Narrator:
0:01
Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts, powered by ENCORE Research Group and hosted by cardiologist and top medical researcher, Dr. Michael Koren.
Dr. Michael Koren:
0:17
Hello, I'm Dr. Michael Koren, hosting our second in our series on advanced lipid profiles with my good friend and colleague, Dr. Al Lopez, DO, and we've been talking about what in fact an advanced lipid profile is and how this can now perhaps be applied to taking better care of our patients. But we left our last session talking about what we like to call the really really, really, really bad cholesterol, and that's lipoprotein-a, and both Al and I have been very involved in clinical research on this particular problem. So, Al just brief everybody. Give them an overview of what Lp(a) is.
Albert Lopez, DO:
0:55
Lipoprotein-a is a protein that is genetically mediated, so it goes from family to family and affects one in five people globally, but it can be passed down to half of your children.
Dr. Michael Koren:
1:12
So it's autosomal dominant inheritance. So if a parent has it, there's a 50-50 chance that a child will have it.
Albert Lopez, DO:
1:20
This is correct. It's a very bad actor because unfortunately, up until recently we didn't have anything to really treat it with. Nothing really worked effectively. We know that diet and exercise didn't really change Lp(a).
Dr. Michael Koren:
1:32
Not at all. How about statins?
Albert Lopez, DO:
1:34
Statins actually may increase it, but the amount that it raises is fairly insignificant and it doesn't really make you any more.
Dr. Michael Koren:
1:39
Well, it doesn't help.
Albert Lopez, DO:
1:41
It doesn't help, but theoretically, in the scheme of things, it's insignificant.
Dr. Michael Koren:
1:45
And in fairness, just to be fair, it does lower other lipid problems, so it reduces overall risk of somebody with high Lp(a), but it doesn't change Lp(a) in and of itself.
Albert Lopez, DO:
1:56
Well, it's true, and what I kind of explain to patients is it's almost like taking metal as a substrate. If you take metal out of salty water it's not going to rust. So you have many ways to get arterial disease or vascular disease, and LDL is probably the biggest one that we can fix and probably the biggest one we have. Lp(a) is a very, very bad actor, but if you can get rid of one variable, then get rid of it, please.
Dr. Michael Koren:
2:21
So the most important point is that we haven't focused as much on Lp(a) as we might have otherwise, because we didn't have any way specifically to treat that lipoprotein, so we just treated other lipoproteins more aggressively.
Albert Lopez, DO:
2:35
Great.
Dr. Michael Koren:
2:35
So a good way to just think about it. And now so jumping back into Lp(a). Are there different types of Lp(a)?
Albert Lopez, DO:
2:42
There are. There are different isoforms. Some are much more atherogenic or plaque-producing than others. We're working on trying to figure those out. We also know that isoforms that are more atherogenic if they become oxidized we make them more atherogenic. So if we, as we talked about in the last segment, oxidized LDL it was an interesting research project again at University of Southern California that if, if we oxidize LDL, it may actually activate I guess that's a bad term, but activate Lp(a) to be more plaque producing and more athrogenic.
Dr. Michael Koren:
3:17
And Lp(a) actually has LDL in it. It's sort of LDL plus.
Albert Lopez, DO:
3:21
Right Plus plus.
Dr. Michael Koren:
3:22
Yeah, and I think we have a slide or a picture of what an Lp(a) molecule looks like and you have this squiggly part on the outside of the lipoprotein core and that's the part that probably determines how dangerous the molecule is.
Albert Lopez, DO:
3:38
Yeah, and it's a bad actor. You know it's pro clotting or pro thrombotic. It increases the risk of vascular disease, whether it's carotid, heart or in the legs, and peripheral vascular disease. We know that increases aortic stenosis at a young age, so that valve tightens very quickly.
Dr. Michael Koren:
4:01
Interestingly in Caucasions but not in African Americans, it is a very, very interesting genetic element is African Americans have a pretty high incidence of Lp(a) compared to other races, but they don't get aortic stenosis for some reason.
Albert Lopez, DO:
4:11
And it's pro inflammatory. So it sets up that whole pro inflammatory cascade which is just as dangerous as high LDL is. So that's important to know as well.
Dr. Michael Koren:
4:22
Right, and so what's a dangerous level of Lp(a)?
Albert Lopez, DO:
4:27
You know we're thinking probably over 100 definitively, but there's some data showing 50 to 75 is probably significant that you want to pay attention to it and just explain the whole unit controversy of people, because 100 is a little bit different depending on the units. Yeah, so we can look at it two different ways from millimole to deciliter or a milligram to deciliter and unfortunately labs do it different ways and we're trying to find a uniform standard of measuring that unit and sticking to that, so we're all speaking the same language.
Dr. Michael Koren:
4:56
An abnormal lipoprotein little a level would be considered greater than 30 milligrams per deciliter or greater than 75 nanomoles per liter.
Albert Lopez, DO:
5:06
Yeah, and it's interesting because you can't calculate from one to the other very well, there isn't a great formula to calculate that and make it, so you can't convert it. It doesn't work well.
Dr. Michael Koren:
5:18
So you have levels and a genetic risk, then certainly you get worried. But what's been your clinical observation of Lp(a)? Does everybody with a high Lp(a) have problems or is there some heterogeneity to that?
Albert Lopez, DO:
5:31
No, that's what really makes it very interesting and we really need to continue the research on it that just because you have a high Lp(a) and I have several patients with very high Lp(a) 200, 300, 350, and there's no sign of cardiovascular disease. We've done quite ultrasounds with them they're wide open. This woman had a chest pain and she had a stress test and stress test she blew it away. She went back in, had a catheterization. She had wide open coronaries well, millennial disease anyway and her lipid profile wasn't that bad. I got her LDL from over 175 down to below 70 at this time with lifestyle changes, but actually she's on a statin which made a big difference.
Dr. Michael Koren:
6:16
Sure, and she's on a statin without Lp(a).
Albert Lopez, DO:
6:21
That's the bugaboo. We have two drugs that we now have that we're researching and we know that it drops them markedly 90% it seems.
Dr. Michael Koren:
6:30
You have two drugs in late stage clinical trials, late stage clinical trials, a bunch in early trials, yeah.
Albert Lopez, DO:
6:36
And they're long-term studies. So the several years studies looking at outcomes as well and seeing if we actually can reduce the event rate, not just lower the number, right. So lowering the number is one thing, that's great, but if it doesn't change event rate, why bother?
Dr. Michael Koren:
6:49
And you're personally involved in these studies.
Albert Lopez, DO:
6:50
Yes, as you are a private investigator and it's been a long-time passion. I've been looking at this Lp(a) and now very excited to be part of research team, hopefully making a change in that.
Dr. Michael Koren:
7:03
Now, these drugs do lower Lp(a), right?
Albert Lopez, DO:
7:09
They do markedly like 90% plus. Yeah, we are looking at some other things. We do know that there's other drugs that also lower Lp(a). If I may, PCSK9 will do that.
Dr. Michael Koren:
7:18
Not as well.
Albert Lopez, DO:
7:19
Not as well, about 28, 24 to 32% somewhere in there. But it's not market and it doesn't have an indication for that.
Dr. Michael Koren:
7:28
So PCSK9 drugs work great on LDL cholesterol, and they work by increasing the effectiveness of the LDL receptor. Actually, they increase the density of the LDL receptor in hepatocytes and literally squeeze cholesterol in the circulation, and we don't know why they work for Lp(a), though, because we don't think that Lp(a) is removed from the body through the LDL receptor.
Albert Lopez, DO:
7:51
No. and aside, they're also anti-inflammatory. When they initially did the study on it, they showed inflammatory markers. All came down markedly, as well as APOB.
Dr. Michael Koren:
8:01
For the PCSK9s, for the.
Albert Lopez, DO:
8:03
PCSK9s, but yet we don't have an indication for that. So it may do it, but you can't write it for that. So you're kind of stuck. But if you have high LDL and have a high Lp(a) and you're on a PCSK9, it will give you some reduction not as much as we want, but some reduction. And then we also have the small interfering RNAs and I'd like you to talk about that, because you were the first author on the first paper on silencing RNA, dropping Lp(a) like 95% or so in Nature.
Dr. Michael Koren:
8:33
Yeah, it was in Nature Medicine. Yeah, thank you for the plug, but anyway, we have these technologies now. These are gene regulating technologies. Whether it be an ASO, an antisense oligol nucleotide, or a small interfering RNA, are both ways of regulating gene expression, and by regulating gene expression we're able to knock down these levels by 90% or more. It's really impressive.
Albert Lopez, DO:
8:59
Yeah, the older I get, the more we're getting into everyday science fiction stuff we read about as kids are actually happening today. So you know this was a fantasy when we were younger to think that we could do something like this, and now we're able to do this in medicine and in science, and every day. It's pretty incredible.
Dr. Michael Koren:
9:17
It's pretty impressive. So, yeah, though, those two types of products are in late-stage clinical trials, looking at whether or not they'll affect the outcomes, as you point out, but we're also working with companies that are earlier in the process, and It'll be interesting. It'll be interesting to see if anybody can come up with a solution that involves a pill, and people are certainly working on that in early-stage ideas at this point.
Albert Lopez, DO:
9:39
Interesting concept. You know, if you go back to 2002 articles up to a year ago, 2023 articles, there's many articles that show that, irrespective of how low you bring LDL and again that number, how low you get to changes every so many years. Right, it's like a limbo contest it has. It gets lower and lower and lower every year. But irrespective of how low you bring it down and that, and with optimal treatment, there's still a percentage of people, if you don't look at advanced lipid, that you're not going to find their hidden risk for a cardiovascular disease.
Dr. Michael Koren:
10:11
So the the take-home message is if you're listening to this and you have an Lp(a) problem, the current drugs on the market will get you down 25% at best. But if you get involved in clinical trial, you may get that Lp(a) down to 10%, what it was, or even less. So something think about. And we are actively involved in clinical research. The other little pearl is that some people, when you put them on statins, their LDL isn't affected that much and you wonder what the heck's going on and what could it be?
Albert Lopez, DO:
10:43
So they're probably using an older methodology of looking at the lipid profile and that includes Lp(a) and so that LDL, when you're measuring it, they're measuring Lp(a) with LDL and if it's not lowering You're not lowering the Lp(a), because statins don't lower Lp(a), raise it. So those statin intolerant as far as not lowering of statin, yeah, so so some of the LDL in effective Lp(a).
Albert Lopez, DO:
11:10
Yeah, it's Lp(a) unless you're measuring the LDL directly.
Albert Lopez, DO:
11:13
Yeah, you're not gonna get that information, so that's immediately should be a light bulb in the back here saying you know, maybe I do have elevated Lp(a). There's two camps. Now that you know we should only screen high-risk patient for Lp(a). I'm of the camp that I think everybody should be screened for Lp(a) and at a younger age better. And so Europe. They're starting to do that in certain countries, you know, looking at young adults, the early teenagers and and even kids, and looking at their Lp(a) levels to try to mitigate that risk over time.
Dr. Michael Koren:
11:56
Right, and so we started our last session talking about advanced lipid profiles and why they're important, and part of that discussion about measuring lipids is this concept of direct versus indirect measurement of LDL and obviously, if you're direct, if you're measuring LDL directly, you don't run into this problem with overlap with Lp(a), and so explains to people what that means, the difference between direct and indirect.
Albert Lopez, DO:
12:06
So when you're measuring indirect LDL, there was originally that the formula was done by a 1975 6 Bedeewald formula, which was never intended to screen the average person for cholesterol. It was intended to screen people that were heterozygous, hypercholesterolemic patients, so people with high, high cholesterol. And it doesn't give you an accurate LDL because it's predicated on a fasting lab draw and it's calculated off of a triglyceride level.
Dr. Michael Koren:
12:38
And it's also an estimate. Yeah, it's a guesstimate, so you're estimating an estimate Exactly. You're not actually measuring. LDL You're measuring, just so everybody knows out there. You're measuring total cholesterol, which we're good at. You're subtracting HDL and then you're subtracting triglyceride-rich particles, using sort of a very loose argument that that number should be triglycerides divided by five.
Albert Lopez, DO:
13:02
So I'm not of the camp that every single person needs a direct LDL, but I think that there is a huge number of patients that do need a direct LDL. People with high triglycerides, people that are not fasting. If they're not doing their labs and I have them in the office and it's two in the afternoon and they ate, it doesn't really matter. I'll measure a direct LDL on them and then do the lipid profile and maybe an advanced lipid profile if indicated, so I can get a direct LDL and know what they are, irrespective if they're fasting or not.
Dr. Michael Koren:
13:32
Yeah, so the technology for direct LDL measurements is also getting better. So now there are analyzers and chemical assays for direct LDL. It used to be you have to go through what's called ultracentrification. We have to spin this down and we call that also beta quantification, and that was a pretty expensive process, but I think it's. How much is it now for direct LDL?
Albert Lopez, DO:
13:52
Direct LDL. I think it's like $25, $30.
Dr. Michael Koren:
13:54
Yeah, it's coming down a lot.
Albert Lopez, DO:
13:55
That's it. I mean it's probably even cheaper than that.
Dr. Michael Koren:
13:57
Yeah, it used to be $200.
Albert Lopez, DO:
13:59
And it's actually if you have the right code. If you have cardiovascular disease or hypertension I don't know why hypertension or hypertension or you have high triglycerides, then direct LDL is acceptable, so you can get it paid for at that point, and so those advanced lipid profiles really are, and direct LDLs are not that expensive anymore and are very, very, very well covered.
Dr. Michael Koren:
14:22
Beautiful. We're going to now move into the clinical space for our next session and really talk about real patients and how we might deal with them.
Narrator:
14:30
Thanks for joining the MedEvidence podcast. To learn more, head over to medevidencecom or subscribe to our podcast on your favorite podcast platform.
