Pleiotropic effects of statins–clinical evidence.
Abstract
The present review considers the potential pleiotropic effects of statins and the evidence indicative of the "real world" benefit from these effects in patients with cardiovascular disease (CVD). Some of these cholesterol-independent effects of statins involve improved endothelial function, stability of atherosclerotic plaques, attenuation of oxidative stress and inflammation, as well as inhibition of the thrombogenic response. Clinical evidence from early statin administration in acute coronary syndromes and in revascularisation procedures is reported. Moreover, the "metabolic" effects of statin treatment, such as renal function improvement and reduction in serum uric acid levels, in patients with stable coronary heart disease are discussed. Evidence suggests that in high CVD risk patient groups pleiotropic effects of statins may play a role in the reduction of morbidity and mortality. However, this concept requires proof in appropriately designed trials that will include clinically relevant end points in order to set specific targets in new CVD-related biomarkers, in addition to lipid levels, that should be used to fully assess the statin contribution to CVD treatment.
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Statins have pleiotropic effects including antioxidative, anti-inflammatory, and immunomodulatory capabilities.
“Statins have various pleiotropic effects that are independent of their serum cholestrol-lowering properties. Some of those reported have included antioxidative, anti-inflammatory and immunomodulatory capabilities (Athyros et al., 2009).”
From Atorvastatin Reduces the Survival of Candida albicans-Infected BALB/c Mice (2015) · cites this paper as Athyros et al., 2009
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“Atorvastatin has also shown beneficial effects on plaque progression (REVERSAL) [59], and like the other statins, some potential pleiotropic effects that affect positively patients with CVD: improvement of endothelial function, oxidative stress, and inflammation and thrombogenic response [60].”
BackgroundSerum Leptin Levels in Patients Undergoing Carotid Endarterectomy: A Pilot Study
Bountouris, I., Paraskevas, K. I., Koutouzis, M., Tzavara, V., Nikolaou, N. I., Nomikos, A., Barbatis, C., Andrikopoulos, V., Mikhailidis, D. P., Andrikopoulou, M., et al. (2009) · Angiology · doi:10.1177/0003319709350133 · Cited by 14 · see citing works
“Furthermore, statins may reduce percentage values of macrophage area, thus further supporting the theory that these agents stabilize carotid atherosclerotic plaques via reduction of the inflammatory responses.(28-33) A limitation of our study is that we did not test whether statin use is associated with macrophage con…”
BackgroundSelf-citationEstimating localization of various statins within a POPC bilayer
Kuba, J. O., Yu, Y., & Klauda, J. B. (2021) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2021.105074 · Cited by 13 · see citing works
Krysiak, R. G., Gilowski, W., & Okopień, B. (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2015.08.009 · Cited by 13 · see citing works
Novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: a patent review
Pfefferkorn, J. A. (2011) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2011.547478 · Cited by 13 · see citing works
“Beyond their lipid lowering effects, statins have also been reported to exhibit various pleiotropic effects such as reducing vascular inflammation, improving endothelial function and normalizing the coagulation--fibrinolysis system that could be complementary in reducing CVD risk [11-13].”
BackgroundFranchi, F., Ortega‐Paz, L., Rollini, F., Been, L. F., Rivas, A., Maaliki, N., Zhou, X., Pineda, A. M., Suryadevara, S., Soffer, D. E., et al. (2023) · EuroIntervention · doi:10.4244/eij-d-22-00719 · Cited by 12 · see citing works
Song, Z., Li, H., Liang, J., Xu, Y., Zhu, L., Ye, X., Wu, J., Li, W., Xiong, Q., & Li, S. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.08.173 · Cited by 12 · see citing works
Krysiak, R. G., Gdula‐Dymek, A., Ścieszka, J., & Okopień, B. (2010) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2010.00633.x · Cited by 11 · see citing works
Kim, Y. H., Her, A., Jeong, M. H., Kim, B., Hong, S., Kim, S., Ahn, C., Kim, J., Ko, Y., Choi, D., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.018 · Cited by 11 · see citing works
Krysiak, R. G., Żmuda, W., & Okopień, B. (2014) · Cardiovascular Therapeutics · doi:10.1111/1755-5922.12088 · Cited by 11 · see citing works
Reduced Health Care Expenditures After Enrollment in a Collaborative Cardiac Care Service
Delate, T., Olson, K. L., Rasmussen, J. R., Hutka, K. A., Sandhoff, B. G., Hornak, R., & Merenich, J. A. (2010) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.30.11.1127 · Cited by 11 · see citing works
“, smoking cessation, weight loss) result in additive or synergistic effects that impact not only cardiac-related but other health care utilization.(23) This study was not without limitations.”
BackgroundMakedou, K., Mikhailidis, D. P., Makedou, A., Iliadis, S., Kourtis, A., Vavatsi‐Christaki, N., & Παπαγεωργίου, Γ. (2009) · Angiology · doi:10.1177/0003319709338174 · Cited by 11 · see citing works
“33 ns Lp(a) (mg/dL) 13 (10-87) 16 (10-35) ns Lag time (min) 77.”
Self-citationStatins and Portal Hypertension: A New Pharmacological Challenge
Ramirez, G., Briceno, J., & Armando Rojas, R. (2012) · Current Vascular Pharmacology · doi:10.2174/157016112803520918 · Cited by 11 · see citing works
Cardiac and skeletal muscle changes associated with rosuvastatin therapy in dystrophic mdx mice
Finkler, J. M. G., de Carvalho, S. C., Neto, H. S., & Marques, M. J. (2019) · The Anatomical Record · doi:10.1002/ar.24341 · Cited by 12 · see citing works
Antoniou, G. A., Georgiadis, G. S., Antoniou, S. A., Murray, D., Smyth, J. V., Serracino‐Inglott, F., & Paraskevas, K. I. (2012) · Angiology · doi:10.1177/0003319712458537 · Cited by 10 · see citing works
“Even if statins may prove not to have an effect on AAA growth, patients with AAA should still receive statins to lower their high cardiovascular burden.(41,42) Potential statin toxicity should always be mentioned to patients.”
BackgroundChoroidal Vessel Wall: Hypercholesterolaemia-Induced Dysfunction and Potential Role of Statins
Ram�rez, J., Jj, S., de, R., Rojas, B. M., Gallego, B. I., Ramrez, A. I., & Trivio, A. (2012) · InTech eBooks · doi:10.5772/47794 · Cited by 10 · see citing works
“release, and activity of endothelial NO [147].”
BackgroundArabi, S. M., Chambari, M., Bahrami, L. S., Hadi, S., & Sahebkar, A. (2024) · Current Hypertension Reviews · doi:10.2174/0115734021280797240212091416 · Cited by 9 · see citing works
López‐Canales, J. S., Lozano‐Cuenca, J., López-Canales, O. A., Aguilar‐Carrasco, J. C., Aranda‐Zepeda, L., López‐Sánchez, P., Castillo, E. F., López, R. M., & Valencia‐Hernández, I. (2015) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12406 · Cited by 9 · see citing works
“rosuvastatin) have a vascular-favourable, lipid-independent pleiotropic effect.(1,2) The vascular effects of these inhibitors”
BackgroundThe Effect of Simvastatin on Lymphocyte Secretory Function in Patients With Impaired Fasting Glucose
Krysiak, R. G., & Okopień, B. (2010) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181f301e0 · Cited by 9 · see citing works
To switch (statins) or not to switch? That is the question
Athyros, V. G., Τζιόμαλος, Κ., Karagiannis, A. I., & Mikhailidis, D. P. (2010) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2010.522991 · Cited by 9 · see citing works
“The reasons for this finding are not clear but may reflect masked differences in lipid levels and in the so-called pleiotropic effects of statins [13,21].”
BackgroundSelf-citationHemostatic effects of simvastatin in subjects with impaired fasting glucose
Krysiak, R. G., Gdula‐Dymek, A., & Okopień, B. (2010) · Pharmacological Reports · doi:10.1016/s1734-1140(10)70371-6 · Cited by 8 · see citing works
“In vitro studies indicate that statin action on prenylation is a pivotal mechanism involved in their effect on some key processes of hemostasis, such as control of tissue factor, tissue plasminogen activator and PAI-1 synthesis and release [2, 10, 15].”
BackgroundKrysiak, R. G., & Okopień, B. (2011) · Pharmacological Reports · doi:10.1016/s1734-1140(11)70403-0 · Cited by 8 · see citing works
“[1, 2, 6, 7].”
Applied Healthspan Engineering
Larrick, J. W., & Mendelsohn, A. R. (2010) · Rejuvenation Research · doi:10.1089/rej.2009.0969 · Cited by 8 · see citing works
“36 Statins also have modest beneficial effects on atrial fibrillation, the most common arrhythmia of the elderly.”
Ezetimibe and Vascular Endothelial Function
Ikeda, S., & Maemura, K. (2010) · Current Vascular Pharmacology · doi:10.2174/157016111793744797 · Cited by 8 · see citing works
“Statins are potent lipid-lowering agents and considerable evidence shows that statins have beneficial pleiotropic effects on cardiovascular diseases that are independent from their lipid-lowering effects [61-64].”
BackgroundKrysiak, R. G., Gdula‐Dymek, A., Marek, B., & Okopień, B. (2015) · Endokrynologia Polska · doi:10.5603/ep.2015.0029 · Cited by 7 · see citing works
“These agents were found to produce anti-inflammatory, antioxidant, and antithrombotic properties, to regulate the growth and migration of smooth muscle cells and to improve endothelial function [4–7].”
BackgroundZhang, X., Li, S., Liu, X., Zhong, M., Zhang, Q., Zhang, Y., An, J., & Luo, Z. (2025) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-025-05487-8 · Cited by 6 · see citing works
Microsomal Prostaglandin E Synthase-1 and -2: Emerging Targets in Non-Alcoholic Fatty Liver Disease
Kotsos, D., & Τζιόμαλος, Κ. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24033049 · Cited by 6 · see citing works
“Statins have been proven to possess anti-inflammatory properties [53,54].”
Background
- Authors
- Athyros, V., Kakafika, A., Tziomalos, K., Karagiannis, A., & Mikhailidis, D.
- Affiliations
- Aristotle University of Thessaloniki (GR)
- Corresponding author
- Mikhailidis, Dimitri
- Venue
- Current Pharmaceutical Design
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2009-02-01
- Volume
- 15
- Issue
- 5
- Pages
- 479-489
- ISSN
- 1381-6128 (ISSN-L)
- OpenAlex
- W2116801503
- Cited by
- 154
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 12 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 15 · 2014: 9 · 2013: 13 · 2012: 16
- FWCI
- 21.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Pharmaceutical Design (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statins, pleiotropy, cardiovascular disease, endothelial function, atherosclerotic plaque stability, oxidative stress, inflammation, acute coronary syndrome, revascularization, renal function, serum uric acid, coronary artery disease, cardiovascular risk reduction
- MeSH terms
- Animals, Cardiovascular Diseases, Clinical Trials as Topic, Humans, Hypercholesterolemia, Risk Factors, Biomarkers, Oxidative Stress, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atherosclerosis
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