Accepted Article

Efficacy and safety of empagliflozin twice daily compared with once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial

S. Ross1, C. Thamer2, J. Cescutti3, T. Meinicke2, H.J. Woerle4 and U.C. Broedl4

1

LMC Endocrinology Centres, Calgary, Alberta, Canada

2

Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

3

Boehringer Ingelheim France S.A.S., Reims, France

4

Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Corresponding author: Dr Stuart Ross, LMC Endocrinology Centres, 102-5940 Macleod Trail SW, Calgary, Alberta, Canada

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12469

Accepted Article

Requirements for research letter: Maximum 1200 words excluding abstract and references (currently 1200 words, not including Acknowledgments) Maximum two figures or tables (currently one figure and one table) Abstract: 150 words, non-structured; currently 150 words References: maximum 12; currently 9

Abstract Patients with T2DM with HbA1c ≥7% and ≤10% were randomized to receive empagliflozin 12.5 mg twice daily (bid) (n=219), 25 mg once daily (qd) (n=218), 5 mg bid (n=219) or 10 mg qd (n=220), or placebo (n=107) as add-on to stable dose metformin immediate release (IR) bid for 16 weeks. The primary endpoint was change from baseline in HbA1c at week 16. At week 16, change from baseline in HbA1c with empagliflozin bid was non-inferior to empagliflozin qd and vice versa. Adjusted mean (95% CI) difference in change from baseline in HbA1c with empagliflozin 12.5 mg bid versus 25 mg qd was -0.11% (-0.26, 0.03), and with empagliflozin 5 mg bid versus 10 mg qd was -0.02% (-0.16, 0.13). All empagliflozin regimens were well tolerated. Thus when used as add-on to metformin IR in patients with T2DM, the therapeutic effect of empagliflozin bid and qd regimens can be considered equivalent. Keywords: empagliflozin, glycaemic control, metformin, once daily, twice daily

Accepted Article

Introduction Metformin is the recommended first-line pharmacological treatment for patients with type 2 diabetes (T2DM) [1]. However, as T2DM progresses, addition of a second agent is often required to maintain glycemic control [1-3]. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption and so increases glucosuria, reducing hyperglycemia in patients with T2DM [4]. Metformin reduces blood glucose principally by reducing hepatic gluconeogenesis [5]. These complementary mechanisms of action, and the benefits seen when empagliflozin is added to metformin in patients with T2DM [6-8] suggest that a fixed dose combination (FDC) of empagliflozin and metformin may offer additional glucose control and weight loss, with a low risk of hypoglycemia. As metformin immediate release (IR) is administered twice daily (bid), an FDC of empagliflozin and metformin IR would require bid administration of empagliflozin. In healthy volunteers, no relevant pharmacokinetic or pharmacodynamic differences are observed between bid and qd empagliflozin regimens [9]. Methods This study compared the efficacy and safety of bid regimens of empagliflozin 25 mg and 10 mg with qd regimens as add-on to metformin IR bid in patients with T2DM. Adults with T2DM with BMI ≤45 kg/m2 and HbA1c ≥7% and ≤10% at screening despite a diet and exercise regimen and treatment with a stable dose of metformin IR (≥1500 mg/day) for ≥12 weeks prior to randomization were eligible to participate. Key exclusion criteria are provided in the Supplementary Appendix. Following a 2-week placebo run-in, patients were randomized 2:2:2:2:1 to receive empagliflozin 12.5 mg bid, 25 mg qd, 5 mg bid, 10 mg qd, or placebo for 16 weeks. Randomization was stratified by region (Europe, North America, Latin America) and by HbA1c (13.3 mmol/l, confirmed by a measurement on a different day. Use of other SGLT2 inhibitors or increasing the dose of metformin was not permitted. The study was registered with the EU Clinical Trials Register (eudract number 2012000905-53), carried out in compliance with the principles of the Declaration of Helsinki, in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice, and approved by relevant Institutional Review Boards and Independent Ethics Committees. The primary endpoint was change from baseline in HbA1c at week 16. The secondary endpoint was change from baseline in FPG at week 16. Exploratory endpoints included the proportion of patients with HbA1c ≥7% at baseline who had HbA1c

Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial.

Patients with type 2 diabetes mellitus (T2DM) with a glycated haemoglobin (HbA1c) level ≥7 and ≤10% were randomized to receive empagliflozin 12.5 mg t...
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