PCSK9 inhibitors: How low can we and should we go?

Thursday, 2 May 2019

Ischaemic heart disease remains the leading cause of death in Australia, with lipids one of the modifiable factors to help mitigate risk, particularly in patients at high risk of cardiovascular events. To discuss the new kid on the block – PCSK9 inhibitors – and the role they will play in therapy, the limbic spoke with Professor Richard O’Brien, Clinical Dean of Medicine at the University of Melbourne and Consultant Endocrinologist at Austin Health and Reservoir Private Hosptial, Melbourne.

“While lipid-lowering therapies like statins and ezetimibe have done a good job at lowering lipids in patients for years, there remains some patients who cannot lower their LDL-c enough on these therapies and remain at high risk for subsequent cardiovascular events.1 It is in these patients that the PCSK9 inhibitors will be of great help as we strive to get LDL-c as low as we can,” notes Professor O’Brien.

For years, despite well-documented evidence that statins and ezetimibe lower LDL-c and reduce CV events in patients with CVD or at risk of developing it, some patients continue to experience CV events on therapy. For decades, there has been little to offer patients beyond these therapies.1 From as far back as 1999, the National Health and Nutrition Examination Surveys (NHANES) study reported that 65.1% of patients with established CV disease did not meet the then conservative target of >2.6 mmol/L.

In 2015, the prevalence of hypercholesterolaemia reported in studies continued to persist above 64%.3 Locally, in the Australian REACH Registry, a majority of patients continued to have hypercholesterolaemia following a primary CV event (61–80% of patients).4 Regretably, there are many barriers to achieving optimal lipid control, with side effects of statin therapy only one of them. Patient understanding and beliefs about treatment and reluctance to take additional medications may affect adherence to guideline recommendations.5-7

Reviews have noted limitations to the use of statins. Specific prevalence data on the rate of treatment in the Australian population is poor, with a 2009 study finding less than half of patients with existing chronic heart disease, stroke or high risk patients were receiving any lipid lowering therapy.8 Drug intolerance is cited as a major challenge, with muscular symptoms associated with statin use reported in around 10% of patients.9

“For many patients, we can lower LDL-c to the levels stated in the guidelines for secondary prevention. However, there are always some patients who cannot even get to target by going all the way with statin and add-on therapies, like those with familial hypercholesterolaemia. For others, the side effects they experience with statin therapy precludes maximal doses to achieve target levels. In these cases we have had to compromise between the patient experience and the risk of subsequent events. Now we have the PCSK9 inhibitors on the scene we might be able to get more patients to target, and beyond,” Professor O’Brien said.

Lowering the threshold meant looking at LDL-c in a different way

PCSK9 plays a role in the metabolism of LDL-c in the liver. PSCK9 (proprotein convertin subtilisin/kexin type 9) is secreted from hepatocytes and binds to the LDL receptor on the cell surface, preventing recycling of the receptor and therefore minimising how much LDL can be degraded by the hepatocyte.10 When the interaction between PCSK9 and the LDL receptor is prevented by an anti-PCSK9 monoclonal antibody, more LDL receptors stay at the cell surface and can degrade more LDL, which reduces the serum LDL concentration.10

Backing up the biochemisty, studies examining the CV risk of individuals carrying a mutation in their PCSK9 genes have found reduced risk compared with non-carriers. The Dallas Heart Study reported a 47% reduction in white carriers compared with non-carriers.11,12 In the Myocardial Infarction Genetics Consortium, individuals carrying a mutation had a 60% reduction in the risk of myocardial infarction compared with non-carriers.13

How low can we and should we go?

The target LDL-c level varies among guidelines, but Professor O’Brien said it seems that the lower we go, the better.14 He noted “…studies like JUPITER where LDL-c below 1.3 mmol/L was achieved and conferred a lower risk of myocardial infarction, stroke, arterial revascularisation, unstable angina or death from CV causes than patients with otherwise normal LDL-c (2.8 mmol/L).14 While we struggle to get some patients to target with existing statin and ezetimibe therapy, what PCSK9 inhibitors will offer is for lowering LDL-c as much as we can in patients not at target, and perhaps those very high risk patients as low as we can go,”14 he said.

The current Australian guidelines recommend a primary prevention target of <2.0 mmol/L in high-risk individuals to prevent a CV event, such as coronary heart disease, stroke and other vascular diseases.15 For patients who have had a CV event, the level is reduced to <1.8 mmol/L).16 But Professor O’Brien said he will not be surprised to see a revision of this criteria to be even lower in the near future given the availability of new therapies like the PCSK9 inhibitors that may help patients lower LDL-c further than ever before.11

When and where should we consider PSCK9 inhibitors?

“PCSK9 inhibitors are a great addition to the treatment options available to lower cholesterol in patients at high risk of CV events. While they are not a first-line therapy, I can see them playing an important role in lowering LDL-c as much as we can in patients at high risk of CV events, particularly in patients not able to tolerate high-dose statins and in special populations such as those at risk of diabetes, which is an additional risk factor for CV events” notes Professor O’Brien. “Already we are thinking more broadly than familial hypercholesterolaemia to primary hypercholesterolaemia as a whole.”17,18

The new American College of Cardiology/American Heart Association Task Force guideline on the management of blood cholesterol released late 2018 now includes recommendations for when to consider PCSK9 inhibitors. The key recommendations from the guideline include:19

  • In patients with clinical atherosclerotic CV disease, reduce LDL-c with a maximally tolerated stating to reduce levels by ³50%
  • In very high-risk patients, continue to use an LDL-c threshold of 1.8 mmol/L and consider the addition of non-statin therapy (e.g. ezetimibe)
    • In patients whose LDL-c remains ³8 mmol/L on maximally tolerated statin and ezetimibe therapy, adding a PSCK9 inhibitor is reasonable

There is considerable evidence for the use of PCSK9 inhibitors in a wide range of Phase I-III trials.1311 For the molecule alirocumab, the extensive ODYSSEY trials have investigated its use in a variety of patient groups and combinations (see Box 1).11

Phase III ODDYSEY trials11

LONG TERM 72-week study in patients with heFH with or without CHD or risk factors, on LLT vs placebo
FH I & II 24-week studies in patients with heFH on LLT
High FH 24-week study in patients with heFH and LDL-c >4.1 mmol/L
COMBO I & II 24-week studies in patients with heFH on LLT
OPTIONS I & II 24-week studies in patients with prior CVD and LDL-c >1.8 mmol/L or risk factors and LDL-c >2.0 mmol/L + LLT vs LLT alone
ALTERNATIVE 24-week study in patients with primary heFH at moderate, high or very-high risk and intolerant to statins vs LLT
CHOICE I & II 24-week studies in patients not at LDL-c target based on individual level of CVD risk
OUTCOMES CV outcomes study in patients with prior ACS

ACS: acute coronary syndrome; CVD: cardiovascular disease; heFH: heterozygous familial hypercholesterolaemia; LLT: lipid-lowering therapy.

Looking at pooled analyses of the studies, the use of PCSK9 inhibitors in specific patients groups, like pre-diabetic patients and those with prior acute coronary syndromes has also been investigated, and pose two interesting populations for their use, says Professor O’Brien.

“From the ODDYSEY trials, they’ve pooled the results for pre-diabetic patients and found alirocumab reduced LDL-c up to 61.8% (range 44.0-61.8%) after six months on therapy. Over a mean follow-up of 104 weeks, the reduction in LDL-c was sustained with no effect on glycaemia and a safety profile similar to the control group.17 This is good news to have the ability to lower LDL-c while not worrying about introducing additional risk factors such as diabetes in some patients,17 he explained. “And the other group of patients I tend to worry about are those with prior CV events, like ACS, who are not at target despite high-dose lipid-lowering therapy.18

Professor O’Brien urges his colleagues to check the lipid-lowering approach taken is for the patient’s individual level of CVD risk. “Also, I find talking patients through the logic, reinforces why they need to get to target and take their treatment. I’ve got patients right now that absolutely get it, and don’t want to risk another CV event and are even willing to consider paying for treatment to reduce their risk. Making sure patients are part of the decision process is very important, and these days I tend to put all options on the table to make sure we can get LDL-c as low as we can go.”


This article was sponsored by Sanofi, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Sanofi


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