Can one prescription deliver broad protection against many conditions generally associated with aging? The statins (5-hydroxy- 3-methylglutaryl-coenzyme A [HMGCoA] reductase inhibitors)?including atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin?just might.
Post hoc analysis of large-scale cardiovascular and lipid-lowering studies uncovered several unexpected trends. In addition to improving lipid profiles, statins seemed to improve bone strength, as well as stroke, fracture, cancer, and arthritis outcomes (Table 1). Other lipid-lowering agents did not. These pleiotropic (having multiple phenotypic expressions) effects stimulated interest in further research.1,2 Only a few effects (Table 2) have been effects proven to be truly pleiotropic; others still await validation.2
Whether statin use changes the overall incidence of cancer is unclear from case-control studies. Different treatment durations, follow-up, and sample size muddy comparisons. Additionally, some studies have examined all cancers, whereas others have selected 1 or 2 subtypes.4
A recently published article in the New England Journal of Medicine provides some of the strongest evidence to date. Matching 1953 colorectal cancer patients with 2015 controls, the researchers adjusted for physical activity, family history, diet, and other confounding variables. After 5 years, they found that statin-treated patients had a 47% risk reduction for colorectal cancer.5 Lipid lowering was not the cause; the risk was unchanged in patients taking fibric acid derivatives. Given the gradual nature of colorectal cancer, a protective effect after only 5 years of exposure is impressive.
Statins also deter breast cancer. In vitro, statins inhibit cancer cell proliferation.6 In a study designed to determine whether statins might increase breast cancer risk, postmenopausal women on statin therapy 5 years or longer had a reduced risk.7 Other studies also have reported this effect.8 In addition, statins may reduce the incidence of prostate cancer.8,9
With established safety records, statins are attractive candidates for cancer prevention. Recommending statins for prevention is premature, but additional research may eventually validate this role.
In vitro and in animals, statins build strong bones,10 probably by increasing important regulators of osteoblast differentiation and activity.3 In humans, fracture is the proxy measure of bone strength, and observational studies and meta-analyses have produced conflicting results. For example, post hoc analysis of 4444 women taking simvastatin or placebo for 5.5 years found no difference in hip or femur fractures between the groups.11 Yet, meta-analysis of 4 large prospective studies found a 38% to 81% reduction of hip fractures and a 5% to 51% reduction of nonspine fractures. The same authors, however, found no risk reduction in a meta-analysis of 8 observational studies and 2 clinical trials investigating statin use and fracture.10
These conflicting results may be the product of the limitations of retrospective analysis: the inability to alter research design or to control confounding variables. Only prospective, randomized double-blind studies will elucidate the effects of statins on bone formation.
Statins suppress T-lymphocyte activation; this action might help transplant recipients.12,13 Cardiac allograft vasculopathy (CAV), an obliterative coronary artery disease, is the leading cause of mortality among long-term cardiac transplant recipients.12 In one study, 97 transplant recipients were randomly assigned to either a pravastatin or a control group. A year later, the pravastatin group had significantly lower cholesterol levels, less cardiac rejection, lower incidence of CAV, and improved survival (94% for pravastatin, 78% for controls.)12 Other studies have produced similar findings for heart transplant patients, but researchers have failed to observe similar trends in renal transplant patients, perhaps due to sample size and methodological flaws.12
Central Nervous System Diseases
Emerging evidence suggests a role for statins in the treatment of diseases of the central nervous system, including multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Although these diseases differ significantly, they have inflammatory and oxidative stress pathways in common.14
Statins inhibit inflammatory components of MS that exacerbate neurologic disability, and significant evidence exists that statins have a positive impact on experimental autoimmune encephalomyelitis, the prototypical animal model of MS.14 A 28-patient trial found positive changes in clinical markers for MS following 6 months on simvastatin.15 Although this small study lacked a control group, other studies are under way.
Beta-amyloid (A?) peptide, a major component of senile plaque that is observed in AD, is cleaved from amyloid precursor protein. In animal studies, simvastatin reduced A?production. Three large-scale, case-control, retrospective studies found that statins reduced the risk of developing dementia by 63% to 70% in elderly patients.14 Smaller prospective, randomized controlled studies have produced less dramatic and conflicting findings.16 (Because age-related macular degeneration shares some characteristics with AD, statins are now being investigated to delay the onset of that disease.17,18)
Although the relationship between low-density lipoprotein and stroke remains controversial, early clinical trials have associated statin use with reduced stroke risk.14 In a combined total of 70,020 ischemic heart disease patients, researchers noted a 21% stroke reduction.18 Recent, well-designed studies confirm the relationship. Equally important, statins reduce poststroke mortality. One case-control study, for example, compared 205 stroke patients who took statins prior to their stroke with 405 stroke patients with no history of statin use. Mortality was 33% lower in the statin-treated arm at 1 month.19
How Do Statins Help?
Exactly how the statins affect so many systems is still a matter for molecular biologists to sort out. Clearly, they have pleiotropic effects (Table 2). Pharmacodynamically, they inhibit HMG-CoA reductase and, consequently, L-mevalonic acid production and several intermediaries of the cholesterol biosynthetic pathway. These compounds modify many cellular proteins that control cell signaling, differentiation, and proliferation. Reducing Lmevalonic acid synthesis will lower cholesterol levels and cause a wide variety of nonlipid effects.18 Pharmacists, when promoting these pleiotropic effects, should note that concurrent vitamin E supplementation seems to blunt the protective effect of statins. They should impress upon patients that such usage is not prudent.20,21
Thus far, statins have not been linked with easy weight loss, the reversal of premature graying, or the disappearance of wrinkles, so they are not the 21st century's miracle drugs. Nevertheless, research indicates that statins are widely used and have potential in multiple disease states. They already have obtained OTC status in Britain, but when their manufacturers proposed similar status in the United States in January 2005, the FDA rejected it. Experts estimate that 20% of the population should be taking a statin (currently, 13 million actually are).22
These facts underscore a dilemma. Until researchers conduct large-scale prospective, randomized, double-blind studies, the promise of statins remains largely speculative. The high prevalence of lipid disorders, the popularity of statins, and their OTC status in some countries, however, are barriers to finding participants meeting inclusion criteria. It will be difficult to identify large-scale control groups of patients (in the tens of thousands) who will not have been exposed to statin use during the study's follow-up phases. Should research confirm the potential of statins, their relative low cost, oral dosing, tolerability, and side-effect profile will impact health care significantly.
Dr. Zanni is a psychologist and health-systems consultant based in Alexandria, Va. Ms. Wick is senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Md. Views expressed in this article are those of the authors and not those of any government agency.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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