Not all cholesterol particles carry the same risk - here's what to really look out for: Wisdom Wednesdays

0:00Everybody, welcome to another edition of Wisdom Wednesdays. So today I want to talk about cholesterol, but in a slightly different way. Because when you go to the GP to get your blood done, they generally look at your total cholesterol, your LDL, your HDL, your triglycerides. And the big thing that they look at is the LDL. And if that comes back in the so-called normal name, range, then the GP generally says that you're all good. But there is a problem with that. And whilst there is evidence that LDL is causally involved in atherosclerosis, and particularly in people with a higher cardiovascular risk, and lower LDL will generally mean lower risk, but that's only part of the story. So what we know from a big American registry study of 136,000 people who were hospitalized with coronary artery disease, almost half of them had normal

1:02LDL cholesterol. Now, that's often translated as half the people who have heart attacks have normal cholesterol. And that's a little bit simplistic. And they were hospitalized with coronary artery disease. And some of them were already on therapy for lowering their LDL. So they were at a bit of a risk. But what we know is that LDL is not the be all and end all of everything. And you can have an LDL number that looks pretty good and still carry significant cardiovascular risk. That's why I like to look at things like LDL particle size. And then something that's a bit more accessible is called APOB. And here's a useful way of thinking about it. So lipoproteins, think of them as trucks moving around your bloodstream carrying cargo. So LDL cholesterol tells you roughly how much cholesterol cargo was being transported inside one particular class of trucks. But APOB gives you a much better idea of how many potentially arthrogenic trucks you actually have on the road. And that

2:09difference matters because every LDL particle carries one APOB molecule. But so did the LDL, very dense LDL particles, remnant particles, and something called lipoprotein little A, which we'll get to in a second. Now, this is one particle and one APOB. So APOB is effectively a particle and if you've lots of relatively cholesterol purer particles, your LDL, LDL cholesterol may look reasonably respectable while your APOB, it's a bit of a mouth thing, and it tells you you've actually got an arthrogenic or a lot of arthrogenic particles circulating. So when LDL cholesterol and APOB disagree in terms of risk, cardiovascular risk is much more aligned to APOB. And the new 2026 American cardiovascular guideline specifically recognize APOB as useful for identifying residual risk that may be missed by your traditional

3:13cholesterol panel. I think it's much more useful. But something that is even more useful is lipoprotein and it's often called lipoprotein little A or Lp with an A small A in brackets. And you might not have heard of this, but it is really important. I structurally, it looks like an LDL particle that somebody has bolted an extra protein onto and it has the usual APOB containing LDL particle, but it's attached to another protein called Apple lipoprotein A. Think of it as LDL with an extra teal that's particularly nasty. And so Lp little A carries oxidized phospholipids or fats and appears not just to have arthrogenic particle properties so they can cause cardiovascular disease, but also pro-inflammatory effects as well. And elevator levels are associated not only with arthroscarosis, but also with calcified

4:19aortic valve disease, which is pretty nasty. And this is where there's a really interesting 2024 paper and by Bjornson was the lead author in his colleagues. And they use genetic data from the UK Biobank study, the one that keeps on giving the gift that I keep talking about the studies that are coming out of this. And if you compare the same number of LDL particles with the same number of Lp little A particles, how much cardiovascular risks does each appear to produce? Now remember each carries one APOB, so that gives them a clever way of comparing particle with particle, right? If you haven't really followed it, this is the take-home. Now, their estimate was striking Lp little A. And in this study was approximately 6.6 times more arthrogenic than ordinary LDL on a per particle basis, right? So that is pretty down significant here. And unlike triglystriides, blood glucose or many other metabolic markers,

5:23you actually don't have a great deal of control over Lp little A, which is a bit of a concern. And your level is overwhelmed by your genes. And it establishes itself relatively early in life and tends to remain fairly stable. And L of it at Lp little A isn't rare at all, but one in five people have levels that are at a risk for cardiovascular disease. And at that level, average cardiovascular risk is estimated to be around 40% higher than someone in the population who's at the normal level, right? Now that is way more impactful than your typical LDL cholesterol. Now, here's the interesting thing. Can we lower it? A lot of the thinking used to be no, you can't lower. And we know that your standard cholesterol-loering toolkit like statins don't do anything to Lp little A. And there was a 2025 meta-analysis looked at 147 randomized control trials with over

6:24140,000 people. They looked at interventions such as statins, zedomide, fibriids, bempidonic acid, omega-3 fatty acids, none of them lowered Lp little A, meaningfully. Now, a new class of drugs to treat cholesterol called the PCSK9 inhibitor that you may have heard of. That did lower it, but about 20 to 30% depending on the treatment protocol. But currently in Australia, I'm not sure what it's like overseas, but you have to have refused statinotherapy in order to qualify for a PCSK9 inhibitor. Now, one thing that did was the vitamin NISIN actually can lower BLP little A, but that's at high doses and there are pretty significant side effects of NISIN at high doses. But there has been a whole new generation of drugs that have been developed specifically

7:24to target Lp little A. Some use RNA, some use something called anti-sense technology. And one particularly interesting one, which is called MOVALPIN, that's an oral drug which interferes with the actual creation of the assembly of the LPA particle itself. And the reductions are actually really big. A 2026 network meta-analysis found reductions approaching 99% with some doses of these new drugs. So I think the take home here is that we're definitely getting better and we're getting more targeted at trying to prevent and manage cardiovascular disease. LDL in general is a pretty blunt instrument. It doesn't tell you what your particle size is. And that's important because you're going to have high LDL, but all of that LDL be big fluffy LDL.

8:24So there's two types of LDL. There's big fluffy and there's small dens. The big fluffy stuff is not pathogenic. It's the small dense stuff that is pathogenic. So you can actually have normal LDL, but lots of small dens LDL. And that's a bit more risking. But we now know that things like APOB and particularly LP, LITLA are much more predictive of your cardiovascular risk. And it certainly appears that there is good news on the horizon in terms of managing it. And something else to throw into the mix is a research paper I just read today that looked at health data for more than 9 million adults in both South Korea and the US. They found that nearly everybody who develops heart disease and suffers a major cardiovascular event has one of four major risk factors in the lead up. And those risk factors were high blood pressure, high cholesterol, high blood sugar, and tobacco smoking. And combined as a group, they actually preceded 99% of

9:33all cardiovascular events during the long term study. And the biggest one that stuck out was actually high blood pressure. So that seems to be the main one in measuring your cardiovascular risk. But there seems to be that cluster of high blood pressure, high cholesterol, high blood sugar, and tobacco smoking. And I would imagine if they were able to look at APOB and LP LITLA rather than just high cholesterol, they would get even stronger predictions. So that's it for this week folks. Catch you next time. This is Ashley Akinetti from the Almost Amidst podcast. You ever notice you and your spouse keep saying we need to get away, but you never actually plan anything. That was us until we did something fun and spontaneous. We went to resort pass.com. There are hundreds of hotel resorts, pools and spots and private beaches that you can enjoy. You can spend the day at a luxury resort, pool,

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