Chen Et Al-2015-Clinical and Experimental Pharmacology and Physiology

Clinical and Experimental Pharmacology and Physiology (2015) 42, 9991024
doi: 10.1111/1440-1681.12455
INVITED REVIEW
Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the

treatment of type 2 diabetes mellitus
Xiao-Wu Chen,* Zhi-Xu He, Zhi-Wei Zhou, Tianxin Yang, Xueji Zhang, Yin-Xue Yang,**
Wei Duan and Shu-Feng Zhou
*Department of General Surgery, The First Peoples Hospital of Shunde, Southern Medical University, Shunde, Foshan,
Guangdong, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research
Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou China,
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, Department of
Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT USA, Research
Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, **Department
of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia China and School of
Medicine, Deakin University, Waurn Ponds, Vic. Australia
SUMMARY
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral
antidiabetic drugs that improve glycaemic control without
causing weight gain or increasing hypoglycaemic risk in
patients with type 2 diabetes mellitus (T2DM). The eight
available DPP-4 inhibitors, including alogliptin, anagliptin,
gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin,
and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety proles in patients
with T2DM. DPP-4 inhibitors may be used as monotherapy
or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of
action, they differ by some important pharmacokinetic and
pharmacodynamic properties that may be clinically relevant
in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability,
elimination half-life, binding to plasma proteins, metabolic
pathways, formation of active metabolite(s), main excretion
routes, dosage adjustment for renal and liver insufciency,
and potential drug-drug interactions. The off-target inhibition
of selective DPP-4 inhibitors is responsible for multiorgan
Correspondence: Professor Shu-Feng Zhou, Global Medical Development, Department of Pharmaceutical Sciences, College of Pharmacy,
University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL
33612, USA. Email: szhou@health.usf.edu
and
Professor Zhi-Xu He, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre &
Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, 9 Beijing Road, Guiyang 550004, Guizhou, China. Email:
hzx@gmc.edu.cn
Received 13 November 2014; revision 11 June 2015; accepted 6 July
2015.
2015 Wiley Publishing Asia Pty Ltd
toxicities such as immune dysfunction, impaired healing, and

skin reactions. As a drug class, the DPP-4 inhibitors have
become accepted in clinical practice due to their excellent tolerability prole, with a low risk of hypoglycaemia, a neutral
effect on body weight, and once-daily dosing. It is unknown if
DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of
DPP-4 inhibitors for the management of T2DM when their
potential toxicities are closely monitored.
Key words: alogliptin, anagliptin, dipeptidyl peptidase-4
inhibitor, gemigliptin, linagliptin, saxagliptin, sitagliptin,
teneligliptin, type 2 diabetes, vildagliptin.
INTRODUCTION
Diabetes mellitus is a major health problem around the world,
with continued expansion of diabetes mellitus associated morbidity, mortality, reduced quality of life and increased healthcare
costs.13 Despite extensive research into diabetes and ongoing
education about diabetes prevention, its prevalence is still on the
rise. According to the International Diabetes Federation (IDF)
Diabetes Atlas Sixth Edition, 382 million people have diabetes;
5.1 million people died due to diabetes in 2013; the greatest
number of people with diabetes are between 40 and 59 years of
age; 175 million people with diabetes are undiagnosed; and at
least 548 billion US dollars were spent on healthcare for diabetes
in 2013.4 The IDF forecasts that the total number of people with
diabetes will rise to 592 million worldwide by 2035. Based on
the data from the 2014 National Diabetes Fact Sheet in the US,
29.1 million people (i.e. 9.3% of the population) had diabetes
with 8.1 million people undiagnosed, and 1.7 million new cases
of diabetes are diagnosed in people aged 20 years and older in
2012.5 Diabetes was the seventh leading cause of death in the
US in 2010 based on the 69 071 death certicates in which diabetes was listed as the underlying cause of death.5 Diabetes
increases the risk of heart disease or stroke by up to four times.
1000
X-W Chen et al.
The estimated total medical cost for diabetes was 245 billion dollars with 176 billion dollars as the direct cost in the US in
2012.5 In China, one in four people with diabetes worldwide
were in China in 2013, where 11.6% of adults had diabetes and
50.1% had prediabetes.6
In adults, type 2 diabetes mellitus (previously called non-insulin-dependent diabetes mellitus or adult-onset diabetes; T2DM)
accounts for about 9095% of all diagnosed cases of diabetes.
T2DM is a chronic endocrine and metabolic disorder characterized
by progressive hyperglycaemia secondary to declining b-cell function, and usually accompanied by a reduced sensitivity to insulin
in peripheral tissues, such as liver and muscles.1,3,7 When b cells
are no longer able to secrete sufcient insulin to overcome insulin
resistance, impaired glucose tolerance progresses to T2DM.
Abnormalities in other hormones such as reduced secretion of the
incretin glucagon-like peptide 1 (GLP-1), hyperglucagonemia, and
raised concentrations of other counter-regulatory hormones also
contribute to insulin resistance, reduced insulin secretion, and
hyperglycaemia in T2DM.3,8 T2DM is associated with older age,
obesity, family history of diabetes, history of gestational diabetes,
impaired glucose metabolism, physical inactivity, and race/ethnicity.1,2,9 Although genetic predisposition establishes susceptibility,
rapid changes in the environment (i.e., lifestyle factors) are the
most probable explanation for the increase in incidence of both
forms of diabetes.1 Key genes, including PPARG, CAPN10,
KCNJ11, TCF7L2, HHEXIIDE, KCNQ1, FTO, and MC4R, act in
conjunction with environmental factors, including pregnancy,
physical inactivity, quality and quantity of nutrients, puberty and
ageing, to promote adiposity, impair b-cell function, and impair
insulin action.9 The decline in b-cell function seems to involve
chronic hyperglycaemia (glucotoxicity), chronic exposure to nonesteried fatty acids (lipotoxicity), oxidative stress, inammation,
and amyloid formation. Insulin is a vital hormone produced by the
pancreas that allows blood glucose passage into the bodys cells,
fuelling the bodys systems. Patients with T2DM usually have pancreatic a-cell dysfunction that results in increased glucagon secretion in the presence of hyperglycaemia and probably reduced
prandial GLP-1 secretion.3,8,9 Without insulin, excess glucose
builds up in the bloodstream that leads to hyperglycaemia, a hallmark metabolic abnormality associated with T2DM. If untreated or
not well managed, long term hyperglycaemia can lead to increased
risk of macrovasulcar (cardiovascular, cerebrovascular and peripheral vascular diseases) and microvasulcar (nephropathy, neuropathy, and retinopathy) complications.1012
Being the key factor underlying complications of T2DM, to
reduce hyperglycaemia and reach target blood glucose level is a
critical goal in T2DM treatment.7,8,1114 Tight glycaemic control,
to maintain an HbA1C concentration of 7%, is recommended
by The American Diabetes Association for T2DM to minimize
the risk of long-term vascular complications.15 Despite the need
for intensive glucose control, only 57.1% of adults in the US
with T2DM reached this target.16 Glycaemic control can be
accomplished via different mechanisms either through the promotion of insulin level in the body or an increase in the insulin sensitivity of target cells, or via other glucose metabolism associated
pathways. These therapeutic effects can be achieved through
insulin sensitisers (e.g. biguanides), insulin secretagogues (e.g.
sulfonylureas and meglitinides) and external insulin delivery (insulin analogues).8,14,15 These therapies can control the glucose
homeostasis, however, they will bring about undesirable side

effects such as hypoglycaemia, weight gain, gastrointestinal disturbances, water retention, peripheral oedema, and potential cardiovascular events. Most of the initial improvements in
glycaemia by pharmacotherapy are not sustained because of continued b-cell dysfunction. A number of newer compounds with
different mechanisms of action have been developed for the treatment of T2DM. These new treatments are expected to sustain
glycaemic control, reverse or halt the decline in b-cell function,
assist with weight loss, improve insulin action, minimize hypoglycaemia, and have a favourable effect on cardiovascular system. This article aimed to highlight our knowledge on currently
clinically approved oral dipeptidyl peptidase 4 (DPP-4) inhibitors
used for the treatment of T2DM.
DPP-4 AND INCRETINS AS THERAPEUTIC

TARGETS FOR T2DM
The DPP family includes DPP-4, broblast activation protein
alpha (FAP; seprase), DPP-7 (DPP II; quiescent cell proline
dipeptidase), DPP-8, DPP-9, and prolyl carboxypeptidase (PCP;
angiotensinase C).1719 Each of them shows different patterns of
distribution, structure and substrate recognition. DPP-4, also
known as adenosine deaminase complexing protein 2 (ADCP2),
adenosine deaminase binding protein (ADABP), TP103 protein,
and T cell activation antigen CD26, is a serine protease that is
widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T lymphocytes, and
in a circulating form.20,21 As a membrane-spanning, cell-surface
aminopeptidase, it is ubiquitously expressed in many tissues,
such as gut, lymphocytes, liver, kidneys, and lungs. DPP-4
cleaves the two N-terminal amino acids from peptides with a proline or alanine in the penultimate (P1) position. DPP-4 has at
least 63 substrates including growth factors, chemokines, neuropeptides, and vasoactive peptides. Chemokines regulated by
DPP-4 include but are not limited to: CCL3/MIP-1a, CCL4/MIP1b, CCL5/RANTES, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP10, CXCL11/I-TAC and CXCL12/SDF-1a.22 The non-enzymatic
function of DPP-4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase.22 DPP-4 may
also regulate inammatory responses in innate immune cells such
as monocytes and dendritic cells. DPP-4 appears to be especially
critical for the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide [also known as gastric inhibitory polypeptide (GIP)].20,21
The human DPP-4 gene is conserved in chimpanzee, Rhesus
monkey, dog, mouse, rat, chicken, zebrash, fruit y, mosquito,
Caenorhabditis elegans, Saccharomyces cerevisiae, Kluyveromyces lactis, Eremothecium gossypii, Schizosaccharomyces
pombe, Magnaporthe oryzae, Neurospora crassa, and frog. It has
been mapped to chromosomal 2q24.3 with 26 exons, encoding a
766-amino acid protein.2325 DPP-4 is a 110-kDa transmembrane
glycoprotein constitutively expressed as a dimer on epithelial
cells of the liver, hepatocytes, kidney and intestinal tissues, as
well as in some endothelial cells, broblasts and lymphocytes. It
also exists in soluble form lacking the cytoplasmic and transmembrane domain, and is present in different biological uids
such as serum, plasma, and seminal uid and in low amounts in
the cerebrospinal uid. DPP-4 cleaves N-terminal dipeptides from
DPP-4 inhibitors in diabetes treatment

polypeptides with either L-proline or L-alanine at the penultimate
position.22 In many instances, this results in regulation of the
substrate, inactivating the ligand activity or altering its function.
Glucagon-like peptide 1 and GIP are intestinal incretin hormones released in response to food ingestion.26 GLP-1, secreted
from intestinal L cells, is an incretin derived from the transcriptional product of the proglucagon gene. GIP is derived from a
153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. It is synthesized by K cells, which are located in the mucosa of the
duodenum and the jejunum of the gastrointestinal tract. Both
GLP-1 and GIP enhance meal-related insulin secretion and promote glucose tolerance, a phenomenon called incretin
effect.21,26 Besides insulin secretion enhancement via cAMP-dependent signalling pathways, GLP-1 also suppress glucagon
secretion from a-cells in the islets of Langerhans in the pancreas
in a glucose-dependent manner, and glucagon secretion is inhibited under hyperglycaemic conditions and even increased under
hypoglycaemia. Animal studies indicate that GLP-1 independently promotes the accumulation of glycogen in the liver,
increases glucose uptake, and lowers concentrations of triglycerides.27 Moreover, GLP-1 slows gastric emptying and gastrointestinal motility, slowing down the rise of blood glucose level.26
All of which result in a glucose-lowering effect. It also acts as a
mediator of satiety in the hypothalamus. In healthy and T2DM
patients, these actions are responsible for decreased caloric intake
and consecutive weight loss followed by GLP-1 infusions.26
GLP-1 also promotes b-cell regeneration and reduces b-cell apoptosis, which provide hope for preservation of b-cell functions in
T2DM patients.26 In patients with T2DM, concentrations of
GLP-1 are reduced but the insulin response to GLP-1 is preserved.
Continuous infusion of GLP-1 for 6 weeks to patients with
T2DM increased insulin secretion, reduced HbA1C by 1.3%, and
normalized both fasting and post-prandial blood glucose levels
without seeing serious adverse effects.28 However, active GLP-1
(GLP-1[736]amide) is rapidly degraded by DPP-4. Endogenously released GLP-1 has a short biological half-life of 1.5
5 min and the serum half-life of GIP is 57 min.26 Upon secretion, GLP-1 and GIP are rapidly degraded and inactivated by
DPP-4. To extend the half-life, DPP-4-resistant GLP-1 analogues
with GLP-1 receptor agonist properties have been developed,
including exenatide, liraglutide, lixisenatide, albiglutide, and
dulaglutide that have been approved by the Food and Drug
Administration (FDA).2933 On the other hand, DPP-4 inhibitors
have been developed and used to prevent degradation of endogenously released GLP-1 and GIP, consequently enhancing plasma
level of active incretins in circulation, prolonging the actions of
the incretin, consequently leading to increased insulin level.34 In
patients with T2DM, the incretin effect is reduced, thus scientists have adopted the incretin concept in attempts to develop
incretin-based therapeutic agents.
Dipeptidyl peptidase-4 inhibitors may be classied into peptidomimetic (i.e., sitagliptin, teneligliptin, vildagliptin, saxagliptin,
and anagliptin) and non-peptidomimetic (i.e., alogliptin and linagliptin) subtypes (Fig. 1, Table 1). Due to the substrate site
specicity, many DPP-4 inhibitors have substituted pyrrolidines
or thiazolidines as a proline mimetic in the P1 part. DPP-4 inhibitors developed initially possess an electrophilic trap such as a
1001
Fig. 1 Chemical structures of clinically approved DPP-4 inhibitors,

including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin.
nitrile group to form a covalent bond with Ser630 of the catalytic

triad in the active site, but these DPP-4 inhibitors possessing the
electrophilic trap are unstable and have a low selectivity against
other related prolyl peptidases, DPP-8 and DPP-9. The chemical
instability is due to intramolecular cyclization between the electrophilic nitrile and the amine of the P2 part, and the poor selectivity is probably due to covalent bond formation with Ser630
which is a conserved amino acid located in the S1 subsite of
DPP-4, DPP-8, and DPP-9.35 Inhibition of DPP-8 and DPP-9 are
associated with multiorgan toxicities in rats and dogs and inhibition of T cell activation and proliferation,36 a high DPP-4 selectivity is critical for DPP-4 inhibitor development and clinical
application.
ALOGLIPTIN
Pharmacodynamics of alogliptin
Alogliptin (Nesina); 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl)benzonitrile)
developed by Takeda Pharmaceuticals (Osaka, Japan), obtained
approval by the Pharmaceuticals and Medical Devices Agency
63.376
1013
95
Renal excretion (%)

Faecal excretion (%)
% Excreted unchanged
73.2
26.0
50
5
85
90
120184
1.56
Renal:
70 mL/min
5.335.1 nmol/L
(2.510 mg oral)
97256 ng/mL
(12.550 mg oral)
4.37
1.8
70
20
21.1
12
233.3 mL/min (renal:
160 mL/min)
368918
29.5
25400 mg
417 (12.5 mg oral)
100
23
34
> 10 000
75
22
24
2.23.8
2
Renal:
76 mL/min
7587
1321
79
416 mL/min;
renal: 340
mL/min
814
38
< 10
7188
80
0.79
> 2600
18
100
Piperazine
198
2454 ng/mL
Sitagliptin
Januvia
151
75
1.52
70
0.70.9
100
0.5
5
Methanoprolinenitrile
+
5
Pyrimidine
Onglyza
Saxagliptin
Tradjenta
Linagliptin
70
Zemiglo
Gemigliptin
7593
> 73
59 000 (DPP-8),
>100 000
(DPP-9)
> 14 000
0.561.77
3.8
Pyrimidine
Suiny
100
Anagliptin
Nesina
6.25, 12.5, and 25
25
Pyrimidine
Alogliptin
t1/2b (h)
Tmax (h)
CL/F
Cmax
Reduction in HbA1C
(%)
% Inhibition of plasma
DPP-4 activity
Fold increase in active
GLP-1 level
Pharmacokinetics
Oral bioavailability
(%)
Linear kinetics (mg)
Volume of distribution
(Vd, L)
Fraction bound to
plasma proteins (%)
Peptidomimetic
Pharmacodynamics
IC50 for DPP-4
inhibition (nmol/L)
DPP-4 selectivity (vs
DPP-8 and 9)
Trade name(s)
Dosage form(s) (mg)
Usual daily dose (mg)
Structural class
Parameter
Table 1 Clinical pharmacokinetic and pharmacodynamics properties of selective DPP-4 inhibitors
35.8
33.3 (faecal)
Renal: 14.8%;
faecal: 26.1%
over 120 h
24.2
1
169 mL/h per kg
187.2 ng/mL
(20 mg oral)
77.682.2
106.8
5883
0.71.2
> 16811 248
0.91.8
Tenelia
20
20
Teneligliptin
(continued)
210397 ng/mL
(25100 mg
oral)
2.8
1.52
546.7 mL/h
per kg
Renal: 192
mL/h per kg
85
24.5
22.6
9.3
50100
70.5
8485
23
80
0.51.2
100
3.5
Galvus
50 and 100
100
Cyanopyrrolidine
Vildagplitin
1002
X-W Chen et al.
M-I (3% of
parent drug
activity; M-II
not active)
Unknown
Unknown
Active metabolite(s)
Substrate for P-gp
Substrate for other

transporters
Toxicology
Adverse effects

Unknown
Unknown
No
Unknown
Anagliptin
Gemigliptin
Unknown
Unknown
No
Linagliptin
Headache,
nasopharyngitis,
upper respiratory
tract infections,
and urinary
tract infections
Unknown
Hydroxylated
metabolite
(50% activity
of parent
drug)
Unknown
Saxagliptin
Cmax, maximal concentration; CL, systematic clearance; i.v., intravenous; SC, subcutaneous injection; tb, elimination half-life.
Nasopharyngitis,
headache, and upper
respiratory tract
infection;
Rare: acute
pancreatitis (0.2%),
hypersensitivity (0.6%),
hypoglycaemia (1.5%)
+ (also for
CYP2D6)
Alogliptin
Substrate for
CYP3A4/5
Parameter
Table 1 (continued)
Gastrointestinal
adverse events
such as diarrhoea
and nausea
No
+ (also CYP2C8)
Sitagliptin
Nasopharyngitis,
increased levels
of alanine
aminotransferase
and c-glutamyltransferase
+ (Km = 16.9
lmol\L)
+ (M1 + M3)
CYP2D6:
M1 + M4
FMO1 and
FMO3: M1
Teneligliptin
Unknown
Unknown
No
No
Vildagplitin
1003
1004
X-W Chen et al.
(PMDA) of Japan in April 2010.37,38 In January 2013, the FDA

of the US approved the drug in three formulations: as a standalone, in combination with metformin (Kazano) or with pioglitazone (Oseni). Alogliptin selectively inhibits DPP-4 with an IC50
of 7 nmol/L and has exhibited more than 14 000-fold selectivity
over the related serine proteases DPP-8 and DPP-9.39,40 It is
intended to be used as an adjunct to diet and exercise to improve
glycaemic control in adults with T2DM. Alogliptin can be used
as monotherapy or in combination with other antidiabetic agents,
including metformin, pioglitazone, sulfonylureas, and insulin.
Alogliptin is available as a 6.25, 12.5, and 25 mg tablet. For
detailed clinical pharmacology of alogliptin, please read recent
reviews about this drug.38,4149
Alogliptin as monotherapy or added to metformin,5052 pioglitazone,5356 glipizide,57,58 glyburide/glibenclamide,59 voglibose,6062 miglitol,62 acarbose,63 or insulin64,65 signicantly
improves glycaemic control compared with placebo or active
comparators in adult or elderly patients with inadequately controlled T2DM. This is associated with good gastrointestinal tolerability and a low incidence of hypoglycaemia.
Single-dose administration of alogliptin to healthy subjects
resulted in a peak inhibition of DPP-4 within 23 h after dosing.
Single doses of alogliptin from 25 to 800 mg produced peak
DPP-4 inhibition ranging from 93.3% to 98.8%. The mean DPP4 inhibition ranged from 74.3% to 97% at 24 h and from 47.5%
to 83% at 72 h. Multiple-dose administration of alogliptin to
patients with T2DM also resulted in a peak inhibition of DPP-4
within 12 h and exceeded 93% across all doses (25, 100, and
400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained
above 81% at 24 h after 14 days of dosing. Following 14 days
of once-daily dosing with doses from 25 to 400 mg alogliptin,
peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 h after the last dose ranged from 82% to 97%.66
Plasma GLP-1 concentrations were increased two to sixfold in
alogliptin-treated subjects.66
glycaemic rescue therapy. There was no body weight gain

observed.
In a 26-week, double-blind, active-controlled, parallel-group
study, a total of 655 drug-nave patients with mean baseline
HbA1C 8.8% were randomized to receive alogliptin 25 mg alone
(n = 160), pioglitazone 30 mg alone (n = 153), alogliptin
12.5 mg with pioglitazone 30 mg (n = 184), or alogliptin 25 mg
with pioglitazone 30 mg once daily (n = 158).53 Patients treated
with 25 mg alogliptin alone (n = 160) had a reduction of 1.0%
HbA1C, with 24% (40/164) of the patients achieving
HbA1C 7.0% at week 26. Combined use of alogliptin 25 mg
and pioglitazone 30 mg once daily resulted in signicant reduction in plasma HbA1C ( 1.7%) and FPG ( 24 mg/dL) compared
to either monotherapy, with 63% (103/164) achieving
HbA1C 7.0% at week 26.53 The combination therapy was as
well tolerated as the monotherapies.53
In the double-blind, placebo-controlled phase of a two-part
study, 480 drug-nave Japanese patients with T2DM inadequately
controlled by diet and exercise were randomized to receive alogliptin, placebo, or voglibose (an a-glucosidase inhibitor).68
Patients were rst treated with alogliptin 6.25, 12.5, 25 or 50 mg
once daily, placebo, or voglibose 0.2 mg three times daily for
12 weeks. In a subsequent open-label, long-term extension phase,
patients continued on the same treatment for an additional
40 weeks (patients in the placebo group were reassigned equally
to one of the four alogliptin dosages). HbA1C was dose-dependently reduced by alogliptin, and the changes versus baseline
were statistically signicant with all four dosages in comparison
with both placebo and voglibose at week 12. In addition, changes
in FPG and PPG AUC12 h values were signicantly greater with
all four dosages of alogliptin in comparison with placebo.68 The
incidence of adverse events with alogliptin over 52 weeks was
not dose-dependent and was lower than with voglibose. Hypoglycaemia occurred infrequently and was generally mild. Changes in
body weight with alogliptin were minimal (< 0.5 kg).
Combination therapy
Monotherapy
A total of 1768 patients with T2DM with inadequate glycaemic
control through diet and exercise were randomized to receive alogliptin or placebo in three double-blind Phase II/III studies.53,67
All three studies had a 4-week, single-blind, placebo run-in period followed by a 26-week treatment period. Patients who failed
to meet prespecied hyperglycaemic goals during the 26-week
treatment periods received glycaemic rescue therapy. In a 26week, double-blind, placebo-controlled study, a total of 329 drugnave patients with a mean baseline HbA1C of 7.9% were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily.67 Treatment with alogliptin 12.5 and 25 mg
resulted in signicant improvements from baseline HbA1C and
fasting plasma glucose (FPG) compared to placebo at week 26.
Patients treated with 25 mg alogliptin (n = 128) had a reduction
of
0.6% HbA1C, with 44% of the patients achieving
HbA1C 7.0% at week 26. Signicant changes in FPG were
seen as early as week 1, and signicant changes in HbA1c were
observed as early as week 4. A total of 8% of patients receiving
alogliptin 25 mg and 30% of those receiving placebo required
In a multicentre, randomized, double-blind, placebo-controlled,

and 26-week study, 784 patients with T2DM (mean baseline
HbA1C = 8.4%) were randomized to receive placebo (n = 102),
metformin 500 mg twice daily (n = 103), metformin 1000 mg
twice daily (n = 108), alogliptin 12.5 mg twice daily (n = 104),
alogliptin 25 mg daily (n = 154), alogliptin 12.5 mg twice daily
with metformin 500 mg twice daily (n = 102), or alogliptin
12.5 mg twice daily with metformin 1000 mg twice daily
(n = 111). Alogliptin 12.5 mg twice daily was paired with twice
daily metformin immediate release in two treatment arms. Both
alogliptin 12.5 mg and metformin 500 or 1000 mg resulted in
statistically signicant improvements in HbA1C and FPG control
when compared to the monotherapies. The coadministration treatment arms also demonstrated improvements in 2-h postprandial
plasma glucose (PPG) and enabled more patients to reach goal
HbA1C compared to the monotherapy arms (47 and 59% vs
2034%). A total of 12.3% of patients receiving alogliptin
12.5 mg plus metformin 500 mg, 2.6% of patients receiving alogliptin 12.5 mg plus metformin 1000 mg, 17.3% of patients receiving alogliptin 12.5 mg, 22.9% of patients receiving metformin

500 mg, 10.8% of patients receiving metformin 1000 mg and
38.7% of patients receiving placebo required glycaemic rescue.
Two clinical studies have investigated the efcacy and safety
of alogliptin as add-on therapy to metformin in 2081 patients
with T2DM.50,55 In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at
the maximum tolerated dose. All patients entered a 4-week, single-blind, placebo run-in period prior to randomization. Patients
who failed to meet pre-specied hyperglycaemic goals during the
26-week treatment periods received glycaemic rescue therapy.
The rst study evaluated the efcacy and safety of alogliptin for
26 weeks at once-daily doses of 12.5 or 25 mg in 527 patients
with T2DM on metformin (median dose = 1700 mg) whose
HbA1c levels were inadequately controlled on metformin alone.50
Patients were randomized to continue a stable daily metformin
dose regimen ( 1500 mg) plus placebo (n = 104) or alogliptin
at once-daily doses of 12.5 (n = 213) or 25 mg (n = 210). Alogliptin at either dose resulted in a signicant decrease in HbA1C
( 0.6%) and FPG ( 17.0 mg/dL) than those observed with placebo. The between treatment differences (alogliptin placebo) in
FPG reached statistical signicance (P < 0.001) as early as week
1 and persisted for the duration of the study. Overall, adverse
events observed with alogliptin were not substantially different
from those observed with placebo. This included low event rates
for gastrointestinal side effects and hypoglycaemic episodes.50
The second 26-week study assessed the efcacy and tolerability
of alogliptin plus pioglitazone in 1554 metformin-treated patients
on stable-dose metformin monotherapy ( 1500 mg/day) with
inadequate glycaemic control.55 The doses for alogliptin were
12.5 or 25 mg once daily alone or combined with pioglitazone at
15, 30, or 45 mg once daily. When added to metformin, the least
squares mean change from baseline HbA1C was 0.9% in the
pioglitazone-alone group and 1.4% in both the alogliptin 12.5
or 25 mg plus pioglitazone groups (P < 0.001).55 Alogliptin at
12.5 or 25 mg plus pioglitazone produced greater reductions in
FPG than pioglitazone alone. In addition, alogliptin at 12.5 or
25 mg plus pioglitazone signicantly improved b-cell function,
but had no effect on insulin resistance. Hypoglycaemia was
reported by 1.0, 1.5, and 2.1% of patients in the 12.5 mg alogliptin plus pioglitazone, alogliptin 25 mg plus pioglitazone, and
pioglitazone alone groups, respectively.
In a randomized, double-blind, placebo-controlled, 26-week
study, T2DM patients (n = 784) received placebo, alogliptin
12.5 mg twice daily or 25 mg once daily, metformin (500 or
1000 mg twice daily), or alogliptin 12.5 mg twice daily plus
metformin 500 or 1000 mg twice daily.52 The mean HbA1C
reduction from baseline (8.45%) was 1.22% and 1.55% for
alogliptin 12.5 mg twice daily plus metformin 500 mg or 1000
twice daily groups versus 0.56%, 0.65%, and 1.11% for
alogliptin 12.5 mg, metformin 500 mg and 1000 mg twice daily
groups, respectively (P < 0.001). FPG reduction was 1.76 and
2.55 mmol/L for alogliptin 12.5 mg twice daily plus metformin 500 mg or 1000 twice daily groups versus 0.54, 0.64
and 1.78 mmol/L for alogliptin 12.5 mg, metformin 500 mg
and 1000 mg twice daily groups, respectively (P < 0.05).52
Alogliptin plus metformin caused only mild to moderate hypoglycaemia (1.95.3%) and weight loss (0.61.2 kg). These data
demonstrate that alogliptin plus metformin initial combination
therapy was more efcacious in controlling glycaemia in
1005
drug-nave T2DM patients than either as monotherapy and well

tolerated.
In a 26-week, placebo-controlled study, a total of 493 patients
inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline
HbA1C = 8%) were randomized to receive alogliptin 12.5 mg,
alogliptin 25 mg, or placebo.54 Patients were maintained on a
stable dose of pioglitazone (median dose = 30 mg) during the
treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median
dose = 10 mg) prior to randomization were maintained on the
combination therapy during the treatment period. All patients
entered into a 4-week single-blind, placebo run-in period prior to
randomization. Patients who failed to meet pre-specied hyperglycaemic goals during the 26-week treatment period received
glycaemic rescue therapy. The addition of alogliptin 25 mg once
daily to pioglitazone therapy resulted in statistically signicant
improvements from baseline in HbA1C and FPG at week 26,
compared to placebo.54 A total of 9% of patients who were
receiving alogliptin 25 mg and 12% of patients receiving placebo
required glycaemic rescue. Improvements in HbA1C were not
affected by gender, age, baseline body mass index (BMI), or
baseline pioglitazone dose. Clinically meaningful reductions in
HbA1C were observed with alogliptin compared to placebo
regardless of whether subjects were receiving concomitant metformin or sulfonylurea ( 0.2% placebo vs 0.9% alogliptin)
therapy or pioglitazone alone (0% placebo vs 0.52% alogliptin).54 The mean increase in body weight was similar between
alogliptin and placebo when given in combination with pioglitazone.
In a randomized, double-blind, placebo-controlled study, 71
patients with well-controlled T2DM (mean HbA1C 6.7%) were
treated with combined alogliptin 25 mg and pioglitazone 30 mg
daily or alogliptin 25 mg daily monotherapy or placebo for
16 weeks.56 Main outcome measures included change in HbA1C
and FPG from baseline to week 16. In addition, change in b-cell
function parameters obtained from standardized meal tests at
baseline and at week 16 was measured. Alogliptin plus pioglitazone and alogliptin decreased HbA1C from baseline by 0.9 and
0.4%, respectively (both P < 0.001 vs placebo).56 FPG was
decreased to a greater extent by alogliptin plus pioglitazone compared with alogliptin alone (P < 0.01). The combination treatment also improved b-cell glucose sensitivity (P < 0.001; vs
placebo) and fasting secretory tone (P = 0.001; vs placebo),
while alogliptin monotherapy did not change b-cell function. All
treatments were well tolerated.
In a 52-week, active-comparator study, a total of 803 patients
inadequately controlled (mean baseline HbA1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least
1500 mg per day or at the maximum tolerated dose were randomized to receive either the addition of alogliptin 25 mg or the
titration of pioglitazone 3045 mg following a 4-week singleblind, placebo run-in period.51 Patients were maintained on a
stable dose of metformin (median dose = 1700 mg). Patients
who failed to meet prespecied hyperglycaemic goals during the
52-week treatment period received glycaemic rescue therapy. In
combination with pioglitazone and metformin, alogliptin 25 mg
was shown to be statistically superior in lowering HbA1C and
FPG compared with the titration of pioglitazone from 30 mg to
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X-W Chen et al.
45 mg at week 26 and week 52.51 A total of 11% of patients in

the alogliptin 25 mg treatment group and 22% of patients in the
pioglitazone up titration group required glycaemic rescue. There
was no body weight gain in both treatment arms.
In a randomized, placebo-controlled study, 500 T2DM patients
inadequately controlled on a sulfonylurea (mean baseline
HbA1C = 8.1%) were randomized to receive alogliptin 12.5 mg,
alogliptin 25 mg, or placebo for 26 weeks.59 Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a 4-week
single-blind, placebo run-in period prior to randomization.
Patients who failed to meet pre-specied hyperglycaemic goals
during the 26-week treatment period received glycaemic rescue
therapy. The addition of alogliptin 25 mg to glyburide therapy
resulted in statistically signicant improvements from baseline in
HbA1C at week 26 when compared to placebo.59 Improvements
in FPG observed with alogliptin 25 mg were not statistically signicant compared with placebo. A total of 16% of patients
receiving alogliptin 25 mg and 28% of those receiving placebo
required glycaemic rescue. No body weight gain was observed in
all treatment groups.
Combination treatment with alogliptin and voglibose for
3 weeks increased active GLP-1 circulation, prevented the development of diabetes and preserved pancreatic b-cells in prediabetic
db/db mice.69 In a randomized, double-blind study, the efcacy
and safety of alogliptin and placebo as add-on therapy were
explored in Japanese patients with T2DM who experienced inadequate glycaemic control on voglibose plus diet/exercise therapy.60 During an 8 week screening phase, patients aged
20 years were stabilized on voglibose 0.2 mg three times daily
plus diet/exercise therapy. Those with HbA1C between 6.9%
and < 10.4% were randomly assigned to treatment with once
daily alogliptin 12.5 or 25 mg, or placebo for 12 weeks. Patients
then entered an open-label, 40 week extension trial (patients in
the placebo group were randomly allocated to alogliptin 12.5 or
25 mg). The mean change in HbA1C at week 12 from baseline
was signicantly greater in the alogliptin 12.5 mg ( 0.96%) and
25 mg ( 0.93%) groups compared with placebo.60 This was
associated with statistically reduced FPS and PPS. These benets
were maintained for the duration of the 1 year study without
detrimental effects on tolerability/safety. Addition of once daily
alogliptin to voglibose monotherapy in Japanese patients with
uncontrolled T2Dm produced clinically signicant improvements
in glycaemic control, and was well tolerated.
In a 26-week, placebo-controlled study, a total of 390 patients
inadequately controlled on insulin alone (42%) or in combination
with metformin (58%) (mean baseline HbA1C = 9.3%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo.64 Patients were maintained on their insulin regimen
(median dose = 55 IU) upon randomization and those previously
treated with insulin in combination with metformin (median
dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the
trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet pre-specied hyperglycaemic goals during the 26 month treatment period received
glycaemic rescue therapy. The addition of alogliptin 25 mg once
daily to insulin therapy resulted in statistically signicant
improvements from baseline in HbA1C and FPG at week 26,
when compared to placebo.64 A total of 20% of patients receiving alogliptin 25 mg and 40% of those receiving placebo
required glycaemic rescue. Improvements in HbA1C were not
affected by gender, age, baseline BMI, or baseline insulin dose.
Clinically meaningful reductions in HbA1C were observed with
alogliptin compared to placebo regardless of whether subjects
were receiving concomitant metformin and insulin ( 0.2% placebo vs 0.8% alogliptin) therapy or insulin alone (0.1% placebo
vs 0.7% alogliptin).64
A pooled analysis of six randomized, double-blind, placebocontrolled Phase II/III studies reviewed patients aged 1880.70 A
total of 455 patients were 65 years of age. The pooled analysis
showed that changes in HbA1C were similar between younger
and elderly patients taking alogliptin 25 mg daily ( 0.6%
younger and 0.8% elderly). The changes in HbA1C and FPG,
although slightly improved in the elderly when compared to the
younger, were not statistically signicant.70 The percentage of
elderly patients achieving goal HbA1C of 7% was slightly
improved over the younger patient but not statistically signicant.
Regardless of age, patients with a baseline HbA1C of > 8% had
larger absolute decreases in HbA1C than those patients with a
baseline HbA1C < 8.0%. The incidence of hypoglycaemia was
8.3% or less in both alogliptin groups for both age groups and
did not seem to be dose related.70 The majority of patients experiencing hypoglycaemia were also taking a sulfonylurea or insulin. In this pooled analysis, alogliptin 12.5 mg and 25 mg were
similarly efcacious in younger and elderly patients. Moreover,
there was no increased risk of hypoglycaemia or other adverse
events in elderly patients taking alogliptin.
Pharmacokinetics of alogliptin
Pharmacokinetics of alogliptin in healthy subjects and T2DM
patients
After administration of single, oral doses up to 800 mg in
healthy subjects or patients with T2DM, the peak plasma alogliptin concentration (Cmax) occurred 12 h postdosing.39,40,71 The
area under the plasma concentration-time curve (AUC) increases
in a dose-dependent manner over a range of doses from 25 to
800 mg.66 The absolute bioavailability of alogliptin is approximately 100%.72 Alogliptin is 20% bound to plasma proteins. At
the maximum recommended clinical dose of 25 mg, alogliptin
was eliminated with an elimination half-life (tb) of about
21 h.39,40 The systemic clearance is 233 mL/min (i.e. 14.0 L/h),
with a renal clearance of 160 mL/min (i.e. 9.6 L/h), indicating
some active renal tubular secretion. Following a single, 12.5 mg
intravenous infusion of alogliptin to healthy subjects, the volume
of distribution (Vd) was 417 L. After multiple-dose administration
up to 400 mg for 14 days in patients with T2DM, accumulation
of alogliptin was minimal with an increase in AUC and Cmax of
alogliptin by 34% and 9%, respectively. The inter-individual
coefcient of variation for alogliptin AUC was 17%. The pharmacokinetics of alogliptin was shown to be similar in healthy
subjects and in patients with T2DM.
Alogliptin exists predominantly as the (R)-enantiomer (> 99%)
and undergoes little or no chiral conversion in vivo to the (S)enantiomer. The (S)-enantiomer is not detectable at the 25 mg
dose. About 10% of alogliptin is metabolized and 6071% of the

dose is excreted as unchanged drug in the urine within 24
72 h.39 Two minor metabolites were detected following administration of an oral dose of [14C]-alogliptin, N-demethylated, M-I
(< 1% of the dose), and N-acetylated alogliptin, M-II (< 6% of
the dose).72 M-I is an active metabolite that inhibits DPP-4 similar to the parent molecule, but M-II is inactive. Alogliptin is
mainly metabolized by CYP2D6 and 3A4.71,73
Pharmacokinetics of alogliptin in specic populations
Alogliptin is mainly cleared renally. However, dose adjustment
for patients with mild renal impairment (creatinine clearance 60 mL/min) is not recommended.74 In patients with moderate renal impairment (creatinine clearance 30 to <60 mL/
min), a 2.1-fold increase in plasma AUC of alogliptin was
observed, and the recommended dose is 12.5 mg once daily.74 In
patients with severe renal impairment (creatinine clearance 15
to < 30 mL/min) and end-stage renal disease (creatinine clearance < 15 mL/min or requiring dialysis), a 3.2- to 3.8-fold
increase in plasma AUC of alogliptin were observed, and the recommended dose is 6.25 mg once daily.74 The Cmax of alogliptin
was increased 1.1- to 1.4-fold. Metabolite exposure remained low
in all subjects. Approximately 7.2% (3.6 mg) of a 50-mg oral
dose was removed after 3 h of hemodialysis.74 The AUC of alogliptin was about 10% lower and Cmax was approximately 8%
lower in patients with moderate hepatic impairment (Child-Pugh
Grade B) compared to healthy subjects.71,75 Alogliptin pharmacokinetics were not signicantly altered in subjects with mild to
moderate hepatic impairment. Age did not have any clinically
meaningful effect on the pharmacokinetics of alogliptin. Race
(white, black, and Asian) did not have any clinically meaningful
effect on the pharmacokinetics of alogliptin.
Adverse effects of alogliptin
Approximately 8500 patients with T2DM have been treated with
alogliptin in 14 randomized, double-blind, controlled clinical
studies with approximately 2900 subjects randomized to placebo
and approximately 2200 to an active comparator.50,54,58,59,64,76
The mean exposure to alogliptin was 40 weeks with more than
2400 subjects treated for more than 1 year. Among these
patients, 63% had a history of hypertension, 51% had a history
of dyslipidemia, 25% had a history of myocardial infarction, 8%
had a history of unstable angina, and 7% had a history of congestive heart failure. The mean duration of T2DM was 7 years,
the mean BMI was 31 kg/m (51% of patients had a
BMI 30 kg/m), and the mean age was 57 years (24% of
patients 65 years of age). Two placebo-controlled monotherapy
trials of 12 and 26 weeks of duration were conducted in patients
treated with alogliptin 12.5 mg daily, alogliptin 25 mg daily and
placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin,
with a sulfonylurea, with a thiazolidinedione, and with insulin.
Five placebo-controlled trials of 16 weeks up through 2 years in
duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy. Three active-controlled trials of
52 weeks in duration were conducted in patients treated with
1007
pioglitazone and metformin, in combination with metformin and

as monotherapy compared to glipizide.51,58
In a pooled analysis of these 14 controlled clinical trials, the
overall incidence of adverse events was 66% in patients treated
with alogliptin 25 mg compared to 62% with placebo and 70%
with active comparator. Overall discontinuation of therapy due to
adverse events was 4.7% with alogliptin 25 mg compared to
4.5% with placebo or 6.2% with active comparator. More than
4% of 5902 patients taking 25 mg alogliptin from 14 randomized, double-blind, controlled clinical trials experience mild
adverse reactions including nasopharyngitis (4.4%), headache
(4.2%), and upper respiratory tract infection (4.2%).
Hypoglycaemia is seen in about 1.5% of the patients. In the
26-week monotherapy study, the incidence of hypoglycaemia
was 1.5% in patients treated with 12.5 or 25 mg alogliptin daily
(n = 264) compared to 1.6% with placebo (n = 65).67 The
26-week use of alogliptin as add-on therapy to glyburide (9.6%
vs 11.1%) or insulin (27% vs 24%) did not signicantly increase
the incidence of hypoglycaemia compared to placebo.59,64 In a
52-week monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycaemia was
5.4% (22/222) with alogliptin compared to 26% with glipizide
(57/219).58
Rare but severe adverse reactions such as acute pancreatitis,
serious hypersensitivity including anaphylaxis, angioedema, and
severe cutaneous reactions such as StevensJohnson syndrome
have been reported from postmarketing monitoring.4146,66 The
overall incidence of hypersensitivity reactions was 0.6% in
patients taking alogliptin 25 mg compared to 0.8% with all comparators including glipizide, glyburide, insulin, metformin, pioglitazone, and placebo. In the clinical trial program, pancreatitis was
reported in 11 of 5902 (0.2%) patients receiving alogliptin 25 mg
daily compared to ve of 5183 (< 0.1%) patients receiving all
comparators. In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with alogliptin 25 mg compared to
0.8% with all comparators. A single event of serum sickness was
reported in a patient treated with alogliptin 25 mg.
Treatment of T2DM patients with alogliptin at 50 or 400 mg
for 7 days does not prolong QTc. White et al.77 have conducted
a pooled analysis and concluded that the incidence rate of
adverse cardiovascular (CV) events in patients treated with 12.5
or 25 mg alogliptin daily is rare. The composite major adverse
cardiovascular event (MACE) end points included CV death,
nonfatal myocardial infarction, and nonfatal stroke. The pooled
analysis included 4168 patients treated with alogliptin compared
to 691 patients treated with placebo and 1169 patients treated
with other antidiabetic agents such as metformin, sulfonylureas
and thiazolidinediones with a duration of 1652 weeks. A total
of 13 MACEs were seen in the 4168 patients randomized to alogliptin and 10 MACEs in 1860 patients randomized to comparator therapies.77 The incidence rates of the combined MACE were
not signicantly different between patients treated with alogliptin
and comparator therapies. A total of 10 non-MACEs occurred in
the 4168 patients randomized to alogliptin and three non-MACEs
in 1855 patients randomized to comparator therapies. The CV
events (MACE and non-MACE) were distributed similarly
between event types. These analyses do not show a signal of
increased CV risk with alogliptin.
X-W Chen et al.
1008
The long-term CV safety of alogliptin was evaluated in a recent

randomized, placebo-controlled, noninferiority trial, Examination
of Cardiovascular Outcomes with Alogliptin versus Standard of
Care (EXAMINE), involving 5380 patients with T2DM and a
recent acute coronary syndrome (ACS).78 The primary end point
included a composite of CV death, nonfatal myocardial infarction,
or nonfatal stroke. Patients were followed for up to 40 months. The
primary end point occurred in 305 (11.3%) patients taking alogliptin and in 316 (11.8%) patients taking placebo (hazard ratio, 0.96;
upper boundary of the one-sided repeated condence interval,
1.16; P < 0.001 for noninferiority). EXAMINE concludes that
among patients with type 2 diabetes who have had a recent ACS,
the rates of major adverse CV events are not increased with alogliptin when compared to placebo.
Drug interactions with alogliptin
Alogliptin is not an inducer or inhibitor of human CYP1A2,
CYP2B6, CYP2C9, CYP2C19, and CYP3A4. Clinically relevant
interactions have not been observed with the CYP substrates or
inhibitors tested or with renally excreted drugs including caffeine
(CYP1A2 substrate), tolbutamide (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), midazolam or atorvastatin
(CYP3A4 substrates), and digoxin and fexofenadine (P-gp/MDR1
substrates). Alogliptin pharmacokinetics were not altered by administration with a potent CYP2C9 inhibitor (uconazole), CYP3A4
inhibitor (ketoconazole), or CYP2C8/9 inhibitor (gembrozil).73
Pharmacokinetic interactions have also not been observed
between alogliptin and glyburide, metformin, or pioglitazone.76
Alogliptin did not have a signicant effect on the pharmacokinetics or pharmacodynamics (prothrombin time or international normalized ratio) of warfarin with coadministration.73 When used in
conjunction with alogliptin, a reduced dose of insulin or insulin
secretagogues, such as sulfonylureas, may be required to minimize the risk of hypoglycaemia.
ANAGLIPTIN
Pharmacodynamics of anagliptin
Anagliptin (Suiny); N-[2-[[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide) was developed by Sanwa Kagaku
Kenkyusho Co. (Mie, Japan) and approved by the PMDA of Japan
in September 2012. It is indicated for the treatment of T2DM
patients given orally at 100 mg once daily. It is a highly selective
and potent inhibitor for DPP-4, with an IC50 of 3.4 nmol/L.79,80
Anagliptin improved glycaemic control in T2DM patients with a
minimal risk of hypoglycaemia and weight gain.
Pharmacokinetics of anagliptin
The pharmacokinetics of anagliptin has been investigated after a
single oral dose of 100 mg [14C]anagliptin to healthy men
(n = 6).81 Almost all the dose (98.2%) was recovered within
168 h, with 73.2% in urine and 25.0% in faeces. Anagliptin was
rapidly absorbed, with peak plasma concentrations of unchanged
drug achieved at a mean time of 1.8 h postdose. Mean fraction
of the dose absorbed was > 73%. Unchanged drug and a
carboxylate metabolite (M1) were the major components detected

in plasma, accounting for 66.0 and 23.4% of total plasma
radioactivity AUC, respectively.81 Anagliptin was partially
metabolized, with approximately 50% dose eliminated as
unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism
to M1 accounted for 29.2% of the dose. The t1/2b of anagliptin
and M1 was 4.37 and 9.88 h, respectively. Renal clearance of
unbound anagliptin and M1 far exceeded glomerular ltration
rate, indicating transporter-mediated active renal elimination.81
Safety of anagliptin
Two phase III trials to evaluate the efcacy and safety of anagliptin in drug-nave T2DM patients and compare the efcacy
and safety of anagliptin as an add-on to metformin in T2DM
patients have shown that the use of anagliptin in patients with
T2DM is considered to be safe and effective for both monotherapy and combination therapy.8284
GEMIGLIPTIN
Pharmacodynamics of gemigliptin
Gemigliptin tartrate sesquihydrate (Zemiglo); previously known
as LC15-0444; (3S)-3-amino-4-(5,5-diuoro-2-oxopiperidino)-1[2,4-di(triuoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin7-yl]butan-1-one) was co-developed by LG Life Science (Seoul,
Korea) and Double-Crane Pharmaceutical Co. (Beijing, China). It
gained approval from Korea Food & Drug Administration in June
2012, indicated for T2DM as a monotherapy or in combination
with metformin.85
Gemigliptin is a potent, competitive, reversible, long-acting
DPP-4 inhibitor (IC50 = 16 nmol/L) with over 3000-fold selectivity over other DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase,
and cathepsin G.85 Gemigliptin resulted in a dose-dependent inhibition of plasma DPP-4 activity and ~80% inhibition of plasma
DPP-4 activity were observed at the plasma gemigliptin levels of
9, 7, and 2 ng/mL in rats, dogs and monkeys, respectively, with
better in vivo potency compared to sitagliptin. In healthy subjects,
a single oral dose of 200 mg of gemigliptin inhibited plasma
DPP-4 activity by > 80% over a 24-h dosing interval, and a 600mg dose increased active GLP-1 levels after a standardized
meal.86 Similar DPP-4 inhibition was observed when healthy volunteers were treated with multiple doses of gemigliptin at 200,
400, and 600 mg once daily for 10 days.87 Inhibition of DPP-4
activity by > 80% was maintained for the whole duration of the
dosing interval after the rst dose, for at least 36 h after the last
dose, and for 48 h in the 600-mg group.87 Multiple doses of
gemigliptin produced 1.82.8-fold increases in weighted active
GLP-1 levels after meals, compared with placebo, at 4, 10 and
24 h after administration. Multiple doses of gemigliptin generally
decreased the PPG levels, and there was a statistically signicant
decrease in glucose at 10 h after dosing on day 10, but had no
remarkable effect on insulin levels.87
Monotherapy
In a multicentre, randomized, placebo-controlled, double-blind
Phase II trial in 145 drug-nave patients with T2DM treated by

diet and exercise, the optimal dose, efcacy and safety of gemigliptin were evaluated.88 The median baseline FPG was
8.1 mmol/L, and the median HbA1C was 7.9% and the median
time since the diagnosis of T2DM was 3 years. After 2 weeks of
an exercise/diet program followed by 2 weeks of a placebo period, the subjects were randomized to one of the four following
groups for a 12-week active treatment period: placebo and 50,
100 or 200 mg of gemigliptin.88 All three doses of gemigliptin
signicantly reduced the HbA1C from baseline compared to the
placebo group ( 0.06 vs 0.98, 0.74 and 0.78% in the placebo and 50, 100 and 200 mg groups, respectively), without a
signicant difference between the doses. Subjects with a higher
baseline HbA1C ( 8.5%) had a greater reduction in HbA1C. Insulin secretory function improved signicantly with gemigliptin
treatment.88 Insulin sensitivity, as assessed using homeostasis
model assessment-insulin resistance, also improved signicantly
after 12 weeks of treatment. The 50 and 200 mg groups had signicantly reduced total cholesterol and low-density lipoprotein
cholesterol levels at 12 weeks compared to the placebo group.
No body weight gain was observed. The incidences of adverse
events were similar and not different from placebo in all study
subjects. This study showed that gemigliptin 50 mg for 12 weeks
improved the HbA1C, FPG level, oral glucose tolerance test
results, b-cell function and insulin sensitivity in T2DM patients.
Based on the results from this Phase II trial, the daily dose of
50 mg gemigliptin was selected for the next Phase III studies.
Next, a 24-week, randomized, double-blind, placebo-controlled
Phase III trial was conducted in 182 patients (74 from Korea and
108 from India) with T2DM.89 After an initial 2 weeks of a diet
and exercise program followed by 2 weeks of a single-blind placebo run-in period, eligible patients were randomized to gemigliptin 50 mg or placebo, receiving the assigned treatment for
24 weeks. HbA1C and FPG were measured periodically, and oral
glucose tolerance test was performed at baseline and weeks 12
and 24. At week 24, gemigliptin treatment led to signicant
reductions in HbA1c compared to placebo (adjust mean after subtracting the placebo effect size:
0.71%).89 A signicantly
greater proportion of patients achieved an HbA1C < 7% with
gemigliptin than with placebo (43% vs 18%). The placebo-subtracted FPG change from baseline at week 24 was 19.80 mg/
dL. The overall incidence rates for adverse events were similar in
the gemigliptin and placebo groups.89 This study showed the efcacy and safety of gemigliptin 50 mg administered once daily as
a monotherapy for T2DM patients.
Combination therapy
The efcacy of gemigliptin as an add-on therapy was evaluated
in a 24-week, multinational, active-controlled, parallel group,
double-blind Phase III study in patients with T2DM inadequately
controlled with metformin alone.90 In this add-on therapy trial,
the efcacy of gemigliptin was compared with sitagliptin as head
to head trial. A total of 425 patients were randomized into one of
three treatments: 50 mg gemigliptin once daily, 25 mg gemigliptin twice daily, or 100 mg sitagliptin once daily as add-on to ongoing metformin therapy. At week 24, both gemigliptin treatments of 50 mg once daily and 25 mg twice daily reduced
HbA1C by 0.81 and 0.77%, respectively, which were non-inferior
to 0.80% with 100 mg sitagliptin once daily.90 The proportion of
1009
patients achieving HbA1C < 7% with gemigliptin 25 mg twice

daily (50%) or 50 mg once daily (54%) was comparable to the
results with sitagliptin 100 mg once daily (49%). There were signicant decreases in FPG and PPG, improvements in glucose tolerance during OGTT, and increases in GLP-1 and b-cell
sensitivity to glucose in patients receiving gemigliptin treatment
with their metformin therapy.90 There was no increased risk of
adverse effects with gemigliptin compared to sitagliptin 100 mg
once daily.
Pharmacokinetics of gemigliptin
In a Phase I single-dose study with 60 healthy male subjects,
gemigliptin was readily absorbed after single oral dosing with
median Tmax occurring at 2.0 h (0.55.1 h) post-dose and its
mean t1/2b was 16.721.3 h at all dose levels from 25 to 600 mg
daily.86 Gemigliptin exhibited linear kinetic properties over the
range of 50400 mg. The mean fraction of unchanged drug
excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.523.6 L/h.86 Pharmacokinetic proles of gemigliptin were not signicantly inuenced by high-fat diet.
The pharmacokinetics of gemigliptin were examined after multiple oral doses at 200, 400 and 600 mg once daily for 10 days
in 30 healthy non-smoking Korean male subjects in a randomized, double-blind, placebo-controlled, parallel group study.87
Gemigliptin was readily absorbed during multiple oral dosing,
reaching maximum plasma levels (Tmax) at 1.05.0 h after dosing
and apparently achieving a steady state after the second dose.
The mean t1/2b was 16.620.1 h across the dose groups. The
mean CL/F by dose groups ranged from 43.0 to 52.7 L/h under
steady state conditions. The AUC during the dosing interval generally increased in proportion to the dose over the dose range
studied. The mean accumulation ratios were between 1.22 and
1.31 among the dose groups.87 The mean renal clearance and
fraction of unchanged drug excreted in urine was independent of
dose in the range of 0.400.48 L/h and 18.621.9 L/h at steady
state, respectively.87 No dose- or time-dependent change in CL/F
or renal CL of gemigliptin was observed. These data demonstrate
that the pharmacokinetics of gemigliptin are linear from 200 to
600 mg.
Following oral administration of 50 mg (5.4 MBq) 14C-gemigliptin to healthy male subjects, its absorption, metabolism and
excretion were investigated.91 A total of 90.5% of administered
dose was recovered over 192 h postdose, with 63.4% from urine
and 27.1% from faeces. Based on urinary recovery of radioactivity, a minimum 63.4% absorption from gastrointestinal tract
could be conrmed. Twenty-three metabolites were identied in
plasma, urine and faeces. In plasma, gemigliptin was the most
abundant component, accounting for 67.2% (approximately
100% of plasma radioactivity). LC15-0636, a hydroxylated
metabolite of gemigliptin, was the only human metabolite with
systemic exposure more than 10% of total drug-related exposure.91 Unchanged gemigliptin accounted for 44.8% (approximately 67.2% of urinary radioactivity) and 27.7%
(approximately 51.8% of faecal radioactivity). The elimination of
gemigliptin was balanced between metabolism and excretion
through urine and faeces. CYP3A4 was identied as the dominant CYP converting gemigliptin to LC15-0636 in recombinant
CYP enzymes.91
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X-W Chen et al.
In an open-label, randomized, single dose, two-period, two-sequence crossover study in 24 healthy male volunteers, the effect of
food on the pharmacokinetics of gemigliptin/metformin sustainedrelease 50/1000 mg (25/500 mg 9 two tablets) xed dose combination tablet was investigated.92 The gemigliptin/metformin
sustained-release tablets (25/500 mg 9 two tablets) were administered in high-fat fed and fasted states on separate occasions, and
each subject was randomly allocated to each sequence with a 7-day
washout period. Pharmacokinetic blood samplings were conducted
from predose to 48 h after dosing. Tolerability assessments were
performed throughout the study. Nine adverse events of mild intensity were reported from eight subjects after study drug administration, and the adverse event frequency was similar between
treatment groups.92 No serious adverse effects were reported. The
pharmacokinetic parameters of gemigliptin and metformin were
compared between fasting and fed states. For gemigliptin, the geometric mean ratios (fed vs fasted state) of the Cmax and AUC were
0.886 and 1.021, respectively.92 For metformin, the geometric
mean ratios of the Cmax and AUC were 0.811 and 1.144, respectively. A prolonged Tmax for metformin was observed. These
results are similar to the effects of food on each component. The
gemigliptin/metformin sustained-release xed dose tablet may have
a similar pharmacokinetic prole as that of individual drugs and is
generally tolerable when administered with food.
Adverse effects of gemigliptin
In early Phase I clinical trials, gemigliptin was well tolerated: in
both a single ascending dose study from 25 mg to 600 mg86 and a
multiple ascending dose study from 200 mg to 600 mg87 in healthy
Korean male subjects. In both the single and multiple ascending
dose studies, none of the subjects developed any serious clinical or
laboratory adverse events or discontinued the study due to an
adverse event.86,87 All adverse events were mild or moderate, and
no dose-related trends were observed. In the single ascending dose
study, 46 adverse events were reported in 18 subjects (30.0%).86
Adverse events considered to be related to the study drug were
headache (six cases), dizziness (two), nausea (three), epistaxis
(four), and increased heart rate (ve). All adverse events resolved
spontaneously.86 In the multiple ascending dose study, 13 of the 30
subjects (43.3%) reported a total of 26 adverse events.87 Of these
adverse events, a total of 14 (11 in the gemigliptin group and three
in the placebo group) were considered to be possibly related to the
study drug. Adverse events considered to be related to the study
drug were headache and dizziness (three cases each), somnolence,
dyspepsia, aphthous stomatitis, rash morbilliform, hyperthermia,
pyrexia, palpitations and increased heart rate (a single case each).87
All adverse events resolved spontaneously without any concomitant medication. In both clinical studies, there were no reports of
hypoglycaemic symptoms or signs, or of any signicant abnormalities on clinical laboratory tests, 12-lead electrocardiogram, or impedance cardiography. This drug was well tolerated in T2DM
patients and the tolerability proles of gemigliptin were similar to
placebo in Phase II and III trials.8890
Drug interactions with gemigliptin
In vitro studies suggested that gemigliptin had no signicant
inhibition or induction potential of major human CYPs and P-gp,
whilst gemigliptin was a substrate of both CYP3A4 and P-gp.85

Co-administration of a single dose of gemigliptin 50 mg and
multiple once daily doses of ketoconazole 400 mg, a potent inhibitor of CYP3A4 and P-gp, increased the total active moiety by
1.94-fold. Calculation of total active moiety was based on both
the systemic exposure and relative activities of gemigliptin and
active metabolite. Rifampin (600 mg once daily at steady state),
a strong inducer of CYP3A4 and P-gp, signicantly decreased
the total active moiety by 70%. These CYP3A-based studies suggested no need of gemigliptin dose adjustment with CYP3A4
inhibitors but efcacy of gemigliptin may be reduced with several CYP3A4 inducers including rifampin, rifabutin, rifapentin,
dexamethasone, phenytoin, carbamazepine, and phenobarbital in
humans.93
Co-administration of multiple once daily doses of gemigliptin
200 mg and pioglitazone 30 mg decreased the plasma Cmax and
AUC of pioglitazone by 16% and 15%, respectively, while it
caused no alteration in the pharmacokinetics of gemigliptin.94
LINAGLIPTIN
Linagliptin (Tradjenta & Trajenta); previously called BI-1356; 8[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione)
was approved by the FDA in May 2011. It is used as a
monotherapy or in combination with metformin (Jenadueto). The
chemical structure of linagliptin has a xanthine base, differing
from other DPP-4 inhibitors, and may reect differences in pharmacokinetic and pharmacodynamic properties.95 For the clinical
pharmacology of linagliptin, please read recent reviews.95123
Pharmacodynamics of linagliptin
Linagliptin is highly potent, selective, long-acting, and orally
bioavailable inhibitor for DPP-4, but not for DPP-8 (40 000-fold)
or DPP-9 (> 10 000-fold) activity in vitro, with a relatively low
selectivity for FAP-a (89-fold).124 It is a competitive, selective
and reversible inhibitor for DPP-4 with a Ki of 1 nmol/L, indicating strong binding, and a low dissociation rate of the enzyme.
The maximal efcacy for in vitro DPP-4 inhibition is similar
among all DPP-4 inhibitors, however, linagliptin has greater
potency than other DPP-4 inhibitors (IC50 = ~1 nmol/L for linagliptin vs 19, 62, 50 and 24 nmol/L for sitagliptin, vildagliptin,
saxagliptin and alogliptin, respectively).95
In healthy male volunteers, linagliptin at 2.5600 mg demonstrated dose-dependent inhibition of DPP-4 over 24 h with a
5 mg dose inhibiting 86.1% of the enzyme activity.125 Early clinical studies with linagliptin suggested a reduction in the HbA1C
levels in patients with T2DM while maintaining a placebo-like
safety and tolerability prole.126
Monotherapy
The efcacy of linagliptin as monotherapy, compared to placebo,
was assessed in two studies of 12 and 24 weeks.127,128 The linagliptin was signicantly more effective than placebo in reducing HbA1C.
Also independent of baseline HbA1C, the results were favourable for
linagliptin; for baseline HbA1C 9.0%, 8.0% to < 9.0%, 7.5%
to < 8.0% and < 7.5%, the respective placebo-adjusted mean

changes were
1.1% (P < 0.0001),
0.71% (P < 0.0001),
0.55% (P < 0.005) and 0.57.127
The results of linagliptin monotherapy were also better than
placebo in the secondary endpoints. There was more reduction in
FPG and 2-h PPG in the linagliptin group. The adjusted mean
change in FPG was 1.3 mmol/L (P < 0.0001), and in 2-h PPG
was 3.2 mmol/L (P < 0.0001). The percentage of patients with
HbA1C < 7% after 24 weeks was 25.2% (77/306) in the linagliptin group compared to 11.6% (17/147) in the placebo group
(OR = 2.9, P = 0.0006).128 Besides, there was signicant
improvement in b-cell function markers in those receiving linagliptin.127,128
Kawamori et al.127 also compared linagliptin monotherapy
with voglibose, an a-glucosidase inhibitor, in a 26-week study.
More patients receiving linagliptin achieved HbA1C 7%
(30.3%) when compared to voglibose (22.2%). The percentage of
patients achieving a reduction 0.5% in HbA1C with linagliptin
(57.2%) was also greater than those with voglibose (37.7%)
(P < 0.0001).
Combination therapy
Graefe-Mody et al.129 evaluated in a randomized, open-label,
crossover, single-centre study, the potential pharmacokinetic and
pharmacodynamic interaction between metformin and linagliptin.
The coadministration of metformin 850 mg, three times daily and
linagliptin (10 mg once daily) did not modify the pharmacological prole of each drug alone. This study suggested that the combination of metformin and linagliptin can be done safely in
patients with T2DM, without requiring dose adjustment.
In a 24-week study with about 700 patients, the addition of
linagliptin to the therapeutic regimen in diabetic patients inadequately controlled on metformin, HbA1C reduction from baseline
was 0.64% with the linagliptin versus placebo.130
Haak115 reported the ndings of early combination of linagliptin and metformin in treatment-nave diabetic patients, in a 24week double-blind study. Compared to metformin monotherapy
(1000 mg), the early combination of metformin (1000 mg) and
linagliptin (5 mg) was more effective in reducing HbA1C ( 1.7%
vs 0.8%, P < 0.0001). Substantial reduction in FPG from baseline to Week 24 was found with the combination therapy.115 The
adjusted mean reduction in FPG was 1.2 mmol/L in the group
with added linagliptin, and in 2-h PPG was 3.7 mmol/L
(P < 0.0001 for all comparisons).115
In a 12-week study, linagliptin 5 mg (single daily dose) was
added to the metformin treatment (n = 333 patients), and was
signicantly more effective than placebo and the 1-mg or 10-mg
doses.131
In a 12-week analysis, 333 T2DM patients inadequately controlled on metformin monotherapy were randomized to receive
linagliptin or glimepiride, in a single daily dose.132 After
12 weeks, HbA1C has decreased both in the linagliptin or glimepiride groups. This study showed that linagliptin has the same
efcacy as sulfonylureas, without risk of weight gain and hypoglycaemia.
Linagliptin was also evaluated in combination with pioglitazone, in a 24-week investigation (n = 389 patients).133 The addition of linagliptin (5 mg) to pioglitazone (30 mg), both
administered in a single daily dose, caused an adjusted mean
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placebo-corrected reduction of 0.5% in HbA1C levels from baseline at the end of 12 weeks, remaining constant until the 24th
week. The group receiving the linagliptin/pioglitazone combination showed more signicant reductions in FPG than placebo/pioglitazone group (P < 0.0001). More patients in the linagliptin/
pioglitazone group (42.9%) achieved the target HbA1C < 7%,
compared to the placebo-pioglitazone group (30.5%,
P < 0.0051). The HbA1C reduction was greater in patients with
baseline HbA1C 9% and treated with linagliptin in combination
with pioglitazone ( 1.49%).133 Body weight remained stable up
to 24 weeks in the two groups. This combination can be interesting, even for early therapy in patients with an intolerance or contraindication to metformin.
In patients inadequately controlled on sulfonylurea alone, the
addition of linagliptin 5 mg (single daily dose) proved more
effective than the combination with placebo.132
In this double-blind study, 245 patients were randomized to
receive linagliptin (n = 161) or placebo (n = 84) for
18 weeks.134 The HbA1c reductions were signicant in favour of
linagliptin at weeks 6, 12 and 18 (P < 0.0001).
In a randomized, double-blind, placebo-controlled study, investigators have screened 1058 T2DM patients inadequately controlled on metformin (> 1500 mg/day) and sulfonylurea
(maximum tolerated dose) to receive the combination with linagliptin 5 mg (single daily dose) or placebo.135 Assessing the total
patients included, the adjusted mean change in HbA1C level was
0.72% in the linagliptin group compared with 0.10% in the
placebo group, resulting in a difference of 0.62% (P < 0.0001)
with placebo. Fewer patients receiving linagliptin required rescue
therapy compared with placebo (5.4% vs 13.0%). More patients
on linagliptin also achieved the target HbA1C. The importance of
this study in practice is the possibility to improve glycaemic control in patients already receiving two oral antidiabetic agents and
who are outside the proposed targets.
Pharmacokinetics of linagliptin
Pharmacokinetics in healthy subjects and T2DM patients
Linagliptin shows modest oral bioavailability, but is rapidly
absorbed. The absolute bioavailability of linagliptin is around
30%. Following oral administration, the majority (about 90%) of
linagliptin is excreted unchanged. After oral administration of a
single 5-mg dose to healthy subjects, peak plasma concentrations
of linagliptin occurred at approximately 1.5 h postdose; the mean
AUC was 139 nmol/h per L and Cmax was 8.9 nmol/L. The Cmax
at steady state was reached on average 1.5 h after administration
of linagliptin 5 mg once daily in T2DM patients.126 Linagliptin
had an elimination half-life of 131 h. High-fat food did not affect
the absorption prole of linagliptin in healthy subjects receiving
a single oral dose of 5 mg linagliptin.136 The concurrent intake
of food increased the Tmax by approximately 2 h and reduced
Cmax by about 15% only.
After a single intravenous dose of 5 mg and a single oral dose
of 10 mg of [14C]linagliptin, the parent compound was detectable
in plasma of 12 healthy male subjects up to 264 h.137 After intravenous administration, the Cmax of linagliptin and its pharmacologically inactive metabolite CD1790 was 82.7 and 5.3 nmol/L at
1.25 and 2.14 h postdose, respectively. CD1790 was identied as
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X-W Chen et al.
S-3-hydroxy piperidinyl derivative of linagliptin with R-conguration at the chiral aminopiperidine moiety. Linagliptin showed a
low total clearance with 150 mL/min and a long terminal half-life
of 142 h in plasma.137 The half-life of CD1790 was 15.9 h. After
oral administration, the absorption of linagliptin was variable,
which demonstrated a biphasic absorption prole.137 CD1790 in
plasma was observed almost simultaneously with linagliptin. The
Cmax of linagliptin and CD1790 of 16.3 and 4.2 nmol/L was
observed at 2.75 and 2.26 h postdose, respectively.137 The total
clearance of linagliptin was 374 mL/min, and the terminal halflife was 155 h in plasma. The half-life of CD1790 was 10.8 h.
The ratio of total radioactivity of plasma to whole blood was
0.679 and 0.703 after intravenous and oral administration, respectively, indicating that most of the radioactivity was associated to
plasma.137
After intravenous administration, the mean recovery of the
administered dose was 89.0% (range, 87.291.6%), with 30.8%
(range, 27.032.7%) excreted in urine and 58.2% (range, 55.5
62.6%) excreted in faeces.137 The renal excretion of linagliptin
accounted for 21.2% of the dose. After oral administration, the
mean recovery of the administered dose was 90.1% (range, 84.0
95.9%), with 5.4% (range, 1.311.6%) excreted in urine and
84.7% (range, 78.391.9%) excreted in faeces.137 After 120 h,
2.4% of the dose was excreted as unchanged linagliptin in urine.
Renal excretion of CD1790 was negligible with less than 0.1%
of the dose after both oral and intravenous administration. Urine
up to 48 h and faeces up to 240 h were analyzed for metabolites
covering 80.7% (i.v.) and 87.0% (oral) of excreted radioactivity.
Linagliptin was predominantly eliminated unchanged after both
oral and intravenous administration.137 The sum of 78.0% of the
oral dose and 61.1% of the intravenous dose was assigned to the
parent compound in excreta corresponding to 89.7% (oral) and
75.7% (i.v.) of recovered radioactivity of the investigated sample
material. M489(1) formed by hydroxylation of the methyl group
of the butinyl side chain was observed as metabolite with highest
abundance in excreta with 9.6% (i.v.) and 4.7% (oral) of the
dose.137 Several minor metabolites accounted for 2.5% (i.v.)
and 4.5% (oral) of the dose in excreta. They were formed by
combinations of the following reactions: oxidation of the butinyl
side chain and the piperidine moiety [M490(1), M478(1), M504
(2)] followed by oxidative degradation of the piperidine moiety
[M506(1), M476(1)], N-acetylation [M515(1), M531(1), M531
(2)], and glucuronidation [M650(1), M665(3) M665(8)].137 The
oxidation of the methyl group at position 4 of the quinazoline
moiety resulted in the corresponding carboxylic acid derivative
M503(1). A cysteine adduct [M636(2)] and its sulphate conjugate
[M716(1)] were additionally observed with 0.1% of the dose after
intravenous administration in urine.137
CD1790 was formed via the corresponding ketone by oxidative
desamination followed by stereoselective reduction predominantly
by cytosolic aldo-keto reductases.137 In plasma after oral administration only CD1790 accounted for more than 10% of total drugrelated compounds (16.9%).137 The turnover of [14C]linagliptin
(50 lmol/L) with human liver microsomes and human hepatocytes in the presence of NADPH was low. CD1790, which was
identied as a major metabolite in vivo, accounted for 23% of
total radioactivity.137 When linagliptin was incubated with recombinant human P450 enzymes, the only enzyme that was active in
metabolizing linagliptin was CYP3A4. A two-step mechanism
was proposed for the formation of CD1790: in the rst step, the
secondary amine of linagliptin was converted by oxidative
desamination to the corresponding ketone CD10604. This step
was rate-limiting and CYP3A4-dependent. Subsequently,
CD1790 was formed by reduction of CD10604, with high stereoselectivity.
Incubations of CD10604 with human liver microsomes and
human liver cytosol demonstrated the preferential contribution of
cytosolic enzymes in the formation of CD1790.137 The formation
of CD1790 was higher by a factor of 25 in cytosol compared
with human liver microsomes, indicating the involvement of
aldo-keto reductase (AKR) enzymes or carbonyl reductases (CR).
Maximal turnover rates were achieved at pH 5.5. Enzyme kinetic
investigations resulted in Km and Vmax values of 12.6 lmol/L
and 1138 pmol/min per mg protein, respectively.137 CD1790 formation was inhibited by phenolphthalein, ufenamic acid,
medroxyprogesterone acetate, and dexamethasone, indicating an
involvement of AKR enzymes. In additional, the ketone-reducing
activity of human whole blood and human plasma was investigated. Twenty-three per cent of CD10604 was converted to
CD1790 in blood within 1 h, whereas no turnover was observed
in human plasma.137
The potential chiral inversion of linagliptin to BI1355 and the
stereoselectivity of the formation of CD1790 were investigated in
human plasma samples after a single oral dose of 600 mg of linagliptin.137 Here, only the parent compound with R-conguration
and the metabolite CD1790 with S-conguration were identied.
The antipodes BI1355 and CD1789 were not detectable. With
mean concentrations of linagliptin and CD1790 of 1736 and
110 ng/mL, the plasma concentrations of linagliptin and CD1790
were at least 7500- and 2300-fold higher than the concentration
of the antipodes.137 Therefore, the enantiomeric excess for both
linagliptin and CD1790 accounted for > 99.9%. The results
demonstrate that there was negligible chiral inversion of linagliptin in vivo in humans, if present it all, and that the formation of
the corresponding S-congured alcohol CD1790 was highly stereoselective.137
The pharmacokinetics of linagliptin were shown to be nonlinear due to target-mediated, concentration-dependent changes in
binding to DPP-4.125,126,138 Unlike other DPP-4 inhibitors, linagliptin excretion was not via the kidneys, but rather through the
enterohepatic system, unchanged.
Most gliptins exhibit a low binding to plasma proteins.40,75
Linagliptin, however, extensively binds to plasma proteins in a
dose-dependent manner, and at the therapeutic dose of 5 mg,
most of the drug is bound to proteins due to a saturable high
afnity binding to the DPP-4 target in plasma.138 In plasma, only
the pharmacologically inactive metabolite CD18790 represents
over 10% of the total drug concentration.137
Pharmacokinetics in specic populations
An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment.139 The study included
six healthy subjects with normal renal function (CrCl 80 mL/
min), six patients with mild renal impairment (CrCl 50
to < 80 mL/min), six patients with moderate renal impairment
(CrCl 30 to < 50 mL/min), 10 patients with type 2 diabetes

mellitus and severe renal impairment (CrCl < 30 mL/min), and
11 patients with T2DM and normal renal function. CrCl was
measured by 24-h urinary creatinine clearance measurements or
estimated from serum creatinine based on the Cockcroft-Gault
formula. Under steady state conditions, linagliptin exposure in
patients with mild renal impairment was comparable to healthy
subjects. In patients with moderate renal impairment under steady
state conditions, mean AUC and Cmax of linagliptin increased by
71% and 46%, respectively, compared with healthy subjects.139
This increase was not associated with a prolonged accumulation
half-life, terminal half-life, or an increased accumulation factor.
Renal excretion of linagliptin was below 5% of the administered
dose and was not affected by decreased renal function. Patients
with T2DM and severe renal impairment showed steady state
exposure approximately 40% higher than that of patients with
T2DM and normal renal function (increase in AUC by 42% and
Cmax by 35%).139 For both T2DM groups, renal excretion was
below 7% of the administered dose.
In an analysis of three Phase III, randomized, placebo-controlled studies, the effect of renal function on the efcacy and
safety of linagliptin was evaluated. Patients (n = 2141) were
grouped according to renal function, and it was found that reductions in HbA1C with linagliptin did not differ among groups
(mild, moderate, or severe renal impairment), as well as adverse
event occurrences that were similar to placebo.140
In patients with mild hepatic impairment (Child-Pugh class A),
steady state AUC of linagliptin was approximately 25% lower and
Cmax was approximately 36% lower than in healthy subjects.141 In
patients with moderate hepatic impairment (Child-Pugh class B),
AUC of linagliptin was about 14% lower and Cmax was approximately 8% lower than in healthy subjects.141 Patients with severe
hepatic impairment (Child-Pugh class C) had comparable exposure
of linagliptin in terms of AUC and approximately 23% lower Cmax
compared with healthy subjects.141 Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not
result in reductions in DPP-4 inhibition.
No dose adjustment is necessary based on BMI. BMI had no
clinically meaningful effect on the pharmacokinetics of linagliptin
based on a population pharmacokinetic analysis. No dose adjustment is necessary based on gender. Gender had no clinically
meaningful effect on the pharmacokinetics of linagliptin based on
a population pharmacokinetic analysis. Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin
based on a population pharmacokinetic analysis. No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on
available pharmacokinetic data, including subjects of white, Hispanic, black, and Asian racial groups.
Adverse effects of linagliptin

Hypoglycaemia
The incidence of hypoglycaemia was 8.2% in patients receiving
linagliptin and 5.1% in those receiving placebo. The somewhat
higher incidence of hypoglycaemia associated with linagliptin was
almost exclusively attributable to the combination with sulphonylurea. In studies where patients were receiving sulphonylurea, the
incidence of hypoglycaemia was 20.7% and 13.3% in the linaglip-
1013
tin- and placebo-treated groups, respectively; 38% of patients on

sulphonylurea background therapy accounted for 96% of all hypoglycaemic events in the linagliptin-treated group.142 As observed
with other gliptins, the combination with linagliptin to patients
inadequately controlled on metformin plus sulfonylurea showed a
higher occurrence of hypoglycaemia than the placebo group
(22.7% vs 14.8%).135
Weight gain
The T2DM treatment with glitazone, sulfonylurea, or insulin may
be associated with weight gain. Most T2DM patients are overweight or obese, so it is not desirable to gain additional weight
due to the treatment. DPP-4 inhibitors have a neutral effect on
body weight. Linagliptin showed no weight increase in monotherapy or in combination with metformin. In combination with pioglitazone, the linagliptin was associated with greater weight gain
than placebo (2.3 kg vs 1.2 kg, P < 0.01), in a 24-week study, but
these changes were minimal from baseline.133 There was also no
change in waist circumference with linagliptin treatment.
Acute pancreatitis
In 2008, the FDA (Food and Drug Administration) recommended the inclusion of a warning on the package insert of
some drugs acting on the incretin system, after case reports of
pancreatitis with the use of GLP-1 analogs. Postmarketing analyses have also identied isolated cases of pancreatitis with DPP-4
inhibitors, but a cause-effect relationship was not identied. It is
important to consider that patients with T2DM and hypertriglyceridemia exhibit increased risk of pancreatitis. In clinical studies,
8 pancreatitis cases were reported in 4687 patients on linagliptin
and no cases among 1183 patients receiving placebo; however,
no relationship between linagliptin and pancreatitis has been
established.143
Cardiovascular risks
The gliptins may exert benecial cardiovascular effects through
different mechanisms. Recent studies also demonstrated that
intensive control may be associated with increased CV risk;
therefore, another potential benet of gliptins would be a low risk
of hypoglycaemia.144 In studies using animal models, activation
of GLP-1 receptor is associated with limiting the size of the area
of myocardial infarction (MI).145 Furthermore, linagliptin has
anti-oxidant properties, probably due to its xanthine-based molecular structure. Even when administered in supratherapeutic doses,
linagliptin does not prolong the QT interval.146
A recent meta-analysis has assessed the cardiovascular safety
prole of linagliptin in patients who participated in eight Phase III
studies.144 Of the 5239 patients, 3319 received linagliptin, and
1920 received a comparator (placebo, glimepiride, or voglibose). A
composite of CV death, stroke, MI, or hospitalization for unstable
angina was considered as the primary endpoint. In the linagliptin
group, the primary endpoint occurred in 11 (0.3%) patients,
whereas in the comparator group there were 23 cases (1.2%),
demonstrating lower risk in those who received linagliptin.144
An important conclusion is that, as other DPP-4 inhibitors have
also demonstrated, linagliptin shows no increase in CV risk.
X-W Chen et al.
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Other side effects of linagliptin
The adverse events most frequently reported with DPP-4 inhibitors are mild infections (such as nasopharyngitis, urinary tract
infection, and upper respiratory tract infections) and diarrhoea,
back pain, headache and hypertension. Data presented with linagliptin indicate an overall incidence similar to placebo for these
most frequently observed adverse events.142
Drug interactions of linagliptin

In vitro studies
Linagliptin weakly inhibited CYP3A4 activity in human liver
microsomes in a competitive manner, with a Ki of 115 lmol/
L.137 In addition, linagliptin was a poor to moderate mechanismbased inhibitor of CYP3A4. KI and the maximal rate of enzyme
inactivation (kinact) were 1.75 lmol/L and 0.041 min 1, respectively, for CYP3A4-mediated testosterone 6b-hydroxylation.137
Linagliptin did not inhibit other main CYPs and was not an inducer of CYPs, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19,
2D6, 2E1, and 4A11. Since linagliptin is only a weak competitive inhibitor of CYP3A4, there would be a less than twofold
decrease in the clearance of other drugs metabolized by this pathway, so linagliptin is considered as having low potential for clinically relevant interactions.
Linagliptin is a P-gp substrate. Linagliptin inhibits P-gp mediated transport of digoxin at high concentrations. Based on these
results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at
therapeutic concentrations.
In vivo studies
In different pharmacokinetic drug-drug interaction studies, linagliptin exhibited low potential for drug interaction. Linagliptin
did not change the pharmacokinetic steady state of ethinyl estradiol and levonorgestrel,147 digoxin,148 warfarin,149 glyburide,150
pioglitazone,151 simvastatin,152 and metformin.117 Rifampicin, in
turn, can reduce the exposure to linagliptin, suggesting that linagliptin efcacy may be reduced by concomitant use with rifampicin.107 Thus, inducers of CYP3A4 or P-gp (e.g., rifampin) should
not be used in combination with linagliptin to avoid therapeutic
failure. For patients who require use of such drugs, an alternative
to linagliptin is strongly recommended.
SAXAGLIPTIN
Pharmacodynamics of saxagliptin
Saxagliptin (Onglyza); (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile)
co-developed by Bristol-Myers Squibb (New York City, USA)
and AstraZeneca (London, United Kingdom) was approved by the
FDA in July 2009. It is also used in combination with metformin
(Kombiglyze XR). In patients with T2DM, administration of saxagliptin inhibited DPP-4 activity for a 24-h period.
After an oral glucose load or a meal, this DPP-4 inhibition
resulted in a two to threefold increase in circulating levels of active
GLP-1 and GIP, decreased glucagon concentrations, and increased

glucose-dependent insulin secretion from pancreatic b-cells.
Pharmacokinetics of saxagliptin
The pharmacokinetics of saxagliptin and its active metabolite, 5hydroxy saxagliptin (BMS510849, 50% potency of saxagliptin),
were similar in healthy subjects and in patients with T2DM. The
Cmax and AUC values of saxagliptin and its active metabolite
increased proportionally in the 2.5400 mg dose range. No
appreciable accumulation of either saxagliptin or its active
metabolite was observed with repeated once-daily dosing at any
dose level. No dose- and time-dependence were observed in the
clearance of saxagliptin and its active metabolite over 14 days of
once-daily dosing with saxagliptin at doses ranging from 2.5 to
400 mg. Following a single oral dose of 5 mg saxagliptin to
healthy subjects, the mean plasma tb for saxagliptin and its
active metabolite was 2.5 and 3.1 h, respectively. Saxagliptin is
mainly metabolized by CYP3A4/5, resulting in an active
metabolite. Saxagliptin is eliminated by both renal and hepatic
pathways. The recommended dose for adult with T2DM is 2.5
or 5 mg orally once a day, regardless of meal. Dose adjustment
for patients with mild renal impairment (creatinine clearance > 50 mL/min) is not recommended; however, the dosage
needs to be reduced to 2.5 mg orally once a day for patients
with moderate or severe renal dysfunction (CrCl 50 mL/
min).153
Safety of saxagliptin
There is a raising concern on the safety of saxagliptin in clinical
practice, such as hypoglycaemia, pancreatitis, hypersensitivity
reactions, and cardiovascular risk. Although there is no evident
association between the application of saxagliptin and the incidence of gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia,
hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, and worsening renal function, the patients still need to be cautious to
initiate the saxagliptin treatment.154 For example, hypersensitivity-related urticaria and facial oedema in the 5-study pooled analysis up to week 24 were reported in 1.5%, 1.5%, and 0.4% of
patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and
placebo, respectively, though none of these events in patients
who received saxagliptin required hospitalization or were
reported as a life-threatening event.155,156 Notably, the concern
about the possible association between saxagliptin and cardiovascular risk has been raised. It has been reported that an increased
rate of hospitalization for heart failure occurred, when the heart
does not pump blood well enough, with use of saxagliptin compared to placebo treatment in a randomized trial with 16 492
patients enrolled in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-thrombolysis
in myocardial infarction (SAVOR-TIMI 53) trial.157 Although
this study did not nd increased rates of death or other major cardiovascular risks, including heart attack or stroke, in patients who
received saxagliptin, other approaches are necessary to reduce
cardiovascular risk in patients with diabetes.157
SITAGLIPTIN
Pharmacodynamics of sitagliptin
Sitagliptin (Januvia; previously known as MK-0431; (R)-4-oxo-4[3-(triuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7
(8H)-yl]-1-(2,4,5-triuorophenyl)butan-2-amine) is the rst DPP-4
inhibitor developed by Merck & Co. (Whitehouse Station, NJ,
USA), approved by the FDA in October 2006. Sitagliptin demonstrates selectivity towards DPP-4 and does not inhibit DPP-8 or
DPP-9 activity in vitro at concentrations approximating those
achieved at therapeutic doses. In healthy subjects, sitagliptin
markedly and dose-dependently inhibited ~80% of plasma DPP-4
activity over 24 h and produced a two to threefold increase in
postprandial active plasma GLP-1 and GIP levels compared to
placebo.158 In patients with T2DM, treatment with sitagliptin
resulted in signicant improvements in HbA1C, FPG and 2-h
PPG compared to placebo. Sitagliptin was well tolerated and was
not associated with hypoglycaemia.158
Further, a xed-dose combination tablet containing 50 mg sitagliptin and 500 or 1000 mg metformin was approved by FDA in
April 2007. This is marketed in the US as Janumet. Coadministration of sitagliptin and metformin resulted in an additive effect
on active GLP-1 concentrations. Sitagliptin, but not metformin,
increased active GIP concentrations. A 24-week, randomized,
double-blind, placebo-controlled factorial study indicates that the
combination provided signicant improvements in HbA1C, FPG,
and 2-h PPG compared to placebo, to metformin alone, and to
sitagliptin alone.
Pharmacokinetics of sitagliptin
After oral administration of a 100 mg dose to healthy subjects,
sitagliptin was rapidly absorbed, with peak plasma concentrations
occurring 14 h postdose. Plasma AUC of sitagliptin increased in
a dose-proportional manner. Following a single oral 100 mg dose
to healthy volunteers, mean plasma AUC of sitagliptin was
8.52 lmol/L per h, Cmax was 950 nmol/L, and apparent tb was
12.4 h. Plasma AUC of sitagliptin increased ~14% following
100 mg doses at steady state compared to the rst dose. Sitagliptin is not extensively bound to plasma proteins. In vitro studies
indicated that sitagliptin was primarily metabolized by CYP3A4,
with contribution from CYP2C8. Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a
minor pathway of elimination accounting for around 16%. Elimination of sitagliptin occurs primarily via renal excretion and
involves active tubular secretion. Sitagliptin is a substrate for
human organic anion transporter-3, which may be involved in the
renal elimination of sitagliptin. Sitagliptin is also a substrate of
P-gp/MDR1, which may also be involved in mediating the renal
elimination of sitagliptin. In clinical studies, sitagliptin did not
meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, digoxin, rosiglitazone, warfarin, or oral contraceptives. Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the
pharmacokinetics of sitagliptin in patients with T2DM. The
recommended dosage for adult with T2DM is 100 mg orally
once a day. Dose adjustment for patients with mild renal impairment (creatinine clearance > 50 mL/min) is not recommended;
1015
however, the dosage needs to be reduced to 50 mg orally once a

day for patients with moderate renal dysfunction (creatinine clearance ranging from 30 to 49 mL/min), and the dosage needs to be
further reduced to 25 mg orally once a day for patients with severe renal insufciency (creatinine clearance 29 mL/min) or end
stage renal disease requiring hemodialysis or peritoneal dialysis.159,160
Safety of sitagliptin
Sitagliptin is a well-tolerated, moderately efcacious, weight-neutral DPP-4 inhibitor for T2DM treatment, with a low incidence of
hypoglycaemia, and it may have a particular role in the management of diabetic patients with kidney or liver dysfunction.161,162
However, there is a safety concern of sitagliptin on the risk of
pancreatitis, inammation of the pancreas, and pancreatic duct
metaplasia in T2DM patients. It has been reported that current
use of GLP-1-based therapy (sitagliptin) within 30 days [adjusted
odds ratio, 2.24 (95% CI, 1.36, 3.68)] and recent use past
30 days and less than 2 years [2.01 (1.373.18)] were associated
with signicantly increased odds of acute pancreatitis relative to
the odds in nonusers, indicating that treatment with sitagliptin
was associated with increased odds of hospitalization for acute
pancreatitis.163
A Trial Evaluating Cardiovascular Outcomes with Sitagliptin
(TECOS) has reported the baseline characteristics and CV risk
management by region, age, sex and CV event type for 14 724
participants,164 which is a randomized, double-blind, placebocontrolled trial to explore whether sitagliptin added to usual
T2DM care affects time to rst event in the composite endpoint
of CV death, non-fatal myocardial infarction (MI), non-fatal
stroke or unstable angina hospitalization. TECOS concludes that
the CV risk factors of enrolled patients are reasonably controlled,
however, there are differences in CV risk management according
to region, sex and history of disease. It indicates that this diversity will enhance the generalizability of the trial results.164
TENELIGLIPTIN
Pharmacodynamics of teneligliptin
Teneligliptin (Tenelia; 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1Hpyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine)
was developed by Mitsubishi Tanabe Pharma (Osaka, Japan) and
gained approval from the PMDA of Japan in September 2012.
Teneligliptin is currently used in T2DM patients showing insufcient improvement in glycaemic control even after diet control and
exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine therapy. Unlike other DPP-4 inhibitors, it
exhibits a unique structure characterized by ve consecutive rings
(Fig. 1) belonging to a peptidomimetic. Teneligliptin signicantly
inhibited human plasma DPP-4 and recombinant human DPP-4
activity, with IC50 of 1.75 nmol/L and 0.889 nmol/L
(Ki = 0.406 nmol/L), respectively.165 In addition, the IC50 values
of teneligliptin for DPP-8, DPP-9, and broblast activation protein
are 0.189, 0.150, and >10 lmol/L, respectively, all of which are
168 to >11 248 times the value for recombinant human DPP-4.165
Oral administration of teneligliptin at 0.031.0 mg/kg to Zucker
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X-W Chen et al.
fatty rats signicantly inhibited DPP-4 activity and normalized the

plasma glucose levels after an oral glucose load of 1.0 g/kg.165
An X-ray co-crystal structure of teneligliptin complexed with
human DPP-4 (33-766; protein database ID: 3VJM) has demonstrated that there are tight interactions between ve rings of teneligliptin and the active site of DPP-4.165 The thiazolidine moiety
fully occupies the S1 hydrophobic subsite; the secondary amino
group of the proline moiety forms salt bridges with Glu205 and
Glu206; the carbonyl oxygen forms a hydrogen bond with
Asn710; and the pyrazolyl ring is stacked with the side chain of
Phe357 and the piperazinyl ring forms CHp interaction with
Phe357.165 In addition, the phenyl substituent on the pyrazolyl
ring is oriented favourably for hydrophobic interactions with the
side chains of Ser209 and Arg358. In the S2 extensive subsite,
C4 of the phenyl ring is highly possible to form hydrogen bond
with the carbonyl oxygen of the main chain of Val207.165 These
ndings support the high therapeutic potency and selectivity
towards DPP-4 of teneligliptin.
In a Phase II clinical study conducted in Japan, 324 T2DM
patients who did not achieve optimal glycaemic control with diet
and exercise treatment alone for more than 12 weeks were randomly assigned into four groups: placebo, 10 mg, 20 mg, or
40 mg teneligliptin.166 The drug was administered once daily for
12 weeks. After 12 weeks, treatment with 10, 20, and 40 mg
teneligliptin reduced the HbA1C levels 0.77%, 0.80%, and 0.91%,
respectively. The FPG and 2-h PPG levels were also reduced in
patients with T2DM with a minimal risk of hypoglycaemia and
weight gain. In a owing Phase III trial with 20 mg teneligliptin
for 12 weeks in 203 T2DM patients, the therapy reduced the
HbA1C level 0.79%. In a Phase III trial, T2DM patients
(n = 151) were treated with 20 mg teneligliptin orally for
52 weeks (the dose was increased to 40 mg if plasma HbA1C
levels were > 7.3% at any time after week 24), the HbA1C level
was reduced by 0.63%.167,168 When 20 mg of teneligliptin was
administered to 96 T2DM patients treated with glimepiride at 1
4 mg/day in addition to diet and exercise treatment, the HbA1C
level and FPG and 2-h PPG levels were reduced by 0.71%,
17.3 mg/dL, and 43.1 mg/dL, respectively, compared to the
values at week 12.
Pharmacokinetics of teneligliptin
In rat, monkey and human, teneligliptin is metabolized to ve
metabolites, M1, M2, M3, M4, and M5, which all show some
DPP-4 inhibitory activity.169 In vitro studies indicate that teneligliptin was metabolized by CYP3A4 and avin-containing
monooxygenases FMO1 and FMO3.167 In T2DM patients
(n = 33 per group), the plasma Cmax of teneligliptin following
the oral administration of 10 or 20 mg once daily for 4 weeks
was 125.0 and 274.5 ng/mL, respectively, with a Tmax of 1.0 h
in both groups and a mean t1/2b of 20.8 and 18.9 h, respectively.
The AUC024 h was 830.9 and 1625.1 ng/h per mL, respectively.
In the meantime, the maximum percentage of the inhibition in
plasma DPP-4 activity (81.389.7%) was achieved within 2 h
after 4-week multiple-dose administration.167
In the mass balance study in healthy male subjects receiving
a single oral dose of 20 mg 14C-labeled teneligliptin, the
cumulative urinary excretion rate of unchanged drug, M1, M2,
and M3 over 120 h was 14.8%, 17.7%, 1.4% and 1.9%, respec-
tively.167 The cumulative faecal excretion rate of teneligliptin,

M1, M2, M3, M4, and M5 was 26.1%, 4.0%, 1.6%, 0.3%, and
1.3%, respectively. These ndings indicate that teneligliptin is
metabolized and eliminated via renal and hepatic excretion.
Because the metabolites of the drug are eliminated via renal and
hepatic excretion, no dose adjustment is needed in T2DM
patients with renal impairment.
Safety of teneligliptin
The safety prole of teneligliptin is similar to those of other
available DPP-4 inhibitors.167 The incidence of adverse drug
reactions was ~10% in all clinical studies of patients (n = 1183)
with T2DM. These mainly included abnormalities in clinical
examination values such as levels of liver and kidney function,
blood cell count, creatinine phosphokinase, and electrolytes. The
main adverse effects included hypoglycaemia (35 patients: 3.0%)
and constipation (11 patients: 0.9%). No adverse effects related
to QT prolongation were detected with 40 mg/day of teneligliptin, which is the maximal dosage used in clinical practice. The
pharmaceutical company warned of serious adverse effects such
as hypoglycaemia, which could occur when other antidiabetic
drugs were coadministered. In addition, they cautioned that
intestinal obstruction could occur with an unknown frequency.
GLP-1 is involved in gastrointestinal motility,21,26 and the
patients with intestinal obstruction had a past medical history of
intestinal obstruction or abdominal surgery. Therefore, we should
be cautious when T2DM patients with a history of these conditions are treated with DPP-4 inhibitors. Continued evaluation of
adverse effects and post-market monitoring is warranted to dene
the benet/risk ratio.
VILDAGLIPTIN
Pharmacodynamics of vildagliptin
Vildagliptin (Zomelis & Galvus; previously known as LAF237;
(S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile) gained approval from the European Medicines Agency
(EMEA) in February 2008, which is the second DPP-4 inhibitor
reaching the market behind sitagliptin. Its approval in the US is
still pending. In the meantime, the EMEA has also approved a
combination use of vildagliptin with metformin (brand name:
Eucreas). Vildagliptin is a potent, competitive, and reversible
inhibitor for DPP-4, with an IC50 of 3.5 nmol/L.170,171 The vildagliptin-DPP-4 complex exhibited a slow dissociation half-life of
55 min. Maximum inhibition of DPP-4 activity was seen 30 min
after a vildagliptin dose, and 50% inhibition of DPP-4 continued for 10 h or longer. DPP-4 levels was dropped to 60% of
baseline 24 h after a 100-mg dose of vildagliptin in patients with
dietary controlled diabetes.172
In the Novartis-sponsored INTERVAL study, elderly patients
with T2DM who were treated with vildagliptin achieved greater
reductions in HbA1C and were three times more likely to reach
individualized treatment goals without major tolerability issues
than those treated with placebo on top of background oral antidiabetic treatment.173 This study was a 24-week, multi-centre,
randomized, double-blind, placebo-controlled study that enrolled
278 patients from 45 outpatient centres across several European

countries including Belgium, Bulgaria, Germany, Finland, Slovakia, Spain and the UK.
Pharmacokinetics of vildagliptin
The absolute oral bioavailability of vildagliptin exceeded 90%
and its average clearance rate from plasma was 1.5 L/h per kg
with a volume of distribution of 0.7 L/kg following a 1-lmol/kg
oral dose administered to cynomolgus monkeys.171 The pharmacokinetics of vildagliptin has been investigated in healthy volunteers and patients with T2DM.174177 Following oral
administration in the fasting state, vildagliptin was rapidly
absorbed, with peak plasma concentrations observed at 12
(mean 1.7) hours. Its oral bioavailability was 85% in healthy volunteers and its pharmacokinetics was not affected by food. The
plasma protein binding of vildagliptin was low (9.3%) and vildagliptin distributed equally between plasma and red blood cells.
The mean volume of distribution of vildagliptin at steady state
after intravenous administration (Vss) was 70.5 L, suggesting
extravascular distribution. Following oral administration of [14C]
vildagliptin, ~85% of the dose was excreted into the urine and
15% of the dose is recovered in the faeces. Renal excretion of
the unchanged vildagliptin accounted for 23% of the dose after
oral administration.
After intravenous administration to healthy subjects, the total
plasma and renal clearances of vildagliptin are 41 and 13 L/h,
respectively. The t1/2b of vildagliptin after oral administration is
2.8 h.
Metabolism was the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose.171 The major
metabolite (LAY151) is pharmacologically inactive and is the
hydrolysis product of the cyano moiety, accounting for 57% of
the dose, followed by the glucuronide (BQS867) and the amide
hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the
major organs contributing to the hydrolysis of vildagliptin to its
major inactive metabolite, LAY151.171 DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study
using DPP-4 decient rats. Vildagliptin is not metabolized by
CYPs to any quantiable extent. Vildagliptin was largely
excreted in the urine with 1822% of the amount excreted as
unmetabolized drug.171 Vildagliptin did inhibit or induce any
human CYPs.
Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in
patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. No dose adjustment
is required in patients with mild renal impairment (creatinine
clearance 50 mL/min), but the recommended dose of vildagliptin is 50 mg once daily in patients with moderate or severe renal
impairment or with end-stage renal disease. No dose adjustments
are necessary in elderly patients.178,179
Safety of vildagliptin
A meta-analysis of independently and prospectively adjudicated
cardiovascular events from 25 phase III clinical studies of up to
more than 2 years duration was performed and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk versus comparators.
1017
CLINICAL CONSIDERATIONS OF DPP-4

INHIBITORS
The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with similar overall
clinical efcacy and safety proles in patients with T2DM. Sitagliptin was the rst gliptin licensed by the FDA in 2006 and is
now available worldwide. Vildagliptin and saxagliptin were
approved in 2007 and 2009, respectively. More recent compounds are alogliptin (available only in Japan in 2010) and linagliptin (authorized by the FDA and EU in 2011). DPP-4
inhibitors may be used as monotherapy or in double or triple
combination with other oral glucose-lowering agents, as metformin, thiazolidinediones, or sulfonylureas.
Dipeptidyl peptidase-4 inhibitors reduce plasma DPP-4 activity
by 7090% in a sustained manner for 24 h with an increase of
GLP-1 levels (1.5- to 4-fold). They do not pass the bloodbrain
barrier, have no direct central effect on satiety, and in contrast
with GLP-1 agonists (incretin mimetics), did not alter gastric
emptying. Although DPP-4 inhibitors have the same mode of
action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some
patients. The main differences between the eight gliptins on the
market include: potency, target selectivity, oral bioavailability,
elimination half-life, extent of binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion
routes, dosage adjustment for renal and liver insufciency, and
potential drugdrug interactions.
Regarding potency, linagliptin, compared with sitagliptin, alogliptin, saxagliptin, and vildagliptin demonstrated the highest
potency of DPP-4 inhibition. The duration of action of DPP-4
inhibitors with comparatively shorter half-lives may be strongly
inuenced by binding strength and reversibility with the receptor.
All gliptins exhibit a greater selectivity for DPP-4 enzyme, ranging from 30- to 40 000-fold superior to the other enzymes, i.e.,
DPP-8 and DPP-9. However, because DPP-8 and DPP-9 are proteases responsible for T-cell activation which play an important
role in immune function, the off-target inhibition of selective
DPP-4 inhibitors is responsible for multiorgan toxicities such as
immune dysfunction, impaired healing, and skin reactions.
After oral administration in humans, all DPP-4 inhibitors are
well absorbed with oral bioavailability ranges from about 30%
for linagliptin to 7587% for all others and are not signicantly
inuenced by food intake. Linagliptin has the longest half-life
(120184 h), followed by alogliptin (12.421.4 h), and sitagliptin (814 h), whereas saxagliptin and vildagliptin have shorter
half-lives (2.23.8 and 23 h, respectively). Due to a sustained
DPP-4 enzyme inhibition and a long half-life, sitagliptin, alogliptin, and linagliptin are generally prescribed once a day. Saxagliptin is also administrated once daily due to the presence of an
active metabolite (5-hydroxy saxagliptin) which is half as potent
as the parent compound. Due to the shorter half-life, vildagliptin
needs twice-daily dosing. The apparent volume of distribution
(Vd) among the gliptins range from 70 to 918 L. Moreover, the
distribution of DPP-4 inhibitors is strongly inuenced by protein
binding. All gliptins are not extensively bound to plasma proteins, except for linagliptin, which has the highest binding level
to proteins.
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X-W Chen et al.
The metabolism of DPP-4 inhibitors varies. While sitagliptin

does not appear to undergo extensive metabolism, both vildagliptin and saxagliptin are extensively metabolized in the liver. However, vildagliptin produces a large amount of inactive metabolites
through several pathways (hydrolysis, glucuronidation, and oxidation) not mediated by the CYP system, while saxagliptin is
mainly metabolized by CYP3A4/5 to a major active metabolite,
5-hydroxy saxagliptin. Both saxagliptin and its major metabolite
are not inhibitors or inducers of various CYPs. Although the
potential for drug interactions with saxagliptin and its metabolite
is low, their pharmacokinetic prole may be inuenced in co-administration with strong CYP3A4/5 inducers (such as rifampicin)
or inhibitors (such as ketoconazole); in these cases, it is recommended to modify the dosage of saxagliptin. The pharmacokinetic proles of the other DPP-4 inhibitors suggest a low risk of
drugdrug interactions, which is especially favourable in patients
older than 65 years.
All DPP-4 inhibitors predominantly (7587%) undergo renal
excretion, with 7687% of each dose eliminated as unchanged
parent compound in the urine. In contrast, linagliptin is excreted
mostly (~90%) unchanged in faeces via biliary excretion, and
therefore appears to be safe in diabetic patients suffering from
renal complications. An appropriate dose reduction of the gliptins
with predominantly renal excretion (sitagliptin, saxagliptin, and
alogliptin, but not vildagliptin) is needed in case of renal impairment. In patients with mild to severe liver impairment, no dose
adjustment seems necessary for linagliptin despite its liver excretion.
The difference in the glucose-lowering efcacy of DPP-4 inhibitors between Asian and non-Asian patients with T2DM was
concluded in a meta-analysis.180 The meta-analysis included 55
randomized controlled trials that compared a DPP-4 inhibitor
with a placebo as either monotherapy or oral combination therapy
for at least 12 weeks with information on ethnicity and HbA1c
values.180 It revealed that DPP-4 inhibitors exhibited a stronger
HbA1c lowering effect in studies with 50% Asian participants
[weighted mean difference (WMD) 0.92%; 95% CI 1.03,
0.82] than that in studies with < 50% Asian participants
(WMD 0.65%; 95% CI 0.69, 0.60), with a between-group

difference of 0.26% (95% CI 0.36, 0.17, P < 0.001).180
The meta-analysis showed that the baseline BMI signicantly
correlated with the HbA1c-lowering efcacy of DPP-4 inhibitors.
The RR of achieving the goal of HbA1c < 7.0% (53.0 mmol/
mol) was 3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0] in studies with 50% Asian participants and in studies with < 50%
Asian participants, respectively. Moreover, there was a stronger
fasting plasma glucose-lowering efcacy in the Asian-dominant
studies with monotherapy, but the postprandial glucose-lowering
efcacy and changes in body weight were comparable between
the two groups. The meta-analysis concludes that DPP-4 inhibitors show higher glucose-lowering efcacy in Asians than that in
other ethnic groups, however, this requires further investigation
to understand the underlying mechanism, particularly in relation
to BMI.180
SAFETY PROFILES OF DPP-4 INHIBITORS

Clinically approved DPP-4 inhibitors are generally well tolerated
in T2DM patients. As a drug class, the DPP-4 inhibitors have
become accepted in clinical practice due to their excellent tolerability prole, with a low risk of hypoglycaemia, a neutral effect
on body weight, and once-daily dosing.
DPP-4 inhibitors can cause mild to moderate adverse effects,
including nasopharyngitis, headache, urinary tract infection,
nausea, and vomiting, have been observed. Other adverse
effects of DPP-4 inhibitors, including hypersensitivity reactions
(e.g. angioedema and StevensJohnson syndrome) and acute
pancreatitis, have been reported post-marketing. A recent
population-based, casecontrol study, conducted on a large
administrative database in the US from 2005 to 2008, showed
roughly a doubling of the risk of acute pancreatitis among
users receiving incretin-based therapy (sitagliptin and exenatide). A study has examined the FDA adverse event reporting system (AERS) database, and has noted a sixfold risk for
pancreatitis with the use of sitagliptin or exenatide as compared with other therapies. Moreover, this analysis showed the
Fig. 2 Mechanism of actions of dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors suppress the enzymatic activity of DPP-4, resulting in an
increase in incretin levels (GLP-1 and GIP), which subsequently inhibit glucagon release and glucose production in the liver and increase insulin secretion and glucose uptake in skeletal muscle. Consequently, it leads to a decrease in blood glucose level. GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide.

reported event rate for pancreatic cancer was 2.9-fold greater
in patients treated with sitagliptin and exenatide compared with
other therapies. However, it is unclear if DPP-4 inhibitors
increase the risk of cancer in T2DM patients. These effects
may be associated with the inhibitory activity of DPP-4 on the
inammatory actions of the chemokine CCL11/eotaxin. Careful
long-term surveillance on the safety prole of DPP-4 inhibitors
is mandatory.
Diabetic patients are at increased risk of cardiovascular
diseases. Rosiglitazone was been withdrawn from the market in
the European Union (EU) in 2010, because of a possible
increased risk of ischemic heart disease associated with its use.
Several preclinical and clinical studies have suggested a possible
benecial effect on cardiovascular risk associated with DPP-4
inhibitors, which also seem to possess a direct effect on the
heart, independent of the incretin system. They may exert some
favourable effects on risk factors, resulting in a reduction of
blood pressure, an improvement of postprandial lipid levels, and
a reduction of high-sensitivity C-reactive protein. The endothelial
dysfunction is also improved by gliptins. Several large randomized Phase III trials are ongoing and will increase our knowledge about the effect on cardiovascular outcomes and safety.
The insulin-release effects of the incretins are glucose-dependent and have no insulinotropic activity at lower glucose concentration (< 4 mmol/L), therefore reducing the chance of
hypoglycaemia, which is one of the major concerns of other
antidiabetic drug classes.
So far, no characteristic pattern of adverse events has been
associated with the DPP-4 inhibitors despite the large number
of potential substrates for DPP-4. DPP-4 inhibitors are less
associated with several specic AEs of traditional antidiabetic
treatments. The neutral effect on body weight of DPP-4 inhibitors can be useful in overweight or obese patients with T2DM,
while the low risk of hypoglycaemia may be an advantage in
the elderly. Hypoglycaemic events are mainly observed when
DPP-4 inhibitors are associated with sulfonylureas (in 20% of
the patients treated in combination) than without sulfonylureas.
CONCLUSIONS AND FUTURE DIRECTIONS

Numerous clinical trials have demonstrated that DPP-4 inhibitors
provide effective and consistent glycaemic control with a good
tolerability prole, including no severe hypoglycaemia and
weight gain. Although different DPP-4 inhibitors are distinctive
in their metabolic properties, excretion, recommended dosage,
and daily dosage, and head-to-head clinical trials comparing the
various DPP-4 inhibitors are scarce, the available data regarding
indirect comparisons suggest that all available DPP-4 inhibitors
have nearly the same efcacy and safety prole. Thus, we may
expect a similar efcacy and safety with the novel DPP-4 inhibitor, teneligliptin, although this drug requires careful long-term
postmarketing surveillance and additional clinical trials to evaluate its efcacy and safety as well as to gain additional indications
for its clinical use.
DPP-4 inhibitors are the rst substances having a glucose-dependent dual action on a- and b-cell functions stimulating insulin
secretion and suppressing glucagon secretion under hyperglycaemic conditions (Fig. 2). This dual action leads to an improved
time course of islet hormone secretion after a meal and hypergly-
1019
caemia. Taken together, the discovery and advance of incretin therapy may help overcome the limitations of the classical treatment
options of T2DM. The National Institute for Health and Clinical
Excellence (NICE) clinical guideline for T2DM suggests adding a
DPP-4 inhibitor instead of a sulfonylurea as second line treatment
to rst line metformin if there is a considerable risk for hypoglycaemia or if a sulfonylurea is contraindicated or not tolerated.
The DPP-4 inhibitors represent a highly promising, novel
class of oral agents for the treatment of type 2 diabetes. Their
novelty lies in their dual action on a- and b-cell function,
leading to an improved prole of glucagon and insulin secretion patterns after meal. These drugs are weight-neutral, do not
provoke hypoglycaemia, and are not associated with gastrointestinal adverse events. Long-term clinical trial data are not yet
available to assess the sustainability of glycaemic control and
protection of b-cell mass. The interference of the DPP-4
inhibitors with immune function is poorly understood and warrants further research. Another potential disadvantage is a
higher cost per day of clinical use as compared to insulin,
metformin, or pioglitazone, which is an economic drawback
for the DPP-4 inhibitors.
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Clinical and Experimental Pharmacology and Physiology (2015) 42, 9991024

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the

toxicities such as immune dysfunction, impaired healing, and

X-W Chen et al.

homeostasis, however, they will bring about undesirable side

DPP-4 AND INCRETINS AS THERAPEUTIC

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

Fig. 1 Chemical structures of clinically approved DPP-4 inhibitors,

nitrile group to form a covalent bond with Ser630 of the catalytic

2015 Wiley Publishing Asia Pty Ltd

2015 Wiley Publishing Asia Pty Ltd

Renal excretion (%)

Table 1 Clinical pharmacokinetic and pharmacodynamics properties of selective DPP-4 inhibitors

> 16811 248

Substrate for P-gp

Substrate for other

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

X-W Chen et al.

(PMDA) of Japan in April 2010.37,38 In January 2013, the FDA

glycaemic rescue therapy. There was no body weight gain

In a multicentre, randomized, double-blind, placebo-controlled,

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

drug-nave T2DM patients than either as monotherapy and well

2015 Wiley Publishing Asia Pty Ltd

X-W Chen et al.

45 mg at week 26 and week 52.51 A total of 11% of patients in

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

pioglitazone and metformin, in combination with metformin and

2015 Wiley Publishing Asia Pty Ltd

X-W Chen et al.

The long-term CV safety of alogliptin was evaluated in a recent

carboxylate metabolite (M1) were the major components detected

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

patients achieving HbA1C < 7% with gemigliptin 25 mg twice

2015 Wiley Publishing Asia Pty Ltd

X-W Chen et al.

whilst gemigliptin was a substrate of both CYP3A4 and P-gp.85

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

2015 Wiley Publishing Asia Pty Ltd

X-W Chen et al.

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

Adverse effects of linagliptin

tin- and placebo-treated groups, respectively; 38% of patients on

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X-W Chen et al.

Drug interactions of linagliptin

GLP-1 and GIP, decreased glucagon concentrations, and increased

2015 Wiley Publishing Asia Pty Ltd

DPP-4 inhibitors in diabetes treatment

however, the dosage needs to be reduced to 50 mg orally once a

2015 Wiley Publishing Asia Pty Ltd

X-W Chen et al.

fatty rats signicantly inhibited DPP-4 activity and normalized the

tively.167 The cumulative faecal excretion rate of teneligliptin,

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DPP-4 inhibitors in diabetes treatment

CLINICAL CONSIDERATIONS OF DPP-4