Dark arts pushing heart drugs

Evidence-based medicine and ‘value for money’ are two of medicine’s Mum and apple pie principles. But like other principles they are all too readily discarded when they conflict with harsh commercial realities – by which of course I mean drug company interests. Watching the contortions involved in demonstrating that abandoning them do not involve disrespecting Mum in any way are both entertaining and depressing.

A fine example of this dance is currently being played out over a new and fearsomely expensive class of cholesterol-lowering drugs known as PCSK9 inhibitors which are lined up to displace statins, now dirt cheap as they are off patent.

Front runner is Amgen’s Repatha (Evolocumub) – list price around $15,000 a year. They all lower cholesterol even more efficiently than statins but via a different pathway. They block a protein called PCSK9 in the liver which increases the number of receptors that remove LDL cholesterol from the blood stream.

Now right away Mum and her pie looks in trouble because you don’t have to be a wild-eyed anti-statin radical to wonder if lowering cholesterol is really such a good way of cutting heart disease risk. The doubts are fairly familiar: cholesterol is not toxic invader but a natural lipid involved in a range of vital functions such as making sex hormones, turning sunlight into vitamin D, building cell walls (notably neurons) and the immune system.

There’s also ambiguity about exactly how statins cut CVD because other cholesterol- lowering substances such as niacin, oestrogen and the fibrates don’t show this benefit in RCTs. The generally accepted answer is that statins also have anti-inflammatory properties which is what protects the heart but that does leave the cholesterol-lowering question hanging.

Then there are the studies on women and the elderly which suggest that cholesterol lowering may well not be protective. In fact a recent Japanese study found it increases mortality rates (DOI:10.1159/000381654 ). One study that recorded the cholesterol levels of people arriving in hospital with a first heart attack found that 75 per cent had a healthy level.1.

At one point the does-lowering-cholesterol-actually-do-any-good question looked as if it might torpedo that whole PCSK9 venture. On 13th November 2013 new American heart health guidelines declared that any drugs would need to show clinical benefit rather than just lower cholesterol. 2. 

Trials of PCSK9 drugs had only demonstrated their cholesterol-lowering abilities; a billion dollar project hung in the balance. However 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.3. 

But there was another spectre hovering over the PCSK9 feast – the cholesterol lowering drug ezetimibe which cut absorption in the guts and had been licensed in 2002, also without any evidence that it cut heart disease risk.

It threatened the new drugs because despite numerous trials and studies they all failed to show any clinical effect. The implication was that just hammering down cholesterol was not a useful strategy.  Not that this had any effect on sales. It was licensed to be combined with a statin in cases where patients couldn’t get their cholesterol low enough and the UK has spent around 60 million a year on it. This abandonment of Mum this involved is another story.

Ezetimibe’s threat to PCSK9s became really serious when Repatha was due to be launched at the American Heart Association conference in 2014. Billions were riding on a trial called IMPROVE-IT. Could it deliver? Mom must have been looking on in horror as the trials’ statistics were ruthlessly tortured to ensure it yielded the desired result.

When the trial failed to find a significant reduction in cardiovascular death or nonfatal MI or nonfatal stroke or rehospitalisation 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 two per cent more effective at cutting heart risks from stroke than a placebo. 4. I’m not sure Mum’s honour was still intact at this point.

But that was not the end of her shame. Mum 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.

Luckily in November 2015 the AHA came to the rescue and announced a new level. 5. According to the veteran cholesterol drug watcher Dr Malcolm Kendrick, this expanded the market in the USA from 640,000 to 1,920,000 people. 6. 

But this isn’t nearly enough for a proper block buster drugs. Remarkably almost overnight a surprising new group of patients have been discovered – people who are intolerant of statins and need something else to bring their cholesterol down.

The surprise is that for years those promoting statins have been claiming they are virtually side-effect free. Only last summer researchers were accused of killing patients by scaring them off the drugs by suggesting in the BMJ that side effects could be higher than claimed.7. 

Meanwhile in America with no new evidence reports from senior medics started appearing warning about the serious problem of statin intolerance.  Dr Patrick Moriarty director of clinical pharmacology at the University of Kansas Medical Centre, for instance, told the journal Cardiovascular Business that as many as half of the patients who present at his clinic are statin intolerant.

‘In other studies, 10 percent to 25 percent of patients report being statin intolerant, making the need for an alternative treatment acute,’ he said. With 40 per cent of UK adults currently advised to take statins, PCSK9s have could be heading for billion dollar sales.

And so the bandwagon rolls on. 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 licensed in Japan and, last month NICE were looking at licensing 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.

  1. http://newsroom.ucla.edu/releases/majority-of-hospitalized-heart-75668
  2. http://www.reuters.com/article/us-usa-cholestrol-drugs-idUSBRE9AC0TH20131114.
  3. http://news.yahoo.com/fda-says-cholesterol-drugs-may-not-outcome-studies-003325631–finance.html
  4. http://www.forbes.com/sites/larryhusten/2014/11/07/what-you-need-to-know-about-improve-it/#4290b5fc3266
  5. http://cardiobrief.org/2015/11/05/new-definition-of-familial-hypercholesterolemia-could-expand-patient-population-for-expensive-cholesterol-drugs/
  6. http://drmalcolmkendrick.org/tag/familial-hypercholesterolemia/
  7. http://www.theguardian.com/society/2014/mar/21/-sp-doctors-fears-over-statins-may-cost-lives-says-top-medical-researcher
Jerome Burne
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