By Jerome Burne
Professor Sir Rory Collins, the austere director of the institute in Oxford that produce much of the evidence supporting the increasing use of cholesterol –lowering statins, is in hot water once more. Last week he declared that he intended to investigate himself.
What needed investigating was his own admission a few months ago that his unit – the CTT (Cholesterol Trialists Collaboration) – hadn’t actually done any research to establish the level of damaging side-effects of the drugs even though he had been claiming for over a decade that they were negligible. Senior medical figures, such as the editor of the BMJ, are outraged.
Regular readers may remember that at the time of that admission, HealthInsightUK posted a blog giving the background to the revelation, pointing out that for years various critics had been claiming that proper data on statin side-effects was missing.
This is an important issue. Something like 12 million people in the UK take these drugs, NICE recently approved a major expansion of the number eligible for a prescription and doctors are paid for prescribing them. But if risk from side-outweighs the benefits the whole project is pointless and dangerous.
Fox and hen house; bank CEO and tax evasion
In the circumstances, allowing Sir Rory to conduct the investigation is like Lord Green offering to uncover what was known about HSBC’s Swiss tax avoidance schemes or nodding through a plan by Fred Goodwin to review the Royal Bank of Scotland’s mergers and acquisitions policies. For a more detailed and less flamboyant account of the ongoing issue of CTT and its lack of transparency see this week’s BMJ.
But this is not just about foxes being allowed to check on the hen houses it’s yet another example, of how our system of evidence based medicine that is supposed to be giving doctors and patients reliable guidance is capable of generating total confusion.
Of course we need to know the risks but ideally without the sticky fingers of vested interests smearing the results. The truth is that as far as the commercial side of cholesterol lowering is concerned, statins are so yesterday. When they were expensive patent-protected drugs there was a strong incentive to keep estimates of their side effects frequency low. But now they are all off patent and so very cheap, powerful forces have a strong interest in pushing up estimates of their risk.
That’s because waiting in the wings is a new class of far more potent, patented and so far more expensive, cholesterol lowering drugs known technically as PCSK9 inhibitors. They work by making the liver pull more cholesterol out of the bloodstream. A simple way to explain why we need them is to point out that they avoid one of the serious problems affecting statins.
Who knew so many were statin intolerant?
This, believe it or not, is that statins caused side-effects in lots of people. It’s been named “statin intolerance” but it means the same thing. Experts have been estimating the percentage of patients suffering from “statin intolerance” at between 10% and 20%. This is a far cry from the level of 1% that Sir Rory had been claiming at various times.
In fact Patrick Moriarty of the University of Kansas Medical Centre put it even higher in a paper he presented at the American Heart Association (AHA) meeting in Chicago in Nov last year. “Statin intolerance is one of the most common causes of an inability to reach goals in patients who need lipid lowering therapy,” he said. ‘It affects up to 25% of all statin-treated patients.’
And the side effect rate might be even higher. An American organisation called “Statin Usage” (funded by pharmaceutical company and The National Lipid Association) recently ran a big survey to find out why patients stop taking statins – described as “one of the biggest barriers to treatment”. The answer was because of side-effects at a level far higher than claimed by those concerned about “statin intolerance”. Sixty two percent said they stopped because of side-effects and 52% who didn’t refill their prescription, did so because of side-effects.
These wildly varying estimates are a long way from the Promised Land of hard data where it is possible to make informed choices. What’s more the story gets even more tangled and absurd. The cholesterol hypothesis that all this statin prescribing is based on is looking as if it could be a house of straw.
Elephant in cholesterol-lowering room
The industry and the medical profession have for years resolutely turned a stone deaf ear to voices pointing out the elephant in the cholesterol-lowering room. There are plenty of sensible careful studies that fail to find a connection between raised cholesterol and risk of heart disease.
This conclusion is virtually unthinkable since it would not only mean that two decades of statin prescriptions has been largely pointless (statins also lower inflammation, which may be beneficial in some cases), but that the new PCSK9 drugs, confidently expected to be multi-billion dollar sellers, will have to be taken off the table. The only thing these drugs do for sure is lower cholesterol.
For years it was only a few mavericks who pointed out that cholesterol did all sorts of valuable things in the body such as generating vitamin D, building the walls of all cells and making sex hormones ,so driving levels ever lower was probably not a good idea.
But recently the idea has been gaining traction in the mainstream press. Last week Matt Ridley, popular science writer and a member of the House of Lords, wrote a piece for the Times in which he made the point that not only was cholesterol essential but that new research had found high cholesterol was linked with living longer.
High cholesterol not an enemy but a friend
The research he referred to was a massive 100+ page report published in the Annals of Nutrition and Metabolism which analysed data from several large Japanese studies. The conclusion was that “cholesterol is not an enemy but a friend.” Having higher levels of cholesterol meant that not only were you less likely to die from heart disease but you were less likely to die from cancer, infection and liver diseases. In the case of liver disease providing your cholesterol was high enough: “serious liver disease does not develop”.
And there are various smaller studies that indicate that something similar is going on. Here is an article published just last week in Critical Care Medicine which investigated the cholesterol levels in 724 heart attack patients.
It found that those with a very low LDL cholesterol level (below 1.6mmol/l) had a 65% INCREASED risk of death compared with those with a level over 1.6. The effect of high or low triglycerides (fats in the blood) was even more dramatic. A 405% increase in risk of death for those with a level below1.24 mmol/L compared to those above that. And if you had low levels of both, your risk of death went up ten times.
In a sane system the fact that the evidence for statins is still so confused and contradictory after twenty years would make for extreme caution before allowing a another cholesterol drug onto the market, especially when it comes with a price tag of $7,000 to $12,000 a year.
But the marketing drums that drown out inconvenient evidence, as the statin saga shows, are already beating.
A new wonder drug with no side-effects
A recent cheerleading article in the UK press claimed that the new drugs can cut the risk of heart attacks by 50% and that one of them (evolocumab) is a ‘new wonder heart drug that has no side-effects’. A company executive is quoted as saying: ‘Overall safety “is very, very encouraging”.
But that ‘halving’ of risk means that the heart attack rate went from 1% to around 0.5% . This standard trick for turning a minor benefit into a major one was widely used to promote statins . As for safety the ‘no side-effects’ claim is a porky that is all too familiar from cholesterol lowering drugs. This one comes from trials that rarely lasted more than 24 weeks; just one ran for a year.
More sober assessments of evolocumab have pointed out that: ‘Neurocognitive problems, such as mental confusion or trouble paying attention, were seen in some of the study participants.’
So Sir Rory’s investigation of himself promises to be uncomfortable. His options are either to discover that he was making claims with no evidence base or that he is going to go head to head with a major marketing claim of several new multi-billion dollar drugs. Hot water indeed.