A promising combination for future treatment of type 2 diabetes: Coadministration of empagliflozin (SGLT-2 inhibitor) with linagliptin (DPP-4 inhibitor)

M Kern; N Klöting; R Grempler; E Mayoux; M Mark; T Klein; M Blüher

doi:10.1055/s-0034-1374910

Diabetologie und Stoffwechsel, Inhaltsverzeichnis

A promising combination for future treatment of type 2 diabetes: Coadministration of empagliflozin (SGLT-2 inhibitor) with linagliptin (DPP-4 inhibitor)

M Kern ¹, N Klöting ², R Grempler ³, E Mayoux ³, M Mark ³, T Klein ³, M Blüher ¹

¹Department of Medicine, University of Leipzig, Leipzig, Germany
²IFB Obesity Diseases, Junior Research Group Animal Models, University of Leipzig, Leipzig, Germany
³Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

Abstract

Background, methods: Here we investigated the effects of long-term treatment with empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development, alone and in combination with the DPP-4 inhibitor linagliptin (LINA; approved antidiabetes drug) on whole body and organ-specific insulin sensitivity in db/db mice using euglycemic-hyperinsulinemic clamps.

Results: In 8-week old female db/db mice (n = 15/group) treated for 8 weeks, the glucose disposal rate was improved in the 10 mg/kg/d EMPAGLIFLOZIN group (5.9 mg/kg/min; p < 0.001), the 3 mg/kg/d LINA group (3.4 mg/kg/min; p < 0.01) and the EMPAGLIFLOZIN+LINA group (combination 10 mg/kg/d EMPAGLIFLOZIN plus 3 mg/kg/d LINA; 7.8 mg/kg/min; p < 0.001) compared with vehicle (1.9 mg/kg/min). Insulin-mediated suppression of hepatic glucose production (HGP) was significantly (p < 0.05) higher in the EMPAGLIFLOZIN (13.1 mg/kg/min) and EMPAGLIFLOZIN+LINA groups (11.8 mg/kg/min) compared with vehicle (26.3 mg/kg/min). LINA monotherapy improved HGP (21.8 mg/kg/min), although statistical significance was not achieved.

issue-specific labeled glucose uptake was higher in liver and kidney with EMPAGLIFLOZIN (liver: 822 dpm/g/ml; kidney: 1580 dpm/g/ml; p < 0.05 for both), LINA (liver: 935 dpm/g/ml; kidney: 1660 dpm/g/ml; p < 0.05 for both) and EMPAGLIFLOZIN+LINA (liver: 1040dpm/g/ml; kidney: 2190dpm/g/ml; p < 0.01 for both) compared with vehicle (liver: 610dpm/g/ml; kidney: 1030dpm/g/ml). Glucose uptake into muscle and adipose tissue was not affected by any treatment. Improvements in liver triglyceride content were also shown with EMPAGLIFLOZIN (9.1%; p < 0.05), LINA (12.1%; p < 0.01) and EMPAGLIFLOZIN+LINA (5.7%; p < 0.01) compared with vehicle (14.6%).

Conclusion: In conclusion, EMPAGLIFLOZIN+LINA is superior to the respective monotherapies in improving insulin sensitivity, in particular, during conditions of severe insulin resistance.