**EP330: Safe Lower Limits For Cholesterol Treatment**
**Dr. Auric Bishop:** Welcome, my name's Dr. Auric Bishop. I'm a cardiologist, an author, and a keynote speaker. I'm CEO of the Healthy Heart Network. I'm all about trying to help people live as well as possible for as long as possible. Heart disease is huge in Australia. Every 20 minutes, someone suffers a heart attack. Most of these could probably have been avoided if only we knew what to do. This podcast is all about helping you understand blood pressure, weight, and cholesterol for better health. If you enjoy this podcast, I would be honoured for a five-star review. You can share it with your family and friends. It may well save someone you love.
**Warwick Bishop:** G'day, Warwick Bishop here and welcome to my podcast and videocast station. I'm super excited to have you join. And for those who are watching this on video, I'm going to share my screen so you can see what's going on. For those who are not watching this but instead are listening, you won't miss out too much.
What I'd like to talk about today is so-called bad cholesterol, our LDL cholesterol, which stands for low-density lipoprotein. And what I'd like to discuss today is how low can you go? Well, why do I want to talk about that? The reason is that over the years, as we've got more and more research, we've started to realise that if we find high-risk people and lower their cholesterol, the more we lower that cholesterol, the greater the reduction in future risk we can provide those individuals.
Why is that super important? Well, the reason is because in recent times, we've now got new, more powerful add-on agents that are really allowing us to get cholesterol levels down to targets, to goals that we really hadn't had the opportunity of reaching before with our standard medications. Now, when I'm talking about standard medications, I'm sort of talking about the statins primarily, because the statins really have the backbone still of our cholesterol care, our cholesterol management strategies.
Well, really importantly, one of the things that we can do is add another agent in. And as we add another agent in, quite reasonably, people say, "Oh, but, oh, hey, wait a second. We need cholesterol for our bodies. We need cholesterol for our... Every cell has cholesterol in it." That's true. We need cholesterol for the lining, or if you like, the wraparound insulation of the nerve cells within our brain. We also need cholesterol for our management of bile and reabsorption processes. We need cholesterol for vitamin D and transport of fat-soluble vitamins, and we need cholesterol for our sex hormones and some of our other hormones which our body produces.
So quite reasonably, you could ask the question, if we lower that cholesterol, are we putting some of these normal bodily functions at risk? Well, there are a number of really important starting points for that.
Number one is I'd like to let you know that when you were born, when I was born, when a baby is born, their LDL cholesterol level is low. It's in the order of about 1.5 or 1.8 millimoles per liter. This is at the individual's most synthetic time in their entire life. You do not grow any faster once you're in the world, excluding in utero when you double in size with your first division, but you don't grow any faster than you do when you're born. So at our most synthetic, at the time we literally would need everything available to give us every opportunity to grow and function as well as possible. Our cholesterol level is really, really low. In fact, that cholesterol is down in the range that we aim for when it comes to our targets or goals for people who have coronary artery disease.
So number one, we've lived with super low cholesterol at our most synthetic, at our most active, cellular building, growing stage in our entire life. So getting it down to that level probably isn't going to impact the sort of baseline cholesterol functions that we were talking about at the start.
Number two is that we know from Mendelian randomisation, and what I mean by that is genetic determination of particular characteristics. We can find people through genetic deletions or genetic additions who have extremely low cholesterol levels, down around the levels that we were just talking about or even lower. When we look at those people and match them up with the standard population who don't have those genetic additions or deletions, what we find is that those individuals with the very low cholesterol live what appear to be extremely normal lives when it comes to sex hormones, brain function, hormone levels and hormone function, vitamin function, and even the digestion of cholesterol.
But what we do also observe is that these people seem to live a long, long life without the impact of cardiovascular disease. So two natural circumstances before we leap into some of the evidence around this space, because it's a super important topic.
When we look at some of the data that's available, of course, we've been very careful as we've lowered cholesterol to keep a close eye on the potential adverse events people may suffer as we do this. Of course, we can't have trials where we implement an intervention and that intervention drives greater problems than the benefit we're hoping for. So all these things are monitored and documented.
In trials where we've used statins plus another agent called ezetimibe, a standard add-on agent to the statins to try and pull cholesterol levels down, that trial showed us that nearly 40% of people in the improver trial, and this trial went for years— we're talking about five, six, seven years— 37% of people had cholesterol levels down at 1.3 millimoles per litre or less, and they had no signal or flag for adverse events. They did demonstrate lower and lower rates of recurrence of cardiovascular disease events, which is just staggering.
And by really drilling in deep on those numbers, and here's a graph particularly on the right-hand side, for those who are looking at this as video, you will see that we've seen the benefit of cholesterol lowering down to LDL cholesterol levels of as low as 0.2 millimoles per litre. Now that's extraordinarily low. And in this group, there was no clear suggestion that this led to other problems, whether that be hormonal, functional, or cognitive.
But we know this is super important. We also know that we can see some statin association with diabetes. One of the concerns that some people would have, quite reasonably, is if we lower cholesterol too much like we've done with statins, could that drive a risk of increased diabetes? Well, pleasingly, by looking at some of this data with the newer agents that are non-statin agents, particularly these PCSK9 inhibitors, we've been able to look at the potential development of diabetes with very low cholesterol levels.
Now, statins do have a mechanism whereby they can increase the risk of diabetes with time. However, when we look at another agent, these PCSK9 inhibitors lowering cholesterol without the same mechanism as statins, there is no suggestion at all that just simply lowering cholesterol drives diabetes or progression to diabetes. A nice reassurance.
Well, what about brain function? There was a study looking at reduced LDL, reduced cholesterol levels. In one of the PCSK9 trials, the trial that really was the overarching trial was the Fourier trial, which looked at really driving LDL targets low. In a subgroup analysis, they took over 1,200 people for nearly two years and did very detailed neuropsychological testing on a regular basis to try and ascertain if lowering those cholesterol levels in these individuals generated any problems with cognitive function using a test called the Cambridge Neuropsychological Test and were unable to demonstrate any problems whatsoever.
Now this is really important because they also did this not just with the Fourier study where they used an agent called Repartha, which is the trade name, or either Locumab, which is the generic name, but they also did it with a similar agent called Alirocumab, A-L-I-R-O-C-U-M-A-B. Elirocumab, a Sanofi drug known as Preluent. And similarly, looking for neurocognitive change, they were unable to see any at all.
So really compelling and really important to get your head around because we've got really good indications that this just doesn't seem to be something that is going to drive problems. But incredibly important to ask and it is nothing but sensible to ensure that we are not generating problems from lowering cholesterol too much. It doesn't seem like that's the case.
I've got one other image here I'm pretty keen to show for those who are looking. I've got, not this study, the recent NCC Congress that I went to was excellent because some of the presentations there really touched on these issues. One of them was, do statins cause dementia? Now, it turns out that statins were associated with a decreased risk of dementia, both Alzheimer's disease, which is the neurofibrillary tangles that we see in the brain, but also the broad, if you like, diagnosis of dementia, which includes vascular dementia.
So for those who are concerned about brain function, it would seem that the systematic review published in the European Journal of Preventative Cardiology in 2022 would support the premise that statins do not increase the risk of dementia. Now, having said all that, that doesn't mean that some people may not take these tablets and feel like they're not able to concentrate, that they may have some brain fog or some such thing. But our data, where we've looked at this in a randomized control way, just doesn't point to there being any major risk when it comes to adverse events with low cholesterol, development of diabetes, development of neurocognitive problems, or development of dementia.
So super important to understand all these aspects. And that's it. Cholesterol lowering and safety. So I'm going to leave it there.
Oh, one of the other things I should add in there, we think about neurohumeral problems. One of the other things is when we think about really low cholesterol levels, many times people are concerned about the cholesterol and its interaction with sex hormones. Let me add in there that when we look at that closely, it turns out that the sex hormone production from cholesterol is more closely linked to HDL cholesterol, the so-called good cholesterol. When we're looking to target LDL, the so-called bad cholesterol, we rarely have much of an impact at all on that HDL and sex hormone process. So again, a nice reassurance.
If we skip back to where we very first started, your cholesterol levels are way, way down when you're born. And that's the time that some of your sex hormones are at their absolute peak as you're starting to grow in the world.
Well, I'm going to leave it there. I'm going to wish you the very best. If you have any queries or questions, drop us a note at info@drwarwickbishop.com. Otherwise, thanks so much for tuning in. I hope you live as well as possible for as long as possible. Take care and bye for now.
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