Ken Johnson, senior vice president of Pharmaceutical Research and Manufacturers of America (PhRMA), says that FDA drug approval procedures are “the gold standard of the world” and that the United States has “one of the strongest drug safety records.” He acknowledges, though, that “adverse reactions are sometimes not detected until a medicine has been approved and made available to an entire population,” adding, “That’s why the postmarket surveillance system is so important.” He notes that under the Food and Drug Administration Amendments Act of 2007, the agency has new authority to “require additional postmarket studies and make faster changes to product labeling.” The intent is to reduce the time it takes to detect adverse drug reactions and protect the public.
An adverse reaction is exactly what Duane Graveline suspects happened to him. Graveline, a former NASA astronaut and flight surgeon, suffered a bizarre episode in 1999 shortly after he was prescribed the popular statin drug Lipitor for his elevated cholesterol. Just six weeks after he began taking the drug, the normally very active and healthy Graveline plunged down the rabbit hole when he abruptly lost his memory. His wife rushed him to the hospital, where doctors examined him carefully but could find no medical or psychiatric problem. His brain scan showed no sign of a stroke or brain disorder. Then, almost as quickly as his memory had disappeared, it came back after just six hours, without any treatment. Doctors termed the strange episode transient global amnesia, or TGA. The cause? Unknown.
Graveline’s case was certainly unusual. Most people with sudden memory loss have suffered a blow to the head, a stroke, or some other medical problem. But Graveline had no history of medical or psychiatric troubles. This made him wonder: Could the episode have been a side effect of Lipitor? Deciding not to test fate, Graveline stopped taking the drug. For the next year he was fine. But when his annual astronaut’s physical exam rolled around, he was told that his cholesterol level had crept up again, and his doctor urged him to restart the Lipitor.
Graveline, still uncertain about the connection between the drug and TGA, complied. Within 10 weeks he suffered another, even more severe episode of amnesia. His wife found him wandering outside their home, unable to recognize her and unaware even that he was a physician. That episode also resolved without treatment. “That’s when I decided never to take statins again,” he said. That’s also when Graveline began scouring the medical literature for an explanation of what had happened. What he found troubled him: There were few studies examining statins’ side effects on memory, even though cholesterol, he says, plays an important role in brain function. Graveline worried: What if he had had an episode while he was driving? What if a pilot developed TGA during flight?
Graveline’s research eventually brought him into contact with Beatrice Golomb, an associate professor of medicine at the University of California, San Diego School of Medicine. Golomb, a dark-haired whiz kid who graduated from the University of Southern California with highest honors at age 19, is an M.D. with a Ph.D. in biology and has been studying cholesterol and statins for more than a decade under research grants given by the Robert Wood Johnson Foundation and the Harry Frank Guggenheim Foundation.
Golomb says that Graveline’s episodes of TGA, and other cases like his, raise questions about the ways statins can affect memory. Her research, she says, shows that although statins can reduce the risk of heart attack, they may also have serious side effects. In Golomb’s opinion, the potential benefits of statins may not outweigh their risks except among middle-aged men who have heart disease—or who are at high risk for it. The only way to weigh risks against benefits, she says, is to evaluate all-cause morbidity (sickness) and all-cause mortality (death).
Christopher Loder, a spokesperson for Pfizer, the maker of Lipitor, says that studies of the drug were “not designed nor powered to look specifically at all-cause mortality.” The studies, he says, “were powered and designed to look at a composite end point consisting of heart attack or death from coronary causes.” In addition, Loder says, “There is overwhelming clinical evidence to support the benefit of Lipitor. All statins have been shown to reduce LDL cholesterol.”
Golomb says one reason many doctors overlook risks and believe statins to be safe is that most controlled studies of statins wind up excluding people who originally begin to participate in a study but stop taking the drug because they experience problems from it; these test participants are then dropped from the study as “noncompliant.” Confusion arises, Golomb says, “because the absence of evidence that statins cause harm—having excluded those who would have permitted detection of harm—is interpreted wrongly as evidence of absence of harm. And the treatment is generalized to a larger population with a very different risk-to-benefit profile.”
John Abramson, a clinical instructor at Harvard Medical School and author of Overdo$ed America: The Broken Promise of American Medicine, says he grew concerned when he learned that the authors of professional guidelines recommending an expanded use of statins had ties to the drugs’ manufacturers. So, Abramson, a tall, dark-haired man with owlish glasses, decided to review the study data. What he found stunned him. Statins could reduce heart attacks and strokes—but only in a small fraction of the people taking the drugs. “Doctors give statins in one of two ways,” Abramson explains. “The first way is to give the drugs to people with elevated cholesterol as primary prevention—to prevent a heart attack, stroke, or other serious cardiovascular event. [These are] people who have never suffered any of those events. The other way to give statins is as secondary prevention, after people have had one of those events or develop diabetes.”
Despite broad recommendations in the National Cholesterol Education Program guidelines, Abramson found that there were no studies that showed statins were beneficial for primary prevention for women of any age or men over 65. Yet more than three-quarters of people taking statins take them for primary prevention—meaning that many patients stand to gain no benefit at all. Abramson, who with a colleague published his findings in the British medical journal The Lancet, says that even when statins are used for men at the highest risk, “you have to treat about 238 men for one year to prevent one heart attack.”
Another problem with statin studies, according to Abramson, is that many do not measure clinically and critically important outcomes like heart attacks, serious adverse events, or all-cause mortality. Instead they measure surrogate markers—outcomes that are associated with a risk of disease—but not a bad outcome itself. In the case of statins, the surrogate marker most commonly used is cholesterol levels. If a drug reduces cholesterol, it is said to be “effective.” But lowering cholesterol doesn’t necessarily mean a drug will reduce the bad outcomes people are worried about—such as death or heart attack.
This was the issue in last winter’s congressional investigation into the nonstatin cholesterol-lowering drug ezetimibe, sold as Zetia and contained in Vytorin. Hearings in January revealed that the release of negative results of a clinical trial of ezetimibe had been delayed. The drug, while lowering cholesterol effectively, failed to slow the progression of carotid artery plaque. While manufacturers Merck and Schering-Plough delayed the negative study’s release for more than 18 months, ezetimibe had turned into a blockbuster drug, even though it had never been shown to reduce heart attacks or deaths.
“You can lower cholesterol levels with a drug, yet provide no health benefits whatsoever,” Abramson says. “And dying with a corrected cholesterol level is not a successful outcome in my book.” Suddenly Abramson, who had taken many hits for his critiques of cholesterol-lowering drugs, was joined by physicians calling for more openness in research and more careful examination of the evidence before drugs are put on the market.
Jerome Hoffman of UCLA agrees, saying it is a shame that in the face of so many medical and pharmacological advances there is such an exposure to risk. “It’s ironic that one of the unintended consequences of the publication of so many untenable claims, based on poorly done research and spin, is that it can obscure true advances when they do occur,” he says. Citing the number of great successes medical research has brought us—lifesaving drugs from penicillin to insulin, along with invaluable treatments and medical devices—he adds, “It’s one more reason why we have to be appropriately skeptical, unafraid to speak out about misleading claims, and insistent upon holding clinical research to the standards of science.”