PCSK9 inhibitors: an alternative to statins?

Statins are the backbone of cholesterol-lowering treatment, but some of the seven million users in the UK find these don’t work well enough or aren’t well tolerated. Siobhan Chan explores how a new treatment class could be a much-needed innovation for patients at high risk of cardiovascular disease.


25 June 2018, by Siobhan Chan

Boxes of PCSK9 inhibitor drugs, Repatha and Praluent

Michael Easton was working on a building site when a nurse called his home to say he needed to come in urgently for cardiac investigations.

It came as a shock for Michael, who thought that the cholesterol-lowering drugs he had been taking for the last four decades were keeping his cholesterol levels under control and preventing coronary heart disease.

The 54-year-old from Bracknell, Berkshire, hadn’t realised how severely narrowed his arteries had become – in spite of the treatment he’d been receiving – until he was asked to come in for an assessment at Harefield Hospital, north-west London. His appointment was scheduled after his daughter received a genetic test that diagnosed her with familial hypercholesterolaemia (FH), and cascade testing revealed Michael also had the condition.

Dr Mahmoud Barbir, a consultant cardiologist at the hospital, noticed a lump on Michael’s foot which he recognised as a tendon xanthomata, which confirmed his clinical diagnosis of FH.

Shortly afterwards, Michael had a double bypass graft.

“I’m glad they caught it when they did,” says Michael, who has a family history of myocardial infarction.

A small number of people have such high cholesterol levels that statins and other treatments like ezetimibe can’t lower them to recommended levels. Others don’t tolerate statins well and soon run out of traditional treatment choices. Yet high, untreated non-HDL cholesterol levels put a patient at increased risk of heart attack, stroke and peripheral arterial disease.

So what can be done for this group of patients? Until recently, there weren’t many additional treatment options, but a new type of drug called a PCSK9 inhibitor is offering fresh hope.

Front of Harefield Hospital

Harefield Hospital is home to one of the few PCSK9 inhibitor clinics in the country

A significant breakthrough in cholesterol trials

PCSK9 inhibitors are a modern class of cholesterol-lowering drugs that are showing great promise in bringing down non-HDL levels in certain groups of high-risk patients.

Developed over the last decade, they work by blocking a protein called PCSK9, which has a role in moderating cholesterol levels in the blood (see: How PCSK9 inhibitors work).

In June 2016, NICE recommended two PCSK9 inhibitor drugs – Repatha (evolocumab)1 and Praluent (alirocumab)2 for treating certain patients with primary hypercholesterolaemia or mixed dyslipidaemia who can’t tolerate statins or who have reached the maximum dose (see: What NICE says).

We tell patients their results – ‘your cholesterol levels have dropped by 70%’ - and they can’t believe it!

Emma Neves, FH specialist nurse

Scientists who worked on a recent study of evolocumab described it as “probably the most important trial result of a cholesterol-lowering drug in over 20 years3”. Results showed a 59% drop in cholesterol levels compared to placebo and a 15% lower risk of cardiovascular events (see: The FOURIER trial).

Emma Neves is a familial hypercholesterolaemia (FH) specialist nurse at Harefield Hospital, where she trains patients to self-administer PCSK9 inhibitor drugs.

“In our patients, we’ve seen a few side-effects, but overall people seem to tolerate PCSK9 inhibitors well,” she says.

Ms Neves says her patients’ cholesterol levels will typically drop significantly after around four weeks of treatment, after which they plateau, and the effect is even more marked when they are taking them alongside statins.

“Patients often don’t feel any different as a result of taking PCSK9s. Then we tell them their results – ‘your LDL [cholesterol] levels have dropped by 70%’ - and they can’t believe it!” she says.

The team who set up the PCSK9 inhibitor service at Harefield Hospital

The team who set up the PCSK9 inhibitor clinic, L-R: Jane Breen, Dr Mahmoud Barbir, and Emma Neves

How do PCSK9 inhibitors work?

PCSK9 inhibitors act on the PCSK9 protein.

This protein breaks down cholesterol receptors in liver cells that are responsible for removing LDL cholesterol from a person’s blood. So the more PCSK9 protein a person produces, the more their cholesterol receptors degrade, and the more cholesterol remains in their blood.

PCSK9 inhibitors target the PCSK9 protein, preventing it from breaking down the receptors, which in turn allows these to continue to reduce blood cholesterol.

 

When statins aren’t enough

Today, around seven million people in the UK take statins4, which have become the mainstay of cholesterol-lowering treatment since their introduction in the 1980s. For the vast majority of people, they are safe, effective and well-tolerated.

But some patients don’t tolerate them as well. Some estimates suggest less than 5% of statin users experience some form of clinical intolerance [1], defined by NICE as significant adverse effects that pose an unacceptable risk to the patient or that may affect adherence. Nevertheless, this could equate to as many as 350,000 statin users.

Some patients can be changed onto a lower dose or a lower-intensity statin group5, but many end up stopping taking their drugs as a result of their side-effects.

Other patients find that despite taking the maximum-tolerated dose, they continue to have high cholesterol levels. This is particularly relevant for the 1 in 250 people with familial hypercholesterolaemia (FH), who tend to have especially high levels of cholesterol from birth.

For some of these patients, PCSK9 inhibitors offer an exciting new treatment option.

The FOURIER trial

The recent results of the FOURIER study into 27,000 patients found that evolocumab, in combination with a statin, lowered LDL-cholesterol by 59% in comparison to a placebo, and reduced the risk of cardiovascular events by 15%6

The research attracted a lot of UK media attention, while the scientists behind the UK arm of the study described it as “probably the most important trial result of a cholesterol-lowering drug in over 20 years”3.

At the time, BHF Medical Director Professor Sir Nilesh Samani described the trial as “a significant advance”. However, he noted that the trial was stopped early after only 2.2 years of average follow-up and it was therefore “difficult to be certain about the actual extent of the longer-term benefit, including the impact on dying from heart disease, as well as longer-term safety," he added (see: The BHF view on PCSK9 inhibitors).

Bringing down cholesterol levels

PCSK9 inhibitors are still a relatively new treatment and Harefield is one of fewer than a dozen clinics in the UK offering the therapy. Patients travel from up to 150 miles away for the treatment.

A team of FH specialist nurses set up the monthly PCSK9 inhibitor clinic with Dr Barbir in September 2016. So far, they have treated around 60 patients.

Referred patients’ eligibility is assessed against the trust’s PCSK9 inhibitor guideline and approved by Dr Barbir. Around 50-60% of the patients seen in Harefield’s clinic are taking PCSK9 inhibitors alone with no statins, usually because they cannot tolerate them, or can only tolerate small doses. The rest remain on statin therapy as well, as this upregulates the effect of PCSK9 inhibitors.

 

What NICE says

NICE’s recommendation restricts use of PCSK9 inhibitors evolocumab and alirocumab to certain groups of patients.

For primary prevention, the drugs can only be offered to patients with familial hypercholesterolaemia and an LDL-C concentration persistently above 5.0mmol/l.

For secondary prevention – including those with a history of a heart event or coronary heart disease, ischaemic stroke, or peripheral arterial disease – patients at high risk of further CVD must have LDL-C concentrations persistently above 4.0mmol/L.

And anyone at very high risk – with recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (i.e. polyvascular disease) – this threshold is persistently above 3.5mmol/L.

These restrictions are partly due to the expense. Evolocumab and alirocumab both cost around £4,400 per patient each year, although NICE has said they were only able to recommend them because of discounts from the manufacturer. The discounted cost is confidential for commercial reasons.

NICE says evolocumab and alirocumab have acceptable safety profiles similar to control groups taking placebo or ezetimibe.

Apheresis

In the past, many patients who could not rely solely on statins were treated with lipoprotein apheresis, where LDL cholesterol is filtered out of the blood using a dialysis system. “Some of our patients have to attend for three hours every fortnight, and it’s an invasive treatment,” says Dr Barbir.

With PCSK9 inhibitors, around 15% of patients who begin treatment no longer need apheresis7.

Indeed, NICE’s recommendation of evolocumab referenced the need for an alternative to lipoprotein apheresis, as it is “costly and onerous for the patient, but also difficult to access because only a few centres offer it.”

“Although PCSK9 inhibitor drugs are expensive, it could reduce the amount of apheresis needed, which costs around £1,200 a session – so we hope the costs will balance out overall,” Dr Barbir says.

Steph White, a healthcare professional who has been benefitting from PCSK9 inhibitor treatment

Steph White has benefitted from taking PCSK9 inhibitors alongside other treatments

Steph White is a healthcare assistant at the hospital, but has also become a patient there too. She now also benefits from needing less apheresis because of PCSK9 inhibitors.

She was diagnosed with FH 15 years ago, as her uncontrolled high cholesterol was causing angina. She had bypass surgery and stents fitted, and was receiving apheresis at the trust when she was assessed for eligibility to receive PCSK9 inhibitors.

Steph has been taking the drug for more than nine months, and her cholesterol is now better controlled. “I’m still on statins and I am on apheresis too, but not as much – I used to have seven litres of blood treated and now I have five,” she says. “I’m lucky it’s worked out for me – it’s a good outcome.”

Several months after his surgery, Michael was referred to the PCSK9 clinic to begin treatment, and the BHF was invited to sit in on Michael’s introduction session. In these appointments, patients are told about the drug and how it works, shown how to administer it via an injection pen, and monitored for a short period.

Michael found using the injection pen fairly simple to use, and hopes the treatments help to control his cholesterol levels.

FH nurse Emma Neves explaining PCSK9 inhibitors to patient

FH nurse Emma Neves talks Michael through using PCSK9 inhibitors for the first time

No direct statin replacement

PCSK9 inhibitors – as a relatively new and expensive treatment option – are by no means a direct replacement for statins for most people. NICE’s criteria currently restrict PCSK9 inhibitor treatment to patients with pre-existing CVD or FH who have already tried the maximum tolerated lipid-lowering therapy, or can’t tolerate statins (see: What NICE says).

Clinical commissioning groups (CCGs) also need to approve their use. At Harefield, the Trust’s supplementary guideline has been agreed with North West London CCG, which acts as a ‘host’ CCG for patients who are referred from outside this area.

The trust’s internal PCSK9 inhibitor supplementary guideline echoes NICE’s and only approves PCSK9 for patients who have FH, are intolerant to statins, with an LDL persistently more than 3.5mmol; or who don’t have FH but do have established cardiovascular disease and have an LDL over 5mmol.

And PCSK9 inhibitors have only been available for use in the last five years. More research is needed to assess their long-term effects.

Nevertheless, there has been a greater focus from researchers on PCSK9 inhibitors as a potential for lowering LDL cholesterol in patients at high risk of a heart event.

Carol Hayes is the lead pharmacist in cardiology at Harefield and helped to develop its PCSK9 inhibitor guideline. She believes that PCSK9 inhibitor use will increase as awareness of the drug grows.

She also hopes NICE relaxes its criteria for treatment in future: “Patients who are at high risk of a heart event but who haven’t already had one aren’t eligible, unless they have a confirmed diagnosis of FH. We’d like to be able to start patients on these drugs earlier.”

Promising new drug

Michael Easton, patient starting PCSK9 inhibitor treatment

Michael Easton hopes PCSK9 inhibitors will help to control his cholesterol levels

As well as bringing down his cholesterol levels, Michael is hopeful that PCSK9 inhibitors could one day benefit his family too, some of whom have also been identified as having FH.

“My two daughters have it too – my older daughter’s cholesterol levels are controlled now, but my younger daughter might need to come in for PCSK9 treatment,” he says.

Ms Neves adds: “The good thing about knowing Michael’s family members have FH is that we can treat them, and get it under control, and prevent them needing more invasive treatments like surgery.”

There have been few developments in cholesterol-lowering treatments since statins were introduced in the 1980s, but the team at Harefield is positive about the fresh hope this brings to patients. 

“Statins work well and don’t cause problems for most people, but life’s been miserable for the few patients who experience terrible side-effects,” says Ms Neves.

“For the patients who don’t see their cholesterol come down on statins, it is exciting to be able to offer them PCSK9 inhibitors. It feels nice to finally be able to do something for them,” she says.

 

The BHF view on PCSK9 inhibitors

“Coronary heart disease is one of the  biggest killers in the UK and worldwide and ‘bad’ LDL-cholesterol is a major cause.

“While statins have had a significant impact in reducing the risk of heart disease for millions of people, they are not tolerated by everyone and only reduce cholesterol by a certain amount.

“A promising new approach is blocking the action of PCSK9, a molecule which reduces the breakdown of LDL-cholesterol in the liver. Creating new treatments which use this approach could prove life-saving for patients with high cholesterol and those who can’t tolerate statins."

 – Professor Sir Nilesh Samani, BHF Medical Director

Images: Timothy Cochrane Photography

References

1. NICE. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia Technology appraisal guidance, 2016 nice.org.uk/guidance/ta394 https://www.nice.org.uk/guidance/ta394/resources/evolocumab-for-treating-primary-hypercholesterolaemia-and-mixed-dyslipidaemia-pdf-82602910172869

2. NICE. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia Technology appraisal guidance, 2016 nice.org.uk/guidance/ta393  https://www.nice.org.uk/guidance/ta393/resources/alirocumab-for-treating-primary-hypercholesterolaemia-and-mixed-dyslipidaemia-pdf-82602908493253

3. BBC News 2017, 'Huge advance' in fighting world's biggest killer http://www.bbc.co.uk/news/health-39305640

4. Heart UK, Key Facts and Figures https://heartuk.org.uk/press/press-kit/key-facts-figures

5. NICE Pathway: Cardiovascular disease prevention overview, 2018. https://pathways.nice.org.uk/pathways/cardiovascular-disease-prevention

6. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) https://www.nejm.org/doi/full/10.1056/NEJMoa1615664

7. Moriarty et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. European Heart Journal, 2016, 37(48), 3588-3595

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