Drugs

https://doi.org/10.1007/s40265-019-01086-0

REVIEW ARTICLE

The Unique Pharmacological and Pharmacokinetic Profile

of Teneligliptin: Implications for Clinical Practice
Antonio Ceriello1,2,3   · Valeria De Nigris1   · Hiroaki Iijima4   · Takahiro Matsui5 · Maki Gouda4 

© The Author(s) 2019

Abstract
Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus
(T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting
DPP-4 inhibitor with a t½ of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome
P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form.
Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment,
and it is considered to have a low potential for drug–drug interactions. Clinical studies and postmarketing surveillance show
that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well
tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has
antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has
shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data,
teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and
those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved
in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the
third globally. The FDC tablet may also provide additional prescribing and adherence benefits.

in low- and middle-income countries, diabetes predomi-

1 Introduction nantly affects individuals aged ≤ 65 years (prevalence 88%
and 77%, respectively); however, in high-income countries,
The prevalence of type 2 diabetes mellitus (T2DM) is almost half (44%) of all individuals with diabetes are aged
increasing worldwide. In 2017, it was estimated that 451 > 65 years [1].
million people aged 18–99  years had diabetes, and that In Japan, more than 60% of T2DM patients are esti-
the disease was responsible for approximately 5.0 million mated to be over 65 years of age [2]. Another report sug-
deaths in that year [1]. There are different trends in diabetes gested that approximately 8.8 million people in Japan had
prevalence by age group, income, and region. For example, T2DM in 2015, with the disease affecting approximately
20% of men and 10% of women aged ≥ 60 years [3]. With
the population aging in Japan, the prevalence of T2DM is
* Antonio Ceriello
[email protected] predicted to rise substantially over the next two decades,
affecting 9.7 million people by 2030 [3]. In elderly T2DM
1
Institut d’Investigacions Biomèdiques August Pi i Sunyer patients, careful treatment is needed because of the high
(IDIBAPS), Rosselló, 149‑153, 08036 Barcelona, Spain
risk of hypoglycemia and drug adverse events (AEs) due to
2
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) the altered pharmacokinetic profile associated with aging
MultiMedica, Milan, Italy
and polypharmacy [4–6]. Therefore, the treatment of elderly
3
Centro de Investigación Biomédica en Red de Diabetes T2DM patients is a growing problem in several countries,
y Enfermedades Metabólicas Asociadas (CIBERDEM),
including Japan.
Barcelona, Spain
4
Hyperglycemia is an important cause of morbidity and
Ikuyaku. Integrated Value Development Division, Mitsubishi
mortality in T2DM and is associated with both macrovascu-
Tanabe Pharma Corporation, Tokyo, Japan
5
lar (coronary artery disease, peripheral arterial disease, and
Ikuyaku. Integrated Value Development Division, Mitsubishi
stroke) and microvascular (diabetic nephropathy, neuropathy,
Tanabe Pharma Corporation, Osaka, Japan

Vol.:(0123456789)
 A. Ceriello et al.

Teneligliptin, a DPP-4 inhibitor, was approved for the

Key Points  treatment of T2DM in Japan in 2012 and in Korea in 2014,
and is being researched in several countries [23]. The
Teneligliptin is a potent, selective, and long-lasting approved dose of teneligliptin is 20 mg once daily. In Japan,
DPP-4 inhibitor with a unique pharmacokinetic profile the dosage can be increased to 40 mg/day, with close moni-
(multiple elimination pathways); no dose adjustment is toring of the clinical course if efficacy is insufficient [24,
needed in patients with hepatic or renal impairment and 25]. In July 2017, Japan’s first DPP-4 inhibitor/sodium glu-
it is considered to have a low potential for drug–drug cose co-transporter 2 (SGLT2) inhibitor combination drug,
interactions. a fixed-dose combination (FDC) tablet of teneligliptin/cana-
Teneligliptin has antioxidative properties and has shown gliflozin, was approved for the treatment of T2DM.
endothelial protective effects in several non-clinical and This review summarizes non-clinical, pharmacokinetic, and
clinical studies. clinical data for teneligliptin, and discusses the role of tenel-
igliptin in clinical practice, in light of the drug’s novel chemi-
Teneligliptin provides a therapeutic option for a broad cal structure, pharmacokinetic profile, and pleiotropic effects.
range of T2DM patients, including elderly subjects and PubMed and Scopus searches were performed using the
those with renal impairment. key word ‘teneligliptin’. In addition, the prescribing infor-
mation for teneligliptin and the other DPP-4 inhibitors was
and retinopathy) complications [7]. The endothelium plays a searched via the Pharmaceuticals and Medical Devices
crucial role in developing diabetic complications: long-term Agency (PMDA) home page using the drug name (e.g. tenel-
hyperglycemia-induced oxidative stress, non-enzymatic gly- igliptin) or brand name (e.g. Tenelia) as keywords.
cation of proteins, epigenetic changes, and chronic inflam-
mation lead to a reduction in vascular endothelial function
[8, 9], perpetuating cellular environment changes (metabolic 2 Chemical Structure
memory) [8, 10] and micro- or macrovascular events. From
a clinical perspective, this theory supports the importance Teneligliptin is a prolylthiazolidine-based DPP-4 inhibitor
of early treatment to prevent diabetic complications [10, 11]. characterized by a unique, rigid, ‘J-shaped’ structure of five
Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance insu- consecutive rings (Fig. 1) [25–27]. DPP-4 inhibitors are cat-
lin secretion and suppress glucagon secretion in a blood glu- egorized into three groups, based on interactions with DPP-4
cose-dependent manner by increasing levels of endogenous binding subsites. Like sitagliptin, teneligliptin is a class 3
intact glucagon-like peptide-1 (GLP-1) and glucose-depend- DPP-4 inhibitor and binds to S1, S2, and S2 extensive sub-
ent insulinotropic polypeptide, thereby reducing blood glu- sites on DPP-4; however, teneligliptin demonstrates fivefold
cose levels with a low risk of hypoglycemia [12–14]. Studies higher activity than sitagliptin. While sitagliptin and tenel-
have shown that DPP-4 inhibitors have postprandial glucose igliptin appear to bind to subsites in the same manner, there
(PPG) lowering effects in patients with T2DM, reducing are three potential factors that may account for differences
glycated hemoglobin (HbA1c) by approximately 0.5–1.0%, in potency. First, the unique, rigid ‘J-shaped’ structure of
with greater glucose-lowering efficacy observed in Asian teneligliptin, formed by five rings, leads to a small entropy
versus non-Asian individuals [15–17]. DPP-4 inhibitors are loss upon binding to DPP-4 [27]. Second, the affinity of
generally considered to have a neutral effect on cardiovas- teneligliptin to the S2 subsite of DPP-4 is derived from the
cular events in high-risk patients [18, 19]. formation of a hydrogen bond between the carbonyl group of
Metformin is the first-line treatment for T2DM in Western teneligliptin and the side chain of Asn710 at the S2 subsite
countries [20], while DPP-4 inhibitors have gained substan- [27]. Finally, teneligliptin binds with the S2 extensive sub-
tial market share as second- or third-line treatment options site of DPP-4 via strong hydrophobic interactions mediated
[21]. In contrast, DPP-4 inhibitors are used extensively in by an ‘anchor lock domain’ [25, 27]. These interactions may
Japan. Over 70% of patients who receive antidiabetic drugs be related to the potency of inhibition and the duration of
are prescribed a DPP-4 inhibitor. Of these patients, 60% are action of teneligliptin observed in vivo [27].
prescribed a DPP-4 inhibitor as first-line therapy, according
to the Japan Medical Data Center claims database [13, 22].
Nine DPP-4 inhibitors are approved in Japan. Several dif- 3 Pharmacological Properties
ferences exist between the DPP-4 inhibitors in terms of their
pharmacokinetic profiles and specific physical properties. 3.1 In Vitro Studies
These differences relate to the need for dose adjustment,
their drug–drug interaction profiles, or their pleiotropic Teneligliptin is a potent, selective, and long-lasting DPP-4
effects [14]. inhibitor that has approximately 700- to 1500-fold greater
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

4 Pharmacokinetic Properties

4.1 Non‑Human Study

Oral administration of teneligliptin (0.1, 0.3, or 1.0 mg/kg)

in rats showed rapid absorption, with mean peak plasma
concentration (tmax) reached in 0.75–0.88 h [26]. After oral
administration of ­[14C]teneligliptin to Sprague–Dawley rats,
teneligliptin was predominantly distributed in the kidney and
liver, followed by the lung, spleen, and pituitary gland [29].
It was reported that tissue DPP-4 activity was greatest in
the kidney, followed by the lung, adrenal gland, jejunum,
Fig. 1  Chemical structure of teneligliptin and liver [30]. The elimination of ­[14C]teneligliptin from
tissues with high DPP-4 activity (kidney, liver, and lung)
was slower in wild-type Fisher rats than in DPP-4-deficient
affinity for DPP-4 than other DPP enzymes, such as DPP-8 rats, although there was no marked difference in low DPP-4
and DPP-9 [26]. Teneligliptin inhibits recombinant human activity tissues (the heart and pancreas). This suggests that
DPP-4 and human plasma DPP-4 in a concentration-depend- the high binding affinity of teneligliptin for DPP-4 has some
ent manner: concentrations producing half maximal inhibi- influence on tissue distribution of the drug [29]. Among
tion ­(IC50) are 0.889 nmol/L and 1.75 nmol/L, respectively DPP-4 inhibitors, teneligliptin and linagliptin have high
[28]. In these respects, teneligliptin is more potent than sit- tissue distribution properties, especially in the kidney. The
agliptin (6.74 nmol/L and 4.88 nmol/L, respectively) and hydrophobic properties of both drugs may influence the high
vildagliptin (10.5 nmol/L and 7.67 nmol/L, respectively), tissue distribution [29].
as demonstrated by lower ­IC50 values [28].
4.2 Healthy Subjects
3.2 In Vivo Studies
Pharmacokinetic data for teneligliptin (20 and 40 mg) in
In rats, single oral administration of teneligliptin inhib- Japanese healthy subjects are outlined in Table 1. Single
ited plasma DPP-4 in a dose-dependent manner, with a oral doses of teneligliptin (2.5, 10, 20, 40, 80, and 160 mg)
median effective dose of 0.41 mg/kg, compared with 27.3 or placebo were administered under fasting conditions, and
and 12.8 mg/kg for sitagliptin and vildagliptin, respectively dose-dependent increases in the maximal plasma concentra-
[28]. At 24 h after drug administration, inhibition of DPP-4 tion (Cmax) and area under the plasma concentration–time
persisted with teneligliptin 10 mg/kg (≥ 50% inhibition), but curve (AUC) of teneligliptin were observed. The tmax and
did not persist with sitagliptin or vildagliptin 100 mg/kg mean elimination half-life (t½) of teneligliptin 20 mg were
(< 3% and < 15% inhibition, respectively) [28]. The effect 1.8 and 24.2 h, respectively. After repeated doses of tenel-
of teneligliptin in an oral mixed meal tolerance test showed igliptin 20 or 80 mg, no remarkable changes were observed
that teneligliptin 0.1 mg/kg had nearly maximum effects for in the pharmacokinetic profile, and teneligliptin reached
reducing glucose excursion and increasing active GLP-1/ steady state by day 7 [24]. The pharmacokinetic profile did
insulin. Plasma DPP-4 inhibition was ≥ 40% for the entire not differ between Japanese and Caucasian subjects [24, 31,
treatment period of the oral mixed meal tolerance test, sug- 32].
gesting that 40% DPP-4 inhibition was required for sufficient The mass balance study using ­[14C]teneligliptin indicated
efficacy [28]. that teneligliptin was metabolized or excreted from the kid-
The effects of teneligliptin on hyperglycemia and hyper- ney, with metabolism and renal excretion contributing to
triglyceridemia were evaluated in Zucker fatty rats [28]. A 65.6% and 34.4%, respectively, of total body clearance [24].
single dose of teneligliptin 1 mg/kg reduced PPG, free fatty Teneligliptin was the most abundant radioactive component
acid, and triglyceride excursions after carbohydrate and fat in plasma (71.1%); the most abundant metabolite in plasma
loading. After repeated administration of teneligliptin for was a thiazolidine-1-oxide derivative (designated as M1,
2 weeks, glucose excursions after carbohydrate loading were 14.7%). The main enzymes responsible for teneligliptin
reduced, as were non-fasting levels of free fatty acids and metabolism are cytochrome P450 (CYP) 3A4 and flavin-
triglycerides [28]. containing monooxygenase 3 (FMO3), with equal contri-
bution [33] (Fig. 2). Because of its elimination via multiple
pathways, teneligliptin is considered a suitable treatment
 A. Ceriello et al.

Table 1  Pharmacokinetic profile of teneligliptin in healthy Japanese subjects [24, 31]

Category Day Dose (mg/day) n tmax (h)a Cmax (ng/mL)b AUC​∞ (ng·h/mL)b t½ (h)b

Single-dose
1 20 6 1.8 (1.0, 2.0) 187.20 (44.70) 2028.9 (459.5) 24.2 (5.0)
1 40 6 1.0 (0.5, 3.0) 382.40 (89.83) 3705.1 (787.0) 20.8 (3.2)
Multiple-dose
1 20 7 1.0 (0.4, 2.0) 160.60 (47.26) 1627.9 (427.8) 25.8 (4.9)
7 20 7 1.0 (1.0, 1.0) 220.14 (59.86) 2641.4 (594.7) 30.2 (6.9)

AUC​∞ area under the plasma concentration-time curve from time zero to infinity, Cmax maximal plasma concentration, tmax time to reach Cmax, t½
elimination half-life
a
 Median (minimum, maximum)
b
 Mean (standard deviation)

impairment, or ESRD, who received a single dose of tenel-

igliptin 20 mg, no greater than a twofold increase in tenel-
igliptin AUC from time zero to infinity (AUC​∞) relative to
healthy controls was observed. Changes in Cmax and t½ were
unremarkable. Dialysis is not expected to affect the pharma-
cokinetic profile of teneligliptin; the removal of teneligliptin
after dialysis was 15.6% [34].
The pharmacokinetics of teneligliptin were compared in
three groups of eight subjects who were categorized accord-
ing to their degree of hepatic impairment [two groups with
chronic (> 6 months), stable, mild (Child–Pugh score 5–6),
or moderate (Child–Pugh score 7–9) hepatic impairment,
and one group of matched healthy subjects] (Table 2) [36].
Hepatic impairment was associated with a mild increase
Fig. 2  Multiple elimination pathways of teneligliptin. Teneligliptin in Cmax and overall exposure (AUC​∞) relative to healthy
is metabolized by CYP3A4 and FMO3, or excreted from the kidney controls; however, no greater than a twofold increase was
as unchanged form. CYP cytochrome P450, FMO3 flavin-containing
monooxygenase 3
observed [36]. Collectively, pharmacokinetic changes were
unremarkable; thus, no dose adjustment of teneligliptin is
required in patients with renal or hepatic impairment.
option for patients with hepatic or renal impairment, and
is considered to have a low potential for drug–drug interac- 4.3.2 Elderly Subjects
tions, as described below.
In a placebo-controlled, randomized, double-blind, paral-
4.3 Special Subject Populations lel-group comparative study in 40 healthy adult patients
[21 non-elderly (aged ≥ 45 and < 65 years) and 19 elderly
The pharmacokinetic properties of teneligliptin in special (aged ≥ 65 and ≤ 75 years) individuals] who received a sin-
populations were evaluated in Caucasian subjects. gle dose of placebo or teneligliptin 20 or 80 mg, the ratio
(elderly/non-elderly) of the geometric least square (LS)
4.3.1 Subjects with Renal Impairment/Hepatic Impairment means of Cmax, AUC from time zero to time t (AUC​t), and
t½ of plasma teneligliptin was approximately 1.0 across all
The pharmacokinetic properties of teneligliptin have been parameters, demonstrating a similar pharmacokinetic profile
evaluated in subjects with normal renal function and renal between elderly and non-elderly individuals. The results of
impairment (Table 2) [34]. Patients were assigned to one of teneligliptin 20 mg administration are shown in Table 2 [31].
four groups based on their renal function [mild, moderate,
severe renal impairment, as assessed using Cockcroft–Gault 4.4 Drug–Drug Interactions
estimates of creatinine clearance [35], or end-stage renal
disease (ESRD)] and two groups of matched healthy sub- The results from drug–drug interaction studies are presented
jects. In individuals with mild, moderate, or severe renal in Table 3. Teneligliptin is metabolized by CYP3A4 and is a
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

Table 2  Pharmacokinetic profile of teneligliptin in special populations

Dose n Cmax (ng/mL)a AUC​∞ (ng·h/mL)a t½ (h)a Ratio to normal subjects (90% CI)b
(mg/
day) Cmax AUC​∞ t½

Renal impairment [34]

 Normal 20 8 176.50 (38.42) 1772.7 (657.3) 26.1 (5.0)
 Mild 20 8 207.96 (53.31) 2234.2 (278.6) 27.7 (7.9) 1.08 (0.86, 1.35) 1.25 (1.01, 1.54) 1.00 (0.76, 1.31)
 Moderate 20 8 203.63 (42.33) 3090.3 (868.6) 36.0 (11.0) 1.12 (0.89, 1.40) 1.68 (1.36, 2.07) 1.36 (1.04, 1.79)
 Severe 20 8 191.63 (49.07) 2833.3 (652.3) 29.8 (11.0) 1.04 (0.82, 1.32) 1.49 (1.19, 1.86) 1.02 (0.77, 1.37)
Renal impairment with ESRD [34]
 Normal 20 8 195.75 (43.28) 1843.1 (450.0) 18.3 (5.7)
 Pre-dialysis 20 8 164.45 (78.85) 2162.5 (488.1) 22.7 (7.7) 0.85 (0.64, 1.13) 1.17 (0.94, 1.47) 1.19 (0.89, 1.59)
 Post-dialysis 20 8 219.00 (118.91) 2472.9 (599.7) 23.6 (5.8) 1.10 (0.82, 1.46) 1.32 (1.06, 1.65) 1.31 (0.98, 1.75)
Hepatic impairment [36]
 Normal 20 8 185.88 (84.65) 1548.8 (209.1) 24.8 (6.4)
 Mild 20 8 229.25 (86.16) 2207.9 (790.0) 27.9 (7.1) 1.25 (0.97, 1.62) 1.46 (1.22, 1.74) 1.22 (0.94, 1.57)
 Moderate 20 8 247.63 (112.95) 2418.9 (505.8) 30.9 (6.6) 1.38 (1.07, 1.78) 1.59 (1.33, 1.90) 1.38 (1.07, 1.78)
Age (years) [31]
 ≥ 45 to < 65 20 12 143.6c 1637.6c 33.8c
 ≥ 65 to ≤ 75 20 12 142.7c 1502.8c 32.1c 1.01 (0.87, 1.16) 1.09 (0.98, 1.22) 1.05 (0.91, 1.22)

AUC​∞ area under the plasma concentration-time curve from time zero to infinity, Cmax maximal plasma concentration, ESRD end-stage renal dis-
ease, t½ elimination half-life, CI confidence interval
a
 Mean (standard deviation)
b
 Results are reported as ratios of geometric means and the respective 90% CIs
c
 Data are expressed as least square means as these were the only data available

weak substrate of P-glycoprotein. The effects of the CYP3A4 or placebo before breakfast for 4 weeks in a randomized,
and P-glycoprotein inhibitor ketoconazole on teneligliptin double-blind, placebo-controlled, parallel-group study. Both
pharmacokinetics in healthy adults were investigated in an teneligliptin-treated groups showed significantly decreased
open-label, fixed-sequence study conducted in 16 healthy PPG after each meal, 24-h mean glucose, and fasting plasma
volunteers (14 of whom were included in the pharmacoki- glucose (FPG) values compared with the placebo group.
netic analysis set) in Germany [37]. Exposure to teneligliptin, The differences between the teneligliptin 20 mg and placebo
when administered in combination with ketoconazole, was groups in changing 2-h PPG [LS means ± standard error
less than twice the exposure to teneligliptin alone, which sug- (SE)] after each meal were − 38.1 ± 7.8, − 28.6 ± 9.2, and
gests that drugs and foods that inhibit CYP3A4 are unlikely − 36.1 ± 7.5 mg/dl at breakfast, lunch, and dinner, respec-
to markedly increase exposure to teneligliptin [37]. No clini- tively (p < 0.001, p < 0.01, and p < 0.001, respectively). Both
cally relevant drug–drug interactions were observed when doses of teneligliptin increased postprandial plasma active
teneligliptin was coadministered with metformin, canagliflo- GLP-1 concentrations compared with placebo after each meal,
zin, glimepiride, or pioglitazone in healthy volunteers; there- and DPP-4 inhibition was sustained over 24 h, with slightly
fore, no dose adjustment of teneligliptin is required when it is stronger inhibition observed with the 20 mg dose. The phar-
coadministered with these drugs. Furthermore, teneligliptin macokinetic profile was similar to that observed in healthy
did not affect the pharmacokinetic properties of metformin, subjects. These PK/PD data provided the evidence required
canagliflozin, glimepiride, or pioglitazone [31, 38, 39]. to support the dosing of teneligliptin 20 mg once daily [40].

5 Pharmacokinetic/Pharmacodynamic Data 6 Clinical Studies in Japan

in Type 2 Diabetes Mellitus
6.1 Monotherapy
A pharmacokinetic/pharmacodynamic (PK/PD) study was
conducted in Japanese patients with T2DM [40]. Ninety- Efficacy data from relevant clinical trials are summarized
nine patients were administered teneligliptin 10 or 20 mg in Table 4. The efficacy of teneligliptin was confirmed in
 A. Ceriello et al.

Table 3  Drug–drug interactions: effect on teneligliptin pharmacokinetics

Combination Dose n Cmax (ng/mL)a AUC​∞ (ng·h/mL)a t½ (h)a Ratio to teneligliptin alone (90% CI)b
(mg/day)
Cmax AUC​∞ t½

Ketoconazole [37]
 Teneligliptin alone 20 14 222.8 (43.5) 2039.6 (265.3) 20.7 (4.2)
 Teneligliptin + keto- 20 14 308.8 (77.6) 3064.1 (523.5) 21.8 (3.9) 1.37 (1.25, 1.50) 1.49 (1.39, 1.60) 1.06 (0.95, 1.18)
conazole
Metformin [38]
 Teneligliptin alone 40 19 446.3 (62.7) 3352.0 (538.5)c
 Teneligliptin + met- 40 19 405.7 (63.9) 3477.9 (459.7)c 0.91 (0.85, 0.97) 1.04 (1.00, 1.09)
formin
Glimepiride [31]
 Teneligliptin alone 40 16 545.4 (169.0) 3970.0 (710.5) 22.6 (5.9)
 Teneligliptin + glime- 40 16 523.1 (134.9) 3663.6 (604.9) 24.9 (5.5) 0.97 (0.87, 1.09) 0.93 (0.89, 0.96) 1.10 (0.97, 1.26)
piride
Pioglitazone [31]
 Teneligliptin alone 40 16 503.3 (151.0) 3820.2 (440.6) 24.7 (5.5)
 Teneligliptin + piogl- 40 16 549.7 (109.0) 3836.1 (412.1) 22.7 (5.3) 1.12 (0.98, 1.27) 1.01 (0.97, 1.05) 0.92 (0.82, 1.03)
itazone
Canagliflozin [39]
 Teneligliptin alone 40 18 458.3 (78.8) 3781.2 (646.3) 24.0 (6.5)
 Teneligliptin + cana- 40 18 444.9 (66.6) 3699.5 (743.6) 22.1 (4.8) 0.98 (0.90, 1.06) 0.98 (0.93, 1.02) 0.93 (0.82, 1.06)
gliflozin

AUC​∞ area under the plasma concentration time-curve from time zero to infinity, AUC​24 AUC from time zero to 24 h, Cmax maximal plasma con-
centration, t½ elimination half-life, CI confidence interval
a
 Mean (standard deviation)
b
 Results are reported as ratios of geometric means and the respective 90% confidence intervals
c
 AUC​24

two randomized, double-blind, placebo-controlled, parallel- in HbA1c (primary endpoint) was − 0.79% (− 0.94, − 0.64).
group studies (phases II and III) in Japanese patients with FPG and 2-h PPG were also improved significantly at week
T2DM inadequately controlled by diet and exercise [24, 25, 12 [24, 25]. The incidence of AEs and serious AEs did not
41]. In the phase II study (3000-A4), 324 patients were ran- differ significantly between the teneligliptin and placebo
domized to receive teneligliptin 10, 20, or 40 mg, or placebo, groups in both studies (Table 5a). In addition, adverse drug
once daily before breakfast for 12 weeks [41]. The primary reactions (ADRs) did not increase in the teneligliptin versus
endpoint was the change in HbA1c from baseline to week placebo groups in both studies. Hypoglycemia was the only
12. A significantly greater reduction in HbA1c was observed ADR reported by ≥ 3% (3000-A4 study), being 2.5% (n = 2),
in all teneligliptin-treated groups compared with the pla- 0% (n = 0), 0% (n = 0), and 3.7% (n = 3) in the placebo and
cebo group from weeks 2 to 12. Differences between the teneligliptin 10, 20, and 40 mg groups, respectively.
teneligliptin 10, 20, or 40 mg groups and the placebo group
for change in HbA1c {LS mean [95% confidence intervals 6.2 Combination Therapy/Long‑Term Therapy
(CIs)]} were − 0.9% (− 1.0, − 0.7), − 0.9% (− 1.1, − 0.7), and
− 1.0% (− 1.2, − 0.9), respectively (all p < 0.001; baseline In phase III studies, the efficacy and safety of teneliglip-
HbA1c values in the placebo, teneligliptin 10, 20, and 40 mg tin 20 mg in combination with a sulfonylurea (glimepiride;
groups were 8.0%, 7.9%, 7.8%, and 7.7%, respectively). FPG 3000-A6) [42] or pioglitazone (3000-A7) [43] were evalu-
and PPG were also significantly improved at week 12 [41]. ated in randomized, double-blind, placebo-controlled,
The phase III study (3000-A5) [24, 25] sought to confirm the parallel-group studies (12 weeks); thereafter, all patients
efficacy and safety of once daily, oral teneligliptin. Patients received teneligliptin once daily for a 40-week period. The
were randomized to teneligliptin 20 mg or placebo in a phase IV study investigating teneligliptin in combination
12-week, double-blind phase. The difference [LS mean (95% with insulin (3000-A15) was conducted in a similar manner,
CI)] between the teneligliptin and placebo groups for change except that the double-blind period was 16 weeks followed
Table 4  Summary of key clinical trials of teneligliptin
Study name Phase Monotherapy/con- Treatment Design Dose N Baseline, mean Change from base- Difference in p value ClinicalTrial.
comitant therapy period (SD) or mean line, LS mean (SE) HbA1c from pla- (vs. pla- gov registration
(weeks) [95% CI] or mean [95% ­CI]e cebo, LS mean cebo) number
[95% CI]

3000-A4 [41] II Monotherapy 12 Double-blind Placebo 80 8.0 (0.7) 0.1 (0.1) NCT00628212
TNL 20 mg 79 7.9 (0.7) − 0.8 (0.1) − 0.9 < 0.001
[− 1.0, − 0.7]
3000-A5 [24, III Monotherapy 12 Double-blind Placebo 104 NDd 0.17 (0.05) NCT00998881
25] TNL 20 mg 99 NDd − 0.62 (0.05) − 0.79 < 0.0001
[− 0.94, − 0.64]
3000-A6 [42] III Add on to glime- 12 Double-blind Placebo 98 8.4 (0.8) 0.3 (0.1) NCT00974090
piride 12 TNL 20 mg 96 8.4 (0.8) − 0.7 (0.1) − 1.0 < 0.001
[− 1.2, − 0.9]
40 Open-label Placebo/TNLa 95 − 0.9 [− 1.1, − 0.8]f
52 TNL/TNLa 96 − 0.6 [− 0.7, − 0.4]
3000-A7 [43] III Add on to pioglita- 12 Double-blind Placebo 101 7.9 (0.8) − 0.2 (0.0) NCT01026194
zone 12 TNL 20 mg 103 8.1 (0.9) − 0.9 (0.0) − 0.7 < 0.001
[− 0.9, − 0.6]
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

40 Open-label Placebo/TNLa 98 − 0.7 [− 0.9, − 0.6]f

52 TNL/TNLa 103 − 0.9 [− 1.0, − 0.7]
3000-A8/A14 III Monotherapy/com- 52 Open-label All ­patientsb 702 7.87 (0.77) − 0.72 [− 077, NCT02314637/
[45] bination therapy − 0.67] NCT01301833
52 Monotherapy 363 7.75 (0.70) − 0.63 [− 0.70,
− 0.57]
52 Combination 339 8.01 (0.80) − 0.81 [− 0.89,
therapy − 0.73]
52 Add on to 89 8.26 (0.67) − 0.81 [− 0.98,
glimepiride − 0.65]
52 Add on to 80 7.90 (0.76) − 0.76 [− 0.92,
glinide − 0.61]
52 Add on to 95 7.97 (0.88) − 0.78 [− 0.93,
biguanide − 0.63]
52 Add on to αGI 75 7.88 (0.84) − 0.89 [− 1.04,
− 0.74]
3000-A15 [44] IV Add on to insulin 16 Double-blind Placebo 71 8.73 (0.81) − 0.07 (0.08) NCT02081599
16 TNL 20 mg 77 8.70 (0.81) − 0.87 (0.08) − 0.80 <0.001
[− 1.02, − 0.58]
36 Open-label Placebo/TNLc 63 − 0.88 [− 1.08,
− 0.68]g
52 TNL/TNLc 77 − 0.81 [− 1.02,
− 0.60]


Table 4  (continued)
Study name Phase Monotherapy/con- Treatment Design Dose N Baseline, mean Change from base- Difference in p value ClinicalTrial.
comitant therapy period (SD) or mean line, LS mean (SE) HbA1c from pla- (vs. pla- gov registration
(weeks) [95% CI] or mean [95% ­CI]e cebo, LS mean cebo) number
[95% CI]
MP_C301 [48] III Add on to 16 Double-blind Placebo 68 7.72 (0.65) − 0.12 (0.09) NCT01805830
biguanide 16 TNL 20 mg 136 7.79 (0.80) − 0.90 (0.07) − 0.78 < 0.0001
[− 0.95, − 0.61]
MP_C302 [47] III Monotherapy 24 Double-blind Placebo 43 7.77 (0.81) 0.03 (0.12) NCT01798238
24 TNL 20 mg 99 7.63 (0.69) − 0.90 (0.09) − 0.94 < 0.0001
[− 1.22, − 0.65]
MP-513-E07 II Add on to 24 Double-blind Placebo 88 7.88 [6.1, 9.8] − 0.28 (0.07) NCT00971243
[49] biguanide 24 TNL 20 mg 91 7.96 [6.7, 10.0] − 0.76 (0.07) − 0.48 < 0.001
[− 0.67, − 0.29]
MT2412-J02 III, for Add on to canagli- 24 Double-blind Placebo 77 8.09 (0.85) 0.00 (0.08) NCT02354222
[50] FDC flozin 24 TNL 20 mg 77 7.98 (0.80) − 0.94 (0.08) − 0.94 < 0.001
[− 1.16, − 0.72]

αGI α-glucosidase inhibitor, CI confidence interval, FDC fixed-dose combination, JDS Japan Diabetes Society, LS least square, ND no data, NGSP National Glycohemoglobin Standardization
Program, SD standard deviation, SE standard error, TNL teneligliptin
a
 Patients who completed the double-blind period entered the open-label period, in which placebo was switched to TNL 20 mg (placebo/TNL group) or TNL was continued (TNL/TNL group).
Patients with HbA1c ≥ 7.3% after week 24, regardless of prior treatment with placebo or TNL, were uptitrated to TNL 40 mg at the next visit if there were no safety concerns. The TNL dose
remained stable from week 40 to the end of the study period
b
 In patients with HbA1c ≥ 7.3% (3000-A8) or ≥ 7.4% (3000-A14) after week 24, TNL was uptitrated to 40 mg at the next visit if there were no safety concerns. The TNL dose remained stable
from week 40 to the end of the study period
c
 Patients who completed the double-blind period entered the open-label period, in which placebo was switched to TNL 20 mg (placebo/TNL group) or TNL was continued (TNL/TNL group).
Patients with HbA1c ≥ 7.5% after week 28, regardless of prior treatment with placebo or TNL, were uptitrated to TNL 40 mg at the next visit if there were no safety concerns. The TNL dose
remained stable from week 40 to the end of the study period
d
 The baseline HbA1c data (National Glycohemoglobin Standardization Program [NGSP] value) are not available: the mean (SD) of HbA1c (Japan Diabetes Society [JDS] value) is 7.58 (0.85)
and 7.53 (0.78) in the placebo and TNL group, respectively
e
 Last observation carried forward was used in all studies except MP_C302
f
 Change from week 12, switching to TNL in the placebo group, to week 52
g
 Change from week 16, switching to TNL in the placebo group, to week 52
A. Ceriello et al.
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

by a 36-week open-label period [44]. Patients with HbA1c (3000-A14). A post hoc pooled analysis using data from two
≥ 7.3% after week 24 (3000-A6, A7) [42, 43] or ≥ 7.5% after phase III clinical studies involving 702 Japanese patients
week 28 (3000-A15) [44] were uptitrated to teneligliptin (3000-A8/A14) was performed [45]. The long-term use of
40 mg at the next visit if there were no safety concerns. teneligliptin as monotherapy or combination therapy sig-
Teneligliptin as an add-on therapy to these drugs produced nificantly improved hyperglycemia in Japanese patients
greater HbA1c-lowering activity than placebo, with sus- with T2DM, with glucose-lowering effects maintained over
tained glucose-lowering effects maintained throughout the 52 weeks (Table 4). No change or a slight increase in body-
studies (up to 52 weeks). The safety profile did not differ weight at the end of 52 weeks was observed.
between the placebo and teneligliptin groups, although As for long-term safety, the incidence of hypoglycemia
hypoglycemia was somewhat higher when teneligliptin was was higher when teneligliptin was used in combination with
administered with insulin (Table 5a). sulfonylurea or insulin (10.7% and 20.0%, respectively)
Two long-term, open-label studies were performed in compared with teneligliptin monotherapy or in other com-
Japanese T2DM patients. The first was a long-term study bination therapies (1.1–5.0%) [42–45]. Overall, the long-
of teneligliptin, both as monotherapy and in combination term treatment of teneligliptin was well tolerated (Table 5b).
with glimepiride (3000-A8), and the second was a long-term In a post hoc pooled analysis of two 52-week, open-label,
study of teneligliptin, both as monotherapy and in combina- phase III clinical trials (3000-A8/A14) that examined the
tion with a glinide, biguanide, or α-glucosidase inhibitor treatment response when teneligliptin dose was increased

Table 5  Summary of key clinical trial results: teneligliptin safety

Study type Phase II (mono- Phase III (mono- Phase III (combination therapy) Phase IV (combination
therapy) therapy) therapy)
3000-A4 [41] [n (%)] 3000-A5 [24] [n (%)] 3000-A6 [42] [n (%)] 3000-A7 [43] [n (%)] 3000-A15 [44] [n (%)]
Placebo TNL Placebo TNL SU SU + TNL PIO PIO + TNL Insulin Insulin + TNL

(a) Double-blind trials

 N 80 79 104 99 98 96 101 103 71 77
 AE 44 (55.0) 40 (50.6) 66 (63.5) 62 (62.6) 61 (62.2) 62 (64.6) 47 (46.5) 63 (61.2) 38 (53.5) 34 (44.2)
 ADR 6 (7.5) 2 (2.5) 5 (4.8) 1 (1.0) 6 (6.1) 8 (8.3) 2 (2.0) 12 (11.7) 5 (7.0) 5 (6.5)
 SAE 1 (1.3) 0 (0.0) 4 (3.8) 0 (0.0) 2 (2.0) 0 (0.0) 1 (1.0) 4 (3.9) 2 (2.8) 1 (1.3)
 Discontinued 2 (2.5) 1 (1.3) 2 (1.9) 2 (2.0) 2 (2.0) 1 (1.0) 2 (2.0) 1 (1.0) 4 (5.6) 0 (0.0)
because of
AE
 Hypoglycemia 3 (3.8) 1 (1.3) 1 (1.0) 1 (1.0) 3 (3.1) 2 (2.1) 0 (0.0) 2 (1.9) 5 (7.0) 9 (11.7)
Study type Phase III (mono- Phase III (combination therapy)
therapy)
3000-A8/A14 [45] 3000-A8/A14 [45] [n (%)] 3000-A6 [42] 3000-A7, ­A8a 3000-A15 [44]
[n (%)] [n (%)] [43, 45] [n (%)] [n (%)]
TNL GLI + TNL BG + TNL αGI + TNL PIO + TNL SU + TNL Insulin + TNL

(b) Long-term trials

 N 363 80 95 75 201 280 140
 AE 320 (88.2) 72 (90.0) 82 (86.3) 60 (80.0) 178 (88.6) 266 (95.0) 102 (72.9)
 ADR 31 (8.5) 10 (12.5) 7 (7.4) 5 (6.7) 23 (11.4) 53 (18.9) 23 (16.4)
 SAE 20 (5.5) 3 (3.8) 6 (6.3) 6 (8.0) 14 (7.0) 16 (5.7) 10 (7.1)
 Discontinued 11 (3.0) 5 (6.3) 5 (5.3) 5 (6.7) 9 (4.5) 19 (6.8) 1 (0.7)
because of
AE
 Hypoglycemia 9 (2.5) 4 (5.0) 1 (1.1) 1 (1.3) 3 (1.5) 30 (10.7) 28 (20.0)

Medical Dictionary for Regulatory Activities/Japanese (MedDRA/J), version 11.1, 13.0, 13.1, and 15.0
ADR adverse drug reaction, AE adverse event, αGI α-glucosidase inhibitor, BG biguanide, GLI glinide, n number of patients, PIO pioglitazone,
SU sulfonylurea, SAE serious adverse event, TNL teneligliptin
a
 Pooled analysis using data from the 3000-A7 and A8 studies
 A. Ceriello et al.

from 20 to 40 mg at week 28 (n = 204), no increasing trends week 24 [50]. Similar results were reported when canagli-
in the incidences of AEs or hypoglycemia were observed flozin was administered as an add-on therapy to teneligliptin
(weeks 28–52 vs. weeks 0–28). Although the incidence of over 24 weeks in a double-blind, placebo-controlled study
serious AEs was elevated with higher doses of teneligliptin, [difference versus placebo in the change from baseline
none of these AEs were related to the study drug. While − 0.88% (− 1.15, − 0.60); p < 0.001] [51] or 52 weeks in
the HbA1c reduction in the dose-increased population was a long-term, open-label study [difference versus baseline
low (approximately − 0.1%), 52.9% of patients showed a − 0.99% (− 1.12, − 0.85)] [52]. No new safety concerns were
response to the teneligliptin dose increase (HbA1c change identified during the studies. A drug–drug interaction was
less than or equal to − 0.1%). Therefore, a dose increase not observed, as described in Sect. 4.4. Results from these
to 40 mg may be an important therapeutic option for some trials led the Japanese PMDA, from July 2017, to approve
patients [46]. the dual therapy (teneligliptin/canagliflozin) as a FDC for
In a subgroup analysis of a 52-week, pooled study (3000- clinical use in T2DM. This was the first approval of a DPP-4
A8/A14) stratified by age (< 65 and ≥ 65 years), there were inhibitor/SGLT-2 inhibitor FDC tablet in Japan.
no differences in efficacy and safety profiles between sub-
groups. Moreover, no elevation in the incidence of hypogly-
cemia was observed in elderly patients treated with tenel- 9 Postmarketing Surveillance
igliptin compared with non-elderly patients [45]. Similarly,
when teneligliptin was used as an adjunct to insulin (3000- Although the efficacy and safety profiles of teneligliptin
A15), there was no trend towards a higher incidence of were characterized in clinical trials, these studies were rela-
hypoglycemia in patients aged < 65 years versus those aged tively short-term (12–52 weeks). Therefore, to assess long-
≥ 65 years [44]. term safety and efficacy, the 3-year, postmarketing surveil-
lance (PMS) RUBY (exploRing the long-term efficacy and
safety including cardiovascUlar events in patients with type
7 Data from Non‑Japanese Studies 2 diaBetes treated bY teneligliptin in the real-world; Japi-
cCTI-153047) is being performed in more than 10,000 Japa-
The 24-week efficacy of teneligliptin was assessed in Korean nese patients. Interim results (data cut-off date 28 June 2017)
patients with T2DM inadequately controlled with diet and are shown in Table 6 [53]. Safety data were available from
exercise (MP_C302) [47]. Patients were randomized to 10,532 Japanese T2DM patients (6338 males/4194 females)
receive placebo or teneligliptin 20  mg once daily for with a median administration period of 731 days. Overall,
24 weeks. At week 24, the difference in change in HbA1c ADRs and serious ADRs were reported in 364 (3.46%)
from baseline [LS mean (95% CI)] between the tenel- and 91 patients (0.86%), respectively, and hypoglycemia,
igliptin and placebo groups was − 0.94% (− 1.22, − 0.65) constipation, and hepatic function abnormal were the most
(p < 0.0001). In addition, two other studies assessed the common ADRs. Hypoglycemia (0.32%) and constipation
efficacy and safety of teneligliptin plus metformin in the (0.27%) were the most common ADRs reported in pooled
treatment of T2DM in Korean (MP_C301) and European data from clinical trials (2.6% and 0.9%, respectively); how-
patients (MP-513-E07) [48, 49]. This combination has ever, hepatic function abnormal, albeit mild in severity, was
complementary effects and the potential to provide better reported more frequently in this survey (0.24%) than in the
blood glucose control than metformin alone. Teneligliptin pooled analysis (0.1%) [53]. Teneligliptin, administered as
plus metformin was well tolerated and significantly reduced monotherapy or as combination therapy for up to 2 years,
HbA1c and FPG versus placebo in both studies. reduced HbA1c from 3 months of treatment, with sustained
glucose-lowering effects observed over 2 years. No change
in mean bodyweight was observed. A subgroup analysis
8 Development of a Fixed‑Dose was also performed across three age groups (< 65 years;
Combination Drug 65–< 75 years; and ≥ 75 years); efficacy and safety pro-
files did not differ markedly among the three age groups
The efficacy and safety of teneligliptin as add-on therapy (Table 6).
to canagliflozin was evaluated in patients with T2DM who A further interim subgroup analysis was performed on
had inadequate glycemic control with canagliflozin mono- data obtained from patient case reports in the RUBY surveil-
therapy (MT2412-J02). Patients were randomized to receive lance to verify the long-term safety and efficacy of tenel-
teneligliptin 20 mg (n = 77) or placebo (n = 77) once daily. igliptin in Japanese patients with T2DM and impaired renal
Teneligliptin as an add-on therapy to canagliflozin provided function [54]. At the start of teneligliptin treatment, patients
a greater HbA1c-lowering effect than placebo [between- were classified into G1–G5 stages of chronic kidney dis-
group difference − 0.94% (− 1.16, − 0.72); p < 0.001] by ease (CKD) according to estimated glomerular filtration rate
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

Table 6  Safety and efficacy profile of teneligliptin in the RUBY postmarketing surveillance program [53]
Categories
All patients [n (%)] < 65 years [n (%)] 65 to < 75 years [n (%)] ≥ 75 years [n (%)]

Safety (safety analysis set)

 ADRs (serious + non-serious)
  No. of patients 10,532 4527 3320 2685
  ADRs 364 (3.46) 135 (2.98) 133 (4.01) 96 (3.58)
  All ­hypoglycemiaa 34 (0.32) 9 (0.20) 18 (0.54) 7 (0.26)
   Hypoglycemia 25 (0.24) 5 (0.11) 15 (0.45) 5 (0.19)
   Blood glucose decreased 8 (0.08) 4 (0.09) 3 (0.09) 1 (0.04)
   Hypoglycemic unconsciousness 1 (0.01) 0 (0.00) 0 (0.00) 1 (0.04)
  Constipation 28 (0.27) 10 (0.22) 12 (0.36) 6 (0.22)
  Hepatic function abnormal 25 (0.24) 15 (0.33) 4 (0.12) 6 (0.22)
 Serious ADRs
  Serious ADRs 91 (0.86) 22 (0.49) 34 (1.02) 35 (1.30)
  All ­hypoglycemiaa 9 (0.09) 2 (0.04) 4 (0.12) 3 (0.11)
   Hypoglycemia 7 (0.07) 2 (0.04) 3 (0.09) 2 (0.07)
   Blood glucose decreased 1 (0.01) 0 (0.00) 1 (0.03) 0 (0.00)
   Hypoglycemic unconsciousness 1 (0.01) 0 (0.00) 0 (0.00) 1 (0.04)
Efficacy (efficacy analysis set)
 HbA1c (%)
  No. of patients at the start 9296 3995 2977 2324
  No. of patients at 2 years 4549 1966 1498 1085
  Change from baseline to 2 years − 0.75 (1.36)
[mean (SD)]
  LS mean (SE) − 0.72 (0.02) − 0.76 (0.02) − 0.77 (0.03)

Medical Dictionary for Regulatory Activities/Japanese (MedDRA/J), version 20.0

ADRs adverse drug reactions, LS least square, SE standard error, SD standard deviation
a
 ‘All hypoglycemia’ included hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness

(eGFR). Patients on dialysis were also included. The inci- teneligliptin 20 mg (n = 14) significantly reduced glycated
dence of ADRs ranged from 2.98–6.98% across subgroups. albumin (GA) compared with controls at week 28 (− 3.1%,
The difference in ADR incidence is possibly attributable to p < 0.05; baseline means of 21.9% in the control group and
bias associated with the limited number of patients in each 21.1% in the teneligliptin group) [55]. Furthermore, Homma
subgroup, especially the small number of patients with G4 et al. showed that treatment with teneligliptin (n = 15) over
(n = 215) or G5 (n = 60) CKD, or ESRD (n = 152); thus, it 12 weeks markedly reduced FPG compared with controls
cannot be concluded that the incidence differs according to (n = 10) [56]. Treatment with teneligliptin was well tolerated
renal function. Irrespective of renal function levels, treat- in both studies, with no episodes of hypoglycemia reported.
ment with teneligliptin over 2 years led to improvements in Wada et al. showed that 4-week teneligliptin treatment
glycemic control in all subgroups. (n = 10; patients had a GA level ≥ 18.3%) improved blood
glucose AUC as assessed by continuous glucose monitoring
(CGM) on both hemodialysis and non-hemodialysis days
10 Efficacy in Patients with Renal (both p = 0.004) and significantly reduced GA and FPG val-
Impairment ues, without severe hypoglycemia [57]. In a randomized,
crossover study in T2DM patients (n = 13) with CKD, Tan-
Because teneligliptin can be used in T2DM patients with aka et al. showed that teneligliptin 20 mg/day or linaglip-
renal impairment, including those on hemodialysis, with- tin 5 mg/day (administered once daily for 6 days and then
out the need for dose adjustment, the efficacy and safety of switching for a further 6 days) had comparable beneficial
teneligliptin in T2DM patients with CKD requiring hemo- effects on mean amplitude of glucose excursion, 24-h mean
dialysis has been assessed in several small observational sensor glucose levels, and AUC for sensor glucose levels
studies [55–59]. Otsuki et al. showed that administration of ≥ 180 mg/dL (AUC ≥ 180), with a comparable incidence of
 A. Ceriello et al.

hypoglycemia [58]. Finally, Yajima et al. assessed the effi- spin resonance spectroscopy using a spin trap agent to detect
cacy of once-daily teneligliptin 20 mg, when coadministered free radicals and estimate radical scavenging properties and,
with insulin in 21 T2DM patients on hemodialysis, by CGM in vivo, by assessing the effect of oral teneligliptin on uri-
and found that coadministration of teneligliptin and insulin nary excretion of 8-hydroxy-2ʹ-deoxyguanosine (8-OHdG)
significantly reduced median (interquartile range) total daily in DPP-4-deficient diabetic rats [63]. Teneligliptin scav-
insulin dose from 18 U (9–24) to 6 U (0–14) (p < 0.0001) enged ·OH in a dose-dependent manner, changing its struc-
and significantly reduced the incidence of asymptomatic ture to form metabolite M1, which is also found in vivo.
hypoglycemia on the hemodialysis day from 38.1 to 19.0% Teneligliptin was shown to have greater ·OH scavenging
(p = 0.049) [59]. Collectively, these results suggest that activity than glutathione, and had direct ·OH scavenging
teneligliptin is a valuable treatment option for glycemic properties that are not attributable to DPP-4 inhibition
control in patients with T2DM undergoing hemodialysis. because it was observed in DPP-4-deficient rats. The novel
chemical structure of teneligliptin may be responsible for its
·OH scavenging properties. In contrast, the DPP-4 inhibi-
11 Effects of Teneligliptin on Oxidative tors alogliptin and linagliptin do not exhibit O ­ 2− and ·OH
Stress and Endothelial Function scavenging properties [63].
Oxidative stress in perivascular adipose tissue (PVAT)
Teneligliptin appears to have multifaceted effects on contributes to systemic inflammation and may promote
endothelial function, via its antioxidant capabilities, anti- endothelial dysfunction and atherogenesis [64]. Oral
inflammatory properties, antiplatelet activity, and hydroxyl- administration of teneligliptin (60 mg/kg/day) to apolipo-
radical (·OH) scavenging properties. Oxidative stress protein-E-deficient (ApoE KO) mice for 20 weeks reduced
induced by elevated glucose levels facilitates cardiovascu- the expression of inflammatory molecules in PVAT, and
lar endothelial damage in T2DM [8, 9]. Two studies sought inhibited atherosclerosis compared with vehicle. Further-
to verify the potential protective action of teneligliptin or more, the administration of teneligliptin for 8 weeks ame-
teneligliptin in combination with GLP-1, in endothelial liorated endothelium-dependent vasodilation and reduced
cells exposed to high glucose (HG) [60, 61]. In both studies, oxidative stress, as determined by urinary 8-OHdG excre-
human umbilical vein endothelial primary cells (HUVECs) tion (p < 0.05), compared with vehicle [64]. Moreover, in
were exposed to normal glucose (NG; 5 mmol/L) or HG spontaneous hypertensive rats, SHR/NDmcr-cp (cp/cp),
(25 mmol/L) for 21 days, or to HG for 14 days followed long-term treatment with teneligliptin (10 mg/kg/day for
by NG for 7 days to mimic a high-metabolic memory state 12 weeks) significantly attenuated endothelial dysfunction
(HM). The cells were continually treated with either tenel- through the upregulation of endothelium-derived nitric oxide
igliptin (0.1, 1.0, and 3.0 μmol/L) or sitagliptin (0.5 μmol/L) synthase mRNA [65].
[60], or with teneligliptin (3.0 μmol/L) [61]. Teneligliptin A case-control study by Sagara et al. sought to elucidate
demonstrated antioxidant properties by reducing reactive the effect of teneligliptin on oxidative stress and endothe-
oxygen species (ROS) levels and initiating the transcriptional lial function in Japanese patients with T2DM and CKD.
cascade of antioxidant genes at the cellular level. Of note, Forty-five patients with T2DM and CKD who had received
the efficacy of teneligliptin 0.1 μmol/L at reducing ROS sitagliptin for at least 12 months were randomized to con-
was similar to that observed with sitagliptin 0.5 μmol/L, tinue sitagliptin (n = 23) or switch to teneligliptin (n = 22)
suggesting that teneligliptin has more potent antioxidant for 24 weeks. From baseline to 24 weeks, no significant
properties. Moreover, it enhanced proliferation and endo- between-group differences were noted regarding changes
plasmic reticulum homeostasis, reduced apoptosis in HG in HbA1c, eGFR, and urinary albumin excretion; however,
conditions, and overcame the metabolic memory effect [60, the switch to teneligliptin was associated with significantly
61]. GLP-1 has a vascular protective effect, which enhances improved values for reactive hyperemia index (RHI), a
the antioxidative pathway; however, hyperglycemia reduces measure of endothelial function. The antioxidant activity
its positive effect, a phenomenon known as ‘GLP-1 endothe- of teneligliptin was demonstrated by decreased levels of
lial resistance’ [62]. The combination of teneligliptin and derivatives of reactive oxygen metabolites, a novel marker
GLP-1 enhanced the antioxidant response of teneligliptin of oxidative stress; this antioxidant effect was strongly linked
in HG- and HM-exposed HUVECs, which suggests that the with the improved RHI values. The suppression by tenel-
simultaneous administration of these two drugs can counter igliptin of glucose fluctuations that induce oxidative stress,
GLP-1 endothelial resistance [61]. together with its antioxidant effects, may have contributed
In addition to inducing the transcriptional cascade of anti- to the improvement in vascular function [66].
oxidant genes, teneligliptin has ·OH scavenging properties. In a clinical study involving 103 individuals with T2DM,
While teneligliptin does not scavenge O ­ 2−, it has been shown 47 of whom were receiving hemodialysis, teneligliptin
to scavenge ·OH. This was confirmed by X-band electron 20 mg administered once daily for 3 months significantly
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

reduced plasma levels of soluble P-selectin, platelet-derived the potential for reduced efficacy [14, 72, 84]. Similarly,
microparticles, and plasminogen activator inhibitor 1 com- metabolism of saxagliptin is mediated via CYP3A4/5; thus,
pared with baseline levels, particularly in those receiving coadministration of CYP3A4/5 inhibitors and inducers can
hemodialysis, and significantly increased adiponectin levels alter its pharmacokinetics, and dose reductions should be
[67]. Similarly, Hashikata et al. showed that the administra- considered when saxagliptin is used in combination with
tion of teneligliptin in T2DM patients (n = 29) for 3 months CYP3A4 inhibitors [14, 74, 85]. Consideration of potential
resulted in improvements in left ventricular function (E/eʹ drug–drug interactions is particularly relevant for elderly
ratio) and endothelial function (based on reactive hyper- patients in whom polypharmacy is common, raising the
emia peripheral arterial tonometry [RH-PAT] value), and potential for diminishing treatment efficacy or increasing
increased serum adiponectin levels compared with baseline the risk of AEs [86].
levels, suggesting possible cardioprotective effects [68]. The
mechanism by which teneligliptin increases circulating adi-
ponectin remains to be determined. 13 Clinical Implications

Teneligliptin has unique pharmacokinetic and pharmacolog-

12 Comparison with Other DPP‑4 Inhibitors ical properties. From a pharmacokinetic perspective, tenel-
igliptin is metabolized by CYP3A4 and FMO3, or excreted
DPP-4 inhibitors have differing pharmacokinetic and phar- from the kidney in an unchanged form. Because of its mul-
macodynamic properties that may be clinically relevant tiple elimination pathways, dose adjustment is not needed
in certain patient groups. The main pharmacokinetic dif- in patients with hepatic or renal impairment, and it is con-
ferences between DPP-4 inhibitors marketed in Japan are sidered to have a low potential for drug–drug interactions.
summarized in Table 7 [69–82]. Elderly T2DM patients, especially those aged ≥ 80 years,
The elimination half-lives of DPP-4 inhibitors are widely frequently have reduced renal function [87]. Moreover,
variable, with half-lives ranging from approximately 2 h to elderly T2DM patients commonly have many medications
more than 100 h (Table 7). DPP-4 inhibitors vary in dosing prescribed [88]. As for FMO, a few drugs are metabolized by
regimens (once-daily, twice-daily, or once-weekly adminis- FMO (approximately 2%) [89, 90] and the enzyme activity
tration) according to their half-lives. of FMO3 does not differ between non-elderly (30–59 years)
A key difference in the pharmacokinetic properties of and elderly (60–79 years) populations [91]. Therefore, FMO
DPP-4 inhibitors is their varied elimination routes, and this is an important back-up mechanism. The involvement of
difference is related to the need for dose adjustments in multiple metabolic enzymes, together with multiple elimi-
T2DM patients with renal dysfunction. Whereas most DPP-4 nation pathways, may make teneligliptin less susceptible to
inhibitors predominantly undergo renal excretion, linagliptin age-related pharmacokinetic changes and drug–drug inter-
is excreted mostly unchanged in feces via biliary action [81], actions. In accordance with these characteristics, the phar-
and teneligliptin is eliminated by hepatic metabolism medi- macokinetic profile of teneligliptin does not differ between
ated by CYP3A4 or FMO3, or excreted from the kidney in non-elderly (45–64 years) and elderly (65–75 years) popula-
an unchanged form; thus, linagliptin and teneligliptin can be tions. Actually, the safety and efficacy profile of teneligliptin
administered without dose adjustments in T2DM patients appears to be unaffected by age in clinical studies or real-
with renal impairment. world clinical data (PMS). The pharmacokinetic profile in
Teneligliptin appears to be less affected by CYP3A4 broader populations, such as individuals aged ≥ 75 years,
and P-glycoprotein inhibitors, because, even if such inhi- has not yet been evaluated, and further research is needed
bition occurs, teneligliptin is still excreted via the kidneys to investigate the pharmacokinetic profile of teneligliptin in
and metabolized by FMO3. Conversely, the AUC from time very elderly patients.
zero to 24 h (AUC​24) of linagliptin used in combination with In addition to its DPP-4 inhibitory effect, teneligliptin
ritonavir, a CYP3A4 and P-glycoprotein inhibitor, increased has antioxidative properties, which induce the antioxidant
twofold compared with the AUC​24 for linagliptin monother- cascade, as well as ·OH scavenging properties. Furthermore,
apy, while the AUC during the dosing interval at steady-state teneligliptin has shown endothelial protective effects in sev-
(AUC​τ,ss) of linagliptin used in combination with rifampicin, eral non-clinical and clinical studies. Because teneligliptin
a CYP3A4 and P-glycoprotein inducer, decreased by 40% has been shown to overcome the metabolic memory effect
[81]. These effects may be the result of the inhibition/induc- in endothelial cells [60, 61], early treatment with teneliglip-
tion of gastrointestinal P-glycoprotein [81, 83] and the par- tin may be useful for preventing diabetic complications, in
tial inhibition/induction of CYP3A4. Therefore, linagliptin addition to its glucose-lowering effect. Collectively, these
needs to be used with caution in combination with CYP unique pharmacokinetic and pharmacological properties of
inhibitors or inducers owing to possible safety risks and


Table 7  Pharmacokinetic differences among dipeptidyl-peptidase-4 inhibitors

Teneligliptin Sitagliptin [69] Vildagliptin [70] Alogliptin [71] Linagliptin [72] Anagliptin [73] Saxagliptin [74] Trelagliptin [75] Omarigliptin [76]

Standard ­dosea Once daily 20 mg Once daily Twice daily Once daily Once daily 5 mg Twice daily Once daily 5 mg Once weekly Once weekly
50 mg 50 mg 25 mg 100 mg 100 mg 25 mg
Dose increasing Yes (40 mg) Yes (100 mg) No No No Yes (200 mg) No No No
Dose adjustment No Yes (12.5, Yes (50 mg, once Yes (6.25, No Yes (once daily, Yes (2.5 mg) Yes (50 mg) Yes (12.5 mg)
required in 25 mg) daily) 12.5 mg) 100 mg)
patients with
renal impair-
ment
t½, h [mean (SD)] 24.2 (5.0) 11.4 (2.4) 1.77 (0.23) 17.1 (2.0) 105 (8.26) b t½,α 2.02 (0.208) 6.47 (0.98) 54.3 (7.9) 38.89 (25.78)
t½,β 6.20 (3.11)
Excretion Metabolism/renal Renal excretion Metabolism Renal excretion Bile excretion Metabolism/renal Metabolism/renal Renal excretion Renal excretion
excretion excretion excretion
Metabolic CYP3A4 Minor Non-CYP Minor Minor DPP-4, car- CYP3A4/5 Minor No
enzyme [77] FMO3 CYP3A4 CYP2D6 CYP3A4 boxyesterase, CYP2D6
CYP2C8 CYP3A4 cholinesterase CYP3A4
Renal impairment 1.17- to 1.68-fold 1.61- to 4.50-fold 1.31- to 2.33-fold 1.7- to 3.8-fold 1.22- to 1.56-fold 1.65- to 3.22-fold 1.16- to 2.08-fold 1.56- to 3.68-fold 0.94- to 1.97-fold
(AUC) [78] [79] [80]
Drug–drug inter- 1.49-fold (keto- 1.29-fold (cyclo- 2.01-fold (ritona- 1.81-fold 2.45-fold (keto-
actions (AUC) conazole) sporine) vir) [81] (probenecid) conazole) [82]
0.61-fold
(rifampin) [81]

AUC​area under the plasma concentration time-curve, CYP cytochrome P450, FMO3 flavin-containing monooxygenase 3, SD standard deviation, t½ elimination half-life
a
 Approval dose in Japan
b
 Geometric mean
A. Ceriello et al.
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin

teneligliptin make it a valuable drug option for the treatment (http://creativecommons.org/licenses/by-nc/4.0/), which permits any
of a broad range of T2DM patients in clinical practice. noncommercial use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the
An FDC tablet of teneligliptin/canagliflozin was also source, provide a link to the Creative Commons license, and indicate
approved in Japan. Owing to the differences in their mecha- if changes were made.
nisms of action, teneligliptin and canagliflozin act in a com-
plementary manner. Body weight management is important
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