Diabetes Metab J.  2017 Oct;41(5):357-366. 10.4093/dmj.2017.41.5.357.

Combination Therapy of Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus

Affiliations
  • 1Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
  • 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 3Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, the Catholic University of Korea, Seoul, Korea.
  • 4Department of Internal Medicine, Gwangmyeong Sungae Hospital, Gwangmyeong, Korea.
  • 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
  • 6Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea.
  • 7Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea.
  • 8Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
  • 9Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea. nhkendo@gmail.com

Abstract

The Korean Diabetes Association (KDA) recently updated the Clinical Practice Guidelines on antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus (T2DM). In combination therapy of oral hypoglycemic agents (OHAs), general recommendations were not changed from those of the 2015 KDA guidelines. The Committee on Clinical Practice Guidelines of the KDA has extensively reviewed and discussed the results of meta-analyses and systematic reviews of effectiveness and safety of OHAs and many clinical trials on Korean patients with T2DM for the update of guidelines. All OHAs were effective when added to metformin or metformin and sulfonylurea, although the effects of each agent on body weight and hypoglycemia were different. Therefore, selection of a second agent as a metformin add-on therapy or third agent as a metformin and sulfonylurea add-on therapy should be based on the patient's clinical characteristics and the efficacy, side effects, mechanism of action, risk of hypoglycemia, effect on body weight, patient preference, and combined comorbidity. In this review, we address the results of meta-analyses and systematic reviews, comparing the effectiveness and safety among OHAs. It will help to choose the appropriate drug for an individual patient with T2DM.

Keyword

Diabetes mellitus, type 2; Efficacy; Oral hypoglycemic agents; Practice guideline

MeSH Terms

Adult
Body Weight
Comorbidity
Diabetes Mellitus, Type 2*
Humans
Hypoglycemia
Hypoglycemic Agents*
Metformin
Patient Preference
Hypoglycemic Agents
Metformin

Reference

1. Korean Diabetes Association. Diabetes Fact Sheet in Korea 2016. cited 2017 Oct 5. Available from: http://www.diabetes.or.kr/pro/news/admin.php?category=A&code=admin&number=1428&mode=view.
2. Nathan DM. DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014; 37:9–16.
3. Ha KH, Kim DJ. Current status of managing diabetes mellitus in Korea. Korean J Intern Med. 2016; 31:845–850.
4. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017; 40:Suppl 1. S64–S74.
5. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm: 2017 executive summary. Endocr Pract. 2017; 23:207–238.
6. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and metaanalysis. Ann Intern Med. 2016; 164:740–751.
7. Mishriky BM, Cummings DM, Tanenberg RJ. The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2015; 109:378–388.
8. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016; 316:313–324.
9. Zhou JB, Bai L, Wang Y, Yang JK. The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type 2 diabetes: accumulated evidence from randomised controlled trial. Int J Clin Pract. 2016; 70:132–141.
10. Foroutan N, Muratov S, Levine M. Safety and efficacy of dipeptidyl peptidase-4 inhibitors vs sulfonylurea in metforminbased combination therapy for type 2 diabetes mellitus: systematic review and meta-analysis. Clin Invest Med. 2016; 39:E48–E62.
11. Amate JM, Lopez-Cuadrado T, Almendro N, Bouza C, Saz-Parkinson Z, Rivas-Ruiz R, Gonzalez-Canudas J. Effectiveness and safety of glimepiride and iDPP4, associated with metformin in second line pharmacotherapy of type 2 diabetes mellitus: systematic review and meta-analysis. Int J Clin Pract. 2015; 69:292–304.
12. Seong JM, Choi NK, Shin JY, Chang Y, Kim YJ, Lee J, Kim JY, Park BJ. Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study. PLoS One. 2015; 10:e0124287.
13. Storgaard H, Gluud LL, Bennett C, Grondahl MF, Christensen MB, Knop FK, Vilsboll T. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2016; 11:e0166125.
14. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013; 382:941–950.
15. Nauck MA, Del Prato S, Meier JJ, Duran-Garcia S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011; 34:2015–2022.
16. Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014; 2:691–700.
17. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016; 18:783–794.
18. Yoon KH, Nishimura R, Lee J, Crowe S, Salsali A, Hach T, Woerle HJ. Efficacy and safety of empagliflozin in patients with type 2 diabetes from Asian countries: pooled data from four phase III trials. Diabetes Obes Metab. 2016; 18:1045–1049.
19. Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ. EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014; 37:1650–1659.
20. Min KW, Ku BJ, Lee JH, Kim MS, Ahn KJ, Lee MK, Kokubo S, Yoshida S, Cho HJ, Cha BS. Addition of ipragliflozin to metformin treatment in Korean patients with type 2 diabetes mellitus: subgroup analysis of a phase 3 trial. Diabetes Metab J. 2017; 41:135–145.
21. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, Meininger G. 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; 56:2582–2592.
22. Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, Capuano G, Canovatchel W. Canagliflozin DIA 2001 Study Group. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012; 35:1232–1238.
23. Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, Iqbal N. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized doubleblind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015; 38:376–383.
24. DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015; 38:384–393.
25. 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; 369:1317–1326.
26. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013; 369:1327–1335.
27. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR. TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 373:232–242.
28. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128.
29. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; 375:323–334.
30. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–657.
31. Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013; 56:696–708.
32. Hong AR, Lee J, Ku EJ, Hwangbo Y, Kim KM, Moon JH, Choi SH, Jang HC, Lim S. Comparison of vildagliptin as an add-on therapy and sulfonylurea dose-increasing therapy in patients with inadequately controlled type 2 diabetes using metformin and sulfonylurea (VISUAL study): A randomized trial. Diabetes Res Clin Pract. 2015; 109:141–148.
33. Jin SM, Park SW, Yoon KH, Min KW, Song KH, Park KS, Park JY, Park IB, Chung CH, Baik SH, Choi SH, Lee HW, Lee IK, Kim DM, Lee MK. Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes Metab. 2015; 17:511–515.
34. Kim MK, Rhee EJ, Han KA, Woo AC, Lee MK, Ku BJ, Chung CH, Kim KA, Lee HW, Park IB, Park JY, Chul Jang HC, Park KS, Jang WI, Cha BY. Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled phase III trial. Diabetes Obes Metab. 2015; 17:309–312.
35. Kim JH, Kim SS, Baek HS, Lee IK, Chung DJ, Sohn HS, Bae HY, Kim MK, Park JH, Choi YS, Kim YI, Hahm JR, Lee CW, Jo SR, Park MK, Lee KJ, Kim IJ. Comparison of vildagliptin and pioglitazone in Korean patients with type 2 diabetes inadequately controlled with metformin. Diabetes Metab J. 2016; 40:230–239.
36. Jin SM, Park CY, Cho YM, Ku BJ, Ahn CW, Cha BS, Min KW, Sung YA, Baik SH, Lee KW, Yoon KH, Lee MK, Park SW. Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes Metab. 2015; 17:599–602.
37. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005; 366:1279–1289.
38. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G. ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355:2427–2443.
39. 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; 60:1552–1560.
40. Mamza J, Mehta R, Donnelly R, Idris I. Important differences in the durability of glycaemic response among second-line treatment options when added to metformin in type 2 diabetes: a retrospective cohort study. Ann Med. 2016; 48:224–234.
41. Downes MJ, Bettington EK, Gunton JE, Turkstra E. Triple therapy in type 2 diabetes: a systematic review and network meta-analysis. PeerJ. 2015; 3:e1461.
42. Lee CM, Woodward M, Colagiuri S. Triple therapy combinations for the treatment of type 2 diabetes: a network meta-analysis. Diabetes Res Clin Pract. 2016; 116:149–158.
43. Lozano-Ortega G, Goring S, Bennett HA, Bergenheim K, Sternhufvud C, Mukherjee J. Network meta-analysis of treatments for type 2 diabetes mellitus following failure with metformin plus sulfonylurea. Curr Med Res Opin. 2016; 32:807–816.
44. Mearns ES, Saulsberry WJ, White CM, Kohn CG, Lemieux S, Sihabout A, Salamucha I, Coleman CI. Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in type 2 diabetes: a network metaanalysis. Diabet Med. 2015; 32:1530–1540.
45. Ahn CH, Han KA, Yu JM, Nam JY, Ahn KJ, Oh TK, Lee HW, Lee DH, Kim J, Chung CH, Park TS, Kim BJ, Park SW, Park HK, Lee KJ, Kim SW, Park JH, Ko KP, Kim CH, Lee H, Jang HC, Park KS. Efficacy and safety of gemigliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus inadequately controlled with combination treatment of metformin and sulphonylurea: a 24-week, multicentre, randomized, double-blind, placebo-controlled study (TROICA study). Diabetes Obes Metab. 2017; 19:635–643.
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