immediately run to the internet. They decide that the doctor is an agent of big pharma and trying to do all kinds of dastardly things to them, because when you google the word 

, glowing reports don’t immediately show up on your doorstep. I invariably listen to them. We talk at length about their diet. We talk about their expectations. I let them know specifically what I anticipate might happen. I let them know that in my approach of aggressively, thoroughly approaching risk factors, I don’t grade on a curve, but I also would like very much for them to have the best possible outcome. In doing that I am giving in to get my own way when I encourage them to follow an enlightened diet or nutritional pattern, to stop smoking, to lose weight, and to exercise. We set realistic goals, and I give them several months to do this. I give them enough time for them to figure out whether they can tolerate the diet, whether they feel put in some culinary hell by what I’m asking them to do, or whether they find that it’s a lifestyle that’s entirely livable. Then we reconvene in 4 months, which is enough time for them to get all this information together and also to be able to see a reasonable impact, if there is 1.

I agree with you. Getting 10% reductions at the end of the year is probably a very realistic number, not what patients believe they should be able to get. They hear about the fantastic stories of people like Dean Ornish and others. They don’t really know what Ornish’s diet and lifestyle are like. They’re not quite ready to give up booze, red meat, and oils, or to have to exercise and meditate, but this is what it is. I find, interestingly, that people come back. If I just tell them, “Here’s a pill,” these are the people who take the medicine for a month and don’t refill it again. These statistics are everywhere. This is something I agree with you about, and by listening, you show that you care and that ultimately, your concern is to improve their cardiovascular outcome. I also tell them, “I can do this with your help or without it. I’d love your cooperation with this, because it means that if you do need medicine, you’ll be on fewer medicines. That means we’ll be able to do this in a way that is more acceptable to you.” I tell them “But if you look at me and say, ‘My life is not going to be worth living unless I have a cheeseburger every week.’ ” I tell them, “Fine. Then understand that you’re going to need to get your LDL down a certain degree, whatever it is, and that we might need to use more medicine.” If I need to do more of the heavy lifting, I’m prepared to do it, but this is part of our agreement. I don’t want to say 

, but this is the agreement that I forge with patients. All these things involve listening and having the patient feel that you care. They must feel that they are not being summarily given a judgment that they don’t have a chance to discuss and don’t completely understand, that they feel might be somewhat arbitrary and is contrary to what they’d like. As you put it, they’d like to be natural. That’s completely correct.

Hypercholesterolemia: Shared Decision-Making 

Now we’re going a step further. You’re now with a patient who has either acquiesced or has demonstrated to both of your satisfactions that a stain is important. How do you make your choices? Which statins do you reflex to? Do you go for the high-intensity statins first? If you know someone needs 40% or 50% LDL [low-density lipoprotein] reduction, do you start with moderate- to high-dose statins, or do you titrate? What is the ground scheme?

That’s a good question. We know from the clinical trials that you can start with high-dose statin, and most patients do just fine. If you remember, almost all the atorvastatin trials started with 80 mg, and people did just fine with that. There’s a slightly higher risk of adverse effects in trials in the higher doses. This starts with listening, as you pointed out. There’s an old Italian saying that there’s a reason God gave you 2 ears and only 1 mouth. You listen to your patient. If they are apprehensive about starting a statin, you might use a statin that is actually more potent, but at a lower dose, such as rosuvastatin 10 or 20 mg. That may sound less concerning to a patient than 80 mg of atorvastatin and you’re going to get fairly similar LDL reductions. You make that judgment based on how the patient feels. You always have the option of choosing a lower-dose statin if it makes them more comfortable, giving them ezetimibe, and telling them it is a drug that has no difference in adverse effects vs placebo. That combination can give you quite potent LDL lowering. It is a judgment. You feel your patients out.

As you well know, years ago most of our referrals were for severe dyslipidemias, and now we still get those rare genetic disorders and then the more common FH [familial hypercholesterolemia] patients. The majority of my referrals are statin-intolerance patients, so we have to deal with patients who have already had problems. There are a lot of different ways to deal with that. No. 1 is to talk about the lower-dose drugs, as I mentioned. No. 2 is to offer patients who’ve had intolerance to statins an opportunity to take a longer-acting statin once, twice, or 3 times a week. Rosuvastatin and atorvastatin get pretty good LDL lowering even if you take it a couple of times a week.

A lot of people forget the only comparative study that was done many years ago and published in a clinical pharmacology journal. In terms of myalgias, it showed that fluvastatin—that was before rosuvastatin came out—had fewer muscle aches. There are some older, generic medicines that one can try—fluvastatin, lovastatin, pravastatin. In my 35 years, I’ve never been able to figure out if there’s any biochemical reason why a patient does well with 1 and not another. Whether they’re synthetic or not synthetic and water soluble or fat soluble has never helped me, in terms of picking a drug that a patient can tolerate. You really have to try multiple statins.

One thing you do have to pay attention to, and we’re now learning the physiology behind it, is the family history. If mom can’t take atorvastatin and neither can the patient, we used to think the patient was nutty. But the reality is, there clearly are genetic snips that affect statin intolerance with certain statins. I do pay attention to it when everyone in the family has intolerance to a certain statin. I try to avoid those things.

Those are my approaches. I think sometimes the psychological effect of using pitavastatin, with only have a 2 or 4 mg dose, is helpful. In my hands, a lot of patients who can’t tolerate other statins seem to be able to tolerate the pitavastatin. Those are some of the approaches we use.

Finally, in terms of statin intolerance, don’t miss other superimposed disorders like hypothyroidism, for example, where the patient is going to be more prone to muscle symptoms if they’re not well replaced on their thyroid.

Selecting a Statin Therapy to Manage LDL-C

There isn’t a week that goes by that I don’t see a patient who is coming in who has been determined to be statin intolerant. I have to tell you that maybe half the time—consistent with the 

 studies that were done with evolocumab and alirocumab in people who were “presumed to be statin intolerant”—many of these people are nowhere near statin intolerant. Tell me how you define statin intolerance. I find that in a very busy primary care office, if a patient is concerned and has maybe a few too many looks on Google, they may have a rotator cuff injury that has been present 10 years before they knew what a statin was. Now their shoulder starts to hurt again, and they’ve made the decision that this is obviously going to be the statin. The doctor or the staff of any kind, being overwhelmed, more or less say, “I’ll do whatever I can to not annoy Mrs Smith or Mr Smith.” There’s nothing gender-wise here. They will acquiesce, and the problem with that comes once the patient has been told that it’s the statin that’s causing it. Then the loop has been closed, and they are officially deemed statin intolerant. How do you address that?

That’s a good question. I think there’s a scientific answer and there’s a practical answer.

The NLA [National Lipid Association] went to great pains to write a beautiful document on statin intolerance and even developed a scoring system to determine whether the patient’s symptoms are consistent with statin intolerance. From a scientific standpoint, if it’s in the proximal muscles, goes away when you stop the drug, etc—there’s some science that many patients, when you rechallenge them, tend to be able to tolerate something that they previously couldn’t.

That’s all interesting from a scientific standpoint, but when you’re in the office, most patients couldn’t care less about that science. If they believe they’re having an adverse effect from the drug, there’s nothing you’re going to say to persuade them to go back on it. The most important thing when you start treatment in a patient is to set expectations and say, “Look, some patients will develop some muscle aches or mild weakness, usually about a month after you start the drug. The good news is, we can almost always find 1 of the statins that people can tolerate. We may have to try a couple of different ones, but we can always come up with 1, so be prepared if you have a symptom to expect that we may try another.” I find that even in people who have had adverse effects from 2 statins, which is usually when the primary care physicians throw up their hands and refer. Of course, NLA documents suggested that you had to have intolerance to 3 statins to be truly statin intolerant. So it’s science that’s not practical. Set that expectation by saying, “Look, this happens to a lot of people. We’re going to try multiple things.” Most of the time, you can find something that works, even if you have to go to the every-2- or 3-day approach that we talked about earlier or go to a lower dose with ezetimibe. There are some patients who, no matter what you give them, have adverse effects. We know that 15% of people have adverse effects on placebo. Either way, it’s irrelevant, because if the patient perceives they’re having an adverse effect, all the science in the world isn’t going to change their mind. You work with them, and you do just what you’ve so eloquently described. You listen to them. You give them options and have them participate in the decision of where you’re going to go next, whether it’s a different class of drug like a PSCK9 inhibitor or bempedoic acid, trying additional statins, or even some nonpharmacological interventions like plant stanols.

Managing Intolerance to Statin Therapy

There are people who are legitimately statin intolerant. Whether you quote the numbers and studies of 7% or 8%, or the perceived value, which is double that, of people at risk, you feel badly when you know the impact of inadequately treated LDL [low-density lipoprotein] cholesterol. I can say, for my own sake, that the advent of the PCSK9 monoclonal antibodies has been an amazing opportunity for me. I am able to offer my patients an opportunity to get their LDLs down to levels that were very rarely obtained, even in the most diligent patient with favorable genetics whose LDL falls like a stone in response to high doses of atorvastatin or rosuvastatin.

That’s a great segue, Howard. As we’re getting on to the PCSK9 inhibitors now, maybe you can spend a few minutes on the available PCSK9 inhibitors’ mechanism of action and whether you think there are any significant differences between the 2 that are on the market. You already mentioned getting LDLs to very low levels and being very satisfied with that. I am too, but you and I both know that a lot of doctors are fearful of that. Could you finish with a bit of data on whether we need worry about very low LDL levels?

That’s a great point, Alan. Thanks. Evolocumab and alirocumab are humanized monoclonal antibodies, which means that these are nonforeign proteins to the human system, unlike partially humanized antibodies. That was a problem with 1 of the PCSK9 inhibitors that was very effective in lowering LDL. It never saw the light of day because of neutralizing antibodies and gradual inactivity. But the good news is that evolocumab and alirocumab are amazing drugs. They act by regulating the LDL receptors. For the listeners, this is a matter of modulating the number of garbage cans that LDL has managed to find a place in. We all know from our studies that the process is a lock-and-key phenomenon. We know that when LDL finds its way into the receptor on the surface of the liver cell, the LDL is taken into the liver cell. What’s supposed to happen is that the receptor is recycled out to the surface of the cell, so you don’t throw away the garbage with the garbage can, and the lipid itself is metabolized and passed on to the bowel. When PCSK9 is present, and it’s made within the same liver cell, this can bind to the complex of the LDL and receptor. Along with the LDL being broken down, so is the receptor. This becomes a very inefficient way of doing things. Just imagine if every time you ended up throwing garbage away in your home, you threw away the garbage can with it. You’d either have to buy long-term garbage cans or you’d have a lot of garbage on the floor. The latter is what happens in the human circulatory system. They tried using small molecules that would inhibit production, which are unsuccessful for a variety of reasons. But the monoclonal antibodies ended up being a great choice. They’re a great choice because they don’t interact with other medicines. They do not require metabolism by the liver or the kidney. A whole variety of conditions that can limit the utility of so many drugs are not concerns with the use of the PCSK9 monoclonal antibodies. At full dosage, both of these drugs can lower LDL as well as any other single drug, besides some very expensive injectables. We can lower this 50% or 60%. The effect of the medication is sustained when looking at outcome studies that have lasted several months up to several years. We’ll have time to talk about the different findings. One of the most important issues was that in the FOURIER trial, which is the study with evolocumab in almost 28,000 patients, about a quarter of them ended up getting LDLs below 25 mg/dL.

In spite of this number, which may make many physicians uneasy and may make patients concerned, when 1 of my patients reaches a value of 25 mg/dL and asks me what to do, I tell them that we should have a party. If there’s 1 food they’d like to try to eat once or twice a month, this is the time to go for it. The people who got below 25 mg/dL in the FOURIER trial, including those in a substudy called EBBINGHAUS, which looked at neurological and cognitive issues, showed absolutely no deleterious effects. The people who identified LDL cholesterol, Drs Michael Brown and Joseph Goldstein, were interviewed a few years ago and asked, “What do you think would be a good level of LDL in the blood?” Their number was 25 mg/dL. We worry about there not being enough LDL, but it turns out that many organs in the body will make their own. It doesn’t need to be in the blood, and all it does when it’s there is get us into trouble, particularly if there are other abnormalities in mechanics. The stuff gets oxidized. Once it’s oxidized, it becomes particularly toxic. This is what starts the cascade of atherosclerosis.

I’m thrilled when LDLs go down. I told you I like the European guidelines because they’re calling for LDLs of under 55 mg/dL. We can talk about the language of the different guidelines, but doctors are still concrete enough that they like the idea of having a number to shoot for. My experience has been that when you get people below 55 mg/dL, you’re paying no price for it. The only price you pay is a benefit in which cardiovascular events are lowered and there may actually be a cessation or slowing of atherosclerosis. There may also be a transition of plaque from a more risky, vulnerable, lipid-rich variety to a more fibrocalcific variety. I tell patients that we turn a risky plaque into a speed bump in the wall of the artery. It may annoy them, but it’s not going to hurt them.

PCSK9 Inhibitors and LDL-C Reduction 

There’s so much more that doctors need to know. As much as I’d love to think it’s not the case, many doctors are not fully aware of the data from the large outcome studies, mainly FOURIER and ODYSSEY. Can you give us what you feel are the important features of these trials and how these data, particularly some of the substudies, motivate your choices?

FOURIER was the study with evolocumab, and ODYSSEY OUTCOMES was a slightly different trial for patients with more acute coronary events but is very similar in its design. Both were outcome trials with the PCSK9 inhibitors. If you use the 140-mg dose of evolocumab vs the 150-mg dose of evolocumab, you get similar LDL [low-density lipoprotein] reductions of about 55%.

You already went through the fact that very low LDLs were achieved in those trials. One thing that’s been misrepresented about FOURIER is that when you look at the primary end point, which was 5-point MACE [major adverse cardiac events], there was about 15% relative risk reduction. The number needed to treat was about 50 people to save an event. Who were these people? These were people who had coronary disease and other risk factors—either a recent coronary event, hypertension, diabetes, or other risk factors to enhance their risk—on top of atherosclerosis. Carotid coronary peripheral vascular disease could get them in with other risk factors. They are who the ACC/AHA [American College of Cardiology/American Heart Association] multispecialty guidelines considered very high-risk patients.

Second, they were only followed for just under 3 years. When we look at the results of those trials, people may say they were a little disappointed that they didn’t see a bigger reduction with a 55% LDL reduction. They expected bigger event reduction, but we’re used to looking at 5- to 7-year trials, not 3-year trials. For 3 years, it was pretty robust risk reduction. It was highly statistically significant. Overall, cardiovascular outcomes including MI [myocardial infarction], stroke, risk of readmission to the hospital with unstable angina, and revascularization were all significantly reduced, which was very encouraging. We would expect the magnitude of reduction to get even greater over time.

Keeping in mind that these were shorter trials, they had a very satisfactory risk reduction. They looked at a lot of subgroup analyses, and what they found was an obvious rule of prevention. The highest-risk people always get the most benefit from anything that works, right? If you take someone who had a recent MI within the last 2 years, they’re going have a higher risk of a recurrent event, as opposed to someone who’s been stable and had an MI 10 years ago. That’s exactly what the study showed. Those with more recent MIs and more multivessel disease tended to have a higher benefit because they had a higher prevalence of disease. An analogy would be, if you had a drug that reduced the risk of breast cancer death, would you save more lives if you gave it to 1000 men or 1000 women? Obviously, the prevalence is so much higher in women. They have more events. The higher-risk individuals in all the subgroup analyses got benefit.

There were a couple of surprises. One was the peripheral arterial group. People who had symptomatic peripheral arterial disease, such as claudication, got a bigger reduction in cardiovascular events than virtually anyone else. I’m not 100% sure why that happened. I have my thoughts. When someone comes in with a recent MI, we always send them home on a statin. I’m not sure everyone thinks that way with someone who comes in with claudication. It may well be that those patients had not been as well treated prior to enrollment in the study, so maybe they were at higher risk. I’m not sure that’s true. Maybe their blood pressures were slightly different. It was a post hoc analysis, so we don’t know. But what was clear was that having symptomatic peripheral arterial disease identified a group that got the most benefit from being on a PCSK9 inhibitor. That comes from FOURIER data in particular. They are very encouraging.

Both groups also showed another interesting phenomenon. On average, LP(a) [lipoprotein (a)] dropped about 30% on the PCSK9 antibodies. That was interesting because we’re still debating how LP(a) is cleared. We’ve felt it might not be an LDL receptor mode of clearance. That was fascinating. Not every patient had a drop in their LP(a), but on average, it dropped about 30%. That was encouraging, and the question that everyone would have is, does that contribute to a reduction in cardiovascular events? It is not clear because there hasn’t been a prospective randomized trial to look at lowering LP(a) with PCSK9 inhibitors and outcomes. It was an observation. But Vera Bittner did a really interesting analysis of ODYSSEY outcomes. It was somewhat conjecture with statistical analysis, but it did suggest that those patients who got an LP(a) drop—in addition to a lowering of their LDL—had better outcomes. That’s very encouraging, especially in an era when we’re going to have some therapies that lower LP(a), in addition to what we saw with the PCSK9 antibodies.

That’s a long-winded answer, but there were a lot of interesting data from both outcome trials. The most important thing is that PCSK9 inhibitors showed definite, statistically significant reduction in events on top of maximally tolerated statin or statin plus ezetimibe.

Cardiovascular Outcomes: FOURIER and ODYSSEY

I’m going to chime in with 1 point. I have a question for you as well. We have found so many cases in which individuals were running around with LDL [low-density lipoprotein] in the 60s, 70s, and 80s mg/dL on statins and ezetimibe and were progressing. In many cases when we drew an LP(a) [lipoprotein (a)], which was often not even thought about, we would find the culprit. The data from ODYSSEY OUTCOMES, with what Vera Bittner wrote, and the data out of Brigham and Women’s Hospital on FOURIER both seem to show that those with the highest LDL and the highest LP(a) got the greatest value out of the use of the PCSK9 monoclonal antibody. Vera’s analysis, as you correctly point out, was very suggestive that there was independent impact from lowering LP(a). It was not just the fact that LDL went down, and that was really what powered the benefit.

What you just pointed out is very important. For the PCSK9-reluctant individual physician, 1 of the best ways to consider the appropriateness is to go after the subgroups that you just discussed. Those are namely individuals with multivessel disease, recent MIs [myocardial infarctions], bad PVD [peripheral vascular disease], diabetes, and high LP(a). We’re not talking about never-heard-of situations. We are talking about a large segment of the population of patients with high-risk cardiovascular disease. If a doctor is not quite certain about whether the work that he or she has to do to get a PCSK9 inhibitor is going to pay off, let them be initially focused on the groups that they already have the data about, except for LP(a). Consider them the people who get it.

Lipoprotein(a) and PCSK9 Utilization

One of the things we didn’t talk about is that in spite of an enormous amount of data, we know that getting LDL [low-density lipoprotein] down, not just into the 20s or below 55 mg/dL but even below 70 mg/dL, is not achieved in a large number of high-risk patients. Both the ACC/AHA [American College of Cardiology/American Heart Association Clinical Practice] Guidelines, and certainly the ESC [European Society of Cardiology Clinical Practice] Guidelines, call for much more aggressive utilization of lipid-lowering agents. The Europeans call for very early experience with 

 modulation. It’s really sad that people are not motivated or feeling confident in using a PCSK9 inhibitor.

I’d love to know your experience. One of the things I’m going to ask you next is, how often do you have to switch people off PCSK9s? We have hundreds of patients on both of these drugs. Multiple times a week, I’m either renewing a prescription or writing a new one. I don’t think I’ve ever stopped a prescription for a PCSK9 because of a legitimate adverse effect. We had 1 patient that had a rash that was transient but not really allergic. She is still on the drug 2 years later. That’s an amazing thing. I can’t say that for aspirin. I can’t say that for many other drugs. There have also been great steps taken by the people who make or sell these drugs to reduce the price. They lowered the cost almost 60%, from a little over $14,000 to below $6000. It’s now close to $5600, putting the cost of these drugs in line with many other drugs that you and I prescribe on a day-to-day basis as antiplatelet drugs, diabetes drugs, or drugs for heart failure. This is important. Please tell me your experience. How often do you use a PCSK9 inhibitor in monotherapy, and how many of them do you use with ezetimibe? Do you use them most with statins?

I’ll give you a synopsis of it. First, like you, I’ve had very few who have had to come off PCSK9 inhibitors. I’ve had 1 true allergic reaction in which the patient developed significant urticaria and had to come off. I’ve had a couple of patients who got absolutely no response, and we’re still analyzing what happened to them.

Because they got no response, their payer would not renew them, and I couldn’t argue with that. As far as the cost-effectiveness piece, the safety and tolerability has been great. You mentioned attributable adverse effects. I did have 1 patient who was fine until he saw that his LDL was 12 mg/dL. Then he had an anxiety attack and stopped taking it. But he was an anxious patient from the beginning, and that’s why he couldn’t tolerate anything else. We do have people who literally have tried every statin and can’t tolerate them. In those patients who have high-risk atherosclerosis and can’t tolerate any statins, for example, we’ve used monotherapy with PCSK9 inhibitors. We’ve published a small group of people who were unable to tolerate anything else and were only on PCSK9 inhibitors. The data were just what you would expect them to be. They got the same reduction in LDL as they would have if they had added the PCSK9 inhibitor to a statin, which was 55% to 60% LDL reduction. That said, many patients who have atherosclerosis and can’t tolerate any statins are on PCSK9 inhibitors alone. If their LDL isn’t adequately controlled, I frequently add ezetimibe to it, and that gives us another 20% LDL reduction. I do that with reckless abandon, and I’ve had good responses to that, as you pointed out.

The last thing is the cost. First, the retail price has little to do with what the patient pays, and we just have to be honest about that. It’s great for politics, but it has very little to do with reality, which is 1 of the problems with health care today. The price that is published as the actual market price for a drug is manipulated over multiple steps before it gets to the patient. All the patients care about is what they have to pay out of pocket, particularly with the retail price reductions that we were all so thrilled about in the PCSK9 inhibitor. As you said, it was a 60% reduction in price. That has brought the co-pays down very low, even for Medicare patients. That’s much better than it was before, which has made it easier to get patients to take it. Medicare was particularly a problem because their out-of-pocket costs are directly related to the retail price of the medication.

If you just assume that the cost is what’s published as the retail price, with that 60% price reduction—we published a paper at the NLA [National Lipid Association] on which Jennifer Robinson was the lead author. I participated in that to investigate whether they are cost-effective according to national standards. For example, most organizations that review cost-effectiveness would say that $50,000 for a quality-adjusted life year is cost-effective.

What we found was interesting. If your LDL is over 100 mg/dL despite maximum tolerated traditional therapy, it was actually highly cost-effective to give a PCSK9 inhibitor, by national standards of cost-effectiveness. You get unquestionable cost-effective benefit if the LDL remains above 100 mg/dL. If the LDL remains above 70 mg/dL, and you have a reasonable value, there is reasonable cost-effectiveness. It still falls into the reasonable range.

People should be quite confident that at the current retail price, knowing that it’s a bit of smoke and mirrors in terms of what patients and payers are actually spending on the drugs, they are cost-effective if your LDL is over 70 mg/dL on maximal therapy. You and I could find patients as you described. You described them beautifully. These are people continuing to have events who have very high LP(a), despite having relatively low LDLs, and who are progressing with their disease to having their second or third bypass operation. We know that they are at such high risk that, even if their LDL is below 70 mg/dL, they’re going to get benefit by adding a PCSK9 inhibitor. That’s always going to be a clinical judgment.

Based on what you and I do in the lipid field, we have the ability to assess risk in a complex patient and make that sort of a judgment. But for the average patient who the primary care doctor or family medicine specialist is treating, who has coronary disease plus some other risk like age or hypertension, whose LDL is still above 70 mg/dL, with the safety data that you described, they should not have any hesitation to consider using a PCSK9 inhibitor. Secondly, as you already described, even with very low LDLs, there’s no evidence of cognitive dysfunction based on a well-done subgroup analysis of FOURIER. That’s the EBBINGHAUS data. When someone says, “How low should your LDL be?” I always say, “You can’t be skinny enough, you can’t be rich enough, and your LDL can’t be low enough.” No one has proven me wrong. I’ve been saying that for 30 years and so far, no one has proven that wrong. The fear of using an injectable should go away. Most primary care physicians do it for diabetes and other things. If it’s appropriate, based on guidelines, this drug does not necessarily have to be given by a lipidologist, or even a cardiologist.

Real-World Experience With PCSK9 Inhibitors

What I have found to be a problem is that a patient will come to me and we’ll recommend a PCSK9 inhibitor. Then the patient goes back to their primary care doctor, who’s a little concerned about what’s going on, and they talk to their local cardiologist, who may not be an aficionado of lipid lowering. It’s not a stretch to say that the average physician has been confused since about 2013, maybe longer. In 2013, there were no longer targets. There were statin-treatment groups, and then it took them 5 years to figure out that maybe there should be some reincorporation. They were then incorporated as thresholds. That was a new term and a new concept for doctors. As any consumer does when confused, a doctor is going to do nothing and figure, “When you guys figure it out, give me a call and I’ll do what’s appropriate.” The problem has been that a lot of the subgroup data, particularly FOURIER, are just that.

There’s a challenge in getting the information that you and I just discussed to the ears and heads of individuals like primary care physicians, internists, and those like nephrologists who see others at risk. I have always tried to empower the individuals who do not start every day looking forward to tackling a lipid problem. I look at every patient with a PCSK9 inhibitor as a possibility, rather than saying, “You know, I don’t know. What should I do,” banging my head against the wall and waiting for someone else to solve the problem.

I hope that the kind of discussion that you and I just had will allow people to feel a bit more comfortable. To summarize, these are highly effective, easy to use, every-2-week medicines. From the time they prep the skin until the time they put a Band-Aid on, it’s usually under 60 seconds. There’s no one who doesn’t have the time for that every 2 weeks. The adverse-effect profile is amazingly benign.

Between the 2 of us, with all the patients that we see and treat with PCSK9 inhibitors, we have had fewer than a handful of people who have to come off. A couple of those are through no fault of the drug but by fault of genetics. They probably had LDL [low-density lipoprotein] receptor abnormality that prevented the PCSK9 inhibitor from working, even though a statin might still work. These are very effective drugs. All doctors want to do what’s best for their patients, and as long as the financial burden is tolerable and surmountable, these are medicines that I’m surprised are not receiving better uptake. Just as a bit of trivia, we were the first office in New York City to start a patient on a PCSK9 inhibitor, which was alirocumab, back in the summer of 2015.

I’m happy to give my thoughts on this. It’s 1 extra burden on the patient to have to go see a specialist and then keep coming back for it. It’s not that I mind, because I’m very happy to see them, and I’m sure you are as well. But this is something I hope gains better traction.

I agree. These have a reasonable cost, very low adverse-effect profile, and no real drug interactions, and the patients have to inject only every 2 weeks. One of the barriers is that the physicians need to see how the drug is given. Many times, if they’re not comfortable explaining to the patient what they’re going to get in the pen and how to do the injection, they avoid the conversation I actually tell the reps, “Make sure you use those demonstration pens and show the doctors how to use the drug.” Once you realize how easy it is, you’re much more likely to think about prescribing it.

In our clinic, we have the ability for the patient take their first injection in the clinic. I find that extremely helpful. But in many health care systems, including ours, they don’t allow samples. That becomes a problem for demonstration. This is 1 situation in which it is worth asking your health care system to make an exception because they’ve already not been adequately controlled on generic medications. It is helpful to have the patient see how to do the injection and also realize that it’s not painful.

As we finish, I want to clarify 1 thing about thresholds vs. goals. You brought it up a couple of times, and it’s true that numbers changed with the 2018 guidelines. For the people who struggle with that, what’s the difference between a goal and a threshold? This was a way to get around the patient who comes in with an acute coronary event whose LDL is relatively low. Imagine a patient who comes in with an acute MI [myocardial infarction], or an angioplasty and a stent, whose LDL is 72 mg/dL. They have a low HDL [high-density lipoprotein] and high triglycerides, and we see more of those cases as we’re seeing more metabolic syndrome patients. If you had a goal of 70 mg/dL and you brought that patient’s LDL from 72 to 69 mg/dL, you would have achieved a goal. But you have done absolutely nothing for that patient’s risk. That’s the reason there was a resistance to the term 

, because more patients are arriving with LDLs that are not sky-high with acute coronary events.

What we know from clinical trials is that if you add a drug to that patient, it may lower LDL another 60%. If you add a drug to that patient who has been proven in a trial to get benefit on top of whatever they’re taking, you’re going to have better outcomes. You aren’t going to have better outcomes if you put them on 5 mg of pravastatin and get their LDL from 72 to 69 mg/dL. The whole idea of switching from a goal to a threshold was to give instruction on what to do in a patient whose LDL is not very high. If their LDL is 160 mg/dL, then having a goal of 70 mg/dL is probably effective. You’re going to lower their LDL at least 50%.

I want to remind everyone that in clinical trials, when they added a drug that’s been proven to work, such as a statin in high-risk patients, they lowered LDL 50%, even if the starting LDL was relatively low at 75 or 80 mg/dL. That’s where a goal would not be adequate and a threshold makes more sense. A threshold is not a number at which you’re good when you get below it. It’s a number above which you would add a potent therapy that’s been proven in a clinical trial to reduce events. That is why the guidelines say if your LDL is still above 70 mg/dL, that’s a threshold in a very high-risk patient at which you would consider adding a PCSK9 inhibitor. If they’re not on a statin, that’s a threshold at which you would add a statin or intensify therapy. It’s not about where you end up.

It’s about a call to action above that threshold. I just wanted to clarify that. If you look at it that way, we’re not far from the European guidelines. We just came at it in a slightly different way.

Increasing Confidence in Prescribing PCSK9 Inhibitors

You brought up a very good point, and I agree with what you said. Certainly, having an LDL [low-density lipoprotein] of 72 vs. 69 mg/dL would be good in the mind of a computer but not in the mind of a plaque. You brought up acute coronary syndromes. There have been several reports looking at the early institution of vigorous LDL reduction, particularly in the non-statin-naïve patients, and starting them on either evolocumab or alirocumab soon after the event. There’s a bit of a language differential between the American and European guidelines. Our prevention group sees a lot of patients, and we are asked to see a lot of patients who come in with PCIs [percutaneous coronary interventions]. It was a decision by the heads of the catheterization laboratory and cardiology to have them get prevention consults before they leave. That is so they don’t become part of a revolving wheel of individuals coming in, having a little done medically but not enough, and then coming back a year later.

Thankfully, we at NYU Langone Health are allowed to have samples. In several cases, before the patient left—because we get a lipid profile when they come in—we have given them a shot of a PCSK9 inhibitor. Then we try to work with the patient and their primary care physician, or they’ll come back and see us and we try to get them on board to use a PCSK9 inhibitor. Along with adoption of the drug, there are also some other issues about early adoption. I find, as I’m sure you do, that there’s a bit of inertia.

We’d asked before whether you titrate or go right to the high dose. Even if the patient comes in and their LDL is 160 mg/dL, you and I know it’s unlikely that they’re going to get where they need to go with a statin alone. They may come close. They may reach the goal with ezetimibe. But the more common patient is someone who comes in with an LDL of 130 mg/dL, and they’re already on 40 mg of atorvastatin or 20 mg of rosuvastatin. The addition of ezetimibe is unlikely to get them down to a place that you and I would be comfortable with. These are individuals who would be well served—along with considering ezetimibe—to recognize that waiting 3 or 6 months for the LDL to come down on ezetimibe is going to be time wasted. How do you feel about that?

Systems turn good doctors into great doctors. If that system is to have anyone with an acute coronary syndrome whose LDL is still elevated get started on therapy before they leave the hospital, that’s reasonable to me. If they’re already on a statin and they come in with an LDL above 70 mg/dL, adding a PCSK9 inhibitor is perfectly reasonable. If that’s the way your system works, and you can make that happen, it’s great. Every step that requires another blood draw and titration reduces the chance that the patient is going to get adequately treated.

If you wait 6 weeks and have them see you in the office then, some of them won’t come back to your office. They may go elsewhere. If you add the ezetimibe, you wait another 6 weeks. You must have a certain sense of urgency after an acute event. You need to have a system in place to make sure people are adequately treated. I don’t have problem with another type of system in which everyone with acute coronary syndrome gets an appointment with prevention within the next 2 weeks and they get started on therapy as an outpatient, especially if the hospital says, “We don’t want to stock X, Y, or Z as an outpatient drug.” But there has to be some sort of system so the patients don’t get missed. As they have 2 or 4 visits, the number of people who are adequately treated drops off exponentially. You have the patient’s attention when they’re in the hospital too.

A final thing is that there has been some suggestion over many years—I’m not sure if it’s true—that when we start something in the hospital, everyone is afraid to stop it. That’s why people are taking Lanoxin [digoxin] for 20 years for PAC [premature atrial contractions].

Some data suggest that may not be true, but there is some inertia behind starting it in the hospital that may make the patient more likely to stay on it.

To elaborate on what you just said, in many cases, the cardiologist who attended to the patient in the hospital is an interventionalist who doesn’t have much of an outpatient presence. The patient goes back to their primary physician, and they look at the patient’s lipid-lowering and say, “You went into the hospital on 20 mg of Lipitor and you’re coming out on 40 mg of Lipitor.” Theoretically, the patient is getting high-dose, high-intensity statin. The primary care physician says, “Look, these smart guys in the hospital thought that this was all you needed. Who am I to say this is wrong?”

There are multiple ways to approach this. We are fortunate in that we have a large, dedicated prevention section. Also, having a dedicated fellow working with us has really been a godsend in this regard, and it makes it very interesting. That, and being able to have a little refrigerator in our office with a mini supply of alirocumab and evolocumab makes it much easier. Even if you give them the drug and they don’t get it for 2 or 3 weeks, most PAs [prior authorizations] are accomplishable within that amount of time.

The only obstacle is when it’s contested. The patient doesn’t show up in prevention, and you’re left with a patient getting dropped. The way we look at it is, if you don’t start it in the hospital, you’re going to lose even more. We are trying this out. We’re doing it on our own. There were some institutions doing it on a trial basis, but we’ve been doing this as a course of good practice. You have to work it out however you can. If you cajole them back to the prevention section for a visit afterward and our note goes out with the catheterization note, we speak to the patient and they know what we’re recommending. We give them their lipid numbers before they leave the hospital, including an A1C [glycated hemoglobin]. We always draw an LP(a) [lipoprotein (a)] in someone appropriate. We have our NP [nurse practitioner], prevention fellow, or 1 of us if necessary, follow up with the patient, particularly if it’s high.

We need to do whatever we can to break the cycle of where things are going. You and I teach. We see people who have had stents and MIs [myocardial infarctions], and they show up again on exactly the same medicines they were on when they came in for the first go-around. To me, this is almost as bad as the patient who’s still smoking, whose blood pressure is untreated, and whose A1C has been left to climb over 8 mg/dL. You’re looking at this going, “Oh my God.” But this is something we have the ease of being able to treat. The nice thing about it is, it’s not another pill that the patient takes.

ACS: Early Intervention With PCSK9 Therapy

Let’s summarize. You know I love talking with you, so this has been a treat for me.

Yes, me too.We haven’t had a chance to do this. We haven’t spoken since we were trading quips at an ASPC [American Society for Preventive Cardiology] board meeting. It’s great to speak with you, particularly when we agree with each other. That’s always the best. It’s certainly much easier than disagreeing. I hope the listeners or viewers have gained a bit of insight. If not, they’ve hopefully been entertained. I thank you very much for joining me.

Yes, Howard. In summary, we covered a lot of ground today. We talked about the importance of lifestyle modification, which is something pivotal in the treatment of people with risk for cardiovascular disease. We talked about certain populations that are at higher risk and the effects of multiple dimensions of diversity from age, to gender, to socioeconomic status, that can affect the risk. We talked about statins, their effectiveness, and how to deal with statin intolerance.

One thing we need to remind everyone is that when you double the dose of a statin, you lower the LDL [low-density lipoprotein] only about 5% to 7%. The idea that taking someone from 20 to 40 mg, or from 40 to 80 mg, is not going to get you more than 5% or 6% percent LDL lowering is something that everyone should be aware of. If you add ezetimibe, you get a 17% to 20% LDL lowering, which is basically the same as tripling the dose of the statin. If you add a PCSK9 inhibitor, you’re talking about 60% additional LDL lowering. It’s important to keep that in mind when you’re deciding your choice of therapy.

We covered the outcome data for PCSK9 inhibitors and the relative safety of those drugs, as well as not to worry about extremely low LDL cholesterol. That doesn’t seem to be a cause of harm. We talked about guidelines, the difference between thresholds and goals, and how to think about that.

Finally, any physician should be comfortable with appropriate LDL lowering therapy, including PCSK9 inhibitors. If you’re not, just have your local pharmaceutical rep show you how it’s done. It’s basically a pen that is refrigerated, and you have to take it out and let it warm up for 30 to 40 minutes so that it’s at room temperature. You put it on your skin and push the button. People should be familiar with that if that’s a barrier for use. We both agree that this is not a medication that has to be given by a specialist, as long as you’re comfortable with the appropriate indications and you use guideline-based therapy.

Finally, you pointed out at the end that having a systematic strategy to treat the highest-risk patients, which are those with acute events, could include initiating it before they leave the hospital. Leaving it to luck that they’re going to follow up and that they’re going to get appropriate adjustments is inadequate.

We covered a lot of ground, and I really enjoyed the conversation. Thanks very much, Howard, for having this conversation with me.

Advances in the Management of Hypercholesterolemia

EP 1: Consequences of Hypercholesterolemia

EP 2: Cardiovascular Disease Risk Factors

EP 3: Socioeconomic Status and Hypercholesterolemia

EP 4: Cardiovascular Disease in Younger Populations

EP 5: Lifestyle Modifications to Manage Hypercholesterolemia

EP 6: Hypercholesterolemia: Shared Decision-Making

EP 7: Selecting a Statin Therapy to Manage LDL-C

EP 8: Managing Intolerance to Statin Therapy

EP 9: PCSK9 Inhibitors and LDL-C Reduction

EP 10: Cardiovascular Outcomes: FOURIER and ODYSSEY

EP 11: Lipoprotein(a) and PCSK9 Utilization

EP 12: Real-World Experience With PCSK9 Inhibitors

EP 13: Increasing Confidence in Prescribing PCSK9 Inhibitors

EP 14: ACS: Early Intervention With PCSK9 Therapy

EP 15: Optimal Management of Hypercholesterolemia