How Lower LDL Levels Forecast Disease

Deepak L. Bhatt, MD, MPH: You really made a good case for cholesterol and its importance, and you sort of implied that lower is better. But there are skeptics out there like Dr Nissen, who for many years has really questioned if lower is better. All kidding aside, there is a lot of skepticism out there, in particular on the Internet in terms of lower LDL [low-density lipoprotein] levels, especially when attained with medical therapy.

Steven E. Nissen, MD: It’s interesting. I’ve written about this Internet cult, which is sort of an anti—cholesterol-lowering cult. We can never quite stamp it out, sort of like the anti-vaxxers. These people are not rational. Something I wanted to comment on that you hinted at, Jamie, is that the best correlate is the area under the lifetime curve, and it raises some provocative questions. I assume others agree, but please disagree if you don’t. If you look at the area under the LDL curve for lifetime, that’s a pretty good predictor of whether you’re going to get disease. If your LDL is low for your entire life, even if you have a lot of other risk factors, you’ve got a relatively low incidence. Our guidelines say you’ve got to reach a certain level of risk to be treated. And I’ve always wondered—and I’m very interested in other people’s comments about whether our whole strategy is wrong and if what we shouldn’t do is find people who are 20 or 25 years old who have a couple of standard deviations above normative levels of LDL. Then we can just treat them with a low-intensity therapy for the rest of their lives.

Deepak L. Bhatt, MD, MPH: That’s an interesting question. Would you guys do that?

Christie M. Ballantyne, MD: Let me take 1 step back in terms of this controversy, because it’s an important one. When this comes up, people say well it’s not cholesterol, or more important lipoproteins; it’s inflammation. That’s where you see sometimes people saying that they’re missing this. This is a disorder, and cholesterol and triglycerides are insoluble in solutions; fat floats on water. You have lipoprotein particles, and the biology of the interaction of the lipoproteins with the arterial wall—it turns out that this is setting up a proinflammatory response. Lipoproteins themselves are pro-inflammatory, as are things like tobacco and diabetes—the issue of endothelial function with hypertension. Inflammation is also a central aspect. This is the problem that comes up in the Twitter world. It’s either inflammation or lipids. And no, in fact, they’re both important. If you treat—as Steve, you’ve shown us very clearly—you treat people with a statin or other medicine, but you lower LDL. And the ones who get a very low LDL and also a low CRP had the lowest event rates or the least progression of atherosclerosis.

Steven E. Nissen, MD: That’s right.

Christie M. Ballantyne, MD: But it is an important concept that we’re not saying it’s all cholesterol. All the risk factors are important, and the pathophysiology is a complex interaction between what’s in the blood, the lipoproteins, the endothelium, and the intima, and inflammation is an important process in this.

Deepak L. Bhatt, MD, MPH: That’s very good. What would you do with that?

Michael Miller, MD: I would like to add to your question about if you identify individuals who are relatively young, should we start them on a low-intensity statin. And I think this question was very aptly brought up by a really nice paper in JACC: Journal of the American College of Cardiology earlier this year that looked at patients in the Framingham Heart Study in their 30s and looked at their non-HDL [high-density lipoprotein] levels and found that that was a really good predictor of stability over time. Those individuals were at high risk of developing disease, so with the high non-HDL levels in their 30s was predictive of staying at high non-HDL untreated, which would predict cardiovascular events. So yes, I do believe that if we go to patients who are younger, have a family history, and may have other predisposing risk factors—you spoke about hypertension—it’s very reasonable to consider placing them on a statin at a younger age than previously thought.

Steven E. Nissen, MD: And there are these data from the Dallas Heart Study and Helen Hobbs, et al, in which people that had SNPs [single-nucleotide polymorphisms] that gave them a very small difference. What was it, like 15% or so lower LDL from birth, had like an 80% lower risk of developing coronary disease in their lifetime. I have always struggled with our guidelines, which seem to get trapped in this idea that, well, you’ve got to wait until you have a high enough 10-year risk to treat people. I feel like we ought to get people before they get to that point. And I’m worried that we’ve really missed the boat. Now, you can’t study it because it would be a 25-year randomized clinical trial, and nobody is going to conduct that. But what do you think would happen if you did that sort of a study?

Deepak L. Bhatt, MD, MPH: I actually think that sort of theoretical study, as you said, practically speaking, is hard and maybe impossible to do, but it would be positive and show benefit.

Transcript edited for clarity.