Managing hypercholesterolaemia

Discussing cholesterol management is a marathon, not a sprint, and undertaking cholesterol-lowering interventions isn't a one-and-done thing, it's something that we're going to work through for many, many years with our patients.

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

I'm Dhineli Perera, your host for this episode. It's a pleasure to be speaking to Associate Professor Adam Nelson today about updates in the management of hypercholesterolaemia. Adam is an Interventional Cardiologist at the Royal Adelaide Hospital as well as a Senior Research Fellow at the Victorian Heart Institute in Melbourne. Together, Adam and Professor Stephen Nicholls have reviewed the current evidence in optimising the management of hypercholesterolaemia, which is actually one of the most common conditions treated by clinicians in Australia today. Adam, welcome to the program.

Thanks for having me, Dhineli.

So Adam, can you level with us here and tell us, is Australia's hypercholesterolaemia situation really as bad as we think?

I think the broader question, Dhineli, is probably that we don't really know, and I think that's a reflection of the fact that our Australian data is so siloed and that we lack a really unifying identifier for our patients in Australia. And so, we don't have good interoperability between primary and tertiary care, so a really good granular understanding of the pattern of cholesterol in Australia is wanting. What data we do have comes from the Australian Bureau of Statistics, from self-reported hypercholesterolaemia. Those rates range from between one in 10 to one in 4 Australians.

If you were to look at a slightly more select population of patients who have engaged with tertiary care with established cardiovascular disease (CVD), we think more than 90% have got elevated cholesterol and over half of them don't reach their LDL cholesterol targets. In short, we think it's very prevalent. The exact numbers around that we don't know with great detail.

So we think it's bad but we just don't know how bad it is.

Fair, fair.

Could you run us through a brief refresher on the different components of the lipid profile and what they mean?

One of the challenges is that [the terms] ‘lipid panel’, ‘lipid profile’, ‘cholesterol profile’ can mean a lot of [different] things to different laboratories, and so clinicians don't necessarily get a standard output of lipids. In general, a lipid panel will include total cholesterol and HDL cholesterol, both of which are directly measured, and then we calculate from that other values that are often reported, including LDL cholesterol, triglycerides, and also often non-HDL cholesterol, sometimes even total cholesterol to HDL cholesterol ratios. So it depends a little bit but the really key elements of the cholesterol profile though in my mind are LDL cholesterol and triglycerides.

How important would you say is the differentiation between triglycerides and LDLs with their conferred risk for CVD?

I think historically we've lent on total cholesterol and the community have got an awareness of what total cholesterol means. They've either been told, yes, ‘my cholesterol is fine’ or ‘my cholesterol is elevated’ in a fairly dichotomous way, but actually there's so much more to total cholesterol. I think if we just rely on such a coarse metric of someone's cholesterol or lipid panel, we really miss the opportunity to have a more granular understanding of that person's cardiovascular risk particularly. The way that I talk about it with patients, and the purists will argue it's an oversimplification, but around good and bad cholesterol. And then, I put triglycerides aside with fatty acids.

I think that helps at least frame the discussion because, in many ways, we know that patients’ good cholesterol, HDL cholesterol, is largely genetically driven and we know that patients with high levels of HDL cholesterol are somewhat resilient and protected from cardiovascular disease and the corollary, therefore, is that those with low levels are at elevated risk. We can't do much about that. Those patients, however, we then frame a discussion around LDL cholesterol, and so we know that LDL cholesterol has got a linear relationship with cardiovascular risk, and then patients with elevated triglycerides we know respond, in large, to lifestyle interventions so discussions around alcohol intake, exercise and weight management, diabetes, a number of other bits and pieces.

So I think the key thing to understand here is that the lipid panel allows us discussions around each of those 3 key areas and that helps us frame management plans.

So I think it's not something to be cast aside necessarily, the triglycerides. It needs to be, as you said, unpacked and then treated and handled differently.

The other thing to say is that patients aren't pot plants anymore. We used to have this sense that they didn't really want to know what was going on or that they would do what they were told, but I turn the screen around and show them what these numbers are. Discussing cholesterol management is a marathon, not a sprint, and undertaking cholesterol-lowering interventions isn't a one-and-done thing, it's something that we're going to work through for many, many years with our patients. So starting with that understanding, and educating and engaging the patient, is a critical piece around shared decision-making.

How confident are we about the risk of cardiovascular disease and the association between those components that you've just discussed? I suspect it's easier for some components than for others.

It is. So LDL cholesterol we have a plethora of data. We have over 30 years of experience with cholesterol-lowering agents like statins. We have genetic studies, Mendelian randomisation, natural history selection studies, showing that patients with elevated LDL cholesterol have got a long, linear relationship with risk, and that relationship holds whether you're in primary prevention, secondary prevention, and across varying levels of baseline LDL cholesterol. And what's really neat about that data is that when you add that all up, one of the key elements here is an understanding around LDL cholesterol years, this idea that not only is it causal, LDL cholesterol and cardiovascular disease, but it's cumulative and it really changes the whole way we view this.

Suddenly, having this arbitrary cut point of turning 50 and then worrying about cholesterol, blood pressure, getting a PSA [prostate specific antigen] or a mammogram, should really be turned back and saying, "Well, okay, well let's have a think about someone's lifetime exposure to LDL cholesterol." Then the discussion centres around in your 30s and 40s. So, LDL cholesterol, I think that’s very, very clear – linear, cumulative, causal relationship. HDL cholesterol has been a little vexing. We have got very good epidemiology studies demonstrating inverse associations between levels of HDL cholesterol and risk, low levels conferring risk, high levels conferring protection.

The challenge though is that any attempt that we’ve made to raise HDL cholesterol hasn’t resulted in a commensurate decrease in cardiovascular risk. So despite 30 years of drug development, trying to raise, improve function of HDL, we haven’t seen it translate to benefit. So we think it’s a marker, but there may be more complexity in understanding whether it truly is causal or not.

Triglycerides have gone through many different iterations. We know there are atherogenic elements of triglycerides, those triglyceride-rich lipoproteins. We think that, pound for pound, that may be as atherogenic as LDL cholesterol, but the coarse evaluation of triglycerides also includes chylomicrons, which are very large, intestinal driven, and they may not be quite as atherogenic. So there’s more than meets the story with triglycerides.

And so, I like to sort of bring it back to practical tips from the experts, Adam, so what would be your 3 top tips for appropriately checking a lipid profile for clinicians out there that are looking at the patients?

I think fasting status is ideal, but let’s not let perfection get in the way of good. If you’ve got a patient who rarely attends, take the opportunity, give them a blood form, go and get a nonfasting sample. We know that in that context a bird in the hand is worth two in the bush and, if we can have normal triglycerides, we can then very confidently assess their LDL cholesterol risk. If their triglycerides are elevated on a nonfasting sample, we should repeat it and see what that looks like, but at least we’ve got some understanding and we can calculate some of their cardiovascular risks. So, fasting status ideal, but don’t miss the opportunity if you’ve got them in clinic.

Probably the second piece for me is around the education piece. Patients, as I said, they’re not pot plants anymore, they want to understand what’s going on and why you are measuring their cholesterol and more importantly the elements within it. So I think tip number 2 is explain what you’re measuring, why you’re measuring, and what each of them means for them. The other piece for LDL cholesterol is that dietary changes, by and large, impact LDL cholesterol fairly modestly so if patients go home expecting to have large dietary changes and come back from red numbers back into black normal numbers, it’s not necessarily going to happen so a really good understanding about expectations for me is a key part of checking your test.

The third piece, frequency. We see changes in LDL cholesterol within 3 to 4 weeks of changing or adding medications, so this arbitrary 3-month review promotes inertia and sends the wrong message to the patient. So I'm repeating LDL cholesterol panels on a 6-weekly basis if I'm changing things, and that helps me frame that discussion around the importance of risk mitigation.

That last one's quite a big practice change, Adam. That 3-month number has been thrown around for a long time. Is that something that you would hope to see changed in the guidelines?

The challenge we've got is that the PBS guidelines will recommend the addition of therapies on a 3-monthly basis. That is, again, historical and arbitrary. I worry about our patients post-ACS [acute coronary syndrome] admission who then wait 3 months for intensification of these therapies so I think we will see a change and, hopefully, that's reflected in reimbursement.

So, Adam, your article runs through a few other lab tests that should be included when reviewing a patient's lipid profile. Can you explain what these are and their link to the LDL-C [cholesterol]?

LFTs [liver function tests] I think are an important part of doing a baseline cholesterol panel. Firstly, to exclude evidence of metabolic-associated fatty liver disease, the old NAFLD or nonalcoholic [fatty] liver disease, because if we do it down the track [once the patient is] on the statin we're unsure if it's the statin.

Then the statin gets blamed.

Exactly right. So baseline assessment of LFTs. I always do an HbA1c when I'm doing a lipid profile because it frames the discussion around absolute cardiovascular risk. If we've got prediabetes, suddenly then the risk–benefit profile changes, so HbA1c I do. I think a thyroid function test is important in [identifying] patients with hypothyroidism. We do see elevated cholesterol levels [in these patients], and that would be an important incidental pick up. It's rarely the whole story but it's important nonetheless. And if I can get a fourth test, the other thing to consider there, Dhineli, would be in a young patient where you're understanding why they've got such elevated cardiovascular risk, they may have had an event at an early age. Lipoprotein(a), this is the evil cousin of LDL cholesterol. We're going to see more and more about that as a worthwhile test.

So you mentioned that there has been a recent estimate of one in 250 people in Australia living with familial hypercholesterolaemia and up to 90% of them are unaware of their condition. What can health professionals do to improve this awareness?

The prevalence we have is based on our best estimates. The challenge we have, Dhineli, is that probably the vast majority of people don't know they have elevated cholesterol because we don't have a really good way of routinely picking up these patients. There's been some interest in doing checks at birth in the same way we do checks for CF [cystic fibrosis] at birth on heel prick testing, that we do cholesterol in the first day of life, but that hasn't reached mainstream guidance yet, so we're still left with relatively incidental pickups of elevated cholesterol early in life.

The people that should prompt a discussion around familial hypercholesterolaemia [are] those with a total cholesterol of 7.5 [mmol/L] or more, or those with an LDL of 5 or more. And those who have got first-degree relatives [with a history of premature cardiovascular events], males less than 55, and females less than 60 or 65, depending on which guidelines you read. Those are people that you should automatically start to think, "Okay, is there something that's going on here?" And then, once you've actually got evidence of probable familial hypercholesterolaemia, and that's done using a Dutch Lipid Network Score, we can then focus and zero in a little bit more on those individuals and consider genetic testing and then cascade screening.

I've digressed a little from your question. For me, it's about encouraging perhaps the Heart Health Check as a way into this. We now have an MBS [Medicare Benefits Schedule] item for general practitioners to see patients for heart health, and then within that discussion hopefully that's going to pick up some more of these patients.

Your article also discusses some of the differences in treatment target approaches for LDL-C across the world. I was interested to see, you mentioned that the Australian guideline does not have explicit targets. Does this mean that the Australian prescribers should ignore targets from international guidelines? I always feel like targets are helpful but they should be approached with caution.

Yeah. And they're often arbitrary too, Dhineli, but it does help us get some goalposts, and patients and clinicians like goalposts. The difficulty is the current guidelines, the CVD Risk Guideline that came out last year – about how to identify patients at risk and then how to consider therapies that would be needed to reduce blood pressure and lipid levels – where the guidance fell short, and to be fair to them it wasn't within their scope and mandate, is a discussion around targets. And so, if we'd look in the guidelines for Australia we'd have to look back almost 10 years to see what was contemporary guidance.

We currently do rest on what is the most contemporary guidance, and the US guidelines from 2018, the European guidelines 2019, and there's some other sub-guidelines for certain populations that are slightly more recent than that. But we do look to those at the moment because, by and large, our patients look relatively similar to those in Europe.

A point of difference would probably be our Indigenous Australians. And so, knowing how significant the cardiovascular risk is in that population, it would be interesting if there were further studies done on explicit targets for that group, given that that's probably the group that is not addressed in the international guidelines.

Completely agree, and I think our representation of Asians in our region is not consistent in Europe and North America so you're right, there's a lot left wanting. There is hope that in the next 12 to 18 months there will be a focused consensus statement around targets. I think it will reflect the contemporary evidence, which is that patients who've got established disease should have an LDL of 1.4 or less and, for those with elevated risk, ‘primary prevention’ targets are between 2.2 and 1.8.

I have patients in front of me with a 5% absolute risk that I could reduce down to 4%. And some patients are like, "Absolutely, I want to embark on lipid lowering." I have other patients with a 20% risk that I can reduce to 14% and they say, "No, the juice isn't worth the squeeze." So it's a very patient-centred decision, and I think that's what's really important here, that when we discuss this, to try and get a sense of what this means and what we're trying to achieve.

Yeah, you're right, that patient-centred approach is essential in that decision. I think you may have actually answered my next question, which was around the different approaches to reducing LDL concentrations, but what are some of the 2- and 3-drug approaches?

We have, as I mentioned, a plethora of data supporting statins. They remain the most effective, cheap, and safe way to lower LDL cholesterol; however, there's often a need to move to other therapies for intolerance. Even beyond that, we know that statins achieve somewhere between 40 and 50% lowering of LDL cholesterol at moderate- to high-intensity doses. That is atorvastatin 40 to 80 [mg] and rosuvastatin 20 to 40 [mg]. But in patients who start with an LDL above 3.5, for example, where you want to achieve very low levels of 1.4, often you need to add in other LDL-lowering agents. And so, we really need to start considering, Dhineli, in the same way that blood pressure is a multidrug condition, so is cholesterol.

And if we want to get patients to the lowest risk, the addition of ezetimibe, additional 15 to 20% [lowering of LDL cholesterol] on top of statins, and then in patients who are sufficiently enriched to have high absolute cardiovascular risk as per the Australian [PBS] reimbursement guidelines, the addition of PCSK9 inhibitors, so evolocumab and alirocumab, which I think is now being withdrawn from the Australian market. But these agents that are injectable [provide] an additional 50% lowering on top of baseline therapy, which included ezetimibe. So really moving to those very high-risk patients.

And that conversation's important. So, you’ve got your patient admitted with an MI [myocardial infarction] in hospital and their LDL cholesterol is 3.5, saying to them, then and there, “Do you know what? We're going to start with a statin but we're going to need to have more tablets and potentially injectables.” That starts that conversation so that in 6 weeks time they don't come back to clinic with their repeat LDL at 2.5 and suddenly feel they've failed; that they actually know we could anticipate the need for this.

You touched on this group in the 3-drug approach, but I'll be honest and say that I've got very little experience with them and I haven't come across people that have used them much. The proprotein convertase subtilisin?

It's a mouthful.

Do they require specialist involvement to be prescribed? Is it prescribed in general practice more frequently than what we're aware of?

The goalposts have moved here recently so let's rehash just quickly the pharmacology. So PCSK9 proprotein, this is a proprotein that is involved in the regulation of the LDL receptor recycling, so it binds the LDL receptor inside the cell and then causes it to be degraded. Now, the theory there is that, if you could soak up PCSK9, the LDL receptor would not be degraded and would just continue to recycle to the liver surface and then keep drawing in LDL. And so, you would increase the clearance of LDL, lower the serum levels, achieve LDL targets. That's the theory with PCSK9 inhibitors. The trouble is that the interaction of the PCSK9 and LDL binding is such that it's hard to get a tablet to actually competitively interact there, and so you need to give these at the moment parenterally, subcutaneously, so evolocumab is the one that is currently reimbursed and available.

This is an agent that's given either fortnightly or monthly. There are requirements for patients to be at sufficiently high risk, such that the absolute benefit is greatest among these patients. These are expensive drugs and so we can't give them to everybody, even if we'd like to. And so, currently the PBS requirements require you to have had either more than one event over a 5-year period, you'd have polyvascular disease, diabetes, more than 60, end-organ dysfunction, a variety of other things that we know are associated with greater absolute benefit of LDL lowering.

And then, historically they've been cardiology-commenced and continued. Now recognising that primary care do the bulk of the work of managing patient's cardiovascular risk appropriately, we are now able to commence these with our GP colleagues. They can have specialist involvement via phone call or interaction with clinic letters to suggest that this patient's eligible. They can commence them. There's a requirement to phone up the authority line to get approval, but then they can be continued thereafter. And this is important because we have patients who've got unmet treatment needs that would benefit [from] PCSK9, but for a variety of reasons aren't necessarily getting them. So this is one way, hopefully, we'll overcome some inertia.

So finally, Adam, what other lipid-lowering drugs are in the pipeline and are they going to shake things up even more?

Alright, it's an exciting space. We've got further PCSK9 inhibitors coming, so we've got inclisiran, which is now TGA-approved. This is a small interfering RNA (siRNA), so if we imagine what a PCSK9 monoclonal is doing, it's currently binding a proprotein that's already in form. What an siRNA does is it actually removes the recipe book for creating the proprotein. The neat thing about that is that, because it acts at the level of the mRNA, the drug actually has activity for up to 4 months inside the cell. And so patients receive a baseline dose, a 3-month booster, and then 6-monthly thereafter. They have reductions in LDL cholesterol of between 40 and 50%, which is kind of almost like a vaccination approach to how we might consider high cholesterol management.

The exciting part of that is, from an adherence point of view, we know that taking daily tablets is a challenge. I know I struggle to get through a course of antibiotics without missing a dose, and so you think of your poor patients taking half a dozen drugs – difficult to do. This is one way perhaps we can address adherence. So that's one, that's just PCSK9.

We have other oral agents. We have bempedoic acid, which has been studied and is available overseas in the US, which is addressing the same sort of pathway as statins but has got a prodrug component to it that means that it's not active in muscles and so may well have a better side effect profile. We'll see whether that comes to Australia or not.

We have icosapent ethyl, which is a highly purified form of omega-3 fatty acids, which has got outcomes data to improve outcomes in patients with elevated triglycerides managing their cardiovascular risk.

We have then a variety of other targets. So we've got Lp(a) [lipoprotein(a)] we discussed briefly. That is a biomarker we have not historically been able to block or to reduce. We now have drugs that are capable of reducing that by up to 90%, with a similar type of approach as I mentioned for inclisiran. The list goes on, Dhineli, it's almost a renaissance in lipids. We've historically had statins and little else to talk about. Now we have 12 to 15 different compounds in phase II and later-phase clinical development that will really start to move the needle around conditions, familial chylomicronaemia syndrome and other types of lipid disorders that we just had unmet treatment needs for.

Fantastic. Well that is very exciting but that's, unfortunately, all the time we've got for this episode today. We could definitely keep talking about this, but thank you so much for joining us today, Adam.

Thanks for having me, Dhineli.

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Associate Professor Nelson's article, Managing Hypercholesterolaemia, is available on the Australian Prescriber website. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Adam has received research support from Amgen, Boehringer Ingelheim, Novartis and AstraZeneca. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber Podcast.