INTRODUCTION
Type 2 diabetes mellitus (T2DM), which accounts for more than 90% of all DM cases, is a progressive disease resulting in gradual decline of insulin secretory capacity.[1, 2] As a result, patients often fail to achieve glycemic goal with monotherapy as treatment continues.[3] Current guidelines on management of T2DM recommend metformin as first-line medication, and glucose-lowering medications including oral agents and injectable medications as second-line if optimal glycemic target is not achieved.[4] Still, additional glucose-lowering medication is required in patients with inadequate glycemic control.
Dipeptidyl peptidase 4 (DPP-4) inhibitors prevent DPP-4 enzyme from degrading incretins including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).[5] Increased incretins subsequently lower blood glucose level by stimulating insulin release and inhibit glucagon production.[6] Evogliptin is an orally bioavailable, selective DPP-4 inhibitor developed for the treatment of T2DM.[7] After repeated once daily administrations in healthy subjects in a first-in-human clinical trial (ClinicalTrials.gov Identifier: NCT00961025), evogliptin was well tolerated with time to reach maximum plasma concentration (Tmax) of 4–5 hours after administration and terminal half-life (t1/2) of 33–39 hours.[8] At steady state, evogliptin showed dose-proportional increase in systemic exposure and sustained inhibition of DPP-4 activity above 80% in dose range of 5–20 mg.[8] In in vitro study, evogliptin was mainly metabolized to 4(S)-hydroxyevogliptin (M7) and 4(R)-hydroxyevogliptin (M8) by CYP3A4 and CYP3A5.[9] Pharmacological activity of the metabolites is currently unknown.[10] The recommended dosage of evogliptin for T2DM is 5 mg once daily.[11]
Pioglitazone, on the other hand, is a thiazolidinedione (TZD) that increases insulin sensitivity by acting as an agonist of peroxisome proliferator–activated receptor gamma (PPAR-γ).[12] After once daily oral administration, Tmax of pioglitazone is about 2 hours and t1/2 is in range of 3–7 hours.[13] Pioglitazone is extensively metabolized, mainly by CYP2C8, CYP3A4 and CYP2C9 to form active metabolites (M3 and M4).[13, 14] The recommended starting dose of pioglitazone is 15 to 30 mg once daily.[13]
Combination of DPP-4 inhibitors with pioglitazone treatment for T2DM has shown potential as an effective treatment owing to their complementary mechanism of action.[15] Recent guideline of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) on T2DM suggests addition of DPP-4 or TZD to subjects who do not achieve target HbA1c level with metformin monotherapy, in case compelling need to reduce hypoglycemia exists. If dual therapy with metformin plus one of DPP-4 and TZD fails to meet target, addition of the other one could be considered for triple therapy according to the guideline.[1]
Since evogliptin and pioglitazone have complementary mechanisms of action, combination of two medications is a promising therapeutic option for T2DM treatment. However, assessment of drug interaction between the two drugs has been lacking. The aim of present study was to evaluate pharmacokinetic and pharmacodynamic interaction between evogliptin and pioglitazone, along with safety profiles in healthy volunteers.