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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 Background
The dipeptidyl peptidase-4 (DPP-4) inhibitors are among the GIP [1] and GLP-1 [2] represent the physiologically important
most recent additions to the therapeutic armamentarium avail- incretins in humans [3]. The finding that GLP-1 rendered
able for the treatment of type 2 diabetes mellitus (T2DM). glucose-insensitive β-cells glucose competent [4] made it an
The basis of the therapeutic efficacy of DPP-4 inhibitors lies attractive therapeutic target. However, the peptidic nature of
in their ability to increase circulating levels of the intact, GLP-1 together with its very short plasma half-life was hurdles
biologically active form of the incretin hormones, glucagon- that needed to be overcome in order to make use of the potential
like peptide-1 (GLP-1) and glucose-dependent insulinotropic therapeutic effects of GLP-1.
polypeptide (GIP), both of which have numerous metabol- Both GLP-1 and GIP are rapidly degraded in plasma, with
ically advantageous effects. With regard to mechanism(s) of half-lives of 2–5 min and 7–9 min, respectively [5,6]. When
action, vildagliptin is the DPP-4 inhibitor studied most thor- DPP-4 was identified as the enzyme responsible for the degrada-
oughly in clinical trials, and substantial progress has also tion and inactivation of both GLP-1 and GIP [7], the possibility
been made towards understanding the molecular interaction of creating an orally available inhibitor of DPP-4 became
between vildagliptin and the DPP-4 enzyme. The aim of this a realistic approach to leveraging the increasingly apparent
work is to review these mechanistic studies of vildagliptin and therapeutic utility of the incretin hormones [8].
to provide an integrated view of its mechanism of action in In 1995, Novartis showed that valine pyrrolidide, an orally
humans. Discussion of studies with other DPP-4 inhibitors active DPP-4 inhibitor which had been identified by its
will be limited to instances where there are differences in immunology group, lowered blood glucose levels in rodent
their respective mechanism of action that are supported by and non-human primate models of diabetes (unpublished).
head-to-head comparisons. 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
Correspondence to: Bo Ahrén, Department of Clinical Sciences, Lund University, B11 BMC,
SE-221 84 Lund, Sweden.
human proof of concept that a DPP-4 inhibitor could improve
E-mail: bo.ahren@med.lu.se 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 enzyme cannot act on any other substrate. Following dissoci-
catalytic site with a slow dissociation rate [11], rather than a ation of vildagliptin from the catalytic side, within a fraction
simple competitive inhibitor. Engineering of the structure in of a second, another vildagliptin molecule will interact with
order to further slow the dissociation rate led to the discovery the catalytic site. This leads to complete blocking of DPP-4
of the compound, LAF237 [12], now known as vildagliptin. activity over the entire time that vildagliptin drug levels are
As illustrated in figure 1A, vildagliptin’s nitrile group rapidly adequate to effectively associate with the catalytic site. This
forms a covalent bond with the catalytic site of DPP-4 to mechanism of enzyme inhibition is best characterized by the
form an imidate group, which stabilizes vildagliptin in the term substrate-like enzyme blocker or ‘substrate-blocker’.
catalytic site of DPP-4 and facilitates hydrolysis of this imidate Medicinal chemistry work around another chemical class
group. Inactive vildagliptin then slowly dissociates from the of molecules resulted in the competitive DPP-4 inhibitor,
catalytic site with a half-life (k2 ) of about 1 h [13]. Although sitagliptin [14]. In contrast to the substrate-blockers, a
vildagliptin is covalently bound to the DPP-4 catalytic site, the competitive inhibitor follows simple Michaelis–Menton
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
Figure 2. (A) Fast binding nature of sitagliptin. Inhibition studies with IGT [32], IFG [31] and in patients with T1DM [33]. In
performed by the addition of enzyme to preincubated mixture of substrate general, the magnitude of the increase in postprandial plasma
and various concentrations of sitagliptin (0, 5, 12.5, 25, 50 and 125 nM levels of intact GLP-1 or GIP with any of the DPP-4 inhibitors
final). (B) Sitagliptin inhibition is reversible. The human recombinant
is a two- to threefold increase, but the absolute concentrations
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
in the portal vein are undoubtedly much higher than those
H-Gly-Pro-AMC and the DPP-IV activity was measured. Both A and B measured in the periphery, as indeed shown with vildagliptin
represent one experiment (n = 3). DPP-4, dipeptidyl peptidase-4; RFU, in dogs [34].
relative fluorescence units (proportional to enzyme activity); VC, vehicle Vildagliptin also increases fasting levels of intact GLP-1 and
control. Adapted with permission from Ref. [15]. GIP [23–26,30,31,35]. As shown in figure 3A, B, vildagliptin
A dinner
20.0 Placebo
Vildagliptin 100 mg
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
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 lunch and dinner) is shown in figure 3C. The immediate
intake, as well as in the postprandial period, and levels remained increase in plasma levels was the same with the two DPP-
significantly elevated throughout the overnight postabsorptive 4 inhibitors. However, intact GLP-1 was maintained at a
period. higher level during the interprandial periods with vildagliptin
A comparison of the effect of sitagliptin with that of than with sitagliptin [36]. This can be explained by a nearly
vildagliptin on intact GLP-1 after meal ingestion (breakfast, complete inhibition of DPP-4 (∼90–95%) produced by the
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
Figure 4. Plasma insulin levels during intravenous glucose tolerance test
dose of vildagliptin increases plasma insulin levels per se when (glucose, 0.3 g/kg) in drug-naı̈ve patients with type 2 diabetes mellitus
given before a 75-g oral glucose tolerance test (OGTT) in before (open triangles) and after 12-week treatment with vildagliptin
patients with T2DM [21], but not in healthy volunteers [39]. (50 mg twice daily). *P < 0.05 or better vs comparator.
Vildagliptin improved insulin secretion in response to both
oral and intravenous (IV) glucose stimuli leading to no change then declined during a first 4-week washout period, then
in the incretin effect [40]. Although not measured in that increased again during a second year treatment and again
study, the improved insulin response following IV glucose may declined during a second washout period. However, ISR/G
be explained by vildagliptin’s effect to increase fasting plasma remained higher after the second washout period than when
levels of intact GLP-1. measured at baseline, and was also higher than that measured
In a study of vildagliptin in metformin-treated patients with in a placebo-treated group (which declined over the >2-year
inadequate glycaemic control, the ratio of the incremental area observation period) [46]. This suggests that although β-cell
under the curve (AUC) for C-peptide to the AUC for function deteriorated in the placebo group, it was preserved by
glucose during standard meal tests was used as an index of vildagliptin.
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 Effects of Vildagliptin on α-Cell Function
trials with vildagliptin, standard meal tests were performed in A glucagonostatic effect of GLP-1 was noted in 1987, in the first
a subset of patients. Insulin secretory rate (ISR) was calculated GLP-1 publication to suggest that this peptide was a physiolog-
by deconvolution of C-peptide levels, and the AUC for ISR/ ical incretin in humans. On the other hand, a stimulatory effect
AUC for glucose (ISR/G) was used as a β-cell function of GIP on glucagon release was observed [2]. Interestingly,
index. This was consistently found to be increased in patients 30 years later, it was reported that inadequate suppression of
receiving vildagliptin in monotherapy [37] or as add-on to glucagon secretion during OGTT but not IVGTT contributes
metformin [42], glimepiride [43] or a thiazolidinedione [44]. to the impaired incretin effect seen in patients with T2DM [47].
Vildagliptin also increased ISR/G in subjects with IGT [32] and As GIP infusion stimulates glucagon release while GLP-1 sup-
in those with IFG [31]. Further, insulin secretion relative to presses inappropriate glucagon secretion and because DPP-4
glucose (ISR/G) was increased significantly after a single dose inhibition increases plasma levels of the intact forms of both
of vildagliptin given before the evening meal throughout the GLP-1 and GIP, it was of great interest to examine the effects
entire overnight postabsorptive period [26]. of DPP-4 inhibition on plasma glucagon levels.
When Mari Modeling was applied to data from a study Vildagliptin was found to suppress the inappropriate
of drug-naı̈ve patients with T2DM and mild hyperglycaemia, glucagon response to oral glucose in patients with T2DM
vildagliptin increased glucose sensitivity and rate sensitivity (figure 5A) [21] as well as the glucagon response to a mixed
as well as insulin secretory tone, but did not influence the meal in patients with T2DM (figure 5B, E) [23,25,26], in
glucose-insensitive excursion of the potentiation factor [45]. subjects with IGT [32] and in those with IFG [31]. The
Hence, according to this model, vildagliptin augments β-cell glucagonostatic effect is sustained as evident by lowering of
function by increasing glucose sensitivity. meal-induced glucagon response also after 2 years of treat-
β-Cell function can also be assessed during IVGTTs; ment in subjects with T2DM [48]. In contrast, however, there
improvements in the acute insulin response to IV glucose seems to be no effect of vildagliptin on glucagon levels in
have been seen following 6 weeks treatment with vildagliptin normoglycaemic individuals [39].
in subjects with IFG [31] and after 12 weeks treatment with Glucagon secretion may also be regulated by endogenous
vildagliptin in patients with T2DM (figure 4) [30]. insulin acting by the well-known paracrine or local endocrine
β-Cell function was assessed as ISR/G during meal tests over effects [49,50]. To determine whether vildagliptin’s effect to
2 years with vildagliptin in patients with T2DM and mild decrease glucagon secretion during meals was simply due to
hyperglycaemia. ISR/G increased during 1-year treatment, increased intra-islet insulin concentrations, vildagliptin was
A 380 B C
1200 60 p=0.039
(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
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.
Kittur. This work was funded by Novartis Pharmaceuticals 11. Hughes TE, Mone MD, Russell ME, Weldon SC, Villhauer EB.
Corporation. NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-
Drs B. A., J. E. F. and B. E. D. each contributed to the original cyano-(S)-pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV.
Biochemistry 1999; 38: 11597–11603.
ideation as well as writing first drafts of different parts of this
review. Dr E. B. V. contributed medicinal chemistry expertise. 12. Villhauer EB, Brinkman JA, Naderi GB et al. 1-[[(3-hydroxy-1-adamantyl)
amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally
All authors have made substantial contributions to the editing
bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic
of the manuscript and Drs B. A., J. E. F., A. S. and S. D. were properties. J Med Chem 2003; 46: 2774–2789.
also critical to conducting many of the clinical trials reviewed.
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Conflict of Interest dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr
B. A. has received research support, honoraria for speaking Top Med Chem 2007; 7: 557–568.
engagements and served on advisory boards for Novartis. A. S., 15. Davis JA, Singh S, Sethi S et al. Nature of action of sitagliptin, the dipeptidyl
E. B. V. and J. E. F. are employed by and own shares in Novartis. peptidase-IV inhibitor in diabetic animals. Indian J Pharmacol 2010; 42:
S. D. is employed by Novartis. B. E. D. received compensation 229–233.
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original ideation as well as writing first drafts of different parts 463–484.
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