Over the past 50 years, great strides have been made in elucidating the role of atherogenic lipoproteins in atherosclerosis. A vast amount of evidence now illustrates that LDL cholesterol (LDL-C) plays a pivotal role in elevating cardiovascular risk and that lowering levels are beneficial. At the Amgen sponsored breakfast symposium at the CSANZ ASM 2019 chaired by Professor Gerald Watts from Royal Perth Hospital, Professor Stephen Nicholls from Monash Health in Melbourne and Associate Professor Karam Kostner, Director of Cardiology at the Mater Hospital in Brisbane, took delegates through the evidence to paint a compelling picture of why it’s crucial for clinicians to identify and treat all patients with elevated LDL-C. 

The rationale for LDL reduction 

“We have data from several population studies throughout the world that show a linear relationship between atherogenic levels of cholesterol and cardiovascular risk¹. We’ve also seen several genetic studies emerge showing that genetic polymorphisms and monogenic disorders are associated with elevated levels of LDL-C that similarly associates with cardiovascular risk²,” Professor Nicholls told delegates attending the symposium.

“Genetics very much reinforces that mutations associated with high levels of LDL-C are associated with high levels of cardiovascular risk² and in a similar notion mutations or polymorphisms that associate with lower levels of LDL-C appear to associate with relative protection,” he added. 

According to Prof. Nicholls, the Dallas Heart Study,³ which showed moderate lifelong reductions in the plasma level of LDL-C was associated with a substantial reduction in the incidence of coronary events, was a seminal observation in the story of PCSK9 and its role in lipid homeostasis, and the eventual development of therapeutics to inhibit the pathway.

“[the study] demonstrated that not only having less PCSK9 was associated with having lower levels of LDL-C but the risk of having a cardiovascular event was substantially lower and to a much greater magnitude than we would have predicted,” Prof Nicholls told the audience. 

“Again, it reflects that lifelong exposure to lower levels of LDL-C translate into much greater cardiovascular protection from events and reinforces the concept that our ability to intervene as early as possible in the life course in the setting of hypercholesterolemia, in terms of trying to lower those levels, has the potential to have a greater effect.” 

LDL-cholesterol – how low should we go?

Over the past three decades many randomised controlled trials have shown that statins consistently lower cardiovascular events and the relationship between the degree of LDL-C lowering that is achieved and cardiovascular protection is linear. ^{4, 5}

 “Not surprisingly, the greater degree of benefit is observed in patients in the secondary prevention setting so not only is LDL lowering important but the degree of absolute benefit is proportional to the baseline level of absolute risk… this can also be seen in imaging studies⁶,” Prof. Nicholls said. 

“We know that familial hypercholesterolemia (FH) is a highly preventable form of premature cardiovascular disease that causes problems for all of us in preventive cardiology throughout the world… thankfully we finally have therapeutics that can have some impact in terms of outcomes for these individuals,” Prof. Nicholls told the audience.

Data⁷ showed that if FH patients were followed for a reasonable length of time, such as over 10 years in the study by Vermissen et al.,⁷ lipid lowering therapy had a favourable impact in terms of cardiovascular outcomes.

“Now as good as the statins have been we know there is residual risk,^8-13 the best relative risk reduction that we have observed in any of the placebo controlled statin trials was 45%, so it tells us that as good as lipid lowering is, in the context of those clinical trials more than 50% of those clinical events that were going to occur will continue to occur,” Prof. Nicholls noted, “it really suggests to us that we need to find additional strategies above and beyond simply writing up a dose for a statin to achieve more effective reductions in CV risk.”

For example, an imaging study¹⁴ identified statin “hypo-responders” who had no greater than 15% lowering of cholesterol and were at risk of disease progression.

“It really goes against the previous American Heart Association guidelines of a “fire and forget” strategy of just simply writing a dose of statin and then not checking LDL-C, because a number of those patients won’t achieve sufficient lowering and will require additional lipid lowering interventions,” he said. 

He added: “We know that if you achieve an LDL cholesterol less than 1.8 mmol/L nearly one third of patients will not demonstrate disease regression, they will continue to progress despite having an LDL cholesterol that we think is OK. And when you look at the predictors of who those individuals are, they have diabetes, their BP is high, their HDL is lower and their apolipoprotein B, a measure of the number of LDL particles in circulation, is high.” 

“There are two take home messages: one is if you have additional risk factors you will still progress and you may need more aggressive lipid lowering. And if your apolipoprotein B is high you have too many LDL particles, and so at a given level of LDL cholesterol your LDL is still too high… it suggests that there will be many individuals who will require additional lipid lowering above and beyond statins.” 

Prof. Nicholls noted that the results of the IMPROVE- IT trial¹⁵ showed that adding ezetimibe to a statin lowered LDL-C further and resulted in fewer cardiovascular events.

“The benefits are modest but they are there,” he told delegates. 

“The PCSK9 inhibitor era has done that again and what it really has allowed us to do is to extend the relationship between LDL cholesterol levels and CV risk essentially down to zero. Post hoc data from the FOURIER¹⁶ trial showed the relationship was linear all the way down it didn’t matter how far you got. The lower you go the better you did and so it does really reinforce that in high risk patients we have the opportunity to derive substantial benefit from aggressive combination lipid lowering therapy,” he concluded.  

What is familial hypercholesterolaemia?

Associate Professor Karam Kostner, Director of Cardiology at the Mater Hospital in Brisbane, told symposium delegates that FH was an autosomal dominant inherited disorder of genes controlling LDL-C metabolism, mostly of the LDL receptor, apolipoprotein B and PCSK9.

Of the two main variants of FH, heterozygous was the most important because it was the most common, Associate Professor Kostner said.

“It affects 1 per 200-500 population in Australia… people with this form of FH have ~50% LDL receptor activity, and that’s important when we talk about treatment. They have very high LDL cholesterol that is usually above 5mmol/L and they develop coronary heart disease in their 40s or 50s depending on other risk factors,” he explained.

The less common homozygous variant was about 1 in 1 million and patients typically had two mutant alleles, very low LDLR activity, extremely high LDL-C levels and developed coronary heart disease in childhood.

According to Associate Professor Kostner, one of the biggest problems with FH is that it is underdiagnosed and undertreated¹⁷.

“If you look at Australia for example less than 5 per cent of FH patients are diagnosed and that means we cannot treat them,” he said, adding that other countries with screening programmes such as the Netherlands and Norway tended to do better.

How to diagnose FH

Associate Professor Kostner said the validated Dutch Lipid Clinic Network Score¹⁸ should be used to assess family history, clinical history, physical examination and biochemical results. Patients are scored based on these findings; a score of between 6 and 8 is probable FH and a score of over 8 is definite FH.

“The clinical management of FH is quite simple, and so it is surprising that we are not doing better in this area, because all you need to do is lower LDL cholesterol to the lowest possible levels, which induces regression of atherosclerotic lesions, prevents their progression and prevents CVD events. We also treat other risk factors and cascade screening is recommended for affected family members,” he told the audience.

Associate Professor Kostner noted that evolocumab (Repatha), the only PCSK9 inhibitor currently reimbursed on the PBS¹⁹ in Australia, is a treatment option for patients with genetic dyslipidaemia such as FH who still had high levels of LDL-C despite being on optimum statin therapy and ezetimibe for three months along with dietary advice and exercise.

“Patients need to have to have a diagnosis of heterozygous FH with the Dutch lipid score of more than 6, or a score of more than 7 in homozygous FH or a positive genetic test,” Associate Professor Kostner explained. “There is a LDL threshold for primary prevention it has to be more than 5 mmol/L and in secondary prevention LDL has to be more than 3.3 mmol/L but it is very important to point out that patients have to be on maximised statin therapy for more than 3 months or they have to be proven statin intolerant or statins are contraindicated and they have to be on ezetimibe for 3 months with dietary therapy and exercise,” he added. 

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19. PBS schedule for evolocumab (Repatha) Link: https://www.pbs.gov.au/pbs/search?term=repatha&analyse=false&search-type=medicines