Metformin is recommended as a first-line pharmacotherapy for patients with type 2 diabetes, but many patients require add-on therapy. Because of the complementary mechanisms of action of SGLT2 inhibitors and DPP-4 inhibitors, a combination of empagliflozin and linagliptin as add-on to metformin may provide a greater reduction in HbA1c than the individual components.

The 686 patients in the Phase 3, randomized, double-blind, parallel-group study included adults ≥18 years with BMI ≤45g/m2 and HbA1c >7 to ≤10.5% (>53 to ≤91mmol/mol) at screening who had been treated with metformin immediate release (≥1,500mg/day, maximum tolerated dose, or maximum dose according to local label) at an unchanged dose for ≥12 weeks prior to randomization and were on a diet and exercise regimen. After a 2-week placebo run-in period, patients were randomized to a combination of empagliflozin 25mg/linagliptin 5mg, empagliflozin 10mg/linagliptin 5mg, empagliflozin 25mg, empagliflozin 10mg, or linagliptin 5mg as add-on to metformin for 52 weeks. The primary endpoint was change from baseline in HbA1C at week 24, along with secondary endpoints of change from baseline in fasting plasma glucose (FPG) at week 24, change from baseline in body weight at week 24, and the proportion of patients with baseline HbA1c ≥7% (≥53 mmol/mol) who had HbA1Cc<7% (<53mmol/mol) at week 24.

Significantly more subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% at week 24 with empagliflozin/linagliptin vs. those receiving empagliflozin or linagliptin; reductions from baseline in FPG were also significantly greater with empagliflozin/linagliptin. Weight reductions at week 24 were significantly greater with empagliflozin/linagliptin vs. linagliptin, but did not differ significantly compared with the respective empagliflozin components. About 62% and 58%of patients who received empagliflozin 25mg/linagliptin 5mg and empagliflozin10mg/linagliptin 5mg reached HbA1c <7% (<53mmol/mol) at week 24, respectively.

A greater proportion of subjects with baseline HbA1c ≥7% (≥53mmol/mol) had HbA1c <7% (<53mmol/mol) at week 52 with empagliflozin/linagliptin compared with the individual components and significantly reduced FPG with empagliflozin 25mg/linagliptin 5mg vs. linagliptin 5mg. There was no significant difference in change in FPG with empagliflozin 10mg/linagliptin 5mg compared with empagliflozin 10mg. Reductions from baseline in weight at week 52 were significantly greater withempagliflozin/linagliptin compared with linagliptin, but were not significantly different compared with the respective empagliflozin components.

For patients who have failed on metformin, immediate use of this triple therapy may provide advantages over the traditional staggered treatment approach, the authors note.

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