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Pharmacologic Treatment of Dyslipidemia in Diabetes: A Case for Therapies in Addition to Statins

  • Abeer Anabtawi
  • Patrick M. Moriarty
  • John M. Miles
Diabetes and Cardiovascular Disease (SR Wright, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Diabetes and Cardiovascular Disease

Abstract

Purpose of Review

The purpose of the study is to review the use of statins and the role of both non-statin lipid-lowering agents and diabetes-specific medications in the treatment of diabetic dyslipidemia.

Recent Findings

Statins have a primary role in the treatment of dyslipidemia in people with type 2 diabetes, defined as triglyceride levels >200 mg/dl and HDL cholesterol levels <40 mg/dL. A number of clinical trials suggest that treatment with a fibrate may reduce cardiovascular events. However, the results of these trials are inconsistent, probably because many of their participants did not have dyslipidemia. The choice of medications used to treat diabetes can have major implications regarding management of dyslipidemia; metformin, GLP-1 agonists, and pioglitazone all have favorable lipid effects. These agents, as well as the new SGLT2 inhibitors, may reduce cardiovascular events.

Summary

Management of dyslipidemia in people with type 2 diabetes should start with statin therapy and optimal glycemic control with agents that have favorable lipid and cardiovascular effects. We believe that there is a role for adding fenofibrate to moderate-intensity statins in selected patients with true dyslipidemia. We propose an algorithm for selecting add-on medications for diabetes (after metformin) based on lipid status.

Keywords

Fibrates Cardiovascular disease Type 2 diabetes 

Notes

Acknowledgments

The study was supported in part by a grant from the USPHS (HL69733). The authors thank David C. Robbins, MD, for helpful comments. JMM remembers the late William L. Isley, MD, for wisdom and inspiration in the study of lipid disorders.

Compliance with Ethical Standards

Conflict of Interest

Abeer Anabtawi declares that he has no conflict of interest.

John M. Miles reports personal fees from Sanofi for service on an advisory board.

Patrick M. Moriarty has research funding from Regeneron, Sanofi-Aventis, Pfizer, Novartis, Amgen, Ionis and Catabasis; he serves as a consultant for Genzyme, Kowa, Duke Clinical Research Institute, Eliaz Therapeutics, Aegerion, Alexion, and Esperion; and he serves on a Data Safety Monitoring Board for Lilly.

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.

References

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

  1. 1.
    Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2):434–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care. 1998;21(7):1138–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Ginsberg HN. REVIEW: efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab. 2006;91(2):383–92.CrossRefPubMedGoogle Scholar
  4. 4.
    McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992;258:766–70.CrossRefPubMedGoogle Scholar
  5. 5.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the NationalCholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):3143–421.Google Scholar
  6. 6.
    Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 1999;83(9b):25f–9f.CrossRefPubMedGoogle Scholar
  7. 7.
    Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arteriosclerosis and thrombosis : a journal of vascular biology. 1992;12(12):1496–502.CrossRefGoogle Scholar
  8. 8.
    Del Pilar SM, Goldberg RB. Management of diabetic dyslipidemia. Endocrinol Metab Clin N Am. 2005;34(1):1–25. v CrossRefGoogle Scholar
  9. 9.
    Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52(5):1210–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, Dhandania VK, Joshi PP, Unnikrishnan R, Nirmal E, Subashini R, et al. Prevalence of dyslipidemia in urban and rural India: the ICMR-INDIAB study. PLoS One. 2014;9(5):e96808.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kissebah AH, Alfarsi S, Evans DJ, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes. 1982;31:217–25.CrossRefPubMedGoogle Scholar
  12. 12.
    Taskinen MR. Pathogenesis of dyslipidemia in type 2 diabetes. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2001;109(Suppl 2):S180–8.CrossRefGoogle Scholar
  13. 13.
    Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995;95(1):158–66.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bolinder J, Kager L, Ostman J, Arner P. Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis. Diabetes. 1983;32:117–23.CrossRefPubMedGoogle Scholar
  15. 15.
    Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, 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. Circulation. 2014;129(25 Suppl 2):S1–45.CrossRefPubMedGoogle Scholar
  16. 16.
    American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2016;1(Suppl 1):S62–S3.Google Scholar
  17. 17.
    Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999;159(22):2661–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH. 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(9435):685–96.CrossRefPubMedGoogle Scholar
  19. 19.
    Sever PS, Poulter NR, Dahlof B, Wedel H, Collins R, Beevers G, Caulfield M, Kjeldsen SE, Kristinsson A, McInnes GT, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA). Diabetes Care. 2005;28(5):1151–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005–16.CrossRefPubMedGoogle Scholar
  21. 21.
    Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25.CrossRefPubMedGoogle Scholar
  22. 22.
    Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S, Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368(9539):919–28.CrossRefPubMedGoogle Scholar
  23. 23.
    Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504.CrossRefPubMedGoogle Scholar
  24. 24.
    Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Naci H, Brugts JJ, Fleurence R, Ades AE. Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials. Eur J Prev Cardiol. 2013;20(4):658–70.CrossRefPubMedGoogle Scholar
  26. 26.
    O'Keefe Jr JH, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43(11):2142–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998;81(5):582–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Bays H, Stein EA. Pharmacotherapy for dyslipidaemia—current therapies and future agents. Expert Opin Pharmacother. 2003;4(11):1901–38.CrossRefPubMedGoogle Scholar
  29. 29.
    Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol. 1997;80(1):106–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403–14.CrossRefPubMedGoogle Scholar
  31. 31.
    Backes JM, Venero CV, Gibson CA, Ruisinger JF, Howard PA, Thompson PD, Moriarty PM. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother. 2008;42(3):341–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol. 2006;97(8a):44c–51c.CrossRefPubMedGoogle Scholar
  33. 33.
    Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. Journal of clinical lipidology. 2012;6(3):208–15.CrossRefPubMedGoogle Scholar
  34. 34.
    Robinson J. In: he Johns Hopkins Textbook of Dyslipidemia, P. Kwiterovich ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, c2010.Google Scholar
  35. 35.
    Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46(7):1225–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard C, Simes J, Byington R, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation. 2000;102(16):1893–900.CrossRefPubMedGoogle Scholar
  37. 37.
    Wakatsuki A, Okatani Y, Ikenoue N. Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type IIa hypercholesterolemia. Atherosclerosis. 2000;150(1):103–11.CrossRefPubMedGoogle Scholar
  38. 38.
    Vakkilainen J, Steiner G, Ansquer JC, Perttunen-Nio H, Taskinen MR. Fenofibrate lowers plasma triglycerides and increases LDL particle diameter in subjects with type 2 diabetes. Diabetes Care. 2002;25(3):627–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Lemieux I, Laperriere L, Dzavik V, Tremblay G, Bourgeois J, Despres JP. A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients. Atherosclerosis. 2002;162(2):363–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95(4):462–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Miyazaki T, Shimada K, Miyauchi K, Kume A, Tanimoto K, Kiyanagi T, Sumiyoshi K, Hiki M, Mokuno H, Okazaki S, et al. Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasia in patients after elective coronary stenting. Lipids Health Dis. 2010;9:122.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Davidson MH, Bays HE, Stein E, Maki KC, Shalwitz RA, Doyle R. Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006;29(6):268–73.CrossRefPubMedGoogle Scholar
  43. 43.
    Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996;37(5):907–25.PubMedGoogle Scholar
  44. 44.
    Shipman KE, Strange RC, Ramachandran S. Use of fibrates in the metabolic syndrome: a review. World J Diabetes. 2016;7(5):74–88.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85(1):37–45.CrossRefPubMedGoogle Scholar
  46. 46.
    Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001;285(12):1585–91.CrossRefPubMedGoogle Scholar
  47. 47.
    Group TBS. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102(1):21–7.CrossRefGoogle Scholar
  48. 48.
    Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61.CrossRefPubMedGoogle Scholar
  49. 49.
    ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. N Engl J Med. 2010;362(17):1563–74.Google Scholar
  50. 50.
    Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med. 2010;363(7):692–4. author reply 4-5 CrossRefPubMedGoogle Scholar
  51. 51.
    Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-Gonzalez I, Briel M. Fibrates for primary prevention of cardiovascular disease events. The Cochrane database of systematic reviews. 2016;11:Cd009753.PubMedGoogle Scholar
  52. 52.
    Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. The Cochrane database of systematic reviews. 2015;10:Cd009580.Google Scholar
  53. 53.
    Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.CrossRefPubMedGoogle Scholar
  54. 54.
    Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.[erratum appears in N Engl J Med. 2012 Jul 12;367(2):189]. N Engl J Med. 2011;365(24):2255–67.CrossRefGoogle Scholar
  55. 55.
    Gonzalez-Molero I, Rojo-Martinez G, Morcillo S, Gutierrez-Repiso C, Rubio-Martin E, Almaraz MC, Olveira G, Soriguer F. Vitamin D and incidence of diabetes: a prospective cohort study. Clin Nutr. 2012;31(4):571–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Muscogiuri G, Annweiler C, Duval G, Karras S, Tirabassi G, Salvio G, Balercia G, Kimball S, Kotsa K, Mascitelli L, et al. Vitamin D and cardiovascular disease: from atherosclerosis to myocardial infarction and stroke. Int J Cardiol. 2017;230:577–84.CrossRefPubMedGoogle Scholar
  57. 57.
    Arunabh S, Pollack S, Yeh J, Aloia JF. Body fat content and 25-hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab. 2003;88(1):157–61.CrossRefPubMedGoogle Scholar
  58. 58.
    Jafari T, Fallah AA, Barani A. Effects of vitamin D on serum lipid profile in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Clin Nutr. 2016;35(6):1259–68.CrossRefPubMedGoogle Scholar
  59. 59.
    Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. Journal of clinical lipidology. 2012;6(1):5–18.CrossRefPubMedGoogle Scholar
  60. 60.
    Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;92(1):15–29.CrossRefPubMedGoogle Scholar
  61. 61.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–79.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Group US. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65.CrossRefGoogle Scholar
  63. 63.
    Anabtawi A, Miles JM. Metformin: nonglycemic effects and potential novel indications. Endocr Pract. 2016;22(8):999–1007.CrossRefPubMedGoogle Scholar
  64. 64.
    Russo GT, Labate AM, Giandalia A, Romeo EL, Villari P, Alibrandi A, Perdichizzi G, Cucinotta D. Twelve-month treatment with Liraglutide ameliorates Visceral Adiposity Index and common cardiovascular risk factors in type 2 diabetes outpatients. J Endocrinol Investig. 2015;38(1):81–9.CrossRefGoogle Scholar
  65. 65.
    Rizzo M, Chandalia M, Patti AM, Di Bartolo V, Rizvi AA, Montalto G, Abate N. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol. 2014;13:49.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Simo R, Guerci B, Schernthaner G, Gallwitz B, Rosas-Guzman J, Dotta F, Festa A, Zhou M, Kiljanski J. Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study. Cardiovasc Diabetol. 2015;14:116.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Blonde L, Pencek R, MacConell L. Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:12.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Torimoto K, Okada Y, Mori H, Otsuka T, Kawaguchi M, Matsuda M, Kuno F, Sugai K, Sonoda S, Hajime M, et al. Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovasc Diabetol. 2015;14:25.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    •• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. This study showed fairly robust reductions in mortality with liraglutide treatment in T2DM. This should increase interest in the use of GLP-1 agonists as a second-line agent in the treatment of selected patients with T2DM, especially those with obesity and dyslipidemia. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Betteridge DJ. Effects of pioglitazone on lipid and lipoprotein metabolism. Diabetes Obes Metab. 2007;9(5):640–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Deeg MA, Buse JB, Goldberg RB, Kendall DM, Zagar AJ, Jacober SJ, Khan MA, Perez AT, Tan MH. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2007;30(10):2458–64.CrossRefPubMedGoogle Scholar
  72. 72.
    Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.CrossRefPubMedGoogle Scholar
  73. 73.
    Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–31.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17(11):1075–84.CrossRefPubMedGoogle Scholar
  75. 75.
    Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, Meininger G. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294–303.CrossRefPubMedGoogle Scholar
  76. 76.
    •• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. The reduction in cardiovascular and all-cause mortality in this study was robust and somewhat unexpected. It adds SGLT2 inhibitors to other agents (metformin, GLP-1 agonists) that both reduce cardiovascular events and have favorable effects on energy balance. CrossRefPubMedGoogle Scholar
  77. 77.
    Emanuele N, Azad N, Abraira C, Henderson W, Colwell J, Levin S, Nuttall F, Comstock J, Sawin C, Silbert C, et al. Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus. Arch Intern Med. 1998;158(22):2485–90.CrossRefPubMedGoogle Scholar
  78. 78.
    Buse JB, Tan MH, Prince MJ, Erickson PP. The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes. Diabetes Obes Metab. 2004;6(2):133–56.CrossRefPubMedGoogle Scholar
  79. 79.
    Yki-Jarvinen H, Ryysy L, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Salo S, Seppala M, et al. Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:4037–43.CrossRefPubMedGoogle Scholar
  80. 80.
    Genev N, Lau I, Willey K, Molyneaux L, Xu Z, Zilkens R, Wyndham R, Yue D. Does insulin therapy have a hypertensive effect in type 2 diabetes? J Cardiovasc Pharmacol. 1998;32:39–41.CrossRefPubMedGoogle Scholar
  81. 81.
    Holman R, Paul S, Bethel M, Matthews D, Neil H. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.82.CrossRefPubMedGoogle Scholar
  82. 82.
    Groop L. Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. Int J Clin Pract Suppl. 2000;(113):3–13.Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Abeer Anabtawi
    • 1
  • Patrick M. Moriarty
    • 2
  • John M. Miles
    • 1
  1. 1.Division of Endocrinology, Metabolism and GeneticsKansas CityUSA
  2. 2.Division of Clinical PharmacologyUniversity of Kansas School of MedicineKansas CityUSA

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