Pleotropic effects of statins: the dilemma of wider utilization of statin

GBD 2015 DALYs and HALE Collaborators (2016) Global, regional, and national disability-adjusted life-years (DALYS) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the global burden of disease study. Lancet 388:1603–1658 WHO-Cardiovascular Diseases accessed at https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1. Accessed 21 Aug 2022 Roth GA, Mensah GA, Johnson CO et al (2020) Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol 76(25):2982–3021 Enas EA, Kuruvila A, Khanna P et al (2013) Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians—a population with the highest risk of premature coronary artery disease & diabetes. Indian J Med Res 138(4):461–491 Marcus ME, Manne-Goehler J, Theilmann M et al (2022) Use of statins for the prevention of cardiovascular disease in 41 low-income and middle-income countries: a cross-sectional study of nationally representative, individual-level data. Lancet Glob Health 10(3):e369–e379 Nissen SE, Nicholls SJ, Sipahi I et al (2006) ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 295(13):1556–1565 Mihaylova B, Emberson J, Blackwell L et al (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380(9841):581–590 Silverman MG, Ference BA, Im K et al (2016) Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 316(12):1289–1297 Ference BA, Ginsberg HN, Graham I et al (2017) Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 38:2459–2472 Baigent C, Keech A, Kearney PM et al (2005) Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267–1278 Kantor ED, Rehm CD, Haas JS et al (2015) Trends in prescription drug use among adults in the United States from 1999–2012. JAMA 314:1818–1831 Egom EEA, Hafeez H (2016) Biochemistry of statins. Adv Clin Chem 73:127–168 Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135 Rikitake Y, Liao JK (2005) Rho GTPases, statins, and nitric oxide. Circ Res 97(12):1232–1235 Sikora J, Kostka B, Marczyk I et al (2013) Effect of statins on platelet function in patients with hyperlipidemia. Arch Med Sci 9:622–628 Diamantis E, Kyriakos G, Quiles-Sanchez LV et al (2017) The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr Cardiol Rev 13(3):209–216 Francis AA, Pierce GN (2011) An integrated approach for the mechanisms responsible for atherosclerotic plaque regression. Exp Clin Cardiol 16(3):77–86 Brown G, Albers JJ, Fisher LD et al (1990) Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 323:1289–1298 Nissen SE, Tuzcu EM, Schoenhagen P et al (2004) Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291:1071–1080 Zeb I, Li D, Nasir K, Malpeso J et al (2013) Effect of statin treatment on coronary plaque progression—a serial coronary CT angiography study. Atherosclerosis 231:198–204 Lee SE, Chang HJ, Sung JM et al (2018) Effects of statins on coronary atherosclerotic plaques: the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed TomoGraphic Angiography Imaging) Study. JACC Cardiovasc Imaging 11(10):1475–1484 Shekar C, Budoff M (2018) Calcification of the heart: mechanisms and therapeutic avenues. Expert Rev Cardiovasc Ther 16:527–536 Shioi A, Ikari Y (2018) Plaque calcification during atherosclerosis progression and regression. J Atheroscler Thromb 25:294–303 Komukai K, Kubo T, Kitabata H et al (2014) Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study. J Am Coll Cardiol 64:2207–2217 Libby P (2012) Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 32:2045–2051 Imprialos KP, Stavropoulos K, Doumas M et al (2018) The potential role of statins in treating liver disease. Expert Rev Gastroenterol Hepatol 12:331–339 Price JC, Tien PC (2017) Statins and liver disease: Is it time to recommend statins to prevent liver disease progression? Am J Gastroenterol 112:1506 Foster T, Budoff MJ, Saab S et al (2011) Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 106(1):71–77 Athyros VG, Alexandrides TK, Bilianou H et al (2017) The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An expert panel. Statement Metab 71:17–32 Bril F, Portillo Sanchez P, Lomonaco R et al (2017) Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. J Clin Endocrinol Metab 102(8):2950–2961 Pose E, Trebicka J, Mookerjee RP (2019) Statins: old drugs as new therapy for liver diseases? J Hepatol 70(1):194–202 Mohammadkhani N, Gharbi S, Rajani HF et al (2019) Statins: Complex outcomes but increasingly helpful treatment options for patients. Eur J Pharmacol 863:172704 Chomphupan S, Leewattanapat P, Kwancharoen R et al (2018) Low intensity statin for primary prevention of non-fatal MI and non-fatal stroke in type 2 diabetes. J Med Assoc Thail 101:55 Honore PM, Jacobs R, Hendrickx I et al (2017) Statins and the kidney: friend or foe? Blood Purif 43:91–96 Mach F, Ray KK, Wiklund O et al (2018) Adverse effects of statin therapy: perception vs. the evidence–focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 39:2526–2539 Stanifer JW, Charytan DM, White J et al (2017) Benefit of ezetimibe added to simvastatin in reduced kidney function. J Am Soc Nephrol 28:3034–3043 Verdoodt A, Honore PM, Jacobs R et al (2018) Do statins induce or protect from acute kidney injury and chronic kidney disease: an update review in 2018. J Transl Intern Med 6:21–25 Nemati MH, Astaneh B (2015) The effects of preoperative statins on the incidence of postoperative acute kidney injury in patients undergoing cardiac surgeries. Interact Cardiovasc Thorac Surg 21:493–498 Billings FT 4th, Hendricks PA, Schildcrout JS (2016) High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: a randomized clinical trial. JAMA 315(9):877–888 Anjum I, Akmal M, Nimra Hasnain MJ (2019) Statins role in preventing contrast-induced acute kidney injury: a scoping review. Hong Kong Med J 25:216–221 Leoncini M, Toso A, Maioli M (2014) Early highdose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy on contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol 63:71–79 Li H, Wang C, Liu C (2016) Efficacy of short-term statin treatment for the prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography/percutaneous coronary intervention: a meta-analysis of 21 randomized controlled trials. Am J Cardiovasc Drugs 16(3):201–219 Prowle JR, Calzavacca P, Licari E (2012) Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery. Nephrology (Carlton) 17(3):215–224 Hsu RK, Truwit JD, Matthay MA et al (2018) Effect of rosuvastatin on acute kidney injury in sepsis-associated acute respiratory distress syndrome. Can J Kidney Health Dis 5:2054358118789158 Malbouisson I, Quinto BM, Durão Junior MS et al (2019) Lipid profile and statin use in critical care setting: implications for kidney outcome. Einstein 17(3):eAO4399 Nayan M, Punjani N, Juurlink DN et al (2017) Statin use and kidney cancer survival outcomes: a systematic review and meta-analysis. Cancer Treat Rev 52:105–116 Zhang HN, Xu H, Yu XB et al (2017) Effect of simvastatin on lipopolysaccharides induced depressive behaviors and neuroinflammation in mice. Chin Pharmacol Bull 33:373–378 Yu XB, Zhang HN, Dai Y et al (2019) Simvastatin prevents and ameliorates depressive behaviors via neuroinflammatory regulation in mice. J Affect Disord 245:939–949 Salagre E, Fernandes BS, Dodd S et al (2016) Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord 200:235–242 Pihl-Jensen G, Tsakiri A, Frederiksen JL (2015) Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs 29:277–291 Chan D, Binks S, Nicholas JM et al (2017) Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol 16:591–600 Carroll CB, Wyse RK (2017) Simvastatin as a potential disease-modifying therapy for patients with Parkinson’s disease: rationale for clinical trial, and current progress. J Parkinson’s Dis 7:545–568 Sheng Z, Jia X, Kang M (2016) Statin use and risk of Parkinson’s disease: a meta analysis. Behav Brain Res 309:29–34 Saeedi Saravi SS, Khoshbin K, Dehpour AR (2017) Current insights into pathogenesis of Parkinson’s disease: approach to mevalonate pathway and protective role of statins. Biomed Pharmacother 90:724–730 Geifman N, Brinton RD, Kennedy RE et al (2017) Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimers Res Ther 9(1):10 Blanchard JW, Tsai LH (2019) Unraveling the paradox of statins with huma neurons: new leads in Alzheimer’s disease. Cell Stem Cell 24:347–349 Mundy G, Garrett R, Harris S et al (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949 Lin TK, Chou P, Lin CH et al (2018) Long-term effect of statins on the risk of new-onset osteoporosis: a nationwide population-based cohort study. PLoS ONE 13(5):e0196713 Tsung K, Grobmyer SR, Tu C et al (2018) Neoadjuvant systemic therapy in invasive lobular breast cancer: Is it indicated? Am J Surg 215:509–512 El-Nabarawi N, El-Wakd M, Salem M (2017) Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study. Drug Des Dev Ther 11:1383 Zhou H, Xie Y, Shi Q et al (2017) The effect of atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoA), on the prevention of osteoporosis in ovariectomized rabbits. J Bone Miner Metab 35:245–254 Park A, Barrera Ramirez J, Ranasinghe I (2016) Use of statins to augment progenitor cell function in preclinical and clinical studies of regenerative therapy: a systematic review. Stem Cell Rev Rep 12:327–339 Gupta S, Del Fabbro M, Chang J (2019) The impact of simvastatin intervention on the healing of bone, soft tissue, and TMJ cartilage in dentistry: a systematic review and meta-analysis. Int J Clin Implant Dent 5(1):17 Shao PL, Wu SC, Lin ZY (2019) Alpha-5 integrin mediates simvastatin-induced osteogenesis of bone marrow mesenchymal stem cells. Int J Mol Sci 20:506 Estanislau IM, Terceiro IR, Lisboa MR et al (2015) Pleiotropic effects of statins on the treatment of chronic periodontitis—a systematic review. Br J Clin Pharmacol 79(6):877–885 Messora M, Apolinario VG, Vanderlei J et al (2017) Rosuvastatin promotes benefits on induced periodontitis in hypertensive rats. J Periodontal Res 52:734–744 Thabit A, Alhifany A, Alsheikh R et al (2014) Effect of simvastatin and atorvastatin on serum vitamin d and bone mineral density in hypercholesterolemic patients: a cross-sectional study. J Osteoporos 2014:468397 Lin SM, Wang JH, Liang CC, Huang HK (2018) Statin use is associated with decreased osteoporosis and fracture risks in stroke patients. J Clin Endocrinol Metab 103:3439–3448 Lu Y, Chang R, Yao J et al (2019) Effectiveness of long-term using statins in COPD—a network meta-analysis. Respir Res 20(1):17 Lahousse L, Loth DW, Joos GF et al (2013) Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 26:212–217 Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A et al (2016) Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism. Respir Res 17:104 Papaporfyriou A, Loukides S, Kostikas K et al (2014) Increased levels of osteopontin in sputum supernatant in patients with COPD. Chest 146:951–958 Mullerova H, Agusti A, Erqou S et al (2013) Cardiovascular comorbidity in COPD: systematic literature review. Chest 144:1163–1178 Young RP, Hopkins RJ (2017) The mevalonate pathway and innate immune hyperresponsiveness in the pathogenesis of COPD and lung cancer: potential for chemoprevention. Curr Mol Pharmacol 10:46–59 Teicher BA, Linehan WM, Helman LJ (2012) Targeting cancer metabolism. Clin Cancer Res 18(20):5537–5545 Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674 Antalis CJ, Uchida A, Buhman KK (2011) Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification. Breast Cancer Res Treat 28:733–741 Murtola TJ, Syvälä H, Pennanen P et al (2012) The importance of LDL and cholesterol metabolism for prostate epithelial cell growth. PLoS ONE 7:e39445 Cruz PM, Mo H, McConathy WJ et al (2013) The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Front Pharmacol 4:119 Zhou Q, Liao JK (2009) Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr Pharm Des 15(5):467–478 Vaughan CJ, Murphy MB, Buckley BM (1996) Statins do more than just lower cholesterol. Lancet 348:1079–1082 Khattri S, Zandman-Goddard G (2013) Statins and autoimmunity. Immunol Res 56:348–357 Cote Daigneault J, Mehandru S, Ungaro R et al (2016) Potential immunomodulatory effects of statins in inflammatory bowel disease. Inflamm Bowel Dis 22:724–732 Cosnes J, Gower-Rousseau C, Seksik P et al (2011) Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140:1785–1794 Torres J, Mehandru S, Colombel JF (2017) Crohn’s disease. Lancet 389:1741–1755 Ungaro R, Mehandru S, Allen PB et al (2017) Ulcerative colitis. Lancet 389:1756–1770 Crockett SD, Hansen RA, Sturmer T et al (2012) Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis 18:1048–1056 Grip O, Janciauskiene S (2009) Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s disease. PLoS ONE 4:e5263 Ungaro R, Chang HL, Cote-Daigneault J et al (2016) Statins associated with decreased risk of new onset inflammatory bowel disease. Am J Gastroenterol 111:1416–1423 Khalil D, Boktor M, Mortensen EM et al (2015) Comparison of frequency of inflammatory bowel disease and noninfectious gastroenteritis among statin users versus nonusers. Am J Cardiol 115:1396–1401 Dhamija P, Hota D, Kochhar R et al (2014) Randomized clinical trial: atorvastatin versus placebo in patients with acute exacerbation of mild to moderate ulcerative colitis. Indian J Gastroenterol 33:151–156 Grip O, Janciauskiene S, Bredberg A (2008) Use of atorvastatin as an anti-inflammatory treatment in Crohn’s disease. Br J Pharmacol 155:1085–1092 Ritchie K, Lovestone S (2002) The dementias. Lancet 360:1759–1766 Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2:539–547 Arnett DK, Blumenthal RS, Albert MA et al (2019) 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 74:e177-232