by Dr Malcolm Kendrick
‘…across the gulf of space, minds that are to our minds as ours are to those of the beasts that perish, intellects vast and cool and unsympathetic, regarded this earth with envious eyes, and slowly and surely drew their plans against us.’ War of the Worlds
An era is coming to an end. Statins, the world’s most widely prescribed and profitable drugs, have, with the exception of Crestor (rosuvastatin), all come off patent and their price has plummeted. Good news for NHS accountants: not so good for company profits.
So a supposedly new, improved, much safer and more effective generation of cholesterol lowering drugs will soon be available at a doctor’s surgery near you. At least that will be the general tone of the marketing. With 80% of the population suffering from “high” cholesterol, according to guidelines drawn up by consultants with links to drug companies, there is obviously a huge need. (For an account of how seriously we should take this “need” see Dr John Briffa’s post.)
This is obviously a great opportunity for the companies but it also faces them with a fascinating dilemma. Statins have been relentlessly promoted as the most beneficial l class of drugs ever, protecting not just against cardiovascular disease but also Alzheimer’s and Parkinson’s and being virtually side-effect free into the bargain.
An alarming press release
But if the companies are going to persuade those NHS accountants and cash-strapped GP commissioning bodies to start paying serious prices for the new drugs, they need to persuade them that statins actually had a serious problem all along but it is one that can be avoided by buying the new products.
Recently I received a press release by email that was the first sign that this process is already underway. It was a warning about something called P9 which, had I been a loyal statin believer, I would have found pretty alarming. After explaining how statins worked by targeting an enzyme known as HMG-CoA in the liver, the email went on to tell me this:
“However, statin treatments have been shown to actually stimulate the production of PCSK9, which is counterproductive, possibly damaging to the liver, and ultimately limits the treatment’s ability to lower LDL cholesterol levels.”
Why weren’t we told about this risk before?
What on earth is PCSK9, you and the medical statin believers might well ask. And if it is not only able to damage the liver but also render the whole purpose of taking a statin self-defeating, why haven’t we been told about it before?
Here was a classic marketing ploy; tell you about a problem and immediately offer a solution in the form of a drug that is able to block the production of damaging PCSK9. The full name of these new drugs is proprotein convertase subtilisin/kexin type 9 inhibitors.
And it’s not the only dauntingly high tech-new cholesterol lowering drug that could be coming your way in the not too distant future. For the sake of completeness here is a list of nearly all the new compounds waiting in the wings. Some will undoubtedly founder on the rocks of side effects that are just too dangerous, never to be seen again.
Other new drugs in the race
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors)
- Antisense oligonucleotides (ASOs) targeting the production of apolipoprotein B-100 (apoB-100)
- Microsomal triglyceride transfer protein inhibitors
- Squalene synthase inhibitors
- Peroxisome proliferator-activated receptor agonists
- Thyroid hormone receptor agonists
For the moment though my money for the first out of the gate are the PCSK9 inhibitors, which I will call P9 inhibitors. So what exactly are they? Well P9 is an enzyme that is found mainly in the liver. It binds to receptors that remove the “bad” LDL (low density lipoprotein) cholesterol and destroys them after they have taken just one LDL molecule out of circulation, meaning that they can’t be reused to remove more LDL.
But if you block P9, you allow LDL receptors to continue removing LDL merrily from the bloodstream, so LDL levels fall dramatically. In fact P9 inhibitors appear to lower LDL far more effectively than statins which, if you sign up to the belief that the lower your cholesterol goes the more protection you get, this can only be another major benefit.
The new statin combo
What’s clever about this is that it avoids taking on statins directly. Given how familiar doctors are with them, how most believe in them and how cheap they are, a head on attack would be doomed to failure. The manufacturers know, damn well, that doctors are not just going to stop using statins, so their P9 inhibitors will be positioned to sit alongside statins, allowing them to work, supposedly, even more safely. At first anyway.
But there is more to this press release and I could pick it apart for hours, marvelling at the ability to say so much – in so few words. But let’s just focus on the phrase…’possibly damaging to the liver’ in relation to statins. Now, I know that statins do damage the liver – to a greater or lesser degree. Liver enzymes in the blood (a sign of liver damage) are often raised to three times normal levels – sometimes more.
But why not focus on the side-effect that is most clearly recognised with statins? Namely muscle damage and pain. This is the true Achilles heel of statins. Yet the press release talks about liver damage…
Danger to your liver
The most likely reason is that P9 inhibitors have been found to cause liver problems themselves in both animal studies and phase 1 studies on human volunteers. Knowing their mechanism of action, it is more than likely that PCSK9 blocking agents could damage the liver. If you over-ride negative feedback mechanisms, the body doesn’t like it very much, as you will be overloading cells with toxic waste products. Enzymes to break down LDL receptors are there for a reason.
So, we can expect P9 inhibitors are going to cause liver damage. However, by attacking statins for causing liver damage, the pharmaceutical companies will be hoping to mask the most serious adverse effect of the new drug. The words used to defuse concerns about this problem will be something along the lines of. ‘With our P9 inhibitor we have seen mild elevations of liver enzymes in clinical studies. However, they are similar to those caused by statins, are reversible and cause no long-term damage.’ Blah, blah…. ‘Move along, nothing to see here.’
This fear is not just based on a vague unease that if you block a feedback mechanism in the body you are probably heading for disaster. It is also based on the fact that, if the companies developing P9 inhibitors are already blaming statins for causing liver damage, they are doing to hide their own problems behind a smokescreen. You heard it here first.
I also predict that severe liver damage problems will take years to emerge. In most people the liver is pretty resilient – it takes a lot of alcohol and a lot of time to destroy it. I fear that clinical studies will not be long enough to demonstrate this effect –before the drugs are launched and widely prescribed. I can say all this because it is what has happened with damaging block buster drugs in the past, such as the anti-inflammatory Vioxx and and the diabetes drugs Avandia.
My predictions for P9 inhibitors:
- They will be widely promoted as the new statins
- Pfizer, or Merck, will buy out the patent to one of the new products (they may have already done this)
- They will be launched without any long-term studies to show they actually cut your chance of dying from a heart attack. They will be approved purely on the basis that they lower cholesterol/LDL cholesterol.
- They will make billions upon billions in the first two years and be hailed around the word as a new generation in cholesterol lowering. The chief executives of the companies selling these drugs will be paid massive bonuses
- Key Opinion Leaders (‘experts’) will promote them ruthlessly at major conferences and press launches
- Reports of a high level of liver damage/deaths will start to emerge
- The companies will deny there is a problem and attack anyone who says there is one
- They will start to be withdrawn from the market two to three years after launch
- There will be lawsuits
- The companies will be fined a small fraction of the profits they made from hyping the drugs
- It will emerge that the problems with liver damage were known by the companies many years before the drugs were launched but not many people will be interested by then, as the next generation of lipid lowering agents will be arriving
- No-one will be held accountable
Yes, the great Nostrokendrickos has spoken.
In the meantime remember that ‘Something unpleasant this way comes’.
Disclosure: I do not believe that a raised LDL/cholesterol level causes heart disease.
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