Evidence for caution: Women and statin use

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Statins are a class of prescription drugs designed to lower cholesterol. The leading statin drugs are Lipitor (generic name atorvastatin), Crestor (rosuvastatin), Mevacor (lovastatin), Pravacol (pravastatin), Zocor (simvastatin) and Lescol (fluvastatin).

The rationale for prescribing these drugs is based on the cholesterol hypothesis which argues that drugs that can lower total cholesterol (TC) or LDL cholesterol (often called “bad” cholesterol) or raise HDL (“good” cholesterol) will prevent heart disease. The measurement of cholesterol lowering is called a surrogate endpoint, which is different from the measurement of the hard endpoints of decreased heart disease or death. Having cholesterol is often thought of as a virtual disease state. However, cholesterol performs many vital functions in the body: it maintains cell wall structure, is crucial for hormone and Vitamin D synthesis, bile salt production and digestion, brain and neuron function. It is critical in fetal development and is an essential component of breast milk.

In the last 20 years, a class of cholesterol-lowering drugs called statins have achieved the status of being the most widely prescribed pharmaceuticals in the world. In Canada, women account for half of the three million people who take statins daily.

Researchers Harriet Rosenberg and Danielle Allard at Women and Health Protection recently reviewed the effectiveness and safety of statin medications for women in Canada. They were looking for the evidence base for use of this widely prescribed class of drugs. What they found was evidence for caution.

In 2006, 23.6 million prescriptions for statins were dispensed in Canada at a cost of $2 billion (CAN). Statin sales were predicted to increase, with projected earnings of $30 to $33 billion (US) worldwide in 2007. Lipitor is the top selling pharmaceutical in Canada. Worldwide sales reached $12.9 billion (US) in 2005.

In their report, Evidence for Caution: Women and Statin Use, Rosenberg and Allard look closely at the available evidence about statin use and discuss research information that challenges the cholesterol hypothesis (see box), in particular for women.

There are significant differences in the way heart disease manifests in men and women. Women have different symptoms; their symptoms are less likely to be recognized and, as a result, women may not receive timely emergency treatment and usually have a higher risk of death after a heart attack. This is especially true for younger women. Heart disease is often described as the leading cause of death for women. This is true only for women in their 80s: women between the ages of 30 and 79 are most likely to die of cancer. For men, on the other hand, heart disease and stroke are much more likely to occur at a younger age. The death rate due to heart disease among women is currently only about half that for men.

In the recent past, these differences were explained by theories of hormonal differences between men and women—theories that led to the widespread prescription of hormone therapy (HT) for menopausal women to protect against heart disease. However, in 2002, the groundbreaking Women’s Health Initiative tested this hypothesis and found the opposite to be true; and, most recently, additional evidence has linked HT with an increased risk of developing breast cancer.

There are many risk factors associated with heart disease, including smoking, diet, poverty and exposure to environmental pollutants which are modifiable, but cholesterol has become the most prominent and feared risk, perhaps because it is the only one that can conveniently be addressed by taking a pill.

The first statin was Mevacor, manufactured by Merck and officially approved for cholesterol lowering in individuals with the rare condition of Familial Hypercholesterolemia (FH) in 1987. Since then statin use has been substantially expanded to larger populations as the cholesterol targets have been lowered. Six additional statins have been approved for sale in Canada, one of which, Baycol, was voluntarily withdrawn from the market in 2001 after it was linked to at least 50 deaths worldwide caused by a serious and potentially fatal muscle disorder.

One of the most in-depth reviews of women and statin trials was undertaken in 2004 by researchers Walsh and Pignone. They evaluated data from every significant clinical trial about cholesterol-lowering drugs (both statins and non-statin drugs) and women. After reviewing over 1,500 articles, they concluded that for women without heart disease, lowering cholesterol does not reduce the death rate from heart disease or the overall death rate. They also noted that there is not enough evidence to know if events such as non-fatal heart attacks or strokes are reduced.

Analysis by researchers at the Therapeutics Initiative at the University of British Columbia, which looked at a total of 10,990 women, also found no evidence that statin therapy reduced coronary events in women without heart disease.

In addition, a recent overview in the medical journal The Lancet (2007) (and cited in Our Bodies Ourselves: Menopause) also emphasized that there has never been a single clinical trial showing that statin therapy is beneficial for women who don’t already have heart disease or diabetes. They question the evidence base for guidelines promoting statin use for this large population of women (75% of women statin users do not have heart disease) which is based on research which even the guideline authors say is “generally lacking” for women and extrapolated from men.

For women with pre-existing heart problems, statin use according to the survey by Walsh and Pignone, has been shown to reduce coronary events and coronary death, but not the overall death rate. This is of concern because a decline in coronary deaths appears to have been negated by an equal number of deaths or even an increase in deaths from other causes. These researchers were unable to fully explore this issue because many of the trials only release data on deaths caused by heart disease, and not other causes of death, making a more detailed analysis impossible.

A different review, looking at three trials where women with pre-existing heart disease are represented found that for women, cardiac events were reduced by only 0.8% per year for a five-year period and there was no decline in overall death rates.

Over the last two decades, guidelines in the United States and Canada have recommended statin therapy for ever larger populations, but researchers have questioned the science behind the “lower is better” hypothesis. Critics have pointed out that guidelines for statin drug use in women are weak and they express concern about possible conflict of interest which may bias the recommendations by guideline writers, the majority of whom have financial ties to the companies manufacturing statins.

Safety concerns

Statins have been described as “so safe they should be in the drinking water.” Yet, evaluating the safety of statin therapy for women is exceptionally difficult due to a lack of gender-based analysis in research. Also, only two of 14 key statin drug trials have released all of their serious adverse events data despite repeated requests by researchers. Access to these unreleased data is urgently needed to thoroughly evaluate the risks as well as the benefits of statins.

There are many on-line groups of former statin users, and their partners, who describe experiences with cognitive and memory impairments, including amnesia, episodes of depression, mood problems, especially extreme irritability, peripheral neuropathy, muscle pain and exercise intolerance, weakness and fatigue, blood sugar problems, and the unmasking of underlying genetic conditions (e.g., Parkinson’s disease, ALS) that are disabling or life-altering.

Since 2004, Dr. Beatrice Golomb and colleagues at the University of California (San Diego) have been compiling information on statin-related problems, including memory loss, mood and violent or aggressive behaviour. Their work has found associations between aggressive behaviour and statin use not seen in clinical trials. This research found that some statin users who had mood and memory problems also had muscle problems and weakness, which would affect their ability to undertake proven heart-protective exercise programs. Their research has estimated that, while clinical trials may report 1 to 7% of patients experience adverse drug reactions, the number of adverse reactions with statin use may be closer to 15%.

In Evidence for Caution, Rosenberg and Allard assessed the impact of statin use on women starting from the assumption that if a woman is put on a drug to prevent heart disease, the reasons for doing so must be based on the highest quality, most credible data possible. There must be solid evidence of advantage over harm and careful analysis of any serious adverse outcomes that may arise immediately or with years or decades of use or when used in combination with other drugs commonly prescribed for women.

In other words, a woman in Canada should be able to take a pill, safe in the knowledge that its benefits and safety were tested on women like her and that she is highly likely to derive a clear advantage in terms of health and longevity.

The authors state that, in terms of statin use, these expectations have not been met. Instead they found a pattern of overestimation of benefit and underestimation of harm—in short, evidence for caution.

Harriet G. Rosenberg, PhD is an Associate Professor in the Health and Society Program at York University doing research on women and health. Danielle Allard is a PhD candidate at the Faculty of Information Studies at the University of Toronto. She works as a research assistant at Women and Health Protection.

The full report, Evidence for Caution can be found at the Women and Health Protection website at www.whp-apsf.ca