For over a decade now, statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have facilitated millions of patients in the management of their atherosclerosis. Statins are known for their ability to reduce hepatic lipoproteins, up-regulate hepatic LDL receptors, and increase apoprotein E- and B-containing lipoproteins. They have become a household name in the genre of lipid-lowering and a touted hero in cardiovascular risk reduction amongst physicians. Excitingly, research has found that statins may be valuable in disease processes outside of their traditional realm.
While studying the specific biological mechanisms statins use to halt atherosclerosis progression, a myriad of in-vitro and some in-vivo beneficial attributes of this drug class surfaced. These discovered benefits have been placed under an umbrella term known as “statin pleiotropy.” Classically, the definition of pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. As a modern twist, the phrase statin pleiotropy has been created to encompass the non-LDL-mediated effects of statin treatment. One explanation for this pleiotropy includes the fact that mevalonate, the enzyme reaction product of statins, is a precursor of many nonsteroidal isoprenoid compounds besides cholesterol. The products of the mevalonate pathway are essential for wide-ranging cellular functions beyond the scope of this article.
Currently believed nonlipid-related pharmacological properties of statins include:
- halting of atherosclerosis by the inhibition of macrophage and smooth muscle growth and plaque stabilization (ACS implications)
- increased posttranscriptional endothelial nitric oxide (NO) synthase expression and bioavailability (cardiovascular and cerebrovascular implications), an ability to recruit endothelial progenitor cells (important in repair of ischemic injury), decreased endothelin-1 expression, and improved endothelial dysfunction secondary to injury (implications in ACS, diabetes)
- direct and indirect antioxidant effects, decreased reactive oxygen species
- improved thrombogenic profile, enhanced expression of tissue plasminogen activator and platelet activator inhibitor-1
- anti-inflammatory effects; reduction of inflammatory cytokines, chemokines, adhesion molecules, and C-reactive protein (CRP) molecules (CARE study), inhibition of a variety of signaling proteins (implications in the treatment of bacterial infections, sepsis)
- inhibition of lymphocyte growth and other blood mononuclear cells (implications for leukemia)
- immunosuppressive activity, linked to inhibition on promoter IV of major-histocompatibility class II (MHC-II) transactivating factor, leading to suppression of T-lymphocyte activation (implications of statins as immunomodulators and applicability in organ transplant)
- inhibition of cardiac hypertrophy- Takemoto et al (2001), using rat animal models, in vivo cardiac hypertrophy induced by angiotensin II infusion (simulating HTN) or by transaortic constriction was inhibited by simvastatin administration over four weeks
It remains unclear if all or just some of the above effects are in true isolation of the LDL-mediated effects of statins. Nevertheless, these effects have important clinical implications for the use of statin therapy.
For example, with annual threats of influenza epidemics, lengthy turn-around times for new medications, and mediocre vaccines and antivirals, researchers are turning to existing approved medications for hope. The anti-inflammatory and immunomodulatory effects found in statins have not been ignored. In 2006, Mortenson et al. and Mancini et al. suggested that statins may protect patients against community-acquired pneumonia and COPD. In 2005, Kruger et al. conducted a retrospective cohort study demonstrating a significant survival benefit in bacteremic patients on continued statin therapy. Now, in April 2007, Frost et al. evaluated whether statin use could reduce the risk of death from pneumonia/influenza and COPD. Using health-care encounter data for members of health maintenance organizations, they conducted a matched cohort study (n=76,232) and two separate confirmatory case-control studies (397 influenza and 207 COPD deaths) to evaluate if statin therapy altered mortality risk and survival time. Study findings among moderate-dose statin users included statistically significant reduced odds ratios (OR) of influenza/pneumonia death (OR, 0.60) and a dramatically reduced risk of COPD death (OR, 0.17). Some limitations of this study include the fact that diagnoses were based on unconfirmed ICD-9 codes, that all statins were considered together, and that deaths occurring outside of the hospital were not included. Still, the results of this study warrant further attention.
So are we to grab simvastatin with the first signs of the flu or to add atorvastain to our COPD regimens? Further investigation is indicated to sufficiently link statins to the improved morbidity and mortality suggested by current studies. Important clinical trials are underway to further divulge the specific pleiotropic effects of statins, attempting to put them to clinical use. Questions also remain as to how many of the observed statin effects are truly non-lipid related pharmacologic properties of the drug. Additionally, research is needed to decipher benefits of specific statins at precise doses in particular patient groups. Nevertheless, statin pleiotropy holds promise for medicine to gain significantly from the multiple unique roles of this common medicine.
Davignon, J. Beneficial cardiovascular pleiotropic effects of statins. Circulation, 2004; 109(23 Suppl 1); III39-43.
Frost, F. J., Peterson, H, Tollestrup, K, Skipper, B. Influenza and COPD protection as pleiotropic, dose-dependent effects of statins. Chest, 2007; 131; 1006-1012. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:17426203&_char_set=utf8
Francois, M. Statins as immunomodulatory agents. Circulation, 2004; 109; 15-17. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:15173058&_char_set=utf8
Halcox, J. P.J. H., Deanfield, J. E. Beyond the laboratory- clinical implications for statin pleiotropy. Circulation, 2004; 109 [suppl II]: II-42-II-48.
Kruger P, Fitzsimmons K, Cook D et al. Statin therapy is associated with fewer deaths in patients with bacteremia. Intensive Care Med 2006; 32(1): 75-79.
Maron, D., Fazio, S., and Linton, M. Current perspectives on statins. Circulation, 2000; 101(2); 207-213. http://sfx.med.nyu.edu/sfxlcl3?genre=article&issn=0009-7322&date=2000&rft.jtitle=
Image: 3D rendering of Atorvastatin, courtesy of wikimedia commons