review article

Diabetes, Obesity and Metabolism 13: 775–783, 2011.

© 2011 Blackwell Publishing Ltd

article
review
Mechanisms of action of the dipeptidyl peptidase-4 inhibitor
vildagliptin in humans
B. Ahrén1 , A. Schweizer2 , S. Dejager3 , E. B. Villhauer4 , B. E. Dunning5 & J. E. Foley4
1 Department of Clinical Sciences, Lund University, Lund, Sweden
2 Novartis Pharma AG, Basel, Switzerland
3 Novartis Pharma S.A.S., Rueil-Malmaison, France
4 Novartis Pharmaceuticals, East Hanover, NJ, USA
5 BDL Communications, Ceresco, MI, USA

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in
patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site
of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin
has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the
counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly
through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the
improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after inges-
tion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body
of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized,
with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.
Keywords: dipeptidyl peptidase-4, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, hypoglycaemia, insulin resistance,
islet function, type 2 diabetes mellitus

Date submitted 10 December 2010; date of first decision 22 February 2011; date of final acceptance 11 April 2011

Introduction
The dipeptidyl peptidase-4 (DPP-4) inhibitors are among the
most recent additions to the therapeutic armamentarium avail-
able for the treatment of type 2 diabetes mellitus (T2DM).
The basis of the therapeutic efficacy of DPP-4 inhibitors lies
in their ability to increase circulating levels of the intact,
biologically active form of the incretin hormones, glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP), both of which have numerous metabol-
ically advantageous effects. With regard to mechanism(s) of
action, vildagliptin is the DPP-4 inhibitor studied most thor-
oughly in clinical trials, and substantial progress has also
been made towards understanding the molecular interaction
between vildagliptin and the DPP-4 enzyme. The aim of this
work is to review these mechanistic studies of vildagliptin and
to provide an integrated view of its mechanism of action in
humans. Discussion of studies with other DPP-4 inhibitors
will be limited to instances where there are differences in
their respective mechanism of action that are supported by
head-to-head comparisons.
Correspondence to: Bo Ahrén, Department of Clinical Sciences, Lund University, B11 BMC,
SE-221 84 Lund, Sweden.
E-mail: bo.ahren@med.lu.se
Background
GIP [1] and GLP-1 [2] represent the physiologically important
incretins in humans [3]. The finding that GLP-1 rendered
glucose-insensitive β-cells glucose competent [4] made it an
attractive therapeutic target. However, the peptidic nature of
GLP-1 together with its very short plasma half-life was hurdles
that needed to be overcome in order to make use of the potential
therapeutic effects of GLP-1.
Both GLP-1 and GIP are rapidly degraded in plasma, with
half-lives of 2–5 min and 7–9 min, respectively [5,6]. When
DPP-4 was identified as the enzyme responsible for the degrada-
tion and inactivation of both GLP-1 and GIP [7], the possibility
of creating an orally available inhibitor of DPP-4 became
a realistic approach to leveraging the increasingly apparent
therapeutic utility of the incretin hormones [8].
In 1995, Novartis showed that valine pyrrolidide, an orally
active DPP-4 inhibitor which had been identified by its
immunology group, lowered blood glucose levels in rodent
and non-human primate models of diabetes (unpublished).
This led to the utilization of combinatorial chemistry tech-
niques to test thousands of related molecules, resulting in
the discovery of DPP-728 [9] which then provided the first
human proof of concept that a DPP-4 inhibitor could improve
glycaemic control in patients with T2DM [10]. Further study
review article DIABETES, OBESITY AND METABOLISM

Figure 1. (A) Covalent interaction between vildagliptin and the active site of DPP-4 enzyme (Ser630 of DPP-4). (B) Schematic depiction of enzyme
(DPP-4) interaction with competitive inhibitor, natural substrate (GLP-1) or substrate-blocker (covalent modifier of enzyme activity). GLP-1 associates
(k1 ) and dissociates (k−1 ) from the DPP-4 catalytic site. If GLP-1 is in the correct transition state, the association will cause GLP-1 to be simultaneously
locked into the catalytic site and weaken the peptide bond of GLP-1 between the N-terminal amino acids 2 and 3. Within about a second this leads to
the breaking of the weakened bond, and then the inactive GLP-1 dissociates from the catalytic site (k2 ). The overall dissociation (k−1 + k2 ) is essentially
determined by the much slower k2 . A competitive inhibitor competes with GLP-1 for each association. However, dissociation is immediate. If a given
dose of the competitive inhibitor results in 90% inhibition of the rate of GLP-1 inactivation, then a 10 times higher dose would be required to achieve
99% inhibition. A substrate-blocker also competes with GLP-1 for each association. However, if the substrate-blocker is in the correct transition state, the
association will cause it to be simultaneously locked into the catalytic site and to weaken a bond. After about 1 h in case of vildagliptin, the bond breaks
and then the inactive substrate-blocker dissociates from the catalytic site. Like GLP-1, the overall dissociation (k−1 + k2 ) is essentially determined by the
very much slower k2 . At doses of the substrate-blocker that effectively compete with GLP-1 for association to the catalytic site, there is only a very brief
period of time after each dissociation where it is possible for GLP-1 to be inactivated by the enzyme. DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like
peptide-1.

of DPP-728 revealed that it was a substrate for the DPP-4
catalytic site with a slow dissociation rate [11], rather than a
simple competitive inhibitor. Engineering of the structure in
order to further slow the dissociation rate led to the discovery
of the compound, LAF237 [12], now known as vildagliptin.
As illustrated in figure 1A, vildagliptin’s nitrile group rapidly
forms a covalent bond with the catalytic site of DPP-4 to
form an imidate group, which stabilizes vildagliptin in the
catalytic site of DPP-4 and facilitates hydrolysis of this imidate
group. Inactive vildagliptin then slowly dissociates from the
catalytic site with a half-life (k2 ) of about 1 h [13]. Although
vildagliptin is covalently bound to the DPP-4 catalytic site, the
enzyme cannot act on any other substrate. Following dissoci-
ation of vildagliptin from the catalytic side, within a fraction
of a second, another vildagliptin molecule will interact with
the catalytic site. This leads to complete blocking of DPP-4
activity over the entire time that vildagliptin drug levels are
adequate to effectively associate with the catalytic site. This
mechanism of enzyme inhibition is best characterized by the
term substrate-like enzyme blocker or ‘substrate-blocker’.
Medicinal chemistry work around another chemical class
of molecules resulted in the competitive DPP-4 inhibitor,
sitagliptin [14]. In contrast to the substrate-blockers, a
competitive inhibitor follows simple Michaelis–Menton

776 Ahrén et al. Volume 13 No. 9 September 2011

DIABETES, OBESITY AND METABOLISM
kinetics and dose dependently inhibits the enzyme. For
example, if a given dose produces 90% inhibition then it
will require a 10-fold higher dose to achieve 99% inhibition.
Thus, as illustrated in figure 1B, with competitive inhibitors,
enzyme activity is determined by the very rapid k−1 , whereas
with substrate-blockers such as vildagliptin, enzyme activity is
determined by the much slower k2 .
Figure 2 illustrates in vitro DPP-4 enzyme activity when
incubated in the presence of increasing concentration of
sitagliptin (figure 2A) and when maximally inhibited with
vildagliptin (50 nM), sitagliptin (500 nM) or vehicle control,
then diluted with excess substrate to allow reversal of inhibition
(figure 2B). When vildagliptin and sitagliptin were brought to
a steady-state maximum inhibition of DPP-4 and then the
concentration of the drugs diluted, there was an immediate
loss of inhibition (first time point was 10 s after dilution) with
sitagliptin while there was no loss of inhibition with vildagliptin
after 500 s and then it was slowly lost over several hours
(figure 2B) [15], consistent with its ∼55-min dissociation half
time [13].
It may be noted that vildagliptin and sitagliptin are marketed
at the same maximum daily doses [of 100 mg, with vildagliptin
Figure 2. (A) Fast binding nature of sitagliptin. Inhibition studies
performed by the addition of enzyme to preincubated mixture of substrate
and various concentrations of sitagliptin (0, 5, 12.5, 25, 50 and 125 nM
final). (B) Sitagliptin inhibition is reversible. The human recombinant
DPP-IV (10 ng) preincubated without (VC) or with sitagliptin (500 nM)
or vildagliptin (50 nM) was diluted more than 100-fold into 0.5 mM
H-Gly-Pro-AMC and the DPP-IV activity was measured. Both A and B
represent one experiment (n = 3). DPP-4, dipeptidyl peptidase-4; RFU,
relative fluorescence units (proportional to enzyme activity); VC, vehicle
control. Adapted with permission from Ref. [15].
Volume 13 No. 9 September 2011
review article
given in divided doses (50 mg twice daily) and with sitagliptin
given once daily], and both regimens are effective to reduce
HbA1c [16]. These facts may lead to the (erroneous) assump-
tion that the inhibitory actions on the catalytic site of DPP-4 by
sitagliptin and vildagliptin are identical. However, as discussed
above, these drugs interact with the DPP-4 enzyme with very
different kinetics. There are also important pharmacokinetic
differences between sitagliptin and vildagliptin. Sitagliptin is
primarily excreted as unchanged drug by the kidneys, consis-
tent with its plasma half-life of ∼12 h, whereas vildagliptin is
rapidly hydrolysed into an inactive metabolite, consistent with
its plasma half-life of ∼2 h [17,18].
When the interaction of these molecules at the catalytic site
of DPP-4 is related to their drug levels, it becomes clear that the
similarity of their daily doses is coincidental. For instance, it has
been found that 24 h after a single dose of sitagliptin (100 mg),
plasma DPP-4 activity is inhibited by ∼80% [19]. According
to Michaelis–Menten kinetics, at 12-h postdose (one half-life
before), DPP-4 inhibition would have been ∼90%, and in the
first hour after administration of sitagliptin, DPP-4 inhibition
would be calculated to be ∼95%. It should be recognized that
the actual degree of DPP-4 enzyme activity, when it is inhibited
by 90–95%, is essentially at the limit of detection of the enzyme
assays. Accordingly, it is not possible to truly distinguish
between values above 90% inhibition. In any case, at the
clinical dose of sitagliptin, the data predict that a small degree
of degradation of GLP-1 and GIP will (still) occur. In contrast,
by virtue of its being a substrate-blocker, vildagliptin maintains
essentially complete inhibition of DPP-4 until the plasma
drug levels have declined to a degree at which vildagliptin no
longer effectively competes with GLP-1 and GIP to occupy the
catalytic site of DPP-4. At (an estimated) plasma concentration
above ∼50 nM, (as seen ∼10 h after a 50 mg dose) [20], the
DPP-4 catalytic site is blocked and no endogenous substrate
can be degraded. On the basis of the enzyme kinetic differences
between a substrate-blocker (vildagliptin) and a competitive
inhibitor (sitagliptin) it is not surprising that elevated levels
of intact incretin hormones are maintained for a longer
period following vildagliptin than sitagliptin, despite the more
prolonged plasma half-life of the latter, as discussed below.
Primary Pharmacology
Vildagliptin increases postprandial plasma levels of intact
GLP-1 [21–30], and when measured postprandial levels of
intact GIP as well [21,22,25,26,29–31] (see figure 3, depict-
ing plasma levels of intact GLP-1 and GIP during meal tests
with vildagliptin treatment). This has also been described with
vildagliptin administered in healthy volunteers [20], in subjects
with IGT [32], IFG [31] and in patients with T1DM [33]. In
general, the magnitude of the increase in postprandial plasma
levels of intact GLP-1 or GIP with any of the DPP-4 inhibitors
is a two- to threefold increase, but the absolute concentrations
in the portal vein are undoubtedly much higher than those
measured in the periphery, as indeed shown with vildagliptin
in dogs [34].
Vildagliptin also increases fasting levels of intact GLP-1 and
GIP [23–26,30,31,35]. As shown in figure 3A, B, vildagliptin
doi:10.1111/j.1463-1326.2011.01414.x 777
review article DIABETES, OBESITY AND METABOLISM

A dinner
20.0 Placebo
Vildagliptin 100 mg

Intact GLP-1 (pmol/l)

15.0
dose

10.0

5.0

0.0
4:00pm 6:00pm 8:00pm 10:00pm 12:00am 2:00am 4:00am 6:00am 8:00am

B
80
Intact GIP (pmol/L)

60

40

20

0
4:00pm 6:00pm 8:00pm 10:00pm 12:00am 2:00am 4:00am 6:00am 8:00am

C 30 Vildagliptin 50 mg bid
Sitagliptin 100 mg qd
Intact GLP-1 (pmol/L)

25

20

15

10

0
-20 0 15 30 60 90 120 180 240 300 0 30 60 90 120 180 240 300 0 30 60 90 120 180 240 300 min

Breakfast Lunch Dinner

Figure 3. (A) Plasma levels of intact GLP-1 before and after a single dose of vildagliptin (100 mg) or placebo immediately before a standard dinner
meal in patients with T2DM. Patients were either drug-naı̈ve (n = 4), receiving concomitant metformin (n = 3), concomitant SU (n = 4) or both SU
and metformin concomitantly (n = 5). *p < 0.05 or better versus placebo. (B) Plasma levels of intact GIP before and after a single dose of vildagliptin
(100 mg) or placebo immediately before a standard dinner meal in patients with T2DM. Patients were either drug-naı̈ve (n = 4), receiving concomitant
metformin (n = 3), concomitant SU (n = 4) or both SU and metformin concomitantly (n = 5). *p < 0.05 or better versus placebo. (C) Plasma levels of
intact GLP-1 during a 24-h period, comprising three meals, in patients with T2DM continuing a stable dose of metformin, after 12-week treatment with
vildagliptin (50 mg twice daily) or sitagliptin (100 mg daily). *p < 0.05 or better, vildagliptin versus sitagliptin. GIP, glucose-dependent insulinotropic
polypeptide; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus. Adapted with permission from Ref. [36].

increased plasma levels of intact GLP-1 and GIP prior to food
intake, as well as in the postprandial period, and levels remained
significantly elevated throughout the overnight postabsorptive
period.
A comparison of the effect of sitagliptin with that of
vildagliptin on intact GLP-1 after meal ingestion (breakfast,
lunch and dinner) is shown in figure 3C. The immediate
increase in plasma levels was the same with the two DPP-
4 inhibitors. However, intact GLP-1 was maintained at a
higher level during the interprandial periods with vildagliptin
than with sitagliptin [36]. This can be explained by a nearly
complete inhibition of DPP-4 (∼90–95%) produced by the

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DIABETES, OBESITY AND METABOLISM
competitive inhibitor sitagliptin and by the complete (essen-
tially 100%) inhibition by the substrate-blocker vildagliptin.
This prolonged and complete inhibition of GLP-1 degrada-
tion also probably explains the increased fasting GLP-1 levels
seen with vildagliptin administration, discussed in the previous
section. Whether these differences in GLP-1 profiles result in
differences in long-term glycaemic control or in safety will
require head-to-head comparisons.
Pancreatic Effects
Effects of Vildagliptin on β-Cell Function
Vildagliptin increases HOMA-β and decreases (improves) the
proinsulin to insulin ratio [37], a marker of β-cell function
which suggests improved proinsulin processing [38]. A single
dose of vildagliptin increases plasma insulin levels per se when
given before a 75-g oral glucose tolerance test (OGTT) in
patients with T2DM [21], but not in healthy volunteers [39].
Vildagliptin improved insulin secretion in response to both
oral and intravenous (IV) glucose stimuli leading to no change
in the incretin effect [40]. Although not measured in that
study, the improved insulin response following IV glucose may
be explained by vildagliptin’s effect to increase fasting plasma
levels of intact GLP-1.
In a study of vildagliptin in metformin-treated patients with
inadequate glycaemic control, the ratio of the incremental area
under the curve (AUC) for C-peptide to the AUC for
glucose during standard meal tests was used as an index of
β-cell function. Insulin secretion (so defined) increased
by >30% after 12-week treatment and this was sustained
throughout 1 year of treatment [41]. In some efficacy and safety
trials with vildagliptin, standard meal tests were performed in
a subset of patients. Insulin secretory rate (ISR) was calculated
by deconvolution of C-peptide levels, and the AUC for ISR/
AUC for glucose (ISR/G) was used as a β-cell function
index. This was consistently found to be increased in patients
receiving vildagliptin in monotherapy [37] or as add-on to
metformin [42], glimepiride [43] or a thiazolidinedione [44].
Vildagliptin also increased ISR/G in subjects with IGT [32] and
in those with IFG [31]. Further, insulin secretion relative to
glucose (ISR/G) was increased significantly after a single dose
of vildagliptin given before the evening meal throughout the
entire overnight postabsorptive period [26].
When Mari Modeling was applied to data from a study
of drug-naı̈ve patients with T2DM and mild hyperglycaemia,
vildagliptin increased glucose sensitivity and rate sensitivity
as well as insulin secretory tone, but did not influence the
glucose-insensitive excursion of the potentiation factor [45].
Hence, according to this model, vildagliptin augments β-cell
function by increasing glucose sensitivity.
β-Cell function can also be assessed during IVGTTs;
improvements in the acute insulin response to IV glucose
have been seen following 6 weeks treatment with vildagliptin
in subjects with IFG [31] and after 12 weeks treatment with
vildagliptin in patients with T2DM (figure 4) [30].
β-Cell function was assessed as ISR/G during meal tests over
2 years with vildagliptin in patients with T2DM and mild
hyperglycaemia. ISR/G increased during 1-year treatment,
Volume 13 No. 9 September 2011
review article
Figure 4. Plasma insulin levels during intravenous glucose tolerance test
(glucose, 0.3 g/kg) in drug-naı̈ve patients with type 2 diabetes mellitus
before (open triangles) and after 12-week treatment with vildagliptin
(50 mg twice daily). *P < 0.05 or better vs comparator.
then declined during a first 4-week washout period, then
increased again during a second year treatment and again
declined during a second washout period. However, ISR/G
remained higher after the second washout period than when
measured at baseline, and was also higher than that measured
in a placebo-treated group (which declined over the >2-year
observation period) [46]. This suggests that although β-cell
function deteriorated in the placebo group, it was preserved by
vildagliptin.
Effects of Vildagliptin on α-Cell Function
A glucagonostatic effect of GLP-1 was noted in 1987, in the first
GLP-1 publication to suggest that this peptide was a physiolog-
ical incretin in humans. On the other hand, a stimulatory effect
of GIP on glucagon release was observed [2]. Interestingly,
30 years later, it was reported that inadequate suppression of
glucagon secretion during OGTT but not IVGTT contributes
to the impaired incretin effect seen in patients with T2DM [47].
As GIP infusion stimulates glucagon release while GLP-1 sup-
presses inappropriate glucagon secretion and because DPP-4
inhibition increases plasma levels of the intact forms of both
GLP-1 and GIP, it was of great interest to examine the effects
of DPP-4 inhibition on plasma glucagon levels.
Vildagliptin was found to suppress the inappropriate
glucagon response to oral glucose in patients with T2DM
(figure 5A) [21] as well as the glucagon response to a mixed
meal in patients with T2DM (figure 5B, E) [23,25,26], in
subjects with IGT [32] and in those with IFG [31]. The
glucagonostatic effect is sustained as evident by lowering of
meal-induced glucagon response also after 2 years of treat-
ment in subjects with T2DM [48]. In contrast, however, there
seems to be no effect of vildagliptin on glucagon levels in
normoglycaemic individuals [39].
Glucagon secretion may also be regulated by endogenous
insulin acting by the well-known paracrine or local endocrine
effects [49,50]. To determine whether vildagliptin’s effect to
decrease glucagon secretion during meals was simply due to
increased intra-islet insulin concentrations, vildagliptin was
doi:10.1111/j.1463-1326.2011.01414.x 779
review article DIABETES, OBESITY AND METABOLISM

A 380 B C
1200 60 p=0.039

Delta IRG during hypo (ng/L)

Glucagon AUC0-4h (ng/L*h)

Postprandial ΔIRG AUC

1000 50
360
+38%
**

(ng/L•min)
800 p=0.019 40

340 600 30
–41%
400 20
320
200 10

300 0 0
Placebo Vildagliptin 50 mg Placebo Vildagliptin Placebo Vildagliptin

D Placebo or Baseline
Vildagliptin –13.1%
125

2–Hr mean postprandial

glucagon (ng/L) 100 –12.0%

75

50
T1DM T2DM
E dinner
dose
20 Placebo (16)
Vildagliptin (16)
Delta Glucagon (ng/l)

–20
*
*
–40 *
* *
* *
–60 *
F
Delta Baseline Endogenous Ra (mg/kg/min)

0.50

0.25

0.00

–0.25

–0.50
* * * * *
–0.75 * * * * * * *

–1.00

–1.25 * *
** * *
–1.50
* ** * * * * * * *
–120 –60
4:00pm 0
6:00pm60 8:00pm
120 180 10:00pm
240 300 12:00am
360 420 2:00am
480 5404:00am
600 6606:00am
720 780 840
8:00am

Figure 5. (A) AUC0 – 4 h for plasma glucagon during OGTT in drug-naı̈ve patients with T2DM performed after single dose of vildagliptin (50 mg, closed
bar) or placebo (open bar). **p < 0.01 versus placebo. (B) AUC0 – 60 min for plasma glucagon during standard meal test in patients with T2DM after 28-day
treatment with vildagliptin (50 mg twice daily) or placebo. (C) Change in plasma glucagon levels during hypoglycaemic (glucose ∼2.5 mmol/l) clamp in
patients with T2DM after 28-day treatment with vildagliptin (50 mg twice daily) or placebo. (D) Two-hour mean postprandial glucagon concentrations
during standard breakfast meal tests performed in insulin pump-treated patients with T1DM or in drug-naı̈ve patients with T2DM who received placebo
or vildagliptin [100 mg twice daily (T1DM) or daily (T2DM)]. *P < 0.05 or better vs comparator. (E) Change from baseline (mean of all predinner values)
in plasma glucagon levels in patients with T2DM following single dose of vildagliptin (100 mg, closed triangles) or placebo (open circles) given before
standard dinner meal. *P < 0.05 or better vs comparator. (F) Change from baseline (mean of predinner/postdose values) in tracer-determined rate of
endogenous glucose production (Ra) in patients with T2DM following single dose of vildagliptin (100 mg, closed triangles) or placebo (open circles) given
before standard dinner meal. AUC, area under the curve; T2DM, type 2 diabetes mellitus; OGTT, oral glucose tolerance test.

780 Ahrén et al. Volume 13 No. 9 September 2011

DIABETES, OBESITY AND METABOLISM
studied in insulinopenic patients with T1DM. Vildagliptin was
found to suppress inappropriate glucagon secretion during
mixed meals in these patients with T1DM to the same extent
as seen in patients with T2DM (figure 5D), indicating that
vildagliptin’s effect to suppress the inappropriate glucagon
secretion was not secondary to increased insulin secretion [33].
This effect is not likely to be a direct effect of GLP-1 on the
α-cell, as GLP-1 receptors on pancreatic α-cells are scarce or
non-existent [51]. Rather, GLP-1’s glucagonostatic effects are
thought to be mediated by a local, paracrine effect of somato-
statin, stimulated by GLP-1, acting on the SSTR2 receptor on
α-cells [52].
In contrast to vildagliptin’s suppressive effect on inappro-
priate glucagon secretion in response to glucose or mixed
meals, vildagliptin enhances α-cell responsiveness to the stim-
ulatory effect of hypoglycaemia [53]. This can be appreciated in
figure 5B, D, E where under the hyperglycaemic condition of a
meal, glucagon levels were inhibited and under hypoglycaemia
induced by a hyperinsulinaemic hypoglycaemic clamp there
was a relative increase in the glucagon levels (figure 5C). The
increase in glucagon during hypoglycaemia may be explained
in part by glucose-sensitive GLP-1 inhibition of glucagon
secretion being attenuated or absent and glucose-sensitive GIP
stimulation of glucagon secretion being maximized. These
effects of vildagliptin could also be mediated in part via the
autonomic nervous system because the increase in glucagon
was accompanied by stimulation of pancreatic polypeptide
secretion (an index of vagal signalling to the pancreas). The
improved counterregulation may explain earlier findings that
hypoglycaemic episodes were less frequent and less severe
with vildagliptin versus placebo added to insulin therapy in
patients with T2DM [54,55]. Although exenatide enhanced
α-cell responsiveness to hypoglycaemia in normal individu-
als [56], the relative importance of GLP-1 versus stimulating
glucagon secretion through GIP remains to be determined.
Vildagliptin acutely suppressed EGP when administered
as a single dose before the evening meal in patients with
T2DM. As shown in figure 5F, there was a prompt suppression
of EGP during meal ingestion which was significantly
greater with vildagliptin than placebo administration, and
this was maintained throughout the overnight postabsorptive
period. The suppression of EGP seen following vildagliptin
administration was attributed to GLP-1-mediated suppression
of glucagon and stimulation of insulin secretion [26].
Extrapancreatic Effects
Vildagliptin was found to decrease the rate of fasting lipolysis as
indicated by a reduction of palmitate flux [25]. As vildagliptin
does not increase fasting insulin levels, and in animal studies,
both GLP-1 and GIP inhibit lipolysis, it is likely that this
effect of vildagliptin is a direct, incretin hormone-mediated
extrapancreatic effect. In contrast to the effect of vildagliptin
to reduce fasting lipolysis, vildagliptin showed an increase in
norepinephrine following meals, which was associated with
increased postprandial lipolysis in adipose tissue and increased
postprandial fat oxidation in muscle, suggesting that the fat
Volume 13 No. 9 September 2011
review article
accumulated in adipocytes during fasting is mobilized and
burned in muscle in the fed state [27].
Postprandial triglyceride (TG)-rich lipoprotein levels were
reduced with vildagliptin treatment compared with placebo and
baseline postmeal levels in vildagliptin-treated patients [24].
Reductions were observed in total serum TGs and chylomicron
TGs, reflecting reductions in chylomicron apolipoprotein B-48
(apo B-48) and chylomicron cholesterol. As chylomicrons are
the initial lipoproteins into which dietary TGs are packaged,
these findings suggest that vildagliptin may have an inhibitory
effect on fat absorption from the gut [57]. This effect is probably
to be GLP-1 receptor-mediated, as it was recently reported to
be seen with exenatide [58].
In patients with T2DM who received vildagliptin or placebo
for 10 days, vildagliptin had no effect on fed or fasting gastric
volume [29], gastric emptying or the rate of entry of ingested
glucose into the systemic circulation [28]. Vildagliptin was also
reported not to influence satiety or gastric volume [29].
After only 6 weeks of vildagliptin treatment there was a
significant increase in the glucose disposal during hyperinsuli-
naemic euglycaemic clamp [25]. This was due to an increase in
the glucose oxidation rate at the expense of fat oxidation and
was also associated with a decrease in fasting lipolysis. Decreas-
ing fasting lipolysis over 6 weeks is predicted to decrease stored
TG in non-fat tissues and may explain the increased glucose
oxidation during the clamp at expense of lipid oxidation. This
apparent reduced lipotoxicity with vildagliptin is not secondary
to reduced glucose toxicity, as the study was designed (low
baseline A1c) to minimize improvement in glycaemic control.
Summary
The DPP-4 inhibitor vildagliptin blocks the inactivation of
GLP-1 and GIP resulting in sustained elevations in plasma
levels of intact GLP-1 and GIP. Vildagliptin improves the sen-
sitivity of both the α- and β-cells to glucose leading to improved
glucose tolerance and reduced FPG. These effects largely explain
the improved A1c levels without increased hypoglycaemia asso-
ciated with chronic treatment [16]. In addition to the improved
insulin sensitivity associated with improved glycaemia, there is
improved insulin sensitivity due to reduced glucagon during
meals. Furthermore, with vildagliptin there is reduced lipo-
toxicity, secondary to reduced fasting lipolysis, which may be
mediated via increased fasting intact incretin hormone levels.
The glucose-sensitive regulation of the endocrine pancreas by
DPP-4 inhibitors presumably attenuates the defensive eating-
induced weight gain associated with SU therapy. Vildagliptin
reduces apo B-48 production and thus presumably fat extrac-
tion from the gut and mobilizes and burns fat during meals.
Vildagliptin’s effect to protect against hypoglycaemia appears
to be mediated by the enhanced glucagon response to hypogly-
caemia. Overall, the favourable profile of vildagliptin is due to
both pancreatic and extrapancreatic effects of GLP-1 and GIP.
Acknowledgements
The authors gratefully acknowledge the editorial and logisti-
cal assistance of Shruti Agarwal, Lakshmi Deepa and Ashwin
doi:10.1111/j.1463-1326.2011.01414.x 781
review article
Kittur. This work was funded by Novartis Pharmaceuticals
Corporation.
Drs B. A., J. E. F. and B. E. D. each contributed to the original
ideation as well as writing first drafts of different parts of this
review. Dr E. B. V. contributed medicinal chemistry expertise.
All authors have made substantial contributions to the editing
of the manuscript and Drs B. A., J. E. F., A. S. and S. D. were
also critical to conducting many of the clinical trials reviewed.
Conflict of Interest
B. A. has received research support, honoraria for speaking
engagements and served on advisory boards for Novartis. A. S.,
E. B. V. and J. E. F. are employed by and own shares in Novartis.
S. D. is employed by Novartis. B. E. D. received compensation
from Novartis for providing editorial support.
Drs. Ahrén, Foley and Dunning each contributed to the
original ideation as well as writing first drafts of different parts
of this review. Dr. Villhauer contributed medicinal chemistry
expertise. All authors have made substantial contributions to
the editing of the manuscript and Drs. Ahrén, Foley, Schweizer
and Dejager were also critical to conducting many of the clinical
trials reviewed.
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