By Jerome Burne
The complicated and confusing debate about statins – are they worth taking or not; are they safe or do they have nasty side effect? – has suddenly plunged into anarchic and uncharted territory by the claims of a new rival drug.
Senior figures in the cardiology establishment have long claimed statin side effects are few and usually mild. Researchers who claimed last year that as many as 20% of patients taking statins suffered side effects, were roundly attacked by Professor Sir Rory Collins of the prestigious Cholesterol Treatment Trialists’ Collaboration (CTT) in Oxford, for spreading alarm.
But this week a big trial of a new sort of cholesterol lowering drug has reported that nearly 50% of a group of patients taking a statin because their risk of heart disease was high had to stop because their muscle pains were so bad.
So where does this leave the poor patient hoping for cardiovascular protection or indeed official bodies like NICE which recently issued new evidence based guidelines recommending that an estimated 6 million more people should be taking statins because they were so safe?
The researchers vilified last year for putting the side effect risk at 20% have now been totally outflanked on the scale of the problem by a drug company. Drug companies are usually accused of hiding side-effects. What is going on?
Many people can’t tolerate statins
A clue can be found in the opening paragraph of the new study which blandly asserts there is a serious problems with statins which, and this is the important bit, the new drug being trialed is able to solve.
‘A significant proportion of patients with clinical indications for statin treatment,’ it reads ‘report an inability to tolerate evidence-based dose (of statins), most commonly because of muscle-related adverse effects.’
The stated aim of the trial was to uncover the scale of the problem. This is what it found. ‘Overall, 209 of 491 patients (42.6%) with a history of muscle-related adverse effects reported intolerable symptoms’ when given atorvastatin compared with a placebo.’
Time for a bit of background to make all his clear. The trial involved a new and fearsomely expensive drug called Repatha (Evolocumub) made by the drug company Amgen which will cost around £4,500 a year (for 12 monthly injections). Statins (now their patent has run out) cost £20 a year.
It is one of a new class of cholesterol lowering drugs known as PCSK9 inhibitors which bring down cholesterol even more efficiently than statins by blocking a protein in the liver called PCSK9 that’s why they are known as PCSK9 inhibitors.
The new problem with statins – intolerance
The purpose of this trial was to establish a market for this heavyweight cholesterol hammer. The first step was to establish that a significant number of statin patients were suffering from really bad muscle pains. As we’ve seen, they did this simply by asserting it.
The next step was not to talk so much about side –effects, something which the drug does to you – but about ‘intolerance’ – a problem that you have with the drug. And if you had this problem, its effect could be very dangerous. As the study says:
‘Patients with muscle-related intolerance often refuse to take statins despite elevated LDL-C levels and a high risk of major cardiovascular events.’
And this was where the new drug Repatha came in. Because it didn’t come with the same risk of unbearable muscle pains it could offer them a way out of this dangerous dilemma. So there is a clear incentive to find that the rate of statin induced muscle pain is sky high.
The fact that this flies in the face of decades papers finding in favour of the official statin line is simply ignored. And you don’t have to look for old research claiming statins tolerability. Here’s what an overview of statin safety says, which was published just over a month ago in the New English Journal of Medicine.
But aren’t statins so-called side effects just a reverse placebo effect?
’Statins significantly reduce the incidence of cardiovascular disease, are generally safe and have an acceptable side-effect profile. Indeed a recent meta-analysis confirmed that mild muscular skeletal problems such as myalgia (muscle pain) occur in approximately equal numbers of persons treated the statins as those given a placebo.’
The mention of a placebo refers to another hurdle that Repatha had to clear in this trial to establish that was a much needed drug that could solve a major drawback to statins. Recently statin supporters had come up with a theory to explain away the rate of statin side effects seen in some trials. They pointed out that it very often closely matched the rate of side effects reported by those getting a placebo. Ben Goldacre was an author on a paper about this.
The idea was that a sort of “reverse placebo” was at work. Patients in trials know statins can cause muscle problems, so as soon as they feel a twinge from the pill they are taking, they think it must be due to a statin. As a result the trials show that there are few “real” side effects on statins; both those getting a pill and those getting a placebo have the same rate of side effects because both are suffering an equal number of false side effects.
This trial shows statin side effects are real after all
This presented a problem for the plan to market Repatha as free of serious muscle pain risk, which they claim comes with statins. If the statin pain is not “real” you don’t need a very expensive drug to avoid it.
This was why the finding that 42.6% of patients given a statin had reported serious muscle pains, many fewer than those getting a placebo, was so important.
The results of this also trial pose a problem for patients – if this new finding that the rate of muscle pains is really high with statins, does the benefit still outweigh the risk? And also for the official view – can the experts like Sir Rory really have missed the ‘intolerance’ problem for so long? Or have they been hiding it?
Whatever the outcome of those debates, the trial certainly highlights yet again extra risks we are all exposed to as a result of privatising most of our clinical trials. What this trial of Repatha did was actually to test patient’s claims of muscle pains, rather than dismiss them as doctors have commonly done.
This was something that could have been done at any time in the last two decades but never was for obvious commercial reasons. Should we really have to wait for the launch of a new drug before we even have a chance of finding out the truth about an existing one?
But are Repatha results any more reliable than statin results?
Of course it is also worth bearing in mind that bias hovers around the Repatha trial. This is a “company” trial if ever there was one. It has 20 authors, sixteen of whom have declared that they have received payment from a variety of drug companies, 10 of them from Amgen (which makes Repatha). Five of them work for the company.
In fact a rigorous control of trials and what seems like a high level of support from regulatory agencies is a striking feature in the history of Repatha’s development. Evidence based medicine and value for money are supposedly two of medicine’s Mom and apple pie principles. But just how happy should Mom be watching the winding lucky road that Repatha has taken to get this far?
From the very beginning you didn’t have to be a wild-eyed anti-statin radical to wonder if lowering cholesterol further than ever before is really such a good way of cutting heart disease risk.
The doubts are fairly familiar: cholesterol is not toxic invader but a natural substance involved in a range of vital functions such as making sex hormones, turning sunlight into vitamin D, building cell walls (notably of neurons) and in immune system activity.
Low cholesterol doesn’t equal low heart attack risk
There’s also reasonable doubt as to whether statins protect the heart by lowering cholesterol. Other substances that do the same, such as niacin, oestrogen and fibrates, aren’t protective. And there are groups of people such as women and the elderly who don’t seem to benefit from lower cholesterol. In fact a recent Japanese study found it increases mortality rates.
One study that recorded the cholesterol levels of people arriving in hospital with a first heart attack found that 75% had a ‘healthy’ level.
In fact so far no trials have actually shown that lowering cholesterol with Rapatha has any beneficial effect on the heart at all. This nearly scuppered the whole PCSK9 venture several years ago when new American Heart Health guidelines declared that any new heart protection drugs would need to show clinical benefit rather than just lower cholesterol.
Then one of those lucky events happened that has helped Rapatha along. The very next day the FDA announced that heart drugs wouldn’t need to show benefits such as cutting heart attack risk after all. Cholesterol lowering was enough for a licence.
The drug that nearly dashed Rapatha’s plans
But there was another spectre hovering over the PCSK9 feast – the cholesterol lowering drug ezetimibe which cuts cholesterol absorption in the guts and had been licenced in 2002, also without any evidence that it cut heart disease risk.
It threatened the Rapatha because the implication was that just hammering down cholesterol was not a useful strategy. In 2014 the results of yet another trial of ezetimibe called IMPROVE-IT were due to be launched at the American Heart Association conference.
If it didn’t show benefit Rapatha could be toast. Mom must have been looking on in horror as the trials’ statistics were ruthlessly tortured to ensure it yielded the desired result.
When IMPROVE-IT had failed to find a significant reduction in cardiovascular death or nonfatal MI or nonfatal stroke or rehospitalization for unstable angina (UA) the researchers had simply doubled the number of patients from 9,000 to 18,000. That did it and the results were triumphantly announced. Ezetimibe was 2% more effective at cutting heart risks from stroke than a placebo. I’m not sure Mom’s honour was still intact at this point.
And then miraculously the market expanded
But that was not the end of her shame. Mom next suffered a low blow from a technique used successfully to boost statin sales – you simply drop the level needed to diagnose a patient as needing treatment. The most obvious candidates for treatment with a very expensive cholesterol pile driver are patients with hypercholesteremia – very high levels of cholesterol. Trouble is there aren’t very many of them.
Cue for another lucky break. In November 2015 the American Heart Association came to the rescue and announced a new level. According to the veteran cholesterol drug watcher Dr Malcolm Kendrick this expanded the market in the USA from 640,000 to 1,920,000.
And that brings us up to the very latest trial of Rapatha which audaciously attempts pull the rug from statin’s safety claim and offers to step into the breach.
The breaks haven’t all gone Rapatha’s way. In December the German drug regulator (IQWIG) declared that Amgen had provided no ‘no suitable data for hypercholesterolaemia’ so there was no hint of an added benefit from treatment with Repatha.
But in January the drug was licenced in Japan and last month NICE were looking at licencing it for use along with – amazingly – ezetimibe.
So it seems a certainty that it won’t be long before Repatha starts showing up in GPs surgeries meanwhile Mom, if she has a shred of self-respect will have had a fatal heart attack.