Drugs (2015) 75:777–796

DOI 10.1007/s40265-015-0385-y

ADIS DRUG EVALUATION

Alogliptin: A Review of Its Use in Patients with Type 2 Diabetes

Mellitus
Gillian M. Keating1

Published online: 9 April 2015

Ó Springer International Publishing Switzerland 2015

Abstract The dipeptidyl peptidase-4 inhibitor alogliptin

(NesinaÒ, VipidiaÒ) is approved in numerous countries
worldwide for the treatment of type 2 diabetes mellitus.
Fixed-dose combinations of alogliptin/metformin (KazanoÒ,
VipdometÒ) and alogliptin/pioglitazone (OseniÒ, In-
cresyncÒ) are also available. This article reviews the clinical
efficacy and tolerability of oral alogliptin in the treatment of
type 2 diabetes. Results of randomized controlled trials
demonstrated that oral alogliptin improved glycaemic control
when administered as monotherapy, as dual therapy in
combination with metformin, pioglitazone, a sulfonylurea,
voglibose or insulin, or as triple therapy in combination with
metformin plus pioglitazone. Alogliptin was generally well
tolerated in patients with type 2 diabetes and was weight
neutral, with a low risk of hypoglycaemia. Results of the
large, well designed EXAMINE trial revealed that alogliptin
was not associated with an increased risk of major cardio-
vascular events in patients with type 2 diabetes and recent
acute coronary syndrome. In conclusion, alogliptin is a useful
option for the treatment of patients with type 2 diabetes.
Alogliptin in type 2 diabetes mellitus: a summary
Oral dipeptidyl peptidase-4 inhibitor with a glucose-
dependent mechanism of action
Improves glycaemic control as monotherapy; as dual
therapy in combination with metformin,
pioglitazone, a sulfonylurea, voglibose or insulin; or
as triple therapy in combination with metformin and
pioglitazone
Generally well tolerated and weight neutral, with a
low risk of hypoglycaemia
No increase in the risk of major cardiovascular
events
1 Introduction

Type 2 diabetes mellitus places a substantial and growing

The manuscript was reviewed by: I. Bourdel-Marchasson,
Department of Gerontology-Centre Hospitalier Universitaire de
Bordeaux, Bordeaux, France; K. Kaku, Division of Diabetes,
Endocrinology and Metabolism, Kawasaki Medical School,
Okayama, Japan; P. Marchetti, Department of Clinical and
Experimental Medicine, University of Pisa, Cisanello AOUP
University Hospital, Pisa, Italy; J. Neumiller, College of Pharmacy,
Washington State University, Spokane, WA, USA; M. Rendell,
School of Medicine, Creighton University, and Association of
Diabetes Investigators, Creighton Diabetes Center, Omaha, NB, USA.
& Gillian M. Keating
demail@springer.com
1
Springer, Private Bag 65901, Mairangi Bay 0754, Auckland,
New Zealand
burden on healthcare systems and society. In 2010, the
global prevalence of type 2 diabetes was estimated to be
6.4 % (i.e. affecting 285 million adults globally); this is
predicted to increase to 7.7 % by 2030 (i.e. affecting 439
million adults globally) [1].
The incretin hormones glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic peptide (GIP) are
released from the gut in response to food intake [2, 3]. Both
incretin hormones enhance insulin secretion in a glucose-
dependent manner, and GLP-1 also inhibits glucagon se-
cretion [2, 3]. Following release, both GLP-1 and GIP are
rapidly inactivated by dipeptidyl peptidase (DPP)-4 [2, 3].
Given that the incretin effect is impaired in patients with
778
type 2 diabetes [2, 3], incretin-based agents (i.e. DPP-4
inhibitors and GLP-1 receptor agonists) represent a rational
approach to treatment. DPP-4 inhibitors prevent the
degradation of incretin hormones by DPP-4, and GLP-1
receptor agonists are resistant to cleavage by DPP-4 [3].
The DPP-4 inhibitor alogliptin (NesinaÒ, VipidiaÒ) is
approved in numerous countries worldwide, including the
US [4] and the EU [5], for the treatment of type 2 diabetes.
Fixed-dose combinations of alogliptin/metformin
(KazanoÒ, VipdometÒ) [6, 7] and alogliptin/pioglitazone
(OseniÒ, IncresyncÒ) [8, 9] are also available. This article
reviews the clinical efficacy and tolerability of alogliptin in
the treatment of type 2 diabetes, as well as summarizing its
pharmacological properties.
2 Pharmacodynamic Properties
2.1 Mechanism of Action
Alogliptin forms noncovalent bonds with the catalytic site
of DPP-4, and is a selective, reversible inhibitor of this
enzyme [2, 10]. In animal studies, the half maximal in-
hibitory concentration (IC50) of alogliptin was 7 nmol/L
for DPP-4, compared with IC50 values of[100,000 nmol/L
for DPP-2, DPP-8 and DPP-9 (i.e. [10,000-fold greater
selectivity for DPP-4) [11].
Alogliptin inhibited DPP-4 in a dose-dependent manner
[12, 13]. For example, mean DPP-4 inhibition at week 12
in patients with type 2 diabetes receiving alogliptin 6.25,
12.5, 25 and 50 mg once daily was 67.8, 73.9, 81.3 and
87.8 %, respectively [12]. Administration of alogliptin
25 mg once daily to patients with type 2 diabetes resulted
in maximum inhibition of plasma DPP-4 activity of 94.7 %
on day 1 and 93.8 % on day 14 [13]. Mean inhibition of
plasma DPP-4 activity 24, 72 and 168 h after the final dose
on day 14 was 81.8, 66.3 and 20.5 %, respectively [13].
Exposure to active GLP-1 in plasma was 2- to 6-fold
higher following administration of alogliptin versus
placebo to healthy volunteers [14, 15], and changes from
baseline in the mean area under the concentration-time
curve from time zero to 2 h for active GLP-1 were sig-
nificantly greater with alogliptin 6.25–50 mg once daily
than with placebo in patients with type 2 diabetes (?4.23 to
?9.04 vs. -1.50 pmol
h/L) [12].
2.2 Effects on b-Cell Function, Glucagon Secretion
and Post-Prandial Glucose
The increase in GLP-1 levels associated with alogliptin
enhanced glucose-dependent insulin secretion. Fasting and
postprandial markers of b-cell function improved in pa-
tients with type 2 diabetes who received alogliptin [12, 16–
G. M. Keating
23]. For example, in terms of fasting markers, improve-
ments in the homeostasis model assessment of b-cell
function (HOMA-b) [12, 17–19, 21–23] and the proin-
sulin:insulin ratio [17–22] were seen with alogliptin alone
[12, 23], alogliptin plus metformin [18–20], alogliptin plus
pioglitazone [21], alogliptin plus glimepiride [17], and
alogliptin plus voglibose [22]. Compared with placebo, the
fasting insulin secretion rate at a fixed glucose level was
significantly (p \ 0.001) increased with alogliptin plus
pioglitazone, but not with alogliptin alone; the difference
between alogliptin plus pioglitazone recipients and
alogliptin recipients was also significant (p \ 0.05) [16].
In some studies, alogliptin also reduced postprandial
glucagon levels in patients with type 2 diabetes who re-
ceived alogliptin alone [24], alogliptin plus pioglitazone
[24], alogliptin plus glimepiride [17] or alogliptin plus
voglibose [22].
In patients with type 2 diabetes receiving alogliptin 25,
100 or 400 mg once daily for 14 days, postprandial glucose
(PPG) levels 4 h after breakfast, lunch and dinner were
reduced to a significantly (p \ 0.05) greater extent than
with placebo [13]. After 16 weeks’ therapy, PPG levels
were reduced to a significantly (p \ 0.01) greater extent
with once-daily alogliptin 25 mg or alogliptin 25 mg plus
pioglitazone 30 mg than with placebo; the reduction
achieved with alogliptin plus pioglitazone was significantly
(p \ 0.001) greater than with alogliptin monotherapy [16].
The effects of alogliptin on PPG levels in large clinical
trials primarily designed to assess glycaemic control are
discussed in Sect. 4.
Enhancement of b-cell proliferation may also contribute
to the beneficial effect of alogliptin on b-cell function. A
tenfold increase in b-cell proliferation was seen in diabetic
immunodeficient mice engrafted with human pancreatic
islets administered alogliptin versus controls (average
proliferation of 0.58 vs. 0.056 %) [25]. In another study,
alogliptin restored b-cell structure and function in a mouse
model of diabetes [26].
2.3 Other Effects
In most studies, no clinically significant changes in fasting
serum lipid levels were reported in patients with type 2
diabetes receiving alogliptin [12, 17, 20, 21, 27–29],
although some studies did report changes in lipid levels
favouring alogliptin [22, 30]. For example, significantly
(p \ 0.05) greater reductions in fasting serum total
cholesterol and low-density lipoprotein-cholesterol levels
were seen with alogliptin 12.5 or 25 mg once daily plus
voglibose than with voglibose alone [22] and a sig-
nificantly (p \ 0.05) greater reduction in fasting total
cholesterol levels was seen with alogliptin plus gliben-
clamide (glyburide) than with glibenclamide alone [30].
Alogliptin: A Review
Postprandial endothelial dysfunction was significantly
(p = 0.03 vs. controls) improved by alogliptin 25 mg once
daily in healthy volunteers [31], and coronary flow reserve
increased from baseline to a significantly (p = 0.006)
greater extent with alogliptin than with glimepiride in pa-
tients with type 2 diabetes and known or suspected coro-
nary artery disease [32]. The corrected QT interval was not
increased in subjects receiving supratherapeutic dosages of
alogliptin 50 or 400 mg once daily for 7 days [4].
In patients with type 2 diabetes (12 postmenopausal
women and 8 men) who received alogliptin 25 mg once
daily for 16 weeks, serum bone alkaline phosphatase levels
significantly decreased from baseline and calcitonin levels
were significantly increased (p-values not stated) [33].
However, no significant changes from baseline were seen
in levels of GIP or biomarkers of bone turnover (e.g. os-
teocalcin and serum N-terminal telopeptide) or in bone
mineral density at the lumbar vertebrae or proximal femur
[33].
Coadministration of alogliptin and warfarin did not alter
the prothrombin time or the international normalized ratio
[34].
3 Pharmacokinetic Properties
3.1 Absorption and Distribution
Alogliptin has an absolute bioavailability of &100 % [4,
5]. Alogliptin was rapidly absorbed following adminis-
tration of single oral doses of 25–800 mg to healthy
volunteers, with the maximum plasma concentration
(Cmax) reached in a median 1–2 h [15]. In patients with
type 2 diabetes receiving alogliptin 25 mg once daily for
14 days, a mean Cmax of 153 ng/mL was reached in a
median 1.1 h [13]. The mean area under the plasma
concentration-time curve from time zero to 24 h was
1474 ng
h/mL [13].
No clinically relevant accumulation was seen with re-
peated administration of alogliptin to healthy volunteers or
patients with type 2 diabetes [5]. The exposure of alogliptin
was not altered to a clinically relevant extent when it was
administered with a high-fat meal [35]; alogliptin can be
administered with or without food [4, 5].
The fixed-dose combinations of alogliptin/metformin [6,
7] and alogliptin/pioglitazone [8, 9] were shown to be
bioequivalent to the corresponding doses of alogliptin and
metformin or pioglitazone coadministered as separate
tablets.
Alogliptin had a volume of distribution of 417 L during
the terminal phase following administration of a single
intravenous dose of 12.5 mg to healthy volunteers [4, 5].
Plasma protein binding of alogliptin was 20–30 % [5].
779
3.2 Metabolism and Excretion
Alogliptin was not extensively metabolized, with 60–70 %
of the dose excreted as unchanged drug in the urine [13–
15]. The minor metabolites M-I (N-demethylated
alogliptin) and M-II (N-acetylated alogliptin) were detected
following administration of radiolabelled alogliptin; M-I
and M-II accounted for \1 % and \6 % of the parent
compound [4, 5]. The active metabolite M-I was a highly
selective inhibitor of DPP-4, whereas M-II had no in-
hibitory activity [4, 5, 36]. The cytochrome P450 (CYP)
enzymes CYP2D6 and CYP3A4 contributed to the meta-
bolism of alogliptin [5].
Following administration of radiolabelled alogliptin, 76
and 13 % of the total radioactivity was recovered in the
urine and faeces [4, 5]. In patients with type 2 diabetes
receiving alogliptin 25 mg once daily, alogliptin had a
mean renal clearance of 175 mL/min, suggesting some
active renal tubular excretion and a mean terminal
elimination half-life of 21.1 h [4, 5, 13].
3.3 Special Patient Populations
The exposure of alogliptin following administration of a
single 50 mg dose was &1.7- to 3.8-fold greater in patients
with mild, moderate or severe renal impairment or end-
stage renal disease than in healthy subjects [37]. The
alogliptin dosage does not need to be adjusted in patients
with mild renal impairment [creatinine clearance (CLCR) of
[50 to B80 mL/min [5] or C60 mL/min [4]], but should
be reduced to 12.5 mg once daily in patients with moderate
renal impairment (CLCR of C30 to B50 mL/min [5] or C30
to \60 mL/min [4]) and to 6.25 mg once daily in patients
with severe renal impairment (CLCR of \30 mL/min [5,
36] or CLCR of C15 to \30 mL/min [4]) or end-stage renal
disease.
No clinically significant changes in alogliptin exposure
were seen in patients with moderate hepatic impairment
who received a single 25 mg dose [38]. The EU summary
of product characteristics (SPC) states that the alogliptin
dosage does not need to be adjusted in patients with mild to
moderate hepatic impairment [5]. Alogliptin is not rec-
ommended for use in patients with severe hepatic impair-
ment because of limited data in this patient group [5]. The
US prescribing information recommends caution when
administering alogliptin to patients with hepatic impair-
ment [4].
The pharmacokinetics of alogliptin were not altered to a
clinically significant extent in elderly patients aged
65–85 years [39]. No dosage adjustment is needed in
elderly patients receiving alogliptin [4, 5], although dosing
should be conservative given the potential for decreased
renal function in the elderly [5]. The pharmacokinetics of
780
alogliptin were not altered to a clinically significant extent
by gender or race [39], including in Japanese patients [14].
3.4 Potential Drug Interactions
This section provides an overview of drug interactions
potentially associated with alogliptin. Data were obtained
from studies in healthy volunteers [34, 35, 40–45], sup-
plemented by data from the US prescribing information [4]
and the EU SPC [5]. Where specified, alogliptin was ad-
ministered at a dosage of 25 mg [34, 40–45] or 100 mg
[35] once daily.
Alogliptin has a low potential for drug interactions.
In vitro, alogliptin did not induce CYP1A2, CYP2B6 or
CYP2C9 and did not inhibit CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 [4, 5]. Mild
induction of CYP3A4 was seen with alogliptin in vitro, but
not in in vivo studies [5]. In vitro, alogliptin was not a
substrate for, nor an inhibitor of, organic anion transporter
(OAT)-1, OAT-2 or organic cation transporter-2 [5].
Clinical data suggest no interaction between alogliptin and
P-glycoprotein inhibitors or substrates [5].
Interactions between alogliptin and CYP inhibitors are
not expected [5]. Indeed, gemfibrozil (a CYP2C8/CYP2C9
inhibitor), fluconazole (a CYP2C9 inhibitor) and keto-
conazole (a CYP3A4 inhibitor) did not alter the pharma-
cokinetics of alogliptin to a clinically relevant extent [40].
Pioglitazone [41], metformin [35], voglibose [5], ci-
closporin [44], digoxin [42], cimetidine [35] and atorva-
statin [43] did not alter the pharmacokinetics of alogliptin
to a clinically relevant extent. Alogliptin did not have a
clinically relevant effect on the pharmacokinetics of pi-
oglitazone [41], metformin [35], glibenclamide [41], caf-
feine [4, 5], (R)- or (S)-warfarin [34], tolbutamide [4, 5],
dextromethorphan [4, 5], atorvastatin [43], midazolam [4,
5], ethinylestradiol/norethisterone [45], digoxin [42], fex-
ofenadine [4, 5] or cimetidine [35].
4 Therapeutic Efficacy
This section mainly discusses studies designed to examine
the effects of alogliptin on glycaemic control. In most
studies, the primary endpoint was the change from baseline
in glycated haemoglobin (HbA1c) [12, 17–22, 27–30, 46–
53]. Several studies were conducted solely in Asian
populations (e.g. studies were conducted in Japan [12, 17,
18, 21, 22, 53] or in China, Taiwan and Hong Kong [47]).
4.1 Monotherapy
The efficacy of monotherapy with alogliptin in type 2
diabetes was examined in four randomized, double-blind,
G. M. Keating
multicentre trials of 12–26 weeks’ duration [12, 27, 46,
47]. One study included additional treatment arms exam-
ining the addition of alogliptin to metformin (see
Sect. 4.2.1.1) or pioglitazone (see Sect. 4.2.2) [47]. Pa-
tients in these studies had inadequately controlled type 2
diabetes and were not currently receiving antidiabetic
therapy [12, 27, 46, 47] or were receiving metformin and/or
a sulfonylurea [27]. Patients not currently receiving an-
tidiabetic therapy were newly diagnosed [27] or were
inadequately controlled by diet and exercise [12, 27, 46,
47]. Where specified, the mean duration of diabetes was 4.1
[47] or 7.9 years [12]. Efficacy was assessed in the full
analysis set (n = 480 [12] and 185 [47]) or intent-to-treat
population (n = 265 [27] and 329 [46]). Two studies are
available as abstracts [27, 47], supplemented by informa-
tion from ClinicalTrials.gov (NCT00755846 and
NCT01289119).
Alogliptin monotherapy improved glycaemic control in
patients with type 2 diabetes. Compared with placebo,
significantly greater reductions from baseline in HbA1c
were seen at week 12 with alogliptin dosages of
6.25–50 mg once daily in a dose-ranging study in patients
inadequately controlled by diet and exercise (mean changes
of -0.51 to -0.82 vs. ?0.06 %; p \ 0.0001) [12], and
with alogliptin dosages of 12.5–100 mg once daily in a
dose-ranging study in patients who were newly diagnosed
or inadequately controlled by diet and exercise or by
metformin and/or a sulfonylurea (least squares mean
changes of -0.44 to -0.56 vs. -0.01 %; p \ 0.05) [27].
Other studies also demonstrated significantly (p \ 0.001)
greater mean reductions from baseline in HbA1c with
alogliptin 25 mg once daily than with placebo after 16
(-0.99 vs. -0.42 %) [47] or 26 (-0.59 vs. -0.02 %) [46]
weeks’ therapy. Significantly (p \ 0.01 where stated) more
alogliptin than placebo recipients achieved an HbA1c target
of B7.0 % (44.3 vs. 23.4 % [46] and 63.3 vs. 30.0 % [47])
or \6.9 % (29.1–44.3 vs. 8.0 %) [12], with significantly
more alogliptin than placebo recipients achieving an HbA1c
target of B6.5 % in one study (36.7 vs. 12.2 %; p \ 0.001)
[47], but not in another study (20.6 vs. 10.9 %) [46].
Mean fasting plasma glucose (FPG) levels were reduced
to a significantly (p \ 0.05) greater extent with once-daily
alogliptin 6.25–50 mg (-0.52 to -1.25 vs. ?0.31 mmol/
L) [12], 25–100 mg (-0.89 to -1.50 vs. ?0.47 mmol/L)
[27] or 25 mg (-0.91 vs. ?0.63 mmol/L) [46] than with
placebo. In addition, hyperglycaemic rescue was required
by significantly (p B 0.001) fewer alogliptin 12.5 or 25 mg
once daily than placebo recipients (9.8 and 7.6 vs. 29.7 %
of patients) [46].
During the 40-week extension phase of one of the
12-week dose-ranging studies (during which placebo re-
cipients switched to alogliptin 6.25–50 mg once daily),
HbA1c and FPG were significantly reduced from baseline
Alogliptin: A Review
with alogliptin 6.25–50 mg once daily at all time-points up
to 52 weeks (p-values not stated) [12].
One of the 12-week dose-ranging studies also demon-
strated that mean HbA1c was reduced to a significantly
greater extent with alogliptin 6.25–50 mg once daily than
with voglibose 0.2 mg three times daily (-0.51 to -0.82
vs. -0.16 %; p-values not stated) [12]. In addition, sig-
nificantly more recipients of alogliptin 12.5–50 mg once
daily than voglibose achieved an HbA1c target of \6.9 %
(35.7–44.3 vs. 19.3 %) and mean FPG was reduced to a
significantly greater extent with alogliptin 12.5–50 mg
once daily than with voglibose (-0.81 to -1.25 vs.
-0.17 mmol/L) [p-values not stated] [12].
4.2 Combination Therapy
4.2.1 In Combination with Metformin
Five randomized, double-blind, multicentre trials com-
pared the efficacy of alogliptin plus metformin with
alogliptin or metformin alone [18–20, 47] or with glipizide
plus metformin [52] in patients with type 2 diabetes
inadequately controlled by metformin [18, 20, 47, 52] or by
diet and exercise [19]. The mean duration of diabetes
ranged from 4.0 to 6.3 years [18–20, 47, 52]. One study is
available as an abstract [47], supplemented by information
from ClinicalTrials.gov (NCT01289119).
4.2.1.1 Comparisons with Alogliptin or Metformin
Alone Combination therapy with alogliptin plus met-
formin improved glycaemic control to a significantly
greater extent than metformin alone in patients with type 2
diabetes inadequately controlled with metformin [18, 20,
47]. After 12–26 weeks’ therapy, HbA1c was reduced from
baseline to significantly greater extent with alogliptin
25 mg once daily plus metformin than with metformin
alone [18, 20, 47] (Table 1). Patients receiving alogliptin
25 mg once daily plus metformin were also significantly
more likely than those receiving metformin alone to
achieve an HbA1c target of B7.0 [20, 47], \6.9 [18] or
B6.5 % [20, 47] (Table 1).
FPG was reduced to a significantly greater extent with
alogliptin 25 mg once daily plus metformin than with
metformin alone [18, 20] (Table 1). In addition, patients
receiving alogliptin 12.5 or 25 mg once daily plus met-
formin were significantly (p \ 0.01) less likely than pa-
tients receiving metformin alone to experience marked
hyperglycaemia (29 and 31 vs. 51 % of patients) or to
require hyperglycaemic rescue (9 and 8 vs. 24 %) [20].
During the 40-week extension phase of the 12-week
study (during which recipients of metformin alone
switched to alogliptin 12.5 or 25 mg once daily plus met-
formin), HbA1c and FPG were significantly reduced from
781
baseline with alogliptin 12.5 or 25 mg once daily plus
metformin at all time-points up to 52 weeks (p-values not
stated) [18]. With alogliptin 12.5 or 25 mg once daily plus
metformin, mean reductions from baseline in HbA1c were
0.44 and 0.58 % and in FPG were 0.91 and 0.98 mmol/L
[18].
In drug-naive patients with type 2 diabetes inadequately
controlled with diet and exercise (HbA1c of 7.5–10 %),
significantly greater reductions from baseline in HbA1c and
FPG were seen with alogliptin 12.5 mg twice daily plus
metformin 500 or 1000 mg twice daily than with alogliptin
12.5 mg twice daily alone or metformin 500 or 1000 mg
twice daily alone [19] (Table 1).
In addition, significantly (p \ 0.05) greater least
squares mean reductions from in baseline in 2-h PPG
levels were seen with alogliptin 12.5 mg twice daily plus
metformin 1000 mg twice daily than with alogliptin
12.5 mg twice daily alone or metformin 1000 mg twice
daily alone (-4.75 vs. -2.38 and -2.99 mmol/L), with
no other significant between-group differences seen [19].
Hyperglycaemic rescue was required in significantly
(p \ 0.05) fewer patients receiving alogliptin 12.5 mg
twice daily plus metformin 500 mg twice daily than
alogliptin 12.5 mg twice daily alone or metformin
500 mg twice daily alone (12.3 vs. 17.3 and 22.9 %) or
alogliptin 12.5 mg twice daily plus metformin 1000 mg
twice daily than alogliptin 12.5 mg twice daily alone or
metformin 1000 mg twice daily alone (2.6 vs. 17.3 and
10.8 %). In general, recipients of alogliptin plus met-
formin were significantly more likely than recipients of
alogliptin or metformin alone to achieve an HbA1c target
of \7.0 or \6.5 % [19] (Table 1).
4.2.1.2 Comparisons with Glipizide plus Metformin The
efficacy of alogliptin plus metformin was maintained over
2 years in patients with inadequately controlled type 2
diabetes [52]. Alogliptin 25 mg once daily plus metformin
was noninferior to glipizide 5–20 mg/day plus metformin
in terms of the reduction from baseline in HbA1c after
104 weeks’ therapy in patients with type 2 diabetes
inadequately controlled with metformin, with superiority
subsequently shown (Table 1). Significantly more patients
receiving alogliptin 25 mg once daily plus metformin than
glipizide plus metformin achieved an HbA1c target of
B6.5 % or B7.0 % after 104 weeks’ therapy (Table 1)
[52].
FPG was reduced from baseline to a significantly greater
extent with alogliptin 25 mg once daily plus metformin
than with glipizide plus metformin after 104 weeks’ ther-
apy (Table 1) [52]. Hyperglycaemic rescue was required in
significantly fewer patients receiving alogliptin 25 mg
once daily plus metformin than glipizide plus metformin
(23.2 vs. 27.4 %; p = 0.03) [52].
782 G. M. Keating

Table 1 Efficacy of alogliptin plus metformin in patients with type 2 diabetes inadequately controlled with metformin alone [18, 20, 47, 52] or
diet and exercise [19]. Results of trials of 12 [18], 16 [47], 26 [19, 20] or 104 [52] weeks’ duration
Study Treatmenta No. of LSM change from LSM change from HbA1c target (% of pts)
ptsb baseline in HbA1cc baseline in FPG (mmol/L)
(%) [baseline [baseline value] B7.0 or \6.9 %d B6.5 %
value]

Comparisons with ALO or MET alone

Ji et al. [47]e ALO 25 od ? MET 98 -0.91*** -1.24f 55.1*** 21.4***
MET 97 -0.22 -0.51f 25.8 4.1
Nauck et al. [20] ALO 12.5 od ? MET 213 -0.6*** [7.9] -1.0*** [9.3] 52*** 20*
ALO 25 od ? MET 210 -0.6*** [7.9] -1.0*** [9.5] 44*** 17*
MET 104 -0.1 [8.0] 0 [10.0] 18 4
Pratley et al. [19] ALO 12.5 bid ? MET 500 bid 111 -1.22***   -1.76*  47.1**   20.6**
ALO 12.5 bid ? MET 1000 bid 114 -1.55***   -2.55*  59.5***   32.4*  
ALO 12.5 bid 113 -0.56 -0.54 20.2 13.5
ALO 25 od 112 -0.52 -0.3 20.2 6.7
MET 500 bid 114 -0.65 -0.64 27.2 6.8
MET 1000 bid 111 -1.11 -1.77 34.3 18.5
PL 109 ?0.15 ?0.7 3.9 1.0
Seino et al. [18] ALO 12.5 od ? MET 92 -0.55**** [7.89] -1.05g 28.3g
ALO 25 od ? MET 96 -0.64**** [8.02] -1.28g 27.1g
MET 100 ?0.22 [8.00] -0.04 2.0
Comparison with GPZ 1 MET
Del Prato et al. [52] ALO 12.5 od ? MET 371 -0.68h [7.6] -0.05ààà 45.6 23.5à
ààà àà
ALO 25 od ? MET 382 h
-0.72 [7.6] -0.18 48.5 24.1àà
GPZ 5–20 daily ? MET 336 -0.59 [7.6] ?0.30 42.8 19.0
ALO alogliptin, bid twice daily, FPG fasting plasma glucose, GPZ glipizide, HbA1c glycated haemoglobin, LSM least squares mean, MET
metformin, od once daily, PL placebo, pts patients
     à àà
* p \ 0.05, ** p \ 0.01, *** p \ 0.001, **** p \ 0.0001 vs. MET; p \ 0.05, p \ 0.001 vs. ALO 12.5 bid; p \ 0.05, p \ 0.01,
ààà
p \ 0.001 vs. GPZ ? MET
a
Pts received a stable MET dosage [18, 20, 47] (500–750 mg/day [18], C1000 mg/day [47] or C1500 mg/day [20]) or MET C1500 mg od or
the maximum tolerated dosage [52]
b
No. of patients in the full analysis set [18–20, 47] or the per-protocol population [52]
c
Primary endpoint
d
HbA1c target of B7.0 % [19, 20, 47, 52] or \6.9 % [18]
e
Available as an abstract, supplemented by data from ClinicalTrials.gov (NCT01289119). This study also included treatment arms in which pts
received ALO vs. PL (see Sect. 4.1 for results) or ALO ? PIO vs. PIO (see Table 2 for results)
f
Statistical analysis not reported
g
Significantly different vs. MET alone (p-value not stated)
h
Noninferiority was shown between ALO 12.5 od ? MET vs. GPZ ? MET and between ALO 25 od ? MET vs. GPZ ? MET, with supe-
riority also shown for ALO 25 od ? MET vs. GPZ ? MET

4.2.2 In Combination with Pioglitazone
Four randomized, double-blind, multicentre trials exam-
ined the efficacy of alogliptin in combination with piogli-
tazone in patients with inadequately controlled type 2
diabetes [21, 28, 47, 48]. Patients were inadequately con-
trolled despite diet and exercise (drug-naive patients) [48]
or despite treatment with pioglitazone alone [21], piogli-
tazone with or without metformin [47] or a thiazolidine-
dione with or without a sulfonylurea or metformin [28].
The mean duration of diabetes ranged from &3 to
7.6 years [21, 28, 47, 48].
Combination therapy with alogliptin plus pioglitazone
significantly improved glycaemic control in patients with
type 2 diabetes inadequately controlled by a thiazolidine-
dione with or without other oral antidiabetic drugs (OADs)
[21, 28, 47]. After 12–26 weeks’ therapy, HbA1c was re-
duced from baseline to a significantly greater extent with
alogliptin 25 mg once daily plus pioglitazone than with
pioglitazone [21, 28, 47] (Table 2). HbA1c targets of
Alogliptin: A Review 783

Table 2 Efficacy of alogliptin plus pioglitazone in patients with type 2 diabetes inadequately controlled with pioglitazone (with or without other
oral antidiabetic drugs) [21, 28, 47] or diet and exercise [48]. Results of trials of 12 [21], 16 [47] or 26 [28, 48] weeks’ duration
Study Treatment (mg) No. of ptsa LSM change from Changec from baseline HbA1c target
baseline in HbA1cb in FPG (mmol/L) (% of pts)
(%) [baseline value] [baseline value]
B7.0 or B6.5 or
\6.9 %d \6.2 %e

Ji et al. [47]f ALO 25 od ? PIOg 60 -0.76*** -1.07h 61.7*** 30.0***

g
PIO 63 -0.25 -0.11h 31.7 9.5
Kaku et al. [21] ALO 12.5 od ? PIO 15 or 30 daily 111 -0.91**** [7.91] -0.83* 49.5* 6.3*
ALO 25 od ? PIO 15 or 30 daily 113 -0.97**** [7.89] -1.05* 49.6* 4.4*
PIO 15 or 30 daily 115 -0.19 [7.92] -0.13 20.0 0
i
Pratley et al. [28] ALO 12.5 od ? PIO 197 -0.66*** [8.1] -1.09** 44.2*
ALO 25 od ? PIOi 199 -0.80*** [8.0] -1.10** 49.2*
PIOi 97 -0.19 [8.0] -0.32 34.0
Rosenstock et al. [48] ALO 12.5 od ? PIO 30 od 163 -1.56* [8.85] -2.7* [11.0] 53.4* 26.4*
ALO 25 od ? PIO 30 od 164 -1.71*  [8.80] -2.8*  [10.2] 62.8*  27.4 
ALO 25 od 164 -0.96 [8.80] -1.4 [10.5] 24.4 11.6
PIO 30 od 163 -1.15 [8.76] -2.1 [10.5] 33.7 16.6
ALO alogliptin, FPG fasting plasma glucose, HbA1c glycated haemoglobin, LSM least squares mean, MET metformin, od once daily, PIO
pioglitazone, PL placebo, pts patients
 
* p \ 0.05, ** p \ 0.01, *** p \ 0.001, **** p \ 0.0001 vs. PIO; p \ 0.05 vs ALO
a
No. of patients in the full analysis set [21, 47] or intent-to-treat population [28, 48]
b
Primary endpoint
c
Mean [21] or least squares mean [28, 47, 48] changes
d
HbA1c target of B7.0 % [28, 47, 48] or \6.9 % [21]
e
HbA1c target of B6.5 % [47, 48] or \6.2 % [21]
f
Available as an abstract and supplemented by data from ClinicalTrials.gov (NCT01289119). This study also included treatment arms in which
pts received ALO vs. PL (see Sect. 4.1 for results) or ALO ? MET vs. MET (see Table 1 for results)
g
Pts continued to receive their stable dosage of PIO with or without MET
h
Statistical analysis not reported
i
Pts continued with their stable dosage of PIO or switched from rosiglitazone to PIO 30 or 45 mg. At baseline, 56.2 and 21.2 % of pts were also
receiving MET or a sulfonylurea, respectively; a stable dosage of these agents was administered throughout the trial

B7.0 % [28, 47],\6.9 % [21], B6.5 % [47] or\6.2 % [21]
were achieved by significantly more alogliptin 25 mg once
daily plus pioglitazone recipients than pioglitazone re-
cipients (Table 2).
Significantly greater reductions in FPG were seen with
alogliptin 25 mg once daily plus pioglitazone than with
pioglitazone [21, 28] (Table 2). In addition, changes from
baseline in PPG levels 2 h after a meal tolerance test were
significantly (p \ 0.05) greater with alogliptin 12.5 or
25 mg once daily plus pioglitazone than with pioglitazone
after 12 weeks’ therapy (-1.76 and -2.30 vs.
-0.25 mmol/L) [21].
Results of the 40-week extension phase of the 12-week
study (during which recipients of pioglitazone alone
switched to alogliptin 12.5 or 25 mg once daily plus pi-
oglitazone) showed that HbA1c, FPG and 2-h PPG levels
were significantly reduced from baseline at all time-points
during the 52-week follow-up period with alogliptin plus
pioglitazone (p-values not stated) [21].
In drug-naive patients with type 2 diabetes inadequately
controlled with diet and exercise, HbA1c was reduced from
baseline to a significantly greater extent with alogliptin
25 mg once daily plus pioglitazone 30 mg once daily than
with pioglitazone 30 mg once daily or alogliptin 25 mg
once daily after 26 weeks’ therapy [48] (Table 2). In ad-
dition, HbA1c targets of B7.0 and B6.5 % were achieved
by significantly more recipients of alogliptin 25 mg once
daily plus pioglitazone 30 mg once daily than with pi-
oglitazone 30 mg once daily or alogliptin 25 mg once daily
[48] (Table 2).
Significantly greater reductions in FPG were also seen
with alogliptin 25 mg once daily plus pioglitazone 30 mg
once daily than with pioglitazone 30 mg once daily or
alogliptin 25 mg once daily [48] (Table 2). Hypergly-
caemic rescue was required by significantly fewer re-
cipients of alogliptin 25 mg once daily plus pioglitazone
30 mg once daily than alogliptin 25 mg once daily (2.5 vs.
11.3 %; p \ 0.05) [48].
784
4.2.3 In Combination with a Sulfonylurea
Two randomized, double-blind, multicentre trials of 12
[17] or 26 [30] weeks’ duration compared the efficacy of
alogliptin plus glibenclamide [30] or glimepiride [17] with
glibenclamide [30] or glimepiride [17] alone in patients
with type 2 diabetes inadequately controlled with a sul-
fonylurea [17, 30]. The mean duration of diabetes was 7.7
[30] or 9.8 [17] years.
Alogliptin plus a sulfonylurea improved glycaemic
control in patients inadequately controlled with a sulfon-
ylurea alone. After 12 [17] or 26 [30] weeks’ therapy,
HbA1c was reduced from baseline to a significantly greater
extent with alogliptin 25 mg once daily plus glibenclamide
or glimepiride than with glibenclamide or glimepiride
alone [17, 30] (Table 3). Patients receiving alogliptin
25 mg once daily plus glibenclamide or glimepiride were
significantly more likely than those receiving gliben-
clamide or glimepiride alone to achieve an HbA1c target of
B7.0 % [30] or \6.9 % [17] (Table 3).
In one trial, FPG was reduced to a significantly greater
extent in patients receiving alogliptin 25 mg once daily
plus glimepiride than in those receiving glimepiride alone
[17] (Table 3). However, in the other trial, changes from
baseline in FPG did not significantly differ between
alogliptin 25 mg once daily plus glibenclamide recipients
and glibenclamide alone recipients [30] (Table 3). Changes
from baseline in PPG 2 h after a meal tolerance test were
significantly (p \ 0.05) greater with alogliptin 12.5 or
25 mg once daily plus glimepiride than with glimepiride
after 12 weeks’ therapy (-2.46 and -1.85 vs. ?0.45
mmol/L) [17]. Patients receiving alogliptin 25 mg once
daily plus glibenclamide were significantly less likely than
those receiving glibenclamide alone to require hypergly-
caemic rescue [30] (Table 3).
Results of the 40-week extension phase of the 12-week
study (during which recipients of glimepiride alone
switched to alogliptin 12.5 or 25 mg once daily plus
glimepiride) showed that HbA1c, FPG and 2-h PPG levels
were significantly reduced from baseline at all time-points
during the 52-week follow-up period with alogliptin plus
glimepiride (p-values not stated) [17].
4.2.4 In Combination with Voglibose
A randomized, double-blind, multicentre, 12 week trial
compared the efficacy of alogliptin plus voglibose with
voglibose alone in patients with type 2 diabetes
inadequately controlled by an a-glucosidase inhibitor [22].
The mean duration of diabetes was 7.7 years [22].
Combination therapy with alogliptin plus voglibose
improved glycaemic control in patients inadequately con-
trolled with an a-glucosidase inhibitor [22]. After
G. M. Keating
12 weeks’ therapy, HbA1c was reduced from baseline to a
significantly greater extent with alogliptin 25 mg once
daily plus voglibose 0.2 mg three times daily than with
voglibose 0.2 mg three times daily alone (Table 3). In
addition, significantly more patients receiving alogliptin
12.5 or 25 mg once daily plus voglibose than voglibose
alone achieved HbA1c targets of \6.9 % (Table 3) or
\6.2 % (5.3 and 10.1 vs. 0 %; p \ 0.05). FPG was re-
duced to a significantly greater extent with alogliptin
25 mg once daily plus voglibose than with voglibose alone
(Table 3). In addition, changes from baseline in PPG levels
2 h after a meal tolerance test were significantly (p \ 0.05)
greater with alogliptin 12.5 or 25 mg once daily plus
voglibose than with voglibose after 12 weeks’ therapy
(-2.62 and -3.00 vs. -0.01 mmol/L) [22].
Results of the 40-week extension phase of the 12-week
study (during which recipients of voglibose alone switched
to alogliptin 12.5 or 25 mg once daily plus voglibose)
showed that HbA1c and FPG were significantly reduced
from baseline at all time-points during the 52-week follow-
up period with alogliptin plus voglibose (p-values not
stated) [22].
4.2.5 In Combination with Insulin
Two randomized, double-blind, multicentre trials exam-
ined the efficacy of alogliptin in combination with insulin
in patients with type 2 diabetes inadequately controlled by
insulin alone [29, 53] or insulin plus metformin [29]. Pa-
tients received alogliptin plus insulin or insulin (with or
without metformin [29]) for 12 [53] or 26 [29] weeks. Most
patients were receiving premixed insulins or insulin com-
binations at baseline (see Table 3 for further details). Pa-
tients had a mean duration of diabetes of 12.6 [29] or 14.9
[53] years.
Combination therapy with alogliptin plus insulin im-
proved glycaemic control in patients inadequately con-
trolled by insulin [29, 53]. After 12 [53] or 26 [29] weeks’
therapy, HbA1c was reduced from baseline to a sig-
nificantly greater extent with alogliptin 25 mg once daily
plus insulin than with insulin (Table 3). FPG was also re-
duced to a significantly greater extent with alogliptin
25 mg once daily plus insulin than with insulin in the
26-week trial [29], but not in the 12-week trial [53], and
significantly fewer recipients of alogliptin 25 mg once
daily plus insulin than insulin required hyperglycaemic
rescue [29] (Table 3). Consistent with the study protocol,
the mean insulin dosage at week 26 was essentially un-
changed from baseline [29]. Similarly, minimal changes in
insulin dosages were seen in the 12-week trial [53].
Results of the 40-week extension phase of the 12-week
study (during which recipients of insulin alone switched to
alogliptin plus insulin) revealed that the efficacy of add-on
Alogliptin: A Review 785

Table 3 Efficacy of alogliptin plus a sulfonylurea, voglibose or insulin in patients with inadequately controlled type 2 diabetes. Results of trials
of 12 [17, 22, 53] or 26 [29, 30] weeks’ duration
Study Treatment (mg) No. of LSM change from Changec from HbA1c target Hyperglycaemic
ptsa baseline in HbA1cb baseline in of B7.0 or rescue
(%) [baseline value] FPG (mmol/L) \6.9 %d (% of pts)
[baseline value] (% of pts)

In combination with a sulfonylurea

Pratley et al. [30] ALO 12.5 od ? GBCe 203 -0.39*** -0.26 29.6 14.9*
ALO 25 od ? GBCe 198 -0.53*** -0.47 34.8** 15.7*
GBCe 99 ?0.01 ?0.12 18.2 28.3
Seino et al. [17] ALO 12.5 od ? GMP 1–4 daily 104 -0.59**** [8.54] -1.24* 9.6*
ALO 25 od ? GMP 1–4 daily 104 -0.65**** [8.54] -0.88* 7.7*
GMP 1–4 daily 103 ?0.35 [8.62] ?0.33 0
In combination with VOG
Seino et al. [22] ALO 12.5 od ? VOG 0.2 tid 76 -0.96   [8.02] -1.06  46.1 
ALO 25 od ? VOG 0.2 tid 79 -0.93   [7.91] -1.03  50.6 
VOG 0.2 tid 75 ?0.06 [8.12] -0.31 12.2
In combination with INS
Rosenstock et al. [29] ALO 12.5 od ? INSf 131 -0.63àà [9.3] ?0.1 [10.5] 21àà
àà à
ALO 25 od ? INS f
129 -0.71 [9.3] -0.6 [10.3] 20àà
INSf 130 -0.13 [9.3] ?0.3 [10.9] 40
Kaku et al. [53] ALO 25 od ? INSg 90 -0.96ààà [8.4] -1.1 [8.6] 23.3
INSg 89 -0.29 [8.4] -0.5 [8.6] 5.7
ALO alogliptin, FPG fasting plasma glucose, GBC glibenclamide, GMP glimepiride, HbA1c glycated haemoglobin, INS insulin, LSM least
squares mean, od once daily, pts patients, tid three times daily, VOG voglibose
     à àà
* p \ 0.05, ** p \ 0.01, *** p \ 0.001, **** p \ 0.0001 vs. sulfonylurea; p \ 0.05, p \ 0.0001 vs. VOG; p \ 0.05, p \ 0.001,
ààà
p \ 0.0001 vs. INS
a
No. of patients in the full analysis set [17, 22, 29, 53] or intent-to-treat population [30]
b
Primary endpoint
c
Mean [17, 22, 29, 53] or least squares mean [30] changes
d
HbA1c target of B7.0 [30, 53] or \6.9 % [17, 22]
e
Pts continued a stable GBC dosage (median 10 mg/day at study entry)
f
Pts continued their existing INS regimen, with premixed INS or INS combinations, long-acting INS and short-acting INS administered to 64,
34 and 2 % of pts, respectively. The mean INS dosage at baseline was 57 IU/day, and 59 % of pts were also receiving metformin
g
Pts continued their existing INS regimen, with premixed INS, long-acting INS and intermediate-acting INS administered to 80, 15 and 5 % of
pts, respectively. The mean INS dosage at baseline was 23 IU/day

therapy with alogliptin was maintained in the longer term
[53]. At week 52, the mean reduction from baseline in
HbA1c was 1.0 % in patients initially randomized to
alogliptin plus insulin or insulin alone [53].
4.2.6 In Combination with Pioglitazone Plus Metformin
The efficacy of triple therapy with alogliptin plus piogli-
tazone and metformin was examined in two randomized,
double-blind, multicentre in patients with type 2 diabetes
inadequately controlled by metformin alone [50] or met-
formin plus pioglitazone or another OAD [49]. The trials
were of 26 [50] or 52 [49] weeks’ duration and patients had
a mean diabetes duration of 6.2 [50] or 7.2 [49] years.
Triple therapy with alogliptin plus pioglitazone and
metformin was more effective than uptitrated pioglitazone
plus metformin in patients with type 2 diabetes
inadequately controlled by metformin plus pioglitazone or
another OAD [49]. In terms of the reduction from baseline
in HbA1c, alogliptin 25 mg once daily plus pioglitazone
30 mg once daily and metformin was deemed to be non-
inferior to pioglitazone 45 mg once daily and metformin at
weeks 26 and 52, with superiority also shown at week 52
(Table 4). In addition, significantly more patients receiving
alogliptin plus pioglitazone and metformin than uptitrated
pioglitazone plus metformin achieved an HbA1c target of
B7.0 or B6.5 % (Table 4). FPG was reduced to a sig-
nificantly greater extent with alogliptin plus pioglitazone
and metformin than with uptitrated pioglitazone plus
metformin (Table 4) [49].
Triple therapy with alogliptin plus pioglitazone and
metformin also improved glycaemic control in patients
786 G. M. Keating

Table 4 Efficacy of triple therapy with alogliptin, pioglitazone and metformin in patients with inadequately controlled type 2 diabetes
Study Treatmenta No. of Time- LSM change from LSM change from HbA1c target (%
ptsb point baseline in HbA1cc baseline in FPG of pts)
(weeks) (%) [baseline value] (mmol/L)
[baseline value] B7.0 % B6.5 %

Bosi et al. [49] ALO 25 od ? PIO 30 od ? MET 303 26 -0.89d [8.3] -0.9* [9.0]
d
52 -0.70 -0.8* 33.2** 8.7**
PIO 45 od ? MET 306 26 -0.42 [8.1] -0.3 [9.0]
52 -0.29 -0.2 21.3 4.3
DeFronzo et al. [50]e ALO 12.5 od ? PIO 15 od ? MET 130 26 -1.34  [8.5] -2.33  [10.2] 49.2f 21.5f
ALO 12.5 od ? PIO 30 od ? MET 128 26 -1.39  [8.5] -2.34  [10.0] 53.1f 30.0f
ALO 12.5 od ? PIO 45 od ? MET 127 26 -1.55  [8.5] -2.85  [9.7] 61.5f 32.3f
    f
ALO 25 od ? PIO 15 od ? MET 127 26 -1.27 [8.5] -2.11 [10.0] 54.6 24.6f
    f
ALO 25 od ? PIO 30 od ? MET 124 26 -1.39 [8.5] -2.31 [9.9] 53.1 30.0f
    f
ALO 25 od ? PIO 45 od ? MET 126 26 -1.60 [8.6] -2.92 [9.9] 60.0 33.1f
f
ALO 12.5 od ? MET 122 26 -0.64 [8.6] -0.73 [10.2] 22.7 8.6f
ALO 25 od ? MET 123 26 -0.90 [8.6] -1.03 [10.2] 27.1f 12.4f
f
PIO 15 od ? MET 127 26 -0.75 [8.5] -1.31 [9.8] 25.6 6.2f
f
PIO 30 od ? MET 123 26 -0.92 [8.5] -1.60 [9.7] 29.5 11.6f
PIO 45 od ? MET 126 26 -1.00 [8.5] -1.80 [10.0] 36.4f 19.4f
PL ? MET 126 26 -0.13 [8.5] ?0.36 [9.8] 6.2f 0.8f
ALO alogliptin, FPG fasting plasma glucose, HbA1c glycated haemoglobin, LSM least squares mean, MET metformin, od once daily, PIO
pioglitazone, PL placebo, pts patients
 
* p \ 0.01, ** p \ 0.001 vs. PIO ? MET; p B 0.001 vs. corresponding dosages of ALO ? MET or PIO ? MET
a
Pts received a stable MET dosage of 1500 mg/day or the maximum tolerated dosage [49] or C1500 mg/day [50]
b
No. of patients in the full analysis set [50] or per-protocol population [49]
c
Primary endpoint
d
Noninferiority was shown between ALO ? PIO ? MET and PIO ? MET at weeks 26 and 52, with superiority also shown at week 52
e
Supplemented by data from ClinicalTrials.gov (NCT00328627)
f
Statistical analysis not reported

with type 2 diabetes inadequately controlled by metformin
alone [50]. When the pioglitazone dosage groups were
pooled, the least squares mean reduction from baseline in
HbA1c at week 26 was significantly (p \ 0.001) greater
with both alogliptin 12.5 and 25 mg once daily plus pi-
oglitazone 15, 30 or 45 mg once daily plus metformin than
with pioglitazone 15, 30 or 45 mg once daily plus met-
formin (-1.4 % for both alogliptin dosages vs. -0.9 %).
The proportion of patients achieving an HbA1c target of
B7.0 % was significantly (p \ 0.001) greater with
alogliptin 12.5 or 25 mg once daily plus pioglitazone 15,
30 or 45 mg once daily plus metformin than with piogli-
tazone 15, 30 or 45 mg once daily plus metformin (54.6
and 55.9 vs. 30.5 %). Results for the individual treatment
arms are shown in Table 4 [50].
The least squares mean reduction from baseline in FPG at
week 26 was also significantly (p \ 0.001) greater with both
alogliptin 12.5 and 25 mg once daily plus pioglitazone 15, 30
or 45 mg once daily plus metformin than with pioglitazone
15, 30 or 45 mg once daily plus metformin (-2.5 mmol/L
for both alogliptin dosages vs. -1.6 mmol/L) [50]. Results
for the individual treatment arms are shown in Table 4. In
addition, significantly (p \ 0.01) fewer patients receiving
alogliptin 12.5 or 25 mg once daily plus pioglitazone 15, 30
or 45 mg once daily plus metformin than pioglitazone 15, 30
or 45 mg once daily plus metformin required hypergly-
caemic rescue (3.9 and 3.4 vs. 11.4 %) [50].
4.3 Special Patient Populations
4.3.1 Elderly Patients
The efficacy of alogliptin monotherapy was compared with
that of glipizide monotherapy in elderly patients aged
65–90 years with type 2 diabetes in a randomized, double-
blind, multicentre, 52-week study [51]. Patients had mild
hyperglycaemia despite diet and exercise with or without
OAD monotherapy. The mean duration of type 2 diabetes
was 6.1 years and the mean baseline HbA1c was 7.50 % in
alogliptin recipients and 7.45 % in glipizide recipients. The
primary efficacy analysis was conducted in the per-protocol
population (n = 342) [51].
Alogliptin: A Review
After 52 weeks’ therapy, alogliptin 25 mg once daily
was noninferior to glipizide 5–10 mg once daily in terms of
the change from baseline in HbA1c [51]. The least squares
mean reduction from baseline in HbA1c was 0.14 % with
alogliptin and 0.09 % with glipizide (mean baseline values
of 7.54 and 7.46 %). An HbA1c target of B7.0 was
achieved in 49 % of alogliptin recipients and 45 % of
glipizide recipients and an HbA1c target of B6.5 % was
achieved in 22 and 18 % of patients in the corresponding
treatment groups [51]. The least squares mean reduction
from baseline in FPG was 0.11 mmol/L with alogliptin and
0.22 mmol/L with glipizide (mean baseline values of 8.21
and 7.99 mmol/L). In addition, the mean change in 2-h
PPG was -0.33 mmol/L in alogliptin recipients (from a
baseline of 10.93 mmol/L) versus ?0.33 in glipizide re-
cipients (from a baseline of 10.21 mmol/L). Hypergly-
caemic rescue was required in 25 % of alogliptin recipients
and in 22 % of glipizide recipients [51].
4.3.2 Patients Undergoing Haemodialysis
Two small (n = 16 [54] and 30 [55]) studies of 48 weeks
[55] or 2 years [54] duration examined the efficacy of
alogliptin in patients with type 2 diabetes who were un-
dergoing haemodialysis [54, 55]. The trials were of non-
comparative, single-centre [54] or open-label, multicentre
[55] design. Patients had inadequate glycaemic control
despite receiving diet and exercise therapy [54] or treat-
ment with dietary modification alone (n = 15) or mit-
iglinide and/or voglibose (n = 15) [55]. At baseline, mean
HbA1c was 7.1 % [54, 55], and mean haemoglobin levels
were 10.8 g/dL [54] and 10.9 g/dL [55]. Given that anae-
mia is common in patients undergoing haemodialysis and
may falsely lower HbA1c levels [55], glycated albumin
levels were also assessed in these trials.
Alogliptin 6.25 mg once daily improved glycaemic
control in patients undergoing haemodialysis who had type
2 diabetes inadequately controlled by diet and exercise
alone [54]. After 24 months’ therapy, mean HbA1c was
significantly (p \ 0.05) reduced from 7.1 % at baseline to
5.8 %. Mean glycated albumin levels were also sig-
nificantly (p \ 0.05) reduced from 22.5 % at baseline to
19.6 % at 24 months [54].
Alogliptin 6.25 mg once daily improved glycaemic
control in patients undergoing haemodialysis who had type
2 diabetes inadequately controlled by diet or by mitiglinide
and/or voglibose [55]. After 48 weeks’ therapy, mean
HbA1c was significantly (p \ 0.0001) reduced from 7.1 %
at baseline to 6.3 %. Significant (p \ 0.0001) reductions
from baseline were also seen in glycated albumin levels
(from 25.6 to 20.7 %) and in PPG (from 11.77 to
8.66 mmol/L) [55].
787
5 Tolerability and Safety
In addition to the trials discussed in Sect. 4, tolerability
data were obtained from a pooled analysis of tolerability
data reported in the US prescribing information [4]. The
pooled analysis included 14 randomized, double-blind tri-
als in &8500 alogliptin recipients (as monotherapy or in
combination with other OADs or insulin), &2200 active
comparator recipients and &2900 placebo recipients [4].
Data regarding cardiovascular outcomes were obtained
from the randomized, double-blind, multinational EXAM-
INE trial [56]. In EXAMINE, patients with type 2 diabetes
and a recent acute coronary syndrome [i.e. acute myocar-
dial infarction (MI) or unstable angina pectoris requiring
hospitalization within the previous 15–90 days] received
alogliptin 6.25–25 mg once daily (dosage dependent on
renal function) [n = 2701] or placebo (n = 2679), in ad-
ditional to standard of care treatment for type 2 diabetes.
The primary endpoint in EXAMINE was a composite of
death from cardiovascular causes, nonfatal MI or nonfatal
stroke. Patients were followed for up to 40 months (median
duration of alogliptin exposure of 533 days) [56]. An ad-
ditional analysis of EXAMINE is available, reporting heart
failure and mortality outcomes [57]. In EXAMINE, 1533
patients (28 %) had a history of heart failure, although
patients with New York Heart Association (NYHA) class
IV heart failure were excluded from the trial [56].
5.1 General Tolerability Profile
Oral alogliptin was generally well tolerated in patients with
type 2 diabetes when administered as monotherapy [27, 46]
as dual therapy in combination with metformin [18–20],
pioglitazone [21, 28], voglibose [22], a sulfonylurea [17,
30] or insulin [29, 53] or as triple therapy in combination
with pioglitazone plus metformin [49, 50]. Most adverse
events were of mild to moderate severity [12, 17–20, 28–
30, 46, 49] and were not considered treatment related [17–
21, 29, 30, 49, 53].
In the pooled analysis, adverse events were reported in
66 % of alogliptin 25 mg once daily recipients, in 70 % of
active comparator recipients and in 62 % of placebo re-
cipients, with discontinuation because of adverse events
occurring in 4.7, 6.2 and 4.5 % of patients in the corre-
sponding treatment groups [4]. Adverse reactions reported
in C4 % of the 5902 alogliptin 25 mg once daily recipients
and in numerically more alogliptin than placebo recipients
included nasopharyngitis (4.4 % of alogliptin 25 mg once
daily recipients vs. 5.0 % of active comparator recipients
and 3.0 % of placebo recipients), headache (4.2 vs. 5.4 and
2.5 %) and upper respiratory tract infection (4.2 vs. 5.0 and
2.1 %) [4].
788
Serious adverse events considered to be possibly or
probably related to treatment occurred infrequently in
alogliptin recipients. For example, no serious adverse
events considered to be related to treatment occurred in
patients receiving monotherapy with alogliptin 25 mg once
daily [46]. In addition, serious adverse events considered to
be possibly or probably related to treatment occurred in
0–1 % of alogliptin 25 mg once daily plus metformin re-
cipients versus 0 % of metformin monotherapy recipients
[18, 20], in 0–1.5 % of alogliptin 25 mg once daily plus
pioglitazone recipients versus 1 % of pioglitazone mono-
therapy recipients [21, 28], in 0 % of alogliptin 25 mg once
daily plus glibenclamide recipients versus 1 % of gliben-
clamide monotherapy recipients [30], in 0 % of alogliptin
25 mg once daily plus insulin recipients versus 0 % of
insulin recipients [29], and in 0.3 % of patients receiving
alogliptin 25 mg once daily plus pioglitazone and met-
formin versus 0.3 % of patients receiving pioglitazone plus
metformin [50].
The good tolerability profile of alogliptin was main-
tained in the longer-term, according to extension studies
examining the use of up to 52 weeks’ alogliptin therapy
[12, 17, 18, 21, 22, 53] and results of a 2-year study [52].
Alogliptin 25 mg once daily was generally well toler-
ated in elderly patients with type 2 diabetes [51]. Adverse
events were reported in 73.4 % of alogliptin recipients and
in 68.9 % of glipizide recipients, with drug-related adverse
events reported in 16.2 and 21.5 % of patients, respec-
tively, and discontinuation because of adverse events oc-
curring in 8.6 and 12.3 % of patients, respectively. The
most commonly reported adverse events included urinary
tract infection, dizziness and headache [51].
Alogliptin was also generally well tolerated in patients
with type 2 diabetes who were undergoing haemodialysis,
with no significant increase in adverse events such as
symptomatic hypoglycaemia, liver impairment, anaemia or
skin rash [55]. Moreover, bodyweight gain between dialysis
sessions was significantly (p = 0.04) reduced from baseline
with alogliptin [55]. In another study in patients with type 2
diabetes who were undergoing haemodialysis, none of the
alogliptin recipients experienced significant adverse events
(e.g. hypoglycaemia), although drug-related rash occurred
in one patient [54].
Death was reported infrequently among patients re-
ceiving alogliptin or comparator agents in trials of 26 [19,
20, 29, 46, 50] or 52 [17, 18, 21, 22, 49] weeks’ duration.
In a 2-year study, death was reported in 0.3 % of alogliptin
12.5 mg once daily plus metformin recipients, 0.3 % of
alogliptin 25 mg once daily plus metformin recipients and
0.6 % of glipizide plus metformin recipients [52].
No clinically relevant changes in vital signs and/or ECG
recordings were reported in alogliptin recipients [12, 17–
22, 29, 30, 46, 49–51, 53]. Changes in laboratory
G. M. Keating
parameters were generally reported as being of no clinical
relevance or of mild severity [12, 17–22, 29, 30, 46, 47,
49–51].
5.2 Adverse Cardiovascular Events
The risk of major cardiovascular events was not increased
with alogliptin in patients with type 2 diabetes and a recent
acute coronary syndrome, according to the results of the
EXAMINE trial [56]. The primary composite endpoint
(death from cardiovascular causes, nonfatal MI or nonfatal
stroke) occurred in 11.3 % of alogliptin recipients and in
11.8 % of placebo recipients [hazard ratio (HR) 0.96, with
an upper limit for the one-sided repeated CI of 1.16;
p \ 0.001 for noninferiority; p = 0.32 for superiority].
When components of the primary composite endpoint were
considered separately, there was no significant difference
between alogliptin and placebo recipients in the rate of
cardiovascular mortality (3.3 vs. 4.1 %) [HR 0.79; 95 % CI
0.60–1.04], nonfatal MI (6.9 vs. 6.5 %) [HR 1.08; 95 % CI
0.88–1.33] or nonfatal stroke (1.1 vs. 1.2 %) [HR 0.91;
95 % CI 0.55–1.50]. In addition, there was no significant
difference between alogliptin and placebo recipients in the
incidences of the key secondary endpoint comprising the
primary composite endpoint plus urgent revascularization
because of unstable angina within 24 h of hospital admis-
sion (12.7 vs. 13.4 %) [HR 0.95; with an upper limit for the
one-sided repeated CI of 1.14], all-cause mortality (5.7 vs.
6.5 %) [HR 0.88; 95 % CI 0.71–1.09] or cardiovascular
mortality when both primary endpoint events and death
occurring after a nonfatal primary endpoint were included
(4.1 vs. 4.9 %) [HR 0.85; 95 % CI 0.66–1.10] [56].
The risk of the prespecified composite endpoint of the first
occurrence of all-cause mortality, nonfatal MI, nonfatal
stroke, urgent revascularization because of unstable angina
and hospitalized heart failure did not significantly differ
between alogliptin and placebo recipients in EXAMINE
(16.0 vs. 16.5 %) [HR 0.98; 95 % CI 0.86–1.12] [57]. Within
this composite endpoint, first hospitalized heart failure oc-
curred in 3.1 % of alogliptin recipients and in 2.9 % of
placebo recipients (HR 1.07; 95 % CI 0.79–1.46). Moreover,
the risk of the post hoc composite endpoint of cardiovascular
death and hospitalized heart failure did not significantly
differ between alogliptin and placebo recipients in the
overall population (7.4 vs. 7.5 %) [HR 1.00; 95 % CI
0.82–1.21] or in the subgroups of patients with (13.9 vs.
15.7 %) [HR 0.90; 95 % CI 0.70–1.17] or without (4.9 vs.
4.2 %) [HR 1.14; 95 % CI 0.85–1.54] a history of heart
failure. In terms of the hospitalized heart failure component,
there was no significant difference between alogliptin and
placebo recipients in the overall population (3.9 vs. 3.3 %)
[HR 1.19; 95 % CI 0.90–1.58] or in the subgroup of patients
with a history of heart failure (8.2 vs. 8.5 %) [HR 1.00; 95 %
Alogliptin: A Review
CI 0.71–1.42]. However, in the subgroup of patients without
a history of heart failure, alogliptin recipients were sig-
nificantly more likely than placebo recipients to experience
hospitalized heart failure (2.2 vs. 1.3 %) [HR 1.76; 95 % CI
1.07–2.90; p = 0.026]. Analysis of the post hoc composite
endpoint by baseline levels of N-terminal prohormone of
brain natriuretic peptide revealed no significant difference
between alogliptin and placebo in all quartiles [57].
5.3 Hypoglycaemia
Alogliptin was generally associated with a low risk of
hypoglycaemia in patients with type 2 diabetes [12, 17–22,
28, 46, 47, 49, 50, 52], and most hypoglycaemic events
were of mild to moderate severity [12, 17–21, 28, 46, 47,
49, 50, 52]. The incidence of hypoglycaemia was reported
to be similar in recipients of alogliptin 25 mg once daily
versus placebo (0 vs. 1.3 % [12]), alogliptin 25 mg once
daily plus metformin versus metformin alone (0 vs. 3 %
[20] and 2 vs. 0 % [18]), alogliptin 25 mg once daily plus
pioglitazone versus pioglitazone alone (7.0 vs. 5.2 % [28]),
alogliptin 25 mg once daily plus voglibose versus vogli-
bose alone (1.3 vs. 1.3 % [22]), and alogliptin 25 mg once
daily plus a sulfonylurea versus a sulfonylurea alone (1.9
vs. 1.0 % [17] and 9.6 vs. 11.1 % [30]).
The incidence of hypoglycaemia was numerically higher
in patients receiving glipizide plus metformin than in those
receiving alogliptin 25 mg once daily plus metformin (23.2
vs. 1.4 %) [52]. Among elderly patients, the incidence of
hypoglycaemia was almost fivefold higher with glipizide
than with alogliptin (26.0 vs. 5.4 %) [51].
The incidence of hypoglycaemia was threefold higher in
patients receiving triple therapy with alogliptin 25 mg once
daily plus pioglitazone and metformin than in patients re-
ceiving uptitrated pioglitazone plus metformin (4.5 vs.
1.5 %) in one trial [49]. However, in a second trial, the
incidence of hypoglycaemia was 1.5 % in patients receiv-
ing alogliptin 25 mg once daily plus pioglitazone and
metformin and 2.1 % in patients receiving pioglitazone
plus metformin [50].
As expected, a higher rate of hypoglycaemia was seen in
patients receiving background insulin therapy [29, 53]. The
incidence of hypoglycaemia was 22.2 % [53] and 27.1 %
[29] in patients receiving alogliptin 25 mg once daily plus
insulin and 22.5 % [53] and 24.0 % [29] in patients re-
ceiving insulin.
5.4 Pancreatitis and Other Gastrointestinal Events
In the pooled analysis reported in the US prescribing in-
formation, pancreatitis was reported in 11 of 5902 (0.19 %)
alogliptin 25 mg once daily recipients and in 5 of 5183
(0.096 %) patients receiving placebo or an active
789
comparator [4]; the analysis included interim data from the
EXAMINE trial [58]. In EXAMINE, there was no sig-
nificant difference between alogliptin and placebo re-
cipients in the incidence of acute pancreatitis (0.4 vs.
0.3 %) or chronic pancreatitis (0.2 vs. 0.1 %), and there
were no reports of pancreatic cancer [56]. The proportion
of patients with serum ALT or AST levels [3 times the
upper limit of normal did not significantly differ between
alogliptin and placebo recipients [56].
5.5 Other Adverse Events of Interest
Alogliptin monotherapy is generally considered weight
neutral [12, 19, 27]. For example, a bodyweight change of
?0.15 kg was seen in patients who received alogliptin
25 mg once daily for 52 weeks [12]. In addition, only
small changes from baseline in bodyweight were reported
in patients receiving alogliptin in combination with met-
formin [19, 20], pioglitazone [21, 28], a sulfonylurea [30]
or insulin [29, 53]. Moreover, changes in bodyweight sig-
nificantly (p \ 0.001) favoured recipients of alogliptin
25 mg once daily plus metformin versus recipients of
glipizide plus metformin after 2 years’ therapy (-0.89 vs.
?0.95 kg) [52].
Malignancy was reported rarely among patients receiv-
ing alogliptin in the trials discussed in Sect. 4 [12, 17, 20].
In the EXAMINE trial, the incidence of malignancy did not
significantly differ between alogliptin and placebo re-
cipients (2.0 vs. 1.9 %) [56].
The incidence of skin reactions (e.g. pruritus, rash) or
skin and subcutaneous disorders in alogliptin recipients
was generally low [18–20, 30, 46, 49, 50], although it was
numerically higher with alogliptin than with comparator
agents in some trials [18, 20, 49]. For example, drug-
related skin and subcutaneous disorders occurred in 5.2 %
of patients receiving alogliptin 25 mg once daily plus pi-
oglitazone and metformin and in 2.3 % of patients re-
ceiving uptitrated pioglitazone plus metformin [49].
Facial oedema and peripheral oedema occurred in 0.9
and 2.7 % of patients, respectively, receiving alogliptin
25 mg once daily plus pioglitazone; oedema-related events
were of mild severity and were generally considered to be
related to treatment [21]. In patients receiving triple ther-
apy, peripheral oedema was reported in 2.6 % of patients
receiving alogliptin 25 mg once daily plus pioglitazone and
metformin versus 3.6 % of patients receiving pioglitazone
plus metformin [50], and drug-related peripheral oedema
was reported in 2.0 % of patients receiving alogliptin
25 mg once daily plus pioglitazone and metformin and in
3.0 % of patients receiving uptitrated pioglitazone plus
metformin [49]. The incidence of angioedema did not
significantly differ between alogliptin and placebo re-
cipients in the EXAMINE trial (0.6 vs. 0.5 %) [56].
790
Bone fractures were reported in 1.5 % of patients re-
ceiving alogliptin 25 mg once daily plus pioglitazone and
metformin and in 1.0 % of patients receiving uptitrated
pioglitazone plus metformin [49], whereas no treatment-
related bone fractures were reported in patients receiving
triple therapy with alogliptin plus pioglitazone and met-
formin in another trial [50], or in patients receiving
alogliptin 25 mg once daily alone or in combination with
pioglitazone [48].
There have been postmarketing reports of serious hy-
persensitivity reactions, including anaphylaxis, angioede-
ma and Stevens-Johnson syndrome, in alogliptin recipients
[4]. In the pooled analysis of clinical trial data reported in
the US prescribing information, hypersensitivity reactions
were reported in 0.6 % of alogliptin 25 mg once daily re-
cipients and in 0.8 % patients receiving placebo or an ac-
tive comparator [4].
6 Dosage and Administration
Alogliptin is approved in the US for use as monotherapy or
combination therapy as an adjunct to diet and exercise to
improve glycaemic control in adults with type 2 diabetes
[4], and in the EU for use in combination with other an-
tidiabetic agents (including insulin) as an adjunct to diet
and exercise to improve glycaemic control in adults aged
C18 years with inadequately controlled type 2 diabetes [5].
In the US, the recommended alogliptin dosage is 25 mg
once daily [4]. In the EU, the recommended alogliptin
dosage is 25 mg once daily as add-on therapy to met-
formin, a thiazolidinedione, a sulfonylurea or insulin, and
as triple therapy in combination with metformin and a
thiazolidinedione or insulin [5].
In the US, the fixed-dose combinations of alogliptin/
metformin and alogliptin/pioglitazone are approved as
adjuncts to diet and exercise to improve glycaemic control
when treatment with both alogliptin and metformin [6] or
alogliptin and pioglitazone [8] is appropriate. Alogliptin/
metformin is available as 12.5/500 and 12.5/1000 mg
fixed-dose tablets and should be taken twice daily with
food; the dose should be gradually escalated and subse-
quently adjusted based on efficacy and tolerability [6]. The
maximum recommended daily dosage of alogliptin/met-
formin is 25/2000 mg [6]. Alogliptin/pioglitazone is
available as 25/15, 25/30, 25/45, 12.5/15, 12.5/30 and 12.5/
45 mg fixed-dose tablets; the alogliptin/pioglitazone
dosage can be titrated to a maximum of 25/45 mg once
daily [8]. The recommended starting dosage of aloglipt-
in/pioglitazone is 25/15 or 25/30 mg for patients
inadequately controlled on diet or exercise or metformin
alone or for patients receiving alogliptin who require ad-
ditional glycaemic control [8]. Starting dosages of
G. M. Keating
alogliptin/pioglitazone 25/15, 25/30 or 25/45 mg (as ap-
propriate based on current therapy) are recommended for
patients receiving pioglitazone who require additional
glycaemic control and alogliptin/pioglitazone 25/15 mg is
recommended in patients with NYHA class I or II con-
gestive heart failure [8]. In patients switching from
alogliptin coadministered with pioglitazone, alogliptin/pi-
oglitazone may be initiated at the same total daily
alogliptin and pioglitazone dosage [8].
In the EU, alogliptin/metformin is available as 12.5/850
and 12.5/1000 mg fixed-dose tablets; the maximum rec-
ommended daily dose of alogliptin/metformin is
25/2000 mg [7]. Alogliptin/metformin is approved as an
adjunct to diet and exercise to improve glycaemic control
in patients inadequately controlled on a maximal tolerated
dose of metformin alone (recommended dosage of
alogliptin/metformin 12.5/850 or 12.5/1000 mg twice dai-
ly), inadequately controlled on maximal tolerated doses of
metformin and pioglitazone (alogliptin/metformin 12.5/850
or 12.5/1000 mg twice daily and the same dosage of pi-
oglitazone) or inadequately controlled on metformin and a
stable insulin dosage (alogliptin 12.5 mg twice daily and a
metformin dosage similar to that already being taken).
Alogliptin/metformin is also approved for use in patients
already receiving combination therapy with alogliptin and
metformin administered separately (maintain the same total
daily dosage of alogliptin and metformin) [7].
In the EU, alogliptin/pioglitazone is available as 25/30,
25/45, 12.5/30 and 12.5/45 mg fixed-dose tablets; the max-
imum recommended daily dosage of alogliptin and piogli-
tazone is 25 and 45 mg, respectively [9].
Alogliptin/pioglitazone is indicated as second- or third-line
treatment as an adjunct to diet and exercise to improve gly-
caemic control in patients inadequately controlled with pi-
oglitazone alone and in whom metformin is inappropriate
(alogliptin/pioglitazone 25/30 or 25/45 mg once daily) or
inadequately controlled on pioglitazone and a maximal tol-
erated dose of metformin (alogliptin/pioglitazone 25/30 or
25/45 mg once daily and the same dosage of metformin) [9].
Alogliptin/pioglitazone is also approved for use in patients
already receiving combination therapy with alogliptin and
pioglitazone administered separately (maintain the same
total daily dosage of alogliptin and pioglitazone) [9].
The US prescribing information for alogliptin/met-
formin contains a black-box warning relating to the risk of
lactic acidosis in patients receiving metformin [6], and the
US prescribing information for alogliptin/pioglitazone
contains a black-box warning relating to the risk of con-
gestive heart failure in patients receiving thiazolidine-
diones, including pioglitazone [8].
Local prescribing information should be consulted for
contraindications, warnings and precautions relating to
alogliptin, alogliptin/metformin and alogliptin/pioglitazone.
Alogliptin: A Review
7 Place of Alogliptin in the Management of Type 2
Diabetes Mellitus
Initial treatment in type 2 diabetes usually comprises life-
style changes, with metformin added at or soon after di-
agnosis [59]. If the HbA1c target (7.0 % for most patients
[60]) is not reached after &3 months of treatment, add-on
therapy with a sulfonylurea, a thiazolidinedione, a DPP-4
inhibitor, a GLP-1 receptor agonist or insulin should be
considered [59]. Both the treatment regimen and the HbA1c
target should be tailored to the individual patient [59].
DPP-4 inhibitors are currently recommended as a first-line
option if metformin cannot be used, as add-on therapy in
patients who do not achieve HbA1c targets with metformin
alone and as a component of triple therapy in patients not
achieving HbA1c targets with metformin plus a sulfonyl-
urea, a thiazolidinedione or insulin [59].
Combining antidiabetic agents with complementary
mechanisms of action represents a rational approach to the
treatment of type 2 diabetes. For example, DPP-4 inhibitors
such as alogliptin improve insulin secretion and suppress
postprandial glucagon in a glucose-dependent manner,
whereas metformin improves insulin sensitivity and re-
duces hepatic glucose production [20]. Indeed, adding
alogliptin to metformin improved glycaemic control in
patients inadequately controlled with metformin alone
(Sect. 4.2.1), whilst preserving the advantages of met-
formin (absence of weight gain and low risk of hypogly-
caemia) (Sect. 5) [20]. Moreover, a recent diabetes
management algorithm recommends the use of initial
combination therapy with metformin and another agent,
such as a DPP-4 inhibitor, in patients with an initial HbA1c
of C7.5 % [61]. Initial combination therapy with alogliptin
plus metformin was shown to be more effective than either
agent alone in drug-naive patients with type 2 diabetes
inadequately controlled by diet and exercise (HbA1c of
7.5–10 % at study entry) (Sect. 4.2.1) [19].
In studies published to date, patients assigned to com-
bination therapy received alogliptin and metformin ad-
ministered as separate tablets. However, alogliptin/
metformin is available as a fixed-dose combination tablet
that has been shown to be bioequivalent to alogliptin and
metformin coadministered separately (Sect. 3.1). A study
currently underway in China, Malaysia and South Korea is
comparing the efficacy of the alogliptin/metformin fixed-
dose combination with that of alogliptin and metformin
alone in patients with type 2 diabetes (NCT01890122; this
study is being conducted to support a regulatory require-
ment in China) [58].
The thiazolidinedione pioglitazone is an insulin sensi-
tizer that increases peripheral glucose uptake [48]. Com-
bination therapy with alogliptin plus pioglitazone improved
791
glycaemic control to a significantly greater extent than
pioglitazone alone in patients with type 2 diabetes
inadequately controlled with pioglitazone (with or without
other OADs) (Sect. 4.2.2). Initial combination therapy with
alogliptin plus pioglitazone was also more effective than
pioglitazone alone in drug-naive patients (Sect. 4.2.2) [48].
Alogliptin is currently the only DPP-4 inhibitor available in
a fixed-dose combination with a thiazolidinedione
(alogliptin/pioglitazone); this fixed-dose combination has
been shown to be bioequivalent to alogliptin and pioglita-
zone coadministered separately (Sect. 3.1). In terms of
other dual OAD regimens, studies have demonstrated the
efficacy of alogliptin plus a sulfonylurea (Sect. 4.2.3) or
voglibose (Sect. 4.2.4).
Given the weight neutrality and low risk of hypogly-
caemia associated with DPP-4 inhibitors, there is a strong
rationale for combining these agents with insulin [62].
Indeed, the addition of alogliptin to insulin improved gly-
caemic control in patients with type 2 diabetes
(Sect. 4.2.5), without exacerbating hypoglycaemia
(Sect. 5.3). However, it should be noted that insulin
dosages were not optimized during these studies, which is
not reflective of standard clinical practice [29].
Triple therapy with three OADs is an option in patients
who have not responded to dual therapy [59]. Alogliptin in
combination with metformin and pioglitazone was effec-
tive in patients with inadequately controlled type 2 dia-
betes, and was more effective than uptitrating the
pioglitazone dosage in patients receiving dual therapy
(Sect. 4.2.6). Trials comparing alogliptin plus metformin
and pioglitazone with an alternative triple therapy regimen
(e.g. metformin plus pioglitazone in combination with in-
sulin or a sulfonylurea) would be of interest [49].
Alogliptin is also approved for use as monotherapy in
the US (Sect. 6). Trials demonstrated that alogliptin
monotherapy improved glycaemic control in patients with
inadequately controlled type 2 diabetes (Sect. 4.1).
Results of a meta-analysis suggested that the magnitude
of the HbA1c reduction decreases as the duration of
alogliptin therapy increases [63]. However, results of long-
term extension studies demonstrated that significant im-
provements from baseline in glycaemic control were
maintained with up to 52 weeks of alogliptin therapy [12,
17, 18, 21, 22], and alogliptin demonstrated sustained ef-
ficacy in a 104-week trial [52] (Sect. 4).
Alogliptin demonstrated efficacy in both Caucasian and
Asian patients (Sect. 4). In terms of differences between
these populations, Asian patients with type 2 diabetes tend to
be leaner and insulin deficiency, rather than increased insulin
resistance, underlies their loss of glycaemic control [18]. In
addition, Asian patients have a lower insulin secretory ca-
pacity, particularly in the early phase when impaired insulin
792
secretion is seen after the ingestion of nutrients, which may
partly reflect lower intact GLP-1 levels [18, 22].
Given that DPP-4 inhibitors act by enhancing b-cell
function, there has been concern that the progressive loss of
b-cell function seen in type 2 diabetes may mean these agents
are less beneficial in patients with more advanced disease
[62]. However, beneficial effects on glycaemic control have
been seen with alogliptin in patients with a relatively long
disease duration (e.g. mean disease duration of[7 years [12,
17, 22, 28–30, 53]), including patients receiving long-term
insulin therapy [29] (Sect. 4). The effect of alogliptin on a-
cell function (i.e. suppressing postprandial glucagon) may
play a greater role in later stages of the disease [62].
Elderly patients with type 2 diabetes present a particular
challenge, given that they are more susceptible to hypo-
glycaemia and more likely to experience disease-related
morbidity and comorbidities, including renal impairment,
frailty, physical disability and cognitive impairment [64].
Thus, DPP-4 inhibitors, with their low risk of hypogly-
caemia and good tolerability profile, are a good choice for
use in the elderly [65]. Indeed, alogliptin was noninferior to
glipizide in terms of the improvement in glycaemic control
(Sect. 4.3.1) and associated with a fivefold lower incidence
of hypoglycaemia (Sect. 5.3) in elderly patients with type 2
diabetes. The low potential for drug interactions associated
with alogliptin (Sect. 3.4) also makes it an appropriate
choice for use in the elderly, given that polypharmacy is
often an issue in this patient population [64, 65].
Treatment options are limited in patients with renal
disease, which is commonly seen in patients with type 2
diabetes [62]. Similar to several other DPP-4 inhibitors,
alogliptin is excreted renally, meaning that reduced dosa-
ges are required in patients with moderate or severe renal
impairment (Sect. 3.3). Alogliptin appeared to improve
glycaemic control in patients with type 2 diabetes who
were undergoing haemodialysis, according to the results of
two small studies (Sect. 4.3.2). Larger, double-blind trials
examining the use of alogliptin in patients with renal im-
pairment would be of interest.
The EXAMINE trial demonstrated that the risk of major
cardiovascular events was not increased with alogliptin in
patients with type 2 diabetes and a recent acute coronary
syndrome [56] (Sect. 5.2). Importantly, the risk of cardio-
vascular outcomes that included the endpoint of hospitalized
heart failure was not increased with alogliptin, and alogliptin
was not associated with an increased risk of first hospitalized
heart failure overall. In addition, alogliptin was not associ-
ated with worsening of heart failure outcomes in patients
with a history of heart failure. The higher rate of hospitalized
heart failure seen in alogliptin versus placebo recipients in
the lower-risk subgroup of patients without a history of heart
failure may be due to chance [57]. Currently, the EU SPC
recommends that alogliptin should be used with caution in
G. M. Keating
patients with NYHA class III or IV heart failure, given that
data are limited in this patient group [5].
In the SAVOR-TIMI 53 trial, saxagliptin had no effect
on the risk of cardiovascular death, MI or stroke (primary
composite endpoint) in patients with type 2 diabetes and a
history of established cardiovascular disease or multiple
risk factors for vascular disease [66]. However, the risk of
hospitalization for heart failure was significantly
(p = 0.007) increased with saxagliptin versus placebo [66].
The reason for the discrepancy between EXAMINE and
SAVOR-TIMI 53 in terms of the risk of hospitalized heart
failure is not clear [57]. Results of the VIVIDD trial
demonstrated that vildagliptin was noninferior to placebo
in terms of the increase in left ventricular ejection fraction
seen in patients with type 2 diabetes and NYHA class I–III
heart failure [67]. More data are needed concerning the risk
of hospitalized heart failure in patients receiving DPP-4
inhibitors. Two other large cardiovascular outcomes trials
examining the use of sitagliptin (TECOS) [68] and li-
nagliptin (CAROLINA) [69] are still underway. In addi-
tion, the SPEAD-A (Study of Preventive Effects of
Alogliptin on Diabetic Atherosclerosis) study is examining
the ability of alogliptin to prevent the progression of
atherosclerosis (assessed using the carotid intima-media
thickness) in patients with type 2 diabetes [70].
There have been concerns that incretin-based therapies
may be associated with an increased risk of pancreatitis and
pancreatic cancer [71–74]. However, type 2 diabetes itself
seems to be associated with an increased risk of pancre-
atitis [75] and pancreatic cancer [76], and no increased risk
of pancreatitis or cancer was seen in other analyses of DPP-
4 inhibitors [77–81]. In addition, no increase in the risk of
pancreatitis, pancreatic cancer and/or cancer was seen with
alogliptin [56] or saxagliptin [66] in the EXAMINE [56]
and SAVOR-TIMI 53 [66] trials. The US FDA and Euro-
pean Medicines Agency (EMA) recently concluded that
assertions regarding a causal association between these
agents and pancreatitis or pancreatic cancer are inconsis-
tent with the current data [82]. The FDA and the EMA state
that they have not yet reached a final conclusion regarding
a causal relationship between incretin-based agents and
pancreatitis or pancreatic cancer, and that while the totality
of data provides reassurance, pancreatitis will continue to
be considered a risk associated with these agents until more
data are available [82].
Patients with type 2 diabetes are at increased risk of
bone fracture and results of a meta-analysis suggest that
DPP-4 inhibitors may reduce the risk of bone fracture [83].
Although it appears that alogliptin may have beneficial
effects on bone quality via the suppression of deleterious
bone metabolism (Sect. 2.3), more data are needed. Bone
fracture rates were low in patients with type 2 diabetes
receiving alogliptin in clinical trials (Sect. 5.5).
Alogliptin: A Review
Several DPP-4 inhibitors besides alogliptin are currently
available for the treatment of type 2 diabetes, including
vildagliptin, sitagliptin, saxagliptin, linagliptin, gemigliptin
(available in South Korea) and teneligliptin (available in
Japan). Although there are pharmacodynamic and phar-
macokinetic differences between the various DPP-4 in-
hibitors (e.g. differences in the potency of DPP-4
inhibition) [3], it is not clear if these differences translate
into differences in efficacy. The once-daily administration
regimen for alogliptin is supported by the finding of DPP-4
inhibition of [80 % 24 h after administration of alogliptin
25 mg once daily (Sect. 2.1) [13].
DPP-4 inhibitors are more expensive than older treat-
ment options such as metformin and sulfonylureas [84].
Data concerning the cost effectiveness of alogliptin are
limited. A US budget impact analysis, available as an ab-
stract, in patients with type 2 diabetes inadequately con-
trolled with a pioglitazone- or DPP-4 inhibitor-containing
regimen concluded that inclusion of the fixed-dose com-
bination of alogliptin/pioglitazone on a managed care
health plan formulary had negligible impact on the annual
pharmacy budget [85].
In conclusion, oral alogliptin is effective and well tol-
erated in the treatment of type 2 diabetes. Results of ran-
domized controlled trials demonstrated that oral alogliptin
improved glycaemic control when administered as mono-
therapy, as dual therapy in combination with metformin,
pioglitazone, a sulfonylurea, voglibose or insulin, or as
triple therapy in combination with metformin plus piogli-
tazone. Alogliptin was generally well tolerated in patients
with type 2 diabetes and was weight neutral, with a low
risk of hypoglycaemia. Results of the large, well designed
EXAMINE trial revealed that alogliptin was not associated
with an increased risk of major cardiovascular events in
patients with type 2 diabetes and recent acute coronary
syndrome. Thus, alogliptin is a useful option for the
treatment of patients with type 2 diabetes.
Data selection sources: Relevant medical literature (including
published and unpublished data) on alogliptin was identified by
searching databases including MEDLINE (from 1946) and
EMBASE (from 1996) [searches last updated 16 March 2015],
bibliographies from published literature, clinical trial reg-
istries/databases and websites. Additional information was also
requested from the company developing the drug.
Search terms: Alogliptin, type-2 diabetes mellitus, diabetes
mellitus, type 2, non-insulin dependent diabetes mellitus.
Study selection: Studies in patients with type 2 diabetes mellitus
who received alogliptin. When available, large, well designed,
comparative trials with appropriate statistical methodology were
preferred. Relevant pharmacodynamic and pharmacokinetic data
are also included.
Disclosure The preparation of this review was not supported by any
external funding. Gillian Keating is a salaried employee of Adis/
793
Springer. During the peer review process, the manufacturer of the
agent under review was offered an opportunity to comment on this
article. Changes resulting from comments received were made by the
author on the basis of scientific and editorial merit.
References
1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the
prevalence of diabetes for 2010 and 2030. Diabetes Res Clin
Pract. 2010;87(1):4–14.
2. Deacon CF, Holst JJ. Dipeptidyl peptidase-4 inhibitors for the
treatment of type 2 diabetes: comparison, efficacy and safety.
Expert Opin Pharmacother. 2013;14(15):2047–58.
3. Capuano A, Sportiello L, Maiorino MI, et al. Dipeptidyl pepti-
dase-4 inhibitors in type 2 diabetes therapy: focus on alogliptin.
Drug Des Dev Ther. 2013;7:989–1001.
4. Takeda Pharmaceuticals America Inc. Nesina (alogliptin) tablets:
US prescribing information. 2013. http://www.takeda.us/
products/default.aspx. Accessed 3 Mar 2015.
5. European Medicines Agency. Vipidia (alogliptin): EU summary
of product characteristics. 2014. http://www.ema.europa.eu/.
Accessed 3 Mar 2015.
6. Takeda Pharmaceuticals America Inc. Kazano (alogliptin and
metformin HCl) tablets for oral administration: US prescribing
information. 2013. http://www.takeda.us/products/default.aspx.
Accessed 3 Mar 2015.
7. European Medicines Agency. Vipdomet (alogliptin/metformin):
EU summary of product characteristics. 2015. http://www.ema.
europa.eu/. Accessed 3 Mar 2015.
8. Takeda Pharmaceuticals America Inc. Oseni (alogliptin and pi-
oglitazone) tablets: US prescribing information. 2013. http://
www.takeda.us/products/default.aspx. Accessed 3 Mar 2015.
9. European Medicines Agency. Incresync (alogliptin/pioglitazone):
EU summary of product characteristics. 2015. http://www.ema.
europa.eu/. Accessed 3 Mar 2015.
10. Feng J, Zhang Z, Wallace MB, et al. Discovery of alogliptin: a
potent, selective, bioavailable, and efficacious inhibitor of
dipeptidyl peptidase IV. J Med Chem. 2007;50(10):2297–300.
11. Christopher RJ, Davenport JM, Gwaltney S, et al. Pharmacoki-
netic and pharmacodynamic profiles of SYR-322, a novel in-
hibitor of dipeptidyl peptidase-IV, in rats, dogs, and monkeys
[abstract no. 452-P]. In: 66th Annual Scientific Sessions of the
American Diabetes Association. 2006.
12. Seino Y, Fujita T, Hiroi S, et al. Efficacy and safety of alogliptin
in Japanese patients with type 2 diabetes mellitus: a randomized,
double-blind, dose-ranging comparison with placebo, followed
by a long-term extension study. Curr Med Res Opin.
2011;27(9):1781–92.
13. Covington P, Christopher R, Davenport M, et al. Pharmacoki-
netic, pharmacodynamic, and tolerability profiles of the dipep-
tidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind,
placebo-controlled, multiple-dose study in adult patients with
type 2 diabetes. Clin Ther. 2008;30(3):499–512.
14. Hirayama M, Matsuno K, Fujita H, et al. Pharmacokinetics,
pharmacodynamics, and tolerability of single and multiple doses
of the dipeptidyl peptidase-4 inhibitor alogliptin in Japanese
healthy male subjects [abstract no. 521-P]. In: 68th Scientific
Sessions of the American Diabetes Association. 2008.
15. Christopher R, Covington P, Davenport M, et al. Pharmacoki-
netics, pharmacodynamics, and tolerability of single increasing
doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy
male subjects. Clin Ther. 2008;30(3):513–27.
16. Van Raalte DH, van Genugten RE, Eliasson B, et al. The effect of
alogliptin and pioglitazone combination therapy on various
794
aspects of beta-cell function in patients with recent-onset type 2
diabetes. Eur J Endocrinol. 2014;170(4):565–74.
17. Seino Y, Hiroi S, Hirayama M, et al. Efficacy and safety of
alogliptin added to sulfonylurea in Japanese patients with type 2
diabetes: a randomized, double-blind, placebo-controlled trial
with an open-label, long-term extension study. J Diabetes In-
vestig. 2012;3(6):517–25.
18. Seino Y, Miyata Y, Hiroi S, et al. Efficacy and safety of alogliptin
added to metformin in Japanese patients with type 2 diabetes: a
randomized, double-blind, placebo-controlled trial with an open-
label, long-term extension study. Diabetes Obes Metab.
2012;14(10):927–36.
19. Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial
combination therapy with alogliptin plus metformin versus either
as monotherapy in drug-naive patients with type 2 diabetes: a
randomized, double-blind, 6-month study. Diabetes Obes Metab.
2014;16(7):613–21.
20. Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of
adding the dipeptidyl peptidase-4 inhibitor alogliptin to met-
formin therapy in patients with type 2 diabetes inadequately
controlled with metformin monotherapy: a multicentre, ran-
domised, double-blind, placebo-controlled study. Int J Clin Pract.
2009;63(1):46–55.
21. Kaku K, Itayasu T, Hiroi S, et al. Efficacy and safety of alogliptin
added to pioglitazone in Japanese patients with type 2 diabetes: a
randomized, double-blind, placebo-controlled trial with an open-
label long-term extension study. Diabetes Obes Metab.
2011;13(11):1028–35.
22. Seino Y, Fujita T, Hiroi S, et al. Alogliptin plus voglibose in
Japanese patients with type 2 diabetes: a randomized, double-
blind, placebo-controlled trial with an open-label, long-term ex-
tension. Curr Med Res Opin. 2011;27(Suppl 3):21–9.
23. Kutoh E, Ukai Y. Alogliptin as an initial therapy in patients with
newly diagnosed, drug naive type 2 diabetes: a randomized,
control trial. Endocrine. 2012;41(3):435–41.
24. Eliasson B, Möller-Goede D, Eeg-Olofsson K, et al. Lowering of
postprandial lipids in individuals with type 2 diabetes treated with
alogliptin and/or pioglitazone: a randomised double-blind place-
bo-controlled study. Diabetologia. 2012;55(4):915–25.
25. Jurczyk A, Dilorio P, Brostowin D, et al. Improved function and
proliferation of adult human beta cells engrafted in diabetic im-
munodeficient NOD-scid IL2rcnull mice treated with alogliptin.
Diabetes Metab Syndr Obes. 2013;6:493–9.
26. Zhang X, Wang Z, Huang Y, et al. Effects of chronic adminis-
tration of alogliptin on the development of diabetes and b-cell
function in high fat diet/streptozotocin diabetic mice. Diabetes
Obes Metab. 2011;13(4):337–47.
27. Fleck P, Christopher R, Covington P. Efficacy and safety of
alogliptin monotherapy over 12 weeks in patients with type 2
diabetes [abstract no. 479-P]. Diabetes. 2008;57(Suppl 1):143.
28. Pratley RE, Reusch JE-B, Fleck PR, et al. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in
patients with type 2 diabetes: a randomized, double-blind, placebo-
controlled study. Curr Med Res Opin. 2009;25(10):2361–71.
29. Rosenstock J, Rendell MS, Gross JL, et al. Alogliptin added to
insulin therapy in patients with type 2 diabetes reduces HbA1C
without causing weight gain or increased hypoglycaemia. Dia-
betes Obes Metab. 2009;11(12):1145–52.
30. Pratley RE, Kipnes MS, Fleck PR, et al. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2
diabetes inadequately controlled by glyburide monotherapy.
Diabetes Obes Metab. 2009;11(2):167–76.
31. Noda Y, Miyoshi T, Oe H, et al. Alogliptin ameliorates post-
prandial lipemia and postprandial endothelial dysfunction in non-
diabetic subjects: a preliminary report. Cardiovasc Diabetol.
2013;12:8.
G. M. Keating
32. Kato S, Kirigaya H, Gyotoku D, et al. DPP-4 inhibition by
alogliptin improves the coronary flow reserve evaluated by phase
contrast cine magnetic resonance imaging in type 2 diabetic pa-
tients with coronary artery disease [abstract no. 16542]. In: 86th
Annual Scientific Sessions of the American Heart Association.
2013.
33. Yamauchi Y, Tunekawa S, Seino Y, et al. The effect of DPP-4
inhibitor, alogliptin, on bone metabolism in patients with type 2
diabetes mellitus [abstract no. 1071-P]. In: 73rd Annual Scientific
Sessions of the American Diabetes Association. 2013.
34. Karim A, Harris S, Fleck P, et al. Assessment of drug interaction
between alogliptin benzoate (SYR-322), a highly selective
dipeptidyl peptidase-4 inhibitor, and warfarin at steady state
[abstract no. 106]. J Clin Pharmacol. 2007;47(9):1207.
35. Karim A, Covington P, Christopher R, et al. Pharmacokinetics of
alogliptin when administered with food, metformin, or cime-
tidine: a two-phase, crossover study in healthy subjects. Int J Clin
Pharmacol Ther. 2010;48(1):46–58.
36. European Medicines Agency. Vipidia (alogliptin): EU public
assessment report. 2013. http://www.ema.europa.eu/. Accessed 3
Mar 2015.
37. Karim A, Fleck P, Hetman L, et al. Single-dose pharmacokinetics
of the dipeptidyl peptidase-4 inhibitor alogliptin in subjects with
renal impairment [abstract no. 538-P]. In: 68th Annual Scientific
Sessions of the American Diabetes Association. 2008.
38. Karim A, Fleck P, Dorsey D, et al. Single-dose pharmacokinetics
of alogliptin benzoate (SYR-322), a highly selective dipeptidyl
peptidase-4 inhibitor, in subjects with moderate hepatic impair-
ment [abstract no. 107]. J Clin Pharmacol. 2007;47(9):1207.
39. Karim A, Fleck P, Harrell RE, et al. Effects of age, race, and
gender on the pharmacokinetics and pharmacodynamics of
alogliptin, a novel and highly selective dipeptidyl peptidase-4
inhibitor in healthy subjects [abstract no. PI-14]. Clin Pharmacol
Ther. 2008;83(Suppl 1):S13.
40. Karim A, Fleck P, Harris S, et al. Effect of fluconazole, keto-
conazole, and gemfibrozil on the pharmacokinetics of alogliptin
benzoate (SYR-322) in healthy subjects [abstract no. 105]. J Clin
Pharmacol. 2007;47(9):1207.
41. Karim A, Laurent A, Munsaka M, et al. Coadministration of
pioglitazone or glyburide and alogliptin: pharmacokinetic drug
interaction assessment in healthy participants. J Clin Pharmacol.
2009;49(10):1210–9.
42. Karim A, Fleck P, Harris S, et al. Lack of pharmacokinetic in-
teraction between multiple doses of the dipeptidyl peptidase-4
inhibitor alogliptin and digoxin in healthy subjects [abstract no.
PI-13]. Clin Pharmacol Ther. 2008;83(Suppl 1):S12–3.
43. Karim A, Fleck P, Harris S, et al. Assessment of drug interaction
between alogliptin, a highly selective dipeptidyl peptidase-4 in-
hibitor, and atorvastatin in healthy subjects [abstract no. PI-17].
Clin Pharmacol Ther. 2008;83(Suppl 1):S14.
44. Karim A, Chiselko P, Fleck P, et al. Lack of effect of cy-
closporine on the single-dose pharmacokinetics of alogliptin, a
novel dipeptidyl peptidase-4 inhibitor, in healthy subjects [ab-
stract no. PI-15]. Clin Pharmacol Ther. 2008;83(Suppl 1):S13.
45. Karim A, Copa A, Fleck P, et al. Effects of alogliptin on the
pharmacokinetics and pharmacodynamics of norethindrone and
ethinyl estradiol (Ortho-NovumÒ 1/35) in healthy adult female
subjects [abstract no. PI-16]. Clin Pharmacol Ther.
2008;83(Suppl 1):S14.
46. DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor alogliptin in patients with
type 2 diabetes and inadequate glycemic control: a randomized,
double-blind, placebo-controlled study. Diabetes Care.
2008;31(12):2315–7.
47. Ji Q, Han P, Li C, et al. Efficacy and safety of alogliptin in
subjects with type 2 diabetes: a randomised, double-blind,
Alogliptin: A Review
placebo-controlled, phase 3 study in mainland China, Taiwan and
Hong Kong [abstract no. 915]. In: 49th Annual Meeting of the
European Association for the Study of Diabetes. 2013.
48. Rosenstock J, Inzucchi SE, Seufert J, et al. Initial combination
therapy with alogliptin and pioglitazone in drug-naive patients
with type 2 diabetes. Diabetes Care. 2010;33(11):2406–8.
49. Bosi E, Ellis GC, Wilson CA, et al. Alogliptin as a third oral
antidiabetic drug in patients with type 2 diabetes and inadequate
glycaemic control on metformin and pioglitazone: a 52-week,
randomized, double-blind, active-controlled, parallel-group
study. Diabetes Obes Metab. 2011;13(12):1088–96.
50. DeFronzo RA, Burant CF, Fleck P, et al. Efficacy and tolerability
of the DPP-4 inhibitor alogliptin combined with pioglitazone, in
metformin-treated patients with type 2 diabetes. J Clin En-
docrinol Metab. 2012;97(5):1615–22.
51. Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide
monotherapy in elderly type 2 diabetes mellitus patients with
mild hyperglycaemia: a prospective, double-blind, randomized,
1-year study. Diabetes Obes Metab. 2013;15(10):906–14.
52. Del Prato S, Camisasca R, Wilson C, et al. Durability of the
efficacy and safety of alogliptin compared with glipizide in type 2
diabetes mellitus: a 2-year study. Diabetes Obes Metab.
2014;16(12):1239–46.
53. Kaku K, Mori M, Kanoo T, et al. Efficacy and safety of alogliptin
added to insulin in Japanese patients with type 2 diabetes: a
randomized, double-blind, 12-week, placebo-controlled trial fol-
lowed by an open-label, long-term extension phase. Expert Opin
Pharmacother. 2014;15(15):2121–30.
54. Nakamura Y, Inagaki M, Shimizu T, et al. Long-term effects of
alogliptin benzoate in hemodialysis patients with diabetes: a
2-year study. Nephron Clin Pract. 2013;123(1–2):46–51.
55. Fujii Y, Abe M, Higuchi T, et al. The dipeptidyl peptidase-4
inhibitor alogliptin improves glycemic control in type 2 diabetic
patients undergoing hemodialysis. Expert Opin Pharmacother.
2013;14(3):259–67.
56. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute
coronary syndrome in patients with type 2 diabetes. N Engl J
Med. 2013;369(14):1327–35.
57. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and
mortality outcomes in patients with type 2 diabetes taking
alogliptin versus placebo in EXAMINE: a multicentre, ran-
domised, double-blind trial. Lancet. 2015. doi:10.1016/S0140-
6736(14)62225-X.
58. Data on file, Takeda, 2014.
59. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of
hyperglycemia in type 2 diabetes: a patient-centered approach.
Position statement of the American Diabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2012;35(6):1364–79.
60. Standards of medical care in diabetes: 2013. Diabetes Care.
2013;36 Suppl 1:S11–66.
61. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE compre-
hensive diabetes management algorithm 2013. Endocr Pract.
2013;19(2):327–36.
62. Charbonnel B, Schweizer A, Dejager S. Combination therapy
with DPP-4 inhibitors and insulin in patients with type 2 diabetes
mellitus: what is the evidence? Hosp Pract (Minneap).
2013;41(2):93–107.
63. Berhan A, Berhan Y. Efficacy of alogliptin in type 2 diabetes
treatment: a meta-analysis of randomized double-blind controlled
studies. BMC Endocrine Disord. 2013;13:9.
64. Bourdel-Marchasson I, Schweizer A, Dejager S. Incretin thera-
pies in the management of elderly patients with type 2 diabetes
mellitus. Hosp Pract. 2011;39(1):7–21.
795
65. Pratley RE. Alogliptin: a new, highly selective dipeptidyl pepti-
dase-4 inhibitor for the treatment of type 2 diabetes. Expert Opin
Pharmacother. 2009;10(3):503–12.
66. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and car-
diovascular outcomes in patients with type 2 diabetes mellitus.
N Engl J Med. 2013;369(14):1317–26.
67. McMurray JJV, Ponikowski P, Bolli GB, et al. The Vildagliptin
in Ventricular Dysfunction Diabetes trial (VIVIDD) [late-break-
ing abstract]. In: Heart Failure 2013. 2013.
68. Green JB, Bethel MA, Paul SK, et al. Rationale, design, and
organization of a randomized, controlled Trial Evaluating Car-
diovascular Outcomes with Sitagliptin (TECOS) in patients with
type 2 diabetes and established cardiovascular disease. Am Heart
J. 2013;166(6):983–9.
69. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome
trials in type 2 diabetes and the sulphonylurea controversy: ra-
tionale for the active-comparator CAROLINA trial. Diabetes
Vasc Dis Res. 2013;10(4):289–301.
70. Katakami N, Mita T, Yoshii H, et al. Rationale, design, and
baseline characteristics of a trial for the prevention of diabetic
atherosclerosis using a DPP-4 inhibitor: the Study of Preventive
Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).
J Atheroscler Thromb. 2013;20(12):893–902.
71. Singh S, Chang H-Y, Richards TM, et al. Glucagonlike peptide
1-based therapies and risk of hospitalization for acute pancreatitis
in type 2 diabetes mellitus: a population-based matched case-
control study. JAMA Intern Med. 2013;173(7):534–9.
72. Faillie J-L, Babai S, Crépin S, et al. Pancreatitis associated with
the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case
study from the French Pharmacovigilance Database. Acta Dia-
betol. 2014;51(3):491–7.
73. Scheen A. Gliptins (dipeptidyl peptidase-4 inhibitors) and risk of
acute pancreatitis. Expert Opin Drug Saf. 2013;12(4):545–57.
74. Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked ex-
pansion of exocrine and endocrine pancreas with incretin therapy
in humans with increased exocrine pancreas dysplasia and the
potential for glucagon-producing neuroendocrine tumors. Dia-
betes. 2013;62(7):2595–604.
75. Yang L, He Z, Tang X, et al. Type 2 diabetes mellitus and the risk
of acute pancreatitis: a meta-analysis. Eur J Gastroenterol
Hepatol. 2013;25(2):225–31.
76. Brodovicz KG, Kou TD, Alexander CM, et al. Impact of diabetes
duration and chronic pancreatitis on the association between type
2 diabetes and pancreatic cancer risk. Diabetes Obes Metab.
2012;14(12):1123–8.
77. Monami M, Dicembrini I, Martelli D, et al. Safety of dipeptidyl
peptidase-4 inhibitors: a meta-analysis of randomized clinical
trials. Curr Med Res Opin. 2011;27(Suppl 3):57–64.
78. Gokhale M, Sturmer T, Gray C, et al. Dipeptidyl peptidase 4
inhibitors and comparative pancreatic cancer risk [abstract no.
111-LB]. In: 73rd Scientific Sessions of the American Diabetes
Association. 2013.
79. Richard KR, Shelburne JS, Kirk JK. Tolerability of dipeptidyl
peptidase-4 inhibitors: a review. Clin Ther.
2011;33(11):1609–29.
80. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4
inhibitors and pancreatitis risk: a meta-analysis of randomized
clinical trials. Diabetes Obes Metab. 2014;16(1):48–56.
81. Faillie JL, Azoulay L, Patenaude V, et al. Incretin based drugs
and risk of acute pancreatitis in patients with type 2 diabetes:
cohort study. BMJ. 2014;348:g2780.
82. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-
based drugs: FDA and EMA assessment. N Engl J Med.
2014;370(9):794–7.
796
83. Monami M, Dicembrini I, Antenore A, et al. Dipeptidyl pepti-
dase-4 inhibitors and bone fractures: a meta-analysis of ran-
domized clinical trials. Diabetes Care. 2011;34(11):2474–6.
84. Marino AB, Cole SW. Alogliptin: safety, efficacy, and clinical
implications. J Pharm Pract. 2015;28(1):99–106.
G. M. Keating
85. Bron M, Ferrufino CP, Samyshkin Y, et al. Evaluation of the
pharmacy budget impact of alogliptin plus pioglitazone fixed
dose combination in the treatment of type-2 diabetes mellitus
[abstract no. PDB25]. Value Health. 2013;16(3):A160.