Dyslipidaemia (11 May 2026)

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Dr Angus Sinclair (AS): Hello and welcome to this episode of Clinical Conversations, brought to you by the Royal College of Physicians of Edinburgh Trainees and Members Committee. My name is Angus Sinclair and I'm a member of the T&MC. Today, I'm delighted to be joined by Doctor Jonathan Malo to talk about Dyslipidaemia. Doctor Marlow is a consultant chemical pathologist at the Department of Clinical Biochemistry in NHS Lothian and is the clinical lead for the Lipid Clinic at the Royal Infirmary of Edinburgh. He currently chairs a Scottish network of lipid clinic specialists and is involved in a Scottish Government group tasked with improving cardiovascular disease prevention. Welcome.

Dr Jonathan Malo (JM): Many thanks, Angus. It's a pleasure to be here and I'm very much looking forward to having a chat about lipids.

AS: Thank you for being here. So, dyslipidaemia is a large and complex area of medicine and is also very common, with over half of the UK population having high levels of total cholesterol. This is a topic that spans primary and secondary care settings as well as public health policy, so I'm sure this will be of use to all of us today. I think it might be a good idea just to start with giving us a brief overview of the different types of dyslipidaemia.

JM: Sure. As you say, it's potentially quite a big topic. I suppose the first thing to say is that there are correspondingly many different types of dyslipidaemia, and a few different ways that we can group them to try and make sense of that. And some of them can be helpful, particularly when we're assessing a patient with dyslipidaemia. And I think perhaps the simplest is also the most useful. So certainly, in the initial stages of assessing a patient with dyslipidaemia and it's based on dividing these dyslipidaemias up into. According to the pattern that we see in a standard lipid profile, which I'm going to define as comprising total cholesterol, HDL cholesterol, triglycerides, and then a calculated LDL cholesterol. And so, if we do that, if we divide or replace dyslipidaemias according to how they appear in a lipid profile, then with a few exceptions, because nothing in life is ever that simple, we can place most of the dyslipidaemias into three main groups. So, the first group is what we refer to as pure hypercholesterolemia. So that's raised LDL cholesterol with normal triglycerides. The second we refer to as mixed hyperlipidaemia. And that involves both a high total cholesterol and a high triglycerides and often a lowish HDL cholesterol. and sometimes the triglycerides are too high for us to actually calculate an LDL cholesterol. So that's not available to us. And then the third group is severe hypertriglyceridemia. And well, I guess the clue is in the name, but that's where the overwhelming feature of the lipid profile is very high triglycerides. And broadly speaking, in terms of clinical consequences and ignoring for a moment the underlying causes of these patterns, persistent pure hypercholesterolemia and persistent mixed hyperlipidaemia. They both drive atherosclerosis, whereas severe hypertriglyceridemia, although it probably isn't benign with respect to cardiovascular risk, with severe hypertriglyceridemia, the more pressing concern tends to be that of pancreatitis.

AS: That's very helpful. Thank you. In terms of the lipid profile, do you see the total cholesterol as being particularly important, or is it the parameters within that that are that more clinically relevant?

JM: Yeah. So, it's as you sort of suggest, you're kind of leading me there. It's the parameters within it which are more important and which ones are most important kind of depends. So, it's going to vary depending on the individual patient. So, for example, if we're talking about a situation where we're suspicious of something called familial hypercholesterolemia, which I'll maybe touch on a little bit later, then the LDL cholesterol is overwhelmingly going to be your focus. And generally speaking, if we're talking about secondary prevention, then you're also going to be interested in LDL cholesterol, because that tends to be the parameter that's used to decide whether you're a statin dose should be increased. Or maybe we should be adding a further cholesterol lowering drug. But then if we've got something like a mixed hyperlipidaemia, you're actually probably going to be best served by concentrating on what's known as non-HDL cholesterol. So that's the total cholesterol minus the HDL cholesterol. And that's because in the context of mixed hyperlipidaemia, non-hdl cholesterol is likely to give the best gauge of how atherogenic that person's lipids are. It may also be better because you may not actually be able to accurately calculate an LDL cholesterol if the triglycerides are high. And in mixed hyperlipidaemia generally. Also, I think HDL cholesterol and triglycerides, if they are going in the wrong direction, then that gives you a kind of idea as to how badly things might be going on in terms of things like insulin resistance and fatty liver, that kind of thing. What's important from the lipid profile depends very much on the context. And as you alluded to at the beginning, well, it's almost certainly true, is that the total cholesterol by itself is not actually that useful. At a minimum, you need an HDL cholesterol to assess cardiovascular risk. And ideally, you want the triglycerides and an LDL cholesterol to figure out whether you're dealing with a pure hypercholesterolemia, a mixed picture, or a severe hypertriglyceridemia.

AS: Thank you. That's very helpful. Before the complications of dyslipidaemia arise in the longer term, it's generally an asymptomatic condition, although we do learn of some stigmata of high cholesterol, such as xanthelasma and tendon xanthoma. In your experience, how reliable are these as indicators of dyslipidaemia?

JM: Yes, it depends on the particular stigmata, the particular sign. So, some of them are pretty reliable in terms of indicating that a chronically raised cholesterol, a tendon xanthoma in particular that's classically seen on the heels, but also, we see it on the elbows and the backs of the hands and tendon. Xanthomas are strong signs of familial hypercholesterolemia, so, so very high LDL cholesterol from early on in childhood. And they should virtually always prompt a workup for familial hypercholesterolemia. Xanthelasma so these are typically yellowish or whitish patches on the skin surrounding the eyes or on the eyelids themselves. They're much less reliable. So, they're certainly seen in patients. Sometimes you have fairly normal cholesterol where they do present alongside a high cholesterol. They're almost certainly driven by high cholesterol. And like xanthomas, they tend to resolve, albeit very slowly, with effective long term cholesterol lowering medication. So, Xanthoma is more reliable certainly, than Xanthelasma. And then we've got a corneal arcus. So, this is a whitish ring which appears on the periphery of the iris. If it's seen in a younger patient. And by that I kind of mean below the age of about forty-five to fifty, then you should be again, seriously considering FH. But above that age, it's not uncommon for it to occur in people with actually relatively normal cholesterols. So, it's an age dependent kind of sign. And then perhaps the last one that's worth mentioning is something called eruptive xanthomata, which is relatively rare, but we sometimes see it in patients with severe hypertriglyceridemia. And it looks a little bit like acne. You get small sort of yellowish red papules that erupt over the elbows, or sometimes the trunk or the buttocks and the legs, and it tends to be pretty transient. So, it's associated, as I say, with very high triglycerides. And it tends to resolve quite rapidly as the triglycerides drop back down. So, these are kind of the main stigmata to be aware of related to dyslipidaemia.

AS: Thank you. If we can move on to thinking about managing Dyslipidaemia, it's a broad question, but what are the general approaches that clinicians use? It's generally not as simple as treating a number. I suppose it really depends on the clinical context. Is that right?

JM: Yeah, absolutely. And it's potentially a big topic in of itself. I mean, I suppose ultimately what we want to do is prevent atherosclerosis or in other instances, prevent its progression. And to do that, particularly where we're talking about prescribing a medication like a statin, we want to be as sure as we can be, that it's going to make a positive difference and be confident that we're not going to do more harm than good. And as you say, it's not as straightforward as treating a number. Now, the group of people where we have most confidence that intervention is to prevent cardiovascular events are going to be worthwhile. Is that comprising people who've had a myocardial infarction or a stroke or have peripheral arterial disease, because we know that they're at really high risk of further events. And we know that secondary prevention would be at smoking cessation or anti-platelets or statins will have a positive impact. But clearly, it would be far better if people didn't develop cardiovascular disease in the first place. And this is where things start to get a little bit less straightforward. Because while most all of us agree that primary prevention is important. I think we don't all agree on the best way to go about it. I think it's pretty much universally agreed that the lifestyle elements are important and should come first. But where it starts to get trickier is when to start a drug like a statin. And there are tensions between the benefits that things like statins can provide and their perceived downsides. And some of those downsides are potentially very subjective. So, you know, up to whether an individual perceives that drug medicalizing them and then somehow makes them feel less healthy and impinges on their well-being. And that's the kind of consideration with a preventative medication that, you know, becomes quite valid because it's not a curative therapy. Now, at a population level, there is ample evidence to support everyone taking a statin and perhaps an antihypertensive and assuming that you had reasonable uptake for that kind of thing, you know, as sort of so-called polypill, then we would see big reductions in cardiovascular disease. But on an individual level, certainly over a short time frames, like five or ten years. A lot of people would have only pretty modest reductions in absolute risk. And obviously this is a debatable point, but I think you might be hard pushed to persuade someone to take a medication if you can't convince them that they're at high risk. So, the current consensus is that we try to identify those at highest risk and have a conversation about it. And depending on the outcome of that conversation, I offer them a statin. And because we know that cardiovascular risk has multiple contributory factors, we've developed cardiovascular risk calculators like assign Q risk score to try and introduce a degree of objectivity and to try and capture the various different cardiovascular risk factors. So, unless we already consider someone to be automatically at high risk, and UK guidelines over the last few years would consider individuals with CKD or perhaps long-standing diabetes or those with FH to be automatically at high risk. But unless you fall into one of those groups, then the approach is to try and calculate a ten-year risk with something like a sign. And if it comes out above a certain set threshold, and currently that's ten percent risk over the next ten years, then you would talk to the patient about potentially starting a statin. But it's not a perfect approach. And even, I think among the most ardent cardiovascular risk calculating enthusiasts, you'll find acknowledgment that it's probably too simple to capture everyone who might be at high risk of atherosclerotic cardiovascular disease. So, there's certainly room for improvement. Probably one of the most obvious things is the addition of further risk factors. So Q risk is definitely gone that way. You may be aware that it has quite a few more risk factors potentially that you can enter when compared to the likes of a sign. And I suspect that trend will continue. And perhaps we'll see other risk factors like for example, lipoprotein A, which we may come to in a bit added into the likes of Q risk. There's also, I suppose, one thing that these risk calculators don't capture is or don't capture it very well is cumulative exposure to things like high cholesterol and high blood pressure, and partly driven by what we know from individuals with familial hypercholesterolemia, but also observational studies of people with different levels of cholesterol over long periods of time. We know that cumulative exposure is important, and as I say, it's not currently captured in a cardiovascular and, you know, the likes of the sign and key risk. And hence it may underestimate risk in people that have that kind of cumulative exposure. And that would certainly be the case in something like FH. And kind of along similar lines. Some would also argue that one of the major shortcomings of our current approach is that we don't consider risk beyond ten years. And obviously, that's going to be particularly relevant to younger people with adverse risk factors whose ten-year risk is not going to breach a threshold for treatment, because age is the overwhelming sort of determinant of your cardiovascular risk. But nevertheless, these young patients have a high risk of developing cardiovascular disease later in life. And we know there's increasing evidence that the earlier we start treating things like high cholesterol, the better outcomes we get in terms of long-term risk. So that's sort of another consideration. And in time, I think we'll see thinking about really long-term risk embedded into guidelines. And one very recent example is a guideline from the American Heart Association, which was published just last week, which for younger patients, now recommends calculating a thirty year cardiovascular risk and offering a statin if that thirty year cardiovascular risk reaches ten percent, or if that individual has an LDL cholesterol that's persistently above about four Millimoles per litre. And indeed, I think the sort of striking thing about that guideline is that it appears to be really moving to a situation where we're hoping to pick up dyslipidaemia much earlier in the life course, and, where appropriate, treat it. So, some of the more sort of eye-catching recommendations from that AHA guideline are that it advocates testing everyone's cholesterol at the age of ten and then doing it again at nineteen years old, and then thereafter every five years. So, it's really driving an approach that intends to reduce early onset cardiovascular disease.

AS: That's so interesting. And clearly it really complex considerations. It's really helpful for you to just outline the holistic sort of individualized approach there in assessing each individual's risk and the benefits. I'm also interested to see that in the assign score is a postcode as well, and it really emphasizes the public health component of this problem.

JM: Yeah. Because I mean, as with a lot of disease and cardiovascular disease is no exception to this. Socioeconomic status is really key. And so, if we were to look at a heat map of the UK, you know, you would see the highest rates of particularly early onset cardiovascular disease being centred on those sorts of post-industrial areas of Britain. And, you know, if you'd taken a heat map of mortality during Covid, it would have exactly the same pattern. And it just shows how powerful socioeconomic status is in driving illness.

AS: Just bringing it back to the internal medical side, I wondered if you wouldn't mind telling us about some of the secondary causes that we should always think about, and some things to rule out.

JM: Sure. Yeah. So, I guess one of the ones that's most common, I think underappreciated is alcohol excess. So, it can produce really quite high levels of cholesterol. Sometimes it'll be in a sort of pure hypercholesterolemia kind of pattern. So high LDL cholesterol. Other times it might be a mixed hyperlipidaemia or even other times as severe hypertriglyceridemia. It does vary from individual to individual, but certainly it's not uncommon cause of quite high lipids and something to exclude before you start considering the likes of familial hypercholesterolemia. Then, in terms of the other sort of non-inherited causes, diet is or can be important. I think it's probably been overplayed as a factor historically and certainly the common perception, you know, when you see patients in the clinic is that, oh, it must be my diet. And people often launch into telling you about how they're only eating lean meat and various things, and they no longer consume butter. But actually, diets probably not that big an influence for most of us. There are some exceptions. So, one very special one is sometimes we see quite eye watering LDL cholesterol levels, occasionally well above the levels that we see in familial hypercholesterolemia from individuals pursuing keto diets, high fat keto diets. So, it's certainly worth asking about diet to find out if someone's pursuing a sort of special diet, I suppose. And if they are pursuing a special diet, then that could be something to pay attention to. I suppose the other group of patients in which diet can be a major influence is those with metabolic syndrome and type two diabetes. And here I think the diet is influential in terms of the extent to which it sort of drives the metabolic syndrome, contributes to insulin resistance and hepatic steatosis, and then, as a consequence, can worsen usually a mixed hyperlipidaemia. But it's not so much, I suppose, a direct relationship between the diet and the dyslipidaemia, if you like, and then other causes to think about, which are sort of not exclusively sort of inherited would be things like uncontrolled hypothyroidism tends to produce a pure hypercholesterolemia nephrotic syndrome, and then sometimes cholestatic liver disease. And sometimes, and this is pretty rare. Cholestatic liver disease can produce super high cholesterol results, which via a sort of rare phenomenon that's known as LP X. So those are the kind of non-inherited drivers to kind of think about in terms of secondary preventative therapy.

AS: As an internal medical trainee, this is when I would see statins most commonly started, most commonly after patients have had a myocardial infarction or stroke. In some situations, the cholesterol levels are normal. And patients will often ask, why am I being recommended a statin if my cholesterol levels are normal? What is the rationale for that?

JM: Yeah, so it does seem a little bit counterintuitive. And you can understand why patients would pose that sort of question. It stems from the finding that lowering cholesterol reduces cardiovascular risk across a whole range of cholesterol concentration. So even if you have a relatively low starting cholesterol Reducing it further will have an impact on your risk in a beneficial way. Now, if you had an MI or a stroke, then on average your baseline risk of having another one is pretty high. So, you stand to benefit from a statin pretty much irrespective of your pre-treatment cholesterol. Now, that doesn't mean that pre-treatment cholesterol isn't also important. So, we estimate that you get about a twenty percent reduction in relative risk for everyone millimole per litre of cholesterol lowering. And because a particular dose of a statin gives you a set percentage reduction in cholesterol, that means that you're going to get the biggest relative risk reductions in those with the highest pre-treatment cholesterols. So, cholesterol does still matter. But ultimately the absolute risk reduction, which is what really counts, is going to depend largely on the baseline risk, which is to say for secondary prevention is very high. And that's the rationale for starting the statin in secondary prevention, irrespective of the pre-treatment cholesterol level.

AS: Thank you. I'd like to come on through talking about statin intolerance. It's a common topic of discussion and even debate, with many people citing the nocebo effect when it comes to common side effects. There have been several large studies now investigating this, including a very large meta-analysis in The Lancet this year. What's your approach to all of this data and what does it tell us about statin side effects in general? So, you're definitely right. The propensity of statins to cause side effects has been and continues to be a topic of some controversy. I think that's a product of the fact that statins are so commonly prescribed. And also, I should have said before, because they're not curative. And they also don't give us a cast iron guarantee against things like heart attack and stroke. And I think as humans, we kind of struggle with that uncertainty and together with a sort of need for us to make sense of the many non-specific symptoms that come and go and crop up in life. I think statins often do incorrectly get the blame. So in terms of the meta-analysis that you mentioned, which is a cholesterol treatment, trialists meta-analysis of the statin randomized control trials, I think it shows that statins do sometimes cause side effects, but that the rate at which those side effects occur and the number of different types which are genuinely associated with statins are probably very much lower than most of us would think. But I mean, clearly, we still get patients quite commonly reporting problems with statins to us. And so there does appear to be a significant disconnect between, you know, our real-world experience and the picture that's coming from those meta-analyses that originate from the statin randomized controlled trials. So, I mean, I suppose the meta-analysis that you mentioned, it looked at the side effects that are listed in the summary of product characteristics for statins. And it looked at whether there was any evidence from the randomized controlled trials that statins actually cause those listed side effects. And they concluded that, you know, a list of sixty-six odd side effects, only about four were found to be more likely if you were taking a statin. And the same group have done similar sort of big meta-analyses previously, and probably the most notable ones in this subject, is on muscular side effects, which are very commonly reported adverse effect with statins. And again, they looked at the sort of what we refer to as the more minor muscular effects. And they found that they would probably occur at a rate of about one percent, which is certainly much lower than I think we generally sort of perceive them to occur at. And so, as I say, I think there is definitely a disconnect between what's reported from the meta-analyses and what we kind of have as a real-world experience. And I think it's maybe worth talking a bit about the N of one studies, because they provide quite a compelling case to try and explain that disconnect, which is being referred to as the nocebo effect. So, I could talk a little bit about those.

AS: Yes. Please do.

JM: Yeah. So, the n-of-1 studies include two relatively small trials. So around one hundred to two hundred participants. Sampson and Staton Wise, which were both conducted in the UK and one of them in primary care. And they have a really interesting design, but they also involved quite a concerted effort to sort of replicate real world practice and measure a full range of symptom severity, a lack of which has often been a criticism of the drug trials. So, they recruited patients who had previously reported adverse effects with statins, and they randomized individual participants over blocks of time to either a statin or a placebo. And they asked patients to keep a record of their experience of symptoms throughout the study. And both studies found similar rates and severity of symptoms, irrespective of whether you were on a placebo or a statin. So, there was no association between symptoms and statin treatment. And one of the studies also measured symptoms during periods where patients knew they were taking neither statin nor a placebo. And during those periods, the level of symptoms dropped significantly. And that's kind of where this sort of notion of the nocebo effect comes from. Now, at the end of both studies, the results were unblinded, revealed to the patient. And interestingly, up to two thirds of patients decided that they were prepared to resume statin treatment for the foreseeable future. And remember that these were patients who previously concluded that they were definitely suffering side effects driven by statins. And so, while these n-of-1 studies, they don't have the scale of the CTT meta-analyses. I think they do make a fairly compelling case for those who believe that while statins certainly will sometimes cause adverse effects, it's certainly not as common as most of us would think. I suppose it's sort of further, kind of tantalizing thing about the N of one studies is you really wonder whether this kind of thing could actually be used as a clinical tool. So, you know, certainly I would love to be able to prescribe a sort of n of one study toolkit to a patient who experienced problems with statins. If it meant that that patient, then concluded that they could take a statin beyond it. The blinded aspect obviously presents some challenges, but if anyone listening to this podcast can make that happen, then I would be very keen to hear from them.

AS: And we will link to that meta-analysis and the N of one studies in the footnotes of this podcast. For anyone that's interested in looking into that in more detail. If somebody has a true intolerance of a statin or indeed the class as a whole, or has a contraindication, such as in pregnancy or active liver disease, what would be the next alternative for lipid lowering treatment?

JM: Yes, it's a good question. So up until a few years ago, there weren't many. But in the last kind of ten years, really, we've seen the development of quite a few new cholesterol lowering drugs. So, for those with intolerance or perhaps a severe adverse reaction to a statin, be that maybe a drug induced liver injury or some kind of myopathy and should stress these things are really rare. But for those kinds of individuals. We've got things like ezetimibe. Something called bempedoic acid and a number of drugs, which are referred to as Pcsk9 inhibitors. Now, with the exception of ezetimibe, these are new, relatively expensive drugs. So, whether we can actually offer them on the NHS is going to depend on the particular patient. And we can maybe come to that a bit later. But in principle there are certainly now alternatives to statins.

AS: As you alluded to with some of the newer therapies. I think it would be useful to go into what those therapies are and what contexts would you be prescribing those? It seems that with a lot of metabolic medicine is a rapidly evolving area. And I suppose there's more and more evidence emerging about the effects of some of these newer therapies.

JM: Yeah, absolutely. So maybe focus on the ones that we actually have access to on the NHS. As I say, being relatively new drugs, they are more expensive and so our ability to prescribe them is limited. It's restricted. There are probably four new sort of cholesterol lowering drugs that we now have access to. Three of these are Pcsk9 inhibitors, and they're all delivered by subcutaneous injection. There are two monoclonal antibodies, evolocumab and alirocumab. And then the third is an RNA therapy called inclisiran. Now they're all very effective at lowering LDL cholesterol. On average, they provide somewhere between forty and eighty percent reduction in LDL cholesterol, which is equivalent or better, you know, to the most potent statin prescriptions. And they can do that on top of an existing statin therapy. And they seem to be pretty safe and well tolerated. I guess of note, Inclisiran is administered six monthly, whereas the monoclonals are given every fortnight, and that six monthly frequency is seen by some as a major advantage, given the issues that we sometimes have with adherence to preventative tablets like statins. But obviously, as I say, all of these drugs remain a lot more expensive than statins. Yeah. So at the moment, in terms of who we can prescribe them to, the likes of Nice and SMC recommend that Pcsk9 inhibitors be reserved for those patients at particularly high risk, which means secondary prevention or those with familial hypercholesterolemia, where those patients LDL cholesterol remains very high despite maximal statin therapy. And that usually means. So, for secondary prevention, that would mean an LDL cholesterol of higher than three and a half to four. Despite best efforts at statin treatment. So, then I've talked about the Pcsk9 inhibitors, which are three of these newer cholesterol lowering drugs that we have available to us on the NHS. In addition to those three. We've also got a fourth drug, which is called bempedoic acid. It's a tablet treatment, and it works by blocking the same cholesterol synthesis pathway as statins do, but it does it a few steps higher up the pathway. And I suppose its main selling point is that it's only metabolized into its active form within the liver. So, in theory, it shouldn't be as likely to cause muscular symptoms as a statin might. Its cholesterol lowering efficacy is somewhat more modest than the Pcsk9 inhibitors. But it's not bad. It's around twenty to thirty percent. And it can be taken as a combination pill with ezetimibe, which then in combination gives comparable cholesterol lowering to the likes of atorvastatin twenty milligrams. It's not as expensive as the Pcsk9 inhibitors, but of course, it's still much more expensive than a statin. And so on. The NHS, we're sort of recommended to make it available only to those who can't tolerate a statin, but it is available to a much wider patient group than the Pcsk9 inhibitors, so it can be offered to anyone at high cardiovascular risk, whether that be primary or secondary prevention. And there's no baseline LDL cholesterol that people have to have.

AS: You talked about the cumulative effects of these treatments on top of statins. Is combination therapy something that's going to become more common in the future?

JM: It's hard to know. It's certainly something that's advocated by many that have been involved in developing these drugs and demonstrating their ability to lower cholesterol and lower cardiovascular risk. And certainly, the science shows, you know, that there is virtually no limit to the benefit in terms of bringing the LDL cholesterol down. I suppose the obstacles that you come up against Are going to be costs, as I've mentioned several times already. And also, sometimes for valid reasons, a reluctance to embark down a road where we're prescribing lots of medications. So, polypharmacy. But as I say, if you're just sort of focusing on the cardiovascular risk, that's a very valid thing to do. There is an argument for a combination therapy to reduce LDL cholesterol in very much the same way as we might argue, for sort of combination therapies in blood pressure.

AS: Are we finding that some of the newer weight loss treatments, like semaglutide and tirzepatide, are having beneficial effects on dyslipidaemia? 

JM: So, in a word, yes. I mean, I'd say that on average, the effects from the drug trials on lipids don't seem maybe quite as dramatic as you might imagine. They're certainly real. They seem to produce modest reductions in LDL cholesterol and more obvious reductions in triglycerides, which very much fits with what you'd expect in terms of enhanced insulin sensitivity and reduction in hepatic fat and that kind of thing. Or perhaps even reduced fat intake with appetite suppression, all of which you'd expect to reduce triglyceride rich lipoproteins. So that's the findings from the trials. I think anecdotally in the lipid clinic we see a mix of responses. Like many other clinics, you know, a lot of our patients are now taking these drugs. And for some of them, it does seem to have quite a dramatic effect. I should stress this is anecdotal in individual cases on both their non-hdl cholesterol and their triglycerides. But then it's also true that some other patients just don't seem to see that bigger shift in their lipids. An interesting sort of subgroup of the ones that do seem to have a benefit are those who have severe hypertriglyceridemia that's driven by metabolic syndrome. So, this is where they're having really high triglycerides and often lipid lowering drugs. And the main one that we tend to use in that context is a fibrate. They just haven't been able to control the triglycerides. But what we've seen in this patient group is that where they can lose a significant amount of weight, we do see dramatic reductions in their triglycerides as weight is lost. And we're hoping that that's going to translate into fewer episodes of acute pancreatitis for them. But it's a slightly strange group because we also know that there are these concerns about a risk of acute pancreatitis with GLP one. So yeah.

AS: So, I just want to come back to something you mentioned earlier, which was about lipoprotein A as an additional risk factor for sclerotic cardiovascular disease. It's not something that I'm particularly aware of. But do you mind just expanding a little bit on that?

JM: Yeah of course. I think there are good reasons that you wouldn't be particularly aware of. So, lipoprotein A is a cholesterol carrying particle. It's very similar to LDL low density lipoprotein in terms of its size and its composition. But unlike LDL, we don't really know what physiological purpose lipoprotein serves. What we do know from epidemiological studies is that its atherogenic and that cardiovascular risk rises continuously the higher that your lipoprotein level is. And we also know that it's largely determined by our genetics rather than environmental factors. Now, the good news is that most of us have very low levels, but about maybe twenty to twenty five percent of us have a level which is associated with an increased cardiovascular risk and a relatively small number, but it's probably similar in frequency to the number of people affected by heterozygous FH, which is about one in two fifty, have really very, very high levels of lipoprotein A, which just by themselves mean that those individuals have a very high risk of early onset cardiovascular disease. Now, the tricky thing about raised lipoprotein A is that it isn't necessarily associated with very raised cholesterol. So, it's a dyslipidaemia, but it doesn't fit into that nice classification of Dyslipidaemias that we talked about at the beginning. So, you can't rely on picking up a raised lipoprotein A through a standard lipid profile. Instead, it has to be measured through a separate specific lab test. And with the exception of a few places in the world, lipoprotein measurement is something that is generally the preserve of the lipid clinic, or maybe upon the explicit recommendation of the lipid clinic. And so, it's not surprising that you wouldn't have heard much about it. And so, at the moment, I'd say the majority of individuals with raised lipoprotein A won't know about it because it won't have been measured. And those that are picked up by lipid clinics and they're picked up there because of unusually early onset cardiovascular disease, or perhaps because they have a family history of early onset cardiovascular disease. That's the only sort of instance in which we're sort of measuring lipoprotein, by and large at the moment. But I think the reason that it's worth mentioning is that there are signs that. Lipoprotein A is about to make kind of leap into the mainstream. So, there are a number of international guidelines that have been advocating its measurement as part of a cardiovascular risk assessment in everyone. And so it may be that we'll see lipoprotein a becoming a standard part of sort of primary prevention, calculating tools like Qrisk and assign. And if it has the potential to significantly improve the accuracy of the risk that we're calculating with those tools. And then the other area where lipoproteins a measurement may quickly become routine is in secondary prevention. So later this year, we're expecting results from the first phase three trials for a drug called Pelacarsen, which is an antisense oligonucleotide that lowers lipoprotein A by about seventy to eighty percent. And that's notable because at present, we don't really have lipid lowering drugs that have a significant effect on lipoprotein, a Pcsk9 inhibitors due to a certain extent, but certainly not to the levels that Pelacarsen could reduce lipoprotein a. And so, if this new drug is found to prevent cardiovascular events, then in the not-too-distant future, I suspect we could be measuring lipoprotein A in our post-mi patients to try and figure out whether they're going to benefit from the likes of Pelacarsen.

AS: That's really interesting and something we need to keep an eye out for. Thank you very much. So, I think that's us coming towards the end. I'm interested to know as you're a clinical biochemist, the sort of patients that you're seeing in specialist lipid clinic and who we should be referring to that clinic in our own local areas.

JM: Sure. Yeah. So definitely patients that you suspect of FH. So that's LDL above five, although more typically a lot higher than that combined with some kind of family history of hypercholesterolaemia and or early onset coronary heart disease. We really want to find patients with FH because we know lipid lowering can significantly lower the risk of cardiovascular disease for these patients. And we have genetic testing available throughout the UK. And if we can identify one patient in a family, then often we can persuade relatives to also get tested. And because this is an autosomal dominant condition, heterozygous FH, then potentially, you know, identifying a family means a lot of people who would otherwise be at high risk of early onset coronary heart disease, getting access to treatment. That's going to prevent that. So, FH for sure, and I can talk a bit more about FH if that's useful.

AS: That would be helpful. Thank you.

JM: So yeah, as I say, FH poses this particularly high risk of early onset cardiovascular disease. And it's driven by a mutation in a handful of genes autosomal dominant. And most commonly it's a loss of function mutation variants within the LDL receptor gene. And what that means is that patients with FH don't remove as much LDL cholesterol from the circulation as others, and that is something that affects them from the word go. So, from the moment that you establish a circulation within the womb, throughout life, and it means that chronic lifelong exposure to high LDL cholesterol. And that's what we understand to drive the early onset cardiovascular disease. That is the sort of hallmark of untreated FH. And I suppose the key thing is that it's underdiagnosed. So, we think the prevalence is probably in the realm of one in two hundred and fifty in the population. But at the moment, we estimate in Scotland that we've probably picked up about twelve percent of that population. And that's not too far off from the situation throughout the whole of the UK. So, as I say, we very much like to increase our diagnostic pick up and offer individuals with FH statin therapy, which we know can really make a huge difference in terms of their lifetime cardiovascular risk.

AS: I think that's a good note to end on. It just really highlights that this is a topic that spans the individual clinical scenario and the public health perspective as well. Doctor, thank you very much for your time. That's been extremely interesting. And I'm sure the listeners will find this very helpful. Thank you.

JM: Thank you so much, Angus. It's been a real pleasure.

AS: We hope you found this podcast useful. If you have, you might be interested in the recent episodes we have on preventative cardiology and cardiorenal metabolic disease. Thank you.