Nov. 14, 2005--Since the late 1980s, statins have made their mark on the pharmaceutical market in unprecedented terms: According to IMS, the world's two top-selling drugs are both statins -- Lipitor (atorvastatin, Pfizer, worth $12.0 billion in 2004) and Zocor (simvastatin, Merck & Co., $5.9 billion in 2004). Med Ad News reported in May 2005 that among the top 200 best-selling global drugs for 2004, these lipid-lowering agents contributed just under $25 billion, or one-fifth of the total for the entire list. Statins thus form the most important subclass of drugs ever sold.

Some of the air will start seeping out of this massive revenue balloon over the next couple of years, as the impact of patent expiry grows. This would mark the beginning of the end of the statin fairy tale, except that some developers and other interested parties, including clinicians, have been looking into new indications for these remarkable medicines.

Most of the indications being explored stay close to the drugs' original purpose.  Pfizer's Lipitor, for example, was most recently approved for stroke and heart attack prevention in patients with type 2 diabetes or other high risk factors (see Peck, MedPage Today, 2005). A recently published trial has also shown that statins reduce the risk of stroke and death after carotid artery surgery (see McGirt, J of Vascular Surgery, 2005).  In addition, effects of statins are being examined in several potential new indications well outside the cardiovascular arena, with intriguing results in at least a couple of cases.  For example, a recent report found statin use was associated with a 47% relative reduction in the risk of colorectal cancer (see Poynter, N Engl J Med, 2005).

With enticing results such as these coming out, it may seem sensible to test these drugs in new therapeutic territories.  But developers must always keep in mind that extending an established blockbuster into an entirely new area can also put existing sales at risk. 

Cardiovascular Beginnings

Statins made their debut as a breakthrough treatment for hypercholesterolemia and were initially approved for lowering risk of heart attack in patients who had already experienced such an event. As understanding of the cardiovascular system grew, the applications for statins also expanded – into coronary heart disease and into occlusive arterial disease including hemorrhagic stroke or transient ischemic attacks. With progress in the understanding of the interrelatedness of different diseases, statins have also become recognized over the past few years for the prevention of myocardial infarction in metabolic syndrome patients.

No doubt this avid mining of the cardiovascular field is partly because of the tremendous scope of such conditions.  It also helps that other types of cardiovascular drugs, such as angiotensin-converting enzyme (ACE) inhibitors, have already followed a similar development path.  It was therefore reasonable to expect that diabetic heart disease might respond to a drug already being used for that same problem in a general population. This strategy of staying close to the "home" indication has worked superbly for the statin companies, giving them unprecedented success entirely within cardiovascular disease.

As research on statins has progressed, it has also become clear that these agents have other effects besides simply lowering blood levels of the "bad" low-density lipoproteins (LDLs).  Statins also work through various, still poorly understood, so-called "pleiotropic" effects – even in cardiovascular disease.  As a result, if statins show promise in a novel indication, it could be because of their lipid-lowering properties or could be due to one or more pleiotropic effects. 

Statins Unleashed

Since these drugs first entered clinical development, people have been attempting to apply them in a variety of new disorders. For example, the first statin, Mevacor (lovastatin), launched by Merck & Co. in 1987, was also investigated as a gallstone therapy, apparently without success.  Since then, statins have been investigated in a wide range of other indications.  Some of the most important of these indications are discussed below.

Dementia.  Lipitor also made an initial foray outside the cardiovascular field when it was tested in dementia. The fundamental mechanism postulated for Lipitor's use in this condition still relates to the drug's best studied effect – lowering levels of LDL in the blood (see Sparks, Int Psychogeriatr, 2003).  In 2001, after some preliminary reports claiming statins prevented dementia, a prospective study of Lipitor's efficacy in mild-to-moderate Alzheimer's disease (AD) was initiated. Because the exact mechanism of AD has been widely debated for years, many people were interested to know whether LDL is a key factor in this incurable and increasingly common condition.

Preliminary results were expected from these studies in 2003 but have not been forthcoming. There may simply be nothing good to say about them. The recent reports that have been published on this topic actually greatly undermine optimism about the use of statins for AD.

A study from Sun Health Research Institute in Arizona did find that Lipitor showed some clinical benefit in mild-to-moderate AD (see Sparks, Arch Neurology, 2005.) The authors of this study suggested the drug could become established as an effective AD therapy if their findings were substantiated by a much larger multicenter trial.  However, at least two other trials have failed to show any such benefit. In a large prospective trial in the over-65 age-group, statin use was not associated with a decreased risk of dementia.  Indeed, former statin use was found to be associated with an elevated risk of this condition (see Rea, Arch Neurology, 2005). The 2005 Cache County study, meanwhile, found no association between statin use and the subsequent onset of dementia (see Zandi, Arch Gen Psychiatry, 2005).

In light of these recent results, pharmaceutical companies seem to have lost interest in pursuing statins for use in dementia. Indeed, the rather unexpected reversal of fortune for statins in AD may have made companies much more hesitant to get involved in other noncardiovascular indications where similar, preliminary reports from clinicians have stirred interest.

Osteoporosis.  A considerable amount of research has been conducted on statins in osteoporosis, with conflicting results. One conclusion seems to be that statins do not reduce the risk of fracture (see Waldman, Drugs, 2003).

Immunosuppression in Transplantation.  Holdaas (Minerva Urol Nephrol, 2003) found that although in vitro studies provided a theoretical basis for the use of statins as immunosuppressive agents, more-recent placebo-controlled clinical studies failed to confirm the initial positive results.

Anti-Infective Activity.  Initial results of studies into statins' effects in infection seem to suggest reason for further investigation.  The following trials have been particularly encouraging:

• In a retrospective review, Liappis and colleagues (Clin Infect Dis, 2001) concluded that statins have potential for use in bacteremic infections.
• A recent Israeli trial found that prior statin therapy dramatically reduced the incidence of severe sepsis (from 19% to 2.4%) in patients with acute bacterial infections.  According to the authors, these data support initiation of prospective controlled trials (see Almog, Circulation, 2004).
• In another recent report, patients hospitalized because of pneumonia who were taking statins were found to be 2.8 times less likely to die from pneumonia than patients not taking these agents (see Mortensen, Respir Res, 2005).

Cancer.  Outside of cardiovascular disease, by far the greatest amount of research on statins has involved cancer.  Work on statins in this area goes back to the early 1990s, far longer than for most other noncardiovascular areas, and involves multiple tumor types (see Table 1).  Only a small percentage of these studies have been completed, but they have produced some intriguing results (see Table 2).

Table 1: Cancers Targeted with Statins
Breast
Colon
Glioma
Leukemia
Lung
Lymphoma
Multiple myeloma
Neuroblastoma
Ovarian
Pancreatic
Renal
Sarcomas
Stomach

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