The near-breakdown of the international financial system and the deep recession it helped create has been attributed to many causes. Greed, of course. A lack of rigorous regulation. An everyone's-doing-it mentality in which traders took bigger and bigger risks as they search for bigger and bigger payoffs.
Now, a Florida physician proposes an alternative explanation. Perhaps many of those supposedly sophisticated speculators who believed the party would never end were acting under the influence of drugs.
"There's a damn good possibility it's related!" said Mark Goldstein, who has been observing his patients' reactions to statins for more than two decades. He noted these widely prescribed drugs can produce a wide array of side effects, including a variety of cognitive disturbances. One reported effect is an increase in impulsive behavior.
"I think it's a real issue, a significant issue — especially in the case of middle-aged and older men," he said. "Aren't those some of the people that were making some of these economic deals?"
The notion that Crestor is responsible for the credit crunch, or that losses can be traced to Lipitor, is highly speculative. But Goldstein's provocative thesis may help alert both his fellow physicians and the public to some underreported and troubling facts about these popular — and, for the pharmaceutical industry, highly profitable — products.
Statins, a class of drugs that include simvastatin (Zocor), atorvastatin (Lipitor) and rosuvastatin (Crestor), reduce the body's production of LDL, or "bad," cholesterol. Certain cardiologists and public health experts, excited by their ability to lower the buildup of harmful plaque in arteries leading to the heart, have suggested they be prescribed to a wider and wider percentage of the population.
Some researchers, including those in a groundbreaking JUPITER study — the largest study of its kind of statins, which led many to call for even greater use of the drugs -- acknowledge there may be side effects but feel the numbers are low and the rates "identical" to those for placebos in side-by-side trials. Jupiter's results saw The New England Journal of Medicine Web site create a special interactive feature, "The JUPITER Trial: Will You Change Your Practice?" Some 48 percent of the 2,553 respondents agreed that "the trial results indicate that the therapeutic use of statins should be changed."
But a cluster of cholesterol contrarians has emerged to challenge the conventional wisdom. These physicians argue that while statins are an appropriate and valuable medication for certain patients - particularly those with pre-existing heart conditions - their value to the general population is questionable. Furthermore, they argue, these powerful drugs create more serious side effects than the public or most doctors realize.
"There is a disparity between the published evidence and the public perception," argues Beatrice Golomb of the University of California, San Diego, who is conducting an ongoing study of the side effect of statins. She has authored a paper, to be published later this year, concluding that the coronary health benefits of statins are "fully offset" by the harm they do elsewhere the body.
"I don't think most doctors understand this — including the ones who do work in this area," she said.
"We're basically saying that most of the people who are taking statins are not going to benefit from them," agreed James Wright of Vancouver. "We think the benefits don't outweigh the harm in primary prevention — that is, for people who don't have evidence of occlusive vascular disease."
As director of the Therapeutics Initiative, an independent group based at the University of British Columbia that looks at evidence-based drug therapy issues, Wright has long been skeptical of the push to put more and more people on statins. An estimated 13 million Americans, and nearly as many outside the U.S., use these drugs, which are meant to be taken every day for the rest of your life.
Goldstein, the medical director of the Fountain Medical Court in Bonita Springs, Fla., argues that Western society suffers from "cholesterol-phobia" — a condition in which healthy people fixate on their LDL level after being bombarded with advertisements warning of potential danger.
To ascertain how thoroughly this condition has penetrated the culture at large, look up the term "wonder drug" on www.yourdictionary.com. The Web site provides this helpful example as to how to properly use the phrase: "Statins are the new wonder drugs now used to prevent everything from heart disease to Alzheimer's."
The sentence accurately reflects much of the media coverage of the topic. In late March, NBC News chief medical editor, Dr. Nancy Snyderman, excitedly proclaimed that "statins absolutely are the medication of the future," brushing off anchor Brian Williams' reminder that the study she was reporting on was funded by a pharmaceutical company.
On the other hand, Business Week magazine reported in a rigorously researched January article that the benefits of statins are overstated. The issue is of great concern to the business media, as these drugs produce huge profits for the pharmaceutical industry.
Indeed, they are the best-selling medicines in history, with nearly $28 billion in sales in 2006. When the pharmaceutical company Pfizer announced a 48 percent drop in profits in 2007, it blamed a decline in sales for its most-prescribed product: Lipitor.
LDL (low-density lipoprotein) is the cholesterol that is produced by the liver and is carried through the bloodstream to cells throughout the body, where it performs a variety of functions. When the amount of LDL being carried to cells is larger than the amount of HDL being taken away from cells, the excess can form deposits on the walls of arteries. This process, atherosclerosis, has been linked to angina and an increased risk of heart attacks.
From a purely coronary perspective, lowering LDL in the bloodstream is a very good thing. So it's not a big surprise that heart specialists tend to be big believers in drugs that block their production. "The specialists — cardiologists and lipid specialists — have really bought into it, and they continue to promote it," Wright said.
But in a case of what might be termed specialization bias, physicians focusing on the circulatory system may fail to consider what affect a lower cholesterol level has on other bodily functions. "Cardiologists will tell you, 'I don't want the patient to die on my watch, or from my disease,'" said Golomb.
"If you get somebody with heart disease who has high cholesterol and you put him on a statin, you can decrease subsequent cardiovascular events like heart attacks," said Goldstein. "But there's a tradeoff. You get side effects with any medicine. It depends on whom you give it to, at what dose and for how long."
Most troublingly, for some patients — since there have been no studies looking at this specific question, the percentage isn't known — a rapid, pronounced drop in LDL cholesterol (as opposed to the gradual decrease that many achieve through diet and exercise) has been linked to cognitive problems ranging from depression to dementia.
"It's not everybody, but there is a group of people out there who react adversely to statins, from a central nervous system standpoint," Goldstein said. "I don't know (how big this group is). It might have to do with how aggressive we are with the statins - how low we make the cholesterol level."
"There are real issues regarding statins and cognition," agreed Golomb. "Cognitive problems are the second most frequently reported (statin-related) problem after muscle problems. This isn't an effect that happens to everybody, but for the people it does effect, it can be quite devastating. We've talked to people who have had their careers decimated."
As director of the UCSD Statin Study group, she conducted a randomized, controlled trial of San Diego-area residents examining effects of low-dose statins on mood, behavior and cognitive abilities. Her team is also conducting an ongoing observational study in which people are invited to e-mail their stories of statin side effects. (The address is email@example.com.) She published a detailed look at her side-effects research in the December issue of the American Journal of Cardiovascular Drugs.
"There's a woman here in San Diego whose family contacted us while they were in the process of looking into assisted living for presumed early Alzheimer's," Golomb said. "By both age and sex, she was in categories in which the expected benefits of statins did not exceed the risk. So they stopped her statins (at our suggestion), and within a week, she was completely back to normal — sharp, fast, funny.
"She went back on statins about five times. I don't know why she and her family didn't fight the doctor harder on that. Each time she developed rapidly progressive cognitive loss and ended up going off the drug.
"We had an emeritus professor at a major university with an IQ of over 180 who lost the ability to read a page. He was diagnosed by two academic medical centers with rapidly progressing Alzheimer's disease. He went to his 50th school reunion with a sign around his neck saying, 'I have Alzheimer's disease,' so people would understand if he repeated things several times. Then his wife took him off the statin. For him, it took two years before he experienced full recovery."
In March, journalist and novelist Christopher Hudson wrote a chilling first-person account titled "Wonder Drug that Stole My Memory." In it, he notes that his doctor called simvastatin "a wonder drug." True enough, in that much of the time he was on it, he was wondering what was happening to him — why he could no longer remember names or places or where keys were located on his computer keyboard.
So what exactly is happening inside the brains of people taking cholesterol-lowering drugs? No one is entirely sure, but there are intriguing clues.
"There is one study from Germany that found taking simvastatin — Zocor — at 80 mg per day alters brain cholesterol metabolism," Goldstein said. "It's from the Archives of Neurology in 2002. It decreased 24S-hydroxy-cholesterol, which is a type that is in the brain, by 50 percent."
And as anthropologist Bernard Wallner of the University of Vienna points out in a recently published paper, low concentrations of serotonin have been related to hostile, aggressive behavior in men.
"The brain is 2 percent of body weight, on average, but it has 25 percent of the body's cholesterol," Goldstein said. "Cholesterol is a major component of all cell membranes. You can change the structure of cell membranes when you change cholesterol levels."
Another researcher who is studying how lowering cholesterol affects the brain is biophysicist Yeon-Kyun Shin of of Iowa State University. He is co-author of a paper on brain chemistry published in February in the Proceedings of the National Academy of Sciences.
"If you deprive cholesterol from the brain, then you directly affect the machinery that triggers the release of neurotransmitters," he said. "Neurotransmitters affect the data-processing and memory functions. In other words, how smart you are and how well you remember things."
In addition to allowing the brain to function properly, LDL cholesterol also performs essential functions throughout the body. The "pivotally important" substance "transports key fat-soluable antioxidants," Golomb said. "Also, the mevalonic pathway, which statins inhibit, actually contains a lot of other products beyond cholesterol, some of which are centrally important. One of them is seminally involved in the electronic transport chain that allows cells to release energy."
"We know there are risks with high blood pressure, but we also appreciate the fact there are significant risks with low blood pressure," said Wright. "That's equally true with cholesterol. We need to get back to the idea that you want to keep your cholesterol within a range. It's probably better to be at the upper limit of that range than the lower limit."
"I see that the bar for 'high cholesterol' keeps lowering," added Shin. "There is a limit that human brain can tolerate, which certainly depends on a lot of factors like age. Therefore, I certainly see the danger. More research needs to be done to determine how much cholesterol is high enough to take medication. I don't think we have enough data to go lower and lower, which is a dangerous and baseless campaign."
Shin was referring to a 2004 report in which a panel of experts stated that cholesterol levels should be lower than previously believed. (The Associated Press subsequently reported that eight of its nine members were receiving money from the pharmaceutical companies that stood to profit from the sale of these drugs.)
The cholesterol study that has received the most press coverage in recent months, the JUPITER study, was stopped after two years because, according to its authors, the results were so impressive. As the Wall Street Journal reported last November, the study concluded that the use of Crestor (a product of the pharmaceutical company AstraZeneca, which sponsored the research) "sharply lowered risk of heart attacks among apparently healthy patients." The article went on to note that the findings "could substantially broaden the market for statins."
A representative of AstraZeneca referred questions on the study to its lead author, Paul Ridker of Harvard Medical School and Brigham and Women's Hospital in Boston. "Side effects of all drugs are important to consider, but must always be placed in perspective with proven benefits, and must also be considered in the context of randomized trials where we can directly compare rates to that of placebo," he said in an e-mail.
"Within JUPITER, as but one example, side-effect rates were very low and for the vast majority of issues (including muscle pain and cognitive function) were identical to rates in the placebo group. When you balance that against a nearly 50 percent reduction in risk of heart attack and stroke, I do not think this a difficult calculation to make."
Wright has a very different view. "The standard of evidence we go by is the randomized controlled trial," he said. "There is randomized controlled trial evidence that statins adversely affect some aspects of cognition.
"I think we need more randomized controlled trials, and we need them to be reported better. Most of the published trials are completely focused on the beneficial outcomes. The studies are not properly reporting and looking more closely at serious adverse events."
Like Wright, Golomb and Goldstein expressed skepticism of JUPITER and other studies sponsored by the companies that stand to benefit from the product being tested. Based on their reading of the evidence, they believe cholesterol-lowering drugs are appropriate only for a relatively small subset of patients.
Golomb noted that "middle-age men with evidence of heart disease make up the group for which the evidence (suggesting the benefits of statins outweigh their risk) is most solid." Wright argues "statins are appropriate for women and men with proven occlusive vascular disease."
Even Ridker, who recently argued that statins are also beneficial for their apparent anti-inflammatory properties, does not see them as a magic bullet. Treatment with these drugs, he asserted, is appropriate "only in the context of already recommending diet, exercise and smoking cessation. Statin therapy is not a replacement, but an adjunct for preventive care."
Clearly, the evidence suggests physicians need to better balance the risks and benefits of these powerful drugs. Unfortunately, they don't get much help from the medical establishment: Golomb laments the fact "there is no neutral arbiter out there," presenting unbiased information on the pros and cons of different drugs to both doctors and patients.
"We expect drug companies to serve the best interests of patients and their stockholders, but those are mutually incompatible," she said. "They can't be expected to do this. But the academic world is not serving that function, either, because industry is supplying the money (to conduct the research)."
So here's where we stand: A hugely profitable, largely self-regulated industry is aggressively promoting a line of newly developed products it assures us are safe and beneficial, when in fact they contain a significant element of risk. Much of the media takes the companies' claims at face value, leaving millions of people ignorant of the fact they are unwittingly participating in a huge, high-stakes gamble.
Sound familiar? Statins may not have caused the financial meltdown, but the parallels between the two stories are positively heart-stopping.