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Why the stats about statins don't tell the whole story

For those without the relevant risk factors, statins aren't the wonder-pill they've been sold as by the media.

Maggie came hot-foot from a “health check” where she’d had her cholesterol measured. “Six point two!” she told me. “The nurse said that’s high.” She sounded rather spooked. “I’d like you to give me a statin.”

I’ve known Maggie for years. She’s a sensible academic in her early fifties. She’d done enough googling to learn that a “high” cholesterol means you are “at risk” of cardiovascular disease (CVD) – heart attacks and strokes – and that statins lower cholesterol and reduce CVD risk by 25 per cent. Her request for treatment made perfect sense to her . . . except she had fallen for the same myth that leads to several million people in the UK swallowing a statin every day for no good reason at all.

Focus for a moment on that 25 per cent risk reduction. If you’re at high risk of something nasty, then lopping off a quarter of that risk makes sense. The people at greatest risk of heart attacks and strokes are those who have previously suffered one. Giving statins to these patients (secondary prevention) does convey modest benefits. If you take 100 heart attack survivors and get them to take a statin for five years, you’ll save one life, prevent two or three non-fatal heart attacks, and avert one stroke. That is worthwhile, even if the statins will fail to prevent at least 15 other heart attacks/strokes, and will cause two patients to develop diabetes, and provoke muscle weakness in ten others. Notice, though: 95 per cent of these highest-risk patients will derive absolutely no benefit from their five years of statin consumption.

Come back to Maggie. Using a statin on someone without existing CVD is termed primary prevention. Maggie has no other risk factors (high blood pressure, smoking, diabetes, and so on) and so her chance of developing heart disease is very low. In Maggie’s case, because her risk is so small to start with, a 25 per cent reduction is minuscule and meaningless. You’d have to treat hundreds of Maggies for years on end to hope to make a jot of positive difference to one of them, and the side effects from statins (we’re still discovering what these are) will far outweigh any putative benefit.

There are large numbers of people just like Maggie who are taking statins and who should come off the tablets. But what about individuals at greater risk – people with high blood pressure or obesity, or smokers? Is there a level of risk at which primary prevention is worthwhile? For some time the UK’s National Institute for Health and Clinical Excellence (NICE) has suggested a threshold of 20 per cent risk over ten years.

At first glance, the trial data does suggest a marginal impact at this sort of level: roughly two heart attacks/strokes are averted among 100 people treated for five years. But, crucially, death rates are not altered; no lives are saved by using statins. This probably reflects the harm also caused by statins, and how any small reduction in CVD is negated by disability and death from other causes.

Taking up regular exercise, or adopting a Mediterranean diet, reduces CVD risk by degrees comparable with statins – in the case of diet, substantially more so. If someone smokes, quitting is similarly helpful. What’s more, once one has adopted these lifestyle changes, statins become virtually redundant. Lifestyle modification is also cheap; there are very few harms besides. And, unlike with statins, these measures protect against other causes of death and disability, such as cancer and the frailties of advancing age. Oh, and they’re good for mental health, too.

This February, NICE initiated a consultation on halving its primary prevention threshold to 10 per cent risk. If achieved, this would add hugely to the six million people in the UK who take statins on prescription. Rather than exacerbate our statin fetish, NICE could design simple decision aids that would help doctors understand the more effective improvements that lifestyle changes can bring to health and well-being – and which would illustrate these benefits to patients.

Once we’d talked things through, Maggie resolved to start attending the university gym a few times a week. She decided to forget the statin prescription, too. As a nation, we’d do well to try the same. 

This article first appeared in the 26 February 2014 issue of the New Statesman, Scotland: a special issue

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Haystack in a haystack: travels around the human genome

Siddhartha Mukherjee’s book is a tourist guide to the twenty-first century’s uncharted continent, the human genome.

My favourite quotation from Charles Darwin: “Ignorance more frequently begets confidence than does knowledge.” In that brief sentence, the founder of modern biology unknowingly summarised in advance the history of genetics, from the eugenical ideas of his half-cousin Francis Galton to Bill Clinton’s statement that the human ­genome sequence was “the most important, the most wondrous map ever produced by humankind”.

The eugenics movement led to ­disasters known to everyone. It is not yet dead: Francis Crick once claimed that “no newborn should be declared human until it has passed certain tests regarding its genetic endowment”, and our own government’s decision to deny child support to poor people irresponsible enough to have more than two offspring (the agent of the policy has four) is in the same tradition. As a reminder of our ignorance, the DNA chart looks more like a medieval atlas than a modern map – with geneticists, in unconscious parallel to Swift’s words, the geographers who “in Afric maps/With savage pictures fill their gaps,/And o’er inhabitable downs/Place ­elephants for want of towns”.

Siddhartha Mukherjee’s book is a tourist guide to the new Africa, the human genome. The chart of that continent does indeed have too many metaphorical elephants and a noticeable shortage of productive towns: there are only about 20,000 working genes in the conventional sense, rather than the millions once assumed to exist (and why do tomatoes have more than we do?). They are surrounded by vast numbers of more or less mysterious molecular beasts, some of them parasites that invaded long ago, others the mouldering corpses of once-noble creatures, and yet more – the so-called junk – known more in its anatomy than in what it actually does. Lengthy as this book is (and Mukherjee might have gained from turning to his own account of the genome’s ability to cut out redundant and repetitive sections), it gives a full and lively account of the development of the subject, from its birth in the 19th century to its infancy in the 20th and its uncertain adolescence in the 21st.

Mukherjee begins the book with a melancholy tale of the schizophrenia that attacked two of his uncles and his cousin, and caused his own father to worry that elements of the illness “may be buried, like toxic waste, in himself”. Other family members had blamed the madness of their relatives on the horrors of Partition in India in 1947, which led to millions of deaths. Now, however, it has become clear that a predisposition to the condition, and particularly to the variety known as bipolar disorder (doctors have abandoned the old name “manic ­depression”), has a strong hereditary component, and Mukherjee confesses that part of the impetus for writing The Gene: an Intimate History was a personal concern about his own offspring. In this it resembles his 2011 work on cancer, The Emperor of All Maladies, which he describes as a biography rather than a work of popular science.

The problem with genetics is that it lends itself too readily to anecdote. When teaching, I begin my own first-year course on the subject by telling the students: “I am a geneticist and my job is to make sex boring.” They look somewhat bemused, but after 20 lectures that fight through pedigrees, linkage mapping, population genetics, inbreeding, heritability, mutation and the like, I can tell that they agree heartily – and I’ve not even started to talk about the mechanics of sequencing or the horrors of bioinformatics, which have turned much of biology into computer science. Instead, to leaven the mix, and much as I secretly regret it, I plunge again and again into the Swamp of Storytelling and revel in colourful and often tragic tales of Sex, Age and Death (a phrase I once planned to use as a book title but made the mistake of mentioning to Bob Geldof, who stole it for one of his albums).

Mukherjee does the same, and often succeeds. I did not know that Gregor Mendel twice failed in his attempts to enter teacher training college; that the founder of (and donor to) the notorious “genius” sperm bank of the 1980s, the Nobel prizewinner William Shockley, may well have had autism, another condition with some genetic component; nor that the human genome paper was the longest ever published in Nature. And I learned perhaps more than I needed to know about the sordid disagreements between public and private genome mappers, the latter anxious to make millions, even billions, from the map, and the former who saw it as a public good. The good guys won in the end, though the American molecular diagnostics company Myriad Genetics managed to leap in just in time to patent the two genes that can cause breast cancer when they go wrong.

On his trek across the genetical landscape Mukherjee gives an exhaustive account of the development of the modern science of inheritance. He has talked to many of the main players and gives deep insights into their moments of discovery. He does sometimes fall a little too hard for the latest scientific fashion, the most glittering (or tawdry) of which is epigenetics, the interaction between gene and environment. The term was coined by one of my own teachers at Edinburgh, C H Waddington, a student of fruit fly development. He found that a sudden heat shock to the embryos led to the appearance of a few flies with abnormal wings among the adults. By breeding from these, he could obtain stocks that in time produced such flies with no need for a shock, proof that an environmental stress could uncover hidden genetic variation. Unfortunately, the term has been hijacked and turned into a universal bridge between chemistry and biology. It is even used to revive the discred­ited idea that an organism can pass on characteristics acquired in its own lifetime.

That bridge goes far too far. The idea that genes respond to external stresses can be traced to the first days of molecular genetics, when it became clear that some genes regulate the activity of others when a creature is faced with a shift in food, or temperature, or some other external stress. In part it is a statement of the obvious: go out in the summer sunshine and the average Briton will get a tan, because skin cells respond to an alarm call by a protein that senses cellular damage to summon up dark granules of melanin around the DNA in order to protect it. His or her children, though, will be born pink. Quite why there has been such a fuss about a concept invented 70 years ago is not clear and is made no clearer here.

The book ends where it began, with schizophrenia. That illness is a microcosm of Darwin’s aphorism on ignorance. Freud blamed the condition on “unconscious homosexual impulses”, while others were just as confident that it was brought on by hostile mothers. Then the pendulum swung towards treating it as a genetic disease almost as straightforward as haemophilia. Some cases, like those described in Mukherjee’s opening pages, do indeed run in families, but many more are sporadic and appear among kindred that have no history of the problem. For the latter, the new genetics has revealed hundreds of gene mutations in affected children that are not present in their parents. For the former, the story is not so simple. Certainly, genes that predispose to the condition can be passed on, but various families may inherit different genes yet show similar symptoms, and particular combinations of genes rather than single elements may be responsible for the illness.

As this book puts it, the search for the genes behind mental disorder is not like searching for a needle in a haystack, but for a haystack in a haystack. Even for highly heritable attributes such as height, the quest for genes has been baffling, given that more than a hundred are known to be involved in such variation but altogether do not represent even a tenth of the number needed to explain the similarity of parents and children. Unpalatable as this may be for us mere Mendelians, almost every human gene, in effect, may influence almost every one of our attributes, which will be no fun for tomorrow’s molecular cartographers. Even so, and tangled as it already is, Mukherjee does a good job of cutting away the web of ambiguity and complexity that scientists have woven since the happy days when Mendel counted the ratio of round to wrinkled peas in the garden of Brno’s abbey.

Another Darwin quotation, this one from The Voyage of the Beagle:

There are several other sources of enjoyment in a long voyage . . . The map of the world ceases to be a blank; it becomes a picture full of the most varied and animated figures. Each part assumes its proper dimensions: continents are not looked at in the light of islands, or islands considered as mere specks, which are, in truth, larger than many kingdoms of Europe. Africa, or North and South America, are well-sounding names, and easily pronounced; but it is not until having sailed for weeks along small portions of their shores, that one is thoroughly convinced what vast spaces on our immense world these names imply. 

Very true, but for his genetical descendants the expedition has only just begun. 

Steve Jones is Emeritus Professor of Human Genetics at University College London and the author of “No Need for Geniuses: Revolutionary Science in the Age of the Guillotine” (Little, Brown)

The Gene: an Intimate History by Siddhartha Mukherjee is published by Bodley Head (608pp, £25)

This article first appeared in the 16 June 2016 issue of the New Statesman, Britain on the brink