COMMENTARY

Preventive Cardiology: Past Reflections, Future Predictions

Henry R. Black, MD; Howard Weintraub, MD

Disclosures

August 20, 2015

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A Review of the Past 20 Years

Henry R. Black, MD: Hi. I'm Dr Henry Black. I am an adjunct professor of medicine at the Langone New York University (NYU) School of Medicine, and I am here today with my friend and colleague, Dr Howard Weintraub. Howard, welcome.

Howard Weintraub, MD: Thank you very much, Henry.

Dr Black: What's your role at NYU now?

Dr Weintraub: I am a clinical professor of medicine, and I am the director of the NYU Center for the Prevention of Cardiovascular Disease.

Dr Black: This is the 20th anniversary of Medscape Cardiology. What do you think have been the biggest advances in cardiology in the past two decades?

Dr Weintraub: Forgive me for looking at this through the eyes of a preventative noninterventional cardiologist.

Dr Black: That's what I expect you to do.

Dr Weintraub: Then I won't disappoint.

Risk Factor Modification

Dr Weintraub: Risk factor modification is something huge. Hypertension is obviously something you know all so well—you and I have lamented on multiple occasions that the risk factor with perhaps the most impact on cardiovascular disease is often not given its due.

What has caught on is the treatment of lipids and the role of statin medications in reducing cardiovascular events. We have gone from the ability to lower cholesterol a modest amount using bile acid resins or the intolerable medicines, such as niacin, to using the statins that have progressed from lovastatin (Mevacor®) to rosuvastatin. The low-density lipoprotein cholesterol (LDL-C) lowering exceeds 50% in many people, and the event reduction is extraordinary. We know in cardiology, there are very few drugs that we can say save lives, prevent the need for surgery, prevent heart attacks and strokes, and have a tolerability that is as good as the statins.

The Attack on Statins: Cognitive Issues

Dr Black: You talk about tolerability, but people seem to be attacking statins over and over again. What do you feel about that?

Dr Weintraub: The conspiratorial theory of medicine says that if you want to find something bad about something, you will. Let's go one step at a time.

The cognitive issues have recently been batted around. There was a recent article[1] that cited that other nonstatin drugs may cause this, and it's a short-term effect that generally abates. There may be a bias insofar as how these results were interpreted.

Our friend Roger Blumenthal and his group did a very noteworthy review[2] several months ago. They went into depth looking at only the studies that had psychologic testing, so that you had objective criteria for cognitive issues, and the problem really was not there. They were able to conclude that there was no statistically significant impact on cognition, although in some patients this may happen. And in the cases where it does, it's up to the physician and the patient [to discuss it]—you stop the drug, and generally it gets better.

Dr Black: Is there any difference in how men and women respond to statins?

Dr Weintraub: Perhaps on an emotional basis, but I would doubt that even. I don't think so.

Dr Black: In my experience, there hasn't been either.

The Blood Sugar Issue

Dr Weintraub: Then there is the issue of blood sugar. That came out in Ridker and colleagues' publication of JUPITER,[3] and in that same population and others, they were able to identify that the people who developed diabetes on a statin were destined to do so. In my way of looking at it, they were a Hershey bar away from developing diabetes.

These were individuals with high A1c levels; their body habitus and other features were those typically seen in the metabolic syndrome-type paradigms; and these were people in whom it would have happened over several months. If anything, the impact of LDL-C lowering may have vastly exceeded whatever risk was there by one tenth of a point or two tenths of a point.

Those are the two big issues that patients run from. The hepatic issues have long been dismissed, and certainly we worry about those in people with active liver issues or who abuse alcohol, but really, that hasn't been much.

Statins and Myalgia

Dr Weintraub: Then comes the issue of myalgia. Another friend of ours, Paul Thompson, is somebody who has been very active in this regard. Paul has written a few papers[4,5,6] recently. In one of them, he estimates that in the hands of a good clinician [it can be managed]—not a busy physician who is inundated with people who go online and read that statins can cause myalgia, and they figure that, "Well, my shoulder pain must be due to the myalgia, so I am going to call my doctor." And the doctor, being busy, says, "All right. Fine. Stop the statin," when it's only one shoulder and more likely to be a rotator cuff than a statin, because most drugs are not smart enough to go to one arm and not the other. But that person is then branded as statin-intolerant. In many cases, they would stop the drug and not restart it, or sometimes they would use another drug.

In several of the PCSK9 trials[7,8,9]—one of them particularly, ODYSSEY ALTERNATIVE,[8] with alirocumab—they were able to identify that about one third of people were actually statin-intolerant. So all these people who were felt to be intolerant, who then got blinded statin medications, were able to tolerate them. I think that corroborates my feeling that a lot of doctors cave in a little too soon, and are maybe allowing patients to not be treated appropriately. Again, the majority of statin drugs are generic, the cost is exceedingly small, and the impact can be very big.

Dr Black: I am sure you recall that we used to have to get ophthalmologic exams because of the corneal opacity capacity in dogs. That was stopped after about a year or so.

Dr Weintraub: That was with the birth of lovastatin (Mevacor®)—we were doing that because they were worried about people developing cataracts. Then they found that as many people developed them as lost them.

Genetics and PCSK9

Dr Black: You mentioned the new approach to lipids. Tell us about PCSK9.

Dr Weintraub: This is a very exciting thing, in my opinion. And the reason I am excited about it is because I am one of the people who does believe in the science of atherosclerosis, and that there are things that drive the development to plaque. Hypertension is one, and hyperlipidemia is another. You can develop plaque simply with hypertension and in the absence of high cholesterol, but when you combine the two, you certainly drive a lot more atherosclerosis.

A lot of this is based on atherogenic lipoproteins becoming entrapped. The one that we think of the most is LDL-C. It would be hard to think that wanting to lower this more would not be effective in trying to reduce the impact of atherosclerosis. I believe that lower is better and that lowering LDL-C matters; and, by and large, I feel the way Chris Cannon did when he closed the IMPROVE-IT[10] presentation at the American Heart Association (AHA) meeting.

These new drugs are interesting. Helen Hobbs at Dallas and the people in ARIC (Atherosclerosis Risk in Communities) looked at genetics of individuals. They measured cholesterol, and for those at the extreme ends, they did genetic studies.[11] They found that some individuals with extraordinarily low cholesterol levels had a polymorphism of a gene for PCSK9.

PCSK9 is a protein that chaperones LDL receptors after they have been bound to the LDL, and they take a trip inside the liver into the vesicles, where ultimately LDL is destroyed. What is supposed to happen is that the receptor is recycled—this way, you don't throw out the garbage can with the garbage. When PCSK9 complexes with the LDL receptor, the LDL receptor is also destroyed. Ultimately, the number of (for lack of a better word) garbage cans on the surface of the liver becomes diminished, and LDL rises.

They took a look at the molecule. It is relatively straight, so a small molecule was not going to work. So they made a monoclonal antibody to this, and they were able to effect LDL-C reductions in the range of 50%-60% when used as monotherapy. When used on top of any other drug, the PCSK9 drug still gets about a 50%-60% reduction.

Dr Black: That includes on top of statins?

Dr Weintraub: Exactly. So you are talking about opportunities to lower LDL-C well beyond what we have had an opportunity to before. We have talked about this many times before—about primordial prevention, and how nice it would be. Certainly the cost of this drug is going to be a real issue in the immediate and probably intermediate term; it would be very nice to have the capability to be able to effect lifelong reductions in LDL-C largely because the genetics studies tell us it works.

Dr Black: Now, this has to be given parenterally, not orally?

Dr Weintraub: Yes. Two companies have come out with very similar compounds: alirocumab (Regeneron Pharmaceuticals; Tarrytown, New York) and evolocumab (Amgen; Thousand Oaks, California). Because they are antibodies, they can't be given orally. The way they work, the minute they are injected, PCSK9 levels in the blood plummet and stay down anywhere from 2-4 weeks, depending on the agent. LDL-C follows suit over the course of several days and then stays down, again either for 2 or 4 weeks.

They have been very clever about this, as they should have been. They have developed injector systems very similar to the insulin flex pens, where there is no mixing and drawing up of liquid. Someone just tightens the plunger and preps the skin; a very, very fine needle is on the end of this, and you give the shot.

We are involved in one of the trials called ODYSSEY[12]; it's an event trial with alirocumab in people post-acute coronary syndrome (ACS). I am just amazed how readily patients accept the technology and the dosing, and how amazing the results are. We are not supposed to know the numbers, but one patient went to his primary care physician and had bloods drawn because he forgot to tell his doctor he's in a trial. He came back with this and said, "What do I do with this number?" His LDL-C was 13 mg/dL. I said, "Have a party."

I think this is going to be a real game changer, and furthermore, it's very well tolerated; there have been no antigen reactions to it thus far, in about 10,000 patients studied. There are two event trials: One called FOURIER is using Amgen's drug evolocumab, with 22,000 patients, and they are nearly done with the ODYSSEY trial, which is 18,000 patients.

And if I am not mistaken, you have been working with this as you have done in the past; there is another company that is coming out with a third agent, and I believe you may be involved in the data safety and monitoring board (DSMB).

We are going to have over 70,000 patients in event trials with data, the first two probably coming out in 2017 or 2018 and the other one maybe a year or two behind that. I think it is a very exciting time.

Residual Risk

Dr Black: Are you going to be able to deal with something that lipidologists talk about, which is residual risk? It assumes that you can get the heart attack rate to zero, which I don't think is possible.

Dr Weintraub: No, you can't do this, because this is not a perfect world. We have not been able to engineer the genome so that someone is never hypertensive, that they have the right genes so their triglycerides are always low or their high-density lipoprotein cholesterol (HDL-C) high. It turns out the mendelian genetics for HDL-C showed us that HDL-C didn't matter. Imagine the HDL aficionados who have been looking at this and going, "Oh, my God."

So now there is a new thing. We're a very productive society of doctors. When the people who study HDL heard this, they looked in a different place, HDL function: How well does HDL act as a reverse transport?

The genetics for LDL are very impressive. Those born with the right genes have lifelong low numbers and very low incidences of coronary artery disease (CAD). There are people blessed with good blood pressure, likewise. Now there are genetic studies with several genes that mediate triglycerides.

The Europeans, in this case, had it all over us, because they have told us since the Paris Prospective Study[13] in the early 1990s that yes, it is important, and we kind of went, "No, we can't figure this out." It turns out that those people with lifelong high triglycerides have higher cardiovascular disease and [those with] loss-of-function genes had lower cardiovascular disease, such that a company is now making antisense agent to one of the apolipoproteins. This is where this has gone. The other amazing part is going from discovery of the gene to near completion of an event study in 10 years.

Dr Black: Remarkable.

Dr Weintraub: Amazing. I mean, just think back to the angiotensin-converting enzyme (ACE) inhibitors—how they went from the venom of some poisonous snake and what kind of circuitous route this took, going through the South American tropics and then eventually coming up in the Bristol-Myers Squibb laboratories. That was captopril (Capoten®), right?

Dr Black: Yes, that was. We are so much better at understand the physiology, pharmacogenetics, and pharmacodynamics of the agents we see. One thing we haven't successfully done is the behavioral part of this. We haven't figured out how to get people to not become overweight, to exercise more, and to eat differently or eat less. That's a big challenge, I think.

Dr Weintraub: You are absolutely right, Henry, which is one of the reasons why we will never eradicate atherosclerosis—and there are many interventionalists around the world who are joyously celebrating that fact.

The COURAGE Trial

Dr Black: Tell me about the COURAGE trial.[14]

Dr Weintraub: I understand a lot of people look at the developments in cardiology—and you can look at it through the eyes of a catheter inserted into the right femoral artery, or you can look at it through the eyes of someone who is looking to prevent that (or certainly after it has been done once, then not having it happen again). Atherosclerosis is a systemic disease. Treating lesions in the coronaries has been shown, with the exception of being done in the setting of an acute myocardial infarction (MI), to not save lives, not prolong lives, and not prevent heart attacks. What they are essentially are very expensive maneuvers that can frequently be done with weight loss, exercise, and drugs, but the drugs are not nearly as sexy.

The COURAGE study, done by our buddy Bill Boden, showed in a cohort in the Veterans Affairs (VA) system that optimal medical therapy was every bit as good at preventing the hard outcomes that we worry about as implanting a stent and giving optimal therapy on top of it.

They could not make people lose weight. They got them to stop smoking to a great degree, but they almost didn't lose an ounce. You've been around so many trials—[you know that] the study coordinators, they mean business and they are going to be on top of these patients, certainly more than most practices can be. That speaks to the idea that we will not get over this, and as long as there are these super-duper things you can buy at Hardees that have almost 1500 calories and almost equal numbers of grams of fat and sodium, then they don't have to worry—there will always be plaque.

What I have been seeing in the prevention arena is patients who are more interested in just walking to a lab, lying down [and getting a procedure], and then hours later they feel fine, and then a couple of days later they are back doing what they want, because there is a very vicious cycle of recidivism. I think that if you don't tend to that, you are going to be in trouble.

Dr Black: I think the hopeful thing is that we are starting to educate children to educate their parents. That happened with smoking, and I think it might happen with diet; at least I hope so.

Dr Weintraub: I would love to see that happen. Although what I understand is that the current generation is one of the first to be expected to not live as long as their parents did. Part of the reason for that is their propensity toward obesity. When you and I were in training (however many hundred years ago that was), type 2 diabetes was synonymous with adult-onset diabetes. That is no longer the case.

Dr Black: No, not at all.

Dr Weintraub: To have type 2s running around who are 7 years of age makes you think about this.

Dr Black: Type 1 diabetes used to be about 40% of the diabetic population, and now it's 5% or 10%.

Dr Weintraub: Exactly right.

Dr Black: But that's going to change. Well, hopefully it can change back.

Dr Weintraub: I think we have learned from the effects of overlay of risk factors that once again, residual risk is something that's very important. There was a very famous news man, Tim Russert, who worked on Meet the Press. His doctor was very happy with his treatment on his statin because his calculated LDL-C was in the 60s. His triglycerides were 300 mg/dL, his HDL-C was 30 mg/dL, his blood sugar was high, and his blood pressure was high. There was chagrin, and in the medical community amazement, that the poor man took a red-eye back from Paris, collapsed in the NBC studios, and died . You have got to look at this and say, "Was this preventable?" The answer is yes.

Dr Black: Just one thing before we close. One of our colleagues has made the point recently that heart disease was a leading killer and still is, but that cancer is catching up. As we prevent heart disease, something else is going to kill us—we are not going to live forever.

I appreciate all your input. I have enjoyed working with you all these years and look forward to doing it some more.

Dr Weintraub: Thank you very much, Henry.

Dr Black: You are very welcome.

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