Reducing Risk in Cardiovascular Events - Episode 8
Deepak L. Bhatt, MD, MPH: Let’s move on now to triglycerides. We’ve talked a bit about LDL [low-density lipoprotein] and HDL [high-density lipoprotein]. Mike, you’ve done a lot of work in terms of triglycerides as a risk factor. What’s the latest thinking? HDL—clearly from what Christie just said, the thinking here has shifted. It’s a powerful risk marker but not clearly something that is associated directly with atherosclerosis. What’s the thinking on triglycerides? That’s also been flip-flopping from year to year.
Michael Miller, MD: Twenty, 30 years ago, triglycerides were basically a stepchild. HDL and LDL were the 2 primary components we would monitor. But triglycerides have certainly been placed up in the mix. The reason for that is we appreciate that it’s not so much triglycerides per se, but it’s the company that triglycerides keep.
Triglycerides are blood fats, but they’re contained in these lipoproteins that, like VLDL [very-low-density lipoprotein], when they are partially broken down, they produce a cholesterol-enriched remnant. Those cholesterol-rich remnants are particularly atherogenic, because they can get into the arterial wall to macrophages in an unregulated manner. LDL needs to be modified to oxidize and so forth to get in. But here is an unregulated uptake. Having a high triglyceride is associated with lots of these remnant particles but also lots of LDL particles. And that combination can be problematic. So the worst combination is having high LDL and high triglycerides. That combination could be particularly devastating, so we view triglycerides as important.
Christie M. Ballantyne, MD: Mike, maybe you could go back a little over 30 years ago. I know back in the early ’80s there were 2 brothers called the Patch brothers, Wolfgang and Dozer Patch, and what they said was, “We live most of our life in the postprandial state.” In fact, their hypothesis was that for the majority of people, a low level of HDL cholesterol was a marker of delayed postprandial lipemia, and that if people have an increased number of triglyceride proteins, they have problems with remnants. I think they probably were right.
It’s just that they get ignored. And what ends up happening is if you have those particles hanging around a long time, via CETP [cholesterol ester transfer protein], you get low levels of HDL cholesterol against LDL. Basically, they said, we all know that glucose in epidemiology studies is a poor marker of risk, but glycated hemoglobin A1C is a better marker of risk because of its variability. So they said HDL cholesterol is the hemoglobin A1C for postprandial lipemia. That basically it’s a more constant. TGs [triglycerides] bounce all over the place, and that’s why it drops out of the multivariate analysis. And that really all along, the problem was triglyceride-enriched lipoprotein remnants. One thing that’s important clinically: when you see the low HDL cholesterol, look at the triglycerides. Don’t try to look at the HDL. Look at the triglycerides in terms of what you may be doing.
Steven E. Nissen, MD: You know, Christie, obviously the 1980s was before I was born, right? But this whole triglyceride story was confounded by the fact that we had these studies of triglyceride-lowering therapies, but they were done in the wrong population, with the wrong agents, in the wrong way. We had a bunch of fibrate trials, and they were used in people who didn’t necessarily have high triglycerides. And we had a bunch of fish oil trials that were using over-the-counter—you know, a gram of over-the-counter fish oil—and they didn’t work out. Of course, we now know fairly recently, thanks to the work of Dr Bhatt, that therapies that were at least nominally addressing triglycerides, although they do many other things—let’s be clear that they do many other things—have now been shown and result in a rather robust reduction in morbidity and mortality, with hazard ratios that are as good as what we see with statin trials.
You know I wouldn’t try to describe the trial. But the REDUCE-IT trial—Deepak, I’m sure you can speak to that—was a real game changer. Because now that we can identify a population with high triglycerides who benefit from therapies that among other things lower triglycerides, it really makes this a target for therapy that now needs to be widely addressed in society.
Deepak L. Bhatt, MD, MPH: So triglycerides are back in.
Steven E. Nissen, MD: They’re back in, but what’s interesting about reducing is that it probably isn’t all about triglycerides. I mean, triglycerides went down. How many percentage points did they go down in your trial, Deepak?
Deepak L. Bhatt, MD, MPH: Of course, it depends on the starting levels at 20%, 25%.
Steven E. Nissen, MD: Yeah, and so you know, I happen to think there’s more going on than just triglyceride lowering. I don’t know whether other people agree or not.
Michael Miller, MD: Well, you need to consider.
James A. Underberg, MD, MS: The major paradigm shift and the way we view triglycerides is in recognizing them again as a risk factor, right? Just the way you were talking about HDL before—that the patient with high triglycerides, especially in the setting of treated LDL, still represents a significant amount of untreated risk that benefits from risk-reducing therapeutics. They may be with omega-3s. They may be with additional LDL-lowering agents or newer agents on the market. But that high triglyceride level is this blinking light, not to be ignored. That, to me, is the big game changer.
Michael Miller, MD: The reason for that is the hypertriglyceridemia patient has endothelial dysfunction, has a prothrombotic tendency, and a proinflammatory tendency. And that might be part of the reason that REDUCE-IT study was so successful.
Before we get further into the details, though, Steve, you mentioned something in terms of how you describe it. I’d just like you to put on your regulatory hat. You’ve done a lot of work with the FDA through the years. I think there’s confusion for patients or people out there and doctors as well about regulation of supplements. I don’t think a lot of doctors even realize that the FDA doesn’t regulate supplements in the way it does medicines. The food is regulated, so there is some degree of oversight. But not the same oversight in terms of the purity of the compound and the safety as a prescription medication. Could you just quickly describe what it is?
Steven E. Nissen, MD: An unmitigated public health disaster, and I’ve written extensively about this. Congress made a terrible mistake in 1994 when it passed the law known as DSHEA [Dietary Supplement Health and Safety Act], which actually bars the FDA from regulating. You call something a dietary supplement, and you can sell it. You can go into your local pharmacy, and you can see rows and rows and rows of these. Probably 10 different fish oils. They all have a different amount of EPA [eicosapentaenoic acid] and DHA docosahexaenoic acid]. Some have very little. Their content is not regulated. You have no idea what you’re getting. Let me tell you how bad this law is.
I could go out in my backyard and cut up grass clippings and put them in a capsule and put them in a bottle that says “Nissen’s Heart Tonic,” and I could sell them on the shelf of the local pharmacy and nobody could stop me, because of this law.
Christie M. Ballantyne, MD: Wait, I saw that last month in CVS.
Steven E. Nissen, MD: What you studied was a pharmaceutical-grade pure EPA drug. Whether that’s going to be the same as EPA and DHA, we don’t have the answer to that. What we know is what you studied. And the regulators took a look at the trial; a panel of peers reviewed it. They voted unanimously that the study was on well enough to warrant a label. The label hasn’t been written yet, but it’s going to be in the next few months.
The lesson here to learn is, what happened is, the earlier therapies had an overreach. They said, “Well, let’s just give it to everybody. Let’s give fenofibrate to everybody and see if there’s a benefit.” There wasn’t. What you studied was a population where we had a very good reason to believe there might well be a benefit. The benefit was probably—would you not agree?—larger than any of us would have anticipated. It was a better result than we could have ever asked for.
Deepak L. Bhatt, MD, MPH: Well, it depends. I don’t know that I’ve actually asked the steering committee about that. We had actually calculated what we thought it might be, based on the literature. We’d come up surveying all the literature subgroups of different trials and so forth. We’d actually anticipated there would be a 22% lower risk reduction.
Steven E. Nissen, MD: But you were powered for something like this.
Deepak L. Bhatt, MD, MPH: We were powered for 15%.
Steven E. Nissen, MD: Exactly. So you did what all good trialists do: you had a conservative figure. And listen, I would have been happy with a 15% relative risk reduction.
Deepak L. Bhatt, MD, MPH: Absolutely.
Steven E. Nissen, MD: You ought to be happier with a 25%. In particular, we didn’t know about things like mortality.
Transcript edited for clarity.