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.