1. MED/109; Total nos of Pages: 11;
MED 109
Dipeptidyl peptidase-4 inhibitors and the management of type 2
diabetes mellitus
Julio Rosenstocka and Bernard Zinmanb
Purpose of review Abbreviations
To review recent clinical trials of oral dipeptidyl peptidase-4 AUC area under the concentration curve
DPP-4 dipeptidyl peptidase-4
inhibitors and examine their role in managing type 2 FPG fasting plasma glucose
diabetes mellitus. GIP glucose-dependent insulinotropic polypeptide
GLP-1 glucagon-like peptide-1
Recent findings HbA1c glycated hemoglobin
Oral dipeptidyl peptidase-4 inhibitors improve islet function
by increasing a-cell and b-cell responsiveness to glucose,
resulting in improved glucose-dependent insulin secretion ß 2007 Lippincott Williams & Wilkins
1752-296X
and reduced inappropriate glucagon secretion. These
agents appear to have physiologically based
antihyperglycemic effects and may modify the progressive
nature of type 2 diabetes mellitus. In clinical trials sitagliptin Introduction
and vildagliptin have modest demonstrated effectiveness, Currently available therapies for type 2 diabetes mellitus
with clinically meaningful reductions of glycated have various limitations, including less than optimal
hemoglobin when used as monotherapy. They appear control of postprandial hyperglycemia, increased risk of
promising in combination or added to ongoing therapy with hypoglycemia, weight gain, gastrointestinal side effects,
other antidiabetic drugs (e.g. metformin, thiazolidinediones, and edema. In general, available agents target either the
or insulin). Of themselves dipeptidyl peptidase-4 inhibitors relative insulin deficiency or the insulin resistance that
are not associated with hypoglycemia or weight gain and characterizes established type 2 diabetes [1]. One new
appear to have a benign safety profile. approach yielding clinical results is the use of agents that
Summary potentiate or enhance the activities of gut-derived hor-
Oral dipeptidyl peptidase-4 inhibitors may prove valuable in mones referred to as incretins, which appear to be abnor-
treatment of diabetes, given their effectiveness in reducing mal in type 2 diabetes and have important effects on
glycated hemoglobin with neutral weight effects and insulin and glucagon biology as well as central nervous
without the adverse events associated with other agents. system effects on appetite [2–8,9,10].
Dipeptidyl peptidase-4 inhibitors appear to improve islet
function and may modify the course of diabetes; this, Incretins in glucose homeostasis
however, must be confirmed with long-term controlled Pancreatic islet cell dysfunction in type 2 diabetes
studies to demonstrate sustained glycemic control that involves both defective insulin secretion from b cells
translates into b-cell preservation. and inappropriately increased meal-related glucagon
secretion from a cells, leading to increased hepatic glu-
Keywords cose production, elevated fasting glucose, and postpran-
dipeptidyl peptidase-4 inhibitor, sitagliptin, vildagliptin dial hyperglycemia [10–13]. Over time there is loss of
b-cell mass, often accompanied by an increase in the
Curr Opin Endocrinol Diabetes Obes 14:1–11. ß 2007 Lippincott Williams a-cell population [14–16]. Understanding the postpran-
Wilkins. dial mechanisms of glucose homeostasis has highlighted
potential roles of gut-derived incretin hormones, the
a
Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas, USA and
most important of which, in a therapeutic sense, are
b
Mount Sinai Hospital, University of Toronto Toronto, Canada glucagon-like peptide-1 (GLP-1) and, to a lesser extent,
Correspondence to Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center glucose-dependent insulinotropic polypeptide (GIP) [5].
at Medical City, 7777 Forest Ln, C-685, Dallas, TX 75230, USA In this context we focus discussion on GLP-1.
Tel: +972 566 7799; fax: +972 566 7399;
e-mail: juliorosenstock@dallasdiabetes.com
Glucagon-like peptide-1 is released immediately after a
Current Opinion in Endocrinology, Diabetes Obesity 2007, 14:1–11
meal and regulates glucose-dependent insulin secretion,
stimulating a meal-related insulin response. It also inhi-
bits glucose-dependent glucagon secretion, slows gastric
emptying, and has effects on suppression of appetite and
food intake [17,18]. Most notably, in-vitro and in-vivo
rodent studies [2,5,7,8,10,19] suggest that GLP-1 can
1

2. MED/109; Total nos of Pages: 11;
2 Diabetes and the endocrine pancreas
have trophic effects, increasing b-cell proliferation and Experimental evidence on dipeptidyl peptidase-4
neogenesis with inhibition of b-cell apoptosis. It is inhibition
important to note that to date these effects have not Proof-of-concept studies [4,5,8,10] demonstrated inhi-
been demonstrated in humans with type 2 diabetes. bition of DPP-4 in animal models of diabetes-enhanced
endogenous incretin activity, resulting in improved glu-
Endogenous GLP-1 and GIP are rapidly degraded in less cose homeostasis. Likewise, several studies [10,36–40]
than 2 minutes by the ubiquitous enzyme dipeptidyl demonstrated that the DPP-4 inhibitors vildagliptin and
peptidase-4 (DPP-4), with almost 50% occurring at the sitagliptin increase endogenous active GLP-1 levels,
intestinal capillaries close to the site of GLP-1 and GIP enhance insulin release, and reduce glucose-related
release, limiting potential therapeutic application of glucagon levels.
these hormones. Attempts to exploit activity of GLP-1
therapeutically have thus focused on development of Long-term treatment with DPP-4 inhibitors resulted in
synthetic agents that mimic incretin action but are resist- preserved islet cell function in diabetic rodents and
ant to DPP-4 degradation (GLP-1 mimetics such as improved b-cell survival, with increased neogenesis
exenatide or analogues such as liraglutide). Controlled and reduced apoptosis [3,41,42]. Vildagliptin increased
clinical trials of these subcutaneously administered b-cell mass and b-cell replication with decreased b-cell
agents [20–24] have demonstrated glycated hemoglobin apoptosis in neonatal rats [41]. Similar effects on b-cell
(HbA1c) lowering potential of 0.8–1%, with weight loss mass preservation and regeneration have been shown in
ranges of 0.9–2.5 kg, associated with clinically relevant streptozotocin-induced diabetic mice with sitagliptin
gastrointestinal side effects that tend to subside over [42].
time. An alternative incretin-related therapy has been
development of oral agents that inhibit the enzyme Specificity of dipeptidyl peptidase-4 inhibition
DPP-4 and thus enhance circulating levels of active With the recognition that inhibition of the closely related
incretins [5,25,26,27]. This review focuses exclusively enzymes DPP-8 and DPP-9 produces potential toxic
on these oral DPP-4 inhibitors as novel therapeutic effects [29], it is important to demonstrate that DPP-4
agents to increase endogenous incretin activity. inhibitors developed as therapeutic agents do not
appreciably inhibit these enzymes – especially at the
doses tested in clinical trials.
Dipeptidyl peptidase-4 inhibitors
Dipeptidyl peptidase 4 is a membrane-bound serine Vildagliptin exhibits a high-affinity inhibitory effect on
dipeptidase, with a soluble form in plasma. It is ubiqui- DPP-4 [10,43,44] and is itself a substrate of the enzyme,
tously found in multiple tissues including vascular endo- binding in a two-step, reversible, competitive process
thelial cells and immune-related cells (it is identical to consisting of a rapid-binding phase followed by a slow
CD26, a marker for activated T cells) [28]. Specific DPP- tight-binding phase, a process that is not representative of
4 inhibition does not affect CD26 immune activation, a simple competitive inhibitor pattern of binding [43,45].
however. Potential involvement in T-cell activation and Using recombinant human enzymes, the Ki for vildaglip-
proliferation is mainly related to DPP-8 and DPP-9, tin was 3 nmol/l, 810 nmol/l, and 97 nmol/l for DPP-4,
demonstrated in vitro by comparing highly selective DPP-8, and DPP-9, respectively, after 100-fold dilution,
and nonselective DPP-4 inhibitors [29]. DPP-4 enzyme and half-life values for dissociation of the enzyme-inhibi-
activity with specificity for cleavage at proline residues is tor complexes of 55 minutes for DPP-4 and less than
critical for the rapid degradation of GLP-1 and GIP 10 seconds for DPP-8 and DPP-9 [44]. The latter finding
[30,31], as indicated by the fact that most of the measur- suggests that the functional selectivity of vildagliptin for
able endogenous GLP-1 and GIP is already cleaved DPP-4 during chronic inhibition, given its slow tight
metabolites and selective inhibition of this enzyme binding, is likely much larger than that suggested by
prevents the in-vivo N-terminal degradation of those comparison of Ki values alone [44].
peptides [31–35].
Sitagliptin is a competitive, reversible inhibitor of
Development of selective oral DPP-4 inhibitors that DPP-4 (median inhibitory concentration ¼ 18 nmol/l,
increase endogenous GLP-1 and GIP provides a more Ki ¼ 9 nmol/l) that is also highly selective over other
physiologic glucose-dependent antidiabetic effect on proline-specific peptidases and does not exhibit inhi-
insulin and glucagon secretion. There are multiple selec- bition of DPP-8 or DPP-9 (Ki 50) or other related
tive DPP-4 inhibitors in development – including the proteases [36,40,46].
recently approved sitagliptin; vildagliptin, which is await-
ing approval in early 2007; saxagliptin; alogliptin; and Pharmacokinetics
PHX1149. Sitagliptin and vildagliptin have been most Vildagliptin is metabolized by hydrolysis. Single-dose
studied and are thus the focus of this review. studies show that although exposure to vildagliptin

3. MED/109; Total nos of Pages: 11;
DPP-4 inhibitors Rosenstock and Zinman 3
increases in elderly patients (!70 years), this increase postprandial glucose, and reduced HbA1c levels. Mech-
does not affect DPP-4 inhibition, and thus, no dosage anisms responsible for this effect on lipid metabolism
adjustment is considered necessary in elderly patients remain to be defined.
[47]. Neither sex nor body mass index affected vildaglip-
tin pharmacokinetics or DPP-4 inhibition. A phase 3 monotherapy study with sitagliptin [54],
described here, showed significant increments of post-
Available information on sitagliptin pharmacokinetics meal insulin and C-peptide area under the concentration
indicates that dosage adjustment is not required for curve (AUC), ratio of insulin AUC/glucose AUC, and
age, sex, or obesity [37,38]. Sitagliptin is eliminated HOMA-B index (homeostasis model assessment),
primarily via the kidney, however, and drug exposure suggesting improvements in b-cell function.
is increased according to degree of renal function. Dose
adjustments are required in patients with renal impair- Long-term efficacy of dipeptidyl peptidase-4 inhibitors
ment [48,49]. Large-scale treatment studies with vildagliptin and sita-
gliptin in monotherapy or combination therapy (as add-on
Vildagliptin and sitagliptin are rapidly absorbed and have ¨
treatment or in drug-naıve patients) in type 2 diabetes
a bioavailability of $80–85%, and the pharmacokinetic have suggested that DPP-4 inhibitors are associated with
and clinical data substantiate the once-daily dosing regi- a remarkably benign safety profile, including infrequent
mens [10,27,38,39]. It has been estimated that approxi- hypoglycemia and absence of weight gain, with adverse
mately 80% of inhibition of DDP-4 activity, resulting in event rates basically comparable to placebo (Table 1)
twofold to threefold increase in active GLP-1 levels, is (Stein P, presented at: American Diabetes Association
needed to achieve near-maximal lowering of postprandial 66th Scientific Sessions; 13 June 2006; Washington, DC)
glucose excursions [10,27]. Single doses of 25 mg and and Table 2 (Nathwani A, presented at: American Dia-
200 mg of sitagliptin dose-dependently inhibited DPP-4 betes Association 66th Scientific Sessions; 13 June 2006;
activity by 47% and 80%, respectively, at 24 hours after Washington, DC).
administration, corresponding to plasma sitagliptin levels
of 22 nmol/l and 96 nmol/l, respectively [38]. Coadminis- Notably, these trials have established consistent efficacy
tration of vildagliptin and sitagliptin with other antidia- in reducing HbA1c levels (Fig. 1 [55,56,57,58,
betic agents has revealed little or no propensity for 59,60,61,62] and Fig. 2 [54,63,64,65,66,67]), with
drug–drug interaction with metformin, rosiglitazone, gly- greatest reductions in HbA1c occurring in patients with
buride, simvastatin, pioglitazone, or warfarin [10,27,50]. the highest baseline levels. There are no head-to-head
studies comparing these two DPP-4 inhibitors, and cau-
Mechanistic studies tion must therefore be exercised in examining relative
¨
An early study on insulin secretion in drug-naıve patients effectiveness. Factors that must be considered in inter-
[51] showed that although insulin response to meals did preting any study include baseline HbA1c and the charac-
not differ between patients receiving placebo and those teristics of the study population, especially the type of
receiving vildagliptin, vildagliptin treatment was associ- diabetes therapy undertaken prior to study entry.
ated with lower fasting and prandial glucose levels,
suggesting augmented glucose sensitivity of b cells. A Several phase 2 and 3 studies with vildagliptin and
subsequent placebo-controlled study [52] susing a math- sitagliptin have been published, but some are available
ematical model describing insulin secretory rate as a only from reported abstracts presented at scientific
function of glycemia showed significant improvements
in b-cell function, manifested as increased insulin
secretion at any given glucose level. Table 1 Sitagliptin adverse event profile (incidence — 3%)a
Sitagliptin 100 mg
The effect of vildagliptin on patterns of glucagon (n ¼ 1082), %
secretion was also examined. In response to a mixed Placebo Difference versus
meal, vildagliptin reduced glucagon release compared (n ¼ 778), % placebo (95% CI)
with placebo [51]. Treatment with vildagliptin also Upper respiratory 6.7 6.8 0.1 (À2.3, 2.4)
demonstrated reduced glucagon levels over a 24-hour tract infection
Headache 3.6 3.6 0
period as compared with placebo [52]. Nasopharyngitis 3.3 4.5 1.2 (À0.7, 3.0)
Diarrhea 2.3 3.0 0.7 (À0.9, 2.2)
Of interest, a recent study examining response to a fat- Arthralgia 1.8 2.1 0.3 (À1.1, 1.6)
Urinary tract infection 1.7 1.7 0
¨
rich meal in drug-naıve patients [53] showed significant
reductions in postprandial triglyceride-rich lipoproteins Adapted from Stein P, presented at: American Diabetes Association
66th Scientific Sessions; 13 June 2006; Washington, DC.
with vildagliptin compared with placebo, as well as a
Pooled phase III population. Adverse events with at least 3% incidence
suppressed glucagon secretion, decreased fasting and and numerically higher in sitagliptin than placebo group.

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4 Diabetes and the endocrine pancreas
Table 2 Vildagliptin adverse event profile (incidence — 5%)
Vildagliptin 100 mg Metformin up to 2 g daily Rosiglitazone 8 mg daily Placebo
dailya (n ¼ 1530), % (n ¼ 252), % (n ¼ 267), % (n ¼ 255), %
Any event 63.6 75.4 64.0 60.0
Nasopharyngitis 7.6 9.5 7.5 7.1
Headache 7.1 7.1 5.2 5.9
Dizziness 5.8 6.0 4.1 4.3
Upper respiratory tract infection 4.6 6.0 3.0 2.7
Diarrhea 3.1 26.2 2.6 3.1
Nausea 2.9 10.3 0.7 3.9
Abdominal pain 1.2 7.1 0.7 1.2
Adapted from Nathwani A, presented at: American Diabetes Association 66th Scientific Sessions; 13 June 2006; Washington, DC.
a
Pooled data from monotherapy trials with 50 mg twice daily and 100 mg once daily.CI, confidence interval.
meetings that should be considered preliminary until full pharmacotherapy for 3 months prior to study entry; base-
peer-reviewed publications are made available. line HbA1c 8.4%) [55], HbA1c decreased by À0.3% with
placebo and to a significantly greater extent in patients
Monotherapy versus placebo studies receiving vildagliptin 50 mg once daily and 50 mg twice
In a 24-week double-blind, randomized, placebo- daily by À0.8% and by À0.9% with vildagliptin 100 mg
¨
controlled study in 632 drug-naıve patients (no once daily. Of note, in patients with higher baseline
Figure 1 Vildagliptin efficacy in monotherapy and add-on combination therapy
HbA1c, glycated hemoglobin. Solid bars, vildagliptin
100 mg/d; hatched bars, vildagliptin 100 mg/d in (a)
Ã
combination. Versus baseline. yVersus placebo.
z
Vildagliptin 100 mg daily. ITT, intention to treat. Data Monotherapy Add-on combination therapy
from [55,56,57,58,59,60,61,62]. vs placebo vs Rosiglitazone vs Metformin Metformin Pioglitazone Pioglitazone† Insulin
1500 mg/d 45 mg qd 30 mg qd 30 U/d
Mean change 0.0 1 2 3 4 5 6 7 8
from baseline −0.2
in HbA1c (%) −0.4
*
−0.6 −0.5
−0.8
* −0.8 * * −0.8 *
−1.0 −0.9 * −0.9
* −1.0
−1.2 −1.1
−1.4
−1.6
−1.8
−2.0 *
−1.9
Study duration (wk) 24 24 24 52 24 24 24 24
n (ITT population) 380 340 697 780 416 398 592 256
Baseline HbA1c (%) 8.4 8.3 8.7 8.7 8.4 8.7 8.8 8.5
(b)
Monotherapy Add-on combination therapy
vs placebo vs Rosiglitazone vs Metformin Metformin Pioglitazone Pioglitazone† Insulin
1500 mg/d 45 mg qd 30 mg qd 30 U/d
Mean change 0.0 55 56 59 60 62 67 68 69
from baseline −0.2
in HbA1c (%) −0.4
*
−0.6 −0.5
−0.8
* −0.8 * * −0.8 *
−1.0 −0.9 * −0.9
* −1.0
−1.2 −1.1
−1.4
−1.6
−1.8
−2.0 *
−1.9
Study duration (wk) 24 24 24 52 24 24 24 24
n (ITT population) 380 340 697 780 416 398 592 256
Baseline HbA1c (%) 8.4 8.3 8.7 8.7 8.4 8.7 8.8 8.5

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DPP-4 inhibitors Rosenstock and Zinman 5
Figure 2 Sitagliptin efficacy in monotherapy and add-on combination therapy
HbA1c, glycated hemoglobin. Solid bars, sitagliptin
100 mg/d. Hatched bars, sitagliptin 100 mg/d in (a)
Ã
combination. Versus baseline. yVersus placebo.
z
Versus placebo þ metformin. ôVersus Monotherapy Add-on combination therapy
placebo þ pioglitazone. ITT, intention to treat. Data vs placebo Metformin 1500 mg/d Metformin† Pioglitazone
from [54,63,64,65,66,67]. vs placebo vs glipzide 200 mg qd 30--45 mg qd
Mean change 0.0 1 2 2 3 4 5 6
from baseline −0.2
in HbA1c (%) −0.4
−0.6 * *
* −0.5 −0.5
−0.8 −0.6 *
−0.7 *
−1.0
−0.85
−1.2
−1.4
−1.6
−1.8
−2.0 *
−1.9
Study duration (wk) 24 24 24 52 24 24
n (ITT population) 711 495 677 1135 1056 337
Baseline HbA1c (%) 8.0 8.1 8.0 7.7 8.8 8.1
(b)
Monotherapy Add-on combination therapy
vs placebo Metformin 1500 mg/d Metformin† Pioglitazone
vs placebo vs glipzide 200 mg qd 30--45 mg qd
Mean change 0.0 54 2 58 63 65 64 66
from baseline −0.2
in HbA1c (%) −0.4
−0.6 * *
* −0.5 −0.5
−0.8 −0.6 *
−0.7 *
−1.0
−0.85
−1.2
−1.4
−1.6
−1.8
−2.0 *
−1.9
Study duration (wk) 24 24 24 52 24 24
n (ITT population) 711 495 677 1135 1056 337
Baseline HbA1c (%) 8.0 8.1 8.0 7.7 8.8 8.1
HbA1c (8.8–9%) there were greater reductions with vildagliptin À placebo) with vildagliptin 50 mg once
both the 100-mg dose regimen (À1.3% and À1.4%) com- daily, 50 mg twice daily, or 100 mg once daily of
pared with 50 mg once daily (À0.8%). Fasting plasma À0.5%, À0.7%, and À0.9%, respectively. Mean HbA1c
glucose (FPG) decreased from an average baseline of decreased progressively in patients receiving vildagliptin
9.9 mmol/lbyÀ1.0, À0.8,andÀ0.8 mmol/lwith vildagliptin 100 mg daily (50 mg twice daily or 100 mg once daily) to
50 mg once daily, 50 mg twice daily, and 100 mg once daily, 7.4% and 7.3%, respectively, by week 12 and remained
respectively, compared with À0.1 mmol/l with placebo. relatively constant for the remainder of the study.
Body weight decreased by À1.8 kg, À0.3 kg, À0.8 kg, and Mean HbA1c changed minimally in patients receiving
À1.4 kg with vildagliptin 50 mg once daily, 50 mg twice placebo. The between-treatment differences in FPG
daily, 100 mg once daily, and placebo, respectively. were À0.6 mmol/l and À1.3 mmol/l in patients receiving
vildagliptin 50 mg once daily and in both groups receiving
In another 24-week double-blind, placebo-controlled, 100 mg daily, respectively, from an average baseline FPG
¨
study in 354 drug-naıve patients with an average baseline of 10.5 mmol/l. Body weight did not change significantly
HbA1c of 8.4% [56], there were significant reductions in any of the three vildagliptin groups, and it decreased
in mean HbA1c (between-treatment difference of by À1.4 Æ 0.4 kg in the placebo group.

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6 Diabetes and the endocrine pancreas
Monotherapy studies with sitagliptin include an early 12- À1.1% and À1.3%, respectively, meeting the statistical
week dose-ranging trial in 552 patients (baseline HbA1c criterion for noninferiority. Among patients with baseline
7.6–7.8%) [68] that showed placebo-subtracted HbA1c HbA1c greater than 9.0%, reductions were À1.8% with
reductions in the range of À0.4% to À0.6% with sitaglip- vildagliptin and À1.9% with rosiglitazone. Compared
tin 25 mg, 50 mg, or 100 mg once daily or 50 mg twice with rosiglitazone, vildagliptin produced significant
daily, compared with placebo. Greater reductions improvements in lipid measures, including triglycerides
occurred in patients with higher initial HbA1c (À9%), total cholesterol (À14%), low-density lipoprotein
levels. In a recent 18-week double-blind, randomized cholesterol (À16%), non-HDL (high-density lipoprotein)
¨
placebo-controlled trial in 521 patients (drug-naıve or cholesterol (À16%), and very low-density lipoprotein
after washout and a placebo run-in period; baseline cholesterol (À8%), but it produced a smaller increase
HbA1c 8.1%) [63], placebo-subtracted HbA1c reductions in HDL cholesterol (À5%). Body weight did not change
of À0.6% and À0.5% were obtained with sitagliptin with vildagliptin (À0.3 kg) but it significantly increased
100 mg and 200 mg once daily, respectively, as the with rosiglitazone (þ1.6 kg).
placebo group had an HbA1c increase of only þ0.1%
by study end. Among patients with baseline HbA1c of In a 1-year randomized, double-blind study in 780 drug-
9.0% or greater, reductions were À1.2% and À1.0% at the ¨
naıve patients [58], vildagliptin 50 mg twice daily
two respective doses, but in those with baseline HbA1c of reduced HbA1c by À1.0% versus À1.4% for metformin
8–8.9% or greater, reductions were À0.6% and À0.4% for 1000 mg twice daily from 8.7% at baseline. The differ-
sitagliptin 100 mg and 200 mg once daily, respectively, ence did not meet noninferiority criteria at year 1. The
compared with placebo, whereas in patients with baseline study has been extended for an additional year to test
HbA1c of less than 8%, reductions were only À0.4% and durability of the glycemic effects. Mild hypoglycemia
À0.3%, respectively. FPG was reduced by À0.7 mmol/l occurred in 0.6% of patients on vildagliptin and 0.4% of
and À0.6 mmol/l with sitagliptin100 mg and 200 mg once patients on metformin. Gastrointestinal side effects were
daily, respectively, from an average baseline of 10 mmol/l. significantly lower in patients on vildagliptin, occurring in
Body weight decreased by À0.7 kg, À0.6 kg, and À0.2 kg 22% versus 44% of patients on metformin, including
with placebo and sitagliptin 100 mg and 200 mg once diarrhea (6% versus 26%), nausea (3% versus 10%),
daily, respectively. abdominal pain (2% versus 7%), and vomiting (2% versus
4%). Weight change was þ0.3 kg with vildagliptin and
In another randomized 24-week, double-blind, placebo- À1.9 kg with metformin.
¨
controlled study in 741 patients (drug-naıve or after
washout and a placebo run-in period; baseline HbA1c Combination therapy studies
8.0%) [54], sitagliptin 100 mg and 200 mg once daily had An early randomized study of vildagliptin in combination
placebo-subtracted HbA1c reductions of À0.8% and with metformin [69] demonstrated that the HbA1c
À0.9%, respectively, as the placebo group had an HbA1c improvement achieved was sustained and deterioration
increase of þ0.2%. Greater placebo-subtracted HbA1c of glycemic control was prevented for up to 1 year. In this
reductions in patients with baseline HbA1c of 9% or study, vildagliptin 50 mg/d or placebo was added to
higher were demonstrated with sitagliptin 100 and metformin for an initial 12-week treatment period, result-
200 mg (À1.5% in both) compared with those with base- ing in a À0.6% reduction in HbA1c from baseline 7.7%
line 8% or higher to less than 9% (À0.8% and À1.1%, with add-on vildagliptin and no changes with placebo.
respectively) or less than 8% (À0.6% and À0.65%), but no In a subsequent blinded extension for an additional
data were provided on the specific HbA1c changes in the 40 weeks, the HbA1c improvements remained stable in
placebo groups included in this subanalysis. Placebo- the combination vildagliptin-plus-metformin group but
subtracted reductions of FPG with sitagliptin 100 and showed progressive deterioration in the metformin-only
200 mg once daily were À1 mmol/l and À1.2 mmol/l, group, resulting in a between-group difference in HbA1c
respectively, and the 2-hour postprandial glucose values that increased from À0.7% at 12 weeks to À1.1% at study
were À2.6 mmol/l and À3.0 mmol/l, respectively. Change end. Of note, despite the sustained improvement in
in body weight was À0.2 kg and À0.1 kg with the two glycemic control, the vildagliptin-plus-metformin group
respective sitagliptin doses and À1.1 kg with placebo. showed no evidence of weight gain (À0.2 kg in both
groups by endpoint).
Monotherapy versus active control studies
In a 6-month head-to-head, randomized, double-blind A recent randomized, 24-week double-blind study of the
trial in 697 drug-naıve patients [57], vildagliptin pro-
¨ addition of vildagliptin 50 mg once daily or 50 mg twice
vided glycemic control similar to that seen with rosigli- daily or placebo to ongoing stable metformin treatment
tazone, but without weight gain. From a baseline HbA1c (!1500 mg/d) in 416 patients with baseline HbA1c 8.4%
of 8.7%, vildagliptin 50 mg twice daily was as effective as [59]. The HbA1c increased from baseline by þ0.2% in
rosiglitazone 8 mg once daily in reducing HbA1c by the placebo group and was reduced by À0.5% and À0.9%

7. MED/109; Total nos of Pages: 11;
DPP-4 inhibitors Rosenstock and Zinman 7
with the addition of vildagliptin 50 mg/d and 100 mg/d, per-protocol population and by À0.5% and 0.6% in the
respectively, with FPG reductions of À0.8 mmol/l and modified intent-to-treat population for sitagliptin and
À1.7 mmol/l. Notably, the addition of vildagliptin glipizide, respectively, establishing the noninferiority
appeared to slightly reduce or at least did not increase criteria between the two agents. Greater reductions in
the frequency of metformin-related adverse gastrointes- HbA1c were seen with progressively higher baseline
tinal effects. levels. Body weight change with sitagliptin was
À1.5 kg compared with þ1.1 kg for glipizide. The inci-
In a 24-week double-blind, randomized trial in 701 dence of hypoglycemia in sitagliptin-treated patients
patients on metformin therapy (!1500 mg/d) (prior naıve ¨ (5%) was significantly less than in glipizide-treated
therapy, metformin only, or any monotherapy; or on prior patients (32%).
metformin in any combination therapy after washout and
followed by a metformin run-in period, baseline HbA1c The potential of a DPP-4 inhibitor in combination with a
8.0%) [64], sitagliptin 100 mg once daily reduced HbA1c thiazolidinedione was recently reported in three separate
by À0.65% compared with metformin plus placebo, and studies. The conventional strategy for both sitagliptin
significantly more patients taking the sitagliptin/metfor- and vildagliptin was to test the addition of the DPP-4
min combination achieved target HbA1c of less than 7% inhibitor in patients with inadequate glycemic control on
than those on metformin plus placebo (47% versus 18%, previous thiazolidinedione monotherapy. In a 24-week,
respectively). The sitagliptin combination was associated double-blind trial [67], 353 patients were randomly
with improvements in b-cell function as assessed by assigned to receive sitagliptin 100 mg once daily or
postmeal insulin and C-peptide AUCs and postmeal placebo following 8–14 weeks on a stable dose of piogli-
insulin AUC/glucose AUC ratio, HOMA-B index, and tazone (baseline 8.1% and 8.0%, respectively). Sitagliptin
proinsulin: insulin ratio. No increases in gastrointestinal add-on to pioglitazone reduced HbA1c by À0.7% as
adverse events or hypoglycemia were reported with the compared with pioglitazone plus placebo, with final
addition of sitagliptin to metformin. Body weight change HbA1c of 7.2% and 7.8%, respectively. More patients
was À0.7 kg with sitagliptin plus metformin and À0.6 kg in the combination sitagliptin/pioglitazone group reached
with metformin plus placebo. target HbA1c of less than 7% (47% versus 23%). Change
in body weight did not differ between the sitagliptin-
Interestingly, the combination of sitagliptin plus metfor- plus-pioglitazone group and the pioglitazone-plus-
min as first-line therapy was comprehensively tested in a placebo group (þ1.8 versus þ1.5 kg).
six-arm randomized 24-week trial [65] that included
sitagliptin 100 mg þ metformin 1000 mg or sitagliptin Another 24-week, double-blind study [60] compared
100 mg þ metformin 2000 mg/d versus monotherapy with the effects of vildagliptin 50 mg once daily or 50 mg
metformin 1000 mg/d or 2000 mg/d, sitagliptin 100 mg/d, twice daily versus placebo as add-on therapy in 463
and placebo in separate groups for 24 weeks (all doses patients receiving ongoing thiazolidinedione mono-
administered twice daily). At study end, the placebo- therapy who had been converted to maximum piogli-
subtracted HbA1c improvements in those receiving sita- tazone 45 mg for at least 4 weeks prior to randomization.
gliptin 100-mg/d monotherapy, metformin 1000-mg and HbA1c improved significantly from a baseline of $8.7%
2000-mg/d monotherapy, and the sitagliptin/metformin in patients receiving vildagliptin 50 or 100 mg daily by
combinations 100/1000 mg and 100/2000 mg/d were À0.8% and À1.0%, respectively, compared with À0.3%
À0.8%, À1.0%, 1.3%, À1.6%, and À2.1%, respectively, in those receiving placebo plus pioglitazone. These
as the placebo group HbA1c increased by þ0.2%. More results probably also reflect the initial increase of thia-
patients in the high-dose combination sitagliptin/metfor- zolidinedione dose during the run-in period in some
min 100/2000-mg group reached target HbA1c of less than patients.
7% than in the metformin 2000-mg monotherapy group
(66% versus 38%, respectively). The frequency of gastro- Most notably, the combination of vildagliptin plus pio-
intestinal side effects was similar with the sitagliptin ¨
glitazone as a first-line therapy in drug-naıve type 2
combinations and metformin monotherapy groups diabetes yielded robust results similar to those of the
and the frequency of hypoglycemia was very low initial combination described above of sitagliptin plus
(0.5–2.2%). metformin. In a randomized, double-blind, active-
controlled study, Rosenstock et al. [61] assessed two
Over a 52-week, double-blind, active-controlled trial different combination doses of vildagliptin plus pioglita-
[66], 1172 patients (baseline HbA1c 7.5%) on a stable zone compared with each agent in monotherapy given as
dose of metformin (!1500 mg/d) were randomly assigned initial treatment. This 24-week, four-arm study was
to add-on sitagliptin 100 mg once daily or glipizide 5 mg designed to assess the effects of vildagliptin (100 mg
once daily titrated up to 10 mg twice daily. At 1 year, each once daily), pioglitazone (30 mg once daily), and
agent reduced HbA1c by À0.7%, in the completers vildagliptin combined with pioglitazone (50/15 mg or

8. MED/109; Total nos of Pages: 11;
8 Diabetes and the endocrine pancreas
Figure 3 Vildagliptin in combination with pioglitazone as first-line therapy
(a) Mean (ÆSE) glycated hemoglobin
(HbA1c) during 24-week treatment with (a)
vildagliptin (100 mg once daily, open
circles), pioglitazone (30 mg once daily, Mean
open squares), or vildagliptin combined HbA1c (%) 9.0
with pioglitazone at doses of 100/30 mg
once daily (closed triangles) or 50/15 mg
once daily (closed diamonds) in drug-
¨
naıve patients with type 2 diabetes
ÃÃÃ
mellitus. P 0.001 for vildagliptin/ 8.0
pioglitazone 100/30 mg once daily
***
versus pioglitazone monotherapy. P
values for vildagliptin / pioglitazone 50/
15 mg once daily versus pioglitazone
monotherapy at weeks 4, 12, 16, and 24
7.0
were 0.039, 0.003, 0.006, and 0.020,
respectively) [61]. (b) Percentage of ***
patients achieving target HbA1c 7%.
Pioglitazone monotherapy (30 mg once *** ***
daily, open bars); high-dose vildagliptin /
pioglitazone combination (100/30 mg 6.0
once daily, checkered bars); low-dose −4 0 4 8 12 16 20 24
vildagliptin / pioglitazone combination Time (Wk)
(50/15 mg once daily, hatched bars);
vildagliptin monotherapy (100 mg once
daily, closed bars).
ÃÃÃ
P 0.001 versus (b)
either monotherapy. Data from [61]. Percent 80
achieve
target
70 ***
65.0
60
53.6
50
42.9 42.5
40
30
20
100/30 mg once daily). At study end, improvements from patients receiving pioglitazone monotherapy (9.3%)
an average baseline HbA1c of 8.7% in patients receiving and was less frequent in those receiving a low-dose
vildagliptin monotherapy, pioglitazone monotherapy, combination (3.5%). The expected increase in body
50/15-mg combination, and 100/30-mg combination were weight from the pioglitazone component (þ2.1 kg) in
À1.1%, À1.4%, À1.7%, and À1.9%, respectively (Fig. 3) the 100/30-mg combination was not significantly differ-
[61], and mean changes in FPG were À1.3, À1.9, À2.4, ent from that seen in the pioglitazone monotherapy
and À2.8 mmol/l, respectively. Of note, HbA1c was group.
reduced by À2.8% (from a baseline of 10.0%) in patients
with initial HbA1c greater than 9.0% who received vil- Finally, the efficacy of vildagliptin 50 mg twice daily or
dagliptin 100 mg once daily plus pioglitazone 30 mg once placebo added to insulin treatment was assessed by
daily. More patients in the combination vildagliptin / Fonseca et al. [62] in a 24-week randomized trial in
pioglitazone 100/30-mg group reached target HbA1c of 256 patients receiving different insulin regimens (total
less than 7% than did patients receiving vildagliptin or dose 30 U/d) with inadequate glycemic control. At
pioglitazone alone in monotherapy (65% versus 42.5% or baseline, mean HbA1c was 8.5% and the mean daily
43%, respectively). Peripheral edema was highest in insulin dose was 82 IU. Insulin regimens were not

9. MED/109; Total nos of Pages: 11;
DPP-4 inhibitors Rosenstock and Zinman 9
optimized, but nevertheless, mean HbA1c was signifi- Acknowledgements
cantly reduced in patients receiving vildagliptin com- The authors would like to thank BioScience Communications
(New York, NY), which provided editorial assistance through an
pared with placebo (À0.5% versus À0.2%). There was a educational grant from Novartis Pharma, AG, which had no previous
trend to slightly lower insulin doses in the vildagliptin access to or input on the content of this paper.
group. Of note, in patients aged 65 years or older, vilda-
gliptin reduced HbA1c by À0.7% compared with no Duality of interests: JR and BZ have received grant support and
change for placebo. Notably, hypoglycemia was less professional consulting honoraria from Merck and Novartis.
common and less severe in patients receiving vildaglip-
tin, which may perhaps be related to improved a-cell References and recommended reading
Papers of particular interest, published within the annual period of review, have
glucose sensing. been highlighted as:
of special interest
of outstanding interest
Conclusion Additional references related to this topic can also be found in the Current
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