Statin Pleiotropy: Unique Roles for a Common Medication

April 26, 2007

AtorvastatinBy: Melissa Freeman, MD, PGY1

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.

References:
Davignon, J. Beneficial cardiovascular pleiotropic effects of statins. Circulation, 2004; 109(23 Suppl 1); III39-43.
http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:15198965&_char_set=utf8

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.
http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:15173062&_char_set=utf8

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.
http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:16283159&_char_set=utf8

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=

Circulation&volume=101&issue=2&spage=207&epage=213

Image: 3D rendering of Atorvastatin, courtesy of wikimedia commons

One Response to Statin Pleiotropy: Unique Roles for a Common Medication

  1. Dan on May 11, 2009 at 7:07 am

    What Is Believed To Be Qualities Of All Statin Medications:

    Statins are a class of medications specifically prescribed to lower LDL- one of five lipid parameters of a person’s lipid profile, which is alto the name of the blood test to measure these parameters. They are beneficial for those patients with dyslipidemia and cardiovascular disease, primarialy.
    There are about 6 available statins to choose for lipid management as needed- with three that are combination drugs that have a statin included in these drugs.
    There are other classes of medications for lipid management, such as bile acid sequestrants and nicotinic acid, which is known as niacin. Yet the side effect profile is more unfavorable of these classes of medications compared with the statin class of drugs.
    One’s cholesterol level is primarily due to how they produce cholesterol in their liver, which is overall genetically determined. This level is also determined by one’s lifestyle and diet as well. If a person has too much cholesterol in their blood, it can lead to hardening and narrowing of their arteries as well as the formation of coronary plaques in the coronary arteries.
    If these plaques break off of the arterial wall, this leads to a myocardial infarction, or heart attack. Statins are believed to stabilize coronary plaques so this does not occur.
    To measure one’s cholesterol, a blood test called a lipid profile is obtained from a person after they have fasted for at least 12 hours. The test should also be performed only if the person is free of any acute illness, as this may affect true lipid measures.
    If the results prove to be abnormal, lipid altering medicinal therapy may be initiated- according to the discretion of the person’s health care provider. This therapy usually involves a statin medication.
    Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular at times that may not be necessary to control their dyslipidemia based on their lipid profile. Side effects may include muscle pain, or possible damage to the patient’s liver.
    However, since this class of statin drugs has existed for use for over 20 years, statins are considered to be overall safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients.
    Also, they have proven to reduce cardiovascular mortality with one who is treated with a statin that has dyslipidemia. In addition to lowering LDL by up to about 60 percent- depending on the choice of the statin prescribed for the patient, and how high the LDL cholesterol is in a patient.
    This class of drugs also has the ability to raise their HDL lipid parameter as well as lower to their benefit their triglyceride parameter of their lipid profile. Both of these additional effects in addition to lowering the LDL parameter from taking a statin drug is ultimately beneficial for the patient on a statin drug for lipid management.
    Statin therapy is also recommended for those patients who have a greater than twenty percent risk of developing cardiovascular disease, or those patients that have clinical evidence of this disease.
    Additionally, there appears to be no comparable reduction in cardiovascular morbidity or mortality, as well as a difference in the increase of one’s lifespan, if one is on any particular statin medication for their lipid management over another, others have concluded. So caution should perhaps be considered if one chooses to prescribe a statin for a patient if they are absent of, or have only mild dyslipidemia to a significant degree.
    Furthermore, research should be done by the health care provider if they are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any choice of statin therapy for their patients should be considered reasonable and necessary if the LDL in their patients need to be reduced.
    Furthermore, the statin selection should be determined by the results that have been shown with a particular statin.
    There exist abstract etiologies for health care providers at times to choose to prescribe statin drugs on occasion for reasons not indicated with the medicinal treatment of these statin drugs. Examples include the speculated benefits associated with statins- such as reducing CRP levels, or for Alzheimer’s treatment, or other reasons not directly related to cholesterol management.
    Statin therapy for such patients may not be considered appropriate, reasonable, or necessary prophylaxis at this point for any patient who does not have the indications for which statins are approved for to treat patients with dyslipidemia.
    All other benefits that appear to have favorable effects in such areas not involved with a patient’s cholesterol are suggested at this point due to minimal research in these other variables aside from lipid management.
    Other reasons for placing a patient on a statin drug at this time require further research for these disease states and dysfunctions that may exist with a patient aside from dyslipidemia.
    Statins as a class of drugs seem to in fact decrease the risk of cardiovascular events significantly, it has been proven. Statins also decrease thrombus formation as well as modulate inflammatory responses (CRP) as additional benefits of the medication.
    For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug.
    Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient presently. Patients should be made aware of potential additional side effects as well, such as myopathy and muscular dysfunctions that occur on occasion when one is on statin therapy.
    Yet some have said that about half of all strokes and heart attacks that do occur are not because of increased cholesterol levels of these patients. So it appears clear that high cholesterol may not be an absolute for cardiovascular events for them to occur.
    Others believe that it is oxidized cholesterol that causes vulnerable plaques to form on coronary arterial walls, which is the catalyst for a heart attack, and that there is no medicinal treatment for the formation or stabilization of these plaques to prevent heart attacks or strokes.
    Some who support statin medicinal therapy for their clinically appropriate patients claim that these drugs, do, in fact, stabilize these plaques as an added benefit, and therefore are beneficial.
    As stated previously, in regards to other uses of statins besides just primarily LDL reduction, there is some evidence to suggest that statins have other benefits besides lowering LDL, but not enough evidence yet.
    These other disease states include aside from what has been stated already, such as those patients with neurological disease, as well as statins being beneficial for certain cancer patients. Some have suggested that statins interfere with cancer treatment with bladder cancer patients as well. Yet again, these other roles for statin therapy have only been minimally explored and researched, comparatively speaking.
    Because of the limited evidence regarding additional benefits of statin medications, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.
    Yet overall, the existing cholesterol lowering recommendations or guidelines should possibly be re-evaluated. The cholesterol guidelines that presently exist may be over-exaggerated possibly due to tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines.
    This is notable if one chooses to compare these cholesterol guidelines with the other guidelines that have existed in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable and unnecessary, as well as possibly have the potential to be detrimental to a patient’s health.
    Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality. What that ideal LDL level is may have yet to be empirically determined.
    Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future, regarding the high cholesterol issue. Treating children with a statin drug for dyslipidemia is controversial presently. Dietary management should be the first consideration in regards to correcting lipid dysfunctions that may exist in patients.
    http://www.americanheart.org
    Dan Abshear

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