The cholesterol-lowering juggernaut that is trundling towards you

By Jerome Burne

Sometime next year you may receive an invitation from your GP to join a large-scale clinical trial of an exciting, new (relatively) cholesterol-lowering drug called Inclisiran that “could” save 30,000 lives in the UK over the next ten years.

Not only is it 50% more effective at reducing your cholesterol levels than the most powerful statins but, says the press release, because treatment involves just two injections a year, it is much more convenient than the fuss of swallowing a daily statin. Inclisiran is being described as a ‘fire and forget’ treatment, a vaccination against heart disease.  Mmmmm well, maybe.

As well as being more convenient, however, Inclisirin could provide an alarming glimpse of the new ‘ready for business’ Britain, complete with a bonfire of regulations.

So before signing up there are some things about this drug, a type known as a PCSk9 inhibitor, that are worth being aware of. Things which the recent press reports about the exciting new trial didn’t make entirely clear.

Does low cholesterol really protect your heart?

*All the dramatic claims assume that the lower your cholesterol, the lower your risk of heart disease. It’s a common assumption but there’s good evidence to challenge it, such as the results of a trial published just before Christmas

*The first generation of injectable PCSK9-inhibitors, which are very similar the new one, never convincingly demonstrated they made anyone live longer, despite their impressive cholesterol-lowering ability. Inclisiran has never been shown to do this either

*There are known short term side-effects with this class of drug but the long-term effects of disabling PCSK9, which is used for many other essential processes in the body, are unknown.

*Even so Inclisiran ‘prescription creep’ is already underway. The first PCSK9 inhibitors, such as one called Rapatha, were licenced for patients with very high cholesterol and a high heart attack risk. The latest announcement indicates that Inclisiran could soon be far more widely available.

But as well as known unknowns, the way the new trial is being organised suggests that it is prioritising profits over patients. It seems to have been born out of the flames from some secret bonfire of tiresome red-tape and regulations that demanded clinical trials showing safety and effectiveness are run before making a drug available to large numbers of patients.

Wild optimism about benefits

The new trial that has just been announced will involve 40,000 patients next year with many more expected to be using the drug soon after that. But all that is known for certain about Inclisiran at the moment is that it can halve cholesterol levels in patients already on high dose statins.

Yet this was enough for a senior NHS spokesperson to make various wildly optimistic claims about the benefits of the drug would bring when announcing the trial at the beginning of January. Giving the drug to 300,000 patients a year would prevent 55,000 heart attacks and strokes and “save” 30,000 lives over the next ten years.

These are very high numbers for a type of drug that is currently only recommended for use on a fairly few high-risk patients. It also shows remarkable optimism about a drug that has never been shown to cut the number of deaths. The purpose of the trial is to get the evidence to support the dramatic claims.

There was something odd going on here. It was almost as if the results were a foregone conclusion. To start treating that many patients with Inclisiran it would have to be approved of by EMA (European Medicine’s Agency) but neither the EMA nor the American FDA has done this yet. However, the press release confidently asserted that ‘it is expected to be filed for approval as a preventative add-on treatment to statins.’

Regulators in bed with the (supposedly) regulated

Another regulatory body that is supposed to be involved before releasing drugs onto the market is NICE, which decides if it is value for money. This is a major issue for Inclisiran because it is very expensive – certainly compared to statins.

A year’s supply has been costed at around £4,000 pounds as compared with £20 for statins. What’s more, the data on other PCSK9 inhibitors suggests that as many as 70 patients have to take the drug to prevent one heart attack or stroke, so the cost of preventing each one is high – an estimated at £600,000. The press release doesn’t see this as a problem either, saying that: ‘It will be put through the NICE approval programme at the earliest possible opportunity.’

Clues to the basis of this confidence that regulatory approval won’t be a problem can be found in the make-up of the consortium running the trial. Rather than being organised by an individual drug company or a university, it involves key NHS bodies in a deal with the manufacturer Novartis.

All the major players in the UK health system are signed up: Department of Health and Social Care for England, NHS England, National Institute for Health Research and Oxford University. This arrangement is described as a “world first” which includes a ‘commercial’ arrangement between NHS England and Novartis to make Inclisiran ‘widely available to patients in the UK by next year’. Again, no worries there will be any holdups getting approval.

Buccaneers launch first and ask questions afterwards

This may be a ‘world first’ but it seems a very alarming one. It bears repeating that this is all apparently done and dusted before evidence that is supposed to support the release of drugs has even begun to be collected.

Could it be that what we are seeing here are signs of the new buccaneering, ready-to-trade-with-anyone Britain? There have been worries that this could depend on the UK accepting less stringent regulations on food and agricultural products. The arrival of this new drug company/NHS consortium suggests the trade-off is already be underway with pharmaceuticals.

 At the launch the UK was described a ‘large scale testbed for innovative medicines.’ It is possibly also a sign of the times that this took place, not in London, but at an investment conference organised annually by JP Morgan in San Francisco.

Health Secretary Matt Hancock enthusiastically backed it up declaring that the deal shows that: ‘the UK continues to be the world leading destination for revolutionary health care….at the centre of a dynamic life sciences ecosystem while delivering great health care.’

 A dynamic drug production ecosystem, where the pressure for favourable results is enormous, doesn’t necessarily lead to safe and effective health care for patients, especially if independent regulation and assessment, never that rigorous, is magicked away.

The drug that takes the brake off

An awful lot is riding on the assumption that the lower you go with cholesterol the better the results will be and that long-term use of a drug as powerful as the PCSK9-inhibitors won’t cause long term problems. The drug silences the gene, which blocks the RNA, which carries the DNA instructions for making PCSK9.

This disables a natural brake on the system that the liver uses to suck cholesterol out of the blood stream, making the amount in your blood plummet to levels way below what is normally achieved by statins.

 ‘What complicates matters is that PSK9 is involved in various other important processes around the body,’ says GP and critic of lowering cholesterol with statins Dr Malcolm Kendrick. ‘It’s found in the brain, the guts, the immune system and the metabolic system, which controls glucose and insulin and the way fat is laid down in the body. It plays a part in recovering from both sepsis (blood poisoning) and viral infections.

‘We already know that lowering it is linked with short-term effects such as muscle pain, swelling of nasal passages, headache, back pain, diarrhoea, fatigue and hypertension, but we have no idea about what switching off  PCSK9 could do when you have to take the drug for life.’ A proper assessment of the risks is vital. There are signs it could raise the risk of diabetes, for instance.

No cholesterol, no sex hormones or brain cells

Cholesterol, of course, is also involved in a range of vital functions such as providing a building block for sex hormones, turning sunlight into vitamin D, building cell walls (notably in the brain) and as part of the immune system. Remove all your cholesterol and you would die immediately.

So with all these factors in mind, it was quite a coincidence that just three weeks before the wave of publicity about the new Inclisiran trial, a very solid research paper appeared which found that for patients being treated with statins, lower LDL cholesterol didn’t automatically protect you, in fact having  a higher level did. Not surprisingly it received no publicity.

However, it was picked up by the indefatigable Dr Kendrick and nutritionist Dr Zoe Harcombe who is an expert at putting the complexities and jargon of medical research into understandable language.

The paper ticked all the reliability boxes. It was published in BMJ Open in December, the research was done at the famous Mayo clinic in the US, and tracked over 23,000 people for a decade, between August 1996 and September 2005, who had been hospitalised for a heart attack or acute heart failure

Live longer with high cholesterol

 ‘These were a super, exceptionally high-risk population,’ writes Dr Kendrick ‘with a super exceptionally high-risk of having another serious event.  The exact group where statins are purported to do the most good – through the specific action of lowering LDL cholesterol levels. What they found, however, is that those with higher LDL levels lived the longest. Full stop, exclamation mark.’

In her account of the research, which you should read if you want more of the biological and technical details,  Dr Harcombe pointed out that if the media reports of the research had followed the usual format for dealing with statin research, headlines would have read something like: ‘High cholesterol levels cut risk of heart attack death by 24%!’ Well that didn’t happen. The study also found that those with the higher LDL cholesterol were more likely to survive other serious conditions such as cancer, kidney disease and diabetes

The study was also directly relevant to Inclisiran in another way. It did find a benefit to taking statins but not by lowering cholesterol. Dr Kendrick noticed that patients getting these drugs cut their risk of developing cardiovascular disease and also of dying from any cause (rather from heart disease specifically). He suggested to the authors that this could because statins have other effects beside lowering cholesterol. They agreed.

This is not a new idea. Three years ago, for instance, writing in the BMJ, Professor Patricia McGettigan, of the William Harvey Research Institute at Barts pointed out that various compounds, such as oestrogen and the vitamin niacin, all lower cholesterol – with zero impact on life expectancy.

One example of many, which was covered in the press at the time, found that: ‘In free-living populations without pre-existing disease, higher LDL-cholesterol predicts a lower risk of death in those over 60, and (with more limited evidence) does not predict an increased risk of death from heart disease or stroke.

I would love to be reassured that this ‘trial’ is not a cross between a juggernaut and a Trojan Horse, designed to make resistance to having your cholesterol lowered futile.

Jerome Burne

Jerome Burne

Jerome Burne is the editor of HealthInsightUK. He is an award-winning journalist who has been specialising in medicine and health for the last 10 years and now works mainly for the Daily Mail. His most recent book “The Hybrid Diet” was written with nutritionist Patrick Holford, published 2018. Award: 2015: Finalist for 'Blogger of the Year' Medical Journalists' Association.

7 Comments

  • and they want to “name” Inclisiran a vaccine.
    The implication is that through convention and some legislation nobody can argue against vaccinnes.
    You therefore cannot reject or fail to take a vaccine.
    That is absolutely horrendous.

    • Editorial

      Don’t think it is used as a medical description for the drug but it is certainly marketing speak, very likely with intention of creating the magic shield against criticism that vaccines have now outrageously been granted. Sure Merck would love to have Inclisiran classed in that way.

  • ” lower HDL cholesterol didn’t automatically protect you”

    I am guessing this is a typo and you meant to say LDL?

  • Is there an antidote to the injection, or will side effects last for 6 months? At least with statins, one can simply stop taking them.

    • Editorial

      My understanding is that once you’ve had the injection effects will continue. Drug companies rarely keen on providing antidotes as involves suggesting things can go wrong

  • Thank you for this information at least some of us will have been forewarned!

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