LDL-C and Cardiovascular Disease Risk

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: Hello, and welcome to this HCPLive Peer Exchange entitled, “New Guidance, New Data, and New Targets for the Management of Hyperlipidemia.” I’m Dr Keith C. Ferdinand, the Gerald S. Berenson Endowed Chair in Preventive Cardiology and professor of medicine at the Tulane University School of Medicine in New Orleans, Louisiana. Joining me today in this discussion are 4 of my favorite colleagues, very diverse, from all parts of the country. Will each of you introduce yourselves? Dr Christie Ballantyne, Dr Mary McGowan, Dr Payal Kohli, and Dr Erin Michos. Christie.…

Christie M. Ballantyne, MD, FACC: I’m Dr Christie Ballantyne from Houston, Texas, and chief of the Section of Cardiovascular Research. Keith, great to be here with you.

Mary McGowan, MD, FNLA: I’m Dr Mary McGowan. I’m at Dartmouth Medical School, and I am the chief medical officer of the Family Heart Foundation.

Payal Kohli, MD, FACC: I’m Dr Payal Kohli. I’m a noninvasive and preventive cardiologist. I’m an associate clinical professor of medicine at the University of Colorado. It’s a pleasure to be here today.

Erin D. Michos, MD, MHS: Hi, I’m Dr Erin Michos. I’m the associate director of preventive cardiology and the director of women’s cardiovascular health research at Johns Hopkins University. I’m also really honored to be part of this program today.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: This program is in partnership with the Family Hearts Foundation, a nonprofit organization dedicated to supporting research, advocacy, and education for individuals with the 2 most common inherited lipid disorders, familial hypercholesterolemia, or FH, and elevated lipoprotein(a), or LP(a). This Peer Exchange will focus more broadly on strategies to improve control of LDL cholesterol [LDL-C ] in high-risk individuals. We will discuss real-world data on reaching LDL-C thresholds and emerging therapies for lipid lowering. We will also review strategies to help implement lipid-lowering therapies into your clinical practice. Welcome, everyone. Let’s get started. Dr Kohli, what is the role of LDL risk? We have various data (eg, experimental, observational, clinical trials).

Payal Kohli, MD, FACC: It’s one of those agents that I feel like we have such a compelling body of evidence about. Mendelian randomization, Dr Ferdinand, I would say, is one of the strongest types of evidence that we have. This essentially means if you’re born with a genetic mutation where you have a loss of function in your LDL receptor, meaning your LDL-C levels are super high, you get premature atherosclerosis. And the opposite is also true. If your LDL levels are low genetically, you have a much-reduced risk of having heart disease. This really establishes a causal relationship of LDL-C being what I like to call an endotoxin, which is a poison to the blood vessels. We really need to start thinking about LDL-C almost like we think about smoking—the cholesterol years of exposure. It’s not just the level, but it’s how long it’s been at that level that really confers the risk; the area under the curve, so to speak. The idea here is to try to lower cholesterol aggressively and to lower it early enough that you can really start to modify that area under the curve. Now, the Cholesterol Treatment Trialists’ Collaboration does tell us that the slope of how much bang for your buck you get when you reduce your cholesterol depends on your underlying risk. But in general, every 39 mg/dL that you drop your LDL-C, you’ll get about a 22% reduction in major adverse cardiovascular events.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: Wow. That’s a lot of evidence coming from different components of science. Erin, do you see anything else that you’d like to add related to LDL-C as an enhancer, or is it a risk factor?

Erin D. Michos, MD, MHS: No, I think there’s overwhelming evidence that LDL-C is causally related to atherosclerotic cardiovascular disease. You heard some of these lines of evidence. We have evidence from genetic studies, from animal studies, from observational data, and also from interventional studies from randomized clinical trials. So this is very consistent. Although statins remain our first line of therapy in both primary and secondary prevention, we see that it is really all about the LDL lowering, not necessarily something magical about statins. Because if we achieve similar LDL reduction per millimole of liter per cholesterol lowering with nonstatin agents, we also see a similar reduction in major adverse cardiovascular events. So that is good news for our patients who either cannot tolerate the right amount of statin to get to their LDL goal, or they’re on the maximally tolerated statin, and because of genetic elevation, they start out so high that they need additional nonstatin therapy to get to our desired thresholds.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: You guys have given me a lot of information, and it indicates that LDL-C is causal for ASCVD [atherosclerotic cardiovascular disease]. But Christie, I remember they used to say the LDL hypothesis. What happened to that concept?

Christie M. Ballantyne, MD, FACC: Well, let me take it back to LDL as an atherogenic lipoprotein vs LDL-C. We measure LDL-C as a surrogate for those particles with it. All these particles that contain apo B [apolipoprotein B], so that’s LDL particles, VLDL [very low-density lipoprotein] remnants, IDL [intermediate-density lipoprotein], and LP(a). I don’t want to get too technical, but basically, all of that could be non-HDL [high-density lipoprotein] cholesterol. LP(a) is also important. So we focus on LDL-C as a surrogate for the bad particles, but there are other tests like apo B and LP(a) that could also be important or non-HDL cholesterol. I do think it’s the lipoproteins in our circulation. There are a lot of bad ones. When you see a high triglyceride level, very frequently that person has a problem, too, even though the LDL-C might appear to be somewhat borderline.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: Mary, I guess you’re going to have to agree. Our colleagues have given us so much information on the importance of LDL-C.

Mary McGowan, MD, FNLA: No, I absolutely agree. The thing that I’d like to drive home is the difference between, as Dr Kohli pointed out, being born with a protective mutation. Say, for example, a loss-of-function mutation in PCSK9 (proprotein convertase subtilisin/kexin type 9). You set yourself up for a lifetime of lower cholesterol vs getting on a statin later in life. It really gives us the message that the earlier we start to reduce LDL-C, the better. So often we don’t initiate therapy until after somebody has already had a cardiac event.

Transcript Edited for Clarity