Abstract
The main role in the pathogenesis of cardiovascular disease (CVD) in diabetes mellitus (DM) belongs to the mechanisms associated with chronic hyperglycemia and diabetic (atherogenic) dyslipoproteinemia (DLP). Effective treatment of DLP, arterial hypertension is accompanied by a decrease in the incidence of macrovascular complications. Therefore, reducing the risk of CVD in patients with DM requires a multifactorial approach, including control of leading atherogenic factors and, above all, the content of low-density lipoprotein cholesterol (LDL-C). The use of 3-hydroxy‑3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors is considered to be a primary link in the pharmacological strategy for the treatment of atherogenic DLP, based on the convincing results of numerous clinical trials. An important aspect is the pleiotropic effects of HMGCoA reductase inhibitors, in particular, improving the endothelial function, increasing the stability of atherosclerotic plaques, reducing oxidative stress, inflammation, and function status of platelets. However, the use of statins has been associated with the development of new cases of DM. The mechanisms by which statins may contribute to the development of type 2 DM are not fully understood, but both targeted and non-targeted effects may be involved in these processes. Effects on the mevalonate pathway, activation of gluconeogenesis, insulin signaling pathways, and glucose transporter type 4 are among them. HMG-CoA reductase inhibitors can cause statin-induced insulin resistance, changes in circulating free fatty acids; adiponectin and leptin; functional and structural state of β-cells; maturation/differentiation of adipocytes; mechanisms of epigenetic regulation mediated by specific miRNAs. In light of the results of numerous observational studies, it has been established that therapy with HMG-CoA reductase inhibitors, although it affects the accession of type 2 DM, but reduces the accession and/or progression of CVD. Thus, in order to achieve the target levels of LDLC, statins should be continued in patients with DM at high or very high risk of CVD, and the risk of developing DM should be assessed before prescribing HMG-CoA reductase inhibitors.
References
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Dec 1;41(2):255-323. doi: 10.1093/eurheartj/ehz486.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al; ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7;42(34):3227-37. doi: 10.1093/eurheartj/ehab484.
ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive bloodpressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056/NEJMoa1001286.
ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987.
Jellinger PS. American Association of Clinical Endocrinologists/American College of Endocrinology Management of Dyslipidemia and Prevention of Cardiovascular Disease Clinical Practice Guidelines. Diabetes Spectr. 2018 Aug;31(3):234-45. doi: 10.2337/ds18-0009.
Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L, et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-88. doi: 10.1093/eurheartj/ehz455.
Gao L, Zhang Y, Wang X, Dong H. Association of apolipoproteins A1 and B with type 2 diabetes and fasting blood glucose: a cross-sectional study. BMC Endocr Disord. 2021 Apr 1;21(1):59. doi: 10.1186/ s12902-021-00726-5.
Rhee EJ, Kim HC, Kim JH, Lee EY, Kim BJ, Kim EM, et al.; Committee of Clinical Practice Guideline of Korean Society of
Lipid and Atherosclerosis. 2018 Guidelines for the management of dyslipidemia in Korea. Korean J Intern Med. 2019 Sep;34(5):1171. doi: 10.3904/kjim.2019.188.e1.
Behbodikhah J, Ahmed S, Elyasi A, Kasselman LJ, De Leon J, Glass AD, et al. Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target. Metabolites. 2021 Oct 8;11(10):690. doi: 10.3390/metabo11100690.
Di Bartolo BA, Scherer DJ, Nicholls SJ. Inducing apolipoprotein A-I synthesis to reduce cardiovascular risk: from ASSERT to SUSTAIN and beyond. Arch Med Sci. 2016 Dec 1;12(6):1302-7. doi: 10.5114/ aoms.2016.62906.
Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol. 2018 Aug 31;17(1):122. doi: 10.1186/s12933-018-0762-4.
Hasheminasabgorji E, Jha JC. Dyslipidemia, diabetes and atherosclerosis: role of inflammation and ROS-redox-sensitive factors. Biomedicines. 2021 Nov 3;9(11):1602. doi: 10.3390/biomedicines9111602.
Zhang T, Chen J, Tang X, Luo Q, Xu D, Yu B. Interaction between adipocytes and high-density lipoprotein: new insights into the mechanism of obesity-induced dyslipidemia and atherosclerosis. Lipids Health Dis. 2019 Dec 16;18(1):223. doi: 10.1186/s12944-019-1170-9.
Heidari F, Rabizadeh S, Mansournia MA, Mirmiranpoor H, Salehi SS, Akhavan S, et al. Inflammatory, oxidative stress and anti-oxidative markers in patients with endometrial carcinoma and diabetes. Cytokine. 2019 Aug;120:186-90. doi: 10.1016/j.cyto.2019.05.007.
Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links. Int J Physiol Pathophysiol Pharmacol. 2019 Jun 15;11(3):45-63.
Zhao Y, Liu L, Yang S, Liu G, Pan L, Gu C, et al. Mechanisms of atherosclerosis induced by postprandial lipemia. Front Cardiovasc Med. 2021 Apr 29;8:636947. doi: 10.3389/fcvm.2021.636947.
Xia XD, Peng ZS, Gu HM, Wang M, Wang GQ, Zhang DW. Regulation of PCSK9 expression and function: mechanisms and therapeutic implications. Front Cardiovasc Med. 2021 Oct 15;8:764038. doi: 10.3389/fcvm.2021.764038.
Mooradian AD. Diabetes and atherogenic dyslipidemia. In Saldaña JR, ed. Diabetes textbook: clinical principles, patient management and public health issues. Basel: Springer, Cham. Springer Nature Switzerland AG4 2019. p. 587-96. doi: 1010.1007/978-3-030-11815-0_38.
Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy. In Saldaña JR, ed. Diabetes textbook: clinical principles, patient management and public health issues. Basel: Springer, Cham. Springer Nature Switzerland AG, 2019. p. 825-50. doi: 10.1007/978-3-030-11815-0_53.
Lazarte J, Hegele RA. Dyslipidemia management in adults with diabetes. Can J Diabetes. 2020 Feb;44(1):53-60. doi: 10.1016/j. jcjd.2019.07.003.
Serhiyenko VA, Serhiyenko LM, Serhiyenko AA. Recent advances in the treatment of neuropathies in type 2 diabetes mellitus patients: focus on benfotiamine (review and own data). In Berhardt LV, ed. Advances in medicine and biology (numbered series). New York: Nova Science Publishers; 2020. p. 1-80.
Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10;140(11): e563-e95. doi: 10.1161/CIR.0000000000000677.
Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, Williams K, Neely B, Sniderman AD, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014 Apr 10;370(15):1422-31. doi: 10.1056/NEJMoa1315665.
Pradhan A, Bhandari M, Sethi R. Ezetimibe and improving cardiovascular outcomes: current evidence and perspectives. Cardiol Res Pract. 2020 Jun 28;2020:9815016. doi: 10.1155/2020/9815016.
Toth PP, Banach M. Statins: then and now. Methodist Debakey Cardiovasc J. 2019 Jan-Mar;15(1):23-31. doi: 10.14797/mdcj‑15-1-23.
Morieri ML, Vitturi N, Avogaro A, Targher G, Fadini GP; DARWINT2D Network of the Italian Diabetes Society. Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucoselowering treatments. A multicenter retrospective study in Italian specialist care. J Endocrinol Invest. 2021 Sep;44(9):1879-89. doi: 10.1007/s40618-021-01501-y.
Pang J, Chan DC, Watts GF. The knowns and unknowns of contemporary statin therapy for familial hypercholesterolemia. Curr Atheroscler Rep. 2020 Sep 1;22(11):64. doi: 10.1007/s11883-020-00884-2.
Ramos R, Comas-Cufí M, Martí-Lluch R, Balló E, Ponjoan A, Alves-Cabratosa L, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018 Sep 5;362: k3359. doi: 10.1136/bmj.k3359.
Daiber A, Chlopicki S. Revisiting pharmacology of oxidative stress and endothelial dysfunction in cardiovascular disease: Evidence for redox-based therapies. Free Radic Biol Med. 2020 Sep;157:15-37. doi: 10.1016/j.freeradbiomed.2020.02.026.
Mach F., Ray K.K., Wiklund O., Corsini A., Catapano A.L., Bruckert E, et al. European Atherosclerosis Society Consensus Panel. 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. 2018 Jul 14;39(27):2526-39. doi: 10.1093/eurheartj/ehy182.
Betteridge DJ, Carmena R. The diabetogenic action of statins — mechanisms and clinical implications. Nat Rev Endocrinol. 2016 Feb;12(2):99-110. doi: 10.1038/nrendo.2015.194.
Chogtu B, Magazine R, Bairy KL. Statin use and risk of diabetes mellitus. World J Diabetes. 2015 Mar 15;6(2):352-7. doi: 10.4239/ wjd.v6.i2.352.
Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, et al; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019 Feb;39(2): e38-e81. doi: 10.1161/ATV.0000000000000073.
Ridker PM, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Khurmi NS, et al; JUPITER Trial Study Group. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 2007 Dec 1;100(11):1659-64. doi: 10.1016/j.amjcard.2007.09.072.
Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22;305(24):2556-64. doi: 10.1001/jama.2011.860.
Livingstone SJ, Looker HC, Akbar T, Betteridge DJ, Durrington PN, Hitman GA, et al. Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS). Diabetologia. 2016 Feb;59(2):299-306. doi: 10.1007/s00125-015-3802-6.
Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS. Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metabolism. 2014 Jun;63(6):735-45. doi: 10.1016/j. metabol.2014.02.014.
Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006 Aug;49(8):1881-92. doi: 10.1007/s00125-006-0269-5.
Zhao W, Zhao SP. Different effects of statins on induction of diabetes mellitus: an experimental study. Drug Des Devel Ther. 2015 Nov 24;9:6211-23. doi: 10.2147/DDDT.S87979.
Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol. 2016 Jul;32(7 Suppl): S35-65. doi: 10.1016/j.cjca.2016.01.003.
Galicia-Garcia U, Jebari S, Larrea-Sebal A, Uribe KB, Siddiqi H, Ostolaza H, et al. Statin treatment-induced development of type 2 diabetes: from clinical evidence to mechanistic insights. Int J Mol Sci. 2020 Jul 2;21(13):4725. doi: 10.3390/ijms21134725.
Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019 Jan 18;124(2):328-50. doi: 10.1161/CIRCRESAHA.118.312782.
Ashcroft FM, Rorsman P. K(ATP) channels and islet hormone secretion: new insights and controversies. Nat Rev Endocrinol. 2013 Nov;9(11):660-9. doi: 10.1038/nrendo.2013.166.
Han KH. Functional implications of HMG-CoA reductase inhibition on glucose metabolism. Korean Circ J. 2018 Nov;48(11):951-63. doi: 10.4070/kcj.2018.0307.
Sadighara M, Amirsheardost Z, Minaiyan M, Hajhashemi V, Naserzadeh P, Salimi A, et al. Toxicity of atorvastatin on pancreas mitochondria: a justification for increased risk of diabetes mellitus. Basic Clin Pharmacol Toxicol. 2017 Feb;120(2):131-7. doi: 10.1111/bcpt.12656.
Curry L, Almukhtar H, Alahmed J, Roberts R, Smith PA. Simvastatin inhibits L-type Ca2+-channel activity through impairment of mitochondrial function. Toxicol Sci. 2019 Jun 1;169(2):543-52. doi: 10.1093/toxsci/kfz068.
Pei G, Dorhoi A. NOD-Like Receptors: Guards of cellular homeostasis perturbation during infection. Int J Mol Sci. 2021 Jun 23;22(13):6714. doi: 10.3390/ijms22136714.
Kuzyk CL, Anderson CC, Roede JR. Simvastatin induces delayed apoptosis through disruption of glycolysis and mitochondrial impairment in neuroblastoma cells. Clin Transl Sci. 2020 May;13(3):563-2. doi: 10.1111/cts.12740.
Eschenhagen T, Laufs U. Statins do more than lower cholesteroldepending on what you eat? Circulation. 2021 May 4;143(18):1793-6. doi: 10.1161/CIRCULATIONAHA.121.054183.
Copps KD, White MF. Regulation of insulin sensitivity by serine/ threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012 Oct;55(10):2565-82. doi: 10.1007/ s00125-012-2644-8.
Ho CK, Sriram G, Dipple KM. Insulin sensitivity predictions in individuals with obesity and type II diabetes mellitus using mathematical model of the insulin signal transduction pathway. Mol Genet Metab. 2016 Nov;119(3):288-92. doi: 10.1016/j.ymgme.2016.09.007.
Moraes-Vieira PM, Saghatelian A, Kahn BB. GLUT4 expression in adipocytes regulates de novo lipogenesis and levels of a novel class of lipids with antidiabetic and anti-inflammatory effects. Diabetes. 2016 Jul;65(7):1808-15. doi: 10.2337/db16-0221.
Li R, Chen LZ, Zhao SP, Huang XS. Inflammation activation contributes to adipokine imbalance in patients with acute coronary syndrome. PLoS One. 2016 Mar 17;11(3): e0151916. doi: 10.1371/ journal.pone.0151916.
García JG, Ansorena E, Milagro FI, Zalba G, de Miguel C. Endothelial Nox5 expression modulates glucose uptake and lipid accumulation in mice fed a high-fat diet and 3T3-L1 adipocytes treated with glucose and palmitic acid. Int J Mol Sci. 2021 Mar 8;22(5):2729. doi: 10.3390/ ijms22052729.
Zhang Q, Dong J, Yu Z. Pleiotropic use of Statins as non-lipidlowering drugs. Int J Biol Sci. 2020 Aug 13;16(14):2704-11. doi: 10.7150/ijbs.42965.
Breen MR, Camps M, Carvalho-Simoes F, Zorzano A, Pilch PF. Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin‑2 in a switchlike fashion. PLoS One. 2012;7(4): e34516. doi: 10.1371/journal. pone.0034516.
Krautbauer S, Neumeier M, Eisinger K, Hader Y, Dada A, Schmitz G, et al. LDL but not HDL increases adiponectin release of primary human adipocytes. Exp Mol Pathol. 2013 Dec;95(3):325-9. doi: 10.1016/j.yexmp.2013.10.002.
Bradley H, Shaw CS, Worthington PL, Shepherd SO, Cocks M, Wagenmakers AJ. Quantitative immunofluorescence microscopy of subcellular GLUT4 distribution in human skeletal muscle: effects of endurance and sprint interval training. Physiol Rep. 2014 Jul 22;2(7): e12085. doi: 10.14814/phy2.12085.
Sadler JB, Bryant NJ, Gould GW, Welburn CR. Posttranslational modifications of GLUT4 affect its subcellular localization and translocation. Int J Mol Sci. 2013 May 10;14(5):9963-78. doi: 10.3390/ijms14059963.
Sanvee GM, Panajatovic MV, Bouitbir J, Krähenbühl S. Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochem Pharmacol. 2019 Jun;164:23-33. doi: 10.1016/j.bcp.2019.02.025.
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 Sep 8;5:13823. doi: 10.1038/ srep13823.
Ling Z, Shu N, Xu P, Wang F, Zhong Z, Sun B, et al. Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem Pharmacol. 2016 Jan 15;100:98-111. doi: 10.1016/j.bcp.2015.11.023.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al; ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016 Aug 1;37(29):2315-81. doi: 10.1093/eurheartj/ehw106.
Gotoh S, Negishi M. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci Rep. 2015 Sep 22;5:14076. doi: 10.1038/srep14076.
Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P. Insulin regulation of gluconeogenesis. Ann N Y Acad Sci. 2018 Jan;1411(1):21-35. doi: 10.1111/nyas.13435.
Fernández-Hernando C, Ramírez CM, Goedeke L, Suárez Y. MicroRNAs in metabolic disease. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):178-85. doi: 10.1161/ATVBAHA.112.300144.
Allen RM, Marquart TJ, Albert CJ, Suchy FJ, Wang DQ, Ananthanarayanan M, et al. miR‑33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity. EMBO Mol Med. 2012 Sep;4(9):882-95. doi: 10.1002/ emmm.201201228.
Vickers KC, Shoucri BM, Levin MG, Wu H, Pearson DS, Osei-Hwedieh D, et al. MicroRNA‑27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology. 2013 Feb;57(2):533-42. doi: 10.1002/hep.25846.
Zhang H, Lamon BD, Moran G, Sun T, Gotto AM Jr, Hajjar DP. Pitavastatin differentially modulates microRNA-associated cholesterol transport proteins in macrophages. PLoS One. 2016 Jul 14;11(7): e0159130. doi: 10.1371/journal.pone.0159130.
Zhang M, Wu JF, Chen WJ, Tang SL, Mo ZC, Tang YY, et al. MicroRNA‑27a/b regulates cellular cholesterol efflux, influx and esterification/hydrolysis in THP‑1 macrophages. Atherosclerosis. 2014 May;234(1):54-64. doi: 10.1016/j.atherosclerosis.2014.02.008.
Alvarez ML, Khosroheidari M, Eddy E, Done SC. MicroRNA‑27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis. Atherosclerosis. 2015 Oct;242(2):595-604. doi: 10.1016/j.atherosclerosis.2015.08.023.
Hakkola J, Rysä J, Hukkanen J. Regulation of hepatic energy metabolism by the nuclear receptor PXR. Biochim Biophys Acta. 2016 Sep;1859(9):1072 82. doi: 10.1016/j.bbagrm.2016.03.012.
Neve B, Le Bacquer O, Caron S, Huyvaert M, Leloire A, Poulain-Godefroy O, et al. Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level. Diabetologia. 2014 Apr;57(4):785-96. doi: 10.1007/s00125-013-3154-z.
Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6.
Maki KC, Diwadkar-Navsariwala V, Kramer MW. Statin use and risk for type 2 diabetes: what clinicians should know. Postgrad Med. 2018 Mar;130(2):166-72. doi: 10.1080/00325481.2018.1402658.