Skip to main content

05-25-2018 | Oral combination medications | Article

Characterization of the Open-Label Lead-In Period of Two Randomized Controlled Phase 3 Trials Evaluating Dapagliflozin, Saxagliptin, and Metformin in Type 2 Diabetes

Journal: Diabetes Therapy

Authors: Chantal Mathieu, Doina Catrinoiu, Aurelian Emil Ranetti, Eva Johnsson, Lars Hansen, Hungta Chen, Ricardo Garcia-Sanchez, Nayyar Iqbal, Aleksander Celiñski

Publisher: Springer Healthcare



To examine the utility of sequential versus dual add-on approaches in patients who have type 2 diabetes and inadequate glycemic control with metformin therapy alone, we characterized the efficacy and safety of dual therapy with dapagliflozin or saxagliptin added to metformin in the open-label lead-in periods of two phase 3 trials (study 1, NCT01619059; study 2, NCT01646320) that evaluated triple therapy in patients with inadequately controlled type 2 diabetes.


During the lead-in periods of each trial, patients [glycated hemoglobin (HbA1c) 8.0–11.5%] who had been receiving metformin ≥ 1500 mg/day for ≥ 8 weeks received metformin immediate release at an equivalent dose plus dapagliflozin 10 mg/day (study 1; N = 482) or saxagliptin 5 mg/day (study 2; N = 349) for 16 weeks. Efficacy end points were assessed at week − 2 before randomization.


Mean change in HbA1c [95% confidence interval (CI)] from lead-in baseline (study 1, 9.3%; study 2, 9.4%) was − 1.6% (− 1.7, − 1.5) in study 1 and − 1.3% (− 1.5, − 1.2) in study 2. Mean changes (95% CI) from lead-in baseline in weight and fasting plasma glucose were − 2.4 kg (− 2.6, − 2.1) and − 47.5 mg/dL (− 52.8, − 42.3) for study 1 and − 0.5 kg (− 0.8, − 0.2) and − 28.5 mg/dL (− 35.8, − 21.2) for study 2. At the end of the lead-in period, 22.0% of patients achieved HbA1c < 7.0% in study 1 and 17.5% in study 2. Dual therapy was well tolerated, with hypoglycemia incidence < 1% in both studies.


Dual therapy improved glycemic control and was well tolerated; however, most patients required additional therapy to further improve HbA1c towards target, suggesting that an early move to triple therapy with oral glucose-lowering drugs rather than a stepwise approach may be beneficial for patients with high HbA1c levels on metformin therapy.

Trial Registration NCT01619059, NCT01646320.


Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care. 2009;32(Suppl 2):S151–6.CrossRefPubMedPubMedCentral
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429–42.CrossRefPubMed
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22:84–113.CrossRefPubMed
American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care. 2017;40(Suppl 1):S1–132.
Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36:3411–7.CrossRefPubMedPubMedCentral
Godinho R, Mega C, Teixeira-de-Lemos E, et al. The place of dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapeutics: a “me too” or “the special one” antidiabetic class? J Diabetes Res. 2015;2015:806979.CrossRefPubMedPubMedCentral
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;38:376–83.CrossRefPubMed
Matthaei S, Catrinoiu D, Celinski A, et al. Randomized, double-blind trial of triple therapy with saxagliptin add-on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38:2018–24.CrossRefPubMed
Mathieu C, Ranetti AE, Li D, et al. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38:2009–17.CrossRefPubMed
Matthaei S, Aggarwal N, Garcia-Hernandez P, et al. One-year efficacy and safety of saxagliptin add-on in patients receiving dapagliflozin and metformin. Diabetes Obes Metab. 2016;18:1128–33.CrossRefPubMed
Mathieu C, Herrera Marmolejo M, Gonzalez Gonzalez JG, et al. Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:1134–7.CrossRefPubMed
Carls GS, Tuttle E, Tan RD, et al. Differences in T2DM therapy outcomes in trials vs. the real-world (RW): identifying the impact of poor adherence. 2016; Abstract 117-LB presented at the American Diabetes Association 76th Scientific Sessions, June 10–14, 2016, New Orleans, LA. http://​app.​core-apps.​com/​tristar_​ada16/​abstract/​e44e3c20f4b9cf62​bd1796c12c16ec46​. Accessed 29 Nov 2017.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:479–84.CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »