快猫短视频

So you think you鈥檙e healthy? You are in your 40s, feel right as rain, normal blood pressure, normal cholesterol, pretty good diet, occasional exercise. How would you react if your doctor suggested you take a powerful drug every day for the rest of your life?

The drug, known as a statin, will lower your cholesterol even further and reduce your risk of a heart attack or stroke. According to one recent estimate, most men and many women over 40 could benefit from the drugs. If you are worried about side effects, your doctor will reassure you that a meta-analysis that pooled data from 14 trials involving more than 90,000 people shows the treatment is very safe. The same study suggests that even if your cholesterol level is normal, taking a statin can still reduce your cardiovascular risk. And the greater your risk 鈥� if you smoke, suffer from high blood pressure or diabetes, or have a family history of heart disease, for example 鈥� the greater the potential benefits.

鈥淟owering cholesterol is beneficial in pretty much everyone who has been studied,鈥� says Colin Baigent, who coordinated the meta-analysis by the Clinical Trial Service Unit (CTSU) at the University of Oxford. 鈥淚t doesn鈥檛 really matter what the cholesterol level is. It could be average or even low, but if you reduce it even further in a person who is at high risk you get benefits.鈥� Statins also have anti-inflammatory properties, and have shown promising results when used to treat diseases like rheumatoid arthritis, multiple sclerosis and Alzheimer鈥檚. Some research even suggests they can help tackle viral infections such as hepatitis C and HIV.

Can any drug really be that good? As enthusiastic doctors put ever more people on statins, sceptics are warning that we don鈥檛 know enough about the possible adverse effects of taking them over a lifetime. Others claim that statins鈥� potency against heart disease has little to do with lowering cholesterol and instead results from their anti-inflammatory properties, leading some to dismiss them as 鈥渆xpensive aspirin鈥�. So could the rush to put millions more people on statins be a costly mistake?

The association between cholesterol, its transport in the bloodstream by a protein called low-density lipoprotein and heart disease is fairly well established. Cholesterol in the form of LDL, so-called 鈥渂ad cholesterol鈥�, can infiltrate the walls of coronary arteries, contributing to the formation of a fibrous plug of immune cells called a plaque. If this ruptures it can trigger the formation of a blood clot that blocks the artery and starves the heart of oxygen 鈥� a heart attack, in other words. Equally disastrously, the clot can break free and block arteries in the brain, triggering a stroke.

Statins were originally isolated from fungi in the 1970s by Japanese biochemist Akira Endo. The first statin on the market, lovastatin, was approved by the US Food and Drug Administration in 1987, and currently there are seven statins sold worldwide, some purified from fungi, others synthetic, which vary slightly in their effects (see right).

Statins are thought to prevent heart attacks and strokes by reducing the level of the 鈥渂ad鈥� LDL cholesterol in the blood. They bind to an enzyme called HMG-CoA reductase and block the first step in the liver鈥檚 cholesterol-synthesis pathway, causing the amount of cholesterol in the membranes of liver cells to plummet. The cells respond by producing more surface receptors for LDL cholesterol, which pull it out of the blood.

It now seems that the further you reduce your LDL cholesterol levels, the better. This was borne out last year by the CTSU meta-analysis (The Lancet, vol 366, p 1267). It found that over a five-year period, statin therapy reduced the risk of major cardiovascular events such as a heart attack or stroke by about a fifth for every millimole reduction in LDL cholesterol per litre of blood, regardless of how high or low people鈥檚 levels were to start with (an LDL cholesterol level below 3.5 mmol/l is usually regarded as healthy).

However, it is also becoming clear that statins have a wide range of other effects on the body, perhaps because blocking HMG-CoA reductase inhibits the production of many other molecules besides cholesterol. There is growing evidence, for instance, that their efficacy in preventing cardiovascular disease could be at least partly due to reducing inflammation. Two studies published last year in The New England Journal of Medicine (vol 352, p 20 and p 29) found that statins鈥� beneficial effects correlated with falls in levels of C-reactive protein, an indicator of general inflammation, independently of any effect from cholesterol reduction.

This makes sense because for some time now doctors have suspected that the build-up of plaques in blood vessels is an auto-immune disease triggered by a bacterial infection (快猫短视频, 11 January 2003, p 36). Statins also seem to help people with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, and they are known to counteract the effects of gamma-interferon, an important immune signalling molecule associated with these diseases.

Expensive aspirin

Aspirin is another drug that reduces inflammation as well as preventing blood clotting. Low daily doses reduce the risk of heart attack in men by around a third. 鈥淧eople have used the term 鈥榚xpensive aspirin鈥� to describe the statins, because the benefit is about the same,鈥� says Morley Sutter, a pharmacologist at the University of British Columbia in Vancouver, Canada. Of course, aspirin is not free of side effects: most notably, it increases the risk of stomach bleeding.

The inflammation findings are highlighted by the minority of researchers who think lowering cholesterol is the wrong way to prevent cardiovascular disease. Yet Richard Peto, an epidemiologist at the University of Oxford, insists that cholesterol must take the lion鈥檚 share of the blame. As evidence, he cites familial hypercholesterolaemia, an inherited condition caused by a defect in the receptor for LDL cholesterol: people with the condition are unable to clear LDL from their blood and have a much higher risk of heart disease. Peto has little time for speculation about statins鈥� anti-inflammatory effects. 鈥淪ome people want to make things too complicated. We know that LDL particles are causative and that these drugs reduce them.鈥�

Even so, there are anomalies that have yet to be explained. These include the so-called French paradox: southern European countries like France where the rate of heart disease is much lower than in the UK, despite the risk factors, including cholesterol levels, being similar. One of the many proposed explanations for this is that more exposure to bright sunlight in these countries protects against heart disease by stimulating synthesis of vitamin D in the skin (快猫短视频, 9 August 2003, p 30). This idea is supported by studies in the US showing a correlation between living at higher altitudes 鈥� where exposure to ultraviolet light is greater 鈥� and lower risk of heart disease.

David Grimes, a doctor at the Royal Blackburn Hospital in Lancashire, UK, goes so far as to suggest that statins bind to the same receptors as vitamin D (The Lancet, vol 368, p 83). He notes that there is a close match between the conditions that statins treat or prevent and those in which vitamin D may play a preventive role, including coronary heart disease, multiple sclerosis, transplant rejection and rheumatoid arthritis. 鈥淭he immense benefits of statins may have nothing to do with cholesterol,鈥� he says. 鈥淚t might turn out to be an expensive way of giving vitamin D.鈥� Michael Holick, a vitamin D specialist at Boston University, says it would be easy to test whether statins bind to vitamin D receptors, and his lab is considering doing just this. 鈥淚t could either give a major new insight about statins and vitamin D, or put the idea to rest.鈥�

Whatever the mechanisms, though, no one doubts that statins do work. The CTSU meta-analysis showed that the greater the cardiovascular risk a patient faces 鈥� whether related to age, smoking, hypertension, diabetes or a previous stroke or heart attack 鈥� the more they benefit. Recent studies suggest that statins not only help prevent heart attacks, but also reduce the damage a heart attack causes. Such findings have made statins the biggest-selling prescription drugs ever, with global sales of $26 billion in 2004, a figure that looks set to rise even higher. 鈥淪tudies indicate that the drugs are very safe, so the question then really just becomes a social and economic one,鈥� says Baigent. 鈥淵ou essentially go down the risk levels until you run out of money.鈥�

So who should get statins? Guidelines vary greatly. The European Society of Cardiology defines a person to be at high risk if they have a 5 per cent chance or greater of suffering a fatal cardiovascular event in the next decade or by age 60 (see Table). One study estimates that in Norway 鈥� one of the healthiest nations in the world 鈥� this would include a staggering 85 per cent of men and 20 per cent of women over 40. The ESC recommends such people should be given lifestyle advice, followed by drug treatment if they fail to reduce their cholesterol levels.

There is no doubt that stopping smoking, improving your diet and getting more exercise can make a big difference. The trouble is that most of us do not change our lifestyle. 鈥淢ost people in industrialised countries probably do need to be on statins if they have risk factors because it鈥檚 so hard to achieve the same cholesterol-lowering using diet alone,鈥� says Michael White of the University of Connecticut, Storrs.

鈥淢ost people probably do need statins if they have risk factors鈥�

Balancing act

Some doctors, however, are alarmed by the trend towards dishing out statins to millions more people and giving higher dosages to lower cholesterol even further. They say the benefits for those who do not already have heart disease are small, while the potential risks are largely unknown. 鈥淲hat price should you pay for a modest effect?鈥� Sutter asks. 鈥淭he price shouldn鈥檛 be very high because the effect is weak at best.鈥� A 20 per cent reduction in cardiovascular risk may sound impressive, but it doesn鈥檛 look quite as good when you realise what it means for each individual: if your risk of having a heart attack over the next five years is 5 per cent, say, then taking statins will reduce it only to 4 per cent.

The CTSU meta-analysis found the chances of dying from any cause fell by just 1.2 per cent for those on statins, while the benefit for people who have not already suffered a heart attack or stroke works out at 25 fewer 鈥渕ajor vascular events鈥� over five years for every 1000 people on the drugs. That means 975 out of 1000 people risk side effects without any clear benefit during the first five years. The meta-analysis, however, also confirms that it takes time for statins to have an effect and that the longer you take them the more difference they make, but it has yet to be shown that this is still true after 20 or 30 years.

Sutter and others say that statin researchers have failed to report adverse effects in enough detail to allow doctors and patients to weigh the potential costs against the benefits. 鈥淭here鈥檚 no good reporting of adverse effects at high doses and very modest reporting even at moderate doses,鈥� Sutter says. 鈥淚f you are prescribed a statin, the doctor expects you to take it for the rest of your life,鈥� says Uffe Ravnskov, an independent researcher and former hospital doctor based in Lund, Sweden, who runs The International Network of Cholesterol Skeptics. He claims almost half of patients have adverse effects.

Alleged side effects include memory loss, extreme irritability, aggression, suicidal impulses and impotence. Evidence for these remains sketchy, however, coming from small trials and case studies. Statins do cause liver damage in around 1 per cent of patients, but this should be picked up by routine liver function tests and can be reversed by coming off the drugs. It is also clear that statins can damage muscles. As many as a fifth of people taking the drugs in trials say they experience some muscle weakness or pain, and exercise seems to make things worse. These symptoms are commonplace anyway in middle-aged and elderly people, however, and a similar number of patients taking a placebo also report them. So it is difficult to determine the exact extent of the problem.

In very rare cases statins cause rhabdomyolysis, a severe form of muscle damage in which the breakdown products cause kidney failure. The rate was especially high with cerivastatin (Baycol), which caused 50 deaths and was withdrawn in 2001.

Confusingly, some small studies have hinted that statins increase the risk of cancer while others suggest they may guard against it. The CTSU meta-analysis found no association between cancer and statins, and a similarly large study from the US, which looked at 26 trials involving 87,000 patients, also found no link (Journal of the American Medical Association, vol 295, p 74).

Most trials, though, have lasted only five years or less. For some this leaves lingering doubts. 鈥淵ou don鈥檛 get lung cancer after smoking for 10 years; it takes much longer to show up,鈥� Ravnskov points out. 鈥淗eavy smokers get lung cancer in their 50s and 60s and they have smoked for decades before that.鈥� Nevertheless, White, who led the US study, is confident that even after five years some signs of increased cancer risk would show up in trials. 鈥淲ithin the period we were looking at you should at least have started to see some trends,鈥� he says.

The crucial issue now facing policy-makers is how and where to draw the line that defines who should be offered statins. In the US and Canada, prescribing guidelines focus on lowering cholesterol below certain thresholds, depending on the individual鈥檚 overall risk of a heart attack or stroke. The lowering of the US target levels in 2004, which is leading to millions more people being put on statins, sparked controversy when it was revealed that eight out of the nine experts involved had ties to statin manufacturers.

In Australia, New Zealand and the UK, the emphasis is on treating those with the highest overall risk rather than on cholesterol targets. This year, a Canadian study that modelled the effects of applying the various guidelines concluded that the high-risk approach is more effective in terms of number of lives saved per number treated (BMJ, vol 329, p 529). It found, for instance, that applying the US guidelines would result in twice as many people taking statins as the New Zealand guidelines without preventing any more deaths.

Yet even the more conservative guidelines will lead to millions more people taking statins for the rest of their lives, often starting younger or being given higher doses. You could be one of them. If the advocates of statins are right, this policy will come to be seen as a triumph for preventative medicine, saving tens of thousands of lives. If the critics are right, for those with a low risk of heart disease statins could do more harm than good. Which will you bet your life on when your doctor mentions the s-word?