Will a statin a day really keep the doctor away?
This year health authorities have recommended most men over 50 take statins to prevent heart attacks and strokes. It’s triggered a ferocious debate. Elizabeth Finkel bravely wades in.
Congratulations to Cosmos Magazine editor in chief Elizabeth Finkel who is the winner of the 2015 Department of Industry and Science Eureka Prize for Science Journalism for this piece of long-form journalism.
Robert Browning, a California-based CFO of a life science company, is in his late 40s, has never been sick, is not overweight, and works out twice a week. But one day early last year when he went out for a walk he felt a sudden, strong pain in a small area of his right calf muscle. “It was as if someone had shot me in the leg,” he remembers. It was a muscle cramp so severe that he had to sit down, unable to walk or even stand.
After some research, Browning found that cramps can be a side effect of the only drug he was taking: Lipitor. His doctor had started him on the cholesterol-lowering statin a few weeks earlier after a test showed elevated cholesterol levels, raising his risk of heart attacks and strokes. Browning had never felt anything like that cramp before and was sure it wasn’t related to his exercises. So when another one happened close to the same area two weeks later, he decided to stop the statins for good. He has not had a problem since.
Plenty of healthy people like Browning have been prescribed statins to lower their cholesterol. Now they are at the centre of a fierce medical debate. On one hand, doctors say cases like Browning’s are common and that debilitating side-effects outweigh the benefits. On the other, researchers who analyse studies of hundreds of thousands of people under carefully controlled conditions say most of these “side-effects” are not related to statins. In their view, the evidence is in: the benefits of taking statins to prevent coronaries and stokes outweigh the risks.
It’s far from an academic debate. In 2014 health authorities in Britain and the US recommended widening the use of statins. These recommendations could see most men over 50 taking the drugs, amounting to a billion people worldwide.
Although statins are going off patent – Lipitor, the most popular, went off patent in 2011 – total revenues will keep rising, reaching one trillion US dollars by 2020 according to an estimate by John Ioannidis, a health policy expert at Stanford University.
There’s no doubt that by lowering cholesterol levels statins save lives in people with clogged arteries.
Naturally, many are suspicious that the long arm of drug companies is behind the push to “statinise” much of the world’s population. But many public health specialists believe the costs of widening the use of statins will be repaid in full by lowering the burden of heart attacks and strokes.
The debate has been explosive, rocking medical circles and reverberating in the media. The Australian TV show Catalyst even retracted two programs on the topic this May. And yet it is nothing new. The debate over whether people should lower their cholesterol levels with statins has been incendiary since the drugs were introduced two decades ago.
There’s no doubt that by lowering cholesterol levels statins save lives in people with clogged arteries, especially in those who’ve already suffered a heart attack or stroke.
But why wait: could taking statins prevent the blockage of arteries? Most heart attacks and strokes take place in people who’ve never had a symptom. That compelling logic has seen doctors prescribe statins to healthy people with high cholesterol for more than 20 years.
Until recently, the recommended threshold for prescribing statins was a 20% risk of having a heart attack or stroke in the next 10 years. That figure was based on a formula in which your doctor plugs in your cholesterol levels, blood pressure, smoking history, gender and age. But many doctors found their patients reported side-effects – muscle cramps, back pain, nausea, memory loss and more. So was it really worth their while taking the drugs?
Studies on human beings are notorious for reaching different findings. They may be poorly designed or there may be unseen “confounding” factors. The prime adjudicator is an international group of independent experts who do not take money from the pharmaceutical industry called the Cochrane Collaboration. They slash their way through the academic thicket, decide which studies are worth analysing, and then do a so-called “meta-analysis”. Typically, the studies that are selected meet the gold standard: randomised placebo-controlled trials. Patients are randomly assigned to a treatment group that receives the real pill, or to a placebo group that receives a drug-free but otherwise identical pill.
Until 2011, Cochrane researchers found no clear benefits to using statins for “primary prevention” – in other words, to treating patients with no symptoms of an impending stroke or heart attack. Then in January 2013 they changed their tune.
Asymptomatic people who took statins were having fewer heart attacks and strokes and were less likely to need surgery to clear blocked arteries. Overall, there were fewer deaths. They concluded:
“Statins are likely to be cost effective in primary prevention.”
The summary did not go unheeded. In January 2014 the American Heart Association published its new cholesterol guidelines. While they stressed the role of diet and lifestyle and the need to consider each patient individually, they also lowered the recommended threshold for using statins to a 7.5% risk over the next 10 years. Six months later Britain’s National Institute for Health and Clinical Excellence lowered its threshold for treatment from a 20% risk to 10% risk over the next decade. They estimated that even if only two million extra people took the drugs, 4,000 heart attack deaths, 14,000 non-fatal heart attacks and 8,000 strokes would be prevented – in health economic terms, a good trade-off for the estimated £29 million cost of using the off-patent drugs.
But not everyone was swayed by the Cochrane Collaborations’ finding.
ABC-TV journalist Maryanne Demasi had been watching with interest. A former PhD medical researcher she had been researching the topic since 2010. During the filming of a story in a cardiologist’s surgery she’d been astonished to find that a patient with a very high cholesterol level of 9mmol/L was not going to be put on statins. “His arteries are clean”, the cardiologist had told her and added: “You should do a story on this.” Demasi started watching the ructions in the medical literature over the role of cholesterol in heart disease.
The Cochrane review of January 2013 was her lighting rod. It seemed at odds with other evidence that questioned the role of saturated fats and cholesterol in the development of heart disease. She also questioned the wisdom of automatically placing people on statins to reduce that risk. Many of her interviews were carried out with John Abramson, a health care policy lecturer at Harvard Medical School who acts as an expert in legal cases against drug companies for people who believe they have been harmed by statins.
On October 24, 2013, the first of Demasi’s two-part program “The Heart of the Matter” went to air. The episodes operated like a one-two knock-out punch. The first questioned the evidence that saturated fats and cholesterol were the villains of heart disease. The second challenged the use of statins, especially in people who had not yet suffered a heart attack.
Watched by one and a half million viewers, Demasi’s program triggered a firestorm. Many in the medical community considered the program had seriously distorted the mainstream view in its first episode, a criticism helped by her choice of “experts”. Media Watch, another ABC-TV program, weighed in with background checks on them.
Nutritionist Johnny Bowden who claimed in the program, “when you look at the data, it’s very clear - everything that we have been told about saturated fat and cholesterol is a bold-faced lie,” turned out to hold a PhD from the Clayton College of Natural Health, an organisation with questionable credentials. Stephen Sinatra, though a bona fide cardiologist, was also found to be partial to “grounding”, the soaking up of electrons from the earth for better health. The two had co-authored a book titled The Great Cholesterol Myth – why lowering your cholesterol won’t prevent heart disease and the statin-free plan that will.
'More than one in five people on statins who saw the program made a change to their medication.'
The second episode was roundly criticised for failing to spell out that statins have been proven beyond doubt to save lives in people at high risk of heart attacks and strokes.
Australia’s National Heart Foundation was “shocked by the disregard for the extensive evidence”. Emily Banks, chairwoman of the Advisory Committee on the Safety of Medicines, commented to ABC news, “there will be people who didn’t have to have a heart attack, who will die through reducing use of statins”.
It was not an idle claim – studies have shown an increased rate of death in people who discontinue their medication. Banks’ concerns were realised. A National Heart Foundation survey of 1094 Australians conducted a month after the Catalyst program in November 2013 found “that more than one in five people on statins who saw the program made a change to their medication. Around a quarter of these people had previously had a heart attack.”
“Serious journalists within the ABC were questioning how a program like that got to air,” commented Norman Swan, presenter of the ABC’s radio program The Health Report and regular COSMOS contributor.
On May 12, 2014, the ABC announced it would pull both programs after an independent commission concluded that part two (on statins) had breached the ABC’s impartiality standards. Demasi remained uncowed. She said her intention had been to encourage debate and critical thinking. Though she had weakened her case by giving much of the airtime to fringe players, there’s no doubt she had support from high places – including the British Medical Journal.
In an extraordinary co-incidence, two days before Demasi’s first program went to air the esteemed journal published two articles that supported her take on the subject. The first was an opinion piece from Aseem Malhotra, a cardiology registrar at Croydon University in London. It took up the cause for saturated fats in an article headed, “Let’s bust the myth of its role in heart disease” which challenged the view that a high cholesterol level is a risk for healthy people.
The second, by Harvard’s John Abramson and colleagues, challenged the findings of the Cochrane Collaboration. In their view the benefits did not outweigh the risks of treating non-symptomatic people with statins.
The two BMJ papers created their own firestorm. Malhotra was criticised for taking the same sort of fringe view on cholesterol and saturated fats that Sinatra and Bowden had expressed on Catalyst – one that could lead high-risk patients to stop their medications. But there was a more serious problem.
Both articles claimed the side-effects of statins caused 20% of patients to stop taking the drugs. The figure came from an April 2013 study published in the Annals of Internal Medicine led by Alexander Turchin at Brigham and Women’s Hospital in Boston and his colleagues. In it, about half of the 107,835 subjects stopped taking their statins regularly. But not everyone stopped for a particular medical reason; some people just don’t like to take pills. Turchin’s study was designed to explore whether the side-effects from statins were serious enough to cause patients to give up on the drug.
Overall, he found 17.4% of the entire group reported a side-effect – the source of the figure cited by Abramson and Malhotra, who rounded it up to 20%. But only 11% of them actually stopped taking their pills. Turchin’s study also looked more closely at a subgroup of 6,500 patients who were encouraged to give statins a second try: 90% of them tolerated the drug, some at lower doses or after trying a different form of statin, and were still taking statins a year later.
The most informative reading of the study is that it was not 20% who could not tolerate statins, but far fewer.
So in fact only 10% of an initial group of refusers could not tolerate the drug. (Applying that fraction to the entire group means that only 10% of the initial 11% fall in this category. In others words, perhaps as few as 1% of people were truly intolerant of statins.) Turchin drew a different conclusion from his findings than Abramson and Malhotra. “We interpret these results as a glass half-full, meaning that there are potentially millions of patients who could take statins again, and ultimately reduce their risk of heart disease,” he wrote in a press release. Arguably then, the most informative reading of the study is that it was not 20% who could not tolerate statins, but far fewer.
Rory Collins, the co-director of Oxford University’s Epidemiological Studies unit, raised the alarm about the BMJ papers arguing that by overstating the true rate of the side effects the articles could influence high-risk patients to stop taking statins. He urged the BMJ to retract both papers. On May 15, 2014, the BMJ agreed to amend the statements about the side-effects. It also said it would ask an independent commission to check whether the articles should be retracted.
Collins had another reason to be chagrined. Abramson had challenged the 2013 Cochrane Collaboration findings. All their previous publications had urged caution in prescribing statins to people at low risk of heart disease and stroke, but then they changed their tune. They did so because of a study led by Collins and his colleague Anthony Keech at the University of Sydney.
“It was this work that set the ball rolling”, says Shah Ebrahim, an author of the Cochrane report. Published in the Lancet in May 2012, the report was based on the Cholesterol Treatment Trialists’ collaboration (CTT). This study of 170,000 patients is the most comprehensive one could imagine on the effects of statins. Begun in 1990, shortly after the introduction of statins, it has collated data on most of the randomised controlled trials of statins in populations around the world for 24 years. Although funded by the drug companies that developed statins, the studies have been run by academic researchers who pool their results, cross-check each other’s analysis and finally report using all the available data. “For the last 23 years we’ve met each November with representatives from each of the trials”, explains Keech.
Studies such as the 1994 Scandinavian Simvastatin Survival Study 4S showed statins reduced deaths in people who had already had a heart attack or stroke or were otherwise at high risk. But over the years the studies tackled different questions: Were statins useful for older people, for women, for people with existing diabetes, for people with high blood pressure?
But what about low-risk people such as Browning? Would they benefit from taking statins? CTT measured the rate of heart attacks, strokes, surgery to unblock arteries, and deaths in such people without evidence of disease. They were compared to a control group who did not take statins. They found that, for every unit of cholesterol lowered, people reduced their risk of a cardiovascular event by about 20%.
“The critical point was that, for the first time, an analysis of the effect of statins in people without disease but at high, moderate, low and very low risk was presented – it showed consistent benefits across all these groups,” explained Ebrahim.
Clinicians believe their patients when they complain of muscle pains or memory loss after taking statins.
Overall, the risk of serious side-effects was low. One in 10,000 reported a rare form of muscle breakdown known as rhabdomyolysis. There also appeared to be a 9% increased risk for developing diabetes. But overall, the patients gained by avoiding cardiovascular events. That was reflected in the final figures – overall a slight reduction (9%) in the risk of death from all causes. And for every unit of cholesterol lowered, there were 11 fewer cardiovascular events per 1,000 people. In an accompanying commentary in The Lancet in April 2012, Ebrahim, who serves as coordinating editor of the Cochrane Heart Group, and colleague Juan Pablo-Casas, paraphrased the findings of the CTT this way: “Men and women, old and young, and people with and without cardiovascular disease all benefit.”
Moreover, they suggested that medical guidelines should lower the threshold for taking statins to people whose risk was greater than 10% over 10 years – which includes 83% of men over 50 and 56% of women over 60. Indeed the title of their Lancet paper was “Statins for all by the age of 50?”
Abramson and colleagues were unconvinced. They re-evaluated the CTT meta-analysis – but in a curious way. They ignored the findings on reductions of heart attacks, strokes or surgery to clear blocked arteries because they considered these endpoints were subject to bias. Instead they focused on deaths from any cause. Their conclusion: for people whose risk was lower than 10%, statins did not significantly reduce the risk of death.
Abramson’s decision to focus only on deaths strikes some cardiologists as strange. “I refuse to believe that I should only do primary prevention to prevent total mortality,” commented Donald Lloyd-Jones at Northwestern University in Chicago, a member of the panel that developed the most recent US statin guidelines. “Patients are much more worried about having a stroke or a major heart attack and living with that; they’re not only focused on what’s going to kill them.”
He adds the only reason Abramson didn’t see a “statistically significant” effect in mortality is that in the lower risk group too few people died over the five-year course of these studies to observe a significant effect. Wait long enough, Lloyd-Jones says, and the “trend” will reach significance.
Nevertheless, Abramson and colleagues had many supporters. By late July, 2014, close to 500 people, including many doctors and researchers, had signed an open letter on the web site of the non-profit Lown Institute asking the BMJ not to retract the articles. This shows that “in the medical community (of) practitioners and researchers, a significant number of people are sceptical about the push to spread the use of statins to lower-risk patients,” says Vikas Saini, a cardiologist and president of the institute. “I certainly haven’t seen enough proof to warrant changing guidelines and prescribing statins to another billion patients on the planet.” On 1 August, the BMJ panel decided against retracting the two papers. But that’s hardly the end of the story.
What is one to make of it when medical titans do battle?
One reading is that the battle lines appear to be drawn between clinicians, who see individual patients, and epidemiologists, who see data on tens or hundreds of thousands of patients.
Clinicians believe their patients when they complain of muscle pains or memory loss after taking statins. When they go off the pills, they stop complaining. “I’m a simple man; that’s good enough for me,” says GP David Bailey in the BBC-TV program Trust me, I’m a doctor. Bailey refers to epidemiologists such as Rory Collins, who was also interviewed for the program, as being in an “ivory tower”.
But when patients are prescribed statins, some would doubtless read the packet information with its long list of possible side effects. What if they are imagining those ailments or falsely attributing new aches and pains and memory loss – all common in middle-age – to statins? It’s known as the nocebo effect – “the evil twin of the placebo effect” as Ben Goldacre, the celebrity author of Bad Science, puts it. To see it in action he suggests: “When sitting on a sofa with friends, suddenly ask: ‘does this thing have fleas in it?’.”
Could many statin side-effects be explained by nocebo?
“I’ve stopped trying to work it all out, because the patients’ beliefs are the most important factor,” admits David Sullivan, a physician and researcher at the University of Sydney. “I see a huge number of patients with these complaints, I don’t know to what degree it is the power of suggestion, but it’s a tragedy if they miss out on the benefits.”
In March this year two studies gave more weight to the power of suggestion. One was a meta-analysis published in the European Journal of Preventive Cardiology. Goldacre, who is also an epidemiologist at the London School of Tropical Medicine and Hygiene, was a co-author. He and colleagues trawled though 62 randomised controlled trials picking out 14 of the best primary prevention trials.
Their findings were stunning: “Cholesterol-lowering statins have almost no side effects,” blared the newspaper headlines.
Indeed, the paper found that with the exception of a slightly increased risk of diabetes, most common side-effects attributed to statins were found in the placebo group at around the same rate. These included:
- muscular weakness
- muscle aches
- a more than 10-fold increase of creatine kinase (a muscle enzyme whose levels rise after injury)
- back pain
- newly diagnosed cancer
- kidney problems
- gastrointestinal disturbance, nausea
- indigestion, diarrhoea or constipation
Despite the findings, Goldacre says he has reservations about concluding that “statins have almost no side-effects”. Most importantly, he has concerns that the data collected by randomised controlled trials, which are mostly funded by drug companies, do not necessarily reflect what happens with ordinary patients. This is because these trials routinely involve a “run-in” period, up to several months, to weed out subjects who won’t take their medication reliably. That’s important for reliable data collection, but also means that some people who really can’t take statins are left out.
Second, there are suspicions that industry-funded trials gild the lily. For instance, a 2012 Cochrane review compared trials that were funded by industry with ones from a non-commercial source. The results of the industry-funded trials were generally better. In another study in PLoS Medicine in October 2013, German researchers compared the final results that companies published to the raw data on which it was based. They found side-effects were significantly under-reported. This suspicion led Goldacre and others to co-found the ALLTrials campaign in January 2013, to petition drug companies to make their raw data freely accessible.
But it seems unwarranted to tarnish the CTT trialists with this broad brush; they are a collaboration of academics and they do have access to the raw data. It is true that they do not share that data outside their collaboration and are criticised by other researchers who would like to be able to check their calculations. But the trialists fear mischief, especially from drug companies seeking to discredit the data of their rivals or from other people with vested interests. Explains Keech, “the problem with ad hoc analyses are that they can use methods to produce a particular result. The most reliable analyses are the ones done using the methods we published in 1995. The rules were set out before we started.” And he points out these analyses are cross-checked by the academic collaborators: “Everything is replicated.”
Nevertheless, Ebrahim agrees randomised clinical trials have their problems and that the people they include may not represent the majority of patients. So he co-authored a paper looking at 90 studies of the side-effects observed in people being prescribed statins in the general population. The findings, published in March 2014 in BMC Medicine, turned out quite similar to those reported in Goldacre’s study: that is, that statins are safe. Interestingly, they found that statin takers appeared to be slightly protected against memory loss.
So how will the statins war be resolved?
More data is on the way from the CTT. Their past analyses focused on major benefits and major risks such as cancer or diabetes. Now Keech says they are collecting the data on the common, milder side-effects. This data, widely agreed to be the best that science can deliver, should finally rule on whether side-effects such as muscle pain or memory loss have anything to do with statins. Could the protective effect on memory be real? Many doctors are anxiously waiting to know. “It’s a mess out there. Doctors are pulling their patients off statins because of concerns over dementia. But mini-strokes are a major cause; I fear this (stopping statins) risks more harm than good,” says Bryce Vissel, who studies brain diseases at Sydney’s Garvan Institute.
So perhaps it’s just a matter of more time? Or not. As Sullivan points out “people have been arguing about statins for an awfully long time. Old habits die hard”.
How saturated fats affect our health
Saturated fats like those in butter, meat and palm oil raise total cholesterol and most health authorities will tell you to go easy: their use raises the risk of heart disease and stroke. Indeed, the rising rates of heart disease in India are believed to be related to the increased use of cheap palm oil instead of soybean oil.
But like statins, saturated fats find themselves embroiled in controversy. Last March a study published in Annals of Internal Medicine reported no benefit to swapping saturated fats for unsaturated fats such as those found in nuts or olive oil. The following June, Time magazine’s cover exhorted us to “Eat Butter”. But not so fast. Walter Willett, chairman of the Department of Nutrition at the Harvard School of Public Health, warned the March study was flawed. If saturated fat is replaced with sugars and starch, then it is true, you don’t see much health improvement. “However, if saturated fat is replaced with polyunsaturated fat or monounsaturated fat in the form of olive oil, nuts and probably other plant oils, we have much evidence that risk will be reduced.”
David Sullivan, a physician and researcher at the University of Sydney, agrees the dietary studies are messy. “The weight of evidence shows saturated fat is more associated with adverse outcomes. Butter should be taken as a treat.” And he warns against swimming with the new tide of “pleasure revenge”, taken by those gleefully embracing the return of animal fat into their diet.
A short history of statins
The 1950s saw a global epidemic of heart disease sweep through the Western world. A three-pronged body of evidence pointed to cholesterol as a prime suspect.
First, the arteries of people who’d suffered a heart attack were clogged by waxy plaques filled with cholesterol. Second, people with a genetic disease called familial hypercholesterolemia (FH) had blood cholesterol levels five times higher than normal, mostly packaged in tiny balls called LDL cholesterol. They had heart attacks as children or in their teens. In the less severe form of the disease, their cholesterol levels were two to three times higher than normal and they suffered heart attacks in their mid-30s. Finally, in many Western populations, cholesterol levels were rising in lockstep with the heart disease epidemic. The cause? It seemed at least in part attributable to a diet grown rich in saturated fats such as those found in butter and juicy steaks. Studies showed that saturated fats caused LDL cholesterol levels to rise. And the higher the levels of LDL cholesterol in the general population, the higher the risk of cardiovascular disease.
By the 1970s the case seemed closed: cholesterol was the villain. For many people, diet and lifestyle changes had only a modest effect on reducing blood cholesterol levels. So the race was on to find a drug that could interfere with the liver’s synthesis of cholesterol – it produces some 70% of the body’s stores. Japanese chemist Akira Endo figured that fungi would be a good place to start looking. Cholesterol is a major component of cell walls and fungi were known for making chemicals such as penicillin that disrupt the cell walls. Based at the Sankyo pharmaceutical company in Tokyo, Endo found an extract of an orange mould that blocked cholesterol synthesis by liver cells. It was the first statin, and went by the name mevastatin.
But statins did not work simply by blocking the synthesis of cholesterol in the liver. That was made clear by Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Centre who won the 1985 Nobel Prize for their discovery.
The clue came from people afflicted by severe FH. It turned out they lacked the gene to make “LDL receptors”. Like little hooks, the receptors sit on the surface of liver cells and haul in LDL cholesterol from the bloodstream. When the liver’s LDL cholesterol stores run low, more hooks are produced to haul in more cholesterol. But when the stores are high, fewer hooks are produced. Brown and Goldstein suspected these hooks were the key to regulating the levels of LDL cholesterol blood levels. People with severe FH had no hooks and had astronomical blood levels. People with a milder version of the disease, where they still had one active gene, produced half the number of hooks as normal people, and their cholesterol levels were about double the normal level.
When Brown and Goldstein tested Endo’s mevastatin in mildly affected patients it dramatically lowered their cholesterol levels. But it had no effect on the severe form of the disease. What that showed was mevastatin had to be lowering blood cholesterol levels in a two-step process. It lowered the liver’s reserve of cholesterol, which triggered liver cells to make more LDL hooks to pull cholesterol from the bloodstream. In patients with severe FH, unable to produce LDL hooks at all, mevastatin had no effects on blood cholesterol levels – proving that the key to lowering blood cholesterol levels was to increase the number of LDL hooks.
Statins were a great advance for the one in 200 people who suffer from mild FH.
But what about people whose cholesterol was high for other reasons?
From the outset there were concerns about the effects of lowering blood cholesterol levels in “normal” people. Cholesterol is a crucial raw material for the body. It is a major component of cell membranes (where 90% of the body’s cholesterol is found), a raw material for making ring-shaped steroid hormones and other important chemicals such as coenzyme Q, and also for bile salts that solubilise fats in the small intestine so they can be absorbed into the bloodstream. Many predicted it would be toxic to tamper with cholesterol – concerns that held back the development of statin drugs by Endo’s company, Sankyo, and also Merck which had developed a similar compound, lovastatin. Yet evidence suggested that cholesterol levels did vary widely between populations. Those of hunter-gatherer societies or rural Chinese villagers are as low as 2.5 mmol/L, half of what we consider normal.
Finally, in 1994 a Merck-funded trial, the Scandinavian Simvastatin Survival trial, ushered in the age of statins. For 4,444 people with high cholesterol (5·5-8·0 mmol/L) and suffering from cardiovascular disease, the study found their LDL cholesterol levels were lowered on average by 35% and their chance of dying of a heart attack was reduced by 30%. There was also a 37% reduction in the risk of needing surgery to unblock an artery. This was proof that people who’d already had a heart attack or angina would benefit from taking statins. The statin age had begun.