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The Association of Statin Therapy with Incident Diabetes: Evidence, Mechanisms, and Recommendations

  • Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
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Abstract

Purpose of Review

Recent studies have demonstrated a higher risk of incident diabetes associated with statin use, causing concern among patients and clinicians. In this review, we will assess the evidence and proposed mechanisms behind statin therapy and its association with incident diabetes. We will then review the current recommendations for statin use in light of this association and suggest next steps for clinicians managing these patients and researchers exploring this phenomenon.

Recent Findings

The annual risk of developing new-onset diabetes with statin treatment is approximately 0.1%. In comparison, the absolute risk reduction of major coronary events with statin use is approximately 0.42% annually.

Summary

Statins are associated with the development of incident diabetes, particularly among those with predisposing risk factors for diabetes. However, the benefit of statin use among these patients in preventing major coronary events strongly favors statin use despite its risk of incident diabetes.

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References

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  1. Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, et al. 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. 2012;380:581–90.

    Article  CAS  Google Scholar 

  2. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, W Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–96.

    Article  PubMed  CAS  Google Scholar 

  3. Writing Group M, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–360.

    Article  Google Scholar 

  4. Ahmed S, Cannon CP, Murphy SA, Braunwald E. Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. Eur Heart J. 2006;27:2323–9.

    Article  PubMed  CAS  Google Scholar 

  5. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–40.

    Article  PubMed  CAS  Google Scholar 

  6. Mabuchi H, Haba T, Tatami R, et al. Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia. 1981. Atheroscler Suppl. 2004;5:51–5.

    Article  PubMed  CAS  Google Scholar 

  7. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.

  9. Freeman DJ, Norrie J, Sattar N, Neely RDG, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357–62.

    Article  PubMed  CAS  Google Scholar 

  10. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.

    Article  PubMed  CAS  Google Scholar 

  11. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–45.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–7.

    Article  PubMed  CAS  Google Scholar 

  14. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, 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;279:1615–22.

    Article  PubMed  CAS  Google Scholar 

  15. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.

    Article  Google Scholar 

  16. Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998–3007.

    Article  Google Scholar 

  17. Sever PS, Dahlof B, Poulter NR, et al. 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;361:1149–58.

    Article  PubMed  CAS  Google Scholar 

  18. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006;29:1478–85.

    Article  PubMed  CAS  Google Scholar 

  19. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368:1155–63.

    Article  PubMed  CAS  Google Scholar 

  20. Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2021–31.

    Article  PubMed  CAS  Google Scholar 

  21. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9.

    Article  PubMed  CAS  Google Scholar 

  22. Post Coronary Artery Bypass Graft Trial I. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153–62.

    Article  Google Scholar 

  23. Long-Term Intervention with Pravastatin in Ischaemic Disease Study G. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57.

    Article  Google Scholar 

  24. Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). Ital Heart J: Off J Ital Fed Cardiol 2000;1:810–20.

  25. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215–22.

    Article  PubMed  CAS  Google Scholar 

  26. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220–8.

    Article  PubMed  Google Scholar 

  27. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.

    Article  PubMed  CAS  Google Scholar 

  28. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.

    Article  PubMed  CAS  Google Scholar 

  29. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KAA, White HD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307–16.

    Article  PubMed  Google Scholar 

  30. Koren MJ, Hunninghake DB, Investigators A. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol. 2004;44:1772–9.

    PubMed  Google Scholar 

  31. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59.

    Article  PubMed  CAS  Google Scholar 

  32. Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G, Armitage J, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658–69.

    Article  CAS  Google Scholar 

  33. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–934.

    Article  PubMed  Google Scholar 

  34. 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;380:565–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 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  PubMed  Google Scholar 

  36. Cederberg H, Stancakova 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.

    Article  PubMed  CAS  Google Scholar 

  37. Castro MR, Simon G, Cha SS, Yawn BP, Melton LJ, 3rd, Caraballo PJ. Statin use, diabetes incidence and overall mortality in normoglycemic and impaired fasting glucose patients. J Gen Intern Med 2016;31:502–508.

  38. Corrao G, Ibrahim B, Nicotra F, Soranna D, Merlino L, Catapano AL, et al. Statins and the risk of diabetes: evidence from a large population-based cohort study. Diabetes Care. 2014;37:2225–32.

    Article  PubMed  CAS  Google Scholar 

  39. Macedo AF, Douglas I, Smeeth L, Forbes H, Ebrahim S. Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice research datalink. BMC Cardiovasc Disord. 2014;14:85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 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  PubMed  PubMed Central  CAS  Google Scholar 

  41. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–42.

    Article  PubMed  CAS  Google Scholar 

  42. 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;305:2556–64.

    Article  PubMed  CAS  Google Scholar 

  43. Dormuth CR, Filion KB, Paterson JM, James MT, Teare GF, Raymond CB, et al. Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases. BMJ. 2014;348:g3244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. 2012. (Accessed 14 Feb 2018, at https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm.)

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

    Article  PubMed  CAS  Google Scholar 

  46. Kruit JK, Kremer PH, Dai L, et al. Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice. Diabetologia. 2010;53:1110–9.

    Article  PubMed  CAS  Google Scholar 

  47. 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;87:98–107.

    Article  PubMed  CAS  Google Scholar 

  48. 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;49:1881–92.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. •• Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385:351–61. This is an important study that addresses the mechanism by which statins increase in the incidence of diabetes. Using a Mendelian randomization technique, Swerdlow et al. suggest that the increased risk is at least partially explained by the reduced activity of HMG CoA reductase.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. •• Labos C, Brophy JM, Smith GD, Sniderman AD, Thanassoulis G. Evaluation of the pleiotropic effects of statins: a reanalysis of the randomized trial evidence using Egger regression. Arterioscler Thromb Vasc Biol. 2017; This study by Labos et al. provides important insight into the mechanism by which statins confer an elevated risk for diabetes. Using an Egger regression, they show and demonstrate that the LDL-lowering properties of statins appear to contribute to incident diabetes rather than pleiotropic effects.

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

    Article  PubMed  CAS  Google Scholar 

  53. Waters DD, Ho JE, DeMicco DA, 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.

    Article  PubMed  CAS  Google Scholar 

  54. 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:e000438.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gumprecht J, Gosho M, Budinski D, Hounslow N. Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia. Diabetes Obes Metab. 2011;13:1047–55.

    Article  PubMed  CAS  Google Scholar 

  57. Ose L, Budinski D, Hounslow N, Arneson V. Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia. Curr Med Res Opin. 2009;25:2755–64.

    Article  PubMed  CAS  Google Scholar 

  58. Stender S, Budinski D, Gosho M, Hounslow N. Pitavastatin shows greater lipid-lowering efficacy over 12 weeks than pravastatin in elderly patients with primary hypercholesterolaemia or combined (mixed) dyslipidaemia. Eur J Prev Cardiol. 2013;20:40–53.

    Article  PubMed  Google Scholar 

  59. •• Park JB, Jung JH, Yoon YE, et al. Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM): study protocol for a randomized controlled trial. Trials. 2017;18:501. The Long-term Effects of high-doSe pitavaStatin on Diabetogenicity (LESS-DM) trial will compare glucose metabolism in patients with metabolic syndrome treated with either high-dose pitavastatin or atorvastatin 20 mg daily. Findings from this study may shed some light on the mechanism of the association with diabetes and differences in the association with diabetes between drugs in the same class of medications.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Navarese EP, Szczesniak A, Kolodziejczak M, Gorny B, Kubica J, Suryapranata H. Statins and risk of new-onset diabetes mellitus: is there a rationale for individualized statin therapy? Am J Cardiovasc Drugs. 2014;14:79–87.

    Article  PubMed  CAS  Google Scholar 

  61. Koh KK, Quon MJ, Sakuma I, Han SH, Choi H, Lee K, et al. Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients. Int J Cardiol. 2013;166:509–15.

    Article  PubMed  Google Scholar 

  62. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013:CD004816.

  63. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–25.

    Article  CAS  Google Scholar 

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Correspondence to T. Maddox.

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A. Agarwala, S. Kulkarni, and T. Maddox declare that they have no conflict of interest.

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Agarwala, A., Kulkarni, S. & Maddox, T. The Association of Statin Therapy with Incident Diabetes: Evidence, Mechanisms, and Recommendations. Curr Cardiol Rep 20, 50 (2018). https://doi.org/10.1007/s11886-018-0995-6

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