BACKGROUND: Empagliflozin is a sodium glucose cotransporter 2 inhibitor in 
clinical development as a treatment for type 2 diabetes mellitus.
OBJECTIVE: The goal of this study was to investigate potential drug-drug 
interactions between empagliflozin and verapamil, ramipril, and digoxin in 
healthy volunteers.
METHODS: The potential drug-drug interactions were evaluated in 3 separate 
trials. In the first study, 16 subjects were randomized to receive single-dose 
empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose 
verapamil 120 mg. In the second study, 23 subjects were randomized to receive 
empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 
mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on 
day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were 
randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD 
for 8 days with single-dose digoxin 0.5 mg on day 5.
RESULTS: Exposure of empagliflozin was not affected by coadministration with 
verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; 
Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing 
interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at 
steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no 
clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% 
CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active 
metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 
98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no 
clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 
96.71-116.41); however, a slight increase in Cmax was observed that was not 
considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All 
treatments were well tolerated. There were no serious adverse events or adverse 
events leading to discontinuation in any of the studies.
CONCLUSIONS: No dose adjustment of empagliflozin is required when coadministered 
with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is 
required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: 
NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).