Fixed-dose empagliflozin/linagliptin combinations improved HbA1c in type 2 diabetes

Whether already on metformin or drug-naive, patients with type 2 diabetes achieved better HbA1c control with fixed-dose combinations of empagliflozin/linagliptin than either therapy alone, according to research presented at the 50th European Association for the Study of Diabetes Annual Meeting.

The fixed-dose combinations were well tolerated and showed overall safety profiles similar to those demonstrated for empagliflozin and linagliptin monotherapies in the randomized, double blind, parallel, 52-week phase 3 study, according to a presentation and poster.

“We are encouraged by the results of this study because it showed clinically meaningful reductions in blood glucose levels with the empagliflozin/linagliptin combination when used with or without metformin,” Hans-J. Woerle, MD, vice president of therapeutic area metabolism for Boehringer Ingelheim, said in a press release.

Added on to metformin

Ralph A. DeFronzo, MD, of the University of Texas Health Sciences in San Antonio, along with Sanjay Patel, MD, of Boehringer Ingelheim Ltd., and colleagues compared empagliflozin 25 mg/linagliptin 5 mg (n=137), empagliflozin 10 mg/linagliptin 5 mg (n=136), empagliflozin 25 mg (n=141), empagliflozin 10 mg (n=140) and linagliptin 5 mg (n=132). Efficacy was assessed in 674 patients (mean age, 56.2 ± 10.2 years; weight, 86.2 ± 18.7 kg; BMI, 31 ± 5.5 kg/m²; HbA1c, 7.98 ± 0.85%).

Ralph A. DeFronzo

The researchers evaluated changes from baseline in HbA1c, body weight, systolic blood pressure, diastolic BP and proportion of patients with HbA1c ≥7% at baseline who reached HbA1c <7%.

At week 52, patients treated with both empagliflozin/linagliptin fixed-dose combinations showed significant HbA1c reductions, with higher percentages achieving HbA1c <7%, compared with the monotherapies. Adjusted mean HbA1c changes from baseline were –1.21 ± 0.08% with empagliflozin 25 mg/linagliptin 5 mg and –1.04 ± 0.07% with empagliflozin 10 mg/linagliptin 5 mg compared with –0.69 ± 0.07% with empagliflozin 25 mg, –0.7 ± 0.08% with empagliflozin 10 mg and –0.45 ± 0.08% with linagliptin 5 mg.

The fixed-dose combinations reduced body weight better than linagliptin alone (empagliflozin 25 mg/linagliptin 5 mg difference, –3.2 kg; 95% CI, –4.2 to –2.2; and empagliflozin 10 mg/linagliptin 5 mg difference, –2.8 kg; 95% CI –3.8 to –1.7) but not empagliflozin alone.

Empagliflozin and fixed-dose combinations reduced systolic BP from baseline by 2.8 mm Hg to 3.6 mm Hg and diastolic BP by 1.8 mm Hg to 2.2 mm Hg; with linagliptin 5 mg, changes from baseline in systolic BP and diastolic BP were 0.3 mm Hg and –0.6 mm Hg, respectively.

Confirmed hypoglycemic adverse events (glucose ≤70 mg/dL) were reported by 3.6% of patients treated with empagliflozin 25 mg/linagliptin 5 mg, 2.2% treated with empagliflozin 10 mg/linagliptin 5 mg, 3.5% treated with empagliflozin 25 mg, 1.4% treated with empagliflozin 10 mg and 2.3% treated with linagliptin 5 mg; none required assistance.
Some patients reported adverse events consistent with a urinary tract infection: empagliflozin 25 mg/linagliptin 5 mg, 10.2%; empagliflozin 10 mg/linagliptin 5 mg, 9.6%; empagliflozin 25 mg, 13.5%; empagliflozin 10 mg, 11.4%; and linagliptin 5 mg, 15.2%. Also, some patients reported adverse events consistent with a genital infection: empagliflozin 25 mg/linagliptin 5 mg, 2.2%; empagliflozin 10 mg/linagliptin 5 mg, 5.9%; empagliflozin 25 mg, 8.5%; empagliflozin 10 mg, 7.9%; and linagliptin 5 mg, 2.3%.

In drug-naive patients

DeFronzo, with Andrew Lewin, MD, of the National Research Institute, Los Angeles, and colleagues, compared empagliflozin 25 mg/linagliptin 5 mg (n=137), empagliflozin 10 mg/linagliptin 5 mg (n=136), empagliflozin 25 mg (n=135), empagliflozin 10 mg (n=134) or linagliptin 5 mg (n=135) in drug-naive patients.
Efficacy was assessed in 667 patients (mean age, 54.6 ± 10.2 years; weight, 87.9 ± 20.1 kg; BMI, 31.6 ± 5.6 kg/m²; HbA1c, 8.02 ± 0.96%). The same exploratory endpoints were evaluated.

At week 52, similar adjusted mean HbA1c changes from baseline were seen: –1.18 ± 0.09% with empagliflozin 25 mg/linagliptin 5 mg; –1.25 ± 0.09% with empagliflozin 10 mg/linagliptin 5 mg; –1.02 ± 0.09% with empagliflozin 25 mg; –0.87 ± 0.09% with empagliflozin 10 mg; –0.51 ± 0.09% with linagliptin 5 mg.

Body weight reduction with fixed-dose combinations was significant vs. linagliptin alone but not vs. empagliflozin alone, similar to results as an add-on therapy. Empagliflozin and fixed-dose combinations reduced systolic BP from baseline by 2.1 mm Hg to 2.5 mm Hg and diastolic BP by 0.2 mm Hg to 1.6 mm Hg; no changes were observed with linagliptin 5 mg.

Similar adverse events were reported, with no hypoglycemic events requiring assistance.

For more information:

DeFronzo R. Abstract #1. Presented at: 50th EASD Annual Meeting; Sept. 16-19, 2014; Vienna.

Patel S. Poster #851. Presented at: 50th EASD Annual Meeting; Sept. 16-19, 2014; Vienna.

Disclosure: This work was supported by Boehringer Ingelheim and Eli Lilly.