What's next after metformin? focus on sulphonylurea: add-on or combination therapy.

Main Article Content

Phei C. Lim
Chee P. Chong


Diabetes Mellitus, Type 2, Drug Therapy, Combination, Drug Combinations, Hypoglycemic Agents, Biguanides, Sulfonylurea Compounds


Introduction: The pathophysiology of type 2 diabetes (T2DM) mainly focused on insulin resistance and insulin deficiency over the past decades. Currently, the pathophysiologies expanded to ominous octet and guidelines were updated with newer generation of antidiabetic drug classes. However, many patients had yet to achieve their target glycaemic control. Although all the guidelines suggested metformin as first line, there was no definite consensus on the second line drug agents as variety of drug classes were recommended.

Objectives: The aim of this review was to evaluate the drug class after metformin especially sulphonylurea and issues around add-on or fixed dose combination therapy.

Methods: Extensive literature search for English language articles, clinical practice guidelines and references was performed using electronic databases.

Results: Adding sulphonylurea to metformin targeted both insulin resistance and insulin deficiency. Sulphonylurea was efficacious and cheaper than thiazolidinedione, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide 1 analogue and insulin. The main side effect of sulphonylurea was hypoglycaemia but there was no effect on the body weight when combining with metformin. Fixed dose sulphonylurea/metformin was more efficacious at lower dose and reported to have fewer side effects with better adherence. Furthermore, fixed dose combination was cheaper than add-on therapy.

In conclusion, sulphonylurea was feasible as the second line agent after metformin as the combination targeted on two pathways, efficacious, cost-effective and had long safety history. Fixed dose combination tablet could improve patient’s adherence and offered an inexpensive and more efficacious option regardless of original or generic product as compared to add-on therapy.

Abstract 2064 | PDF Downloads 1427


1. Aguiree F, Brown A, Cho NH, et al. IDF diabetes atlas. 6th ed. Brussels: International Diabetes Federation; 2013.

2. Organisation for Economic Co-operation and Development (OECD). OECD Health Data: Social protection. OECD Health Statistics (database); 2014. Available from: http://dx.doi.org/10.1787/data-00544-en (Accessed 17 February 2015).

3. International Diabetes Federation. IDF diabetes atlas sixth edition poster update 2014. Brussels: International Diabetes Federation; 2014. Available from: http://www.idf.org/diabetesatlas/update-2014 (Accessed 24 February 2015).

4. Colagiuri S. DiabCo$t Australia: assessing the burden of type 2 diabetes in Australia, Canberra: Australian Centre for Diabetes Strategies; 2002.

5. Riewpaiboon A, Pornlertwadee P, Pongsawat K. Diabetes cost model of a hospital in Thailand. Value Health. 2007;10(4):223-230.

6. Wang W, Fu CW, Pan CY, Chen W, Zhan S, Luan R, Tan A, Liu Z, Xu B. How do type 2 diabetes mellitus‐related chronic complications impact direct medical cost in four major cities of urban China? Value Health. 2009;12(6):923-929. doi: 10.1111/j.1524-4733.2009.00561.x

7. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther. 2003;25(Suppl B):B32-B46.

8. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131(4):281-303.

9. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. doi: 10.2337/db09-9028

10. Spellman CW. Islet cell dysfunction in progression to diabetes mellitus. J Am Osteopath Assoc. 2007;107(Suppl):S1-S5.

11. 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):442-448.

12. DeFronzo RA. Overview of newer agents: where treatment is going. Am J Med. 2010;123(3 Suppl):S38-S48. doi: 10.1016/j.amjmed.2009.12.008

13. 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(6):787-794.

14. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102-110.

15. Unger R. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 1985;28(8):574-578.

16. Dunning B, Foley JE, Ahrén B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia. 2005;48(9):1700-1713.

17. Freeman JS. The pathophysiologic role of incretins. J Am Osteopath Assoc. 2007;107(Suppl):S6-S9.

18. Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus. Curr Med Res Opin. 2009;25(3):671-681. doi: 10.1185/03007990802710422

19. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD).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):1364-1379. doi: 10.2337/dc12-0413

20. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez G, Davidson MH; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19(2):327-336.

21. Ministry of Health Malaysia. Clinical practice guidelines: management of type 2 diabetes mellitus. 4th ed. Putrajaya: Ministry of Health Malaysia; 2009.

22. American Diabetes Association. Approaches to glycemic treatment. Diabetes Care. 2015;38(Suppl 1):S41-S48. doi: 10.2337/dc15-S010

23. Colagiuri S, Dickinson S, Girgis S, Colagiuri R. National evidence based guideline for blood glucose control in type 2 diabetes. Canberra: Diabetes Australia and the NHMRC; 2009.

24. International Diabetes Federation. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation; 2013.

25. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589. doi: 10.1056/NEJMoa0806470

26. Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19):2070-2080. doi: 10.1001/archinte.168.19.2070

27. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. 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(6):1577-1596. doi: 10.1007/s00125-012-2534-0

28. Mafauzy M, Hussein Z, Chan SP. The status of diabetes control in Malaysia: results of DiabCare 2008. Med J Malaysia. 2011;66(3):175-181.

29. Mafauzy M. Diabetes control and complications in public hospitals in Malaysia. Med J Malaysia. 2006;61(4):477-483.

30. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(Suppl 1):S11-S61. doi: 10.2337/dc11-S011

31. Mohan V, Shah SN, Joshi SR, Seshiah V, Sahay BK, Banerjee S, Wangnoo SK, Kumar A, Kalra S, Unnikrishnan AG, Sharma SK, Rao PV, Akhtar S, Shetty RV, Das AK; DiabCare India 2011 Study Group. Current status of management, control, complications and psychosocial aspects of patients with diabetes in India: results from the DiabCare India 2011 Study. Indian J Endocrinol Metab. 2014;18(3):370-388. doi: 10.4103/2230-8210.129715

32. Pan C, Yang W, Jia W, Weng J, Tian H. Management of Chinese patients with type 2 diabetes, 1998-2006: the Diabcare-China surveys. Curr Med Res Opin. 2009;25(1):39-45. doi: 10.1185/03007990802586079

33. Liebl A, Mata M, Eschwège E; ODE-2 Advisory Board. Evaluation of risk factors for development of complications in type II diabetes in Europe. Diabetologia. 2002;45(7):S23-S28.

34. Cheung BM, Ong KL, Cherny SS, Sham PC, Tso AW, Lam KS. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122(5):443-53. doi: 10.1016/j.amjmed.2008.09.047

35. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27(1):17-20.

36. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in US adults? Diabetes Care. 2008;31(1):81-86.

37. UK Prospective Diabetes Study (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). Lancet. 1998;352(9131):837-853.

38. Brunton S, Reid TS. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, for the management of type 2 diabetes. Hosp Pract (1995). 2014;42(3):96-108. doi: 10.3810/hp.2014.08.1122

39. Haas B, Eckstein N, Pfeifer V, Mayer P, Haas MD. Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin. Nutr Diabetes. 2014;4:e143. doi: 10.1038/nutd.2014.40

40. Burki TK. FDA rejects novel diabetes drug over safety fears. Lancet. 2012;379(9815):507.

41. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W, Jiang J, Vercruysse F, Meininger G, Matthews D. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-223. doi: 10.1016/j.ahj.2013.05.007

42. Gupta V. Glucagon-like peptide-1 analogues: an overview. Indian J Endocrinol Metab. 2013;17(3):413-421. doi: 10.4103/2230-8210.111625

43. Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C, Melchiorri D, Pani L; AIFA Anti-diabetics Monitoring Group. Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutr Metab Cardiovasc Dis. 2014;24(12):1346-1353. doi: 10.1016/j.numecd.2014.07.014

44. Drucker DJ. Incretin-based therapies a clinical need filled by unique metabolic effects. Diabetes Educ. 2006;32(Suppl 2):65S-71S.

45. Pottegård A, Bjerregaard BK, Larsen MD, Larsen KS, Hallas J, Knop FK, Moreno SI. Use of exenatide and liraglutide in Denmark: a drug utilization study. Eur J Clin Pharmacol. 2014;70(2):205-214. doi: 10.1007/s00228-013-1595-4

46. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62(7):2595-2604. doi: 10.2337/db12-1686

47. McIntosh B, Cameron C, Singh SR, Yu C, Ahuja T, Welton NJ, Dahl M. Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis. Open Med. 2011;5(1):e35-48.

48. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1–based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173(7):534-539. doi: 10.1001/jamainternmed.2013.2720

49. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah ND, Denton BT. Second-line agents for glycemic control for type 2 diabetes: are newer agents better? Diabetes Care. 2014;37(5):1338-1345. doi: 10.2337/dc13-1901

50. European Medicines Agency (EMA). European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. 2010. London :EMA; 2010. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&mid=WC0b01ac058004d5c1 (accessed 5 September 2014).

51. 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):2457-2471.

52. U.S. Foods and Drug Administration (US FDA). FDA drug safety communications: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Rockville, MD: US FDA; 2011. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM381108.pdf (accessed 24 March 2015).

53. Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs. 2004;64(12):1339-1358.

54. Canadian Optimal Medication. Second-line therapy for patients with diabetes inadequately controlled on metformin: a systematic review and cost-effectiveness analysis. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010.

55. Klarenbach S, Cameron C, Singh S, Ur E. Cost-effectiveness of second-line antihyperglycemic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin. CMAJ. 2011;183(16):E1213-E1220. doi: 10.1503/cmaj.110178

56. Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, Kravitz BG, Herman WH, Viberti G, Holman RR; ADOPT Study Group. Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes. 2011;60(5):1552-1560. doi: 10.2337/db10-1392

57. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30(2):389-394.

58. Monami M, Balzi D, Lamanna C, Barchielli A, Masotti G, Buiatti E, Marchionni N, Mannucci E. Are sulphonylureas all the same? A cohort study on cardiovascular and cancer‐related mortality. Diabetes Metab Res Rev. 2007;23(6):479-484.

59. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha‐glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(2):CD003639.

60. Dicker D. DPP-4 inhibitors impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011;34(Suppl 2):S276-S278. doi: 10.2337/dc11-s229

61. Singh AK. Deciding oral drugs after metformin in type 2 diabetes: an evidence-based approach. Indian J Endocrinol Metab. 2014;18(5):617-623. doi: 10.4103/2230-8210.139214

62. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326. doi: 10.1056/NEJMoa1307684

63. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25(4):1019-1027. doi: 10.1185/03007990902820519

64. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord. 2002;26(Suppl 3):S18-S24.

65. Meece J. Dispelling myths and removing barriers about insulin in type 2 diabetes. Diabetes Educ. 2006;32(1 Suppl):9S-18S.

66. Blonde L, Wogen J, Kreilick C, Seymour AA. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide-metformin tablets as compared to glyburide co-administered with metformin. Diabetes Obes Metab. 2003;5(6):424-431.

67. Lim PC, Lim SL, Oiyammaal C. Glycaemic control and cost analysis when changing from gliclazide co-administered with metformin to pre-combined glibenclamide-metformin tablets in type 2 diabetes mellitus. Med J Malaysia. 2012;67(1):21-24.

68. Duckworth W, Marcelli M, Padden M, Kellick K, Duhancik T, Wilhardt M, Colgan K, Romie A. Improvements in glycemic control in type 2 diabetes patients switched from sulfonylurea coadministered with metformin to glyburide-metformin tablets. J Manag Care Pharm. 2003;9(3):256-262.

69. Garber A, Klein E, Bruce S, Sankoh S, Mohideen P. Metformin‐glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2006;8(2):156-163.

70. Hwang YC, Kang M, Ahn CW, Park JS, Baik SH, Chung DJ, Jang HC, Kim KA, Lee IK, Min KW, Nam M, Park TS, Son SM, Sung YA, Woo JT, Park KS, Lee MK. Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes. Int J Clin Pract. 2013;67(3):236-243. doi: 10.1111/ijcp.12071

71. González-Ortiz M, Guerrero-Romero JF, Violante-Ortiz R, Wacher-Rodarte N, Martínez-Abundis E, Aguilar-Salinas C, Islas-Andrade S, Arechavaleta-Granell R, González-Canudas J, Rodríguez-Morán M, Zavala-Suárez E, Ramos-Zavala MG, Metha R, Revilla-Monsalve C, Beltrán-Jaramillo TJ. Efficacy of glimepiride/metformin combination versus glibenclamide/metformin in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Complications. 2009;23(6):376-379. doi: 10.1016/j.jdiacomp.2008.09.002

72. Hermann LS, Scherstén B, Bitzén PO, Kjellström T, Lindgärde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations: a double-blind controlled study. Diabetes Care. 1994;17(10):1100-1109.

73. Feher MD, Munro N, Watters K. Fixed-dose combinations in diabetes—do they improve medication adherence? Diabet Med. 2010;27(7):735-736. doi: 10.1111/j.1464-5491.2010.03023.x

74. Cheong C, Barner JC, Lawson KA, Johnsrud MT. Patient adherence and reimbursement amount for antidiabetic fixed-dose combination products compared with dual therapy among texas medicaid recipients. Clin Ther. 2008;30(10):1893-1907. doi: 10.1016/j.clinthera.2008.10.003

75. Schernthaner G. Fixed-dose combination therapies in the management of hyperglycaemia in type 2 diabetes: an opportunity to improve adherence and patient care. Diabet Med. 2010;27(7):739-743. doi: 10.1111/j.1464-5491.2010.03000.x

76. Melikian C, White TJ, Vanderplas A, Dezii CM, Chang E. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Clin Ther. 2002;24(3):460-467.

77. Bartels D. Adherence to oral therapy for type 2 diabetes: opportunities for enhancing glycemic control. J Am Acad Nurse Pract. 2004;16(1):8-16.

78. Ray JA, Huet D, Valentine WJ, Palmer AJ, Cugnardey N, Renaudin C. Long-term costs and clinical outcomes associated with metformin-glibenclamide combination tablets (Glucovance®) in patients with type 2 diabetes sub-optimally controlled by metformin: a modelling study in the French setting. Br J Diabetes Vasc Disease. 2008;8(1):39-44. doi:10.1177/14746514080080010901