US Pharm. 2008;33(10):56-61.
Landmark clinical trials such as the Scandinavian Simvastatin Survival Study (also known as 4S), the West of Scotland Coronary Prevention Study, the Long-Term Intervention with Pravastatin in Ischemic Disease Trial, the Heart Protection Study, and the Cholesterol and Recurrent Events Trial have solidified the utility of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, for primary and secondary prevention of cardiovascular disease.1-5 Recent studies suggest that statins have pleiotropic effects, or, in this case, effects beyond simply a reduction in cholesterol. Recent in vitro, in vivo, case study, and epidemiologic data have suggested that these pleiotropic effects are responsible for statins' benefits in a variety of noncardiac conditions, such as cancer, infectious disease, Alzheimer's disease (AD), chronic obstructive pulmonary disease (COPD) and other lung-function diseases, contrast-induced nephropathy (CIN), and polycystic ovarian syndrome (PCOS). To date, strong conclusions have not been drawn regarding the appropriate place for statins in the treatment of these diseases. This article aims to educate pharmacy professionals about the most recent scientific data, clinical literature, and uses of statins for these conditions.
Pleiotropic Mechanisms of Action
Statins have been shown to have antiproliferative, anti-inflammatory, and immunomodulatory actions; improve endothelial dysfunction; and enhance the availability of nitric oxide (NO).6 Statins inhibit HMG-CoA reductase from converting HMG-CoA to mevalonate, which is the rate-limiting step of cholesterol synthesis.7 This inhibition further prevents the synthesis of important downstream isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are important lipid components for the posttranslational modification of small GTPase proteins such as Ras and Rho. These small guanosine triphosphate (GTP)–binding proteins have important actions in intracellular signaling pathways involved with cancer, inflammation, and immunomodulation.8
Much research has been conducted to delineate the anti-inflammatory actions of statins. Lee et al demonstrated that the anti-inflammatory action of atorvastatin was due to inhibition of isoprenylation of Ras and Rho, which further caused inhibition of inflammatory signaling cascades and gene expression.9 Cho et al reported inhibition of nuclear factor–kappa B (NF-kB), which helps explain the statins' anti-inflammatory effects.10 (NF-kB is a transcription factor that is involved in inflammation, infection response, cancer, and autoimmune disorders.) Statins also have been shown to cause the upregulation of endothelial NO synthase and to induce expression of heme oxygenase-1, a stress-response protein.8 A recent study showed that simvastatin and fluvastatin selectively reduced P-selectin– and E-selectin–mediated interactions between endothelial cells and neutrophils by blocking cell-surface expression of adhesion molecules, which are implicated in inflammation.11 Statin administration has been associated with the depletion of peripheral blood monocytes, which play a pivotal role in immune response.12 Statins also have been shown to reduce levels of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, all of which are associated with the inflammatory cascade.
Several recent studies have demonstrated the anticancer effects of statins. Cho et al reported that simvastatin induced apoptosis in human colon cancer cells by acting on the NF-kB pathway.10 They also found that simvastatin inhibited vascular endothelial growth factor–mediated angiogenesis and prevented colitis-associated colon cancer in a mouse model.10 A similar result was seen in a Hodgkin's lymphoma (HL) cell line, where simvastatin induced apoptosis in HL cells and impaired HL tumor growth.13 Statins' anticancer activity has been reported in combination with the epidermal growth factor receptor inhibitor gefitinib; gefit inib plus lovastatin has demonstrated enhanced cytotoxic effects against squamous-cell cancer, colon carcinoma, non–small-cell lung cancer, and glioblastoma cells.7 Lovastatin and simvastatin have been discovered to increase the phagocytic activity of peripheral blood phagocytes; this action is thought to play a role in the immune-modulating actions of statins.14
The statins' neuroprotective effects are believed to be brought about by their anti-inflammatory effects on GTPase proteins, but recent data suggest additional mechanisms of action. Haviv et al concluded that the use of simvastatin significantly delayed the onset of prion disease in mice by promoting an overall balance of microglially-induced chemokine and cytokine activity.15 Independent of cholesterol-lowering actions, simvastatin caused cell-cycle arrest at the G1/S phase in AD-vulnerable lymphocytes.16 Statins have been shown to limit the production of beta-amyloid (responsible for the beta-amyloid plaques of AD) through actions on protein isoprenylation.17 As noted above, there is an abundance of in vivo and in vitro research supporting the pleiotropic effects of statins in inflammation, immune response, and proliferation, but analysis of the clinical and epidemiologic data has not produced a clear clinical benefit.
Statins and Specific Diseases
Cancer: Owing to statins' reported antiproliferative and immune-modulating effects, researchers have suggested that these agents may have a clinical benefit in cancer. While initial case studies and epidemiologic analyses suggested that statins decreased the incidence of cancer, several recent meta-analyses concluded that the use of statins was not associated with a reduced risk of cancer.18-20 Some researchers have contended that this conclusion may not be valid because the trials included in the meta-analyses were not designed to evaluate statins as a preventive agent for cancer, and the mean age of less than 65 years and follow-up of less than five years may have been inadequate to detect a difference in cancer incidence between statin users and nonusers.19 A recent long-term retrospective study by Farwell et al of a population of U.S. veterans showed a reduced overall risk of cancer in statin users compared with nonusers, with the most significant risk reduction occurring in lung and colon cancers.21
Although previous meta-analyses evaluated the overall risk of cancer of any type, many studies are now investigating the risk of specific cancers. The most abundant data have been collected about statins and breast, colon, and lung cancers. In a recent multicenter, population-based, case–control study, Pocobelli et al concluded that statin use was not associated with a reduced risk of breast cancer, but noted that individual use of fluvastatin was associated with a reduced risk of breast cancer (odds ratio [OR] 0.5, 95% CI 0.3-0.8).22 Interestingly, another study found an 18% reduction in risk of breast cancer in patients who took hydrophobic statins (simvastatin, fluvastatin, and lovastatin) versus no reduction in those taking hydrophilic statins.23 This result was corroborated in a study that found a reduced incidence of cancer in patients taking hydrophobic versus hydrophilic statins.24 These findings led the authors to suggest that further studies of individual statins' effects on cancer incidence may be warranted.23,24
The use of statins for colon cancer has been evaluated in several large studies. Vinogradova et al reported that prolonged use of statins was not associated with a decreased risk of colorectal cancer (OR 0.94, 95% CI 0.79-1.11).25 A meta-analysis of six randomized, controlled trials and three prospective cohort studies found no evidence of a reduced risk of colon cancer, but analysis of nine retrospective case–control studies showed an 8% risk reduction in colorectal cancer (relative risk [RR] 0.92, 95% CI 0.89-0.95). When all 18 studies were combined, there was a statistically significant reduced risk of colorectal cancer (RR 0.92, 95% CI 0.90-0.95).26 In a retrospective case–control analysis of 1,809 patients, Coogan et al found no overall reduced risk of colon cancer with the use of statins, but did note a statistically significant reduction in stage IV colon cancer in patients who had been treated with statins (OR 0.49, 95% CI 0.26-0.91).27 These results prompted the authors to suggest additional studies, for a treatment benefit of statins may exist even if a preventive one does not.27
In addition to Farwell et al's findings, a large study of U.S. veterans determined that use of statins for longer than six months led to a 55% reduction in risk of lung cancer (OR 0.45, 95% CI 0.42-0.48, P <.01).28 Moreover, this effect was seen across age and racial groups.28
The effectiveness of statins in reducing cancer risk is still up for debate. While many researchers disagree about whether statins confer a benefit in cancer, they all suggest the need for randomized clinical trials to fully elucidate the role of statins in the prevention and treatment of cancer. At this time, more than 20 clinical trials are being conducted to evaluate statins' utility for cancer.29
Infectious Disease: The use of statins for infectious diseases has mostly been evaluated in sepsis, pneumonia, and influenza. A recent meta-analysis pointed to a benefit from statins in septic patients.30 Falagas et al found that the majority of reviewed studies suggested a clinically significant advantage from statins with regard to mortality in patients with bacteremia or community-acquired pneumonia, a decreased risk of sepsis, and a decreased risk of pneumonia.30 In a literature review, Gao et al concluded that there is evidence from cell-based studies, animal models of sepsis, and observational clinical studies that the use of statins in septic patients could be beneficial.31 The authors of both studies concede that additional prospective studies are needed to draw a safe conclusion regarding the use of statins in sepsis, but the current evidence cannot be overlooked.30,31 Interestingly, Yang et al reported that statins did not result in an increase in the 30-day survival rate of septic Asian patients who were statin users, further suggesting that future studies should evaluate race or ethnicity.32
A large matched cohort study and two separate case–control studies recently found a significantly reduced risk of death from influenza or pneumonia in moderate-dose statin users (hazard ratio [HR] 0.61, 95% CI 0.41-0.92). The study also indicated that the statin-related benefit of reduced mortality in these patients was not explained by an observed reduction in COPD-related mortality risk.33 As is the case with bacterial infections, the specific protective role of statins in influenza must be validated with prospective, randomized clinical trials.
AD: Much debate has taken place concerning the role statins may play in the prevention and treatment of AD. In the Alzheimer's Disease Cholesterol-Lowering Treatment trial, the use of atorvastatin was associated with improved cognition and memory after six months of treatment, and this benefit persisted at one year (P = .003).34 Other retrospective studies have suggested that statins have a protective effect against AD.35,36 A community-based cohort of 1,146 African American subjects was examined for cognitive decline and statin use.37 Baseline statin use was associated with less cognitive decline (P = .0177), and logistic regression showed a nonsignificant reduction in incident dementia with statin use (OR 0.32, P = .0673). When statin use over time was investigated, the benefit was not clear, indicating that a significant advantage remained only for patients who discontinued statin use prior to follow-up, compared with those with continuous use and those who started use after baseline.37 A total of 929 older clergy enrolled in the Religious Orders Study were assessed for incident AD, change in cognitive function, and neuropathology. Patients were assessed annually for up to 12 years. End results found no relationship between statins and incident AD or change in global cognition.38 The authors commented that their findings need to be replicated in a more diverse population, but that the results add to the growing evidence of statins' lack of benefit for AD.38
Respiratory Disease: Due to their postulated anti-inflammatory actions, statins have been investigated for use in COPD and other lung illnesses associated with inflammatory damage. A Veterans Affairs (VA) study evaluating the effect of statins on lung function in current and former smokers showed a slower decline in lung function (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) in patients with obstructive or restrictive respiratory illness who took statins compared with nonusers (P <.05).39 The study also noted a decrease in respiratory-related emergency-room visits in statin users versus nonusers (P = .01).39 Alexeeff et al, in the VA Normative Aging Study, concluded that statins conferred a protective effect on lung function in the elderly regardless of smoking history (P <.001).40 The rates of decline of FVC and FEV1 were reduced by at least 50% in longtime quitters and recent quitters taking statins compared with those who were not.40 A recent population-based analysis in Japan found a statistically significant negative correlation with COPD (r = 0.574, P <.0001), suggesting that statins have a beneficial effect on incidence of mortality from COPD.41 In a study by Frost et al, there was a dramatically reduced risk of death from COPD among statin users versus nonusers (HR 0.23, 95% CI 0.13-0.42).33 To date, the role of statins in COPD and maintenance of lung function is not fully defined, but recent evidence points to a significant protective effect. Currently, there are more than 40 clinical trials evaluating the use of statins in respiratory conditions; once these results are published, a clearer picture will emerge.29
CIN: Statins have been evaluated for the prevention of CIN because of their effects on the NO system and free-radical scavenger actions. Three studies have validated the utility of preprocedural statins for decreasing CIN in patients undergoing percutaneous coronary intervention (PCI). Attallah et al, in a study of 250 patients who received preprocedural statins and 752 who did not, reported a statistically significant decrease in postprocedural serum creatinine (P = .001), length of stay (P = .01), and cases of acute renal failure (P = .028) in statin users versus nonusers.42 Khanal et al found that, of 29,409 PCI patients, those who received statins preprocedurally had a significant reduction in CIN (OR 0.87, 95% CI 0.77-0.99, P = .03) compared with those not receiving statins.43 A long-term analysis of statin use for CIN determined that statin-treated patients had a 90% decreased risk of CIN (P <.0001) and better postprocedural creatinine clearance (P <.0001), and that four-year event-free survival was better in statin-treated patients who did not develop CIN (P <.015).44
PCOS: Statins are thought to be beneficial for PCOS because of their positive effects on insulin, oxidative stress, and inflammatory factors.45 Several studies have reported statins' benefits in PCOS. Duleba et al found that PCOS patients who received simvastatin plus an oral contraceptive (OC) versus those who received OC alone had decreased testosterone levels (P = .006), reduced luteinizing hormone (LH) levels (P = .02), and a lessened LH–follicle stimulating hormone ratio (P = .02).46 Another study comparing simvastatin plus an OC versus OC alone determined that patients receiving the combination had better clinical outcomes and biochemical markers compared with patients receiving the OC alone.47 Based on current data, statins appear to have a role as adjunctive therapy for PCOS.
A sizable amount of data exists concerning statins' mechanisms of action and pleiotropic effects and their use in a variety of conditions. Because pharmacists are often the most accessible health care providers for patients, it is important to understand recent scientific advances and keep abreast of the latest clinical literature.
Statins are no longer indicated simply for reducing cholesterol levels. Current findings suggest their utility for certain types of cancer (lung, breast, colorectal); infectious diseases such as sepsis, pneumonia, and influenza; COPD and maintenance of lung function; CIN; and PCOS. Statins may be beneficial for patients with these conditions, and pharmacists should educate patients about their appropriate use. It is equally important to recognize that current findings do not indicate a clinical benefit for other types of cancer or for AD. Pharmacists should educate health care providers and patients about the current clinical data and the lack of support for statins' use in these conditions, since the unwarranted use of statins is not without risk.
Most of the clinical literature reviewed for statins' effects on various noncardiac conditions is based on retrospective observational data, so it is important to remember that such studies have an inherent bias and that strong conclusions cannot always be drawn from these data sets. At the present time, multiple randomized, prospective clinical trials are being conducted to examine the effect of statins on many of the abovementioned conditions. Until these results are published, the precise role of statins in noncardiac conditions cannot be fully known.
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4. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
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7. Cemeus C, Zhao TT, Barrett GM, et al. Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neuro-Oncol. Epub June 20, 2008.
8. Wang CY, Liu PY, Liao JK, et al. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med. 2008;14:38-44.
9. Lee JK, Won JS, Singh AK, Singh I. Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett. 2008;440:260-264.
10. Cho SJ, Kim JS, Kim JM, et al. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer. 2008;123:951-957.
11. Eccles KA, Sowden H, Porter KE, et al. Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow. Atherosclerosis. 2008;200:69-79.
12. Fildes JE, Shaw SM, Mitsidou A, et al. HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation. Transpl Immunol. 2008;19:152-157.
13. von Tresckow B, von Strandmann EP, Sasse S, et al. Simva statin-dependent apoptosis in Hodgkin's lymphoma cells and growth impairment of human Hodgkin's tumors in vivo. Haematologica. 2007;92:682-685.
14. Salman H, Bergman M, Djaldetti M, Bessler H. Hydrophobic but not hydrophilic statins enhance phagocytosis and decrease apoptosis of human peripheral blood cells in vitro. Biomed Pharmacother. 2008;62:41-45.
15. Haviv Y, Avrahami D, Ovadia H, et al. Induced neuroprotection independently from PrPSc accumulation in a mouse model for prion disease treated with simvastatin. Arch Neurol. 2008;65:762-775.
16. Sala SG, Muñoz Ú, Bartolomé F, et al. HMG-CoA reductase inhibitor simvastatin inhibits cell cycle progression at the G1/S checkpoint in immortalized lymphocytes from Alzheimer's disease patients independently of cholesterol-lowering effects. J Pharmacol Exp Ther.2008;324:352-359.
17. Ostrowski SM, Wilkinson BL, Golde TE, Landreth G. Statins reduce amyloid-‚ production through inhibition of protein isoprenylation. J Biol Chem. 2007;282:26832-26844.
18. Dale KM, Coleman CI, Henyan NN, et al. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74-80.
19. Bonovas S, Filioussi K, Tsavaris N, Sitaras NM. Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol. 2006;24:4808-4817.
20. Browning DRL, Martin RM. Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer. 2006;120:833-843.
21. Farwell WR, Scranton RE, Lawler EV, et al. The association between statins and cancer incidence in a veterans population. J Natl Cancer Inst. 2008;100:134-139.
22. Pocobelli G, Newcomb PA, Trentham-Dietz A, et al. Statin use and risk of breast cancer. Cancer. 2008;112:27-33.
23. Cauley JA, McTiernan A, Rodabough RJ, et al. Statin use and breast cancer: prospective results from the Women's Health Initiative. J Natl Cancer Inst. 2006;98:700-707.
24. Karp I, Behlouli H, Delorier J, Pilote L. Statins and cancer risk. Am J Med. 2008;121:302-309.
25. Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF. Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study. Gastroenterology. 2007;133:393-402.
26. Bonovas S, Filioussi K, Flordellis CS, Sitaras NM. Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol. 2007;25:3462-3468.
27. Coogan PF, Smith J, Rosenberg L. Statin use and risk of colorectal cancer. J Natl Cancer Inst. 2007;99:32-40.
28. Khurana V, Bejjanki HR, Caldito G, Owens MW. Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans. Chest. 2007;131:1282-1288.
29. ClinicalTrials.gov. Search for clinical trials. www.clinicaltrials.gov/ct2/. Accessed July 2008.
30. Falagas ME, Makris GC, Matthaiou DK, Rafailidis PI. Statins for infection and sepsis: a systematic review of the clinical evidence. J Antimicrob Chemother. 2008;61:774-785.
31. Gao F, Linhartova L, Johnston AM, Thickett DR. Statins and sepsis. Br J Anaesth. 2008;100:288-298.
32. Yang KC, Chien JY, Tseng WK, et al. Statins do not improve short-term survival in an oriental population with sepsis. Am J Emerg Med. 2007;25:494-501.
33. Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;131:1006-1012.
34. Sparks DL, Sabbagh M,Connor D, et al. Statin therapy in Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:78-86.
35. Wolozin B, et al. Decreased prevalence of Alzheimer's disease associated with 3-hydroxy-3-methyglutaryl [sic] coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439-1443.
36. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet. 2000;356:1627-1631.
37. Szwast SJ, Hendrie HC, Lane KA, et al. Association of statin use with cognitive decline in elderly African Americans. Neurology. 2007;69:1873-1880.
38. Arvanitakis Z, Schneider JA, Wilson RS, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008;70:1795-1802.
39. Keddissi JI, Younis W, Chbeir E, et al. The use of statins and lung function in current and former smokers. Chest. 2007;132:1764-1771.
40. Alexeeff SE, Litonjua AA, Sparrow D, et al. Statin use reduces decline in lung function: VA Normative Aging Study. Am J Respir Crit Care Med. 2007;176:742-747.
41. Ishida W, Kajiwara T, Ishii M, et al. Decrease in mortality rate of chronic obstructive pulmonary disease (COPD) with statin use: a population-based analysis in Japan. Tohoku J Exp Med. 2007;212:265-273.
42. Attallah N, Yassine L, Musial J, et al. The potential role of statins in contrast nephropathy. Clin Nephrol. 2004;62:273-278.
43. Khanal S, Attallah N, Smith DE, et al. Statin therapy reduced contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med. 2005;118:843-849.
44. Patti G, Nusca A, Chello M, et al. Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2008;101:279-285.
45. Kodaman PH, Duleba AJ. Statins in the treatment of polycystic ovary syndrome. Semin Reprod Med. 2008;26:127-138.
46. Duleba AJ, Banaszewska B, Spaczynski RZ, Pawelczyk L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial. Fertil Steril. 2006;85:996-1001.
47. Banaszewska B, Pawelczyk L, Spaczynski RZ, et al. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective randomized crossover trial. J Clin Endocrinol Metab. 2007;92:456-461.
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US Pharm. 2008;33(10):56-61.