Treating Type 2 Diabetes Mellitus

  • Alexandra L. Migdal
  • Susan Herzlinger
  • Martin J. Abrahamson
Living reference work entry

Latest version View entry history


Type 2 diabetes is a growing problem within the United States and worldwide. Lifestyle modification remains the cornerstone of management, though additional treatment with antihyperglycemic agents is often required. Appropriate management of hyperglycemia is necessary to prevent acute complications and to reduce the risk of long-term complications, including microvascular and macrovascular disease. Treatment goals and management strategies should be individualized to each patient. Fortunately, the majority of patients can be well controlled with currently available agents if managed appropriately. Herein, we review the basic pathophysiology of type 2 diabetes and use this knowledge to review different therapeutic options for managing hyperglycemia associated with type 2 diabetes.


Type 2 diabetes Metformin SGLT-2 inhibitors GLP-1 receptor agonists Sulfonylureas Thiazolidinediones Insulin 


  1. 1.
    Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Centers for Disease Control and Prevention. National diabetes statistics report: Estimates of diabetes and its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014.Google Scholar
  3. 3.
    American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36(4):1033–46.PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Standards of medical care in diabetes – 2015: summary of revisions. Diabetes Care. 2015;38(Suppl):S4.Google Scholar
  5. 5.
    Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Group AC, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.CrossRefGoogle Scholar
  8. 8.
    The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545–59.Google Scholar
  9. 9.
    Hayward RA, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197–206.PubMedCrossRefGoogle Scholar
  10. 10.
    Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Selvin E, et al. Trends in prevalence and control of diabetes in the United States, 1988–1994 and 1999–2010. Ann Intern Med. 2014;160(8):517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Flegal KM, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307(5):491–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Look ARG, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007;30(6):1374–83.CrossRefGoogle Scholar
  14. 14.
    Chiu KC, et al. Insulin sensitivity differs among ethnic groups with a compensatory response in beta-cell function. Diabetes Care. 2000;23(9):1353–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Shulman GI, et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13 C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990;322(4):223–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Consoli A, et al. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes. 1989;38(5):550–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Hosker JP, et al. Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism. 1989;38(8):767–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Porte D. Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes. 1991;40(2):166–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Campos C. Chronic hyperglycemia and glucose toxicity: pathology and clinical sequelae. Postgrad Med. 2012;124(6):90–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Evert AB, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2014;37 Suppl 1:S120–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Tuomilehto J, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Lindstrom J, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368(9548):1673–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.PubMedCrossRefGoogle Scholar
  25. 25.
    Diabetes Prevention Program Research Group, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677–86.PubMedCentralCrossRefGoogle Scholar
  26. 26.
    Vessby B, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU study. Diabetologia. 2001;44(3):312–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Estruch R, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Brehm BJ, et al. One-year comparison of a high-monounsaturated fat diet with a high-carbohydrate diet in type 2 diabetes. Diabetes Care. 2009;32(2):215–20.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Schulze MB, et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. Am J Clin Nutr. 2004;80(2):348–56.PubMedGoogle Scholar
  30. 30.
    Liese AD, et al. Whole-grain intake and insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Am J Clin Nutr. 2003;78(5):965–71.PubMedGoogle Scholar
  31. 31.
    Liese AD, et al. Dietary glycemic index and glycemic load, carbohydrate and fiber intake, and measures of insulin sensitivity, secretion, and adiposity in the Insulin Resistance Atherosclerosis Study. Diabetes Care. 2005;28(12):2832–8.PubMedCrossRefGoogle Scholar
  32. 32.
    UKPDS Group. UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, UKPDS Group. Metabolism. 1990;39(9):905–12.Google Scholar
  33. 33.
    Franz MJ, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes mellitus. J Am Diet Assoc. 1995;95(9):1009–17.PubMedCrossRefGoogle Scholar
  34. 34.
    Delahanty LM, Halford BN. The role of diet behaviors in achieving improved glycemic control in intensively treated patients in the Diabetes Control and Complications Trial. Diabetes Care. 1993;16(11):1453–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Pastors JG, et al. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care. 2002;25(3):608–13.PubMedCrossRefGoogle Scholar
  36. 36.
    Wood AJJ, Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9.CrossRefGoogle Scholar
  37. 37.
    Bailey CJ, Puah JA. Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metab. 1986;12(4):212–8.PubMedGoogle Scholar
  38. 38.
    DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):541–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Stumvoll M, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992;15(6):755–72.PubMedCrossRefGoogle Scholar
  43. 43.
    UKPDS Group. 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.Google Scholar
  44. 44.
    Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol. 2012;29(2):1314–27.PubMedCrossRefGoogle Scholar
  45. 45.
    Franciosi M, et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One. 2013;8(8):e71583.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ting RZ-W. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med. 2006;166(18):1975.PubMedCrossRefGoogle Scholar
  47. 47.
    Liu Q, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014;9(6):e100379.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Inzucchi SE, et al. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668–75.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gan SC. Biguanide-associated lactic acidosis. Arch Intern Med. 1992;152(11):2333.PubMedCrossRefGoogle Scholar
  50. 50.
    Salpeter SR, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.Google Scholar
  51. 51.
    Lebovitz HE, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab. 2001;86(1):280–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs. 2003;63(13):1373–405.PubMedCrossRefGoogle Scholar
  53. 53.
    Tan M, et al. Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: a multicenter, randomized, double-blind, parallel-group trial. Clin Ther. 2004;26(5):680–93.PubMedCrossRefGoogle Scholar
  54. 54.
    Fonseca VA. Rationale for the use of insulin sensitizers to prevent cardiovascular events in type 2 diabetes mellitus. Am J Med. 2007;120(9):S18–25.PubMedCrossRefGoogle Scholar
  55. 55.
    Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–18.PubMedCrossRefGoogle Scholar
  56. 56.
    Nyenwe EA, et al. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 2011;60(1):1–23.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Fonseca V. Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Am J Med. 2003;115(8):42–8.CrossRefGoogle Scholar
  58. 58.
    Miyazaki Y, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87(6):2784–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.PubMedCrossRefGoogle Scholar
  60. 60.
    Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129–36.PubMedCrossRefGoogle Scholar
  61. 61.
    Lincoff AM, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2007;298(10):1180.PubMedCrossRefGoogle Scholar
  62. 62.
    Mahaffey KW, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(2):240–9. e1.PubMedCrossRefGoogle Scholar
  63. 63.
    Vaccaro O, et al. The TOSCA.IT trial: a study designed to evaluate the effect of pioglitazone versus sulfonylureas on cardiovascular disease in type 2 diabetes. Diabetes Care. 2012;35(12):e82.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lewis JD, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34(4):916–22.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Colmers IN, et al. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis. CMAJ. 2012;184(12):E675–83.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lewis JD, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA. 2015;314(3):265–77.PubMedCrossRefGoogle Scholar
  67. 67.
    Kahn SE, et al. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008;31(5):845–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009;180(1):32–9.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Schwartz AV, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91(9):3349–54.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Grey A. Skeletal consequences of thiazolidinedione therapy. Osteoporos Int. 2008;19(2):129–37.PubMedCrossRefGoogle Scholar
  71. 71.
    Rosenstock J, et al. Glimepiride, a new once-daily sulfonylurea: A double-blind placebo-controlled study of NIDDM patients. Diabetes Care. 1996;19(11):1194–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Schade DS, Jovanovic L, Schneider J. A placebo-controlled, randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. J Clin Pharmacol. 1998;38(7):636–41.PubMedCrossRefGoogle Scholar
  73. 73.
    UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53.Google Scholar
  74. 74.
    Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA. 2002;287(3):360.PubMedCrossRefGoogle Scholar
  75. 75.
    Wright A, et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25(2):330–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA. 1971;218(9):1400–10.PubMedCrossRefGoogle Scholar
  77. 77.
    Simpson SH, et al. Dose–response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006;174(2):169–74.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Forst T, et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res. 2013;10(4):302–14.PubMedCrossRefGoogle Scholar
  79. 79.
    Gerich JE. Metabolic abnormalities in impaired glucose tolerance. Metabolism. 1997;46:40–3.PubMedCrossRefGoogle Scholar
  80. 80.
    Owens DR. Repaglinide – prandial glucose regulator: a new class of oral antidiabetic drugs. Diabet Med. 1998;15 Suppl 4:S28–36.PubMedCrossRefGoogle Scholar
  81. 81.
    Black C, et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;2:CD004654.Google Scholar
  82. 82.
    Wolffenbuttel BH, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care. 1999;22(3):463–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Goldberg RB, et al. A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabetes Care. 1998;21(11):1897–903.PubMedCrossRefGoogle Scholar
  84. 84.
    Madsbad S, et al. Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1-year multicentre study. Diabet Med. 2001;18(5):395–401.PubMedCrossRefGoogle Scholar
  85. 85.
    Dornhorst A. Insulinotropic meglitinide analogues. Lancet. 2001;358(9294):1709–16.PubMedCrossRefGoogle Scholar
  86. 86.
    Landgraf R, et al. Prandial glucose regulation with repaglinide: its clinical and lifestyle impact in a large cohort of patients with Type 2 diabetes. Int J Obes Relat Metab Disord. 2000;24:S38–44.PubMedCrossRefGoogle Scholar
  87. 87.
    Chiasson J-L. The efficacy of acarbose in the treatment of patients with non–insulin-dependent diabetes mellitus: a multicenter, controlled clinical trial. Ann Intern Med. 1994;121(12):928.PubMedCrossRefGoogle Scholar
  88. 88.
    Johnston PS, et al. Advantages of alpha-glucosidase inhibition as monotherapy in elderly type 2 diabetic patients. J Clin Endocrinol Metab. 1998;83(5):1515–22.PubMedGoogle Scholar
  89. 89.
    Catalan VS, Couture JA, LeLorier J. Predictors of persistence of use of the novel antidiabetic agent acarbose. Arch Intern Med. 2001;161(8):1106.PubMedCrossRefGoogle Scholar
  90. 90.
    van de Laar FA, et al. Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care. 2005;28(1):154–63.PubMedCrossRefGoogle Scholar
  91. 91.
    Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients. Am J Med. 1997;103(6):483–90.PubMedCrossRefGoogle Scholar
  92. 92.
    Elrick H, et al. Plasma insulin response to oral and intravenous glucose administration1. J Clin Endocrinol Metab. 1964;24(10):1076–82.PubMedCrossRefGoogle Scholar
  93. 93.
    Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705.PubMedCrossRefGoogle Scholar
  94. 94.
    Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes. JAMA. 2007;298(2):194.PubMedCrossRefGoogle Scholar
  95. 95.
    Farilla L, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;144(12):5149–58.PubMedCrossRefGoogle Scholar
  96. 96.
    Retnakaran R, et al. Liraglutide and the preservation of pancreatic beta-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care. 2014;37(12):3270–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Turton MD, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69–72.PubMedCrossRefGoogle Scholar
  98. 98.
    Verdich C, et al. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety – effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001;25(8):1206–14.PubMedCrossRefGoogle Scholar
  99. 99.
    Naslund E, et al. Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects. Br J Nutr. 2004;91(3):439–46.PubMedCrossRefGoogle Scholar
  100. 100.
    DeFronzo RA, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092–100.PubMedCrossRefGoogle Scholar
  101. 101.
    Riddle MC, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006;22(6):483–91.PubMedCrossRefGoogle Scholar
  102. 102.
    Drucker DJ, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240–50.PubMedCrossRefGoogle Scholar
  103. 103.
    Madsen K, et al. Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J Med Chem. 2007;50(24):6126–32.PubMedCrossRefGoogle Scholar
  104. 104.
    Buse JB, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39–47.PubMedCrossRefGoogle Scholar
  105. 105.
    Buse JB, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381(9861):117–24.PubMedCrossRefGoogle Scholar
  106. 106.
    Russell-Jones D, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046–55.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Weissman PN, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57(12):2475–84.PubMedCrossRefGoogle Scholar
  108. 108.
    Pratley RE, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2(4):289–97.PubMedCrossRefGoogle Scholar
  109. 109.
    Wysham C, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37(8):2159–67.PubMedCrossRefGoogle Scholar
  110. 110.
    Giorgino F, et al. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Dungan KM, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349–57.PubMedCrossRefGoogle Scholar
  112. 112.
    Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 Suppl 2:S279–84.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Cefalu WT, et al. Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors’ expert forum. Diabetes Care. 2014;37(9):2647–59.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Balas B, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249–55.PubMedCrossRefGoogle Scholar
  115. 115.
    DeFronzo RA, et al. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin. 2008;24(10):2943–52.PubMedCrossRefGoogle Scholar
  116. 116.
    Karagiannis T, et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369.PubMedCrossRefGoogle Scholar
  117. 117.
    Crickx E, et al. DPP4 inhibitor-induced polyarthritis: a report of three cases. Rheumatol Int. 2014;34(2):291–2.PubMedCrossRefGoogle Scholar
  118. 118.
    Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.PubMedCrossRefGoogle Scholar
  119. 119.
    DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5–14.PubMedCrossRefGoogle Scholar
  120. 120.
    Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract. 2014;104(3):297–322.PubMedCrossRefGoogle Scholar
  121. 121.
    Stenlof K, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372–82.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217–24.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Lavalle-Gonzalez FJ, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582–92.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wilding JP, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405–15.PubMedCrossRefGoogle Scholar
  125. 125.
    Rosenstock J, et al. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35(7):1473–8.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Neal B, Matthews D, Fulcher G, et al. 52-week effects of canagliflozin, an inhibitor of sodium glucose co-transporter 2 (SGLT2), added to insulin therapy in type 2 diabetes (T2D). Poster presented at: 22nd Biennial World Diabetes Congress of the International Diabetes Federation (IDF); December 2 -6, 2013; Melbourne, Australia.Google Scholar
  127. 127.
    Vasilakou D, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.PubMedCrossRefGoogle Scholar
  128. 128.
    Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28Google Scholar
  129. 129.
    Scheen AJ. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus. Clin Pharmacokinet. 2014;53(4):295–304.PubMedCrossRefGoogle Scholar
  130. 130.
    Weir MR, et al. Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin. 2014;30(9):1759–68.PubMedCrossRefGoogle Scholar
  131. 131.
    Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849–52.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Erondu N, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680–6.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3(1):8–10.PubMedCrossRefGoogle Scholar
  134. 134.
    Watts NB et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2015;101(1):157–66Google Scholar
  135. 135.
    Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes. 2004;53 Suppl 3:S233–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Riddle M, et al. Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. Diabetes Care. 2007;30(11):2794–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Riddle M, et al. Randomized comparison of pramlintide or mealtime insulin added to basal insulin treatment for patients with type 2 diabetes. Diabetes Care. 2009;32(9):1577–82.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Hollander P, et al. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res. 2004;12(4):661–8.PubMedCrossRefGoogle Scholar
  139. 139.
    UKPDS Group. U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44(11):1249–58.Google Scholar
  140. 140.
    Turner RC, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005–12.PubMedCrossRefGoogle Scholar
  141. 141.
    Peyrot M, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care. 2005;28(11):2673–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Lin J, et al. Does clinical inertia vary by personalized A1c goal? A study of predictors and prevalence of clinical inertia in a U.S. managed care setting. Endocr Pract. 2015;22(2):151–61Google Scholar
  143. 143.
    Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81(2):442–8.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Brunelle BL, et al. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 1998;21(10):1726–31.PubMedCrossRefGoogle Scholar
  145. 145.
    Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis. Diabetes Obes Metab. 2009;11(1):53–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Rosskamp RH, Park G. Long-acting insulin analogs. Diabetes Care. 1999;22 Suppl 2:B109–13.PubMedGoogle Scholar
  147. 147.
    Raskin P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28(2):260–5.PubMedCrossRefGoogle Scholar
  148. 148.
    Coscelli C, et al. Use of premixed insulin among the elderly: reduction of errors in patient preparation of mixtures. Diabetes Care. 1992;15(11):1628–30.PubMedCrossRefGoogle Scholar
  149. 149.
    Testa MA, et al. Comparative effectiveness of basal-bolus versus premix analog insulin on glycemic variability and patient-centered outcomes during insulin intensification in type 1 and type 2 diabetes: a randomized, controlled, crossover trial. J Clin Endocrinol Metab. 2012;97(10):3504–14.PubMedCrossRefGoogle Scholar
  150. 150.
    Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26(3):881–5.PubMedCrossRefGoogle Scholar
  151. 151.
    Philis-Tsimikas A, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28(10):1569–81.PubMedCrossRefGoogle Scholar
  152. 152.
    Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080–6.PubMedCrossRefGoogle Scholar
  153. 153.
    Yki-Järvinen H, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia. 2006;49(3):442–51.PubMedCrossRefGoogle Scholar
  154. 154.
    Pittas AG, Westcott GP, Balk EM. Efficacy, safety, and patient acceptability of Technosphere inhaled insulin for people with diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(11):886–94.PubMedCrossRefGoogle Scholar
  155. 155.
    Binder C, et al. Insulin pharmacokinetics. Diabetes Care. 1984;7(2):188–99.PubMedCrossRefGoogle Scholar
  156. 156.
    Bolli GB, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naive people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17(4):386–94.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    The Diabetes Control and Complications Trial Research Group. Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the Diabetes Control and Complications Trial. Diabetes Care. 2001;24(10):1711–21.Google Scholar
  158. 158.
    The Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. J Pediatr. 1994;125(2):177–88.Google Scholar
  159. 159.
    Vora J, et al. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther. 2014;5(2):435–46.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Dailey G, et al. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care. 2004;27(10):2363–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Alexandra L. Migdal
    • 1
  • Susan Herzlinger
    • 1
  • Martin J. Abrahamson
    • 1
  1. 1.Beth Israel Deaconess Medical Center, Joslin Diabetes CenterHarvard Medical SchoolBostonUSA

Personalised recommendations