Download Dipeptidyl peptidase4 inhibitors in the treatment of type 2

Diabetes, Obesity and Metabolism 13: 7–18, 2011.
© 2010 Blackwell Publishing Ltd
Dipeptidyl peptidase-4 inhibitors in the treatment of type 2
diabetes: a comparative review
C. F. Deacon
Department of Biomedical Sciences, University of Copenhagen, Panum Institute, Copenhagen N, Denmark
The dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antihyperglycaemic agents which were developed for the treatment of type 2
diabetes by rational drug design, based on an understanding of the underlying mechanism of action and knowledge of the structure of the
target enzyme. Although they differ in terms of their chemistry, they are all small molecules which are orally available. There are some
differences between them in terms of their absorption, distribution, metabolism and elimination, as well as in their potency and duration of
action, but their efficacy, both in terms of inhibiting plasma DPP-4 activity and as antidiabetic agents, appears to be similar. They improve
glycaemic control, reducing both fasting and postprandial glucose levels to lower HbA1c levels, without weight gain and with an apparently
benign adverse event profile. At present, there seems to be little to distinguish between the different inhibitors in terms of their efficacy as
antidiabetic agents and their safety. Long-term accumulated clinical experience will reveal whether compound-related characteristics lead to
any clinically relevant differences.
Keywords: alogliptin, antidiabetic drug, diabetes mellitus, DPP-4, GLP-1, glycaemic control, incretin, linagliptin, saxagliptin, sitagliptin, vildagliptin
Date submitted 14 July 2010; date of first decision 8 September 2010; date of final acceptance 14 September 2010
Introduction
Therapies for type 2 diabetes (T2DM) based on the actions
of the incretin hormone, glucagon-like peptide-1 (GLP-1),
were first introduced in 2005. GLP-1 is an intestinal hormone,
which has been shown to play an important role in the normal
regulation of glucose homeostasis. It has a number of effects
that contribute to the maintenance of glucose tolerance, such as
improvements in α- and β-cell function, including the glucosedependent stimulation of insulin and suppression of glucagon
secretion, as well as non-pancreatic effects such as delaying
gastric emptying and suppression of appetite [1]. These actions
are preserved in patients with T2DM, and the first clinicalproof-of-concept study, published in 2002, showed that GLP-1
could reduce HbA1c levels in T2DM patients when given by
continuous subcutaneous infusion [2].
GLP-1 is, however, a labile peptide and is rapidly removed
from the circulation by a combination of degradation and
renal clearance. The enzyme that is responsible for the initial
cleavage of GLP-1 (whereby it loses its insulinotropic action)
in vivo is the serine protease dipeptidyl peptidase (DPP)-4. The
identification of its key role in the metabolic clearance of GLP-1
in humans provided the rationale for inhibiting the enzyme (in
order to increase the levels of endogenous intact GLP-1) as a
therapy of T2DM [3]. Preclinical studies showing that DPP-4
inhibition could prevent the degradation of GLP-1 in vivo,
leading to increased insulinotropic activity [4], were followed
Correspondence to: Carolyn F. Deacon, Department of Biomedical Sciences, University of
Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
E-mail: [email protected]
by the first demonstration in humans, that a DPP-4 inhibitor
could improve glycaemic control in subjects with T2DM [5].
The principle of using DPP-4 inhibitors as therapy of
T2DM [1,6] is now firmly established, and numerous inhibitors
are in varying stages of clinical development, with four
already approved: sitagliptin in 2006, vildagliptin in 2007
and more recently, saxagliptin in 2009 and alogliptin in
2010 (presently only in Japan). The purpose of this article
is to review briefly the five leading compounds in the DPP-4
inhibitor class (sitagliptin, vildagliptin, saxagliptin, alogliptin
and linagliptin, currently in phase 3 clinical development), with
special emphasis on any features which may help to distinguish
between them.
Chemistry
As a therapeutic class, the DPP-4 inhibitors comprise a
diverse group of compounds, which can be broadly divided
into those that mimic the dipeptide structure of DPP-4
substrates and those which are non-peptidomimetic. Compounds such as sitagliptin (β-amino acid based) [7–9], and
vildagliptin [10–12] and saxagliptin [13,14], which are nitrilecontaining inhibitors, belong to the former class, whereas
alogliptin (modified pyrimidinedione) [15,16] and linagliptin
(xanthine-based) [17,18] are members of the latter (figure 1,
Table 1).
The compounds which have been developed for therapeutic
use are all competitive reversible inhibitors, which display
high affinity for DPP-4, resulting in inhibition constants (Ki )
in the low nanomolar range [13,19–21]. There are, however,
differences in the way in which they interact with the enzyme.
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DIABETES, OBESITY AND METABOLISM
Figure 1. Structures of dipeptidyl peptidase (DPP)-4 inhibitors approved or in late stage clinical development.
Thus, sitagliptin, alogliptin and linagliptin form non-covalent
interactions with residues in the catalytic site [7,15,17]. In
contrast, inhibition of DPP-4 by vildagliptin and saxagliptin
has been described as a two-step process that involves the
formation of a reversible covalent enzyme–inhibitor complex
in which there is a slow rate of inhibitor binding and a slow
rate of inhibitor dissociation, resulting in the enzyme slowly
equilibrating between the active and inactive forms [22–24].
This means that the catalytic activity will be inhibited even
after the free drug has been cleared from the circulation and
may help to explain why vildagliptin and saxagliptin inhibit
DPP-4 activity for longer than their relatively short half-lives
would suggest. This may have repercussions in terms of their
durations of action and dosing frequencies (see below).
Potency and DPP-4 Inhibitory Efficacy
Although the described DPP-4 inhibitors are all competitive
reversible inhibitors, it can be difficult to compare them
using data reported in individual studies, because these are
influenced by differences in the assay conditions used to
estimate the extent of DPP-4 inhibition. However, one study
in which the inhibitors were directly compared under identical
experimental conditions reported that all five inhibitors showed
similar efficacy (i.e. maximal effect) for inhibition of DPP-4
in vitro, but that there were differences in potency (i.e. amount
of compound needed; IC50 = ∼1 nM for linagliptin vs. 19,
62, 50 and 24 nM, for sitagliptin, vildagliptin, saxagliptin
and alogliptin, respectively) [19]. With regard to half-life,
there are also differences between the various inhibitors.
Vildagliptin [12,25] and saxagliptin [14,26] are cleared from
the plasma relatively quickly, whereas sitagliptin [9,27],
alogliptin [28] and linagliptin [29] have much longer survival
times (Table 2, figure 2). These differences are reflected in
the therapeutic doses, which range from 5 mg for saxagliptin
to 100 mg for sitagliptin, and in the dosing frequency (once
daily for most of them, twice daily for vildagliptin; Table 2).
Nevertheless, despite the differences in potency, when used
at their therapeutic doses, the effects of the inhibitors, in
terms of the extent of DPP-4 inhibition in vivo, are broadly
Table 1. Chemistry, metabolism and elimination of dipeptidyl peptidase (DPP)-4 inhibitors.
Inhibitor
Chemistry
Metabolism
Sitagliptin [7–9]
β-amino acid-based
Vildagliptin [10–12] Cyanopyrrolidine
Renal (∼80% unchanged as parent)
Renal (22% as parent, 55% as primary metabolite)
Saxagliptin [13,14]
Renal (12–29% as parent, 21–52% as metabolite)
Alogliptin [15,16]
Linagliptin [17,18]
8 Deacon
Not appreciably metabolized
Hydrolysed to inactive metabolite (P450
enzyme independent)
Cyanopyrrolidine
Hepatically metabolized to active metabolite
(via P450 3A4/5)
Modified pyrimidinedione Not appreciably metabolized
Xanthine-based
Not appreciably metabolized
Elimination route
Renal (>70% unchanged as parent)
Biliary (>70% unchanged as parent); <6% via kidney
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DIABETES, OBESITY AND METABOLISM
Table 2. Half-life, potency (dose) and dipeptidyl peptidase (DPP)-4 inhibitory efficacy of DPP-4 inhibitors.
Inhibitor
Compound t1/2 (h)
Dosing
DPP-4 inhibition∗
Sitagliptin [9,27]
Vildagliptin [12,25]
Saxagliptin [14,26]
Alogliptin [28]
Linagliptin [29]
8–24
1 1/2 –4 1/2
2–4 (parent) 3–7 (metabolite)
12–21
10–40
100 mg qd
50 mg bid
5 mg qd
25 mg qd
5 mg qd (anticipated)
Max ∼97%; >80% 24 h postdose
Max ∼95%; >80% 12 h postdose
Max ∼80%; ∼70% 24 h postdose
Max ∼90%; ∼75% 24 h postdose
Max ∼80%; ∼70% 24 h postdose
∗
DPP-4 activity measured in human plasma ex vivo; not corrected for sample dilution in the assay.
similar. Over 90% inhibition is attained within 15 min of
inhibitor administration, with around 70–90% inhibition
being sustained at 24 h postdose (Table 2, figure 2); for
vildagliptin, although the extent of plasma DPP-4 inhibition
drops to around 50% after 24 h with the 50 mg dose, the twice
daily therapeutic dosing regimen maintains plasma DPP-4
inhibition at >80% over the full 24-h period. However, it
should be pointed out that plasma DPP-4 activity is assessed
ex vivo (i.e. in plasma samples taken after in vivo dosing) and is
generally not corrected for the inherent dilution of the sample
in the assay. Hence, the true extent of DPP-4 inhibition in vivo
is probably higher than the measured values suggest.
Selectivity
DPP-4 is a member of a family of proteases, two of which
(DPP-8 and -9) have been implicated in preclinical toxicities
and suppression of T-cell activation and proliferation in
some [30,31], but not all [20] studies; in order to minimize
any potential off-target side effects, the inhibitors intended to
be used therapeutically have, therefore, been chosen with this in
mind (Table 3). Thus, in this respect, sitagliptin and alogliptin
can both be described as being highly selective; they essentially
show no inhibitory activity against other members of the DPP-4
family when tested in vitro [7,15]. Vildagliptin and saxagliptin
are somewhat less selective with regard to inhibition of DPP-8/9
in vitro [20,21], although whether this has any significance in
vivo is questionable because DPP-8/9 are located intracellularly.
Linagliptin, while being selective with regard to DPP-8/9, is
less selective with regard to fibroblast activation protein-α
(FAPα)/seprase [19]. FAPα is an extracellular enzyme which
is not generally present in normal adult tissue (although it is
expressed in stromal fibroblasts and upregulated during tissue
remodelling) [32]. However, the extent of any FAPα inhibition
in vivo with the therapeutic dose of linagliptin in humans has
not been reported.
Figure 2. Extent of plasma dipeptidyl peptidase (DPP)-4 activity in
humans after DPP-4 inhibitor administration. (A) Vildagliptin, modified
from He et al. [25]; (B) saxagliptin, modified from Boulton et al. [26];
(C) sitagliptin, modified from Bergman et al. [27]; (D) alogliptin, modified
from Covington et al. [28] and (E) linagliptin, modified from Heise
et al. [29].
None of the inhibitors have been reported to have any
significant inhibitory activity on a panel of different enzymes,
including the CYP450 enzymes (sitagliptin [7]; vildagliptin [12];
saxagliptin [14]; alogliptin [15] and linagliptin [19]), although
linagliptin was reported to inhibit CYP3A4 activity weakly in
a competitive manner (Ki = 115 μM) and to be a poor-tomoderate mechanism-based inhibitor of CYP3A4 [18].
Table 3. In vitro selectivity of dipeptidyl peptidase (DPP)-4 inhibitors (fold selectivity for DPP-4 vs. other enzymes).
Inhibitor
Selectivity
QPP/DPP-2
PEP
FAPα
DPP-8
DPP-9
Sitagliptin [7]
Vildagliptin [10,20]
Saxagliptin [21]
Alogliptin [15]
Linagliptin [19]
High
Moderate
Moderate
High
Moderate
>5550
>100 000
>50 000
>14 000
>100 000
>5550
60 000
Not reported
>14 000
>100 000
>5550
285
>4000
>14 000
89
>2660
270
390
>14 000
40 000
>5550
32
77
>14 000
>10 000
QPP, quiescent cell proline dipeptidase; PEP, prolyl endopeptidase; FAPα, fibroblast activation protein-α.
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Absorption
The DPP-4 inhibitors are all orally available and are rapidly
absorbed (figure 2), with significant inhibition of plasma DPP-4
activity being seen within 5 min of administration. Oral biovailability in humans is generally high (∼87% for sitagliptin [33],
85% for vildagliptin [34] and ∼67% for saxagliptin [35]),
although somewhat lower for linagliptin (∼30%) [36].
Distribution
Where available, data indicate that the volume of distribution
of the various inhibitors in humans is greater than the total
body water (∼70 l for vildagliptin [12], 198 l for sitagliptin [9],
300 l for alogliptin [28] and ∼2.7 l/kg for saxagliptin [35]),
suggesting that these compounds distribute widely into the
tissues. However, although their chemistries suggest that
they are unlikely to diffuse freely over the cell membrane,
whether or not they actually cross the cell membrane has
not been studied in detail and no information is available for
sitagliptin, alogliptin or linagliptin. The intrinsic membrane
permeability of saxagliptin is reported to be very low, and
neither saxagliptin nor its major metabolite (BMS-510849) is
a prominent substrate for multidrug resistance P-glycoprotein
(Pgp) transporters or for cellular uptake transporters [26].
There is some indirect evidence that vildagliptin may be able to
cross the cell membrane. Thus, it has been reported that at very
high doses (>600 times the human dose), vildagliptin inhibits
DPP-8/9 in vivo in rats [20]; because DPP-8/9 are located
in the cytosol, this would suggest that vildagliptin does have
some access to the intracellular compartment, but it is unclear
whether this occurs in humans with the therapeutic dose.
In the plasma, most of the inhibitors display low,
reversible protein binding (38% for sitagliptin [33], 10% for
vildagliptin [11,12] and negligible for saxagliptin [14]). In
contrast, linagliptin binds extensively to plasma proteins in
a concentration-dependent manner and it has been calculated
that at the therapeutic dose (5 mg) most of the drug will be
protein bound (primarily to DPP-4) [37].
Preclinical studies have revealed that the highest concentrations of the drugs are found in the intestines, kidney and
liver [9,12,14,38], which, notably, are also the tissues with the
highest expression of DPP-4. Available information indicates
that very low levels of the inhibitors are found in the brain
(saxagliptin and its primary metabolite [35], vildagliptin [12]
and linagliptin [38]), suggesting that the compounds may
not cross the blood–brain barrier. However, they do appear
to be able to cross the placenta freely (saxagliptin [14],
vildagliptin [12] and sitagliptin [9]).
Metabolism
Sitagliptin, alogliptin and linagliptin do not undergo appreciable metabolism in vivo in humans; around 80% of the dose
is eliminated unchanged as the parent compound (Table 1).
For sitagliptin, the limited metabolism produces six metabolites in trace amounts (each accounting for <1% to 7% of
sitagliptin-related material in plasma), with in vitro studies
indicating that the primary enzyme responsible is CYP3A4
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DIABETES, OBESITY AND METABOLISM
with a lesser contribution from CYP2C8 [8]. Three of these
metabolites (M1, M2 and M5) are active, but are not expected
to contribute to the pharmacodynamic profile of sitagliptin
because of the combination of low plasma concentration and
low affinity for DPP-4 [8,9]. For alogliptin, the parent molecule
accounts for >80% of alogliptin-related material in plasma and
two minor metabolites have been identified, N-demethylated
(active) and N-acetylated (inactive) alogliptin, accounting for
less than 1% and approximately 5%, respectively [16]. In the
case of linagliptin, the parent compound made up around 70%
of drug-related material in plasma, while exposure to the major
metabolite (CD1790, identified as S-3-hydroxypiperidinyl
derivative of linagliptin) was around 18% of that of the parent
compound. Formation of CD1790, which is pharmacologically
inactive, is dependent upon CYP3A4. In addition, seven minor
metabolites (each accounting for 0.3 to <5% of linagliptinrelated material in plasma) were identified [18].
In contrast, both vildagliptin and saxagliptin undergo
extensive metabolism in humans (Table 1). The major
metabolic pathway for vildagliptin is hydrolysis at its cyano
moiety, which occurs in the liver and other tissues via
a CYP450 -independent mechanism, to produce a carboxylic
acid metabolite (M20.7/LAY151) and four minor metabolites.
The parent molecule and the major metabolite, which
is pharmacologically inactive, account for the majority of
vildagliptin-related material in the plasma (approximately
22 and 55%, respectively) [11,12]. Saxagliptin is hepatically
metabolized by CYP 3A4/5 to produce a major metabolite (5hydroxy saxagliptin; BMS-510849), which is also a competitive,
reversible inhibitor of DPP-4 with approximately 50% of
the potency of the parent drug. Systemic exposure to
saxagliptin-related material is accounted for by the parent
molecule (22%) and BMS-510849 plus other unidentified
minor monohydroxylated metabolites (76%) [14].
Excretion
Generally, the DPP-4 inhibitors are eliminated primarily via
the kidney, with the rate of renal clearance exceeding glomerular filtration, suggesting that active transport is involved. For
sitagliptin, around 70% of the dose is excreted as the parent
molecule and active transport has been shown to account for
around 50% of its clearance [39]; the human organic anion
transporter (OAT)-3, organic anion transporting polypeptide
(OATP)-4C1 and Pgp transporters in the proximal tubule have
been indicated to be involved [40]. Alogliptin (and its minor
metabolites) is renally eliminated, with around 60–70% of the
dose appearing in the urine as the parent compound [28,41].
Clearance of alogliptin is greater than normal glomerular filtration, but the renal transporters involved have not been
identified, although drug-interaction studies suggest that Pgp
is unlikely to be involved [28]. Similarly, both saxagliptin and
its primary metabolite (BMS-510849) are primarily renally
eliminated, accounting for 24 and 36% of the dose, respectively [14]. Again, renal clearance of the parent compound
is greater than the glomerular filtration rate, indicating the
involvement of active renal secretion, but the mechanism is
unknown; saxagliptin is reported not to be a substrate for OAT1,
OAT3, OATPA, OATPC, OATP8, organic cation transporter
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(OCT)-1, OCT2, sodium taurocholate co-transporting peptide
or peptide transporters (PepT1 and PepT2) [14]. In contrast,
clearance of BMS-510849 is similar to the glomerular filtration, suggesting that this is a main mechanism involved in its
elimination [14]. Data for vildagliptin also indicate the kidneys
to be the predominant route of elimination, with 22% of the
dose appearing in the urine unchanged and 50% appearing
as the major metabolite (M20.7); active transport in addition
to glomerular filtration was indicated to be involved in the
elimination of both compounds [11].
Linagliptin is the exception, with <6% of the dose being
excreted in the urine [29]. This may be, at least in part,
because of the high degree of protein binding [37], meaning
that the drug escapes glomerular filtration. Rather, linagliptin
has a hepatic route of elimination, with 78% appearing in the
faeces unchanged. Renal excretion of the primary metabolite
(CD1790) is negligible; this undergoes further metabolism and
is also eliminated in the faeces [18].
Potential for Drug–Drug Interactions
In general, the DPP-4 inhibitors have not been reported
to result in any meaningful activation or inhibition of
the CYP enzyme system, suggesting that they are unlikely
to be involved in clinically meaningful drug interactions
involving these systems. There are data suggesting that
there is no great propensity for the DPP-4 inhibitors to be
involved in any clinically relevant drug–drug interactions with
other commonly prescribed medications [9,12,14], including
metformin [42–45], pioglitazone [46–48], rosiglitazone [49],
glyburide [46,47,50] and simvastatin [51–53], suggesting that
these agents can be co-administered with the DPP-4 inhibitors
without the need for dose adjustment of either drug.
As mentioned, CYP3A4/5 is involved in the conversion of
saxagliptin to the active metabolite (BMS-510849), and strong
inhibitors of CYP3A4/5, such as ketoconazole, increase the
exposure to the parent compound. For this reason, dose reduction by half (2.5 mg qd) is recommended when saxagliptin
is co-administered with strong CYP3A4/5 inhibitors [54].
Linagliptin is also a substrate for CYP3A4, and ketoconazole
prevents the generation of the metabolite, CD1790. However,
because this is of only minor importance in the clearance of
linagliptin, inhibition or induction of CYP3A4 by concomitantly administered drugs was not considered likely to alter the
overall exposure to linagliptin [18]. Additionally, linagliptin
has been identified as a weak competitive and a poor-tomoderate mechanism-based inhibitor of CYP3A4, resulting in
a decrease in the clearance of other compounds metabolized
by this pathway by less than twofold; linagliptin was therefore
considered to have only a weak potential for clinically relevant
interactions with drugs metabolized by this system [18].
Safety/Tolerability
Some differences between the different DPP-4 inhibitors have
arisen from preclinical safety studies and observations made
during the course of the clinical trial programmes.
Thus, vildagliptin and saxagliptin, but not sitagliptin or
alogliptin, were reported to be associated with adverse skin
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toxicology in monkeys. However, this may be a finding
which is specific to monkeys, as it has not been observed
in other preclinical species, and importantly, there have been
no reports of skin problems in the clinical trials with any of the
inhibitors [12,14,55–57].
For saxagliptin, small, reversible, dose-dependent reductions
in absolute lymphocyte count have been noted in some of the
clinical trials, but this has not been reported for the other
DPP-4 inhibitors. The effect was more apparent at saxagliptin
doses ≥20 mg (which is greater than the therapeutic dose),
but values still remained within normal limits [14,58]. There
was no effect on white blood cell or neutrophil count and no
evidence of altered immune function. At present, the clinical
significance of this (if any) remains unknown.
At the time of initial registration of vildagliptin (in EU), a
meta-analysis of the clinical trial data revealed that the 100 mg
qd dose was associated with small numerical elevations in
liver transaminases compared to placebo or 50 mg bid. For
this reason, the recommended therapeutic dose was changed to
50 mg bid, with the recommendation that liver function tests be
performed before initiation and at three monthly intervals for
the first year of treatment and periodically thereafter [12,59].
Subsequently, the trend for mild increases (greater than three
times the upper limit of normal) in liver enzymes was confirmed
in the larger pooled safety analysis, but notably, this was
not associated with any increased incidence of actual hepatic
adverse events [56]. Nevertheless, liver function tests are still
recommended and vildagliptin is not approved for use in
patients with hepatic insufficiency (see later).
Despite the above observations, overall, the DPP-4 inhibitors
as a class appear to be very well tolerated, and rates of
adverse effects have been low, and generally not different
to placebo or comparator. An early meta-analysis of incretinbased therapies (in which inhibitor data were available only
for sitagliptin and vildagliptin) did, however, suggest that
there was an increased risk of some infections (urinary tract
infections with both inhibitors and nasopharyngitis more
evident with sitagliptin) and headache (more evident with
vildagliptin) [60,61]. Since then, updated safety analyses (each
>10 000 patients, exposed for up to 2 years) of the sitagliptin
and vildagliptin clinical trials have been published, showing
no increased risk for urinary tract or respiratory infections or
headache (and indeed, no increased risk of any other adverse
effect) with the DPP-4 inhibitors compared to placebo or
comparator [55,56]. Notably, recent debate over potential links
between some antidiabetic medications and cancer [62] or bone
fracture [63] does not seem to extend to the DPP-4 inhibitors,
with no evidence for increased signals being observed in the
safety analyses [55,56]. Cardiovascular safety of new drugs,
including antihyperglycaemic agents, has also been the focus
of concern, with the FDA requiring pharmaceutical companies
to show that new agents to not increase the risk of adverse
cardiovascular events. Retrospective analyses of data from the
clinical development programmes of sitagliptin, vildagliptin
and saxagliptin do not appear to indicate any increased
cardiovascular risk with the DPP-4 inhibitors relative to
comparators [55,64,65], but large prospective trials, designed
specifically to evaluate the effect of sitagliptin, saxagliptin and
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Table 4. Prescribing characteristics of dipeptidyl peptidase (DPP)-4 inhibitors.
Renal insufficiency∗
Inhibitor
Sitagliptin
(launched EU, USA)
Vildagliptin‡
(launched EU)
Saxagliptin§
(launched EU, USA)
Alogliptin
(launched Japan)
Linagliptin
(not yet approved)
Mild (CrCl
≥50 ml/min)
√
√
√
√
√
(likely)
Hepatic insufficiency
Moderate (CrCl
≥30–<50 ml/min)
Severe/ESRD (CrCl
<30 ml/min)
Presently not
recommended (EU)
1/2 dose (USA)†
Presently not
recommended†
Presently not
recommended (EU)
1/2 dose (USA)†
1/2 dose
Presently not
recommended (EU)
1/4 dose (USA)†
Presently not
recommended†
Presently not
recommended (EU)
1/2 dose (USA)†
1/4 dose
√
√
(likely)
(likely)
Mild/moderate
√
Not recommended
√
(Moderate: use with
caution)
√
Unknown
Dose adjustment? / not
recommended?
Severe
Presently not
recommended†
Not recommended
Presently not
recommended†
Presently not
recommended†
Unknown
Dose adjustment? /
not recommended?
CrCl, creatinine clearance; ESRD, end-stage renal disease.
∗ Assessment of renal function recommended prior to initiation of treatment and periodically thereafter.
† Not studied/no clinical experience.
‡ Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter.
§ Dose reduction (2.5 mg) when saxagliptin co-administered with strong cytochrome P
450 3A4/5 inhibitors (e.g. ketoconazole).
alogliptin on cardiovascular outcomes are underway. There has
also been some debate over whether incretin-based therapies,
including the DPP-4 inhibitors, are associated with elevated risk
of pancreatitis [66]. This does not seem to be borne out by the
pooled safety analyses [56,67] or retrospective analyses of large
healthcare data bases [68,69]. Continued vigilance and longer
term reports are still needed to confirm these observations.
Use in Patient Subpopulations
Renal Insufficiency
Because most of the described DPP-4 inhibitors are eliminated
renally, it might be expected that their pharmacokinetic profile
would be influenced by impairments in renal function. In line
with this, exposure to sitagliptin increased proportionately to
the degree of renal failure, but the drug was well tolerated,
even in patients with end-stage renal disease (ESRD), including
those on dialysis; the fraction removed by dialysis was small
(∼13% for haemodialysis started at 4 h postdose) [70]. Based
on this study, it was concluded that no dose adjustment was
necessary in subjects with mild renal insufficiency [creatinine
clearance (CrCl) 50–80 ml/min]. However, in order to maintain plasma sitagliptin exposure comparable to that in subjects
with normal renal function, in subjects with moderate renal
insufficiency (CrCl 30–50 ml/min) or severe renal insufficiency
(CrCl <30 ml/min)/ESRD, dose reductions of 50 and 75%,
respectively, are required [70]. In T2DM patients with moderate or severe chronic renal insufficiency (including those with
ESRD on dialysis), sitagliptin provided effective glycaemic control over 1 year and was generally well tolerated [71]. Exposure
to vildagliptin and saxagliptin is also similarly increased in subjects with impaired renal function [12,14], and as for sitagliptin,
vildagliptin is reported to be well tolerated in patients with mild
renal insufficiency, with the rate of adverse events being similar
12 Deacon
to comparators [56]; no data are yet available in patients with
moderate or severe renal impairment (Table 4).
On the bais of these observations, sitagliptin, vildagliptin and
saxagliptin have been approved for use in subjects with mild
renal insufficiency without dose adjustment, and where the
indication is approved, sitagliptin and saxagliptin can be used
in patients with moderate or severe renal insufficiency/ESRD
with appropriate dose adjustment (Table 4). Alogliptin is also
eliminated renally and can be used in subjects with moderate
or severe renal impairment with dose reduction (Table 4).
Because linagliptin is not predominantly eliminated via the
kidneys, it could be anticipated that this drug might be able
to be used in renal disease patients, including those with
severe renal insufficiency/ESRD without the need for any dose
adjustment [72].
Hepatic Insufficiency
The DPP-4 inhibitors generally appear to be well tolerated in
patients with hepatic impairment and there seems to be no
clinically meaningful impact of hepatic insufficiency on their
pharmacokinetics. Thus, in subjects with moderate hepatic
impairment, exposure to sitagliptin was slightly, but nonsignificantly increased [73], whereas exposure to alogliptin was
slightly decreased [74]. For vildagliptin, exposure to the parent
drug showed non-significant trends to decrease in patients
with mild or moderate hepatic impairment and to increase
in patients with severe hepatic impairment, whereas exposure
to the primary (inactive) metabolite (M20.7) increased nonsignificantly in all groups, compared with healthy subjects [75].
In line with its hepatic metabolism, saxagliptin exposure
increased and that of the active metabolite (BMS-510849)
decreased in subjects with hepatic impairment [14].
Overall, these studies suggested that no dose adjustment will
be necessary in patients with hepatic impairment. Vildagliptin
Volume 13 No. 1 January 2011
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DIABETES, OBESITY AND METABOLISM
is, however, not recommended for use in patients with hepatic
insufficiency or those with pretreatment alanine aminotransferase or aspartate aminotransferase at greater than three
times the upper limit of normal (because of the association
of vildagliptin with mild increases in hepatic transaminases; see
above). The other DPP-4 inhibitors which have been approved
can be used in patients with mild/moderate hepatic insufficiency without dose adjustment (Table 4), although because
hepatic impairment increases exposure to saxagliptin (in accord
with its hepatic metabolism; see above), caution is required if
used in subjects with moderate hepatic insufficiency [14]. At
present, limited data in subjects with severe hepatic impairment
mean that the DPP-4 inhibitors are currently not recommended
for use in this patient group. Because the liver is the primary
route of elimination for linagliptin, it could be anticipated
that linagliptin may require dose adjustment or may not be
recommended for use in subjects with hepatic impairment.
Antidiabetic Efficacy
As might be expected from their similar efficacy in inhibiting
DPP-4 activity (see above), broadly speaking, the DPP-4
inhibitors all seem to show similar efficacy in lowering HbA1c
levels, although it must be stressed that these are observations
made in different studies and so must be interpreted with some
caution (figure 3). At present, data are available only from
one direct head-to-head comparison between the inhibitors,
in which the efficacy of saxagliptin and sitagliptin as addon therapy in metformin-treated patients was compared [76].
This showed non-inferiority of saxagliptin to sitagliptin in
terms of HbA1c lowering (−0.5 vs. −0.6% from a baseline
of ∼7.7%; i.e. from 60 to 55 mmol/mol for saxagliptin
vs. from 61 to 54 mmol/mol for sitagliptin) at week 18,
Figure 3. HbA1c lowering efficacy of dipeptidyl peptidase (DPP)-4
inhibitors in relation to baseline HbA1c levels, as monotherapy or add-on
therapy (open symbols) or initial combination therapy (closed symbols)
in studies of ≥12 weeks duration (see Appendix for references). Triangle,
sitagliptin (100 mg qd); circle, vildagliptin (50 mg bid or 100 mg qd);
square, saxagliptin (5 mg qd); diamond, alogliptin (25 mg qd) and star,
linagliptin (5 mg qd).
Volume 13 No. 1 January 2011
with similar proportions of subjects (26 vs. 29%) reaching
target HbA1c levels of <6.5% (<48 mmol/mol). However,
in terms of the reduction in fasting plasma glucose, it did
appear that there might be a small difference, with sitagliptin
being more efficacious (−0.6 vs. −0.9 mmol/l; difference
0.30 ± 0.115 mmol/l, 95% confidence interval: 0.08–0.53);
this could potentially be related to differences in the half-life
of the compounds (Table 2, figure 2). In other direct headto-head studies, the DPP-4 inhibitors have shown similar
efficacy to metformin [77,78], the sulphonylureas [79,80], the
glitazones [81,82] and the alpha-glucosidase inhibitors [83]. In
line with other antidiabetic agents [84], greater reductions in
HbA1c are seen in subjects with higher baseline levels (figure 3).
Conclusions
The DPP-4 inhibitors are the first new therapeutic class of
oral antihyperglycaemic drug for T2DM for many years. They
were designed for the treatment of the disease based on prior
knowledge of the physiology of the incretin hormone GLP-1
and an understanding of the target (DPP-4), contrasting with
the development of other antidiabetic agents whose blood
glucose-lowering effects were initially discovered more by
chance than by design without fully knowing the underlying
mechanisms (e.g. metformin, sulphonylureas and glitazones).
Identification of the 3-dimensional/tertiary structure of the
DPP-4 protein allowed the rational design of small molecule
inhibitors which interact only with the catalytic site without
interfering in any of the other functions of the DPP-4/CD26
molecule. This, together with the understanding of the role of
GLP-1 in glucose homeostasis and its unique susceptibility to
cleavage by DPP-4, probably accounts for the remarkable lack
of adverse effects so far associated with the therapeutic use of
the DPP-4 inhibitors.
As a class, the DPP-4 inhibitors comprise of a group
of chemically diverse compounds, which differ in terms of
their potency to inhibit the DPP-4 enzyme, their duration
of action and their metabolism and elimination, as well
as isolated compound-specific characteristics (Table 5). They
are all apparently well tolerated (side-effect profile resembles
placebo) and result in clinically meaningful reductions in blood
glucose (fasting and postprandial) and HbA1c levels, with
minimal risk of hypoglycaemia and without weight gain—in
this latter respect, they are better than all other agents except
metformin and the incretin mimetics. They are used without
the need for dose titration and give broadly similar HbA1c
lowering efficacy to other oral antidiabetic agents; they are
compatible with first-line therapy and they give predictable
additivity to other agents, where they can be used without dose
adjustment of either agent.
At present, although there are some practical differences
between the different DPP-4 inhibitors with respect to dosing
frequency and their ability to be used in different patient
subpopulations, there seems to be little to distinguish between
them in terms of their efficacy as antidiabetic agents and their
safety. Only long-term accumulated clinical experience will
reveal whether compound-related characteristics lead to any
clinically relevant differences.
doi:10.1111/j.1463-1326.2010.01306.x 13
review article
DIABETES, OBESITY AND METABOLISM
Table 5. Differences and similarities between dipeptidyl peptidase
(DPP)-4 inhibitors.
11. He H, Tran P, Yin H et al. Absorption, metabolism, and excretion of
[14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans.
Drug Metab Dispos 2009; 37: 536–544.
Differences
Similarities
Chemical structures
In vitro selectivity
Metabolism (changed/unchanged,
active/inactive metabolite)
Elimination (renal/hepatic)
Preclinical toxicities
Potency (therapeutic dose)
Dosing frequency (once/twice daily)
Use in patient subpopulations (e.g.
impaired renal/hepatic function)
Efficacy (HbA1c lowering)
Tolerability
Safety
12. European Medicines Agency (EMEA). Galvus (vildagliptin)—European
public assessment report (EPAR)—scientific discussion. Available from
URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/galvus/H771-en6.pdf. Accessed 5 July 2010.
Conflict of Interest
As this is a single author review, C. F. Deacon was
responsible for all aspects of the manuscript. CFD has received
consultancy/lecture fees from companies with an interest in
developing and marketing incretin-based therapies for the
treatment of type 2 diabetes (Astra Zeneca/BMS, Lilly, Merck,
Novartis, Novo Nordisk, Servier). Spouse is employed by Merck
and holds stock options in Merck and Novo Nordisk.
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77. Aschner P, Katzeff HL, Guo H et al. Efficacy and safety of monotherapy of
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79. Ferrannini E, Fonseca V, Zinman B et al. Fifty-two-week efficacy and safety
of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus
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Aschner P, Katzeff HL, Guo H et al. Efficacy and safety of monotherapy of
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Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman
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on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29:
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Bergenstal RM, Wysham C, Macconell L et al. Efficacy and safety of exenatide
once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for
treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;
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Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin
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Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE.
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inhibitor, and metformin on glycemic control in patients with type 2 diabetes.
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Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily
sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with
type 2 diabetes. Curr Med Res Opin 2007; 23: 1329–1339.
Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and
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diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride
and metformin. Diabetes Obes Metab 2007; 9: 733–745.
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea,
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Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for patients with
type 2 diabetes who did not have adequate glycaemic control with metformin:
a 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375:
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Raz I, Chen Y, Wu M et al. Efficacy and safety of sitagliptin added to ongoing
metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 2008;
24: 537–550.
Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy
and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in
patients with type 2 diabetes mellitus. Diabetologia 2006; 49: 2564–2571.
Reasner CA, Olansky L, Seck TL et al. Initial therapy with the fixed-dose
combination (FDC) of sitagliptin and metformin (JANUMET™) in patients
with type 2 diabetes mellitus (T2DM) provides superior glycemic control and
A1C goal attainment with lower rates of abdominal pain and diarrhea vs.
metformin alone (Abstract 610-P). Diabetes 2009; 58(Suppl. 1): A164.
Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone
therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized,
double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28:
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Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when
added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes
Obes Metab 2008; 10: 959–969.
Vilsbøll T, Rosenstock J, Yki-Järvinen H et al. Efficacy and safety of sitagliptin
when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes
Metab 2010; 12: 167–177.
Yoon KH, Shockey GR, Teng R et al. Initial combination therapy with sitagliptin
and pioglitazone improves glycemic control and measures of β-cell function
compared with pioglitazone alone in patients with type 2 diabetes (Abstract
522-P). Diabetes 2009; 58(Suppl. 1): A139.
Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and
safety of saxagliptin in combination with metformin compared with sitagliptin
in combination with metformin in adult patients with type 2 diabetes mellitus.
Diabetes Metab Res Rev 2010; 26: 540–549.
Vildagliptin
Ahrén B, Pacini G, Foley JE, Schweizer A. Improved meal-related betacell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor
vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.
Diabetes Care 2005; 28: 1936–1940.
Blonde L, Dagogo-Jack S, Banerji MA et al. Comparison of vildagliptin and
thiazolidinedione as add-on therapy in patients inadequately controlled with
metformin: results of the GALIANT trial—a primary care, type 2 diabetes study.
Diabetes Obes Metab 2009; 11: 978–986.
Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs.
pioglitazone when added to metformin: a 24-week, randomized, double-blind
study. Diabetes Obes Metab 2008; 10: 82–90.
Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin
on glucose control over 24 weeks in patients with type 2 diabetes inadequately
controlled with metformin. Diabetes Care 2007; 30: 890–895.
Bosi E, Dotta F, Jia Y, Goodman M. Vildagliptin plus metformin combination
therapy provides superior glycaemic control to individual monotherapy in
treatment-naive patients with type 2 diabetes mellitus. Diabetes Obes Metab
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Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naı̈ve patients
with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled,
multiple-dose study. Horm Metab Res 2007; 39: 218–223.
Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition
of vildagliptin to insulin improves glycaemic control in type 2 diabetes.
Diabetologia 2007; 50: 1148–1155.
Garber AJ, Foley JE, Banerji MA et al. Effects of vildagliptin on glucose control
in patients with type 2 diabetes inadequately controlled with a sulphonylurea.
Diabetes Obes Metab 2008; 10: 1047–1056.
Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in
combination with pioglitazone improves glycaemic control in patients with
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type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebocontrolled study. Diabetes Obes Metab 2007; 9: 166–174.
Pan C, Yang W, Barona JP et al. Comparison of vildagliptin and acarbose
monotherapy in patients with type 2 diabetes: a 24-week, double-blind,
randomized trial. Diabet Med 2008; 25: 435–441.
Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of
vildagliptin monotherapy in drug-naı̈ve patients with type 2 diabetes. Diabetes
Res Clin Pract 2007; 76: 132–138.
Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl
peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237)
dose response. Diabetes Obes Metab 2005; 7: 692–698.
Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of
vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a
24-week, double-blind, randomized trial. Diabetes Care 2007; 30: 217–223.
Rosenstock J, Kim SW, Baron MA et al. Efficacy and tolerability of initial
combination therapy with vildagliptin and pioglitazone compared with
component monotherapy in patients with type 2 diabetes. Diabetes Obes
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Scherbaum WA, Schweizer A, Mari A et al. Efficacy and tolerability of vildagliptin
in drug-naı̈ve patients with type 2 diabetes and mild hyperglycaemia. Diabetes
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Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin
and metformin to sustain reductions in HbA(1c) over 1 year in drug-naı̈ve
patients with type 2 diabetes. Diabet Med 2007; 24: 955–961.
Schweizer A, Dejager S, Bosi E. Comparison of vildagliptin and metformin
monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind,
randomized trial. Diabetes Obes Metab 2009; 11: 804–812.
Saxagliptin
Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. Saxagliptin
added to a submaximal dose of sulphonylurea improves glycaemic control
compared with uptitration of sulphonylurea in patients with type 2 diabetes: a
randomised controlled trial. Int J Clin Pract 2009; 63: 1395–1406.
DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety of saxagliptin
when added to metformin therapy in patients with inadequately controlled type
2 diabetes with metformin alone. Diabetes Care 2009; 32: 1649–1655.
Hollander P, Li J, Allen E, Chen R. Saxagliptin added to a thiazolidinedione
improves glycemic control in patients with type 2 diabetes and inadequate
control on thiazolidinedione alone. J Clin Endocrinol Metab 2009; 94:
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Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin
given in combination with metformin as initial therapy improves glycaemic
control in patients with type 2 diabetes compared with either monotherapy: a
randomized controlled trial. Diabetes Obes Metab 2009; 11: 611–622.
Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of
saxagliptin monotherapy in treatment-naı̈ve patients with type 2 diabetes. Curr
Med Res Opin 2009; 25: 2401–2411.
Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl
peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes.
Diabetes Obes Metab 2008; 10: 376–386.
Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and
safety of saxagliptin in combination with metformin compared with sitagliptin
in combination with metformin in adult patients with type 2 diabetes mellitus.
Diabetes Metab Res Rev 2010; 26: 540–549.
Alogliptin
Bosi E, Ellis G, Moneuse P, Wilson C, Fleck P. Addition of alogliptin vs
uptitration of pioglitazone dose in type 2 diabetes mellitus (T2DM) patients
on metformin plus pioglitazone therapy (Abstract 545). Diabetes 2010;
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DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Effect
of alogliptin combined with pioglitazone on glycemic control in metformintreated patients with type 2 diabetes (Abstract 752-P). Diabetologia 2009;
52(Suppl. 1): S295.
DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. 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 2009; 31: 2315–2317.
Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of adding
the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients
with type 2 diabetes inadequately controlled with metformin monotherapy:
a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin
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Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin
added to insulin therapy in patients with type 2 diabetes reduces HbA(1C)
without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab
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Linagliptin
Del Prato S, Barnett A, Huisman H, Neubacher D, Woerle HJ, Dugi KA.
Linagliptin monotherapy improves glycemic control and measures of β-cell
function in type 2 diabetes (Abstract 695). Diabetes 2010; 59(Suppl. 1): A189.
Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of
initial combination therapy with linagliptin and pioglitazone in patients with
inadequately controlled type 2 diabetes (Abstract 551). Diabetes 2010; 59(Suppl.
1): A150.
Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. 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: 167–176.
Owens DR, Swallow R, Jones P, Woerle HJ, Dugi KA. Linagliptin improves
glycemic control in type 2 diabetes patients inadequately controlled by
metformin and sulfonylurea without weight gain and low risk of hypoglycemia
(Abstract 548). Diabetes 2010; 59(Suppl. 1): A149.
Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q. 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: 2361–2371.
Taskinen MR, Rosenstock J, Tamminen I et al. Efficacy and safety of linagliptin
in type 2 diabetes inadequately controlled on metformin monotherapy (Abstract
579). Diabetes 2010; 59(Suppl. 1): A158.
Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial
combination therapy with alogliptin and pioglitazone in drug-naı̈ve patients
with type 2 diabetes. Diabetes Care 2010; [epub ahead of print].
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Uhlig-Laske B, Ring A, Graefe-Mody U et al. Linagliptin, a potent and selective
DPP-4 inhibitor, is safe and efficacious in patients with inadequately controlled
type 2 diabetes despite metformin therapy (Abstract 535-P). Diabetes 2009;
58(Suppl. 1): A143.
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