Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus

Postgraduate Medicine

Volumn 127, Issue 5, 2015, Pages 463-479

  Guthrie, Robert M ^a  

^a OHIO STATE UNIVERSITY   (United States)

Author keywords

Combination therapy; Dipeptidyl peptidase 4 inhibitor; Metformin; Sodium glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EMPAGLIFLOZIN; GASTRIC INHIBITORY POLYPEPTIDE; GLIBENCLAMIDE; GLIPIZIDE; GLUCAGON LIKE PEPTIDE 1; HEMOGLOBIN A1C; INCRETIN; LINAGLIPTIN; METFORMIN; PIOGLITAZONE; ROSIGLITAZONE; SAXAGLIPTIN; SITAGLIPTIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; ANTIDIABETIC AGENT; SODIUM GLUCOSE COTRANSPORTER 2;

CELL PROLIFERATION; GLYCEMIC CONTROL; HUMAN; HYPOGLYCEMIA; INSULIN RELEASE; INSULIN RESISTANCE; NON INSULIN DEPENDENT DIABETES MELLITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STOMACH EMPTYING; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; ANTAGONISTS AND INHIBITORS; COMBINATION DRUG THERAPY; DIABETES MELLITUS, TYPE 2; DRUG COMBINATION;

DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG THERAPY, COMBINATION; HUMANS; HYPOGLYCEMIC AGENTS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 84964058550     PISSN: 00325481     EISSN: 19419260     Source Type: Journal    
DOI: 10.1080/00325481.2015.1044756     Document Type: Review

References (104)

1. American Diabetes Association. Fast facts: data and statistics about diabetes. Available from http://professional.diabetes.org/admin/UserFiles/0%20-%20Sean/14_fast_facts.pdf. Last accessed 16 March 2015.
2. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773–95.
3. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States. 2014. Available from http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Last accessed 16 March 2015.
4. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care 2015;38:S1–94.
5. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement–executive summary. Endocr Pract 2013;19:536–57.
6. Glucophage_(metformin). Full Prescribing Information, Bristol-Myers Squibb Company. Princeton, NJ: 2009.
7. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:541–9.
8. Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus. Pharmacotherapy 2010;30:463–84.
9. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929–40.
10. Wilding JP, Hardy K. Glucagon-like peptide-1 analogues for type 2 diabetes. BMJ 2011;342:d410.
11. Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T, Knop FK. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 2013;56:965–72.
12. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86:3717–23.
13. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on betacell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003;52:380–6.
14. Nisal K, Kela R, Khunti K, Davies MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Med 2012;10:152.
15. Mathieu C. The scientific evidence: vildagliptin and the benefits of islet enhancement. Diabetes Obes Metab 2009;11:9–17.
16. Poucher SM, Cheetham S, Francis J, Zinker B, Kirby M, Vickers SP. Effects of saxagliptin and sitagliptin on glycaemic control and pancreatic beta-cell mass in a streptozotocin-induced mouse model of type 2 diabetes. Diabetes Obes Metab 2012;14:918–26.
17. Craddy P, Palin HJ, Johnson KI. Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther 2014;5:1–41.
18. Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther 2014;8:1335–80.
19. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427–34.
20. Kasichayanula S, Chang M, Hasegawa M, Liu X, Yamahira N, LaCreta FP, et al. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose cotransporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes Metab 2011;13:357–65.
21. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. 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;33:2217–24.
22. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract 2009;63:46–55.
23. Del Prato S, Camisasca R, Wilson C, Fleck P. Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study. Diabetes Obes Metab 2014;16:1239–46.
24. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q; Alogliptin Study 007 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab 2009;11:167–76.
25. Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naive patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes Metab 2014;16:613–21.
26. Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes Care 2010;33:2406–8.
27. DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab 2012;97:1615–22.
28. Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52- week, randomized, double-blind, active-controlled, parallelgroup study. Diabetes Obes Metab 2011;13:1088–96.
29. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1C without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab 2009;11:1145–52.
30. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebocontrolled study. Curr Med Res Opin 2009;25:2361–71.
31. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2012;14:565–74.
32. Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo controlled study. Diabetes Obes Metab 2011;13:653–61.
33. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, Woerle HJ. Safety and efficacy of linagliptin as addon therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:65–74.
34. Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 2012;380:475–83.
35. Bajaj M, Gilman R, Patel S, Kempthorne-Rawson J, Lewis-D’Agostino D, Woerle HJ. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, doubleblind study. Diabet Med 2014;31:1505–14.
36. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011;28:1352–61.
37. Yki-Jarvinen H, Rosenstock J, Duran-Garcia S, Pinnetti S, Bhattacharya S, Thiemann S, et al. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a ‡52-week randomized, double-blind study. Diabetes Care 2013;36:3875–81.
38. Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013;382:1413–23.
39. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32:1649–55.
40. Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R; CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab 2009;11:611–22.
41. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract 2011;94:217–24.
42. Goke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I; D1680C00001 Investigators. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract 2010;64:1619–31.
43. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R; CV181-040 Investigators. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract 2009;63:1395–406.
44. Hollander P, Li J, Allen E, Chen R; CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009;94:4810–9.
45. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin 2012;28:513–23.
46. Moses RG, Kalra S, Brook D, Sockler J, Monyak J, Visvanathan J, et al. A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab 2014;16:443–50.
47. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638–43.
48. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979–87.
49. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194–205.
50. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. 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 Ther 2006;28:1556–68.
51. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:733–45.
52. Vilsboll T, Rosenstock J, Yki-Jarvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010;12:167–77.
53. Fonseca V, Staels B, Morgan JD 2nd, Shentu Y, Golm GT, Johnson-Levonas AO, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications 2013;27:177–83.
54. Onglyza_(saxagliptin). Full Prescribing Information, Bristol- Myers Squibb and AstraZeneca Pharmaceuticals LP. Princeton, NJ, and Wilmington, DE: 2014.
55. Januvia_(sitagliptin). Full Prescribing Information, Merck. Whitehouse Station, NJ: 2015.
56. Tradjenta_(linagliptin). Full Prescribing Information, Boehringer Ingelheim. Ridgefield, CT: 2014.
57. Nesina_(alogliptin). Full Prescribing Information. Takeda Pharmaceuticals America, Inc; Deerfield, IL: 2013.
58. 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;56:2582–92.
59. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. 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;382:941–50.
60. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 2013;36:2508–15.
61. Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 2013;67:1267–82.
62. Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, Stein P. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014;16:467–77.
63. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995) 2013;41:72–84.
64. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463–73.
65. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, doubleblind, placebo-controlled trial. Lancet 2010;375:2223–33.
66. Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 2012;66:446–56.
67. Nauck MA, Del Prato S, Meier JJ, Durán-García 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;34:2015–22.
68. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012;35:1473–8.
69. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928–38.
70. 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 double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2015;38:376–83.
71. Jabbour SA, Hardy E, Sugg J, Parikh S; Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, doubleblind, placebo-controlled study. Diabetes Care 2014;37:740–50.
72. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, 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;156:405–15.
73. Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S; Study 05 Group. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 2015;38:365–72.
74. Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebocontrolled study with a 28-week extension. J Am Geriatr Soc 2014;62:1252–62.
75. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962–71.
76. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014;37:1650–9.
77. 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, activecontrolled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2014;2:691–700.
78. Lewin A, DeFronzo R, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care 2015;38:394–402.
79. Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2013;36:3396–404.
80. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16:147–58.
81. 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;38:384–93.
82. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014;2:369–84.
83. Farxiga_(dapagliflozin). Full Prescribing Information, Bristol- Myers Squibb and AstraZeneca. Princeton, NJ, and Wilmington, DE: 2015.
84. Jardiance: (empagliflozin). Full Prescribing Information, Boehringer Ingelheim Pharmaceuticals and Eli Lilly and Company. Ingelheim, Germany, and Indianapolis, IN: 2014.
85. Invokana_(canagliflozin). Full Prescribing Information. Janssen Pharmaceuticals; Titusville, NJ: 2015.
86. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from http://clinicaltrials.gov/ct2/show/NCT01730534? term=declare&rank=2. Last accessed 16 March 2015.
87. Fujita Y, Inagaki N. Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: clinical data and mechanism of action. J Diabetes Investig 2014;5:265–75.
88. Liu X, Xiao Q, Zhang L, Yang Q, Liu X, Xu L, Cheng W. The long-term efficacy and safety of DPP-IV inhibitors monotherapy and in combination with metformin in 18 980 patients with type-2 diabetes mellitus-a meta-analysis. Pharmacoepidemiol Drug Saf 2014;23:687–98.
89. Leiter LA, Yoon KH, Arias P, Langslet G, Xie J, Balis DA, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 2015;38:355–64.
90. Goke B, Gallwitz B, Eriksson JG, Hellqvist A, Gause-Nilsson I. Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term (52-week) extension of a 52-week randomised controlled trial. Int J Clin Pract 2013;67:307–16.
91. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin- 4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27:2628–35.
92. Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2005;27:1535–47.
93. Pi-Sunyer FX. The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. Postgrad Med 2009;121:94–107.
94. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509–14.
95. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508.
96. Hansen L, Iqbal N, Ekholm E, Cook W, Hirshberg B. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract 2014;20:1187–97.
97. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26.
98. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35.
99. Zannad F, Cannon C, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015. [Epub ahead of print].
100. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, 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;38:140–9.
101. Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013;10:289–301.
102. Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013;166:983–989 e7.
103. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus high vascular risk (CARMELINA). US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1, Last accessed 16 March 2015.
104. Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes 2011;60:890–8.