STATINS are among our most-prescribed medicines, with the cholesterol-lowering drugs being taken to prevent cardiovascular deaths for the past 35 years.
Supporters call them the best-studied drugs ever. Yet arguments still rage over whether they are even worth taking - or if patients are getting the right ones.
Now evidence is emerging that there may be more uses for these pills - from preventing cancer to staving off Parkinson's disease - with some suggesting that they may turn out to be more useful for these conditions than they are for heart disease.
In one example of this wider use for statins, in February, German scientists reported that statins may stop cancer tumours from spreading around the body - a process called metastasis - in more than 20 types of cancer, including breast, liver, stomach and bowel, by targeting a gene, MACC1, which drives the spread of the cancer.
This was based on data from 300,000 people who had been prescribed statins. The researchers, from the Max Delbrück Centre for Molecular Medicine in Berlin, also found that those taking statins had half the incidence of cancer compared with the general population.
If further trials confirm such findings, it would significantly add to the already huge market for these medicines.
Since the drugs first won approval in 1987, global sales have exceeded £765 billion.
The drugs were designed to protect people at high risk of dying from cardiovascular disease. Here, they work by limiting the production of 'bad' low-density lipoprotein (LDL) cholesterol, which can harden or narrow arteries.
They were developed originally for the secondary prevention of heart attacks or strokes - that is, reducing the risk of future events in patients who have already suffered one.
Now they are increasingly used for primary prevention - in people who haven't had a heart attack or stroke, but are deemed to be at risk. However, this use has been controversial, with critics saying it over-medicates people who will never suffer a cardiovascular event, and subjects them to possible side-effects that range from muscle ache to memory loss.
A new row broke out in March when a powerful study suggested that the evidence for statins' real-world benefit is "weak or inconsistent". International researchers, who reported their results in the prestigious journal JAMA Internal Medicine, had analysed 21 studies conducted between 1987 and 2021, which involved more than 140,000 people.
The investigators reported that overall for people on statins, the reduction in relative risk for heart attacks is 29 per cent, and 14 per cent for stroke. That sounds impressive.
However, the reduction in absolute risk was minute - 1.3 per cent for heart attacks and 0.4 per cent for stroke.
The difference between these two measurements is crucial.
If, say, your risk of getting a disease is two in 1,000 and a drug cuts it to one in 1,000, your risk compared with what it was before taking the drug would be an impressive-sounding 50 per cent. This is your relative risk.
However, your absolute risk reduction - meaning your overall risk in the real world - would still be cut by only one in 1,000, or 0.1 per cent, which is tiny.
This "modest" absolute risk reduction means that, according to the JAMA Internal Medicine study, 77 patients would need to take statins for 4.4 years on average to prevent one heart attack, the authors said, adding: "Most trial participants who took statins derived no clinical benefit."
Current NHS advice offers a slightly more impressive result - saying that around one in 50 people who takes a statin for five years will avoid a serious event such as a heart attack or stroke as a result.
The new findings call into question the fundamental point of statins: that by cutting 'bad' LDL cholesterol they save patients' lives, says Dr Paula Byrne, a researcher at the Royal College of Surgeons at the University of Medicine and Health Sciences in Ireland, who led the new study.
In fact, she says: "The evidence to show that cutting LDL cholesterol as much as possible to reduce the risk of heart attack or stroke is surprisingly weak and inconsistent. In some studies, it simply didn't reduce the risk at all."
Dr Byrne warns that while thresholds for 'high' LDL cholesterol levels have been steadily lowered, the proportion of people in Europe eligible for statins has risen (from 8 per cent in 1987 to 61 per cent in 2016), and the drugs may not actually help many patients.
"The overall benefit of taking statins may be small and will vary depending on an individual's personal risk factors, such as smoking, having high blood pressure, being overweight and having a family history of heart disease," she says.
Such small benefits have to be weighed against the potential risks of side-effects - and other unintended consequences. If patients think their statins are protecting them from heart attack and stroke (when they aren't), they may not exercise, lose weight or stop smoking, which are vital preventative steps.
Such fears are dismissed by Naveed Sattar, a professor of metabolic medicine at Glasgow University. "This study does not consider that most people use statins for several years or decades," he said.
"Statins do lower mortality if you give them to people with high enough risks for long enough.
"I take statins," he adds. "If you speak to cardiologists who know the evidence, quite a lot of them are taking them, too. In terms of drugs, they are the best studied of everything, and all the clinical trials show benefit.
"My statistical risk of having a heart attack is 13 per cent to 15 per cent," he says. "I'm 54, fit and active and don't smoke, but my father and brother both had heart attacks before the age of 55.
"Years ago, Nice [the National Institute for Health and Care Excellence] recommended that anyone with a risk of 10 per cent should be considered for statins." Professor Sattar acknowledges that significant levels of 'bad' LDL cholesterol alone may not itself be a danger.
"The toxicity of cholesterol depends on your other risk factors," he says. "If, for example, you're overweight, smoke, are male and [of] South Asian [heritage] - all risk factors for heart disease and stroke - then your cholesterol may form dangerous plaques."
And he argues that many more people could benefit: "Statins are so cheap that it's now cost-effective to treat people with risks that are down to about 6 per cent."
While UK statin prescriptions almost doubled between 2008 and 2018, dispensing costs plummeted from £460 million to £96 million, thanks to commonly used statins, such as atorvastatin, coming off patent. Generic versions cost as little as £1.50 for 28 days' worth.
As for sceptical studies about statins' worth, Professor Sattar says: "It's often about how they write the narrative, rather than the facts. My sense is that there is a proportion of society that does not like the concept of a simple pill that can reduce heart disease.
"It is perfectly good to offer people statins: you just have to ask what level of risk outweighs the benefits," he argues.
"I know for a fact that a statin does not cause me any side-effects. Risks of serious harm are very rare."
Nevertheless, a new report says that as many as half of UK patients stop taking statins or take them only irregularly due to side-effects such as muscle aches, headaches, dizziness, nausea and insomnia. Rarer problems include memory loss and erectile dysfunction.
And yet the cardiologists from the Medical University of Lodz in Poland who wrote this report claim that up to 70 per cent of the side-effect symptoms are, in fact, just in patients' minds.
The paper, published in the Journal of Cachexia, Sarcopenia and Muscle, dismissed most patients' troubles as imaginary, driven by fears of side-effects stoked by stories on the internet, cautions on drug leaflets and gossip from friends and family.
Yet questions about statins' benefits remained before the JAMA Internal Medicine report.
The drugs don't lower cholesterol in half of British patients who have taken them for two years, according to a study of more than 165,000 people by Nottingham University.
The target for statins set by Nice is a reduction of 40 per cent or more in LDL cholesterol.
The Nottingham Heart study, published in 2020, found that patients who failed to reach the 40 per cent reduction after two years were 22 per cent more likely to develop cardiovascular disease than those who responded well.
The researchers said that patients' genetic make-up may cause some of the treatment failure, which highlights a need for doctors to treat each patient as an individual.
This was reinforced last month by Manchester University research which discovered the three statins best for people with type 1 or type 2 diabetes.
The study, published in The BMJ, analysed the effects of seven statins in 42 trials involving more than 20,000 adults. It didn't solely measure LDL cholesterol, but used a newer measure adopted by Nice last year. Known as 'non-HDL-C', it can be simply calculated by doctors by subtracting HDL (or 'good cholesterol') from patients' total cholesterol levels.
Previously NHS cholesterol tests primarily examined levels of 'bad' LDL cholesterol. Experts say the new approach is "more accurate and cost effective".
The BMJ study found that rosuvastatin at moderate and high doses, and simvastatin and atorvastatin at high doses were the most effective for patients with diabetes.
Dr Alexander Hodkinson, a health data scientist at Manchester University, who led the study, said that despite statins having been prescribed for decades, we still know comparatively little about which might work best for whom.
"We looked at diabetic patients because often statins don't work too well for them," he says.
But while investigators are beginning to use better measures to discover which statins might work best for individual patients, other doctors are pioneering new potential uses for the drugs.
They hope that statins might prove to be a medical Swiss Army knife that can help with a wide range of diseases.
The researchers at the Max Delbrück Centre for Molecular Medicine in Berlin said that the spread of cancer is driven by the MACC1 gene. When they then ran computer tests to see which drugs might suppress the MACC1 gene, they hit upon statins.
The scientists then gave statins to mice genetically modified to have highly active MACC1. The cholesterol drugs almost completely suppressed the formation of metastases.
"We are still at the very beginning," stresses the lead researcher, oncology professor Ulrike Stein.
"Mice are not human beings, so we cannot directly transfer the results." She plans to run clinical trials on people.
Professor Stein's work may explain results published last year in the journal Cancer, which reported a 58 per cent greater survival rate among patients taking statins who had a particularly aggressive form of breast tumour called triple-negative breast cancer.
Breast cancers normally have one of three known gene receptors that drugs can be used to target. About one in six breast cancers lacks these, making them harder to treat. These are the triple-negative breast cancers.
The new research, from the University of Texas, looked at data from 23,192 women with triple-negative breast cancer and found that those who had coincidentally started taking statins in the year following their diagnosis were 58 per cent more likely than usual to have survived for three years at least.
The association was strongest in women with early stage triple-negative breast cancer taking a high dose of statins.
Dr Kevin Nead, a radiation oncologist who led the research, says: "We know that statins decrease breast cancer cell division and increase cell death in laboratory studies."
Dr Nead plans a trial using statins as a cancer therapy.
More controversially, experts at Rush University in Chicago are exploring whether statins might protect against Parkinson's disease, after finding that older people taking the drug to lower cholesterol had a 16 per cent reduced risk of developing the debilitating neurological condition.
They monitored nearly 3,000 healthy people in their 70s for six years, a third of whom were taking statins. At the end of the six-year study, 53 per cent of those who did not take the drugs developed Parkinson's, compared with 45 per cent among statin-users. The researchers reported in the journal Neurology that they believe the drugs may protect the brain by keeping blood vessels clear of cholesterol.
Parkinson's is caused by nerve cell damage in the brain, which affects levels of chemicals such as dopamine, involved in regulating movement.
Their findings are controversial because a two-year British trial in 2020 of simvastatin, conducted by The Cure Parkinson's Trust charity at 23 hospitals across England, with 235 participants with moderate Parkinson's, concluded that the drug did not slow the disease's progression.
Moreover, in 2017, Pennsylvania State University researchers who studied the health records of 2,300 patients with newly diagnosed Parkinson's disease warned that taking statins may speed up the condition's onset in susceptible people. Some evidence suggests that cholesterol may protect the brain against Parkinson's.
A more promising use of statins may be for preventing dementia. Last year researchers at the University of Milan published analysis of 57 studies and found that older people taking high-dose statins had a 20 per cent lower risk of dementia, while people on low-dose statins had a 16 per cent reduced risk.
Writing in the European Journal of Preventive Cardiology, the researchers speculated that the brain-protective benefits may stem from the fact that statins have both anti-inflammatory and antioxidant effects, as well as promoting healthy bloodflow.
Professor Sattar says properly targeted clinical trials are crucial to find the truth behind these hopes.
"Much of the evidence we have on statins' potential other uses is only observational - we've noticed good things happening in patients who were taking statin drugs to cut their cholesterol levels," he explains.
"The unexpected benefits may just be coincidence, or due to things such as the act of taking statins makes people more aware of their health, so they may have improved their lifestyle as a result."
In the meantime, we must hope that better-targeted prescribing can ensure that those taking statins to prevent heart attack and stroke are getting the benefit they hoped for.
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