Magic bullet or massive missfire?

    31 May 2014

    Forty years ago Henry Gadsden, chief executive of the drug company Merck, expressed his frustration that the potential market for his company’s products should be limited to those with treatable illness. Ideally, he said, he would like ‘to sell to everyone’. ‘Henry Gadsden’s dream has long since come true,’ observes the medical commentator Ray Moynihan. ‘The marketing strategy of drug companies now targets the hundreds of millions of the apparently well, persuading them they have some medical condition that warrants treatment.’

    The jewel in the crown of modern pharmaceuticals and the apotheosis of Henry Gadsden’s vision of selling ‘to everyone’ are cholesterol-lowering statins. They are the wonder drugs of our age, credited with saving tens of thousands of lives and generating for their manufacturers £15 billion a year in annual revenues. They are, by far, the single most profitable drug ever discovered. Already the most widely prescribed class of drugs in Britain, they could soon become even more so following the recent recommendation by a committee of cholesterol experts advising the National Institute for Health and Clinical Excellence (Nice) that those eligible for statins should be extended to everyone aged 60 and over, boosting the numbers taking them to an eye-watering 12 million — or one in four of the adult population.

    Intuitively, this seems a bad idea for any number of commonsensical reasons but, claims Sir Rory Collins, Professor of Medicine and Epidemiology at the University of Oxford, ‘The evidence supports these recommendations — the drugs are effective.’ He concedes that some ‘may not like the idea of mass medication’ but they can be reassured at least that statins have been found to have ‘virtually no side effects’. Dr Judith Finegold of the National Heart and Lung Institute, in a recent, much-publicised study scrutinising nearly 80,000 patients, found the incidence of symptoms commonly attributed to statins to be no different from those of volunteers taking a placebo.

    Both Sir Rory Collins’s endorsement of the benefits of statins and Dr Finegold’s reassurances about the low incidence of side effects are based on the findings of drug company-sponsored clinical trials — not perhaps the most reliable source of evidence, given their well-known reputation for consistently reporting ‘favourable efficacy and safety results’.

    Professor John Abramson of Harvard Medical School has a rather different take, drawing attention in a critical review in the British Medical Journal last year to the main difficulties in assessing the findings of these clinical trials. First, the claim that statins are ‘effective’ conceals the minuscule benefit they confer on the vast majority for whom they have ‘no significant effect on overall mortality’ (in other words, they do nothing to prolong life in the majority of people taking them). Statins reduce the absolute risk of heart attack and stroke in just 2 per cent of cases. The outcome in those at ‘high risk’ (with markedly elevated cholesterol levels or a previous history of circulatory disorders) is only marginally better — preventing a further episode in just 4 per cent, with a 1 per cent reduction in ‘overall mortality’.

    Thus the promotion of ‘statins all round’ — given these modest benefits — could really be justified only if indeed they have ‘virtually no side effects’. This is hotly disputed. Statins were in the press earlier this month after the British Medical Journal accepted that it had published flawed research last autumn over-estimating the side effects of statins. The research had claimed that 18 to 20 per cent of patients suffered debilitating side effects, and this statistic has now been withdrawn by the authors. But while their figure may have been an over-estimate, that doesn’t necessarily mean statins have no side effects.

    Indeed, this would be most unlikely — not least, as Professor Abramson observes, because it appears that some clinical trials may have excluded patients unable to tolerate the drugs. It is certainly contradicted by independent surveys of those taking statins that suggest the prevalence of muscular aches and pains to be 100 times greater than reported in trials, along with numerous other problems of fatigue, depression, poor memory and concentration, sleep disturbances and reduced libido.

    I first became aware of the scale of this hidden epidemic of apparent statin-induced symptoms after describing in my Telegraph column the experience of a man in his seventies whose general health following the successful repair of an aortic aneurysm had gradually deteriorated to a state (as he described it) of ‘chronic decrepitude’ — such that when flying to Hawaii to attend his son’s wedding he had required a wheelchair at the various stopovers. Yet returning three weeks later he had walked back through Heathrow — having forgotten to pack the statins he had been taking since his operation.

    This account of his near-miraculous recovery following his statin-free excursion prompted hundreds of letters and emails from readers describing their own similar experiences. Those who had been previously fit and well were usually quick to spot the adverse effects on their wellbeing: ‘Within a couple of weeks I went from an active 65-year-old to a doddering old man,’ as one put it. Most only realised the devastating impact of statins on their lives when advised by friends and relatives to stop taking them.

    Thus the ‘bottom line’, as Professor Abramson describes it, is that for more than 95 per cent of those taking statins, they neither prolong their lives nor prevent serious illness while some may experience side effects ranging from the ‘minor and reversible to the serious and irreversible’.

    Abramson’s trenchant critique of this unprecedented experiment in mass medication — and its consequences — raises the question of how it has come about. Here two distinct, if interrelated, factors are highly relevant. The first is the progressive entanglement and blurring of the boundaries of interest between the pharmaceutical industry and the medical profession. Many of the ‘key opinion leaders’ (or KOLs as they are known to the industry), the senior physicians and experts involved in one way or another with evaluating and promoting the widespread use of statins, have ties with the drug companies that manufacture them and are rewarded for their efforts. Next, if more obscurely, the argument for widening the constituency of those taking statins is predicated on an influential, if speculative, theory much favoured by epidemiologists and public health experts known as ‘the population approach’. This maintains that, rather than focusing efforts on those at ‘high risk’, the prevention of common illnesses – such as heart disease – is best achieved by lowering the average cholesterol level in everyone (‘the population’).

    Within this context it is possible to trace the rise of statins over the past 30 years, starting with the presumed link established back in the 1980s of the causative role of cholesterol in circulatory disorders — the thesis that those indulging in (for example) bacon and eggs for breakfast raised the levels of cholesterol in the blood and this in turn clogs up the arteries, increasing the risk of a heart attack. The imagery is powerful, if simplistic. There is (perhaps surprisingly) no correlation in the pattern of heart disease over the past 60 years with trends in the consumption of ‘high fat’ foods such as meat and dairy products. Cholesterol cannot be entirely innocent, even if it plays a vital role in many bodily functions. Those with a genetic defect resulting in markedly elevated levels are undoubtedly at greater risk of heart disease.

    The many attempts to encourage people to switch to a ‘healthy’ low fat diet were not successful, prompting a switch of emphasis in favour of cholesterol-lowering drugs. The results of the trial of the first statin, Lovastatin — developed by Henry Gadsden’s company and launched in 1987 — were certainly encouraging in this regard. Soon enough several other drug companies, recognising its bounteous potential, came up with their own versions and in the subsequent scramble to secure a share of this lucrative market, the clinical trials assessing their efficacy were transformed into an ingenious and highly successful form of marketing. Organised on a massive scale involving up to 10,000 patients, their favourable results — announced with great razzmatazz at major medical conferences — generated an almost evangelical zeal for the project of ‘statins for all’.

    Meanwhile, successive expert committees charged with establishing ‘clinical practice guidelines’ have invoked the principle of ‘the lower the cholesterol the better’ to reduce the cut-off point for initiating treatment to well below the ‘normal’ or mean cholesterol level — expanding by millions the number eligible for statin therapy. Doctors were still free to use their clinical judgement as to whether or not to adhere to these guidelines. But this changed in 2003 when the Department of Health, strongly influenced by the proponents of the ‘population approach’, linked general practitioners’ remuneration to their success in achieving predetermined targets obliging them to assess the ‘cardiovascular risk’ in all their patients and prescribe medication to lower it. Circulatory disorders are strongly age-determined, so general practitioners can maximise their income by the simple expedient of routinely prescribing statins to the elderly — who are, of course, more vulnerable to their potential side effects.

    By now it will be apparent that in one way or another a considerable proportion of the medical profession from the KOLs to humble general practitioners, epidemiologists and public health doctors are committed to supporting statins — and they have no avenue of retreat. They can scarcely concede it might not, after all, be a good idea to prescribe potent drugs to vast sections of the population. And it has recently emerged that statins, besides everything else, may also cause diabetes in almost 2 per cent of those taking them — a small percentage, one might think, until one does the sums and realises this adds up to more than 5,000 new cases a year, and 27,000 over a five-year period. And diabetes, as we all know, is a serious condition, not least in predisposing people to those circulatory disorders the statins are intended to prevent — along with impaired vision, neuropathy and impotence.

    The drug companies have obviously played a central role in orchestrating the rise of statins. That is only to be expected and indeed one can almost imagine the shrewd Henry Gadsden admiring the elegance of the strategy with which his successors have realised his vision — recruiting those KOLs to the cause and exploiting to their considerable advantage the epidemiologists’ ‘population approach’ and government policy on the remuneration of family doctors. Many might rightly be concerned at the unflattering insight into the current intellectual state of medicine where doctors should so uncritically endorse the findings of industry-funded clinical trials.

    But there is more than this. Biology is complex and the biology of cholesterol very complex, since cholesterol is the foundation for several important hormones and integral to the structure of cell membranes. There is little doubt that it plays a role as a contributory — if not determinant — factor to circulatory disorders, but it is folly to suppose it might be possible to reduce its concentration in the body without running into unexpected problems.

    I am haunted by an image drawn from the many experiences of readers related to me over the last few years. It is of a woman in her mid-seventies whose physical aches and pains, progressive immobility and deteriorating memory are, her family doctor has advised her, only to be expected at her age. That evening before retiring to bed she takes a daily dose of the most commonly prescribed drug in Britain.