Non-Insulin Agents for Diabetes

  • Gayatri Sreemantula
  • Santosh Shankarnarayan


A variety of oral medications are available to treat type 2 diabetes and play an important role in maximizing blood glucose control and minimizing morbidity and mortality. These agents are summarized in Figure 4.1 and discussed individually in this chapter.


Bladder Cancer Glycemic Control Insulin Glargine Severe Renal Impairment United Kingdom Prospective Diabetes Study 
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  1. 1.
    Florez H. Sanchez A, Marks J. Type 2 diabetes. In: Diabetes in The Brain. London: Springer; 2009.Google Scholar
  2. 2.
    Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574-583.Google Scholar
  3. 3.
    DeFronzo R, Goodman A. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:541-549.Google Scholar
  4. 4.
    Turner R. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.Google Scholar
  5. 5.
    Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(3):CD002966.Google Scholar
  6. 6.
    Bolen S, Wilson L, Vassy J, Feldman L, Yeh J, Marinopoulos S. Comparative effectiveness and safety of oral diabetes medications for adults with type 2 diabetes. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed September 5, 2012.
  7. 7.
    Brown JB, Connor C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care. 2010;33:501-506.Google Scholar
  8. 8.
    Salpeter S, Greyber E, Pasternak G, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006;(1):CD002967Google Scholar
  9. 9.
    National Insititute for Health and Clinical Excellence. Type 2 diabetes NICE clinical guideline 87; 2009. Accessed September 5, 2012.
  10. 10.
    Turner R. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.Google Scholar
  11. 11.
    Schernthaner G, Grimaldi A, di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004;34:535-542.Google Scholar
  12. 12.
    Wright A, Burden AC, Paisey RB, et al; for the UK. Prospective Diabetes Study Group. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25:330-336.Google Scholar
  13. 13.
    Patel A, MacMahon S, Chalmers J, et al; for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.Google Scholar
  14. 14.
    Leese GP, Wang J, Broomhall J, et al. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care. 2003;26:1176-1180.Google Scholar
  15. 15.
    Shorr RI, Ray WA, Daugherty JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc. 1996;44:751-755.Google Scholar
  16. 16.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia 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). Diabetologia. 2012;55:1577-1596.Google Scholar
  17. 17.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2010;304:411-418.Google Scholar
  18. 18.
    Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189-1195.Google Scholar
  19. 19.
    Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-2135.Google Scholar
  20. 20.
    Dormandy JA, Charbonnel B, Eckland DJA, et al; for the PRO active investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PRO active Study (Prospective pioglitazone clinical trial in macrovascular events): a randomized controlled trial. Lancet. 2005;366:1279-1289.Google Scholar
  21. 21.
    Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180-1188.Google Scholar
  22. 22.
    Graham DJ, Ouellet-Hellstrom R, Macurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010;304:411-418.Google Scholar
  23. 23.
    Yki-Jarvinen H. Thiazolidinediones. N Eng J Med. 2004;351:1106-1118.Google Scholar
  24. 24.
    Nissen SE, Nissen SE, Wolski K. Effect of rosglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Eng J Med. 2007; 2457-2471.Google Scholar
  25. 25.
    Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetes patients. J Clin Endocrinol Metab. 2002;87:2784-2791.Google Scholar
  26. 26.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009;180:32-39.Google Scholar
  27. 27.
    Scheen AT. Hepatotoxicity with thiazolidiones: is it a class effect? Drug Saf. 2001;12:873-888.Google Scholar
  28. 28.
    Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogs for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD004654.Google Scholar
  29. 29.
    Bischoff H. Pharmacology of alpha-glucose inhibition. Eur J Clin Invest. 1994;24 (suppl 3):3-10.Google Scholar
  30. 30.
    van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH, Rutten GE, van Weel C. Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care. 2005;28:154-163.Google Scholar
  31. 31.
    Bolen S, Wilson L, Vassy J, Marinopolous S. Comparative effectiveness and safety of oral diabetes medications for adults with type 2 diabetes. Rockville, MD: Agency for healthcare research and disability; 2007.Google Scholar
  32. 32.
    Taira M, Takasu N, Komiya I, Taira T, Tanaka H. Voglibose administration before the evening meal improves nocturnal hypoglycemia in insulin-dependent diabetic patients with intensive insulin therapy.Metabolism. 2000;4:440-443.Google Scholar
  33. 33.
    Hanefeld M. Alpha-glucose inhibitors. In: Goldstein BJ, Muller-Wieland D, eds. Type 2 Diabetes: Principles and Practice. Second edition. New York: Informa; 2008: 127.Google Scholar
  34. 34.
    Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194-206.Google Scholar
  35. 35.
    Lovshin, JA, Drucker, JD, et al. Incretin-based therapies for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2009;5:262-269.Google Scholar
  36. 36.
    Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(10):CD006423.Google Scholar
  37. 37.
    Kim D, MacConell L, Zhuang D, et al. Effects of once-weekly dosing of a long-acting release formation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007;30:1487-1493.Google Scholar
  38. 38.
    Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Therapeutics. 2006;28:1556-68.Google Scholar
  39. 39.
    Ahren B, Foley JE. The islet enhancer vildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract Suppl. 2008;159:8-14.Google Scholar
  40. 40.
    Keating GM. Vildagliptin: a review of its use in type 2 diabetes mellitus. Drugs. 2010;70:2089-2112.Google Scholar
  41. 41.
    Fonseca V, Baron M, Shao Q, Dejager S. Sustained efficacy and reduced hypoglycemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes mellitus. Horm Metab Res. 2008;40:427-430.Google Scholar
  42. 42.
    Matthews DR, Dejager S, Ahren B, et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab. 2010;12:780-789.Google Scholar
  43. 43.
    Halimi S, Raccah D, Schweizer A, Dejager S. Role of vildagliptin in managing type 2 diabetes mellitus in the elderly. Curr Med Res Opin. 2010;26:1647-1656.Google Scholar
  44. 44.
    Pratley RE, Rosenstock J, Pi-Sunyer FX, et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care. 2007;30:3017-3022.Google Scholar
  45. 45.
    Schweizer A, Dejager S, Foley JE, Shao Q, Kothny W. Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population > 75 years: a pooled analysis from a database of clinical trials. Diabetes Obes Metab. 2011;13:55-64.Google Scholar
  46. 46.
    Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: A prospective 24-week randomized placebo-controlled trial. Diabetes Obes Metab. 2011;13:947-954.Google Scholar
  47. 47.
    Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes Obes Metab. 2012; [Epub ahead of print].Google Scholar
  48. 48.
    Campbell RK, Cobble ME, Reid TS, Shomali ME. Safety tolerability and nonglycemia effects of incretin-based therapies. J Fam Pract. 2010;59(suppl 1): S20-S27.Google Scholar
  49. 49.
    White WB, Bakris GL, Bergenstal RM, et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162:620-626.Google Scholar
  50. 50.
    Marrs JC. Colesevelam for the management of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2009;5:187-194.Google Scholar
  51. 51.
    Fonseca VA, Rosenstock J, Wang AC, et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31:1479-1484.Google Scholar
  52. 52.
    Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab. 2010;12:384-392.Google Scholar
  53. 53.
    Welchol product information – cholesevelam hydrochloride. 2007. Accessed May 22, 2012.
  54. 54.
    Holt RIG, Barnett AH, Bailey CJ, et al. Bromocriptine: old drug, new formulation and new indication. Diabetes Obes Metab. 2010;12:1048-1057.Google Scholar
  55. 55.
    Scranton R, Cincotta A. Bromocriptine – unique formulation of a dopamine agonist for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2010;11:269-279.Google Scholar
  56. 56.
    Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: A meta-analysis. Diabetologia. 2006;49:2819-2823.Google Scholar
  57. 57.
    El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: A systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4:369-380.Google Scholar
  58. 58.
    Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076-2083.Google Scholar
  59. 59.
    Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: A meta-analysis. J Natl Cancer Inst. 2005;97:1679-1687.Google Scholar
  60. 60.
    Mitri J, Castillo J, Pittas AG. Diabetes and risk of non-Hodgkin’s lymphoma: A meta-analysis of observational studies. Diabetes Care. 2008;31:2391-2397.Google Scholar
  61. 61.
    Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:2056-2062.Google Scholar
  62. 62.
    Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: A meta-analysis. Diabetologia. 2007;50:1365-1374.Google Scholar
  63. 63.
    Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer. 2007;121:856-862.Google Scholar
  64. 64.
    Gallagher EJ, Fierz Y, Ferguson RD, LeRoith D. The pathway from diabetes and obesity to cancer: insulin and IGF-1 signalling. Endocrine Practice. 2010;16:864-873.Google Scholar
  65. 65.
    Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E: Sulphonylureas and cancer: a case-control study. Acta Diabetol. 2009;46:279-284.Google Scholar
  66. 66.
    Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766-77.Google Scholar
  67. 67.
    Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODI AC-16. Diabetes Care. 2010;33:322.Google Scholar
  68. 68.
    Niraula S, Stambolic V, Dowling RJO, et al. Clinical and biologic effects of metformin in early stage breast cancer. Cancer Res. 2010:70(Suppl 24):104S.Google Scholar
  69. 69.
    Hadad SM, Dewar JA, Elseedawy E et al. Gene Signature of metformin actions on primary breast cancer within a window of opportunity randomized clinical trial. J Clin Oncol. 2010;28(Suppl):560.Google Scholar
  70. 70.
    Dowling RJO, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Medicine. 2011;9:33.Google Scholar
  71. 71.
    Elstner E, Muller C, Koshizuka K, et al. Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci. USA. 1998;95:8806-8811.Google Scholar
  72. 72.
    Clay CE, Namen AM, Astumi G, et al. Magnitude of peroxisome proliferator-activated receptor-gamma activation is associated with important and seemingly opposite biological responses in breast cancer cells. J. Investig. Med. 2001;49:413-420.Google Scholar
  73. 73.
    Dormandy JA, Charbonnel B, Eckland DJ, et al; for the PRO active investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PRO active Study (PRO spective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.Google Scholar
  74. 74.
    Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PRO active. Drug Saf. 2009;32:187-202.Google Scholar
  75. 75.
    Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34:1369-1371.Google Scholar
  76. 76.
    Food and Drug Administration. FDA Drug Safety Communication. “Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer.” FDA Website. Accessed September 5, 2012.
  77. 77.
    Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS). “Use of medications containing pioglitazone (Actos®, Competact®) suspended.” June 9th, 2011. AFSSAPS website. 02a0958.pdf. Accessed September 5, 2012.
  78. 78.
    Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM). “Pioglitazon – Europaische Arzneimittelagentur empfiehlt neue Kontraindikationen und Warnhinweise fur pioglitazonhaltige Arzneimittel aufgrund eines leicht erhohten Blasenkrebsrisikos [Pioglitazone: The European Medicines Agency recommends new contraindications and warnings for medicinal products containing pioglitazone due to a slightly increased risk of bladder cancer].” July 22, 2011. BfArM Website. risikoinfo/2011/pioglitazon.html?nn = 1016416. Accessed September 5, 2012.
  79. 79.
    Lewis JD, Ferrara A, Peng T et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916-922.Google Scholar
  80. 80.
    European Medicines Agency. European Medicines Agency recommends new contraindications and warnings for pioglitazone to reduce small increased risk of bladder cancer. EM A website. Accessed September 5, 2012.
  81. 81.
    European Medicines Agency. “European Medicines Agency clarifies opinion on pioglitazone and the risk of bladder cancer. Positive benefit-risk balance confirmed as second and third line treatment.” EM A Website. October 21, 2011. library/Press_release/2011/10/WC500116936.pdf. Accessed September 5, 2012.

Copyright information

© Springer Healthcare 2012

Authors and Affiliations

  • Gayatri Sreemantula
    • 1
  • Santosh Shankarnarayan
    • 2
  1. 1.Glan Clwyd HospitalBodelwyddanUK
  2. 2.Royal Liverpool University HospitalLiverpoolUK

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