Skip to main content
SpringerLink
Log in

Diabetogenic Action of Statins: Mechanisms

  • Statin Drugs (M. Tikkanen, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Observational studies and meta-analyses of randomized clinical trials data have revealed a 10–12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins.

Recent Findings

Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus.

Summary

The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. • Catapano AL, Graham I, De Backer G, Wikklund O, Chapman MT, Drexel H, et al. 2016 ESC/EAS Guidelines for the management of dyslipidemias. Eur Heart J. 2016;37:2999–3058. These Guidelines from the two leading European Societies of Cardiology and Atherosclerosis provide an excellent review of dyslipidemias and its management, supporting the use of statins to lower LDL-C and reduce the cardiovascular risk including diabetic persons.

    Article  Google Scholar 

  2. • Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393:407–15. Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease.

    Article  Google Scholar 

  3. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano, et al. 2016 European Guidelines 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. Eur Heart J. 2016;37:2315–81.

    Article  Google Scholar 

  4. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781–90.

    Article  CAS  Google Scholar 

  5. • Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207. The first prospective primary prevention trial to document the onset of new cases of diabetes associated to the administration of rosuvastatin.

    Article  CAS  Google Scholar 

  6. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172:144–52.

    Article  Google Scholar 

  7. • Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6-year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–17. An important study concentrating on the association of metabolic syndrome and statin-induced diabetes in a large cohort of men free of diabetes at baseline and treated with different statins for 6 years.

    Article  CAS  Google Scholar 

  8. Lee J, Noh Y, Shin S, Lim HS, Park RW, Bae SK, et al. Impact of statins on the risk of new onset diabetes mellitus: a population-based cohort study using the Korean National Health Insurance claims database. Ther Clin Risk Manag. 2016;12:1533–43.

    Article  CAS  Google Scholar 

  9. Jones M, Tett S, Peeters GM, Mishra GD, Dobson A. New-onset diabetes after statin exposure in elderly women: The Australian Longitudinal Study on Women’s Health. Drugs Aging. 2017;34:203–9.

    Article  CAS  Google Scholar 

  10. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risk of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–71.

    Article  CAS  Google Scholar 

  11. Crandall JP, Mather K, Rajpathak SN, Goldberg RB, Watson K, Foo S, et al. Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ Open Diabetes Res Care. 2017;5(1):e000438corr1.

    Article  Google Scholar 

  12. • 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;375:735–42. A comprehensive meta-analysis of 13 randomized clinical trials involving over 90,000 subjects free of diabetes at baseline and showing a 9% increase in new-onset diabetes with statin use.

    Article  CAS  Google Scholar 

  13. • Preiss D, Seshasai SR, Welhs 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;305:2556–64. The risk of new-onset diabetes is increased with intensive dose statins.

    Article  CAS  Google Scholar 

  14. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32:1924–9.

    Article  CAS  Google Scholar 

  15. Thakker D, Nair S, Pagada A, Jamdade V, Malik A. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25:1131–49.

    Article  CAS  Google Scholar 

  16. Cai R, Yuan Y, Yi Z, Xia W, Wang P, Sun H, et al. Lower intensified target LDL-C level of statin therapy results in a higher risk of incident diabetes: a meta-analysis. PloS One. 2014;9(8):e104922.

    Article  Google Scholar 

  17. • Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun C-C, et al. Predictors of new-onset diabetes in patients treated with atorvastatin. Results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57:1535–45. Emphasizes the predictive importance of baseline prediabetes and metabolic syndrome components as predictors for new-onset diabetes in subjects treated with atorvastatin.

    Article  CAS  Google Scholar 

  18. FDA. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. FDA (online) http://www.fda.gov/drugs/drugsafety/ucm293101.htm . 2012.

  19. • Betteridge DJ, Carmena R. The diabetogenic action of statins: mechanisms and clinical implications. Nat Rev Endocrinol. 2016;12:90–110. A wide-ranging review of the topic including 10 statin trials and offering clinical considerations stressing the statin benefit in prevention of cardiovascular disease events vs. the potential harm of new-onset diabetes.

    Article  Google Scholar 

  20. Cybulska B, Klosiewicz-Latoszek L. How do we know that statins are diabetogenic, and why? Is it an important issue in the clinical practice? KardiologiaPolska. 2018;76:1217–23.

    Google Scholar 

  21. • Mach F, Ray KK, Wiklund O, Corsini A, Catapano AL, Bruckert E, et al. 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;39:2526–39. Detailed review of the adverse effects of statins with special attention to new-onset diabetes and its possible mechanisms.

    Article  Google Scholar 

  22. Angelidi AM, Stambolliu E, Adamapoulou KI, Kousoulis AA. Is atorvastatin associated with new onset diabetes or deterioration of glyacemic control? Systematic review using data from 1.9 million patients. Int J Endocrinol. 2018;2018:8380192. https://doi.org/10.1155/2018/8380192 eCollection 2018.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Robinson JG. Statins and diabetes risk: how real is it and what are the mechanisms? Curr Opin Lipidol. 2015;26:228–35.

    Article  CAS  Google Scholar 

  24. Maki KC, Dicklin MR, Baum SJ. Cardiol Clin. Statins and diabetes. Cardiol Clin. 2015;33:233–43.

    Article  Google Scholar 

  25. Laakso M, Kuusisto J. Diabetes secondary to statins. Curr Diab Rep. 2017;17(2):10. https://doi.org/10.1007/s11892-017-0837-8.

    Article  CAS  PubMed  Google Scholar 

  26. • Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385:351–61. A Mendelian randomization study indicating that the diabetogenic effect of statins is related to a reduction in HMGCoA reductase activity. This effect was associated with an appreciable increase in body weight.

    Article  CAS  Google Scholar 

  27. Frayling TM. Statins and type 2 diabetes: genetic studies on target. Lancet. 2015;385:310–2.

    Article  Google Scholar 

  28. Hoon HK. Functional implications of HMGCoA reductase inhibition on glucose metabolism. Korean Circ J. 2018;48:951–63.

    Article  Google Scholar 

  29. Roehrich ME, Mooser V, Lenain V, Herz J, Nimpf J, Azhar S, et al. Insulin-secreting β-cell dysfunction induced by human lipoproteins. J Biol Chem. 2003;278:18368–75.

    Article  CAS  Google Scholar 

  30. Hao M, Head WS, Gunawardeana SC, Hasty AH, Piston DW. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic β-cell dysfunction. Diabetes. 2007;56:2328–38.

    Article  CAS  Google Scholar 

  31. Kruit JK, Brunham LR, Verchere CB, Hayden MR. HDL and LDL cholesterol significantly influenceβ-cell function in type 2 diabetes mellitus. Curr Opin Lipidol. 2010;21:178–85.

    Article  CAS  Google Scholar 

  32. Sturek JM, Castle JD, Trace AP, Page LC, Castle AM, Evans-Molina C, et al. An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β-cell. J Clin Invest. 2010;120:2575–89.

    Article  CAS  Google Scholar 

  33. Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretionfrom normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins. Biochem. 1993;295:31–40.

    Article  CAS  Google Scholar 

  34. 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;126:1205–13.

    Article  CAS  Google Scholar 

  35. Zhou J, Li W, Xie Q, Hou Y, Zhan S, Yang X, et al. Effects of simvastatin on glucose metabolism in MIN6 cells. J Diabetes Res. 2014;2014:376570. https://doi.org/10.1155/2014/376570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen Z, Liu SN, Li CN, Sun SJ, Liu Q, Lei L, et al. Atorvastatin helps preserve pancreatic β-cell function in obese C57BL/6J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress. Lipids Health Dis. 2014;13:98. https://doi.org/10.1186/1476-511X-13-98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Järvinen H, Van Haeften T, et al. Use of the oral glucose tolerance test to assess insulin releae and insulin sensitivity. Diabetes Care. 2000;23:295–301.

    Article  CAS  Google Scholar 

  38. Matsuda A, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.

    Article  CAS  Google Scholar 

  39. Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJP, Messig M, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy. J Am Coll Cardiol. 2013;61:148–52.

    Article  CAS  Google Scholar 

  40. Skoumas J, Liontou C, Chrysohoou C, Masoura C, Aznaouridis K, Pitsavos C, et al. Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia. Atherosclerosis. 2014;237:140–5.

    Article  CAS  Google Scholar 

  41. Climent E, Pérez-Calahorra S, Marco-Benedí V, Plana N, Sánchez R, Ros E, et al. Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia. Sci Rep. 2017;7(1):5596. https://doi.org/10.1038/s41598-017-06101-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. • Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313:1029–36. In a cross-sectional analysis in the Netherlands, including 63,320 individuals who underwent DNA testing for familial hypercholesterolemia the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives.

    Article  CAS  Google Scholar 

  43. Xu H, Ryan KA, Jaworek TJ, Southam L, Reid JG, Overton JD, et al. Familial hypercholesterolemia and type 2 diabetes in the old order amish. Diabetes. 2017;66:2054–8.

    Article  CAS  Google Scholar 

  44. Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA. 2016;316:1383–91.

    Article  CAS  Google Scholar 

  45. Sliz E, Kettunen J, Holmes MV, Williams CO, Boachie C, Wang Q, et al. Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment. Circulation. 2018;138:2499–512.

    Article  CAS  Google Scholar 

  46. • Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5:97–105. PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes.

    Article  CAS  Google Scholar 

  47. • Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375:2144–53. Variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive.

    Article  CAS  Google Scholar 

  48. Colhoun HM, Ginsberg HN, Robinson JG, Leiter LA, Müller-Wieland D, Henry RR, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J. 2016;37:1200–10.

    Article  Google Scholar 

  49. Sattar N. PCSK9 inhibitors and diabetes risk: a question worth asking? Eur Heart J. 2016;37:2990–2.

    Article  Google Scholar 

  50. • Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled. Lancet Diabetes Endocrinol. 2017;12:941–50. PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes.

    Article  Google Scholar 

  51. Monami M, Sesti G, Mannucci E. PCSK9 inhibitor therapy: a systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes. Diabetes Obes Metab. 2018. https://doi.org/10.1111/dom.13599.

    Article  Google Scholar 

  52. Ganesan S, Ito MK. Coenzyme Q10 ameliorates the reduction in GLUT4 transporter expresioninduced by simvastatin in 3T3L-1 adipocytes. Metab Syndr Relat Disord. 2013;11:251–5.

    Article  CAS  Google Scholar 

  53. Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61:44–53.

    Article  CAS  Google Scholar 

  54. Olefsky JM. Mechanisms of decreased insulin responsiveness of large adipocytes. Endocrinology. 1977;100:1169–77.

    Article  CAS  Google Scholar 

  55. Friedman JM. Obesity in the new millennium. Nature. 2000;404:632–4.

    Article  CAS  Google Scholar 

  56. Parpal S, Karlsson M, Thorn H, Stralfors P. Cholesterol depletion disrupts caveolae and insulin receptor signalling for metabolic control via insulin receptor substrate-1 but not for mitogen-activatedprotein kinase control. J Biol Chem. 2001;276:9670–8.

    Article  CAS  Google Scholar 

  57. Malenda A, Skrobanska A, Issat T, Winiarska M, Bil J, Oleszczak B, et al. Statins impair glucose uptake in tumor cells. Neoplasia. 2012;14:311–23.

    Article  CAS  Google Scholar 

  58. Chamberlain LH. Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes. Febs Lett. 2001;507:357–61.

    Article  CAS  Google Scholar 

  59. • Zuñiga-Hertz JP, Rebelato E, Kassan A, Khalifa AM, Ali SS, Patel HH, et al. Distinct pathways of cholesterol biosynthesis impact on insulin secretion. J Endocrinol. 2015;224:75–84. The study illustrates the different contributions of cholesterol biosynthesis to glucose stimulated insulin secretion and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper β-cell function.

    Article  Google Scholar 

  60. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98–107.

    Article  CAS  Google Scholar 

  61. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    Article  CAS  Google Scholar 

  62. Jager J, Gremeaux T, Commont M, LeMarchand-Brustel Y, Tanti JF. Interleukin-beta induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241–51.

    Article  CAS  Google Scholar 

  63. Lagathu C. Long term treatment with interleukin-1 beta induces insulin resistance in murine and human adipocytes. Diabetologia. 2006;49:2162–73.

    Article  CAS  Google Scholar 

  64. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NALP3/NLRP3 inflammasome instigates obesity-induced autoinflammation and insulin resistance. Nat Med. 2011;17:179–88.

    Article  CAS  Google Scholar 

  65. Lee H-M, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome in patients with type 2 diabetes. Diabetes. 2013;62:194–204.

    Article  CAS  Google Scholar 

  66. Henriskbo BD, Lau TC, Cavallari JF, Denou E, Chi W, Lally JS, et al. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes. 2014;63:3742–7.

    Article  Google Scholar 

  67. Baker WL, Talati R, White CM, Coleman CI. Differing effects on insulin sensitivity in no-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87:98–107.

    Article  CAS  Google Scholar 

  68. • Chan DC, Pang J, Watts GF. Pathogenesis and management of the diabetogenic effect of statins: a role for adiponectin and coenzyme Q10? Curr Atheroscler Rep. 2015;17(1):472. https://doi.org/10.1007/s11883-014-0472-72015. The association of statin therapy with the development of diabetes may be partly mediated by a statin-induced decrease in circulating adiponectin and coenzyme Q10. The available evidence suggests that statin therapy does not impair glycemic control in diabetic patients.

    Article  PubMed  Google Scholar 

  69. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784–92.

    Article  CAS  Google Scholar 

  70. Li S, Shin HJ, Ding EL, van Dam RM. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2009;302:179–88.

    Article  CAS  Google Scholar 

  71. Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, et al. Association of T-G polymorphism in adiponectin exon 20 with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes. 2002;51:37–41.

    Article  CAS  Google Scholar 

  72. Kondo H, Shimomura I, Matsukawa Y, Kumada M, Takahashi M, Matsuda M, et al. Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes. 2002;51:2325–8.

    Article  CAS  Google Scholar 

  73. Anagnostis P, Selalmatzidou D, Polyzos SA, Panagiotou A, Slavakis A, Panagiotidou A, et al. Comparative effects of rosuvastatin and atorvastatin on glucose metabolism and adipokine levels in non-diabetic patients with dyslipidaemia: a prospective randomised open-label study. Int J Clin Pract. 2011;65:679–83.

    Article  CAS  Google Scholar 

  74. Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci. 2017;18(6). https://doi.org/10.3390/ijms18061321.

  75. Mita T, Watada H, Nakayama S, Abe M, Ogihara T, Shimizu T, et al. Preferable effect of pravastatin compared to atorvastatin on β-cell function in Japanese early-state type 2 diabetes with hypercholesterolemia. Endocr J. 2007;54:441–7.

    Article  CAS  Google Scholar 

  76. Teramoto T, Shimano H, Yokote K, Urashima M. New evidence on pitavastatin: efficacy and safety in clinical studies. Expert Opin Pharmacother. 2010;11:817–28.

    Article  CAS  Google Scholar 

  77. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Grassi G, et al. Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension. J Hypertension. 2009;27:1672–8.

    Article  CAS  Google Scholar 

  78. 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):e0195459.

    Article  Google Scholar 

  79. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–83.

    Article  CAS  Google Scholar 

  80. Montonen J, Drogan D, Joost HG, Boeing H, Fritsche A, Schleicher, et al. Estimation of the contribution of biomarkers of different metabolic pathways to risk of type 2 diabetes. Eur J Epidemiol. 2011;26(1):29–38. https://doi.org/10.1007/s10654-010-9539-0.

    Article  CAS  PubMed  Google Scholar 

  81. Cochran BJ, Bisoendial RJ, Hou L, Glaros EN, Rossy J, Thomas SR, et al. Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism. Arterioscler ThrombVasc Biol. 2014;34:2261–7.

    Article  CAS  Google Scholar 

  82. Von Eckardstein A, Widman C. High-density lipoprotein, beta cells, and diabetes. Cardiovasc Res. 2014;103:384–94.

    Article  Google Scholar 

  83. • Barter PJ, Cochran BJ, Rye KA. CETP inhibition, statins and diabetes. Atherosclerosis. 2018;278:143–6. As has been shown in the REVEAL trial, anacetrapib, unlike statins, decreases the risk of developing diabetes. These findings should be confirmed in other CETP inhibitor outcome trials.

    Article  CAS  Google Scholar 

  84. Group HTRC, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217–27.

    Article  Google Scholar 

  85. Masson W, Lobo M, Siniawski D, Huerín M, Molinero G, Valéro R, et al. Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk. Diabetes Metab. 2018;44(6):508–13. https://doi.org/10.1016/j.diabet.2018.02.005.

    Article  CAS  PubMed  Google Scholar 

  86. • Sattar N, Ginsberg H, Ray K, Chapman MJ, Arca M, Averna M, et al. The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice. Atherosclerosis Suppl. 2014;15:1–15. https://doi.org/10.1016/j.atherosclerosissup.2014.04.001. An international consensus document providing practical guidance for primary care physicians on the use of statins in people with or at risk of developing diabetes.

    Article  Google Scholar 

  87. Qiu S, Cai X, Yang B. Association between cardiorespiratory fitness and risk of type 2 diabetes: a meta-analysis. Obesity (Silver Spring, Md.) 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30604925.

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of Valencia, Avenida Blasco Ibáñez, 17, 46010, Valencia, Spain

    Rafael Carmena

  2. Endocrinology and Metabolism, University College, London, UK

    D. John Betteridge

Authors
  1. Rafael Carmena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. John Betteridge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Carmena.

Ethics declarations

Conflict of Interest

Rafael Carmena and D. John Betteridge declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of Topical Collection on Statin Drugs

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carmena, R., Betteridge, D.J. Diabetogenic Action of Statins: Mechanisms. Curr Atheroscler Rep 21, 23 (2019). https://doi.org/10.1007/s11883-019-0780-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-019-0780-z

Keywords

Search

Navigation