Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial

Abstract

Background: To investigate the long-term efficacy and safety of empagliflozin monotherapy compared with placebo and sitagliptin in drug-naïve patients with type 2 diabetes mellitus.

Methods: Of 899 patients randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, placebo, or sitagliptin 100 mg once daily for 24 weeks, 615 continued in a double-blind extension trial for ≥52 weeks. Exploratory endpoints included changes from baseline in HbA1c, weight and blood pressure at week 76.

Results: Compared with placebo, adjusted mean changes from baseline in HbA1c at week 76 were -0.78 % (95 % CI -0.94, -0.63; p < 0.001) and -0.89 % (95 % CI -1.04, -0.73; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, adjusted mean changes from baseline in weight at week 76 were -1.8 kg (95 % CI -2.4, -1.3; p < 0.001) and -2.0 kg (95 % CI -2.6, -1.5; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Empagliflozin led to reductions in systolic blood pressure (SBP) compared with placebo in the primary analysis but not in sensitivity analyses. Compared with sitagliptin, empagliflozin 25 mg reduced HbA1c and both empagliflozin doses reduced weight and SBP. Adverse events (AEs) were reported in 76.8, 78.0, 76.4 and 72.2 % of patients on empagliflozin 10 mg, empagliflozin 25 mg, placebo and sitagliptin, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in two patients (0.9 %) per treatment group.

Conclusions: Empagliflozin monotherapy for ≥76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo.

Trial registration: clinicaltrials.gov NCT01289990.

Fig. 1

Study flow

Fig. 2

Glycaemic control a HbA1c over time [mixed model repeated measures (MMRM) in the full analysis set (FAS), observed cases (OC)]. b Patients with HbA1c ≥7 % at baseline who had HbA1c <7 % at week 76 (logistic regression in patients from the FAS treated in the extension trial using non-completers considered failures approach). c Change from baseline in FPG over time (MMRM in the FAS, OC). Empagliflozin 10 mg versus placebo odds ratio 4.17 (95 % CI 2.31, 7.51); empagliflozin 25 mg versus placebo odds ratio 3.96 (95 % CI 2.20, 7.14); sitagliptin versus placebo odds ratio 2.42 (95 % CI 1.32, 4.43). Empagliflozin 10 mg versus sitagliptin odds ratio 1.72 (95 % CI 1.04, 2.86); empagliflozin 25 mg versus sitagliptin odds ratio 1.64 (95 % CI 0.99, 2.72)

Fig. 3

Body weight Change from baseline in body weight over time [mixed model repeated measures (MMRM) in the full analysis set (FAS), observed cases (OC)]