Abstract
Introduction
This randomized, open-label, crossover study investigated potential drug-drug interactions between the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin and the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin. Empagliflozin is a potent and selective SGLT-2 inhibitor that lowers blood glucose levels by inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion. Sitagliptin lowers blood glucose through an insulin-dependent mechanism of action.
Methods
Sixteen healthy male volunteers received three treatments (A, B, C) in one of two treatment sequences (AB then C, or C then AB). In treatment AB, 50 mg empagliflozin was administered once daily (q.d.) for 5 days (treatment A), immediately followed by coadministration of 50 mg empagliflozin q.d. and 100 mg sitagliptin q.d. over 5 days (treatment B). In treatment C, 100 mg sitagliptin was administered q.d. for 5 days. A washout period of ≥7 days separated treatments AB and C.
Results
Coadministration of sitagliptin with empagliflozin did not have a clinically relevant effect on the area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) (geometric mean ratio [GMR] 110.4; 90% confidence interval [CI] 103.9, 117.3) or maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (C max,ss) (GMR 107.6; 90% CI 97.0, 119.4) of empagliflozin. Coadministration of empagliflozin with sitagliptin did not have a clinically meaningful effect on the AUCτ,ss (GMR 103.1; 90% CI 98.9, 107.3) or C max,ss (GMR 108.5; 90% CI 100.7, 116.9) of sitagliptin. Empagliflozin and sitagliptin were well tolerated when given alone or in combination. Five subjects (31.3%) reported at least one adverse event (AE): three (18.8%) experienced an AE while receiving empagliflozin monotherapy and three (18.8%) while receiving sitagliptin monotherapy. No adverse events were reported during the coadministration period. No AEs were regarded as drug-related by the investigator.
Conclusion
These results indicate that empagliflozin and sitagliptin can be coadministered without dose adjustments.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24:382–91.
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci. 2011;32:63–71.
Kipnes M. Sodium-glucose cotransporter 2 inhibitors in the treatment of Type 2 diabetes: a review of Phase II and III trials. Clin Investig. 2011;1:145–56.
Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.
Port A, Macha S, Seman L, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of BI 10773, a sodium glucose cotransporter-2 (SGLT-2), in healthy volunteers. Diabetes. 2010;59(Suppl. 1):A155.
Seman L, Macha S, Jones P, et al. Safety and tolerability of BI 10773, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, following 8-days treatment in patients with type 2 diabetes. Diabetes. 2010;59(Suppl. 1):A156.
Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48:141–51.
Januvia (sitagliptin) [package insert]. 2010; Merck & Co, Inc. Whitehouse Station, NJ, USA.
Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60:470–512.
Bergman AJ, Stevens C, Zhou Y, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28:55–72.
Herman GA, Stevens C, Van DK, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78:675–88.
Cheung BM, Ong KL, Cherny SS, Sham PC, Tso AW, Lam KS. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443–53.
Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540–59.
MedDRA Introductory Guide. 12th ed. Chantilly, VA: MedDRA Maintenance and Support Services Organization; 2009.
Gallwitz B. Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc). 2007;43:13–25.
Keating GM. Vildagliptin: a review of its use in type 2 diabetes mellitus. Drugs. 2010;70:2089–112.
Kania DS, Gonzalvo JD, Weber ZA. Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Clin Ther. 2011;33:1005–22.
Scott LJ. Linagliptin: in type 2 diabetes mellitus. Drugs. 2011;71:611–24.
Friedrich C, Metzmann K, Rose P, Mattheus M, Pinnetti S, Woerle H-J. Pharmacokinetics and pharmacodynamics of BI 10773, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, following co-administration in healthy volunteers. Diabetes. 2011;60(Suppl. 1):A616–7.
Author information
Authors and Affiliations
Corresponding author
Additional information
EudraCT registration number: 2008-006088-35
To view enhanced content go to www.advancesintherapy.com
Rights and permissions
About this article
Cite this article
Brand, T., Macha, S., Mattheus, M. et al. Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor, Coadministered with Sitagliptin in Healthy Volunteers. Adv Therapy 29, 889–899 (2012). https://doi.org/10.1007/s12325-012-0055-3
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-012-0055-3