REVIEW

Inhibition of dipeptidyl peptidase-4 with

vildagliptin: a potential new treatment for type
2 diabetes
RICHARD E PRATLEY,1 AFSHIN SALSALI,1 GLENN MATFIN2
Abstract

Introduction

Diabetes mellitus currently affects more than 170 million people

worldwide and its prevalence is increasing dramatically.1 By 2025,
the number of affected individuals is expected to exceed 330 million, globally.1 The chronic microvascular and macrovascular complications of diabetes associated with poor glycaemic control
account for much of the morbidity, mortality and economic costs
associated with the disease. Although substantial evidence indicates that good glycaemic control can lower the risk for
microvascular complications (and probably macrovascular disease as well), most patients are not treated to recommended glycaemic goals.2-5 In the recent US National Health and Nutrition
Examination survey, HbA1C was less than 7% in only ~40% of
patients with diabetes.5 In part, the failure to achieve glycaemic
goals in a larger fraction of the population reflects limitations in
current treatment options for patients with type 2 diabetes mellitus, who represent the overwhelming majority (~95%) of
patients with diabetes in most regions. All available oral antidiabetic agents are associated with side effects that limit their use.6
Sulphonylureas, meglitinides, and insulin are associated with
weight gain and hypoglycaemia; TZDs also cause weight gain
and may cause peripheral oedema and metformin and -glucosidase inhibitors are associated with gastrointestinal side
effects. Moreover, with the possible exception of the TZDs, glycaemic control gradually worsens over time with most treatments.3,7 The United Kingdom Prospective Diabetes Study
(UKPDS) demonstrated that < 40% of patients with type 2 diabetes could be controlled (HbA1C < 7%) on a single agent after
three years. The high rate of monotherapy failure necessitates
the use of combinations of multiple agents and eventually insulin
in many patients. To understand why this is the case, a working
knowledge of the pathophysiology of type 2 diabetes is helpful.

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ype 2 diabetes mellitus is a growing problem in

most parts of the world. There is now good
evidence that controlling hyperglycaemia can help
prevent many of the serious complications associated
with the disease. Despite this evidence and the
availability of several classes of oral antidiabetic agents
and insulin, many people with diabetes do not achieve
adequate glycaemic control (i.e. HbA1C < 6.5 or 7.0%).
Thus, there is an urgent unmet medical need to develop
new and better treatments for type 2 diabetes.
Among the most promising new classes of drugs for
type 2 diabetes are those that leverage the incretin
hormone glucagon-like peptide-1 (GLP-1). Vildagliptin,
an orally available, potent and specific inhibitor of
dipeptidyl peptidase-4 (DPP-4), the enzyme that rapidly
inactivates GLP-1, augments endogenous active GLP-1
and gastric inhibitory polypeptide/glucose-dependent
insulinotropic polypeptide (GIP) and reduces
hyperglycaemia in patients with type 2 diabetes.
Studies to date in patients exposed for up to one year
indicate that vildagliptin produces clinically significant
reductions in HbA1C when used as monotherapy and in
combination with metformin, glimepiride, or insulin. In
general, the drug has proved to be well tolerated with
low rates of hypoglycaemia and gastrointestinal side
effects (including nausea) and no weight gain or
oedema.
Br J Diabetes Vasc Dis 2006;6:1506
Key words: GLP-1, GIP, incretin hormone, incretin enhancer,
DPP-4, diabetes.

Diabetes and Metabolism Translational Medicine Unit, Division of

Endocrinology, Diabetes and Metabolism, Department of Medicine,
University of Vermont College of Medicine, USA.
2
Novo Nordisk Inc. 100 College Road West, Princeton, New Jersey 08540,
USA; and Division of Endocrinology and Diabetes, Department of Medicine,
New York University School of Medicine, New York, New York, USA.
1

Correspondence to: Professor Richard E Pratley

Diabetes and Metabolism Translational Medicine Unit, FAHC/UHC - Arnold
3412, One South Prospect Street, Burlington, VT 05401, USA.
Tel: +1 802 847 8901; Fax: +1 802 847 3401
E-mail: rpratley@uvm.edu

150

Multiple metabolic defects contribute to

hyperglycaemia in type 2 diabetes
While there is general agreement that both genetic and environmental factors play critical roles in the development of type 2 diabetes, there is growing awareness that it is a heterogeneous disorder, with differences in the phenotype, presentation and
course between populations, pedigrees and individuals.8
Nevertheless, most patients with type 2 diabetes manifest a common set of abnormalities, including obesity (especially an
abdominal distribution), insulin resistance in the liver, skeletal
muscle and adipose tissue, and quantitative and qualitative

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Abbreviations
DPP-4
FDA
GIP
GLP-1
HbA1C
IC50
OAD
Tmax
TZD

dipeptidyl peptidase-4 (4 also written as Latin numeral IV)

Food and Drug Administration
glucose-dependent insulinotropic polypeptide (gastric
inhibitory polypeptide)
glucagon-like peptide-1
haemoglobin A1C
inhibitory concentration (50%)
oral antidiabetic
Time to maximal plasma concentration
thiazolidinedione

Figure 1. Biological actions of GLP-1 and GIP on organs and peripheral

tissues
Following meal ingestion GLP-1 and GIP are released from
intestinal L-cells and K-cells, respectively. GLP-1 and GIP
lower glucose by stimulating insulin release from the
endocrine pancreas and improve glucose uptake and
utilisation in peripheral tissues (liver, muscle and adipose). In
contrast to GIP, GLP-1 brings about feelings of satiety and
fullness by interaction with its receptors in the brain. GLP-1
also exerts inhibitory effects on gastric emptying

Meal
ingestion
Stomach
Gastric
emptying

Gut

L-cells

K-cells

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defects in insulin secretion.9 These abnormalities precede and

predict type 2 diabetes and worsen during its development, and
can accordingly be considered the primary metabolic defects in
the pathogenesis of the disease.9-11 In addition, hypersecretion of
glucagon in the fasting state and failure to normally suppress
glucagon following a meal contributes to dysregulation of
endogenous glucose production, which is elevated in proportion
to the degree of hyperglycaemia in patients with type 2 diabetes.12 Similar abnormalities in glucagon secretion can be seen
in subjects with impaired glucose tolerance, however, it is not
clear whether they predict type 2 diabetes akin to insulin resistance and impaired insulin secretion. Finally, autopsy studies performed in recent years indicate that beta-cell mass is decreased
in people with diabetes and, to a lesser degree, also in those with
impaired fasting glucose.13 Thus, the pathogenesis of type 2 diabetes is characterised by multiple metabolic abnormalities including insulin resistance in key tissues and islet dysfunction, with
impaired insulin secretion, glucagon dysregulation, and structural lesions. While the relative contributions of these abnormalities
may vary from patient to patient and among individual patients
over time, all are undoubtedly significant in the development of
hyperglycaemia and thus represent important therapeutic targets.

GLP-1 and the therapeutic potential of incretin

hormones

The demonstration that the incretin hormone GLP-1 can improve

glycaemic control in patients with type 2 diabetes has led to the
rapid development during the last decade of a promising new
class of therapeutic agents for type 2 diabetes.14-16 GLP-1 (7-36)
is a 30 amino acid polypeptide that is encoded by the
proglucagon gene and secreted from the L-cells in the ileum in
response to nutrients in the gut15 (figure 1). GLP-1 is an incretin
hormone, meaning that it potentiates the insulin response to an
oral glucose challenge relative to an isoglycaemic intravenous
glucose challenge.15 In vivo, the incretin effect is substantial,
accounting for as much as two thirds of the insulin response to
an oral glucose challenge in normal individuals. GIP, a 40 amino
acid peptide secreted by the K cells of the duodenum, also manifests incretin activity in normal humans.16 GLP-1 and GIP account
for approximately 90% of incretin activity.
The incretin response is largely absent in patients with type 2

VOLUME 6 ISSUE 4 . JULY/AUGUST 2006

GLP-1

GIP

Pancreas

Brain

Satiety

Insulin

Liver

Glycogensynthesis

Muscle

Glucoseuptake

Adipose

Lipogenesis

Reproduced with permission from Green et al. Br J Diabetes Vasc Dis

2005;5:13440

diabetes due to abnormalities in both GLP-1 and GIP. GLP-1

secretion is decreased by 2025% and the beta-cell response to
GLP-1 is impaired in patients with diabetes.17-20 Despite this, infusions of GLP-1 are capable of normalising glucose levels in
patients with type 2 diabetes.14 In contrast, GIP levels are either
normal or slightly increased in patients with type 2 diabetes and
insulin responses to infused GIP (but not pulse administration)
are markedly blunted, additionally GIP does not appear to correct
hyperglycaemia to the same extent as infused GLP-1.19,21 Thus,
GLP-1 and to a lesser extent GIP, analogues are actively being
explored as possible treatments for diabetes.22
GLP-1 has multiple physiological effects that could lead to
improved glycaemic control in diabetes.15,16 Acting through a specific G-protein coupled receptor on beta-cells it increases insulin
secretion in a glucose dependent manner and increases transcription of the proinsulin gene, thus increasing availability of
insulin for secretion from beta-cells. Importantly, GLP-1 also has
independent effects on alpha-cells to inhibit glucagon secretion
('glucagonostatic'). This effect may explain much of the acute
glucose-lowering effect of GLP-1. Both the alpha- and beta-cell
effects are glucose-dependent, therefore, the risk for hypoglycaemia is low with GLP-1 based therapies. Some studies also

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Table 1.

Some key characteristics of GLP-1 agonists compared with

DPP-4 inhibitors15,16,29,35

Category

Characteristics

Islet
function

glucose-dependent
insulin secretion

glucagon secretion

Safety and
tolerability

GLP-1 agonists DPP-4 inhibitors

i.e. incretin
i.e. incretin
mimetics
enhancers

Improve beta-cell function

Increase beta-cell mass in

rodents

Increase beta-cell mass in

humans

Injection
Oral

Lower risk of
hypoglycaemia than
insulin secretagogues
and insulin

Specificity

Induce satiety and

weight-loss

Slows gastric emptying

Increased nausea and

vomiting

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suggest that GLP-1 has independent effects to increase insulin

action in skeletal muscle.23 At high concentrations, GLP-1 slows
gastric emptying, resulting in delayed absorption of glucose and
nutrients from the gut.24 GLP-1 receptors in the hypothalamus
may modulate satiety and food intake, leading to weight loss
with prolonged exposure. Finally, both GLP-1 and GIP have been
shown to induce beta-cell proliferation, differentiation and neogenesis and decrease apoptosis in multiple preclinical models.25,26
The net effect of these changes is to increase beta-cell mass.
Thus, GLP-1 has both acute metabolic effects to improve glycaemia and long-term effects that may reverse progressive loss of
beta-cells over time.
Although promising as a novel therapeutic approach for
type 2 diabetes, the practical utility of native GLP-1 is limited.
GLP-1 (7-36) is rapidly inactivated by an enzyme called DPP-4
that cleaves the two N-terminal amino acids to form inactive
GLP-1 (9-36).27,28 Consequently, the half-life of active GLP-1
(736) in the circulation is only 12 minutes and the majority
(80%) of circulating GLP-1 is the inactive form. To address this,
a number of GLP-1 analogues that are resistant to inactivation
by DPP-4 and have prolonged activity relative to native GLP-1
have been synthesised (termed 'incretin mimetics').15,16 A GLP-1
mimetic, exenatide (Byetta), has recently been approved in the
US for treatment of type 2 diabetes in patients failing to
achieve adequate glycaemic control on oral antidiabetic therapy.29,30 Exenatide, like GLP-1, is a peptide, and must be given
twice a day by injection.
An alternative approach, which obviates the need for injections, is to inhibit the enzymatic activity of DPP-4, to augment
levels of endogenous active GLP-1 and GIP, such agents are
termed 'incretin enhancers'. DPP-4 (also known as CD26) is a
membrane associated protein ubiquitously expressed on the surface of endothelial cells and T-cell lymphocytes, and is also present in the circulation in a soluble form which retains its enzymatic function.28 Cell surface CD26, in addition to the DPP-4
enzymatic activity related to its extracellular segment, has other
signal transferring functions independent of DPP-4. The latter
does not appear to be affected by DPP-4 inhibitors, and may be
the reason why the immune activating component of CD26 is
not affected by DPP-4 inhibitors. DPP-4 is an amino terminal serine peptidase with in vitro activity against many hormones and
chemokines.28 DPP-4 appears to be the major pathway for the in
vivo inactivation of GLP-1 and GIP. In contrast, most other regulatory peptides that are substrates for DPP-4 in vitro appear to be
metabolised by alternative pathways.28 Mice and rats in which
the DPP-4 gene has been knocked-out or is mutated have
increased GLP-1 levels and improved glucose tolerance relative to
wild-type animals, demonstrating the importance of the incretin
system in normal glucose homeostasis and providing proof-ofconcept that inhibition of DPP-4 can improve glycaemic
control.31,32 Several pharmaceutical companies have synthesised
orally available, small molecule inhibitors of DPP-4 (termed
'gliptins') and a number of these compounds are in various
stages of development. Two of these 'gliptins', vildagliptin
(LAF237, Novartis, NJ, USA, with the proposed trade name

152

Key: X = No; = Yes; ? = Unknown

'Galvus') and sitagliptin (MK-O431, Merck, NJ, USA, with the

proposed trade name 'Januvia'), were both submitted for FDA
approval in early 2006. Vildagliptin will be the main focus for this
brief review. A comparison of some of the key characteristics of
incretin mimetics versus incretin enhancers are noted in table 1.

Vildagliptin: a potent and specific inhibitor of DPP-4

Vildagliptin is an N-substituted glycyl-2-cyanopyrrolidine (figure

2). It is a potent competitive and reversible inhibitor of human
and rodent DPP-4 in vitro, with a median inhibitory concentration (IC50) ~23 nmol/L.33 Importantly, vildagliptin inhibits DPP-4
with high specificity relative to other similar peptidases where its
IC50 exceeds 200 mol/L.33 This specificity is of potential clinical
importance as inhibition of DPP-8 and DPP-9 has been associated with immune, histopathological and gastrointestinal toxicity
in various animal models.34
In healthy humans, vildagliptin is rapidly and almost completely absorbed (~85% of administered dose) after oral administration with a tmax of 12-hours.33,35,36 Plasma levels were linearly related to dose and the plasma half-life ranged from 1.54.5
hours with doses from 25 to 200 mg. The drug does not appear
to accumulate with multiple dosing and the pharmacokinetics
are not affected by food. Most of the drug is metabolised with
hydrolysis of the cyano moiety dominating (55%), but a fraction
(22%) is also excreted unchanged by the kidneys.33,35,36 The drug
is minimally metabolised by the major cytochrome P450 enzymes
that metabolise many other drugs and is neither an inhibitor nor

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Figure 2. 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 GLP-1

Vildagliptin (Galvus)
H

HO

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Mixed meal

Intestinal
release of GLP-1

Inhibition
DPP-4
DPP-4

inadequately controlled with diet and exercise alone. A 12-week

dose-ranging study in 279 patients compared dosing regimens
of 25, 50 and 100 mg once daily and 25 mg twice daily.39 From
a mean baseline HbA1C of ~7.7%, vildagliptin at doses of 50
and 100 mg a day produced significant reductions in HbA1C of
~0.5%. Another 12-week study in 98 patients demonstrated
that vildagliptin at a dose of 25 mg twice daily decreased HbA1C
by 0.6% (p=0.0012) relative to placebo from a baseline of
8.0%.40 In a subset of subjects with a higher initial baseline
ranging between 8.09.5%, a 1.2% reduction in HbA1C was
observed. In this study, fasting and prandial glucose levels were
reduced by 1.1+0.4 (p=0.0043) and 1.9+0.5 mmol/L
(p<0.0001), respectively. In a 24-week phase 3 study in 380
patients managed with diet and exercise (baseline HbA1C
7.511%), vildagliptin at doses of 50 and 100 mg per day and
50 mg twice daily (these are the predominant doses used in the
published phase 2/3 studies) reduced HbA1C by 0.80.9% from
baseline. The reduction in HbA1C was highly significant for all
doses of vildagliptin relative to placebo (which reduced HbA1C
by 0.3% in this study), but none of the dosing regimens was significantly different from one another. Two additional phase 3
studies of vildagliptin monotherapy have recently been reported. In the first, a 52-week head-to-head study versus metformin, vildagliptin 50 mg twice daily (n=526) reduced HbA1C
by 1.0% from a starting HbA1C of 8.7%, whereas metformin at
a dose of 2,000 mg per day (n=254) reduced HbA1C by 1.4%
(p<0.05 compared to vildagliptin in the intention-to-treat analyses).41 The reductions in HbA1C were sustained for the entire 52
weeks with both vildagliptin and metformin. In the second
study, vildagliptin 50 mg twice daily for 24 weeks was similar to
rosiglitazone 8 mg per day.42 In a subset of subjects with higher
HbA1C levels at baseline (mean 10%), vildagliptin (n=166)
reduced HbA1C by 1.82% while rosiglitazone (n=88) reduced
HbA1C by 1.86%.42

Active GLP-1

Inactivation of
GLP-1 blocked

Inactive GLP-1

Adapted from J Shannon, Development Pipeline 2006, www.novartis.com,

accessed 25th May 2006

an inducer of these enzymes. In the circulation, vildagliptin is not

extensively protein bound (417%). No adjustment of dose is
necessary in either hepatic or renal insufficiency.37
Single doses of vildagliptin (25200 mg) rapidly inhibit plasma DPP-4, achieving > 90% inhibition within 3060 minutes.33,35
The duration of inhibition is dose dependent; with the anticipated therapeutic doses of 50 mg and 100 mg, DPP-4 activity is
inhibited by ~70 and 90% at 12 hours and remains inhibited by
~40% at 24 hours with the higher dose.
In drug nave patients with type 2 diabetes, four weeks of
treatment with vildagliptin at a dose of 100 mg per day reduced
both fasting and postprandial plasma glucose levels, resulting in
significant decreases in HbA1C.38 Vildagliptin treatment also
improved insulin secretion, as assessed by the insulin responses
relative to the glucose responses to a standard mixed meal,
increased both basal and postprandial GLP-1 levels, and
decreased glucagon levels. The drug appeared well tolerated.
The results of additional phase 2 and phase 3 studies of
vildagliptin in patients with type 2 diabetes have recently been
made available and are summarised below.

Vildagliptin as monotherapy
Several phase 2 and phase 3 studies have examined the use of
vildagliptin as monotherapy for patients with type 2 diabetes

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Vildagliptin in combination

Two studies have examined the glucose lowering effects of

vildagliptin when added-on to metformin monotherapy. The
first, a 12-week phase 2 study in 107 patients on metformin
demonstrated that vildagliptin at a dose of 50 mg per day
reduced HbA1C by 0.6% from a mean baseline of 7.7%, whereas HbA1C was unchanged in the group randomised to placebo.43
Patients in this study were followed during a 40-week extension
for a total of 52 weeks. The reductions in HbA1C were sustained
in the group receiving metformin plus vildagliptin, whereas
HbA1C increased over the course of the year in subjects treated
with metformin plus placebo. At the end of the extension,
HbA1C was 1.1% lower in those who received vildagliptin in
addition to metformin compared to those who received metformin alone. Notably, fasting and prandial glucose concentrations were significantly lower, whereas insulin responses to a
standard meal challenge were significantly higher after 52 weeks
of treatment with vildagliptin. A 3-arm 24-week phase 3 study in
416 patients on metformin monotherapy (baseline HbA1C
7.511%) compared the effects of vildagliptin at doses of 50 mg

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Table 2.

Potential safety and tolerability issues with DPP-4 inhibitors

Potential issue

Current status

Supraphysiological GLP-1 levels (e.g. nausea and vomiting seen with

incretin mimetics may be related in part to higher GLP-1 levels than normal)

No nausea and vomiting. GLP-1 levels with incretin enhancers are more
physiological compared to the pharmacological levels with incretin-mimetics

Potential effects on immune function due to CD26 (marker of T-cell

activation and proliferation) inhibition

No apparent immune activation/suppression seen/expected in preclinical

and clinical studies to date. Further surveillance indicated

Effects of DPP-4 inhibitors on other DPP isoforms (i.e. DPP 8/9

inhibition is associated with significant toxicity in animals)

Current DPP-4 inhibitors in advanced development are highly DPP-4 specific

and do not exhibit toxicity of the type seen with DPP 8/9 inhibition in animals

Effects of DPP-4 inhibition on other putative DPP-4 substrates

(e.g. substance P, NPY, PYY, GLP-2, GHRH and various chemokines)

Although a wide variety of peptides are substrates for DPP-4 in vitro, most
appear to have alternative metabolic pathways in vivo. Further studies are
required including post-marketing surveillance

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Key: NPY = neuropeptide Y; PYY = peptide YY, GLP-2 = glucagon-like peptide -2; GHRH = Growth Hormone Releasing Hormone

per day (n=143) and 50 mg twice a day (n=143) to placebo

(n=130).44 Starting from a mean HbA1C of ~8.5%, both the
50 mg per day and 50 mg twice daily doses of vildagliptin significantly decreased HbA1C relative to placebo by 0.7% and
1.1%, respectively, although the difference between doses was
not statistically significant.
A similar phase 3 study examined the effects of vildagliptin
added to sulphonylurea monotherapy. This study compared
vildagliptin 50 mg per day (n=132) and 50 mg twice a day (n=132)
to placebo (n=144) added-on to glimepiride 4 mg per day.
Starting from a mean HbA1C ~8.7%, the 50 mg per day and
50 mg twice daily doses of vildagliptin significantly decreased
HbA1C relative to placebo by 0.8 and 0.9%, respectively.
Finally, a phase 3 study of vildagliptin 50 mg twice a day
(n=144) or placebo (n=152) in insulin-treated type 2 diabetic
patients demonstrated significant reductions in HbA1C in the
group treated with vildagliptin (-0.5%) compared to those
receiving placebo.45 Of note, the improvements in HbA1C with
vildagliptin occurred in association with a lower total daily insulin
dose and no episodes of significant (defined as blood glucose
levels < 3.1 mmol/L with symptoms of hypoglycaemia and
patient unable to initiate self-treatment) hypoglycaemia (compared with six episodes in those treated with insulin plus placebo).
Collectively, the results to date indicate that vildagliptin
monotherapy at daily doses of 50100 mg produces clinically significant reductions in HbA1C, comparable to those observed with
rosiglitazone, although possibly less than those observed with
metformin at one year. Vildagliptin also produces clinically significant reductions in HbA1C in patients already treated with metformin, glimepiride or insulin who are not at goal. The reductions
in HbA1C with vildagliptin are attributable to improvements in
both fasting and postprandial glucose levels and are associated
with higher active GLP-1 levels, lower glucagon levels and
improvements in insulin secretion. Improvements in insulin sensitivity have also been demonstrated in some studies, however,
whether these changes are direct or indirect remains to be determined. Vildagliptin appears to work well in patients with higher

154

baseline HbA1C levels and effects are durable for up to one year.
Interestingly, small, but statistically significant reductions in blood
pressure have been noted with vildagliptin therapy.46 Finally, a
study in 31 drug nave patients with type 2 diabetes suggests
that vildagliptin reduces post-prandial lipemia.47

Safety and tolerability of vildagliptin

In general, vildagliptin as monotherapy and in combination with

other antidiabetic treatments has proved to be well tolerated for
periods up to 52 weeks.35,41,43 The incidence of hypoglycaemia is
low and similar to that with metformin or rosiglitazone.39,41,42
Even with treatment of up to 52 weeks, there is no apparent
weight gain or oedema.41,43 The incidence of GI side effects is
comparable to placebo and is much less than in metformin-treated patients.39,41 In addition, the incidence of cardiac adverse
events (including arrhythmias and conduction abnormalities) and
hypertension with vildagliptin is comparable to placebo and is
also less than with metformin.41 Table 2 highlights some of the
uncertainties regarding the safety of DPP-4 inhibitors.

Summary

Orally available DPP-4 inhibitors, which augment endogenous

active GLP-1 to lower glucose, are promising additions to the
therapeutic armamentarium for diabetes treatment. Vildagliptin,
a potent and specific DPP-4 inhibitor, exemplifies the promise of
the class. It produces clinically significant reductions in HbA1C as
monotherapy and in combination with metformin, sulphonylureas, TZDs and insulin, bringing many patients to glycaemic
goal. Since it is well tolerated, not associated with weight gain
and has a low potential to provoke hypoglycaemia, it may be an
appropriate first choice for many patients when diet and exercise
have failed and is also suitable as add-on therapy when patients
do not achieve glycaemic goals. Further studies in patients with
pre-diabetes will elucidate the potential utility of this class of
drugs in the prevention of diabetes, whereas longer-term studies
will clarify whether DPP-4 inhibition, through augmented GLP-1,
can modify the progressive nature of type 2 diabetes and result
in durable control.

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Key messages

Incretin hormones like GLP-1 and GIP physiologically

augment glucose-dependent insulin secretion after
meals

GLP-1 and GIP display multiple biological actions that

result in improvements in islet function (e.g. both alphaand beta-cell) and other important metabolic effects

GLP-1 (incretin) mimetics (e.g. exenatide) are already on

the market in the US, with proven efficacy in glucose
control in type 2 diabetes patients

DPP-4 inhibitors ('incretin enhancers') are an attractive,

new class of OAD agents that are in advanced clinical
development for type 2 diabetes

Vidagliptin is a good example of the DPP-4 inhibitor

class ('gliptins'), and to date, has been shown to be an
effective and well-tolerated OAD in type 2 diabetes
during clinical development

References

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15. Nauck MA, Meier JJ. Glucagon-like peptide 1 (GLP-1) and its derivatives
in the treatment of diabetes. Regul Pept 2005;124(suppl):135-48.
16. Drucker DJ. Enhancing Incretin Action for the Treatment of Type 2
Diabetes. Diabetes Care 2003;26:2929-40.
17. Vilsbll T, Krarup T, Deacon CF et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001;50:609-13.
18. Toft-Nielsen MB, Damholt MB, Madsbad S et al. Determinants of the
impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.
J Clin Endocrinol Metab 2001;86:3717-23.
19. Nauck MA, Heimesaat MM, rskov C et al. Preserved incretin activity of
glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric
inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin
Invest 1993;91:301-07.
20. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2
and nondiabetic subjects. Diabetes 2003;52:380-6.
21. Meier JJ, Gallwitz B, Kask B et al. Stimulation of insulin secretion by intravenous bolus injection and continuous infusion of gastric inhibitory
polypeptide in patients with type 2 diabetes and healthy control subjects.
Diabetes 2004;53(suppl 3):S220-4.
22. Irwin N, O'Harte FP, Gault VA et al. GIP(Lys16PAL) and GIP(Lys37PAL):
novel long-acting acylated analogues of glucose-dependent
insulinotropic polypeptide with improved antidiabetic potential. J Med
Chem 2006;49:1047-54.
23. Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin
Endocrinol Metab 2002;87:3768-73.
24. Nauck MA, Niedereichholz U, Ettler R et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy
humans. Am J Physiol (Endocrinol Metab) 1997;273:E981-8.
25. Perfetti R, Hui H. The role of GLP-1 in the life and death of pancreatic
beta cells. Horm Metab Res 2004;36:804-10.
26. Trumper A, Trumper K, Trusheim H, Arnold R, Goke B, Horsch D.
Glucose-dependent insulinotropic polypeptide is a growth factor for beta
(INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001;15:1559-70.
27. Deacon CF, Nauck MA, Toft-Nielsen M-B et al. Both subcutaneously and
intravenously administered glucagon-like peptide-1 are rapidly degraded
from the amino-acid terminus in type 2 diabetic patients and in healthy
subjects. Diabetes 1995;44:1126-31.
28. Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of
regulatory peptides. Regul Pept 1999;85:9-24.
29. Ahrn B: Exenatide: a novel treatment of type 2 diabetes. Therapy 2005;
2:207-22.
30. Buse JB, Henry RR, Han J et al. Effects of Exenatide (Exendin-4) on
Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With
Type 2 Diabetes. Diabetes Care 2004;27:2628-35.
31. Marguet D, Baggio L, Kobayashi T et al. Enhanced secretion and
improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci
USA 2000;97:6874-9.
32. Nagakura T, Yasuda N, Yamazaki K et al. Improved glucose tolerance via
enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IVdeficient Fischer rats. Biochem Biophys Res Commun 2001;284:501-06.
33. Villhauer EB, Brinkman JA, Naderi GB et al. 1-[[(3-hydroxy-1-adamantyl)
amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally
bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic
properties. J Med Chem 2003;46:2774-89.
34. Lankas GR, Leiting B, Roy RS et al. Dipeptidyl peptidase IV inhibition for
the treatment of type 2 diabetes: potential importance of selectivity over
dipeptidyl peptidases 8 and 9. Diabetes 2005;54:2988-94.
35. Ahren B. Vildagliptin: an inhibitor of dipeptidyl peptidase-4 with antidiabetic properties. Expert Opin Investig Drugs 2006;15:431-42.
36. Tran P, Yin H, Smith T, Fischer F: Disposition of (14C)LAF237 in rats and
humans. Drug Metab Rev 2002;34:293.
37. He Y-L, Sabo R, Wang Y et al. The Influence of Hepatic Impairment on
the Pharmacokinetics of Vildagliptin. Diabetes 2006;55(suppl 1):A469.
38. Ahren B, Landin-Olsson M, Jansson P-A et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduces glucagon
levels in type 2 diabetes. J Clin Endocrinol Metab 2004;89: 2078-84.
39. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with

1. Wild S, Roglic C, Green A et al. Global prevalence of diabetes: estimates

for the year 2000 and projections for 2030. Diabetes 2004;27:1047-53.
2. Diabetes Control and Complications Trial (DCCT) Research Group. N Engl
J Med 1993;329:977-86.
3. Turner RC. The UK Prospective Diabetes Study: A review. Diabetes Care
1998;21(suppl 3):C35-C38.
4. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents
the progression of diabetic microvascular complications in Japanese
patients with non-insulin-dependent diabetes mellitus: a randomized
prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.
5. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from
1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care 2004;27:17-20.
6. Inzucchi SE. Oral antihyperglycemia therapy for type 2 diabetes: scientific review. J Am Med Assoc 2002;287:360-72.
7. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:85465.
8. Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res 2005;
36:197-209.
9. Pratley RE, Weyer C, Bogardus C. Metabolic abnormalities in the development of type 2 diabetes mellitus. In: Diabetes Mellitus: A Fundamental
and Clinical Text, 2nd edition. LeRoith D, Taylor SI, Olefsky JM, editors;
Lippincott Williams & Wilkins: Philadelphia; 1999, pp 548-557.
10. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin
secretory dysfunction and insulin resistance in the pathogenesis of type
2 diabetes mellitus. J Clin Invest 1999;104:787-94.
11. Pratley RE, Weyer C. The role of impaired early insulin secretion in the
pathogenesis of type 2 diabetes mellitus. Diabetologia 2001;44:929-45
12. Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease:
influence of glucagon-like peptide-1. Diabetologia 2005;48:1700-13.
13. Butler AE, Janson J, Bonner-Weir S et al. Beta-cell deficit and increased
beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:
102-10.
14. Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagonlike peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997;40:
205-11.

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REVIEW

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46.

47.

HUMALOG MIX25* CARTRIDGE AND PEN (100U/ML)

HUMALOG IS INSULIN LISPRO (HUMAN INSULIN ANALOGUE)
ABBREVIATED PRESCRIBING INFORMATION
Humalog Mix25 is a white, sterile suspension of 25% insulin lispro solution and
75% insulin lispro protamine suspension. Uses: Treatment of patients with
diabetes mellitus who require insulin. Dosage and Administration: The
dosage should be determined by the physician, according to the requirement
of the patient. Humalog Mix25 may be given shortly before meals and, when
necessary, can be given soon after meals. Humalog Mix25 should only be given
by subcutaneous injection. Humalog Mix25 cartridges are to be used with a CE
marked pen. Follow the pen manufacturers directions for loading the pen and
priming it. Patients should be advised to always keep a spare pen and/or
cartridge. Humalog takes effect rapidly (approximately 15 minutes). See
Summaries of Product Characteristics for additional information, including
time-action profiles. Contra-indications: Hypoglycaemia. Hypersensitivity to
insulin lispro or to any of the excipients. Special Warnings and Special
Precautions for Use: Usage in pregnancy: Data on a large number of
exposed pregnancies do not indicate any adverse effect of insulin lispro on
pregnancy or on the health of the foetus/newborn. Insulin requirements usually
fall during the first trimester and increase during the second and third
trimesters. Patients should be advised to inform their doctors if they are
pregnant or contemplating pregnancy. Insulin lispro should be used in children
only when an advantage is expected compared to soluble insulin, for example,
in the timing of the injection in relation to meals. Insulin requirements may be
reduced in the presence of renal impairment, hepatic impairment, illness or
emotional disturbances. In patients with chronic hepatic impairment, an
increase in insulin resistance may lead to increased insulin requirements.
Transferring to another type or brand of insulin should be done under strict
medical supervision. Changes in strength, brand, type, species, and/or method
of manufacture may result in the need for a change in dosage. Changes in early
warning symptoms of hypoglycaemia may occur on transfer between different
types of insulin products. The patients ability to concentrate and react may be
impaired as a result of hypoglycaemia or hyperglycaemia. This may constitute
a risk in situations where these abilities are of special importance (eg, driving a
car or operating machinery). Side-effects: Hypoglycaemia is the most
frequent undesirable effect of insulin therapy. Lipodystrophy and
hypersensitivity have been reported rarely. Legal Category: POM. Prices:
29.46 - 5 x Mix25 cartridges. 30.98 - 5 x Mix25 prefilled pens. Marketing
Authorisation Numbers: Humalog Mix25 cartridge: EU/1/96/007/008,
Humalog Mix25 Pen 3ml: EU/1/96/007/016. Date of Preparation or Last
Review: March 2005. Full Prescribing Information is Available From:
Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke,
Hampshire, RG24 9NL. Telephone: 01256 315 999.

CO
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PR AR RI
O DI GH
DU O T
CT LOG M
IO Y ED
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PR IM EW
O ITE S
HI D
BI
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D

40.

dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes:

vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005;7:6928.
Pratley R, Jauffret-Kamel S. Galbreath, E. Holmes D. Twelve-week
monotherapy with the DPP-4 inhibitor LAF237 improves glycemic control in patients with type 2 diabetes (T2DM). In Press: Hormone and
Metabolic Research 2006.
Dejager S, Lebeaut A, Couturier A, Schweizer A. Sustained Reduction in
HbA1c during One-Year Treatment With Vildagliptin in Patients with
Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl 1):A29.
Rosenstock J, Baron MA, Schweizer A et al. Vildagliptin Is As Effective As
Rosiglitazone In Lowering HbA1C but Without Weight Gain In DrugNaive Patients With Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl 1):
A133.
Ahren B, Gomis R, Standl E et al. Twelve- and 52-week efficacy of the
dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients
with type 2 diabetes. Diabetes Care 2004;27:2874-80.
Garber A, Camisasca RP, Ehrsam E et al. Vildagliptin Added to Metformin
Improves Glycemic Control and May Mitigate Metformin-Induced GI
Side Effects in Patients with Type 2 Diabetes (T2DM) Diabetes
2006;55(suppl 1):A29.
Fonseca V, Dejager S, Albrecht S et al. Vildagliptin as Add-On to Insulin
in Patients with Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl
1):A111.
Nathwani A, Lebeaut A, Byiers S et al. Reduction In Blood Pressure In
Patients Treated With Vildagliptin As Monotherapy or in Combination
with Metformin for Type 2 Diabetes. Diabetes 2006;55(suppl 1):A113.
Matikainen N, Manttari S, Schweizer A et al. Vildagliptin Decreases
Postprandial Chylomicron Triglycerides (TGs) in Drug-Naive Patients with
Type 2 Diabetes (T2DM) Diabetes 2006;55(suppl 1):A125.

* HUMALOG MIX25 (insulin lispro) is a trademark of

Eli Lilly and Company.
HM408 February 2006

Information about adverse event reporting

can be found at www.yellowcard.gov.uk
Adverse events should also be reported to
Eli Lilly and Company Limited
(Tel. no. 0870 2401125)

156