Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks.

Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813.

Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious).

Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment.

Funding: Boehringer Ingelheim and Eli Lilly.