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OBJECTIVEWe investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSPatients inadequately controlled on MDI insulin 6 metformin (mean HbA 1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m 2 ; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1-18, adjusted to meet glucose targets in weeks 19-40, then stable in weeks 41-52. The primary end point was change from baseline in HbA 1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA 1c at week 52. RESULTSAdjusted mean 6 SE changes from baseline in HbA 1c were 20.50 6 0.05% (25.5 6 0.5 mmol/mol) for placebo versus 20.94 6 0.05% (210.3 6 0.5 mmol/mol) and 21.02 6 0.05% (211.1 6 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA 1c of 20.81 6 0.08% (28.9 6 0.9 mmol/mol), 21.18 6 0.08% (212.9 6 0.9 mmol/mol), and 21.27 6 0.08% (213.9 6 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA 1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA 1c <7% (<53 mmol/mol) with empagliflozin (31-42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (29 to 211 international units/day) and weight (22.4 to 22.5 kg) versus placebo (all P < 0.01) at week 52. CONCLUSIONSIn obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.

BackgroundTo investigate the long-term efficacy and safety of empagliflozin monotherapy compared with placebo and sitagliptin in drug-naïve patients with type 2 diabetes mellitus.MethodsOf 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.ResultsCompared 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.ConclusionsEmpagliflozin monotherapy for ≥76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo.Trial registration: clinicaltrials.gov NCT01289990Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0314-0) contains supplementary material, which is available to authorized users.

In this predefined analysis that was based on >9000 patient-years' exposure to empagliflozin, empagliflozin 10 mg, and empagliflozin 25 mg were well tolerated in patients with T2DM.