Combination Linagliptin and Empagliflozin Therapy Improves Diastolic Function in Female Diabetic db/db Mice

Abstract

We recently reported that linagliptin (LINA) and empagliflozin (EMPA) monotherapies exhibit favorable effects in the heart, vasculature and kidneys in murine models of prediabetes and diabetes. Herein, we extend those studies by testing whether these two drugs used in combination improve diastolic function in diabetic female db/db mice. Eleven week old db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks (dbE10, dbL10). Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA (dbE10/L5) or EMPA added to LINA (dbL10/E5)). One group received LINA and EMPA combination therapy for the entire 10 week test period (dbL10/E10). One group was untreated (DbC). Glycemia, cardiac function, fibrosis and hypertrophy were examined by HbA1c, tissue Doppler ultrasound and histology. With the exception of LINA monotherapy, HbA1c was reduced in all other treated groups (p<0.05). Compared to lean mice on background strain (CkC), myocardial wall motion during diastole was impaired in untreated db/db mice, indicated by increased E/E’ ratio (LV filling pressure), and this was improved with mono- and add-on therapies. Myocardial fibrosis and hypertrophy were improved with mono- and add-on therapies. In summary, the combination of LINA and EMPA appeared to be as cardioprotective as monotherapies of each drug.# weeks on E or LType of therapyDiastolic FunctionGlycemiaCardiac RemodelingE, EMPA L, LINAE/E’ RatioHbA1c %Intersititial Fibrosis (AGSI)Cardiomyocyte cross sectional area (μm2)CkCuntreated18 ± 34.3 ± 0.2---368 ± 33DbCuntreated56 ± 3*11.0 ±0.6*4.9 ± 0.6533 ± 34†db E10mono38 ± 3*†5.9±0.2*†2.8 ± 0.2†433 ± 15†dbL10mono36 ± 2*†10.8±0.5*2.8 ± 0.2†411 ± 11†dbE10/L5L added to E35 ± 4*†6.5±0.2*†3.2 ± 0.2†421 ± 26†dbL10/E5E added to L34 ± 2*†6.9±0.3*†2.8 ± 0.1†358 ±12†dbL10/E10combo44 ± 6*†6.1±0.2*†3.2 ± 0.1†430 ± 21†*p<0.vs CkC †p<0.vs DbC Disclosure J. Habibi: None. A.R. Aroor: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..