More nails in the coffin of the "cholesterol hypothesis" | by Alan Cassels

New studies provide further evidence that cholesterol-lowering statins and other new drugs may be a costly dead end.

THREE NEW STUDIES in the past few months are like nails in the coffin of the Cholesterol Hypothesis, which has only seemed to become more questionable as our knowledge advances.

This hypothesis, simply put, posits that by measuring your blood cholesterol levels, and then altering those levels by taking cholesterol-lowering drugs, people can avoid heart attacks, strokes and an early death.

Society has developed a near obsession with cholesterol over the last few decades, despite the fact that some patients with high cholesterol levels do not go on to develop heart disease, while many heart attack victims don’t have high cholesterol levels.

 
The emergence of statins, a class of drugs designed to alter cholesterol levels, seems to have fuelled the obsession. Their ability to lower cholesterol has led to them being prescribed to many patients without cardiovascular disease—including the elderly, women, children and men—as a form of “primary prevention.” Statins now constitute the leading drug cost in all provincial drug programs, amounting to a cost of almost $2 billion annually in Canada.

Unsurprisingly, it has been the juggernaut marketing of the pharmaceutical industry, and not the science, that has turned statins into one of the most lucrative classes of prescription drugs in the history of the world.

High quality studies do show statins can effectively change your cholesterol levels. But they only show a modest effect in reducing cardiac events in people with established heart disease, and an even more modest effect for those at low risk of heart disease.

 
Gordon B. (who asked that I not use his surname) from Kelowna had no personal or family history of heart disease, yet was put on Lipitor (atorvastatin) in 1997 at age 50. He told me, “My family doctor said I had elevated cholesterol levels, particularly with the bad cholesterol.” By “bad” cholesterol, he means low-density lipoprotein, or LDL. When Lipitor didn’t change his cholesterol levels he was switched to Crestor (rosuvastatin). He said the drug “worked almost immediately at lowering my bad cholesterol,” and he took it for nearly eight years before the side effects grew intolerable. “I experienced sleeplessness and erectile dysfunction (ED) at the onset, and later, anxiety, sharp abdominal pains, muscle weakness, and loose teeth,” he said. He believes that while “the sleeplessness and ED may have been coincidental,” the other side effects he attributed directly to Crestor. Now, with more than 20 years of statin experience behind us, those adverse effects are widely known.

Part of the reason that statins grew to be so popular is that physicians and patients believed that the drugs were both very effective and very safe. Now with new research coming out, much of it highlighted at the American College of Cardiology’s annual conference in Chicago in early April, both those assumptions are being directly challenged.

A Canadian-led study, the HOPE-3 trial, looking at the effects of statins mixed with various antihypertensives (drugs to lower blood pressure) in 12,000 patients, was published with much hoopla. The authors said their study provided an “extensive body of evidence of a significant clinical benefit in a broad group of persons of diverse ethnic backgrounds.” They reported that the risk of muscle pain, the most commonly-reported statin adverse effect, was “low.”

How effective were statins in this trial? A close reading of HOPE-3 found that over five years, the rate of heart attack, stroke or heart-related effect was 3.7 percent on statins versus 4.8 percent on placebo, a difference of 1.1 percent. People taking the statins had an increased risk of cataracts (3.8 percent of patients on statins had cataract surgery, versus 3.1 percent on placebo) and muscle pain (5.8 percent on the drug versus 4.7 percent on placebo). In other trials, statin users also report higher rates of diabetes and memory loss.

Dr John Abramson, a health policy expert from Harvard Medical School, looked at the HOPE-3 trial and told me the effects were meagre indeed: “91 people have to be treated with a statin for 5.6 years in order to prevent 1 non-fatal heart attack or stroke.” Another way to say this is 90 of the 91 people who take statins for that long won’t see a benefit (and some will experience adverse side effects).

Another trial, called GAUSS-3, reported an unusually high level of statin adverse effects. The drug company Amgen, which makes an injectable LDL-lowering drug called evolocumab (Repatha), was testing its drug in a special type of population: people who don’t tolerate statins because of the muscle-related statin adverse effects.

 
Evolocumab was extremely good at lowering LDL cholesterol over another non-statin drug, ezetimibe, often used for those intolerant of statins. But both drugs caused muscle symptoms in a significant number of patients: 28.8 percent of ezetimibe-treated patients and 20.7 percent of evolocumab-treated patients.

It’s something else, however, that most concerns Dr Jim Wright of UBC’s Therapeutics Initiative in Vancouver. He told me the research so far hasn’t reported outcomes data from long-term studies of drugs like evolocumab (known as PCSK9 drugs) so no one really knows if these new drugs will ultimately prevent cardiovascular events. The PCSK9s can expertly lower LDL cholesterol, likely at a cost in excess of $10,000 per patient per year, but it’s premature to think about covering them through drug programs like Pharmacare. Dr Wright says there are some patients and physicians clamouring for approval for these drugs in BC but “paying for them through the public purse, without long-term outcomes data would be wrong.”

A third study, this one looking at another class of drugs to alter cholesterol, was being carried out with much excitement, but then suddenly halted. The patients taking the drug evacetrapib lowered their LDL cholesterol by 37 percent and increased their HDL cholesterol by 130 percent compared with patients taking a placebo. (HDL is sometimes referred to as “good cholesterol” because it can transport fat molecules out of artery walls.) Dr Stephen Nicholls, the study’s lead author, told ScienceDaily that despite this effect on cholesterol, the drug had “no effect on clinical events.” Surprised and disappointed by the research, his team stopped the study.

The lack of effect on cardiac events didn’t surprise Dr Wright who has seen other drugs in this class, known as CETP inhibitors, fail. In fact this is the third drug in that class that has failed in crucial clinical trials and been sidelined. What surprised Dr Wright most is how much money the industry has been pouring into drugs like the CETP inhibitors to chase lower LDL targets. “The study of evacetrapib was a huge trial,” he said, “and they abandoned a huge trial.” The vast amounts of money that companies like Eli Lilly have poured into these kinds of trials is mindboggling and, in Dr Wright’s opinion, it’s proving to be futile. “It tells you that they’re grasping at straws,” he told me.

Three pretty definitive studies in one month have definitely revved up the need to rethink whether it is even worth bothering to chase lower cholesterol. Said Dr Wright: “This is strong proof that the cholesterol hypothesis is wrong.”

It’s worth stressing that drug research trying to develop drugs to prevent heart attacks or strokes is a laudable, even commendable endeavour given the toll that heart disease takes on our society. Even drugs with small benefits in individuals could have a huge benefit for the population. Yet driving for lower and lower LDL targets, with new drugs aiming to replace statins, may well be a dead-end task (though lucrative for some pharmaceutical companies).

It also seems that the one sure thing we have learned about the experience with statins is that we have an incomplete picture of their possible adverse effects. Even if costly drugs like the PCSK9s or the CETP Inhibitors get approved and are prescribed widely to people with high cholesterol, chances are we won’t know about the rates of adverse effects until they are used by many thousands of patients.

For Gordon B. in Kelowna, the side effects stopped right after he stopped taking Crestor. He said the improvement to his health was “immediate.” He was left feeling happier, without the sharp pains and loose teeth. He has since been avidly following new research on cholesterol-lowering drugs and so I asked him what he would say to a relative, a friend, a stranger about his experience with statins. He didn’t hold back: “I’d tell them about the scam, the payola, the side effects, the class action suits” which, he says, are now well known in relation to statins. He adds that “the conversation with doctors who want to prescribe statins should be one-sided. Just say NO!”

Research marches on. There are a raft of new drugs coming that may alter cholesterol levels. Given what we are learning, maybe more physicians and patients will think twice about eagerly tinkering pharmaceutically with cholesterol levels.

Alan Cassels is a Victoria author and pharmaceutical policy researcher. He has written four books on the medical screening and pharmaceutical industry including the latest, The Cochrane Collaboration: Medicine’s Best Kept Secret.