Empagliflozin, 10 or 25 mg, used as an add-on to metformin therapy for ≥ 76 weeks among patients with type 2 diabetes mellitus (T2DM) produces significant and sustained decreases in glycated hemoglobin (HbA_1c), body weight, and systolic blood pressure (SBP), compared with placebo. The results of the extension portion of a randomized Phase 3 trial involving 637 patients were reported by Ludwig Merker, MD, Diabetes- und Nierenzentrum, Dormagen, Germany.

Empagliflozin is a potent and selective inhibitor of sodium glucose cotransporter 2 [Grempler R et al. Diabetes Obes Metab 2012]. A prior Phase 3 trial [EMPA-REG MET; Häring H-U et al. Diabetes Care 2014] showed improved glycemic control as measured by HbA_1c and fasting plasma glucose, as well as body weight and blood pressure, among T2DM patients who received empagliflozin, 10 or 25 mg, as an add-on to metformin therapy over 24 weeks of treatment, compared with placebo. The present extension study, the Safety and Efficacy of Empagliflozin (BI 10773) and Sitagliptin Versus Placebo Over 76 Weeks in Patients With Type 2 Diabetes study [EMPA-REG EXTEND MET; NCT01289990], assessed the long-term safety, tolerability, and efficacy of the empagliflozin add-on regimen.

The full analysis population included 637 patients with HbA_1c between 7.0% and 10% despite a diet and exercise regimen. All patients received metformin (≥ 1500 mg daily) and were randomly assigned to receive a daily add-on of placebo (n = 207); empagliflozin, 10 mg (n = 217); or empagliflozin, 25 mg (n = 213). The main outcomes were changes from baseline to Week 76 of treatment in HbA_1c, body weight, and SBP. Safety was assessed among 463 patients (72.7% of total) who were treated at least once with empagliflozin. Patient demographics and characteristics for the full analysis population (N = 637) were similar among groups (Table 1).

Comparison of baseline and Week 76 values of HbA_1c revealed changes from baseline of −0.01% for the placebo group. The difference to placebo was −0.61% (95% CI, −0.75 to −0.48) for the empagliflozin−10 mg group and −0.73% (95% CI, −0.88 to −0.58) for the empagliflozin– 25 mg group. Both treatment groups differed significantly from the placebo group (both, p < .001). The greatest declines in HbA_1c with 10 or 25 mg of empagliflozin occurred between Weeks 0 and 12. The use of rescue medication was 34.3% with placebo, 15.2% with empagliflozin−10 mg (OR versus placebo, 0.31; 95% CI, 0.19 to 0.50; p < .001), and 8.9% with empagliflozin−25 mg (OR versus placebo, 0.17; 95% CI, 0.09 to 0.30; p < .001).

Baseline and Week 76 comparison of body weight revealed changes from baseline of −0.5 kg for the placebo group. The difference to placebo was −1.9 kg (95% CI, −2.5 to −1.3) for the empagliflozin−10 mg group and −2.2 kg (95% CI, −2.8 to −1.6) for the empagliflozin−25 mg group. Both treatment groups differed significantly from the placebo group (both, p < .001).

Comparison of baseline and Week 76 SBP revealed changes from baseline of −0.8 for the placebo group. The difference to placebo was −4.4 (95% CI, −6.6 to −2.3) for the empagliflozin−10 mg group and −3.7 (95% CI, −5.9 to −1.5) for the empagliflozin−25 mg group. Both treatment groups differed significantly from the placebo group (both, p < .001).

There was a small but statistically significant increase in high-density lipoprotein cholesterol for the empagliflozin treatment groups, as well as total cholesterol, compared to placebo. Lipid parameters are summarized in Table 2.

The proportion of patients reporting ≥ 1 adverse events was similar in the treatment groups. The researchers concluded that the use of 10 or 25 mg of empagliflozin as an add-on to metformin therapy for 76 weeks is well tolerated and produces significant and sustained reductions of HbA_1c, body weight, and systolic blood pressure compared with placebo in patients with T2DM.