Randomized, Double-Blind, phase 3 trial of triple therapy with dapagliflozin Add-on to saxagliptin plus metformin in type 2 diabetes

Diabetes Care

Volumn 38, Issue 11, 2015, Pages 2009-2017

  Mathieu, Chantal ^a   Ranetti, Aurelian Emil ^b   Li, Danshi ^c   Ekholm, Ella ^d   Cook, William ^e   Hirshberg, Boaz ^f   Chen, Hungta ^e   Hansen, Lars ^c   Iqbal, Nayyar ^c  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY   (Romania)

^c BRISTOL MYERS SQUIBB   (United States)

^d ASTRAZENECA R AND D   (Sweden)

^e ASTRAZENECA   (United Kingdom)

^f MEDIMMUNE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCOSE; HEMOGLOBIN A1C; METFORMIN PLUS SAXAGLIPTIN; PLACEBO; 2-(3-(4-ETHOXYBENZYL)-4-CHLOROPHENYL)-6-HYDROXYMETHYLTETRAHYDRO-2H-PYRAN-3,4,5-TRIOL; ADAMANTANE; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; DIPEPTIDE; GLUCOSE BLOOD LEVEL; GLUCOSIDE; METFORMIN; SAXAGLIPTIN;

ADD ON THERAPY; ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BODY WEIGHT; BREAST CANCER; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; DRUG WITHDRAWAL; FEMALE; GENITAL TRACT INFECTION; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HEADACHE; HEART FAILURE; HEART VENTRICLE TACHYCARDIA; HEMOGLOBIN BLOOD LEVEL; HUMAN; INFLUENZA; KIDNEY FAILURE; MAJOR CLINICAL STUDY; MALE; MIDDLE AGED; MULTICENTER STUDY; NON INSULIN DEPENDENT DIABETES MELLITUS; OPEN STUDY; OUTCOME ASSESSMENT; PHASE 3 CLINICAL TRIAL; POLLAKISURIA; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; THROMBOCYTOPENIA; URINARY TRACT INFECTION; VAGINITIS; AGED; ANALOGS AND DERIVATIVES; CHEMICALLY INDUCED; CLINICAL TRIAL; COMBINATION DRUG THERAPY; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; HYPOGLYCEMIA; METABOLISM; PROCEDURES; TREATMENT OUTCOME; URINARY TRACT INFECTIONS;

ADAMANTANE; ADULT; AGED; BENZHYDRYL COMPOUNDS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FEMALE; GLUCOSIDES; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; MALE; METFORMIN; MIDDLE AGED; TREATMENT OUTCOME; URINARY TRACT INFECTIONS;

EID: 84958650333     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc15-0779     Document Type: Article

References (45)

1. De Fronzo RA. Banting lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-795.
2. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412.
3. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care 2009;32(Suppl. 2):S151-S156.
4. Kahn SE, Haffner SM, Heise MA, et al.; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443.
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose controlwith sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
6. Garber AJ, Abrahamson MJ, Barzilay JI, et al.; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013;19:327-336.
7. American Diabetes Association. Approaches to glycemic treatment. Diabetes Care 2015;38 (Suppl. 1):S41-S48.
8. Cheng AY; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction. Can J Diabetes 2013;37(Suppl. 1):S1-S3.
9. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-165.
10. Jabbour SA. SGLT2 inhibitors to control glycemia in type 2 diabetes mellitus: A new approach to an old problem. Postgrad Med 2014; 126:111-117.
11. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 2013;36:3169-3176.
12. Bailey CJ, Morales Villegas EC, Woo V, Tang W, Ptaszynska A, List JF. Efficacy and safety of dapagliflozin monotherapy in people with type 2 diabetes: A randomized double-blind placebocontrolled 102-week trial. Diabet Med 2015;32: 531-541.
13. DeFronzo RA, Hissa MN, Garber AJ, et al.; Saxagliptin 014 Study Group. 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;32:1649-1655.
14. 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;33:2217-2224.
15. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-näive patients with type 2 diabetes. Curr Med Res Opin 2009;25:2401-2411.
16. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment- näive patients with type 2 diabetes mellitus: A randomized controlled trial. Diabetol Metab Syndr 2012;4:36.
17. 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, double-blind, placebo-controlled trial. Lancet 2010;375: 2223-2233.
18. Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment comparisons in randomized clinical trials: A principled yet flexible approach. Stat Med 2008;27: 4658-4677.
19. Zhang M, Tsiatis AA, Davidian M. Improving efficiency of inferences in randomized clinical trials using auxiliary covariates. Biometrics 2008;64:707-715.
20. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369.
21. Leibowitz G, Cahn A, Bhatt DL, et al. Impact of treatment with saxagliptin on glycaemic stability and b-cell function in the SAVOR-TIMI 53 study. Diabetes Obes Metab 2015;17:487-494.
22. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8:495-502.
23. 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;37:740-750.
24. 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, doubleblind clinical trial. Diabetes Care 2015;38: 365-372.
25. 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;20:1187-1197.
26. Rosenstock J, Hansen L, Zee P, et al. 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;38:376-383.
27. Rosenstock J, Vico M, Wei L, Salsali A, List JF. 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;35:1473-1478.
28. 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- 1406.
29. 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;94:4810-4819.
30. 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, placebocontrolled trial. Diabetes Obes Metab 2011;13: 928-938.
31. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602-613.
32. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508.
33. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509-514.
34. 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;9:733-745.
35. Lukashevich V, Del Prato S, Araga M, Kothny W. Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes Obes Metab 2014;16: 403-409.
36. Moses RG, Kalra S, Brook D, 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;16:443-450.
37. 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; 28:1352-1361.
38. Häring HU, Merker L, Seewaldt-Becker E, et al.; EMPA-REG METSU Trial Investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebocontrolled trial. Diabetes Care 2013;36:3396- 3404.
39. Wilding JP, Charpentier G, Hollander P, 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;67:1267-1282.
40. Schernthaner G, Gross JL, Rosenstock 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: 2508-2515.
41. Fonseca V, Staels B, Morgan JD 2nd, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebocontrolled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications 2013;27:177-183.
42. 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, double-blind study. Diabet Med 2014;31:1505-1514.
43. 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;97:1615-1622.
44. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014;16:467-477.
45. Kovacs CS, Seshiah V, Swallow R, et al.; EMPA-REG PIO Trial Investigators. Empagliflozin improves glycaemic and weight control as addon therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16:147-158.