Review Article

Emerging Role of Dipeptidyl Peptidase-IV (DPP-4)

Inhibitor Vildagliptin in the Management of Type 2
Diabetes
Sanjay Kalra*
Abstract
Diabetes mellitus (DM) is one of the most common chronic disorders, with increasing prevalence worldwide.
Type 2 diabetes (T2DM), a multifaceted disease involving multiple pathophysiological defects, accounts for nearly
8595% of total reported cases of DM. Chances of developing T2DM are increased by obesity and physical inactivity
and are augmented further with age. Two most important unmet needs associated with the management of T2DM
are the lack of lasting efficacy in reducing hyperglycemia and failure to target primary causes. Different classes
of Oral Hypoglycemic Agents (OHAs) with nearly equipotent efficacy are now available targeting the different
pathophysiologic factors contributing to T2DM; however, almost all of them are associated with one or the other
kind of adverse effect. Several studies have found that certain diabetes drugs may carry increased cardiovascular
(CV) risks compared to others. The new approach in management of T2DM based upon the effects of incretin
hormones; Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Vildagliptin
is a drug from a new class of medications called dipeptidyl peptidase IV (DPP4) inhibitors. By inhibiting DPP-4,
vildagliptin causes an increase in GLP-1, an intestinal hormone that aids in glucose homeostasis and insulin
secretion. Vildagliptin has a half-life of about 90 minutes; however, 50% of DPP4 inhibition continues for more
than 10 hours, allowing for once- or twice-daily dosing. Clinical trials have shown that vildagliptin is effective
in significantly lowering glycosylated hemoglobin (HbA1c), fasting plasma glucose, and prandial glucose levels.
-cell function may also be improved. The drug has placebo like tolerability and rate of hypoglycemia events.
Vildagliptin expands non-injectable treatment options available for management of T2DM patients, who are
poorly controlled with monotherapy.

Introduction

iabetes mellitus (DM) is one of the most common chronic

disorders attaining epidemic proportions worldwide. The
prevalence of diabetes is rapidly rising globally at a distressing
rate, affecting both developed and developing countries alike.
Worldwide DM is currently estimated to affect 285 million
(6.4%) adults aged 2079 years and this number is projected to
increase to 439 million (7.7%) adults by the year 20301. Diabetes
Atlas 2009 published by the International Diabetes Federation
estimated diabetic population in India to around 50.8 million,
which is expected to rise to 87 million by 2030,1 earning India
the dubious distinction of being called the diabetes capital of
the world. Type 2 diabetes (T2DM) accounts for nearly 8595%
of total reported cases of diabetes2. T2DM is a multifaceted
disease involving multiple pathophysiological defects, including
impaired islet function and insulin resistance, which results in
impaired glucose tolerance and inappropriately high fasting
hepatic glucose production. Chances of developing T2DM are
increased by obesity and physical inactivity and are further
augmented with age.

for metabolic control of patients with T2DM, but with course of

time this approach alone is insufficient to attain glycemic control,
calling for introduction anti-hyperglycemic pharmacotherapy.
Different classes of Oral Hypoglycemic Agents (OHAs) are
now available that target the different pathophysiologic factors
contributing to T2DM:a-glucosidase inhibitors to delay intestinal
carbohydrate absorption, biguanides to target hepatic insulin
resistance, insulin sensitizers or thiazolidinediones (TZDs)
to target adipocyte and muscle insulin resistance and insulin
secretagogues or sulfonylureas (SU) to increase pancreatic
insulin secretion.6 These compounds have nearly equipotent
efficacy; however, almost all of them are associated with one or
the other kind of adverse effect.7
An alternative approach based on targeting incretin
hormones, founded on better understanding of their potential
has in turn led to the development of incretin analogs and
incretin enhancers for treatment of T2DM. In this article we
will review the pharmacology, clinical efficacy and role of
incretin enhancer vildagliptin, a potent and selective inhibitor
of dipeptidyl peptidase-4 (DPP-4) in the management of T2DM.

Two most important unmet needs associated with the

management of T2DM are the lack of lasting efficacy in reducing
hyperglycemia and failure to target primary causes. Poor
glycemic control accounts for much of the morbidity, mortality
and economics associated with T2DM. 3-5 Though Lifestyle
modification (Exercise, dietary management) provides the basis

Present Treatment Regimes and

Cardiovascular Risks
In the past, several studies have found that certain diabetes
drugs may carry increased cardiovascular (CV) risks compared
to others. A recent study of over 90,000 T2DM patients compared
the CV effects in individuals treated with either metformin or SU.

Consultant Endocrinologist and Diabetologist, Bharti Hospital, Wazir

Chand Colony, Kunjpura Road, Karnal, Haryana - 132 001
Received: 02.09.2010; Revised: 01.11.2010; Accepted; 07.12.2010

JAPI april 2011 VOL. 59

237

These researchers found an increased likelihood of death from

any cause in the patients treated with SU (24-61% increased risk
depending on the specific drug), along with an increased risk of
congestive heart failure (18-30%).8 These results reinforced the
similar findings of a 2006 study and an earlier 2009 study.9 Also
concerns have been raised about CV risks associated with TZDs,
which are increasingly being used to treat T2DM. Rosiglitazone
monotherapy was found to be associated with higher risk for any
CV event (HR 1.89; 95%CI 1.57, 2.28)10 and significant increase
in the risk of myocardial infarction (43%),11 moreover as add-on
rosiglitazone and pioglitazone were associated with comparable
CV risk.10
SU were the first widely used OHAs and have been available
in the United States since 1954 and still remain a cornerstone of
T2DM therapy. Second-generation SUs (glyburide, glipizide,
and glimepiride) are more potent and probably safer than firstgeneration SUs (chlorpropamide, tolbutamide, acetohexamide
and tolazamide) but essentially of equal efficacy.12 Unfortunately,
SUs do not always succeed in controlling diabetes. With SU
therapy, some 10%-20% of people will immediately fail to
control their blood glucose levels adequately on the highest
recommended dose (Primary failure). 13 Another concern
with SUs is their tendency to overwork the pancreas until it
eventually exhaust -cell function and is unable to secrete an
adequate amount of insulin, so roughly 5% to 10% of people
who initially respond to SU therapy will subsequently fail each
year (Secondary failure).7,13
The utmost practical concern of SU therapy is associated with
two common adverse effects, weight gain and hypoglycemia.
About 80% to 90% of people with diabetes are obese and SUs tend
to make them gain even more weight, typically from 2 to 5 kg and
SU associated hypoglycemia affects the elderly with worsening
renal function and irregular meal schedules.14-16 Jennings et al
demonstrated that up to 20% of patients taking oral SU agents
experience symptoms consistent with hypoglycemia over a
6-month period.17 Seltzer et al in a comprehensive retrospectively
review of 1418 cases of severe drug-induced hypoglycemia,
identified SU ingestion, advanced age and fasting as the major
risk factors for the development of hypoglycemia requiring
hospitalization. Specifically, SU ingestion was a factor in 65% of
adult cases and 86% of these cases were of patients older than
50 years.18 Hypoglycemia results in significant morbidity and in
younger patients with T2DM (aged from 2049 years), between 6
and 18% of deaths have been attributed to hypoglycemia.19 Case
fatality rates of 4%10% have been reported with SUs, with about
5% of survivors having permanent neurological impairment.20
Although much attention has been paid to neurologic
consequence of SUs induced hypoglycemia but its CV side effect
can not be overlooked. In addition to this weight gain associated
with SUs is also marker of increased CV risk, which is the main
cause of death in people with T2DM.21 Ischemic preconditioning
in human myocardium relies on KATP channels, which plays an
important role in regulation of coronary blood flow but also
protect cardiac cells from ischaemia/reperfusion injury. However
in diabetic patients KATP channel function are already impaired
and the long-term inhibition of KATP channels with KATP channel
inhibitors like older generation SUs, especially the ones with
less selectivity, may explain the excess CV mortality in these
patients. The ACCORD study has reported an increased CV risk
and total mortality associated with intensive glucose control,22
with an excess of fatal vascular events being associated with
a higher frequency of severe hypoglycemia. Hypoglycemia
secondary to insulin and SU therapy is often associated with
238

serious morbidity; anecdotal evidence has long implicated

hypoglycemia as a potential cause of myocardial ischaemia or
a cardiac arrhythmia.23
A new study has found that SUsthe mainstay of glucose
control in T2DM, increase the risk of both CV and all-cause
mortality. The researchers found higher daily doses of first and
second-generation SUs increased mortality risk by more than
200% and 30%-40%, respectively.24 Even though cardiotoxic effect
of SUs therapy has been debated for long, studies have provided
pathophysiological plausibility as SUs appear to aggravate the
hypoxaemic damage to the myocardium in the case of coronary
occlusion or artery disease.25 Furthermore every SU drug
needs to be studied individually for its effectiveness and safety
vis--vis the relevant endpoints for T2DM, i.e. cv morbidity
and mortality, rather than being limited to surrogate markers

New Approach in Management of

T2DM
The new approach in management of T2DM is based upon
the effects of incretin hormones; Glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic peptide (GIP),
gastrointestinal hormones released from -cells of the islets of
Langerhans into the bloodstream primarily in response to meal
ingestion. They enhance meal-induced insulin secretion and play
an important part in maintenance of normal glucose homeostasis
by a process termed as incretin effect. GLP-1 has also shown
to suppress glucagon secretion, slow gastric emptying, reduce
food intake and body weight.26-27 In T2DM patients, reduced
incretin effect combined with constant decline in pancreatic
and a-cell function leads to progressive loss of glycemic control.
This decline in and a-cell function is evident as progressive
loss of glucose-dependent insulin release and as a progression
to unregulated glucagon production, respectively.
In T2DM effects of GLP-1 functions are preserved and
in contrast GIP secretion remains normal but with reduced
insulinotropic effect, giving rise to hypothesis that reducing
degradation of GLP-1 may compensate for its decreased secretion
in T2DM.23 However the role of GLP-1 and GIP in glucose
regulation is limited because of their short half life, since they
are rapidly degraded and inactivated by the enzyme dipeptidyl
peptidase 4 (DPP-4), resulting in loss of their insulinotropic
activity.28
Two approaches have been developed to negate this problem
and prolong duration of GLP-1 action. One is the development
of long-acting stable analogues of GLP-1, which maintains the
physiologic effect of native GLP-1 but is resistant to action of
DPP-4, so-called Incretin Mimetics and second, inhibition of
DPP-4 using low molecular weight inhibitors which decrease
the inactivation of GLP-1, thereby increasing its concentration
as well as its duration of action on target tissue, called Incretin
Enhancers.29-30 This approach was first encapsulated by Holst
and Deacon, who showed that DPP-4 inhibition increases
circulating levels of GLP-1 in experimental animals and that
the insulinotropic action of exogenously administered GLP-1 is
augmented by DPP-4 inhibition.31 Later studies demonstrated
that the prevention of inactivation of GLP-1 by DPP-4 inhibition
markedly increases the active GLP-1 in the circulation.
As a therapeutic application in T2DM, the prolongation of the
endogenous GLP-1 and GIP effect produced by DPP-4 inhibition
has several advantages compared with conventional therapies
and newer GLP-1 analogues. Also being small molecule DPP-4
JAPI april 2011 VOL. 59

Table 1: Comparison of Incretin Enhancers and

Incretin Mimetics32-35
Incretin Enhancers
Differences
Orally available
Multiple targets
GLP-1 PK favorable
Short vs. long acting
Drug overdose nontoxic
Mild CNS side effects
Mild nausea and vomiting
Commonalities
Lower risk of hypoglycemia
than insulin
Induces satiety and weight
loss
Improves -cell function
Increases glucose dependent
insulin secretion
Decreases glucagon secretion

Incretin Mimetics

Mixed meal

Intestinal
release of GLP-1

Lower risk of hypoglycemia

than insulin
Induces satiety and weight
loss
Improves -cell function
Increases glucose dependent
insulin secretion
Decreases glucagon secretion

Active GLP-1

Inhibition
DPP-4

Inactivation of
GLP-1 blocked

DPP-4

Inactive GLP-1

Fig. 1 : Vildagliptin (chemical structure is based on the common

design for DPP-4 inhibitors: a L-amino acid with a protonable
N-terminal primary amine in the P-2 site) exhibits high-affinity,
reversible, DPP-4 inhibition resulting in increased levels of active

inhibitors are orally available and relatively free from side effects
(Table 1), with ability of potentiating the actions of GLP-1 as
well as GIP.32-35 Oral DPP-4 inhibitors, therefore, represent a
potentially important addition to the oral treatment options
currently available for the management of T2DM.

with any type of meal.43

Plasma concentrations of vildagliptin increase in an
approximately dose-dependant manner; the absolute
bioavailability of the drug is 85%. Vildagliptin is primarily
metabolized in the kidney to inactive cyano and amide
metabolites and approximately 85% of the drug is eliminated
in the urine (2123% as the unchanged drug) and 15% into the
faeces,43,45 with a terminal elimination half life of approximately 3
hours following oral administration, irrespective of drug dosage
or food intake.41

Vildagliptin
The DPP-4 inhibitor vildagliptin is approved in the Europe
for the treatment of T2DM. It is a potent, selective and orally
active 2nd generation inhibitor of DPP-4, with a reversible and
competitive mechanism of action (MOA) that binds and forms
a complex with DPP-4, causing its inhibition.36 This results
in improved glycemic control as determined by glycosylated
haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels
plus an enhancement of pancreatic a-and -cell function.
Structurally, vildagliptin is 1-([(3-hydroxy-1-adamantyl) amino]
acetyl)-2-cyano-[S]-pyrrolidine. Its molecular weight is around
303.41 gm.

Therapeutic Efficacy
The unique action of Vildagliptin, a second member of
DPP-IV inhibitor class of drugs, has encouraged new outlook in
treatment and pathobiology of T2DM. The therapeutic efficacy
of oral vildagliptin once-daily (OD) or twice-daily (BID) has
been investigated as monotherapy, in placebo-controlled or
active comparator-controlled trials in drug naive patients or in
combination with metformin pioglitazone, glimepiride or insulin
in treatment-experienced patients. The trials were randomised,
double-blind, placebo or active comparator controlled,
multicentre studies in patients with T2DM (n =71780).42 The
mean age of the patients was 5359 years. Mean duration of
diabetes, where stated, was 2.04.7 years in the monotherapy
trials and 4.66.2 years in the combination studies.46 BID dosages
where stated were administered at breakfast and dinner, whereas
as OD dosage was administered before breakfast. 39 Mean
baseline HbA1c of patients considered for monotherapy was
between 6.27.5%.42 FPG baseline means were 8.810.3 mmol/L
in all studies.46 The primary efficacy endpoint for all trials was
change in HbA1c levels. Other endpoints included FPG, PPG,
bodyweight and blood lipids

Pharmacologic Overview
The effect of vildagliptin in humans is reflected by the 50%
inhibitory constant (IC50 4.5 nmol/L) of DPP-4 inhibition, which
is more potent than that reported for another DPP-4 inhibitor,
sitagliptin (IC50 26 nmol/L).37-38 Vildagliptin has demonstrated
the ability to inhibit DPP-4, increase plasma concentrations of
intact GLP-1 and GIP, reduce FPG and postprandial glucose
(PPG) and suppress plasma glucagon in clinical trials in T2DM
patients.39-41 The drug improves hyperglycemia primarily by
prolonging the half-lives of GLP-1 and GIP, thus enhancing their
action on islet cells and promoting glucose-dependent insulin
secretion and suppression of inappropriate glucagon secretion.
Vildagliptin appears to attenuate the decline in glucosedependent -cell function and improve insulin sensitivity, and
also to enhance the sensitivity of -cells to glucose.42
Drug is quickly absorbed after oral administration, reaching
peak plasma concentrations (Cmax) achieved in a time (tmax)
of 1.51.7 hours after administration.43-45 Although the tmax is
delayed to 2.5 hours and Cmax reduced by 19% when drug is
administered with a high-fat meal, however these effects are not
thought to be of any clinical significance and drug can be taken
JAPI april 2011 VOL. 59

HO

Injectable
Single known target
Higher levels of GLP-1
Longer acting, daysweeks
Drug overdose, a concern
Potential for side effects
Increased levels of nausea
and vomiting

Monotherapy
In a randomised, placebo-controlled, phase II trials (n=27939
and 9840), considerably greater reduction in HbA1c levels from
baseline was seen with Vildagliptin 50mg (between-group

239

difference;0.43%39 and 0.6%40) and 100mg (0.4%39) daily,

compared with placebo (all p0.004) after 12 weeks treatment.3839
In one of the dose-finding study in Japanese patients
(n=291), 12 weeks of vildagliptin 10, 25 or 50mg BID treatment
significantly reduced HbA1c levels by 0.53%, 0.67% and 0.92%
respectively (p<0.001 vs. placebo) from baseline levels of 7.4%.
Similarly, plasma FPG and 2-hour PPG levels were significantly
reduced with all vildagliptin dosages.47 Furthermore, 12 weeks
vildagliptin 50mg BID (n=188) was shown to be more effective
than Voglibose 0.2mg three times daily (TID) (n=192) in reducing
HbA1c levels in Japanese patients, with a mean between-group
difference of 0.6% (95%CI;0.68 to 0.46%; p<0.001) amid this
vildagliptin provided a significantly greater response rate in
achieving HbA1c levels of 6.5% compared with voglibose
(50.8% vs. 24.2%;p<0.001).48

Furthermore decrease in mean FPG levels after 24 week

treatment with vildagliptin 50mg BID were -0.856 and -1.255
mmol/L and -1.056 and -0.555 mmol/L with vildagliptin 50mg OD,
which were significantly greater compared to placebo. Data from
the pooled analysis of vildagliptin 50mg BID (n=1135) indicated
a significant (p<0.05) reduction of 1.08 mmol/L from a mean
baseline FPG of 10.3 mmol/L after 24 weeks.57 However in active
comparator trials reduction in baseline FPG were significantly
greater with rosiglitazone51 or metformin54 (both p=0.001), than
with vildagliptin 50mg BID though it significantly reduced FPG
levels from baseline. But noninferiority of vildagliptin 50mg BID
when compared to acarbose 300 mg/day in reducing FPG levels
was not established after 24 weeks of treatment.50

In study of diet-treated T2DM subjects, monotherapy with

vildagliptin 25mg BID (n=70) was well tolerated and significantly
improved glycemic control in comparison to placebo (n=28).
Between-group difference in adjusted mean change in HbA1c
from baseline to endpoint was -0.60.2% (p=0.0012) for the
whole cohort (baseline HbA1c 8.0%) and -1.2% for subjects
with baseline HbA1c of 8.0-9.5%. Associated improvements
in -cell function were also observed with vildagliptin 25mg.49
In the active comparator trials, the reduction from baseline
mean HbA1c levels with vildagliptin 50mg BID in drug-naive
T2DM patients was non-inferior to that with acarbose 300mg/
day50 or rosiglitazone 8mg OD,51 after 24 weeks of treatment. A
pooled analysis of five trials further confirmed that dosages of
vildagliptin 50mg BID (n=1138) provides a significant (p<0.05)
reduction of 1.0% from a mean baseline HbA1c of 8.7% after 24
weeks.52

Vildagliptin has been evaluated in randomized, double-blind

trials as add-on therapy to metformin, SU, TZDs and insulin
treatment and in initial combination with pioglitazone.

In a 52 week study conducted to evaluate efficacy and

tolerability of vildagliptin 50mg OD in 306 drug-nave T2DM
patients with mild hyperglycemia, vildagliptin 50mg OD
significantly reduced HbA1c, FPG and PPG and improved -cell
function without weight gain or hypoglycemia.53 In patients
with baseline HbA1c>8%, reductions in HbA1c was 1.1% with
vildagliptin 50mg BID and 1.7% with metformin 2000mg/day,
whereas in patients with baseline HbA1c 8%, the reductions
were 0.6% and 0.7% respectively.52 Also the effect of vildagliptin
50mg OD was shown to be dose-related in the higher baseline
group (HbA1c >8%) in two placebo controlled trials.55-56
Clinical guidelines for the management of T2DM recommend
target level of HbA1c to be between 6.5% and 7.5%, to reduce
risk of CV complications. The overall population achieving
HbA1c levels of <7% ranged from 30% to 46%, following
treatment with vildagliptin 50mg.50,52,54,55 In addition, data from
pooled monotherapy trials57 indicated that 65% of vildagliptin
recipients achieved an HbA1c reduction of >0.7%. A doubleblind, randomized, multicentre, active-controlled, parallelgroup study evaluated comparative efficacy and tolerability of
the vildagliptin (100mg daily, n=169) and metformin (titrated
to 1500mg daily, n=166) in drug-nave elderly (65 yrs.) T2DM
patients, with prime objective of demonstrating non-inferiority
of vildagliptin vs. metformin in HbA1c reduction. Vildagliptin
was as effective as metformin, improving HbA1c by -0.640.07%
and -0.750.07% respectively, meeting the predefined statistical
criterion for non-inferiority. This study established that the
Vildagliptin is an effective and well-tolerated treatment option
in elderly patients with T2DM, showing similar improvement
in glycemic control as metformin, with superior Gastrointestinal
(GI) tolerability.58

240

Combination Therapy

The mean age of enrolled patients across all combination

trial was 5460 years with a mean BMI of 3133 kg/m2, mean
duration of T2DM 4.614.9 years and mean HbA1c and FPG
levels at baseline ranging between 6.5-10% and 8.711.0mmol/L
respectively. Vildagliptin and metformin were administered as
separate agents in all the trials.59-68 Out of this Four trial were
placebo controlled59-61,63 and one each had pioglitazone63 and
TZDs65 and two had glimepiride64,66 as comparative agent. In
T2DM patients Vildagliptin achieved greater glycemic control
as compared with placebo, as an add-on to metformin, 59
pioglitazone60 and glimepiride61 therapy and was as effective
as pioglitazone (noninferiority established), when added
to metformin but without weight gain as associated with
pioglitazone therapy.62
In a comparative trial evaluating effect of vildagliptin
50mg BID to glimepiride up to 6mg OD on prandial glucagon
levels, as add on therapy to metformin in T2DM patients
inadequately controlled by metformin mono therapy. Prandial
glucagon levels decreased by 3.41.6 pmol.h/L by vildagliptin
(n=137) and increased by 3.81.7pmol.h/L by glimepiride
(n=121), with between-group difference of 7.32.1 pmol.h/L
(P<0.001). This established that vildagliptin 50mg significantly
improves postprandial alpha-cell function when compared to
SU glimepiride.64 Another trial evaluated non-inferiority of
vildagliptin vis--vis glimepiride in reducing HbA1c levels as
add-on to metformin over the period of 2 years. Result from
study showed that Vildagliptin as add-on to metformin had
similar efficacy as that of glimepiride, but with markedly reduced
hypoglycemia risk and no weight gain, with more patient
on vildagliptin therapy reaching target (HbA1c<7%) without
hypoglycemia when compared to glimepiride (36.0% vs. 28.8%;
p=0.004).65 Similar results were shown in a 52-week, randomized,
double-blind, active-controlled study demonstrating noninferiority of vildagliptin in comparison with gliclazide, as an
add-on therapy in T2DM patients inadequately controlled with
metformin. Similar proportion of patients reached HbA1c <7.0%,
but the total number of hypoglycemic events were lower in the
vildagliptin group (6 vs. 11 events); moreover vildagliptin did
not induce weight gain. Also the number of AEs were similar in
both groups but the number of SAEs was higher in the gliclazide
group (8.7 vs. 6.7%).66
Addition of Vildagliptin 50mg OD or BID to existing oral
therapy or insulin therapy produced significantly greater
reduction in HbA1c baseline levels as compared to placebo;
JAPI april 2011 VOL. 59

with rare treatment related discontinuations.43

which were 0.5,59 0.860 and 0.663 for Vildagliptin 50mg OD

and 0.9,591.060 and 0.662 for Vildagliptin 50mg BID. In an
extension of the vildagliptin plus insulin trial60 the reduction
in HbA1c seen with vildagliptin at 24th week was sustained at
week 52.63 When added to metformin, the reduction in mean
baseline HbA1c with Vildagliptin 50mg BID (-0.90.1%) was
noninferior to pioglitazone 30mg OD (-1.00.1%), after 24
weeks of treatment.62 The mean HbA1c of <7% was achieved in
considerably more recipients of vildagliptin 50mg OD or BID
than placebo recipients when administered as adjuvant therapy
to pioglitazone (28.7% or 36.4% vs 14.8%)59 or glimepiride (21.2%
or 24.8% vs 12%)63 (all p < 0.05).

AEs were reported by 5570% of vildagliptin recipients,

5974% of placebo recipients, 3475% of active comparator
recipients (metformin, pioglitazone, rosiglitazone and insulin
with or without matching placebo) and 2669% of vildagliptin
plus active comparator (metformin, pioglitazone and insulin)
recipients. 46 The most common AEs reported in patients
receiving vildagliptin during clinical trials included headache,
nasopharyngitis, cough, constipation, dizziness, and increased
sweating.
The pooled monotherapy data showed that frequency of AEs
in patients with normal renal function compared to patients with
mild renal impairment did not differ significantly in recipients
of vildagliptin 50 mg OD (54.3% vs. 55.2%), vildagliptin 50 mg
BID (60.3% vs. 65.3%) rosiglitazone 8 mg/day (64.9% vs. 61.5%),
pioglitazone 30 mg/day (50.4% vs. 48%) or placebo (63.8% vs.
57.4%).70

Galiant trial compared efficacy and tolerability of vildagliptin

100mg with TZDs (agent and dose at the investigators discretion)
as add on therapy to stable dose of metformin (1000 mg/day),
in T2DM patients with inadequately controlled HbA1c (7-10%).
The mean change in HbA1c from baseline was -0.680.02%
and -0.570.03% in vildagliptin and TZD group respectively.
Between the groups difference was -0.11% (95%CI:-0.17% and
-0.04%), establishing the non-inferiority of vildagliptin (p=0.001)
after 3 months of treatment.67 In a 52 week interim analysis of
large randomized, double-blind, multicentre study, examining
the efficacy and safety of vildagliptin vs. glimepiride as add-on
therapy in patients inadequately controlled on metformin
monotherapy (HbA1c 6.5-8.5%). Mean change from baseline
HbA1c (7.3%) at week 52 endpoint was -0.44% (0.02%) and
-0.53% (0.02%) with vildagliptin and glimepiride respectively,
demonstrating non-inferiority of vildagliptin (97.5% CI; 0.02%,
0.16%), but a greater proportion of patients reached this target
without hypoglycemia in the vildagliptin group (50.9 vs. 44.3%;
p<0.01).68

Cardio and Cerebrovascular Safety

Cardiovascular and cerebrovascular (CCV) events are highly
prevalent co-morbidities of T2DM, over the past couple of
years, the link between OHAs and CV disease has been a area
of concern with some of new compounds have unexpectedly
been linked with excess CV AEs. USFDA has issued guidance
for industry with recommendations for methodology to show
that a new therapy does not cause any unacceptable increase
in CV risk.71
There is considerable preclinical evidence that DPP-4
inhibitors, which act by increasing plasma levels of active
GLP-1, may actually exert cardio-protective effects,72 also limited
human studies that are available have suggested that GLP-1 may
improve CV function.73-74 It is well known that hypoglycemia
is associated with increased CCV risk and as discussed in this
article DPP-4 inhibitor vildagliptin has been associated with
reduced incidence and severity of hypoglycemia.

In vildagliptin plus insulin trial, subgroup analysis showed

that patient age was an important factor in achieving glycemic
control. Patients aged >65 years had a significant lowering
of adjusted mean HbA1c levels (between-group difference
vildagliptin 50mg BID vs. placebo 0.6% [95% CI 1.0, 0.3;
p=0.001]) unlike patients aged <65 years (0.1% [95% CI 0.4, 0.1;
p=0.361])61 and this effect was sustained in extension trial at week
52.69 Similarly in combination with glimepiride, vildagliptin
showed greater lowering of adjusted mean HbA1c levels in the
older patients.63

A study conducted as per Food and Drug Administration,

USA (USFDA) guidance, showed that vildagliptin does not lead
to an increase in CCV events in a T2DM population. This metaanalysis by Schweizer et al and colleagues,75 pooled the data from
25 phase III vildagliptin trials lasting from 12 weeks to over 2
years, where the drug was used either alone or in combination
with other therapies. Patients received either a 50-mg dose of
vildagliptin once daily (OD) (n = 1,393), twice daily (BID) (n =
6,166) or active and placebo comparators (n=6,061), to evaluate
CCV safety of vildagliptin. The RRs for both vildagliptin
regimens were <1 (RR=0.88; 95% (CI)=0.37, 2.11 for 50 mg OD and
RR=0.84; 95% CI=0.62, 1.14 for 50 mg BID). Similar results were
seen across all subgroups including elderly patients (RR=1.04;
95% CI=0.62, 1.73), males (RR=0.87; 95% CI=0.60, 1.24) and those
with higher CCV risk (RR=0.78; 95% CI=0.51, 1.19). The results
of this meta-analysis established that vildagliptin was not
associated with an increased risk of adjudicated CCV events in
a T2DM population, including among those at most risk.

Vildagliptin 50mg OD or BID showed significantly greater

reduction in baseline FPG levels as add on therapy to metformin
when compared with placebo59 at 24th week. However reduction
in baseline FPG levels compared to placebo, when evaluated as
add-on therapy to pioglitazone,60 glimepiride61 or insulin69 was
not significant. However in comparator trial of Vildagliptin
50mg BID daily, drug failed to establish the noninferiority to
pioglitazone 30mg OD in reducing mean FPG, levels when
added to metformin.62

Safety and Tolerability of Vildagliptin

T2DM itself is characterized by increased risk of organ
specific complications like CV disease, hepatitis-C infection
and pancreatitis and these complications could be aggravated
by drug treatment. Subsequently alongside efficacy, the safety
profile of any new OHA is of utmost importance for treatment
of chronic and progressive disease like T2DM. The tolerability
profile of oral vildagliptin has been reviewed previously,46 drug
as monotherapy or in combination was well tolerated for periods
up to 52 weeks. The majority of reported adverse events (AEs)
were of mild to moderate severity and transient in nature53-54,57-62
JAPI april 2011 VOL. 59

Hepatic Safety Profile

To date, there is little evidence that vildagliptin or other
DPP-4 inhibitors are associated with significant hepatic risk.
Although cases of ALT elevations with concomitant increase in
bilirubin have been reported recently for sitagliptin, these cases
resolved on treatment and overall no increased risk of hepatic
events was reported.76

241

The meta-analyses conducted by Kothny W et al and

colleagues,77 pooled the safety data from 36 phase 2 and 3 clinical
trials to investigate hepatic safety profile vildagliptin. The results
from this meta-analysis showed that the greater proportion of
vildagliptin recipients had mild elevations in liver enzymes
versus comparator recipients (ALT/AST levels >= 3 x upper limit
of normal [ULN]).However, vildagliptin was not associated
with an increased risk of having severely elevated liver enzymes
(AST/ALT 10 x ULN, or AST/ALT 3 x ULN and bilirubin 2x
ULN). Nor was vildagliptin associated with an increased risk of
hepatic AEs. Two patients experienced severe elevations in liver
enzymes attributable to vildagliptin treatment. Both cases were
asymptomatic and resolved upon discontinuation of treatment.
Since a small number of these hepatic enzyme elevations were
reported on vildagliptin as well, liver enzyme monitoring
after initiation of therapy is prudent and consistent with the
vildagliptin product information.

Pancreatic Safety Profile

As mentioned earlier T2DM has also been associated
with increased risk of pancreatitis, as cholelithiasis,
hypertrygliceridaemia associated with disease are acknowledged
risk factors for acute pancreatitis.78 GLP-1 agonists such as
exenatide79 and DPP-4 inhibitor sitagliptin80 have been associated
with some cases of acute pancreatitis.
With aim of assessing whether treatment with the DPP-4
inhibitor vildagliptin is associated with an increased risk of
pancreatitis, Ligueros-Saylan M et al,81 pooled safety data from 24
phase 2 and 3 double-blind controlled clinical trials, to investigate
its association with pancreatitis-related AEs. The odds ratio for
pancreatitis-related AEs was <1 for vildagliptin 50mg OD and
BID (OR = 0.90 and 0.78, respectively), indicating no increased
risk relative to all comparators. The result from this meta-analysis
established that there was no evidence of an increased risk of
pancreatitis related AEs following treatment with vildagliptin
at the marketed doses of 50mg OD and BID relative to the all
comparators group.
The safety of vildagliptin versus comparators on the liver,
the pancreas, the immune system, the skin and in patients with
impaired renal function has been discussed in detail in metaanalysis by Ligueros-Saylan M and colleagues.82

Hypoglycemia
The incidence of hypoglycemia reported by vildagliptin
monotherapy were low and similar to that with metformin or
rosiglitazone, (0.7%50,53,56 vs. 0.4%53 in metformin, 0.04% in
rosiglitazone and 0% in placebo56 recipients).50 In three trials,
no hypoglycemic events were observed.49,53-54 Hypoglycemic
events were rare (3.6%) in all combination therapy trials.57, 58, 60,61
In combination with metformin, one hypoglycemia event each
was reported from vildagliptin 50mg OD and BID recipient57
and one recipient of vildagliptin 50mg BID experienced three
hypoglycemic events (vs. no events with pioglitazone). 60
Moreover, when used in combination with insulin, vildagliptin
50mg BID resulted in a significant (p<0.001) reduction in the
frequency of hypoglycemic events compared with placebo.59

Gastrointestinal (GI) AEs

The incidence of GI AEs reported with vildagliptin 50mg is
comparable to placebo and is much less than in metformin or
acarbose treated patients. The frequency of reported GI AEs with
metformin 2000 mg daily were twice than that of recipients of
242

vildagliptin 50mg BID (43.7% vs. 21.8%; p<0.001).53 This resulted

in 3-4 times higher incidence of diarrhoea, nausea, abdominal
pain, dyspepsia and flatulence with metformin than with
vildagliptin. More notably, approximately five times as many
patients withdrew because of AEs following treatment with
metformin when compared with vildagliptin (4.4% vs. 0.8%).53
Also incidence of GI AEs was considerably lower in vildagliptin
50mg OD plus metformin (1500 mg/day) recipients (p=0.022),
when compared to placebo plus metformin recipients.57 The
occurrence of GI-related AEs in acarbose recipients was more
than twice than that in vildagliptin recipients (25.5% vs. 12.3%;p
< 0.001).49

Bodyweight
The DPP-4 inhibitor vildagliptin appear to be bodyweight
neutral, as change in bodyweight associated with vildagliptin
treatment is neutral or modest in nature and not significantly
different from placebo.49,51,53,54,56-62 However there was a tell apart
difference in weight neutral effect of vildagliptin to weight gain
effect of rosiglitazone,51 pioglitazone,60 in phase 3 comparator
trial. All the same, vildagliptin treatment was not associated
with the weight loss that is coupled with some other antidiabetic
agents.
In addition to this, the occurrence of cardiac AEs (including
arrhythmias and conduction abnormalities) and hypertension
with vildagliptin was comparable to placebo and also less than
with metformin.83

Role of Vildagliptin in T2DM Therapy

The primary aim of T2DM therapy is a prompt and sustained
lowering of elevated glucose levels, thereby reducing associated
microvascular and vascular co-morbidities. The availability and
accessibility of a new class of therapeutic agents is key to lessen
burden of T2DM. In the last couple of years, a number of new
medications have been approved by USFDA for treatment of
diabetes. However with exception of inhaled insulin, no other
recently approved medications are orally administrable. Despite
the fact that injectable therapies like insulin and exenatide are
effective treatments, but patient resistance and fear of needle,
regimens complicatedness, inconvenience, time and cost are
main barriers to patient non-compliance to these therapies.
In the new group of drugs orally administered DPP-4 inhibitor
vildagliptin proves to be a very efficacious drug for improving
glycemic control in a wide range of T2DM patients, ranging
from the IGT population to patients with advanced disease
on insulin. Vildagliptin is indicated as second-line therapy as
part of an oral combination therapy regimen in T2DM patients
whose hyperglycemia is poorly controlled by monotherapy
with metformin, a SU or a TZDs.43 Existing data indicates that
HbA1c lowering potential of Vildagliptin is in range of TZDs and
acarbose, with sustained reductions to clinically significant levels
for up to 2 years. When used as monotherapy or in combination
with metformin or insulin, modest reductions in HbA1c values
(0.41.1% reductions) have been observed in patients receiving
vildagliptin.
T2DM is a disease associated with a progressive decline
in -cell function. Unlike many other antihyperglycemic
medications, oral inhibitor of DPP-4 vildagliptin improves
glycemic control in patients with T2DM through physiological
mechanisms that result in an attenuation of -cell decline
and thus restoration of the incretin effect.32-35 As a result of
their diverse mechanism of action, DPP-4 inhibitor such as
JAPI april 2011 VOL. 59

available for management of T2DM patients, who are poorly

controlled with monotherapy.

vildagliptin presents several advantages over other antidiabetic

medications. Vildagliptin enhances a-cell responsiveness to both
the suppressive effects of hyperglycemia and the stimulatory
effects of hypoglycemia. These effects contribute to the efficacy
of vildagliptin to improve glycemic control as well as to its low
hypoglycemic potential.84 The effect of improving postprandial
glycemia provides a good alternative for the up till now limited
therapeutic options of affecting postprandial glycemia excursion.

Acknowledgments
Dr. Sanjay Kalra appreciatively acknowledges the editorial
assistance provided by medONE Pharma solutions, New Delhi,
India, in the production of this manuscript.
Disclosures
Dr. Sanjay Kalra has no conflicts to disclose.

Vildagliptins unique MOA permits a number of combination

regimens for effective control of glucose levels. Combining
drug with existing medications with complementary MOA,
should be a welcome option to available treatment regimes
for T2DM. Vildagliptin is particularly useful in combination
with metformin or TZDs, with most appealing combination
of drug being with metformin, since from a pathogenic point
of view combining metformin principally targeting insulin
resistance with vildagliptin primarily targeting the -cell is a
rational approach. As add-on therapy to metformin, vildagliptin
provided better glycemic control than placebo57 and in an active
comparator noninferiority trial; it was shown to be as effective
as pioglitazone60. Also in other combination trials, vildagliptin
as add-on therapy to insulin,59 glimepiride61 and pioglitazone58
provided more effective glycemic control than placebo.

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Conventional treatments for T2DM do not address the
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