Cholesterol is innocent. OK. Real cause of heart disease revealed

By Jerome Burne

A powerful, injectable, cholesterol-lowering drug called Inclisiran, described by NHS medics as ‘game changing’ and a ‘cholesterol vaccine’, is about to become available from your GP, so long as your cholesterol level and risk of heart disease is sufficiently high.

It can drive your cholesterol level way below what is possible with statins – to 1.3 mmol – and, because you only need two shots a year, it has been dubbed a ‘fire and forget’ treatment.  The ‘healthy’ cholesterol level for patients without heart disease is 3mmols (it used to be five recently and seven before that).

The consortium marketing the drug which, curiously, includes the NHS, (more about that later) trumpets its potential to save ‘up to 30,000 lives over the next 10 years. The assumption is that 300,000 patients will get it every year. 

The bad boys of our diet

This is a big gamble because the hypothesis that cholesterol is a major cause of heart disease has taken a knock from the mounting evidence that saturated fat is not a major killer. For decades fat and cholesterol have been in lockstep; the bad boys of our diets.  Cholesterol supposedly blocks arteries and lots of fat pushes up LDL cholesterol levels.  But if that isn’t true, the link between the two disappears.

And there is another very small cloud on the horizon threatening this vast billion (trillion?) dollar market. It is the tiny David who has been unsuccessfully challenging this pharmaceutical Goliath for decades.    

He is the Lancashire GP Malcolm Kendrick, recently labelled (libelled??) a dangerous ‘statin denier’ in the Mail on Sunday. He has just published a book called ‘The Clot Thickens’, which explains why cholesterol is innocent and what is actually happening when your risk of a heart attack rises. 

His previous book and detailed blogs have forensically exposed the flaws in the ‘cholesterol hypothesis’ but the response has been the growing and unscientific practice of excommunicating those who disagree with official medical theory.   

The upside-down trial

The Clot Thickens is trying a new tactic. He’s setting out an alternative theory of what causes heart disease and why it’s not cholesterol Some of the familiar players are there, together with new unfamiliar ones, but they all fit plausibly together, backed up with hundreds of references. It’s quixotic, brave and deserves to be taken seriously.  

There are novel elements in the way Inclisiran is being launched but they are not reassuring.  I described them in a post last year, so some of this may be familiar.

Another concern is the lack of any evidence that the drug cuts deaths from heart disease. The company has said this was not a problem, because it would be tested in a big trial next year to show it was safe and effective. Last month it was announced that the trial was about to start and that high-risk patients would soon be able to sign up and get the drug from their GP.

But it is a very unusual trial.  Normally drugs are tested to show they and safe and beneficial before they are licenced. Inclisiran has reversed this. First, it is being given to 300,000 patients a year and then in a few years’ time, the organisers hope to have the evidence it was worth licensing. 

Drug companies and regulators get cosy

This unconventional set-up is only possible because of a deal Novartis has done with the NHS which is also odd and worrying. The company has formed a consortium with the NHS to run the trial.  Rather than the drug company running the trial and the NHS using that data to decide if to make it available, the two arms of the system are wrapped around one another, leaving patients reliant on drug company trustworthiness 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. 

There is a ‘commercial’ arrangement between NHS England and Novartis, described as a “world-first”. So now the NHS has a financial incentive for the trial to produce the ‘right’ results, along with the drug company.

So, is Inclisiran actually safe and effective? Well, there are reasons to think not: certainly, ones that indicate it should be tested more rigorously. We know for sure is that it is really, really good at lowering cholesterol. But is that automatically a good thing? 

It’s a common assumption but there are many trials that have found the opposite – those with a higher level fight off infection more effectively or simply live longer. Given cholesterol’s many important functions – such as providing the raw material for hormones, the walls of brain cells and for making vitamin D – that’s not surprising.

Sometimes higher cholesterol is better than lower

In fact, just three weeks before the first wave of publicity about the new Inclisiran trial broke last year, a very solid research paper appeared which found that for patients being treated with statins, lower HDL cholesterol didn’t automatically protect you. Even though it ticked all the reliability boxes, the result was almost totally ignored. 

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. What they found, however, was that those with higher LDL levels lived longer. 

If you are interested in more of the biological and technical details, the excellent nutrition researcher Dr Zoe Harcombe did one of her forensic blogs on it. 

Taking off the brakes on the recycling program

There are similar warning bells over safety. Inclisiran is a type of drug known as a PCSk9 inhibitor, and there are reasons to suspect a range of side effects, a risk not highlighted in the press reports. 

The liver is where cholesterol is made and sent out into the bloodstream in the form of “bad” LDL cholesterol. It is then returned to the liver in form of “good” HDL cholesterol and re-absorbed for recycling. 

The job of PCSK9 is to act as a brake on the recycling rate, making sure HDL isn’t pulled out too fast.  Inclisiran disables PCSK9 so cholesterol extraction speeds up, leaving you with impressively lower cholesterol. It is a dramatic interference; could it have long term effects? 

‘What complicates matters is that PSK9 is involved in various other important processes around the body,’ says 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. 

Telling lies about cholesterol

‘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.’.

Inclisiran is a way of testing the cholesterol theory to destruction. Kendrick doesn’t believe it will benefit those with a high risk of heart disease because the theory of heart disease it is based on doesn’t fit the facts. 

This is the story we have all been told about heart disease for decades. “Saturated fat causes LDL (low-density cholesterol) levels to rise, some of which gets into an artery, causing cholesterol-filled plaque to form which eventually creates a blockage.” 

‘Every part of that description is a lie,’ Kendrick writes. For instance, fat doesn’t cause a rise in LD; what does is a rise in blood glucose due to eating carbohydrates, especially refined. The excess glucose is turned into fat, which is saturated.  Surely someone in Novartis’ research arm should have noticed this.’

The combo that can play havoc with your heart

So, what does cause heart disease? Well, sugar is one of the promoters along with dozens of other factors such as smoking, diabetes, air pollution, rheumatoid arthritis, stress and lead. All can raise the risk.

So far so familiar. But what is puzzling is how can they all threaten the heart? They are all so different. How can stress have the same effect as Lead in the atmosphere?

Kendricks answer is that there are just three things that need to go wrong in your body to start the process of heart disease. There is damage to the lining of your arteries called the endothelium, there is a drop in the supply of nitric oxide – a gas that is vital, for keeping the endothelium healthy – and there is an increase in blood clotting. 

Diabetes and smoking and all the rest of the heart risk factors cause problems for one or more of those three systems. Once you know that, there is a lot that you can do to keep them healthy rather than harmful. 

Clotting – getting it wrong after all these years 

The endothelium is the core of the new hypothesis. Damage to it can push up cardiovascular risk even if the other two are unaffected. It is made up of two very thin layers of cells that line all blood vessels and would cover a football pitch if flattened out. It is a barrier to the movement of substances from the blood into the artery wall among them LD cholesterol.

It can be damaged by high blood pressure which batters it like a fast-flowing river and also by high glucose, while protein helps protect it, suggesting a low carb diet would be a good strategy for heart health.

Blood clots are obviously involved in heart attacks – they are central to cholesterol theory – but Kendrick goes into detail as to why the supposed mechanism involved is completely wrong. This blog is a drone over the territory, to see the fine detail of the new cardiovascular landscape – you need to buy the book.
Clotting involves a very delicate balance. It needs to be fast and effective, or we would soon bleed to death but not enough to stop blood flowing. So, there are dozens of factors that speed it up or slow it down. Among the top factors that increase the rate are hot or cold physical stress, dehydration, mental stress and the widely prescribed NSAID Ivermectin 6mg drugs such as ibuprofen and volterol used to treat pain and inflammation. Aspirin is the NSAID that doesn’t

The gas that makes heart health fun

The last of the heart disease risk trio is nitric oxide. ‘It’s almost impossible to overstate its importance,’’ writes Kendrick. ‘It dilates blood vessels and lowers blood pressure, as well as stimulating the production of endothelium repair cells. Ensuring a good supply can be fun – sunbathe, enjoy dark chocolate and red wine and, if necessary, Viagra. 

It’s not surprising that there are so many flaws in the cholesterol hypothesis because it was formulated over 50 years ago when both the endothelium and nitric oxide were unknown. They were discovered in the 1980s, yet despite their major role in heart health and disease, the dominance of the cholesterol hypothesis has ensured there’s been no interest in them and no funding to research them. 

Patients have been the losers. A major analysis of data on nearly 400,000 GP patients in 2017 listed 48 heart risk factors in order of importance. At the top were the likes of steroids, severe mental illness and social deprivation. – LDL cholesterol came in at 46th.

The massive spend on the Incisiran trial, quite apart from the concerns about its independence, could be so much more usefully spent investigating the findings of the clotting hypothesis and its potential to create new approaches to heart disease. Kendrick’s book reports serious scientific research in a very readable way; it deserves serious attention.

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.


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