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.

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.

Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes.

This study investigated the long-term efficacy and safety of empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes mellitus (T2DM). Of 666 patients treated with empagliflozin 10 mg, empagliflozin 25 mg or placebo once daily for 24 weeks, 472 patients (70.9%) were treated in a double-blind extension trial for ≥52 weeks. Pre-specified exploratory endpoints included changes from baseline in HbA(1c), weight and blood pressure at week 76. At week 76, adjusted mean differences versus placebo in change from baseline in HbA(1c) were -0.7% (-8 mmol/mol) with empagliflozin 10 mg or 25 mg (both p<0.001), in weight were -1.8 kg and -1.6 kg with empagliflozin 10 mg and 25 mg, respectively (both p<0.001), and in systolic blood pressure (SBP) were -2.2 mmHg with empagliflozin 10 mg (p=0.021) and -2.1 mmHg with empagliflozin 25 mg (p=0.029). Sensitivity analyses provided consistent results for HbA1c and weight, but showed no significant difference between empagliflozin and placebo in change from baseline in SBP. Adverse events (AEs) were reported in 81.7%, 82.0% and 81.3% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in 23.7%, 19.4% and 15.6% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively; one patient each on empagliflozin 10mg and placebo required assistance. In conclusion, empagliflozin as add-on to metformin plus sulphonylurea for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight versus placebo. CLINICALTRIALS.GOV: NCT01289990.

Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus.

PURPOSE: To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. METHODS: Of 498 patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks in the EMPA-REG PIO™ study, 305 (61.2%) were treated in a double-blind extension trial for ≥52 weeks (total duration ≥76 weeks). Exploratory end points at week 76 included changes from baseline in glycosylated hemoglobin (HbA1c), weight, and blood pressure assessed using ANCOVA in patients who received ≥1 dose of study drug and had a baseline HbA1c measurement in the initial study. FINDINGS: Compared with placebo, adjusted mean (95% CI) changes from baseline in HbA1c level at week 76 were -0.59% (-0.79% to -0.40%; P < 0.001) for empagliflozin 10 mg (-6.5 [-8.6 to -4.4] mmol/mol) and -0.69% (-0.88% to -0.50%; P < 0.001) for empagliflozin 25 mg (-7.5 [-9.6 to -5.4] mmol/mol). Compared with placebo, adjusted mean (95% CI) changes from baseline in weight at week 76 were -2.0 kg (-2.7 to -1.2 kg; P < 0.001) and -1.7 kg (-2.4 -1.0 kg; P < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, only empagliflozin 25 mg led to significant reductions in systolic blood pressure (adjusted mean [95% CI] change: -3.7 mmHg [-6.1 to -1.3 mmHg]; P = 0.003) and diastolic blood pressure (adjusted mean [95% CI] change: -2.2 mmHg [-3.7 to -0.7 mmHg]; P = 0.004). Sensitivity analyses were consistent with these results for HbA1c level, fasting plasma glucose concentration, and weight, but revealed no significant difference between empagliflozin and placebo in change from baseline in systolic or diastolic blood pressure at week 76. Confirmed hypoglycemic adverse events (glucose ≤3.9 mmol/L and/or requiring assistance) were reported in 4.2%, 1.8%, and 3.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively; 1 patient each taking placebo and empagliflozin 25 mg required assistance. Adverse events consistent with urinary tract infection were reported in 26.7%, 22.4%, and 22.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Adverse events consistent with genital infection were reported in 3.0%, 10.3%, and 4.2% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. IMPLICATIONS: Empagliflozin 10 mg or 25 mg as add-on therapy to pioglitazone with or without metformin for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo in patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01210001.

Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.

BACKGROUND: Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. METHODS AND RESULTS: In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79). CONCLUSION: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.