Targeting LDL Cholesterol



Alan Brown, MD: Pam, thank you for that eloquent description. A thought came to mind as I was listening to it about thresholds vs goals. I always remind folks of something. Let’s say you choose a goal of 70 mg/dL, and you have a patient arrive with an acute infarction who has an LDL [low-density lipoprotein] of 72 mg/dL, an HDL [high-density lipoprotein] of 25mg/dL, and high triglycerides. That’s the typical metabolic syndrome patient who we’ve all seen come in with an acute MI [myocardial infarction]. If the goal were 70 mg/dL and you lowered the LDL to 69 mg/dL, you’d be done. None of us thinks that would improve the patient’s risk at all, right? A threshold is a number above which, as you so eloquently stated, you add intensification of therapy. That means getting at least a 50% reduction in LDL as the starting point.

When we look at the European guidelines and the endocrine guidelines, they set a goal of 40 mg/dL. That takes care of that problem. It’s unlikely that someone is going to have an infarct with an LDL of 40 mg/dL. If you drop an extreme-risk patient below 40 mg/dL, you’re going to get a marked reduction.

That was also part of the thinking about leaving goals and moving toward thresholds. You add a drug that’s been proven in a clinical trial to give reduction in events when you’re above that threshold, as opposed to being happy with being 1 point below a goal. Does that make sense to everyone?

Do you have any other thoughts on that?

Keith C. Ferdinand, MD: Yes, Alan. As a primary preventive approach, lower is better. Clearly, we don’t want patients who have LDLs that are elevated to maintain those levels just because they’re not having events. Once the person is very high risk, the European Society of Cardiology/European Atherosclerosis Society Guidelines for Management of Dyslipidemia suggest driving the LDL down below 55 mg/dL. It doesn’t have the same level of evidence as you do in the ACC/AHA [American College of Cardiology/American Heart Association] Multisociety Guidelines. On the other hand, when you look at non-Western, nonindustrialized societies, people walk around with LDLs of 30 and 40 mg/dL on a regular basis and have a much lower burden of atherosclerotic cardiovascular disease [ASCVD]. Based on observational data, it does make sense that lower is better.

We’re going to discuss the PCSK9 inhibitor shortly, but they give us new evidence that lowering the LDL to as low as 25 mg/dL may be protective. It doesn’t mean that if the person who has had an MI or has demonstrated ASCVD has an LDL of 71 mg/dL, and 1 day, we draw the blood and it’s 69 mg/dL, they’ve had appropriate therapy.

Seth J. Baum, MD: I wanted to add something to Pam’s very eloquent description of threshold, goal, and target and give another example much like the 1 you gave. Another example in which this is so important is when adding a therapeutic in a stable but very high-risk patient who has an LDL of 72 mg/dL, just like your patient who just had an infarct. You have someone in the office who’s very high risk by ACC/AHA guidelines standards and is on maximally tolerated statin therapy. Many clinicians might say, “Are we going to add a PSCK9 inhibitor with a 72 mg/dL,” and resist that. Whereas we know from clinical data that that person is going to benefit just as much from the addition of that drug as someone whose LDL is higher. That has been observed in at least 1 of the outcomes trials; therefore, the drug should be added.

There are so many places where that distinction of threshold and goal has clinical importance. I just wanted to share that.

With regard to how low is too low, as everyone here would hopefully agree, we don’t have any evidence right now that there is a number that is too low for LDL. We have multiple levels of evidence, from observational data to Mendelian randomization data, showing that lifelong LDLs as low as 15 mg/dL have no impact. We have biological data where we’ve done kinetic studies and tagged the LDL. They have shown that the LDL doesn’t cross the blood-brain barrier. We can’t start wondering about the impact LDL is going to have on the brain, which requires cholesterol, because the brain makes its own cholesterol, as does every cell in the body. Also, steroidogenic tissue is not affected by very low LDL.

We have many RCTs [randomized controlled trials] that have not been able to show an adverse consequence of low LDL. The answer is, no, there is no level too low at this point.

Alan Brown, MD: The safety of achieving low LDLs, at least over a 5- to 7-year period, seems to be well established now. Of course, we don’t have 20-year data, but that’s important, because a lot of our students ask us all the time about the long-term effect of having a low LDL. I have a lot of patients ask me about the most common adverse effect of statin therapy. My answer is always, “longevity.”

Seth J. Baum, MD: Right. Regarding the low LDL, we do have the few people who have homozygous PCSK9 loss of function mutations with LDLs in the low teens, and they’re fine lifelong. I don’t know.

Alan Brown, MD: You can never be skinny enough, you can never be rich enough, and your LDL can’t be low enough.

Transcript Edited for Clarity

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