The last time Dr. Beatrice Golomb told an interviewer that a class of drugs taken daily by millions of Canadians might cause severe irritability and aggression in some people, another doctor called her crazy.
The California physician understands that her views about the cholesterol-lowering drugs known as statins are controversial. Still she’s pressing ahead with a large study of the possible downsides of some of the most widely prescribed drugs in the world.
Golomb is an associate professor of medicine and lead researcher of the Statins Effects Study at the University of California, San Diego. So far, more than 3,000 people — including Canadians — have reported the experiences they’ve had while taking the blockbuster drugs.
Golomb says her group has found a small but statistically significant increase in aggression, on average, among people on statins — particularly women and the elderly.
“Among both men and women, the older you got the more it shifted toward an increase in aggression,” she said.
In 2004, Golomb published the first case series hinting at a provocative link between the cholesterol-lowering pills and severe anger and irritability.
The six patients felt more than a little edgy: One 63-year-old man who stopped and started five different statins over five years said he experienced such uncontrolled pent-up tension and rage soon after starting each one, “I wanted to kill someone.”
Golomb says she believes the risk of profound irritability is likely rare — so rare that a signal wasn’t picked up in pre-market studies of the drugs.
She stresses it isn’t high enough to warrant changing prescribing practices, but she says doctors and patients should be aware of it, so they can recognize it should it occur, and adjust treatment if necessary.
Other doctors say there is no evidence from any of the scientifically controlled studies of statins that the drugs are capable of making normally even-tempered people violent or so irritable they want to smash things.
Millions of Canadians take the cholesterol-lowering pills. An estimated 30.3 million prescriptions worth $2 billion were filled last year for statins, up from about 21 million in 2006, according to IMS Brogan, which tracks prescription-drug sales.
The drugs have become so ubiquitous, British researchers last year suggested they be handed out free at fast food restaurants to “neutralize” the fat from burgers and fries. “It would cost less than 5p per customer,” Dr. Darrel Francis, of the National Heart and Lung Institute at Imperial College London, said in a news release — “not much different to a sachet of ketchup.”
Golomb says statins are important drugs with “incontrovertible” heart benefits. For people with a history of cardiovascular disease, the drugs have been shown to save lives.
But statins are now commonly prescribed to people at low risk of heart attack or of dying of a cardiovascular-related cause over the next 10 years.
Meanwhile, enthusiasm is growing to prescribe the drugs earlier and more aggressively — expanding the pool of people who ultimately will be put on the pills.
Last month, an expert panel appointed by the U.S. National Heart, Lung and Blood Institute recommended that even children be routinely tested for high cholesterol between ages nine and 11 — a move that led Canadian drug policy researcher Alan Cassels to question, in an opinion piece published in the Vancouver Sun: “Have we all gone stark raving nuts?”
Cassels, of the University of Victoria and co-author of Selling Sickness, said the evidence for statins in low-risk people “is still very, very shaky — including the evidence of using statins in women and the elderly.”
With any new drug “the benefits come out fast and quick, and it takes years for the harms to catch up,” Cassels said.
“On the statin front, the harms are really starting to catch up.”
The most well known side effect is myopathy — severe muscle pain or weakness. Cassels says new data shows the incidence has been seriously underestimated and that it may affect 20 to 25 per cent of patients.
Researchers at the Therapeutics Initiative at the University of British Columbia, an independent drug review body, are currently looking at whether the statins can be toxic to the kidneys.
Co-managing director Dr. Jim Wright said that his group’s previous research showed that, over all, among people without cardiovascular disease, total serious adverse events — meaning the chance of dying or being hospitalized for any cause — isn’t reduced with statins.
“This means that the small benefit — a decrease in cardiovascular serious adverse events — is offset by a small harm, an increase in other serious adverse events.”
A study published last year in the British Medical Journal involving more than two million men and women from England and Wales linked statin use to decreased risks of esophageal cancer, but increased risks of liver dysfunction, kidney failure, moderate or serious myopathy and cataracts.
In Golomb’s database, cognitive problems have emerged as the second most frequently cited complaint, after muscle pain, among statin users. People have reported losing their way home from work, she said; they have trouble finding words or balancing cheque books.
One retired professor with a reported IQ of 180 was diagnosed with a rapidly progressive form of Alzheimer’s disease. Golomb said the man went to his 50th high school reunion “with a sign around his neck saying, ‘my name is so-and-so and I have Alzheimer’s.’ ”
The man would repeat things over and over, she said; he didn’t recognize people he had known for decades and couldn’t read more than a page of text at a time.
After he was taken off statins, he was screened for participation in an Alzheimer’s drug study at Duke University. “They re-evaluated him and said, ‘Not only do you not have Alzheimer’s disease, you don’t have dementia,’ ” Golomb said.
“By his report it was about two years before he felt he had recovered completely.
Other reported side effects include peripheral neuropathy, or pain or numbness in the fingers and toes, she said.
When it comes to irritability and aggression, Golomb said the problem emerges when people go on a statin, stops once they go off and recurs again if they go back on.
“These people meet criteria for definite adverse event causality,” she said.
“I think the irritability — in a low form — is more common. But in its severe form, it’s relatively uncommon — maybe one in 100 adverse event reports that come to us relate to that.”
What might account for the connection? Numerous studies have linked low cholesterol levels to suicides, accidents and violence, Dr. Mary Deans, clinical instructor at Harvard Medical School, said in a recent blog in Psychology Today.
Cholesterol “plays a vital role in neuron signaling and brain structure,” she said. “It would make sense that if your cholesterol drops too low then mood and behaviour could be affected.”
But an Ottawa doctor said no evidence of cognitive side effects or severe irritability have emerged in randomized controlled trials — “and these are huge databases,” said Dr. Ruth McPherson, professor of medicine and director of the lipid clinic at the University of Ottawa Heart Institute.
“Any patient can have almost any side effect on any medication. But cognitive effects, irritability — this simply has not been a clinical issue whatsoever,” she said.
“You can’t argue from anecdote.”
McPherson says the bigger issue is, as more studies suggest statins are protective, at what stage and age do you decide who benefits enough that it’s worth prescribing?
The lifetime risk of cardiovascular disease is one in two for men, and one in three for women.
Strokes can be “catastrophic,” McPherson said; heart failure slowly destroys lives. A study published in October in the Canadian Medical Association Journal found that statins help prevent death and non-fatal heart attacks and strokes in people at low risk — defined as people who have less than a 20 per cent chance of having a non-fatal heart attack or dying from a cardiovascular cause in the next 10 years.
Overall, death from any cause was lower among people on a statin than not, the researchers reported.
Wright, of the Therapeutics Initiative, remains unconvinced that the benefits of statins outweigh the harms in people who do not have cardiovascular disease.
He said the risk of increased irritability is a real phenomenon, and that he has seen it in patients himself. “What if irritability leads to more likelihood of a motor vehicle accident?” he said. That kind of outcome would be hard to tease out, he says. “But nobody has really ever looked at those kinds of things.”
Wright says the enthusiasm for statins is being driven by a “massive uptake” of the cholesterol hypothesis — “this idea that cholesterol is the cause of all cardiovascular events, and we can prevent them” — and the sense, which he says is inappropriate, that statins are relatively safe drugs.
“It’s not like when you take a statin you have a high risk of having something bad happen to you,” Wright said.
“But I don’t think we know all the possible long-term risks. I wouldn’t consider them safe drugs.”