COMMENTARY

ESC 2017: Lipids and Prevention Takeaways

Sanjit S. Jolly, MD, MSc, FRCPC; Christopher B. Granger, MD; Eva Prescott, MD, DMSC

Disclosures

September 13, 2017

Sanjit S. Jolly, MD, MSc, FRCPC: Hello. I'm Sanjit Jolly, an interventional cardiologist and associate professor at McMaster University in Canada. I'm joined by Eva Prescott, a professor of cardiology at the University of Copenhagen in Denmark. It is our pleasure to have you. I am also joined by Professor Chris Granger, who I know well. He's a professor of medicine at Duke University. Welcome, and thank you for joining us today.

We're at the 2017 European Society of Cardiology meeting in Barcelona, and there's really been a lot of important information. We're first going to talk about lipids and prevention. You may say, "Interventional cardiologist talking about prevention?" Well, it's important. I think the first trial that is of interest is FOURIER, particularly this low LDL-cholesterol (LDL-C) analysis. FOURIER,[1] we all know, was a large PCSK9 inhibitor trial that showed a benefit for clinical outcomes. Eva, why don't you tell us about the low LDL-C analysis?

Eva Prescott, MD, DMSC: We've all been worried, even when we started with the statins, that it might be dangerous to lower our LDL-C levels. We feel comfortable with the statins, but now we are going to new levels of LDL-C. Are we going to lower it to nonphysiologic levels and see other side effects of that? We were very reassured by the data from FOURIER.[2]

Dr Jolly: Chris, what do you think?

Christopher B. Granger, MD: It's exciting that it seems like no matter how low the LDL-C went, there seemed to be additional benefit in this observational analysis but from a randomized dataset. It also creates a challenge, because, especially with the cost of PCSK9 inhibitors, it would be nice to know who gets the greatest benefit.

Is it the people who have very high LDL-C levels, or does everybody benefit from a PCSK9 inhibitor who has a risk for cardiovascular events? It looks to me like maybe everybody benefits. That's going to create a challenge for us—who should we use these drugs in? Should it be patients who have high LDL-C, should it be patients who can afford them? Of course, cost-effectiveness is going to be really important to sort out. Or should it be patients who have high vascular risk? And that may be the most important factor when we're making these decisions.

A Return to LDL-C Targets?

Dr Jolly: It's important to note the one caveat: This was a nonrandomized analysis. They looked at whether you were on PCSK9 or whether you were on placebo, they looked at your LDL-C level in one of five groups and looked at your outcomes. If your LDL is < 0.5 mmol/L (20 mg/dL)—very, very low levels—you had somewhere in the range of a 20%-25% reduction of events compared with higher LDL-C [> 2.6 mmol/L]. One question I have for you both is, should the guidelines change? Should the threshold that we target for patients with established vascular disease—should the target actually be lower? Then, if so, what is the target?

With PCSK9 inhibitors, I would suspect that you have to go back to targets because there will be nonresponders and it's so costly.

Dr Prescott: We have to remember that although we are very impressed with PCSK9 inhibitors, the absolute risk reduction wasn't all that great and there's no effect on mortality. European and US funding of healthcare is different, but that fact, combined with the cost, [gives me pause]. We have recommendations in the new ESC STEMI guidelines[3] which say that if your LDL level is > 1.8 mmol/L (70 mg/dL) [on statins], and you are estimated to be still at high risk, then we give a IIb recommendation for either ezetimibe or a PCSK9 inhibitor (maybe anacetrapib is going to be included at some point). The costs are really prohibitive, combined with relatively small risk reductions. That brings us back to your point: Should we limit it to those who are really at high absolute risk?

Dr Granger: I think you almost need all three of those right now, right? High risk, have coverage, and have high LDL-C. We'll also get more data with ODYSSEY and other trials, but before long, it's really going to be helpful to see whether there is a larger benefit with longer treatment. As you know, the US guidelines[4] actually deemphasize a target and just say that if you have vascular disease or are high-risk, you need to be on a high-intensity statin. For somebody with familial hypercholesterolemia, I think, we all agree that using these drugs is something that we should be doing if we can afford them.

Dr Prescott: With PCSK9 inhibitors, I would suspect that you have to go back to targets because there will be nonresponders and it's so costly.

Dr Granger: I think you're right; I think we are going to need to go back to some degree of target. It's amazing—even LDL-C levels < 10 mg/dL in FOURIER seemed to be associated with the lowest risk.

Dr Jolly: It's interesting, for me, as a clinician when you have patients who come back 3 months, 6 months after an MI and they're on, let's say, a high-dose statin and want to come down to a lower dose. You ask them why, and maybe they think that a lower dose is going to be easier on them.

The interesting thing is going to come 10, 20 years from now when we have agents that are perhaps oral and less expensive, that target the PCSK9 pathway, and now we can very easily achieve LDL-C levels that are barely detectable. The question is, will we change our targets? Will everybody who is at high vascular risk be on these drugs? Obviously that's not yet ready for prime time.

PURE Nutrition

Dr Jolly: Let's move on to one of the most talked-about studies from ESC: PURE[5]. It goes back to what your mother used to tell you about what to eat and what not to eat. Eva, do you want to talk about the results of PURE? What did they look at in fat and saturated fat?

We seem to be coming out with a very simple message about carbohydrates. We say that you should avoid carbohydrates, but all carbohydrates are not the same.

Dr Prescott: They looked at total fat, saturated fat, and the other unsaturated fats, and they also looked at carbohydrates and also at protein. They found that carbohydrate intake was associated with higher all-cause mortality. The surprise was that saturated fat intake was associated with lower all-cause mortality, but it wasn't associated with cardiac outcomes, although there was a reduced incidence of stroke. Of course, that is the surprising finding and that's why the authors are challenging current guidelines both with respect to the total fat intake and also with the saturated fat.

Dr Jolly: Chris, are you going to change your diet?

Dr Granger: My interpretation of PURE is that it's really interesting and it's provocative; I think it appropriately challenges whether we really know, based on high level of evidence, based on randomized evidence, the best diet to prevent cardiovascular disease. I think the answer is no. The data on the Mediterranean diet is our best randomized data showing that olive oil and nuts, tree nuts, and fish seem to be important, combined with exercise and avoiding smoking.

There's still some uncertainty about what the best diet is. The idea of limiting total fat and having more carbohydrates is probably wrong. I think we agree with that; there's no good evidence for that. We need more information about what's the very best diet to prevent cardiovascular disease.

Dr Prescott: The question is whether we are going to get that from observational studies. There are so many things; you can't change one thing in your diet without changing another. Can you adjust your way out of that? That's very difficult. Also, in such a setting like this, where the dietary patterns are so different, as they stress in the paper, that in some places—all our evidence until now has been in Western populations. It's hugely relevant to get some more information from non-Western populations. As they stress in the paper, they may not all have the same basic nourishment that we have, so that might also impact these results.

We seem to be coming out with a very simple message about carbohydrates. We say that you should avoid carbohydrates, but all carbohydrates are not the same. There are some that are easily digested and others that are not. I'm concerned that we may be back to giving an overly simplistic message about carbohydrates, like we did with fats. I think we should be careful with that.

Dr Jolly: I asked Salim Yusuf (PURE investigator) for his perspective. He said that one of the major challenges is that the highly processed refined carbohydrates that are very easy to eat are being propagated. That's his concern. These are very different carbohydrates from what we had 20 or 30 years ago. Everything is prepackaged now. Certainly, if you have the choice between the prepackaged bag of chips or the fruit and vegetables, this would tell us that you better take the fruit and vegetables.

The fruit-and-vegetables finding didn't seem like a surprise to me.[6] There was a reduction in mortality with higher fruit intake, with raw vegetables (less with cooked vegetables, not so much with legumes). To me, that was what my mother told me years ago. Was that a surprise to either of you, that there was a benefit from fruit and vegetables?

Dr Prescott: The way I understood it is that the point they were making was that you don't need to eat as much as we've been recommending. Also, as far as I could see, they found the association with all-cause mortality, but not with cardiovascular disease outcomes which would certainly be a surprise. What I understood is that we can ease up a little bit on recommending the portion of fruit and vegetables that we're recommending.

They saw a benefit from three to four portions per day, so that's certainly more modest. I think the interesting thing is that we're seeing effects on overall all-cause mortality and not as much of an effect on cardiovascular outcomes. I think that's important because cardiovascular outcomes are improving; we certainly have better therapies. Other forms of mortality are increasing relative to cardiovascular, such as cancer and so on.

Dr Prescott: Could I make another point about the interpretation of PURE, [the one] that says you should move away from the diet recommendations about not eating too much fat? We haven't actually been recommending that you should reduce your total fat, at least not in cardiovascular guidelines in Europe. In fact, when you talk about the Mediterranean diet, in the PREDIMED[7] study, one of the arms that was beneficial was adding spoonfuls of olive oil and also nuts—and you get lots of fats in nuts. We're not really afraid of fat; that's a misinterpretation of our guidelines, to be fair.

Dr Jolly: I think it's probably been the common belief for many years. While the guidelines are changing, common wisdom perhaps hasn't changed as much.

REVEAL CETP Inhibitor Anacetrapib

Dr Jolly: The next study we're going to talk about is REVEAL[8]. Do either of you have thoughts about REVEAL? What was REVEAL and what did they look at?

I don't see this as a major breakthrough. The question is, where would this fit in the armamentarium?

Dr Prescott: REVEAL is a fantastic study because we've been so disappointed with CETP inhibition. We have these trials with torcetrapib which had bad side effects and actually increased mortality. The other CETP inhibitors haven't had any effect and now we see that there is an effect. The level of effect seems to fit with what you would expect from LDL-C lowering. You saw a great HDL-C increase and moderate LDL-C lowering, but the effect on cardiovascular outcomes were what you would expect from the LDL-C lowering. Whether it's the LDL-C lowering or the increase in HDL-C, we don't really know at present, but maybe when they do more analysis, we might get a hint about that.

Dr Granger: I would just also comment that it was a big study—30,000 patients. It took a long time before the curves began to separate for this modest 9% relative risk reduction. In the shorter-duration ACCELERATE trial,[9] which studied evacetrapib—another CETP inhibitor where there is even a greater increase in HDL-C and reduction in LDL-C—there was no effect in that study. I agree with your interpretation that the effect is really quite modest. There are some challenges with anacetrapib; it has a fat-depot effect, so it stays in the body for a long time. The modest effect, I think, makes us think that it may not be something that's going to be important to use in clinical medicine.

Dr Prescott: The effects are similar to ezetimibe, actually—a little greater, I think. Ezetimibe had 7% [relative risk reduction].[10]

Dr Jolly: I think that's a good point. Ezetimibe is used clinically in a minority of patients—those who don't reach target and in whom we are trying to avoid using PCSK9 inhibitors because of their cost. This study was a surprise for me because all of the CETP inhibitors have been a failure. I think you're absolutely right, that the curve separated beyond a year and the 9% reduction in outcomes is modest. One of the interesting things is that it prevented new-onset diabetes but it raised blood pressure a little bit.

Dr Prescott: There were also some effects on renal function, but small.

Dr Jolly: I don't see this as a major breakthrough. The question is, where would this fit in the armamentarium?

To summarize, there have been some really important trials that have come out in terms of prevention. Perhaps guidelines will change around LDL-C. PURE was very interesting in terms of dietary guidelines, but we really need future randomized trials looking at specific dietary recommendations. I would hope to see that. I think we now have another lipid-lowering agent in the armamentarium. Thank you for joining us.

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