[Rhonda]: But here's my next question for you.
So we spend, as a country, you know, tens of billions of dollars every year on this
drug that you mentioned, LDL-lowering drugs like statins, and this, as far as I understand,
is on the premise mostly that when someone goes to get their lipid panel measured from
their doctor, from their primary care physician, it's based on their total LDL cholesterol,
because most physicians do not measure all the different particle sizes of LDL cholesterol.
[Ron]: Yeah.
I mean, it's not always...
I'll just say, it's not something that has to be done across the entire population.
But certainly, when one is considering treatment, there, I think, it does have a role.
[Rhonda]: Yes.
And so what are the effects of statins on the small, dense LDL particles and in health,
in general?
[Ron]: So you've hit on another one of my lives, because more than half of my research
program, and in fact, the majority of my research program now that's NIH-funded is through a
grant to study statin effects and the basis for response to statins and the basis particularly
for differential response across a population.
So, as we've gotten deeply involved in studying statins effects, we certainly have had an
interest in determining how that relates to the lipoprotein profile.
And if you think back to what I described about the role of the LDL receptor in clearing
LDL particles, and the fact that the small LDL particles are less efficiently removed
by the LDL receptor, and one accepts the well-established fact that a major mechanism by which statins
lower LDL is by increasing LDL receptor activity to take all that information and put it together,
you come out with a conclusion, or the hypothesis, perhaps, to start with, that statins would
have a lesser effect on smaller VLDL particles because they are more dependent on receptor-mediated
uptake.
And in fact, we've shown that.
So we've done...
Now, we've studied almost every statin and shown that the effects on smaller LDL particles,
particularly the very smallest LDL particles, are blunted compared with the larger LDL.
It's not as if there's no effect at all, but they are less efficiently cleared.
So statins tend to work primarily on the larger cholesterol-rich LDL particles and the lowering
of LDL cholesterol by statins is more strongly related to that effect than the effect on
smaller LDL, which are cholesterol-depleted.
Now, having said that, there is absolutely no doubt that the LDL-lowering effect of statins
contributes to reduced heart disease risk.
I think that's unquestionable.
There are other mechanisms involved, I'm sure, that we've been studying that can be influenced
by statins, including adverse effects, which is a very important part of our current research.
But the benefits are absolutely well-established.
One of the most effective treatments we have for any medical condition, other than maybe
antibiotics for infections, are statins for lowering LDL, 30%, 40% reduction of risk,
big time.
And so that's because there are a set of LDL particles that are lowered by statins that
are bad.
And so it's not as if it's all or none, it's just statins could be more effective if they
were able to lower the smaller particles.
[Rhonda]: The ones that play a bigger role in heart disease risk.
Well, the way I think about it is if you're lowering the larger LDL particles, even though,
in a way, I don't think that's good because you need larger LDL, but you're also lowering,
you have less of it around to be processed into lower or smaller LDL particles.
[Ron]: Yeah, yeah.
Although a part of that effect...
Yeah, that's right.
Although part of the effect in the small LDL is coming through the triglyceride axis, which
we're very interested in that effect, as well.
Statins may affect triglyceride metabolism in ways that could affect small LDL production.
But the net effect is less than it could be if we had a drug that lowered the small LDL
particles more effectively.