Statins Drugs: How Safe? How Effective?
Posted by medconsumers on November 1, 2003
(Almost) Everything You Need to Know About Statin Drugs
Though the first of the statins went on the market over 17 years ago, they unofficially reached miracle drug status last summer when these cholesterol-lowering medicines made the front cover of Newsweek. The magazine’s breathless coverage started with the inevitable anecdote about a middle-aged man who was unable to lower his total cholesterol level of 290 through diet and exercise alone.
Six months of trying, and his level dropped a mere 27 points, so his doctor put him on “one of the class of powerful cholesterol-lowering drugs,” Lipitor. “He knows he should try harder to eat right,” continued the Newsweek article, “but he also knows he doesn’t have to worry about cholesterol as long as he takes that little pill every day. ‘It’s better living through chemistry,’ he says. Or perhaps more to the point, longer living.”
Well, that just about sums up the current rosy view of statins. It is also indicative of the unrealistically optimistic, one-sided information consumers get about these drugs from their doctors, the media and drug industry advertising. Too often, people get little more than this from their doctors: “Your cholesterol is too high, take this drug.” Or, if pressed for more information, a doctor might say: “Take this drug, it will reduce your chances of dying from a heart attack.”
Statins are intended as a lifelong treatment. Any drug taken by a healthy person every day for the rest of his or her life should be backed with clear evidence from carefully conducted studies that the benefits outweigh the risks. Such studies should have included people just like you, be they older women whose only risk factor is high cholesterol or middle-aged men with high cholesterol and several other risk factors for heart disease.
A Critical Look is Needed
This article will address such questions as: Are statins safe and effective for everyone? What exactly have they been proven to do? Will they increase longevity, as the Newsweek article implies? It will also describe a new analysis of all statin studies, which contradicts the prevailing belief that these drugs are of great preventive benefit to most older people. You will learn that the case for statin therapy is stronger for people with heart disease and/or diabetes than it is for healthy people with high cholesterol and another risk factor or two.
When statins were first introduced, they were prescribed primarily to people with heart disease. In time, they became an appropriate prescription for all older people. Lest you think that’s an exaggeration, recall the news out of England in the summer of 2003, when a respected team of researchers proposed the “ polypill ” for all adults over the age of 55, with a statin as one of six chosen lifesaving components (along with aspirin, folic acid, and three anti-hypertensive drugs at half dose).
The polypill might not have caught on yet, but the idea that just about every middle-aged and older person is a candidate for statin therapy certainly has. In fact, you needn’t have high cholesterol to get a prescription. And for older women, statins have begun to replace postmenopausal hormones as the drug of choice to prevent heart disease.
One can hardly make it through the TV evening news without viewing at least one statin ad, usually conveying the idea that diet and exercise are not enough to lower cholesterol in most people. (True enough, but more on that later.) The most egregious statin ad, however, is Pfizer’s campaign in Canada where, ironically, it is against the law to advertise prescription drugs to consumers.
Pfizer Canada gets around the law by not mentioning the name of its drug (a familiar tactic used in the U.S. to circumvent the mandated requirement of describing side effects). In what is known as a “heart disease awareness” ad, Canadians are encouraged to ask their doctors for a cholesterol test. The ad shows the bare feet of a corpse on a morgue drawer with a toe tag that reads: Male, age 42; cause of death: heart attack. The ad’s headline: “What would you rather have, a cholesterol test or a final exam?”
Six statin drugs are now available: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor). Altogether statins drive a $20 billion a year world-wide market, with Lipitor No. 1– of all prescription drugs–in retail sales in the U.S. No head-to-head comparison has ever been conducted to determine whether one is superior to the others.
Statins are widely regarded as safe, and perhaps the safest of all cholesterol-lowering drugs, though no one has done a study comparing them against their older counterparts. The acknowledged side effects of statins include muscle pain and weakness, suppression of the body’s formation of Co-enzyme Q10 and, rarely, a potentially fatal muscle-wasting disorder called rhabdomyolysis. One statin, Baycol, has been withdrawn because it was linked to 31 deaths from rhabdomyolysis. The other statins still pose a rare risk for this disorder, especially at doses of 80 mg/daily. Another rare side effect is peripheral neuropathy, which is nerve damage that causes numbness or tingling in the hands and feet. Chief among the unacknowledged side effects are memory loss and other cognitive problems, which have been reported anecdotally by people who were not in clinical trials.
There is a controversy among researchers over the very real possibility that the benefit of statins has less to do with cholesterol reduction than the drugs’ other biochemical effects, most notably anti-inflammatory properties. Atherosclerosis is thought to be due to an inflammatory response to arterial injury–an injury caused by high blood pressure, smoking or other risk factors.
Cholesterol as a Disease:
To understand today’s obsession with cholesterol, it helps to have a little background regarding this particular risk factor and how it came to be treated as if it were a disease. High blood levels of cholesterol emerged as a risk factor for heart disease in the Framingham Heart Study, whose results have been misrepresented, according to some researchers. Begun in 1948, it followed 5,000 healthy men and women living in Framingham, Massachusetts, to determine which factors distinguished those who eventually suffered a heart attack.
Cholesterol was identified as one, but only one of 240 risk factors that included short stature, male baldness, creased ear lobes, and being married to a highly educated woman. Research focused on cholesterol because it is a modifiable risk factor (translation: drug industry opportunity). Though the Framingham Study found a strong association between blood levels of cholesterol and heart disease only in young and middle-aged men, the entire population was, in time, instructed to fear this particular risk factor.
Contrary to conventional medical wisdom, the Framingham study did not find that a high-fat diet doomed people to a heart attack. A subgroup of Framingham participants was assessed for their intake of saturated fats, dietary cholesterol and overall calories. None had any effect on the development of heart disease.
The idea that a low-fat diet prevents heart disease lives on, despite a 2001 review of all relevant clinical trials. The combined results showed that reducing or modifying dietary fat intake had no effect on heart disease mortality or total mortality (Hooper et al. British Medical Journal, 3/31/01).
However, modest reductions in non-fatal cardiovascular “events” (e.g., strokes, heart attacks) were shown in the few trials in which the participants remained on the diet for more than two years.
Several books have been written about the overrated importance of cholesterol (both dietary and blood levels) in the development of heart disease, most notably Heart Failure (1989) by Thomas J. Moore, The Cholesterol Myths (2000) by Uffe Ravnskov , MD, PhD, and Tales from the Other Drug Wars (1999: Chapter on Lipid-Lowering Drugs by Isabelle Savoie www.chspr.ubc.ca/misc/drugwars2.pdf) Such skeptics are usually fond of pointing out that half of all heart attacks occur in people who have normal cholesterol levels.
Lifestyle Changes Often have Small Effect
Once a person’s blood test shows high cholesterol, a low-fat diet is recommended, along with the admonition to get regular exercise. Most people will find that these two lifestyle changes bring only minimal reductions in cholesterol, making statin therapy the inevitable next step.
Given the emphasis on cholesterol “numbers,” it is easy to lose sight of the fact that the ultimate goal of drug therapy is not to lower cholesterol but to reduce the odds of dying of a heart attack or stroke. A pharmaceutical company seeking approval from the FDA, however, need only prove its drug can lower cholesterol. The more important, long-term studies are initiated many years later.
When researchers began conducting clinical trials to prove that lowering cholesterol will prevent cardiac deaths, they ran into some major snags over the course of several decades. Despite millions of dollars spent on clinical trials, researchers simply could not prove that lowering people’s cholesterol had any effect on life expectancy. Whether the study participants lowered their cholesterol with diet, exercise, smoking cessation, and/or drugs, the heart disease death rate went down but the over-all death rate, that is, the death rate from all causes, went up. In other words, their total death rate was no different from that of the people who did not lower their cholesterol.
Statins are Different…or are They?
Proof that statin drugs can benefit people without heart disease comes from five clinical trials in which the participants had been randomly assigned to take a statin or a placebo daily. Altogether about 40,000 healthy but high-risk people, aged 55 to 82 years, participated in these clinical trials, with the statin doses ranging from 10 mg to 40 mg a day. Participants were primarily males with high cholesterol and other risk factors, such as smoking and angina (chest pain caused by constrictions in the coronary arteries). In one trial, the men and women had either normal or borderline levels of cholesterol. Several reviews of the five clinical trials came to the conclusion that statins can reduce the rate of non-fatal heart attacks and strokes. The drugs also reduce cardiovascular mortality, but they did not reduce all-overall mortality.
Conveying the Benefit to the Public:
Interestingly, the Newsweek article devoted only one sentence to the critical question of what has been proven regarding statins. Without further explanation, the article says a large study “showed that cholesterol-lowering drugs reduced the risk of heart attack and stroke by at least one quarter for those at highest risk.” While this is roughly accurate, it appears more impressive than the reality. The one-quarter reduction refers to the difference in the rate of heart attack between the study participants taking statins and those on the placebo.
What makes the statistic misleading is the fact that healthy people–even those with high cholesterol–have a low risk of having a heart attack to begin with. And reducing their odds of having a heart attack by one-fourth simply means that 3% of the statin-treated study participants had a heart attack or stroke, as compared to 4% of the untreated participants (the placebo group). Or put another way: There were 1% fewer statin-treated people had heart attacks. The studies lasted only about five years so these statistics apply to taking the drug only for that length of time. (See Web sites listed at the end of this article for help in understanding risk assessment.)
It is not unusual for reviewers to look at the same trials and come to different conclusions about what has been proven. This is what happened when a Canadian team of researchers conducted its own review of the five statin trials. This new analysis took issue with the generally agreed upon conclusion that these five trials proved that the benefit of statins far outweigh the risks.
The New Analysis:
The analysis of the five trials was conducted by a team of researchers at the University of British Columbia led by James M. Wright, PhD, who came to the alarming conclusion that statins harm as many people as they help. True, the combined results of the five trials did, in fact, show a lower rate of non-fatal heart attack and stroke. However, once serious adverse events* were taken into account, the results were not so positive. The statin users did have 1.4% lower rate of heart attack within the next five years, compared with untreated people, but that small benefit was offset by a 1.8% rate of serious adverse events associated with the drug.
Dr. Wright and colleagues might be the first reviewers to step back and look at the big picture–assessing the serious risks as well as the benefits of statins. Only two of the five trials reported serious adverse events. “Based on the two trials, we are suspicious that some serious adverse events are being increased by statins and that this appears to be canceling the benefit of the reduction in heart attacks and strokes,” Dr. Wright wrote in an e-mail interview. The new analysis was published in the April-June 2003 issue of Therapeutics Initiative, an evidence-based drug therapy newsletter (“Do Statins Have a Role in Primary Prevention?” Available free at http://www.ti.ubc.ca).
Dr. Wright is associated with the Cochrane Collaboration, an international network of experts who conduct systematic reviews of the supporting evidence for drugs and other medical, surgical or behavioral interventions. In a move that distinguishes many Cochrane reviewers, Dr. Wright and his colleagues at the University of British Columbia contacted the authors of the three trials that did not publish the number of serious adverse events suffered by their study participants. The reviewers have yet to receive the requested data.
Yet to be Proved for Women:
In the e-mail interview, Dr. Wright was asked about statins’ proven benefit specifically to women–something omitted from the analysis as it appeared in Therapeutics Initiative. To answer this question, Dr. Wright did a separate analysis of women who participated in four of the five primary prevention trials, emphasizing that they made up only 28% of all the study participants. “Combined results of all trials do not support the use of statins by women without heart disease,” concluded Dr. Wright. This is explained by the fact that women were not only underrepresented in the trials, but also, as a group, have a very low risk of having a heart attack in a five-year period.
The University of British Columbia researchers are not the first to notice that the benefit of statin therapy to women remains an open question. High cholesterol has never been proven to be an important risk factor for women. At every stage of life, women tend to have higher blood levels of cholesterol than men of the same age; yet they are about 15 years older then men at the age of a first heart attack.
Statins have begun to replace postmenopausal hormones as the all-purpose drug to prescribe to healthy older women whose only risk factor is high cholesterol. It is noteworthy that many of the additional benefits claimed for statins–beyond cholesterol reduction–are similar to those made prematurely for estrogen. For example, some women are told that statins will also reduce their risk of Alzheimer’s disease and osteoporosis. The latter has been disproved, and the former comes only from preliminary studies.
More cases of breast cancer have shown up among statin users in three trials. In all three, the finding was described as “not statistically significant.” One trial involving people with heart disease who either took a placebo or 40 mg of Pravachol daily found that breast cancer developed in 12 out of 286 women taking the drug, compared to one out of 290 on the placebo.
People over 70
Whether high cholesterol is a problem for elderly people has been the subject of a long-running controversy. So has the question of whether cholesterol-lowering drugs can provide any benefit to this age group. The controversy was theoretically settled by a large multi-center European trial published in 2002 when The Lancet published a major trial, known by the acronym PROSPER. It showed that statins lowered the incidence of coronary events but had no effect on longevity. The PROSPER trial, however, lasted only three years.
The participants, aged 70-82 years either had heart disease (44%) or had risk factors for heart disease (56%). The PROSPER results showed an ominous increase in the frequency of new cancer diagnoses in the people taking Pravachol, which was dismissed as a “chance finding” by the authors. In response to the PROSPER trial three of five letters to the editor of The Lancet took issue with the description of “chance finding.” One letter noted that the cancer incidence over three years was 6.8% in the placebo group and 8.5% in the people taking Pravachol.
Another letter to the editor expressed concern that the PROSPER will encourage the use of statins in elderly people: “Surely one relevant statistic is that by treating 5,804 high-risk patients with pravastatin [Pravachol] or a placebo, the overall death rate [sic] was reduced from 306 to 298 over three years. This was achieved at what cost to the perception of good health, comfort, or anxiety among the participants?” wrote Peter J. Little of New Zealand (Lancet, 2/1/03). Such critics recently gained support from the new analysis by the University of British Columbia researchers who concluded that the cardiovascular benefit shown in the PROSPER trial was offset by serious risks.
Reaction to the New Analysis
The new analysis met with criticism from cardiologists in Canada, but it has been largely ignored in the U.S. The criticism centers on the fact that the University of British Columbia research team came to entirely different conclusions about statins than virtually all other medical organizations that have reviewed the same studies. In a recent article for the Toronto Globe & Mail, Dr. Ruth McPherson dismissed the research team because it did not include specialists in cholesterol metabolism and treatment. Furthermore, the findings were published in Therapeutics Initiative (TI) which “does not have the status of a peer-reviewed journal.”
TI, which is based at the University of British Columbia, is a newsletter that is peer-reviewed, according to its Web site, by family physicians, specialists, academic researchers, pharmacologists, pharmacists and epidemiologists. TI is funded by the Canadian Government to help doctors make evidence-based treatment choices. The average practicing physician does not have the time to pick through each statin trial to determine, say, whether women are represented in large enough numbers, or whether the odds of being harmed by a drug are equal to its odds of a benefit.
People with Heart Disease or Diabetes
Statins clearly benefit diabetics and people with heart disease who want to avoid a heart attack or stroke, as well as those who have already suffered one and want to prevent another. Such people are more likely to benefit from statin therapy because their odds of having a heart attack or stroke are so high. Pravachol and Zocor are the best assessed statins for people who have diabetes and/or heart disease. Altogether more than 35,000 people who fit this profile took part in trials that compared a statin with a placebo.
The most recently published large trial was conducted in the United Kingdom; 25% of the participants were women and 46% were over age 65 years. All had been randomly assigned to take Zocor or a placebo for five years. Results showed that the participants who took Zocor decreased their odds of overall mortality by 1.8% in the next five years, compared to those who were untreated (placebo group). Coronary deaths were reduced by 1.2% among statin users within five years. The reductions were higher for people who have already had a heart attack or angina and for diabetics. Contrary to expectations, Zocor showed no beneficial effect on fractures or dementia. As for the cancer-related concerns, Zocor did not alter the overall incidence of cancer ( Prescrire International, 8/03). No separate analysis has been done for women.
As for the importance of reducing fat intake, this particular lifestyle change has more relevance to people who have heart disease than it does to healthy people. Combined results of seven clinical trials involving participants with heart disease showed that dietary changes provided a 6.6% lower incidence of heart attacks and/or cardiovascular deaths than those who did not reduce fat intake.
Maryann Napoli, Center for Medical Consumers(C)
*Serious adverse events includes “any medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant liability.”