The Skinny on Ultralow LDL-C

An Interview With Robert Giugliano

Melissa Walton-Shirley, MD; Robert P. Giugliano, MD


September 19, 2022

This transcript has been edited for clarity.

Melissa Walton-Shirley, MD: Hi, I'm Dr Melissa Walton-Shirley, today, with Dr Bob Giugliano. We're going to be talking about low-density lipoprotein cholesterol (LDL-C). Welcome to this conversation for | Medscape Cardiology.

Robert P. Giugliano, MD: Glad to be here. Thank you.

Are There Risks With Ultralow LDL-C?

Walton-Shirley: The first time we probably heard about the theory of ultralow LDL levels was in the late 80s. Science magazine was published, and it talked about perhaps looking at what happens to patients when we lower LDL to ultralow levels. Can you bring me up to speed for the last three and a half decades of how we got here?

Giugliano: Sure. It's an interesting story. In part, it begins with the Nobel Prize — Brown and Goldstein, in 1985, first describing the potential benefits of very low LDL cholesterol. In one key part of their speech, which was also published, they talk about physiologic LDL maybe being on the order of 25-40 mg/dL. That really started the ball rolling with therapies and trying to achieve lower and lower LDL-C levels.

Walton-Shirley: There are early on many concerns like neurocognitive impact and dementia. I read information about vitamin D metabolism and cancer risk. Can you address where we are with that today?

Giugliano: Most of those data, in fact, all of those data were observational. If you think about who naturally has an LDL-C that low, generally, those patients are more likely to be older, frail, malnourished, or have cancer.

In the general population, if you eat a Western diet, it's very hard to achieve such low LDL-C. You either have a genetic predisposition or you may be frail, malnourished, have cancer, or some other chronic disease. If you compare those patients with folks who have more typical LDL-C of the population, well, of course, you'll see associations that aren't necessarily causative. We were misled by those early observations that weren't adjusted for these other confounders.

ApoB vs LDL

Walton-Shirley: Let's switch gears a bit to the apolipoprotein B (ApoB) camp. There are those that advocate that ApoB should be measured in every patient and we really don't know where we are unless we measure that. How do you feel about that? Do you use ApoB measurement?

Giugliano: I use ApoB measurements occasionally and I could view an alternate universe where we stumble across ApoB assays first before LDL assays, and then that's just the language we used. ApoBs are, I think, a more accurate measurement because it incorporates not only LDL but other atherogenic particles.

In practice, the LDLs are probably good enough. They're so widespread and entrenched in our practice of medicine, and every laboratory around the world can measure them or at least give you a calculated LDL based on one of many formulas that we now have with total cholesterol and the other particles we're familiar with. If you wanted to be more precise, apolipoprotein B would be a better integrator and has a slightly better correlation with outcomes and risk than does LDL cholesterol.

Does It Matter How You Get to a Low LDL-C?

Walton-Shirley: Does it matter how we get to an LDL-C of 40 mg/dL (1.03 mmol/L)? Specifically, is the person who achieved an LDL of 40 mg/dL with a statin and diet, perhaps maybe even ezetimibe… Are they less safe or less protected than someone who got there with a PCSK9 inhibitor, for instance?

Giugliano: That's a great question. We don't know the answer for sure. I'll share my opinions and observation from decades of study in this area. If you take two equal people who have the same demographics and risk factors, and one gets to an LDL, let's say, by your example on a statin plus ezetimibe, because the potency of a high-intensity statin plus ezetimibe is roughly that of a PCSK9 inhibitor, I think that their risk moving forward would be very similar.

There are some potential off-target benefits of high-dose statins, an anti-inflammatory effect. That remains still a bit debated. Maybe early post-ACS we see a signal, but I'm not sure about over the long-term. By and large, they generally would be at similar risk for future cardiovascular events if you got there with a statin plus ezetimibe or with a PCSK9 inhibitor.

Walton-Shirley: I want to ask you about your clinical approach to two different patients with the same LDL-C level of 150 mg/dL (3.9 mmol/L). One is a postmenopausal female who is 60 years of age. She has no known coronary disease. The person in the next room is a male with an LDL-C of 150 mg/dL, with no coronary disease. They're both asking you, "Do I need to have my LDL-C treated?" How do you approach those patients? Is your approach different?

Giugliano: My approach is similar in that I would first look at their risk for future cardiovascular events. I use a 10-year atherosclerotic cardiovascular disease (ASCVD) risk score. In Europe, there's a different risk score that is used. I try to identify patients who are going to likely benefit the most from LDL-C lowering. It also gives us an idea of where we're going, how low of an LDL-C we want to target.

We don't have the full profile to know if they have other risk factors for ASCVD. Are they diabetic? Are they hypertensive? I suspect you probably end up wanting to treat both of these patients. Then it's a question of how intensively would you want to lower their LDL-C?

Walton-Shirley: Screening is a hot topic these days. Would you employ a calcium score? Let's say the female had a calcium score of 0 and they're postmenopausal with an LDL-C of 150. Would you then invite that patient to consider treatment?

Giugliano: They're aged 60, if I recall.

Walton-Shirley: Right.

Giugliano: I would have a discussion with the patient. I would say that the calcium score of 0 is good news for your coronary. But we do not have an image of the arteries of the head, neck, the abdomen, the lower extremities. I would want to also consider all the other potential risk factors. I would say that a calcium score of 0 would be good news in a 60-year-old patient. If they were 40, I would say, "Well, the calcium score may underestimate your risk because it may be mostly a lipid-rich plaque and not much calcium there."

Mortality Reductions

Walton-Shirley: There are also some studies that suggest there's not a huge mortality benefit. If you look across the major trials, even in those trials that LDL-C levels were achieved that were on target, we still didn't see a huge mortality benefit in some of those trials. How do you address that criticism?

Giugliano: A couple of things. One is patients who are higher risk, secondary prevention, for example, with elevated LDL, it's clear that that LDL lowering with statins, in particular, reduces cardiovascular mortality. For all-cause mortality, we all have to die of something. I don't expect an effect on noncardiovascular deaths. Of course, the point estimates for all-cause mortality are less robust than they are for cardiovascular mortality, which is the target with statins.

With PCSK9 inhibitors, we certainly saw signals with alirocumab in higher-risk patients who are post-ACS. We're going to hear at the European Society of Cardiology (ESC) meeting data from the open-label extension trial of FOURIER with evolocumab in a somewhat lower-risk population.

With ezetimibe, there's really only one good long-term study, the IMPROVE-IT trial, which did not show any reduction in mortality. In patients with established ASCVD or ACS, you're most likely to see mortality reductions in the highest-risk patients and those who were treated longer and aggressively.

In primary prevention, the data are a bit more sparse, but I have no reason to think that we wouldn't see a similar signal for reduction in cardiovascular mortality. We just have to follow patients much longer because these patients have less severe disease. This could be answered in future trials followed longer and more intensively. That's kind of part one of my answer.

Part two would be that it's not all about death. Sure, we'd like to live longer and increase the length of life, but we'd also like to live without a myocardial infarction, without a stroke, without a need for peripheral procedures to treat peripheral arterial disease. Even if we didn't see much of a difference in mortality and one group of patients lived without myocardial infarction, stroke, et cetera, well, that would be a big gain.

Walton-Shirley: My last question is this: Do you think that we have followed patients long enough that we're completely satisfied that we aren't going to see some deleterious effects of significant LDL lowering?

Giugliano: That's a great question. I would like to follow patients longer for sure. For the active comparisons of treatment and placebo, 5 years is generally what we consider long-term trials. Again, at the ESC we will be presenting some data out to 8 years. There'll be additional information forthcoming.

As clinicians, when we treat our patients with hyperlipidemia, that's usually a lifelong decision, so we're treating patients for many decades. There, we don't have great data for long-term follow-up with a placebo comparison or some kind of reasonable control population. Sure, I'd like to see much longer-term data to give additional reassurance that there aren't very late complications or adverse events related to long-term suppression of the LDL.

I'd have to say that if you look in nature at patients who have won the gene lottery and for whatever reason don't produce or can easily excrete cholesterol and have low levels, they do very well over the long-term, over decades, over their lifespan with lower LDLs than the typical Western patient who follows a Western diet.

Walton-Shirley: Sure. That's the real definition of all natural, isn't it? Well, it's been a real pleasure. Thank you so very much for your time today. We appreciate it.

We appreciate you joining us today on | Medscape Cardiology.

Giugliano: Thank you.

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