Login Register Cart 0
Review Article

Role of Statins in New-onset Diabetes Mellitus: The Underlying Cause, Mechanisms Involved, and Strategies to Combat

Author(s): Raghuvir Keni, Abinitha Sekhar, Karthik Gourishetti, Pawan G. Nayak, Manas Kinra, Nitesh Kumar, Rekha R. Shenoy, Anoop Kishore and Krishnadas Nandakumar*

Volume 22, Issue 10, 2021

Published on: 20 January, 2021

Page: [1121 - 1128] Pages: 8

DOI: 10.2174/1389450122666210120125945

Price: $65

Abstract

Statins have transformed the treatment of cardiovascular diseases through primary and secondary prevention of events. Despite the success of statin's management of cardiovascular conditions, certain clinical trials, reviews, and meta-analysis point out that statins have the propensity to induce diabetes. The risk further increases with intensive statin therapy or in patients with diabetes. A proper mechanism for the induction of the diabetic condition has not yet been determined. The involvement of statin with beta cells in insulin secretion and peripheral cells in insulin resistance has been widely studied and established. The present review provides an update on the recent understanding of statin-induced diabetes. This covers the origin of statins, their development, possible mechanisms that explain the adverse effects in glucose homeostasis, and probable targets to remedy the condition.

Keywords: Statins, diabetes, metabolic syndrome, hypercholesterolemia, drug-induced diabetes, cholesterol.

« Previous Next »
Graphical Abstract

[1]
Lee SE, Sung JM, Cho IJ, Kim HC, Chang HJ. Risk of new-onset diabetes among patients treated with statins according to hypertension and gender: Results from a nationwide health-screening cohort. PLoS One 2018; 13(4)
[http://dx.doi.org/10.1371/journal.pone.0195459] [PMID: 29630642]
[2]
Yoon D, Sheen SS, Lee S, Choi YJ, Park RW, Lim HS. Statins and risk for new-onset diabetes mellitus: A real-world cohort study using a clinical research database. Med (United States) 2016.
[http://dx.doi.org/10.1097/MD.0000000000005429]
[3]
Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation 2012; 126(18): e282-4.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.122135] [PMID: 23109518]
[4]
Ooba N, Tanaka S, Yasukawa Y, et al. Effect of high-potency statins on HbA1c in patients with or without diabetes mellitus. J Pharm Heal Care Sci 2016; 2: 8.
[5]
Rezende PC, Hlatky MA, Hueb W, et al. Association of longitudinal values of glycated hemoglobin with cardiovascular events in patients with type 2 diabetes and multivessel coronary artery disease. JAMA Netw Open 2020; 3(1): e1919666.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.19666] [PMID: 31968117]
[6]
Enas EA, Kuruvila A, Khanna P, Pitchumoni CS, Mohan V. 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 2013; 138(4): 461-91.
[PMID: 24434254]
[7]
Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013.
[http://dx.doi.org/10.1002/14651858.CD004816.pub5]
[8]
Endo A, Tsujita Y, Kuroda M, Tanzawa K. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Eur J Biochem 1977; 77(1): 31-6.
[http://dx.doi.org/10.1111/j.1432-1033.1977.tb11637.x] [PMID: 908337]
[9]
Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. 1976. Atheroscler Suppl 2004; 5(3): 39-42.
[http://dx.doi.org/10.1016/j.atherosclerosissup.2004.08.021] [PMID: 15531273]
[10]
Endo A. The origin of the statins. 2004. Atheroscler Suppl 2004; 5(3): 125-30.
[http://dx.doi.org/10.1016/j.atherosclerosissup.2004.08.033] [PMID: 15531285]
[11]
Rosenson RS, Baker SK. Statin muscle-related adverse events - UpToDate. Up To Date 2019.
[12]
Raju SB, Varghese K, Madhu K. Management of statin intolerance. Indian J Endocrinol Metab 2013; 17(6): 977-82.
[http://dx.doi.org/10.4103/2230-8210.122602] [PMID: 24381870]
[13]
DiNicolantonio JJ. CoQ10 and L-carnitine for statin myalgia? Expert Rev Cardiovasc Ther 2012; 10(10): 1329-33.
[http://dx.doi.org/10.1586/erc.12.92] [PMID: 23190071]
[14]
Zhou Q, Liao JK. Pleiotropic effects of statins. - Basic research and clinical perspectives -. Circ J 2010; 74(5): 818-26.
[http://dx.doi.org/10.1253/circj.CJ-10-0110] [PMID: 20424337]
[15]
Grobbee DE, Bots ML. Statin treatment and progression of atherosclerotic plaque burden. Drugs 2003; 63(9): 893-911.
[http://dx.doi.org/10.2165/00003495-200363090-00004] [PMID: 12678574]
[16]
Niu N, Xu S, Xu Y, Little PJ, Jin Z-G. Targeting Mechanosensitive Transcription Factors in Atherosclerosis. Trends Pharmacol Sci 2019; 40(4): 253-66.
[http://dx.doi.org/10.1016/j.tips.2019.02.004] [PMID: 30826122]
[17]
Ridker PM, Danielson E, Fonseca FAH, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21): 2195-207.
[http://dx.doi.org/10.1056/NEJMoa0807646] [PMID: 18997196]
[18]
Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol 2016; 12(2): 99-110.
[http://dx.doi.org/10.1038/nrendo.2015.194] [PMID: 26668119]
[19]
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305(24): 2556-64.
[http://dx.doi.org/10.1001/jama.2011.860] [PMID: 21693744]
[20]
Erqou S, Lee CC, Adler AI. Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia 2014; 57(12): 2444-52.
[http://dx.doi.org/10.1007/s00125-014-3374-x] [PMID: 25245638]
[21]
Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380(9841): 565-71.
[http://dx.doi.org/10.1016/S0140-6736(12)61190-8] [PMID: 22883507]
[22]
Sever PS, Dahlöf B, Poulter NR, et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361(9364): 1149-58.
[http://dx.doi.org/10.1016/S0140-6736(03)12948-0] [PMID: 12686036]
[23]
Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333(20): 1301-7.
[http://dx.doi.org/10.1056/NEJM199511163332001] [PMID: 7566020]
[24]
Yusuf S, Bosch J, Dagenais G, et al. HOPE-3 Investigators. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016; 374(21): 2021-31.
[http://dx.doi.org/10.1056/NEJMoa1600176] [PMID: 27040132]
[25]
Nakamura H, Arakawa K, Itakura H, et al. MEGA Study Group. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368(9542): 1155-63.
[http://dx.doi.org/10.1016/S0140-6736(06)69472-5] [PMID: 17011942]
[26]
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279(20): 1615-22.
[http://dx.doi.org/10.1001/jama.279.20.1615] [PMID: 9613910]
[27]
Rha S-W, Choi BG, Seo HS, et al. Impact of Statin Use on Development of New-Onset Diabetes Mellitus in Asian Population. Am J Cardiol 2016; 117(3): 382-7.
[http://dx.doi.org/10.1016/j.amjcard.2015.11.009] [PMID: 26732422]
[28]
Kain V, Kapadia B, Misra P, Saxena U. Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism. Sci Rep 2015; 5: 13823.
[http://dx.doi.org/10.1038/srep13823] [PMID: 26345110]
[29]
Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006; 112(1): 71-105.
[http://dx.doi.org/10.1016/j.pharmthera.2006.03.003] [PMID: 16714062]
[30]
Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract 2010; 87(1): 98-107.
[http://dx.doi.org/10.1016/j.diabres.2009.10.008] [PMID: 19913318]
[31]
Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins. Biochem J 1993; 295(Pt 1): 31-40.
[http://dx.doi.org/10.1042/bj2950031] [PMID: 8216234]
[32]
Darchen F, Senyshyn J, Brondyk WH, et al. The GTPase Rab3a is associated with large dense core vesicles in bovine chromaffin cells and rat PC12 cells. J Cell Sci 1995; 108(Pt 4): 1639-49.
[PMID: 7615682]
[33]
Kowluru A. Small G proteins in islet beta-cell function. Endocr Rev 2010; 31(1): 52-78.
[http://dx.doi.org/10.1210/er.2009-0022] [PMID: 19890090]
[34]
van de Bunt M, Gloyn AL. A tale of two glucose transporters: how GLUT2 re-emerged as a contender for glucose transport into the human beta cell. Diabetologia 2012; 55(9): 2312-5.
[http://dx.doi.org/10.1007/s00125-012-2612-3] [PMID: 22696037]
[35]
Zhou J, Li W, Xie Q, et al. Effects of simvastatin on glucose metabolism in mouse MIN6 cells. J Diabetes Res 2014; 2014376570
[http://dx.doi.org/10.1155/2014/376570] [PMID: 24995341]
[36]
Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet β-cells. Br J Pharmacol 1999; 126(5): 1205-13.
[http://dx.doi.org/10.1038/sj.bjp.0702397] [PMID: 10205010]
[37]
Urbano F, Bugliani M, Filippello A, et al. Atorvastatin but not pravastatin impairs mitochondrial function in human pancreatic islets and rat β-cells. Direct Effect of Oxidative Stress. Sci Rep 2017; 7(1): 11863.
[http://dx.doi.org/10.1038/s41598-017-11070-x] [PMID: 28928397]
[38]
Larsen S, Stride N, Hey-Mogensen M, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol 2013; 61(1): 44-53.
[http://dx.doi.org/10.1016/j.jacc.2012.09.036] [PMID: 23287371]
[39]
Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res 2005; 97(12): 1232-5.
[http://dx.doi.org/10.1161/01.RES.0000196564.18314.23] [PMID: 16339495]
[40]
Takaguri A, Satoh K, Itagaki M, Tokumitsu Y, Ichihara K. Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes. J Pharmacol Sci 2008; 107(1): 80-9.
[http://dx.doi.org/10.1254/jphs.FP0072403] [PMID: 18469500]
[41]
Henriksbo BD, Lau TC, Cavallari JF, et al. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes 2014; 63(11): 3742-7.
[http://dx.doi.org/10.2337/db13-1398] [PMID: 24917577]
[42]
Henriksbo BD, Tamrakar AK, Xu J, et al. Statins promote interleukin-1β-dependent adipocyte insulin resistance through lower prenylation, not cholesterol. Diabetes 2019; 68(7): 1441-8.
[http://dx.doi.org/10.2337/db18-0999] [PMID: 31010959]
[43]
Balaz M, Becker AS, Balazova L, et al. Inhibition of mevalonate pathway prevents adipocyte browning in mice and men by affecting protein prenylation. Cell Metab 2019; 29(4): 901-916.e8.
[http://dx.doi.org/10.1016/j.cmet.2018.11.017] [PMID: 30581121]
[44]
Lasar D, Rosenwald M, Kiehlmann E, et al. Peroxisome proliferator activated receptor gamma controls mature brown adipocyte inducibility through glycerol kinase. Cell Rep 2018; 22(3): 760-73.
[http://dx.doi.org/10.1016/j.celrep.2017.12.067] [PMID: 29346772]
[45]
Singh P, Zhang Y, Sharma P, et al. Statins decrease leptin expression in human white adipocytes. Physiol Rep 2018.
[http://dx.doi.org/10.14814/phy2.13566]

Rights & Permissions Print Cite
Article Metrics
32
1
© 2024 Bentham Science Publishers | Privacy Policy