One tablet of empagliflozin and linagliptin significantly reduced HbA_1c in patients with type 2 diabetes. Andrew J. Lewin, MD, National Research Institute, Los Angeles, California, USA, and colleagues conducted a randomized, double-blind, parallel-group, phase 3 study, the Safety and Efficacy of the Combination of Empagliflozin and Linagliptin Compared to Linagliptin Alone Over 24 Weeks in Patients With Type 2 Diabetes study [Lewin A et al. Diabetes Care. 2015].

Empagliflozin reduces renal glucose reabsorption, thereby increasing urinary glucose excretion. This leads to a decline in plasma glucose levels in an insulin-independent manner [Heise T et al. Diabetes Obes Metab. 2013]. Linagliptin prevents the inactivation of incretin peptides, such as glucagon-like peptide-1 (GLP-1), stimulates insulin release, and inhibits glucagon secretion [Gallwitz B. Diabetes Metab Syndr Obes. 2013]. Each drug is an FDA-approved treatment for patients with type 2 diabetes. As compared with the single agent treatment groups, those treated with the dual combination achieved lower A_1c levels.

Efficacy was evaluated in 667 patients who had not received antihyperglycemic therapy for ≥ 12 weeks. Their mean (standard deviation) age was 54.6 (10.2) years; mean weight was 87.9 (20.1) kg; average body mass index was 31.6 (5.6) kg/m²; and mean HbA_1c level was 8.02% (0.96). Baseline characteristics were balanced between treatment groups.

Patients were randomized (1:1:1:1:1) to receive empagliflozin 25 mg/linagliptin 5 mg as a fixed-dose combination (FDC) tablet; empagliflozin 10 mg/linagliptin 5 mg as an FDC tablet; empagliflozin 25 mg; empagliflozin 10 mg; or linagliptin 5 mg for 52 weeks. The primary end point was the change from baseline in HbA_1c at week 24.

At week 24, reductions from baseline in HbA_1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < .001), but not compared with empagliflozin 25 mg (P < .179), and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with individual doses (P < .001 for both). At week 24, 55.4% of patients with baseline HbA_1c ≥ 7% reached HbA_1c< 7% with empagliflozin 25 mg/linagliptin 5 mg; 62.3% did so with empagliflozin 10 mg/linagliptin 5 mg; 41.5% with empagliflozin 25 mg; 38.8% with empagliflozin 10 mg; and 32.3% with linagliptin 5 mg. Efficacy was maintained at week 52.

The proportion of patients with adverse events over this time was similar across groups (68.9% to 81.5%), with no confirmed hypoglycemic adverse events in either combination group. Empagliflozin/linagliptin was well-tolerated, with an overall safety profile similar to those of the individual drugs.

This was the first randomized controlled trial to evaluate the efficacy and safety of the initial combination of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (empagliflozin) and a DPP-4 inhibitor (linagliptin) in patients with type 2 diabetes.