Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study

Abstract

Introduction: Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by inducing urinary glucose excretion. Combination therapy with empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonists had not previously been assessed, so we investigated the safety, tolerability and efficacy of empagliflozin as an add-on therapy to liraglutide, a GLP-1 receptor agonist.

Methods: This was a randomised, double-blind, parallel-group phase 4 trial of empagliflozin (10 mg or 25 mg) for 52 weeks as an add-on therapy to liraglutide (0.9 mg/day) in Japanese patients with T2DM insufficiently controlled by liraglutide alone.

Results: 59.4% (19/32) and 66.7% (22/33) of patients in the empagliflozin 10 mg and 25 mg groups, respectively, reported at least one adverse event (AE). 9.4% (3/32) and 21.2% (7/33) of patients, respectively, reported drug-related AEs (primary endpoint). From baseline to week 52, adjusted mean changes with empagliflozin 10 mg and 25 mg, respectively, were: - 0.55 (standard error: 0.15) and - 0.77 (0.14)% for glycated haemoglobin; - 32.5 (4.6) and - 36.0 (4.5) mg/dL for fasting plasma glucose; - 2.6 (0.4) and -3.1 (0.3) kg for body weight; - 6.7 (2.2) and - 8.4 (2.1) mmHg for systolic blood pressure; and - 3.0 (1.2) and - 4.7 (1.1) mmHg for diastolic blood pressure.

Conclusion: Empagliflozin as an add-on to liraglutide for 52 weeks was well tolerated and led to clinically meaningful and sustained improvements in glycaemic control, body weight and blood pressure in Japanese patients with T2DM.

Trial registration: ClinicalTrials.gov with the identifier NCT02589626.

Funding: Nippon Boehringer Ingelheim Co. Ltd.

Keywords: Add-on therapy; Empagliflozin; GLP-1 receptor agonist; Liraglutide; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes.

Figures

Fig. 1

Study design. OAD oral antidiabetic drug, R randomisation

Fig. 2

Patient disposition

Fig. 3

Changes from baseline to week 52 in a HbA1c, b FPG, c body weight, d SBP and e DBP. Data are shown as the mean ± standard error (SE). For HbA1c, the model includes baseline HbA1c as a linear covariate and baseline eGFR, treatment, visit, visit by treatment interaction and baseline HbA1c by visit interaction as fixed effects. A similar model was used for FPG, body weight, SBP and DBP. The model included baseline value for the corresponding endpoint and its interaction with visit as additional covariates. DBP diastolic blood pressure, FPG fasting plasma glucose, HbA1c glycated haemoglobin, SBP systolic blood pressure