Worldwide sales of cholesterol-lowering statin drugs are set to hit $1 trillion next year—but two new studies question whether they are fit for purpose. In other words, can some of the world's best-selling drugs actually do what they're designed to do, and reduce levels of the 'bad' LDL (low-density lipoprotein) cholesterol that is supposed to clog arteries and cause coronary heart disease (CHD)?
Statins fail to lower LDL cholesterol by any meaningful level in more than half of the patients taking the drug, the first study has discovered. After two years, 51.2 percent of patients hadn't seen their levels fall by the 40 percent target set by medical guidelines.1
Researchers from Nottingham University analyzed data from 165,400 patients who didn't have CHD but were considered at risk. The drugs were effective in some patients—so why didn't they work in the majority?
Lead researcher Dr Stephen Weng surmised that it could be because of the patients' genetic makeup, or because they suffered side-effects so bad that they gave up on the drugs.
However, other researchers who have come up with similar results found the drugs' ineffectiveness didn't have much to do with patients stopping their treatment.
Reviewing the health records of more than 86,000 people who had taken a statin for up to 18 months, researchers from the Regenstrief Institute in Indiana found that LDL cholesterol had not fallen to the 'safe' levels of under 100 mg/dL (milligrams per deciliter of blood) in 33 percent of them.
More worryingly, statins were not effective in 58 percent of those with preexisting cardiovascular disease (CVD), who needed to get their score down to 70 mg/dL.2
But over half of patients in both the at-risk group and the general population were taking the drugs properly and as prescribed, which suggests the drugs aren't effective even when taken regularly.
Despite their findings, both research groups were at pains to point out that statins are effective and save lives.
"Statins are first-line therapies because they clearly prevent cardiovascular events," said Robert Moggs, a coauthor and researcher at Merck, a statin manufacturer and sponsor of the trial. Or as Dr Weng, from the Nottingham study, commented: "Statins are very effective and offer significant protection against cardiovascular disease."
Even if statins were effective in reducing LDL cholesterol—the clinical 'endpoint' of the therapy—it should follow that the benefit in real life would be fewer people developing, and ultimately dying from, heart disease.
Although scores of studies have concluded that statins must save lives because they have reduced cholesterol levels, other researchers who have tracked the only endpoint that really matters—the patient didn't die from heart disease—haven't seen that benefit.
For years, Pfizer, the manufacturer of the best-selling statin Lipitor, was forced to add at the end of advertisements in the US: "Lipitor has not been shown to prevent heart disease or heart attacks."
That's because the science wasn't there, and still isn't. Those who are considered to be at a higher risk of developing CHD—the elderly, patients with heart failure and others with renal failure—haven't had their lives extended by having their cholesterol levels reduced with a statin,3 and those with peripheral arterial disease haven't been helped by statins either.4
The Cholesterol Treatment Trialists (CTT) Collaboration, led by Sir Professor Rory Collins at Oxford University—one of the fiercest statin advocates—believes otherwise. After reviewing 27 previously published studies, the group concluded that the drugs were saving lives and were "clearly beneficial in reducing cardiovascular events."5
But when another group of researchers looked at the same data, they discovered that, whether or not there were fewer cases of heart disease, the patients weren't living longer.6
How can that be? One heretical possibility is that LDL cholesterol doesn't cause heart disease, and so lowering levels doesn't reduce the chances of CHD. The idea flies in the face of years of research that started in earnest in 1939 with the discovery of an association between a genetic disorder that raised cholesterol levels, called hypercholesterolemia, and the risk of heart attack.
Research from the 1950s onward continued to show an association between cholesterol levels and atherosclerosis, or hardening of the arteries, one of the early signs of CHD. But, as researchers from the University of New Mexico School of Medicine have pointed out, association is not necessarily causation.7
The Framingham Heart Study—which has been researching heart disease and its causes since the 1950s—found that there was hardly any difference in the total cholesterol levels of people with heart disease and others who were healthy.
Forty percent of healthy people had cholesterol levels of around 220 mg/dL, while similar levels were seen in just 32 percent of people with CHD—so more healthy people had 'high' cholesterol levels than those already with heart disease.8
Despite these anomalies, research into a cholesterol-lowering agent continued, and in the early 1980s, Japanese researcher Akira Endo isolated a chemical he called lovastatin. It became the basis of three blockbuster drugs, Zocor, Lipitor and Crestor, and, of those, Lipitor became the most profitable drug in the history of medicine.
Statins were originally intended as 'secondary prevention' agents—in other words, for people who already have heart disease—and for those with hypercholesterolemia, but that's hardly the stuff of blockbusters. For that, a drug needs to be a 'primary preventative,' that is, intended for healthy people who could be at risk of CHD, possibly because of their age, having a raised cholesterol level or being a diabetic.
In 2004, the US National Cholesterol Education Program dramatically reduced the threshold of what is considered to be 'high cholesterol.' Suddenly millions of healthy people became eligible for a statin—but a year later it was revealed that eight of nine members of the panel had financial ties to statin manufacturers.
Statins for children
Despite the conflict of interest, this started the statin bandwagon rolling. The CTT released its own reviews of clinical trials and said there was overwhelming evidence for the benefits of statins, even arguing that "everyone over the age of 50 should be taking a statin, regardless of their cholesterol levels." 9
Catching the expansive mood, one American cardiologist suggested the drugs should be given out as condiments at fast-food outlets,10 while drug manufacturer Pfizer began producing a grape-flavored chewable version of Lipitor for children.
Eventually, the CTT's mission to see everyone over the age of 50 prescribed a statin became enshrined in guidelines set on both sides of the Atlantic.
In 2013, the American College of Cardiologists and American Heart Association issued guidelines stating that anyone with a 7.5 percent risk of heart disease over the next 10 years—essentially everyone over the age of 50—should start taking the drug.
The same year, the UK's National Institute for Health and Care Excellence (NICE) announced they were recommending the drug for anyone with a 10 percent risk.
It was later revealed that eight of the 12 NICE panel members had ties to statin manufacturers, and this 'statins for everyone' policy was based on no evidence whatsoever.
Even the risk calculators were wrong. Of the five calculators commonly used to evaluate a person's risk of CVD, four overestimated this risk by as much as 154 percent, researchers have determined.11
The two recent studies that demonstrate statins reduce LDL cholesterol levels in just half of patients are part of a new wave of research that has slowly emerged since 2005, a watershed year for medical trials.
In that year, and in the wake of the Vioxx and Celebrex scandals when vital data about the drugs' lethal effects were 'lost,' rules for the way research should be carried out were tightened.
Before 2005, statin research invariably discovered that statins were lifesavers; after 2005, hardly any study has come to the same conclusion.
The findings of the new studies are medicine's equivalent of the airline industry discovering that one out of every two planes will crash. While that would be the end of the airline industry, only a fool would bet that this will be the fate of the lucrative statin industry.
Aches and pains
Compactin was one of the earliest statins, developed in Japanese laboratories in the 1970s. One early guinea pig of the new compound was an 18-year-old Japanese woman with severe familial hypercholesterolemia, the genetic disorder that raises levels of 'bad' LDL cholesterol.
She was taken off the drug after just two weeks because she developed muscle dystrophy, or muscle weakness. Her muscle strength came back almost immediately after the therapy was halted.
As the lead researcher Akira Endo observed: "Cholesterol is essential for the functioning of all human organs."1 It's therefore not surprising that drugs designed to reduce cholesterol levels are probably some of the least tolerated, with side-effects so severe that people have to stop taking them.
Around 75 percent of elderly people who took a statin to prevent CHD stopped treatment within the first two years in one study,2 and even 53 percent of people in a younger population (average age of 61) also abandoned treatment.3
The largest ever statin survey, carried out by the National Lipid Association, discovered that 30 percent of patients experienced muscle pain and weakness—just like the first statin guinea pig—and 62 percent of former statin users stopped taking the drugs due to side-effects.4
Others have suggested that statins could be responsible for dementia and memory loss in the elderly because LDL cholesterol is an essential fat for healthy brain functioning as we age.
One study, due to be published in the medical journal Current Vascular Pharmacology, discovered that 49 percent of 556 statin patients suffered side-effects that included mental health disorders and sleep and brain function problems. Around 20 percent suffered thinking and memory difficulties.5