Beyond Statins: PCSK9 Inhibitors, Ezetimibe, and Diet

Stephen L. Kopecky, MD; Vaibhav R. Vaidya, MBBS; R. Scott Wright, MD


November 30, 2018

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Medscape &

Vaibhav R. Vaidya, MBBS: Greetings. I'm Vaibhav Vaidya, cardiology fellow at Mayo Clinic. Today, we'll be discussing updates in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe. I'm joined by my colleagues Dr Scott Wright and Dr Stephen Kopecky, who both specialize in this area. Welcome, Dr Wright and Dr Kopecky.

R. Scott Wright, MD: Thank you.

Stephen L. Kopecky, MD: Thank you, Vaibhav.

Nonstatin Alternatives for Cholesterol Reduction

Vaidya: What is the spectrum of effective nonstatin alternatives for cholesterol reduction?

Wright: There are a number of options for treatment. The most important, which we almost always overlook because we take it for granted, is lifestyle and diet. You can achieve a tremendous amount of prevention with a healthy diet (which largely is a Mediterranean-type diet), appropriate caloric consumption, and then regular exercise.

Statins in almost all patients should be first-line or first-attempted therapy, but we also have such drugs as ezetimibe. For triglycerides, we have fibrates, and for people with really elevated low-density lipoprotein cholesterol levels (LDL-Cs) who might have familial hypercholesterolemia (FH), we have the new monoclonal antibodies to the PCSK9 antigen. All of these are very well tolerated; some are very inexpensive, and some are very expensive.

Lowering Risk for Cardiovascular Morbidity and Mortality

Vaidya: Do we have any evidence that these nonstatin alternatives lower cardiovascular morbidity and mortality?

Wright: Let me ask my colleague Dr Kopecky to comment first on diet, because he knows those data as well as anyone.

Kopecky: The diet data are really overwhelming. The Mediterranean diet, as defined in the PREDIMED study, lowers cardiac and noncardiac events and mortality.[1] The more you adhere to it, the more it reduces your events. Certainly, the nonprescription alternative therapy agents, such as stanols and sterols, soluble fiber, and oat bran, will lower your cholesterol, but we don't have evidence that it really lowers your event rates.

Wright: This includes the statin-like vitamin alternatives that many of our patients like to take that they buy in the health food store.

When it comes to looking at preventing cardiovascular events, let's divide patient populations into two groups. Let's think about those who have never had a diagnosis of cardiovascular disease or any event, such as a heart attack, stroke, or need for revascularization, and those who have had a very serious event, such as an acute coronary syndrome (ACS).

For the people who have had an ACS, we have very good evidence that adding either ezetimibe[2] or statin plus ezetimibe with a PCSK9[3] inhibitor can reduce future cardiovascular events beyond what the statin or the statin plus ezetimibe can do alone. The incremental benefit is maybe 2 to 3 additional absolute percent reductions in total events, such as recurrent heart attacks and stroke, but not mortality.

For patients who have never had a serious cardiovascular event, the evidence is indirect. We don't have trial-based evidence that the drugs reduce events. Many of us believe that lowering LDL-C is the appropriate mechanism and that reduces events, so we use them, but I think to be transparent, we need to say that we just don't have the clinical trial data, unless I'm forgetting something with ezetimibe in that population.

Kopecky: No, I'd agree.

Wright: I think it is a totally different story for people who have very high cholesterol levels from FH. The PCSK9 inhibitor drugs have pretty good evidence there,[4] as do all cholesterol-lowering agents. You need to do something. You just can't live with an LDL-C of 190 mg/dL (4.9 mmol/L) or 290 mg/dL (7.5 mmol/L). If you do, you are not going to live many decades, because you'll have a cardiovascular event or sudden death.

Do PCSK9 Inhibitors Need Concurrent Statin/Ezetimibe Therapy?

Vaidya: Thanks for that insight. While using PCSK9 inhibitors, do patients still need to be on statin therapy or ezetimibe?

Kopecky: Without a doubt. We see many patients in our clinics here. They are not quite at goal on one of the PCSK9 inhibitors because they are off the ezetimibe or statin, and if you actually add the statin [or ezetimibe] back in, they can get tremendous reduction. For instance, putting someone on a PCSK9 inhibitor will lower their LDL-C maybe 55% or 60%, whether that's at baseline on nothing or on top of what you already have done with lowering it with high-dose rosuvastatin or atorvastatin. By adding in ezetimibe, it goes even lower. They need to be on combination [therapy].

Wright: Except for those who maybe have statin intolerance or an allergy to the statins, or for the rare patients who might have ezetimibe intolerance. If you tolerate those drugs, please do not stop them. The PCSK9 monoclonals have not been tested in any ongoing trial without patients being on maximally tolerated statins or maximally tolerated statins plus ezetimibe.

Kopecky: That is an interesting point. The US Food and Drug Administration has approved statin use on a daily basis. It's not approved for less than a daily basis. However, many patients can take a statin maybe once or twice a week and, although it's not approved, they get a tremendous reduction when it's added with a PCSK9 inhibitor. Just a little bit of it once or twice a week can really help the PCSK9 response.

Wright: It's important to note that the half-lives of both rosuvastatin and atorvastatin are long. Many years ago, Dr Kopecky taught me and others that you could use these drugs once, twice, three times a week and almost have the same benefit from an LDL-lowering standpoint as you could from taking it daily in those who are either intolerant or have intolerable side effects. What is really important for physicians to recognize is that people are statin-intolerant. Some physicians remain in denial that it's not a real issue, but it is. Probably 10%-20% of patients on statins find some degree of intolerance and need a dose adjustment.[5,6]

When Should Ezetimibe or a PCSK9 Inhibitor Be Added?

Vaidya: When evaluating patients in clinic, when should we start thinking about adding ezetimibe or a PCSK9 inhibitor?

Kopecky: There are three groups. One is the patient with FH; clearly, they can benefit. The second group is the patient above goal having recurrent events and you just can't get them to where they need to be, even on full-dose statins and ezetimibe.

The third group is the statin-intolerant patient, which we just talked about. This allows you to get away with a little less statin. These are the toughest patients to get approved, however, and you need a lot of documentation showing they've tried different statins. But it can be very helpful, especially if they are having recurrent events.

Wright: I use a fourth group that Kopecky is alluding to. If I have someone who has had a myocardial infarction and their LDL-C is perhaps 70-75 mg/dL (1.8-1.9 mmol/L) on a reasonably high dose of statin, I say to them that the statin has done a good job, but it has not done enough because their LDL-C is not low enough. So I will add additional LDL-C-lowering therapy.

Routinely in my practice, if you had an ACS, I now aim for your LDL-C to be less than 50 mg/dL (1.3 mmol/L), and your C-reactive protein (CRP) to be at a normal level. I like to treat both the lipid and inflammatory cascades. I realize that is not label-approved yet, but I think it is cutting-edge where the science has taken us. To date, no study has shown that we can lower LDL-C to a point that it's harmful. We keep watching for that. We are worried about that, but we have not seen any evidence. Most of us probably don't go to an LDL below 20 mg/dL or 30 mg/dL (0.5-0.8 mmol/L) anyway, but you can achieve those in patients who either have a high burden of disease or have had a lot of recurrent events.

Importance of Lifestyle Management

Vaidya: Circling back to what you were talking about in the beginning of the conversation, with all of these potent nonstatin alternatives now available, how important are diet and exercise in the management of these patients?

Kopecky: Extremely important. There were some very interesting studies done with statins—the ONTARGET trial[7] and a couple of others—where they found that if patients did not eat Mediterranean-diet healthy, as defined by PREDIMED, they would get the LDL-C reduction, but not the benefit of the event reduction. We could probably find the same with PCSK9 inhibitors, but no one has done that analysis. Clearly, the drugs are just not enough. You have to have lifestyle [modification].

Wright: Remember, unstable coronary disease or unstable vascular disease is not a single hypothesis or mechanistic disease. It's not just lipids; it's also thrombosis and inflammation. So diet and lifestyle, including exercise, favorably alter thrombotic factors and inflammatory factors. The next webinar we may have to do is a discussion on when to start using anti-inflammatory therapy, at least for a limited time, in people post-myocardial infarction, because there are pretty strong data now from a single large trial[8] [CANTOS] that that made a huge difference. Once it's replicated and we have agents that we can use, we are going to have to seriously think about that.

Kopecky: However, Dr Wright, as you know, the Mediterranean diet is an excellent anti-inflammatory diet, and regular physical activity has also been shown to lower CRP and many of the inflammatory markers. We bring home both of your points. We have to get patients to comply.

Wright: I agree. Diet and exercise are really hard things to be compliant with, so they should be addressed on frequent office visits. Remind patients, because almost no one is perfect on those for an entire decade or entire lifetime.

Kopecky: For many of our patients, we have them preset on appointments with us and with our dietitian and exercise physiologist. We try to circle that loop and help them every way we can.

Wright: For those watching us today, that is one of the real benefits of a Mayo model of care, which is that we have a multidisciplinary team approach and not just physicians. We have dietitians, nurses, and exercise physiologists. This is something you can replicate in your own practice. You may not be able to hire the staff or people, but you can collaborate in your community and set up a network that you can refer to, because it truly takes a group of us to help individual patients. As the book says, it takes a village. It takes a number of medical personnel to holistically treat patients, and not just the doctor or provider and the patient. It's a team-based approach.

Vaidya: Wonderful. Thanks, Dr Wright and Dr Kopecky, for these important insights. Thank you, the audience, for joining us on Medscape Cardiology.


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