Latest / Hardiness with Dr Paul Taylor / Not all cholesterol particles carry the same risk - here's what to really look out for: Wisdom Wednesdays

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Not all cholesterol particles carry the same risk - here's what to really look out for: Wisdom Wednesdays · Hardiness with Dr Paul Taylor

• 0:06
  Speaker 1: Hey everybody, welcome to another edition of Wisdom Wednesdays. So
• 0:09
  Speaker 1: today I want to talk about cholesterol, but in a
• 0:12
  Speaker 1: slightly different way. Because when you go to the GP
• 0:16
  Speaker 1: to get your bloods done, they generally look at your
• 0:19
  Speaker 1: total cholesterol, your LDL, your HDL, your triglycerides. And the
• 0:24
  Speaker 1: big thing that they look at is the LDL. And
• 0:27
  Speaker 1: if that comes back in the so-called normal range, then
• 0:30
  Speaker 1: the GP generally says that you're all good. But there
• 0:33
  Speaker 1: is a problem with that. Whilst there is evidence that
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  Speaker 1: LDL is causally involved in atherosclerosis, and particularly in people
• 0:43
  Speaker 1: at higher cardiovascular risk, lower LDL will generally mean lower risk,
• 0:49
  Speaker 1: but that's only part of the story. So what we
• 0:52
  Speaker 1: know from a big American registry study of 136,000 people
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  Speaker 1: who were hospitalized with coronary artery disease, almost half of
• 1:01
  Speaker 1: them had normal LDL cholesterol. Now, that's often translated as
• 1:06
  Speaker 1: half the people who have heart attacks have normal cholesterol.
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  Speaker 2: And that's a little bit simplistic.
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  Speaker 1: They were hospitalized with coronary artery disease, and some of
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  Speaker 1: them were already on therapy for lowering their LDL, so
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  Speaker 1: they were at a bit of a risk.
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  Speaker 2: But what we know is that LDL is not the
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  Speaker 2: be-all and end-all of everything.
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  Speaker 1: You can have an LDL number that looks pretty good
• 1:30
  Speaker 1: and still carry significant cardiovascular risk, That's why I like
• 1:34
  Speaker 1: to look at things like LDL particle size. And then
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  Speaker 1: something that's a bit more accessible is called ApoB. And
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  Speaker 1: here's a useful way of thinking about it.
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  Speaker 2: So lipoproteins, think of.
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  Speaker 1: Them as trucks moving around your bloodstream carrying cargo. So
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  Speaker 1: LDL cholesterol tells you roughly how much cholesterol cargo is
• 1:57
  Speaker 1: being transported inside one particular class of trucks. But ApoB
• 2:02
  Speaker 1: gives you a much better idea of how many potentially
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  Speaker 1: atherogenic trucks you actually have on the road. And that
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  Speaker 1: difference matters because every LDL particle carries one ApoB molecule,
• 2:15
  Speaker 1: but so did VLDL, very dense LDL particles, remnant particles,
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  Speaker 1: and something called lipoprotein little a, which we'll get to
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  Speaker 1: in a second. Now, this is one particle and one
• 2:27
  Speaker 1: ApoB molecule. So ApoB is effectively a particle count. And
• 2:32
  Speaker 1: if you've lots of relatively cholesterol-poor particles, your LDL cholesterol
• 2:40
  Speaker 1: may look reasonably respectable, while your ApoB, it's a bit
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  Speaker 1: of a mouthful, it tells you you've actually got an
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  Speaker 1: atherogenic or a lot of atherogenic particles circulating. So when
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  Speaker 1: LDL cholesterol and ApoB disagree in terms of risk, cardiovascular
• 2:58
  Speaker 1: risk is much more aligned to ApoB. And the new
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  Speaker 1: 2026 American Cardiovascular Guidelines specifically recognize ApoB as useful for
• 3:08
  Speaker 1: identifying residual risk that may be missed by your traditional
• 3:13
  Speaker 1: cholesterol panel. And I think it's much more useful. But
• 3:17
  Speaker 1: something that is even more useful is lipoprotein A, and
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  Speaker 1: it's often called lipoprotein little a, or LP with an a,
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  Speaker 1: small a in brackets. And you might not have heard
• 3:31
  Speaker 1: of this, but it is really important. Now, structurally, it
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  Speaker 1: looks like an LDL particle that somebody has bolted an
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  Speaker 1: extra protein onto. And it has the usual ApoB-containing LDL particle,
• 3:45
  Speaker 1: but it's attached to another protein called apolipoprotein A. Think
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  Speaker 1: of it as LDL with an extra tail that's particularly nasty.
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  Speaker 1: So LP little a carries oxidized phospholipids or fats and
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  Speaker 1: appears not just to have atherogenic properties so they can
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  Speaker 1: cause cardiovascular disease, but also pro-inflammatory effects as well. And
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  Speaker 1: elevated levels are associated not only with atherosclerosis, but also
• 4:18
  Speaker 1: with calcified aortic valve disease, which is pretty nasty. And
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  Speaker 1: this is where there's a really interesting 2024 paper by Bjornsson,
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  Speaker 1: who was the lead author and his colleagues. And they
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  Speaker 1: used genetic data from the UK Biobank study, the one
• 4:34
  Speaker 1: that keeps on giving the gift. I keep talking about
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  Speaker 1: the studies that are coming out of this. And if
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  Speaker 1: you compare the same number of LDL particles with the
• 4:43
  Speaker 1: same number of LP little a particles, how much cardiovascular
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  Speaker 1: risk does each appear to produce? Now, remember, each carries
• 4:50
  Speaker 1: one ApoB, so that gave them a clever way of
• 4:54
  Speaker 1: comparing particle with particle, right? If you haven't really followed it,
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  Speaker 1: this is the take-home. Now, their estimate was striking LP
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  Speaker 1: little a in this study was approximately 6.6 times more
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  Speaker 1: atherogenic than ordinary LDL on a per particle basis, right?
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  Speaker 1: So that is pretty damn significant here. And unlike triglycerides,
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  Speaker 1: blood glucose, or many other metabolic markers, you actually don't
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  Speaker 1: have a great deal of control over LP little a,
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  Speaker 1: which is a bit of a concern.
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  Speaker 2: And your level is overwhelmingly determined by your genes.
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  Speaker 1: And it established itself relatively early in life, and tends
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  Speaker 1: to remain fairly stable. And elevated LP little a isn't
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  Speaker 1: rare at all, but one in five people have levels
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  Speaker 1: that are at a risk for cardiovascular disease. And at
• 5:49
  Speaker 1: that level, average cardiovascular risk is estimated to be around 40%
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  Speaker 1: higher than someone in the population who's at the normal level, right?
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  Speaker 1: Now that is way more impactful than your typical LDL cholesterol.
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  Speaker 2: Now, here's the interesting thing. Can we lower it?
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  Speaker 1: A lot of the thinking used to be, no, you
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  Speaker 1: can't lower. And we know that your standard cholesterol lowering toolkit,
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  Speaker 1: like statins, don't do anything to LP little a. And
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  Speaker 1: there was a 2025 meta-analysis looked at 147 randomized control
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  Speaker 1: trials with over 140,000 people. They looked at interventions such
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  Speaker 1: as statins, ezetimide, fibrates, benpedonic acid, omega-3 fatty acids.
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  Speaker 2: None of them lowered LP little a meaningfully.
• 6:39
  Speaker 1: Now, a new class of drugs to treat cholesterol called
• 6:44
  Speaker 1: the PCSK9 inhibitor that you may have heard of. That
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  Speaker 1: did lower it, but about 20% to 30%, depending on
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  Speaker 1: the treatment protocol.
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  Speaker 2: But currently in Australia, I'm.
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  Speaker 1: Not sure what it's like overseas, but you have to
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  Speaker 1: have refused statin therapy in order to qualify for a
• 7:02
  Speaker 1: PCSK9 inhibitor. Now, one thing that did was the vitamin
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  Speaker 1: niacin actually can lower be LP little a but that's
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  Speaker 1: at high doses and there are pretty significant side effects
• 7:15
  Speaker 1: of niacin at high doses but there has been a
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  Speaker 1: whole new generation of drugs that have been developed specifically
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  Speaker 1: to target LP little a and some use RNA some
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  Speaker 1: use something called anti-sense technology and one particularly interesting one
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  Speaker 1: which is called muvalpin And that's an oral drug which
• 7:40
  Speaker 1: interferes with the actual creation of the assembly of the
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  Speaker 1: LPA particle itself.
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  Speaker 2: And the reductions are actually really big.
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  Speaker 1: A 2026 network meta-analysis found reductions approaching 99% with some
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  Speaker 1: doses of these new drugs. So I think the take
• 8:02
  Speaker 1: home here is that we're definitely getting better and we're
• 8:04
  Speaker 1: getting more targeted at trying to prevent and manage cardiovascular disease.
• 8:11
  Speaker 1: LDL in general is a pretty blunt instrument. It doesn't
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  Speaker 1: tell you what your particle size is. And that's important
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  Speaker 1: because you can have high LDL, but all of that
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  Speaker 1: LDL be big, fluffy LDL.
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  Speaker 2: So there's two types of LDL. There's big, fluffy, and
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  Speaker 2: there's small, dense.
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  Speaker 1: The big, fluffy stuff is not pathogenic. It's the small,
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  Speaker 1: dense stuff that is pathogenic. So you can actually have
• 8:36
  Speaker 1: normal LDL, but lots of small dense LDL, and that's
• 8:40
  Speaker 1: a bit more risky. But we now know that things
• 8:43
  Speaker 1: like ApoB and particularly LP little a are much more
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  Speaker 1: predictive of your cardiovascular risk. And it certainly appears that
• 8:53
  Speaker 1: there is good news on the horizon in terms of
• 8:56
  Speaker 1: managing it. And something else to throw into the mix
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  Speaker 1: is a research paper I just read today that looked
• 9:03
  Speaker 1: at health data for more than 9 million adults in
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  Speaker 1: both South Korea and the US. They found that nearly
• 9:10
  Speaker 1: everybody who develops heart disease and suffers a major cardiovascular
• 9:14
  Speaker 1: event has one of four major risk factors in the
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  Speaker 1: lead up. And those risk factors were high blood pressure,
• 9:21
  Speaker 1: high cholesterol, high blood sugar and tobacco smoking. And combined
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  Speaker 1: as a group, they actually preceded 99% of all cardiovascular
• 9:34
  Speaker 1: events during the long-term study. And the biggest one that
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  Speaker 1: stuck out was actually high blood pressure. So that seems
• 9:42
  Speaker 1: to be the main one in measuring your cardiovascular risk.
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  Speaker 1: But there seems to be that cluster of high blood pressure,
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  Speaker 1: high cholesterol, high blood sugar, and tobacco smoking. And I
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  Speaker 1: would imagine if they were able to look at ApoB
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  Speaker 1: and LpA rather than just high cholesterol, they would get
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  Speaker 1: even stronger predictions.
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  Speaker 2: So that's it for this week, folks.
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  Speaker 1: Catch you next time.