Exploring Statins: What Does the Evidence Say?

By Electra Kaczorowski

Statin drugs are the best-selling class of drugs in the U.S. These medications (sold under the brand names Lipitor, Crestor, Pravachol, and Zocor, to name a few) block an enzyme in the liver that aids in the production of cholesterol, thereby reducing cholesterol levels and, hopefully, rates of coronary heart disease (CHD). (Most of the cholesterol in the human body is produced by the liver; we also get smaller amounts from our diet). Between 1987, when the Food and Drug Administration (FDA) approved Mevacor, the first statin, and 2002, statins became one of the most widely prescribed class of drug in the U.S, with 13.1 million monthly prescriptions from June 2006-December 2006.¹

With tens of millions of people -- most of whom are healthy -- taking statins daily, important questions must be asked. What have statins been proven to do? What do they prevent or treat? Who is taking them? Who benefits from them? How do women fit into this picture? Although the answers to all of these questions should have been established long ago, they remain unclear, inconsistent, and largely unavailable to the public.

The Role of Cholesterol in Coronary Health
What is the connection between high cholesterol and heart health? Cholesterol is a waxy substance found in the lipids (fat) in our bodies. It plays an important role in our health, such as in brain function and hormone development. Cholesterol is transported through the blood by attaching itself to different proteins. Many kinds of proteins transport cholesterol -- the two that get the most medical attention are “high-density lipoprotein” (HDL) and “low-density lipoprotein” (LDL). HDL cholesterol (the so-called “good cholesterol”) is the term used for cholesterol that is transported from the arteries. LDL cholesterol (“bad” cholesterol) is transported through the body the arteries near the heart and the brain, causing a build up of white blood cells and other matter, collectively referred to as “plaque”.

The Framingham Heart Study, launched in 1948 and continuing today, established that high LDL levels are a risk factor for coronary heart disease. (The study also found that several other modifiable risk factors have an impact on coronary health. These include smoking, high blood pressure, diabetes, physical inactivity, and obesity, and are just as critical to address as an individual’s cholesterol levels.) Complicating the issue is the fact that it remains unclear what a healthy level of LDL is in the first place -- and how varying LDL levels impact overall health, including coronary heart disease, in people of all ages.

Just the Facts: The Effect of Statins on Heart Disease and Cholesterol
Statins are often reputed to be miracle drugs -- safe, effective tools against heart disease, dubbed America’s leading killer. While CHD is a major health problem, and statins do provide effective treatment for some, the facts are not so simple, however.

There are two ways in which statins can affect heart disease: through primary prevention or secondary prevention. Primary prevention refers to risk reduction of cardiac events, such as angina (chest pain), heart failure, or heart attack in individuals who do not have heart disease, and secondary prevention refers to risk reduction among those who have already been diagnosed with CHD.

The evidence for secondary prevention is stronger than that for primary prevention. Statins clearly reduce the risk of subsequent heart attacks for both men and women with CHD. But, reducing the risk of recurrent CHD is not the only goal; it is also important to look at death rates from CHD and other causes. Here, the results for men and women differ: statins reduce mens' risk of dying from a heart attacj and the overall mortality rate, but the available evidence suggests that they do not have an effect on either of these factors in women.

When it comes to primary prevention, the evidence gets a bit murkier. Clinical trials have shown that statins reduce the rate of CHD in men with a very high risk of developing the disease (we do not have enough evidence to make the same claim for women). But, the drugs still do not provide as much risk reduction as the public has been led to believe. For every 50 high-risk men aged 30-69 who take statins for five years, a cardiac event will be prevented for only one of them.² In men and women with a moderately elevated risk, statins reduce the risk of CHD, but do not decrease overall mortality. In this population, statins also appear to increase the risk of developing other serious diseases such as cancer.

Faulty Guidelines for Statin Use
The widespread use of statins was immeasurably boosted by revisions of the National Cholesterol Education Program’s (NCEP) guidelines. NCEP, a national effort to educate the public on the dangers of high cholesterol, is sponsored by the National Heart Lung and Blood Institute, a part of the National Institutes of Health (NIH). In 2001, and again in 2004, NCEP updated its physician guidelines with recommendations that patients who either have coronary heart disease, or are at moderately elevated risk for developing it, should substantially reduce their LDL cholesterol. The guidelines outline specific cholesterol screening practices for physicians, and recommend statin therapy if lifestyle changes have failed to sufficiently reduce cholesterol levels.

As noted, these guidelines were recently expanded again in 2004. One update is the recommendation of achieving even lower levels of LDL (70mg/dL) for patients identified at very high risk of CHD (including those who already have the disease). Another change is the suggestion that those at moderately high risk (individuals who have two or more risk factors combined with a 10--20 percent risk of heart attack within the next 10 years) lower their LDL levels to under 100 mg/dL. (The previous desired level, set in 2001, was 130mg/dL or lower).³

NCEP’s 2001 and 2004 recommendations resulted in dramatic increases in the number of people for whom statin therapy is considered appropriate. These guidelines are problematic, however, because there is simply not enough evidence to uphold their application on such a broad basis. The theory of significantly reducing LDL levels among high-risk and moderate-risk individuals may be interesting, but it has not been proven to be effective in preventing CHD. Lower LDL levels have not been proven to decrease the risk of CHD in people of all ages; the Framingham study only found a strong association between high LDL cholesterol and CHD in people up to age 60. And, LDL levels were found to increase the risk of overall death rates only through age 40.

As John Ambramson, MD and James Wright, MD write in The Lancet, “The current guidelines are based on the assumption that cardiovascular risk is a continuum and that evidence of benefit in people with occlusive vascular disease (secondary prevention) can be extrapolated to primary prevention populations.”(2) In other words, just because high LDL levels are a risk factor for CHD, it cannot be assumed that very low LDL levels are beneficial. The guidelines also attempt to apply data on people with CHD to healthy individuals generally.

It just isn't good medicine to make such broad assumptions about the benefits of taking any drug at the potential expense of the health of millions of individuals. Further, the drops in LDL levels called for by the guidelines are so dramatic as to be difficult (if not impossible) to attain through lifestyle and diet changes -- thus guaranteeing an increase in the number of people who are prescribed statins after failing to reduce LDL levels on their own. Finally, the fact that the majority of the NCEP guideline-writers have financial ties to the drug industry is extremely troubling. Eight of the nine authors of the 2004 recommendations have ties to statin manufacturers, a fact that was not originally disclosed when the guidelines were first published. These conflicts of interest among the guideline-writers severely damage the credibility of their recommendations.

Where Are the Women?
Although statins are being aggressively marketed to women, their effects on women have not been sufficiently studied. There is no solid evidence, as yet, that women benefit from taking these drugs, and women make up less than one third of all research subjects in statin trials.⁴ The scant evidence that we do have is spotty, at best. Women who have CHD experience fewer cardiac events while taking statins -- which may certainly be a good reason for these women to take the drug. But, it has never been shown that these women’s overall mortality rates decrease as a result of statin use. There is currently no indication that women of any age or any risk level will benefit from taking statins to prevent CHD and other heart conditions – yet this is precisely how statins are being marketed to women. More research on women and statins is sorely needed.

What About Older Adults
Another interesting aspect is the debate over statins’ use as primary prevention in individuals over 65. The NCEP guidelines recommend lowering cholesterol levels in this age group, but the link between high cholesterol and CHD present in younger adults has not been observed in those over 65. As with women, there is not enough compelling evidence to recommend statin therapy for older adults who do not already have heart disease.

The Bottom Line
Because of the weak evidence and questionable medical guidelines, the NWHN, along with other health advocacy groups, has concluded not only that statins are over-sold, but also that their benefits have not been sufficiently proven to justify such large-scale use. The fact that the adverse effects of statins (such as muscle damage) have been downplayed and are rarely published with other (more positive) results adds to the growing list of concerns about this class of drug.

Statins remain a good choice for most men with heart disease, and may be an option for some men who are at significant risk of developing CHD. But women with heart disease need better treatment than statins currently seem to offer; moreover, there is no evidence that women who are at risk of developing CHD will benefit from the therapy.

Statins need to lose their status as miracle drugs -- and coronary heart disease and cholesterol need to be studied more carefully, free of assumptions about what we think we know. Heart disease remains a significant health concern, but putting millions of healthy people on statins has not yet been shown to improve overall public health or reduce mortality.

Electra Kaczorowski is the former NWHN Health Information Coordinator.

REFERENCES
1. Consumer Reports, "The Statin Drugs: Prescriptions and Price Trends, October 2005 to December 2006", Consumer Reports 2007, February. p.5.

2. Abramson, J, and JM Wright, "Are lipid-lowering-guidlines evidence-based?", The Lancet 2007; 369(9557):168-9.

3. Grundy, SM, Cleeman, JI, CN Merz et al., "ATP III Update 2004: Implications of Recent Clinical Trials for the ATP III Guidelines", Circulation 2004; 110(2): 227-39.

4. Napoli M, "Do Cholesterol Lowering Drugs Benefit Women?" New York: Center for Medical Consumers, June 2004. p.1.