Dpp4 beta cell preservation

Dipeptidyl Peptidase-4 Inhibitors and Preservation of Pancreatic Islet-Cell Function: A
Critical Appraisal of the Evidence

R.E. van Genugten, D.H. van Raalte, M. Diamant
Diabetes Center, Department of Internal Medicine, VU University Medical Center,
Amsterdam, The Netherlands

Corresponding author R.E. van Genugten, MD, Diabetes Center, Dpt. of Internal Medicine,
VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands,
PO Box 7057. Tel: +31 20 444 2264, Fax: +31 20 444 3349, E-mail: r.vangenugten@vumc.nl

Manuscript word count: 5305
Abstract word count: 220
Number of tables: 6

Keywords type 2 diabetes, incretins, GLP-1, GIP, beta cell, beta-cell mass, alpha cell,
sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin

Disclosure statement RvG and DvR declare no conflict of interest. Through MD, the VU

University Medical Center received research grants from Amylin, Eli Lilly, Glaxo Smith

Kline, Merck, Novartis, Novo Nordisk, Sanofi Aventis and Takeda, consultancy fee from Eli

Lilly, Merck, Novo Nordisk, Sanofi Aventis and speaker fee from Eli Lilly, Merck and Novo

Nordisk.

Acknowledgements RvG is supported by the EFSD/MSD clinical research programme 2008
and DvR is supported by the Dutch Top Institute Pharma (TIP) grant T1-106.

This is an Accepted Article that has been peer-reviewed and approved for publication in the Diabetes,
Obesity and Metabolism, but has yet to undergo copy-editing and proof correction. Please cite this
article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01473.x

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Abstract
Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive beta-cell
dysfunction in the presence of insulin resistance. None of the currently-available T2DM
therapies is able to change the course of the disease by halting the relentless decline in
pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin
enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering
agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4.
DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-
related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent
studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) beta-cell mass and
pancreatic insulin content. Studies in humans with T2DM have indicated improvement of
islet-cell function, both in the fasted state and under postprandial conditions and these
beneficial effects were sustained in studies with a duration up to two years. However, there is
at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on
beta-cell function after cessation of therapy. Long-term, large-sized trials using an active
blood glucose lowering comparator followed by a sufficiently long washout period after
discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably
preserve pancreatic islet-cell function in patients with T2DM.

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Introduction
Prevention and treatment of type 2 diabetes mellitus (T2DM) and its complications are
worldwide major health care issues given the alarming global increase in the prevalence of
T2DM due to the obesity pandemic [1]. Abdominal obesity and hepatic steatosis decrease
peripheral and hepatic insulin sensitivity. Under normal circumstances, pancreatic beta cells
compensate for this reduced insulin sensitivity by enhancing insulin secretion. However, in
susceptible individuals, this compensatory response is hampered by incipient beta-cell
dysfunction resulting in a gradual rise in blood glucose concentrations and finally, the
development of T2DM [2]. Beta-cell dysfunction is not only a prerequisite for the
development of T2DM, but, due to its progressive nature, it additionally determines the
progressive course of the disease. Accordingly, T2DM is characterised by progressive loss of
glycaemic control and increased need for multiple therapies to sustain normoglycaemia [3]. In
the United Kingdom Prospective Diabetes Study (UKPDS) the decline of pancreatic beta-cell
function in newly diagnosed patients with T2DM was estimated to occur at an annual rate of
approximately 4% [3]. In addition to loss of beta-cell function, autopsy studies have shown
that patients with T2DM have decreased beta-cell mass as compared to age- and BMI-
matched non-diabetic individuals [4]. Thus, it is likely that both reduced number of beta-cells
and impaired beta-cell function, leading to a diminished functional islet mass, contribute to
the development and subsequently, the progressive course of T2DM. More recently, reduced
inhibition of glucagon-secreting alpha-cells has also been identified to contribute to
hyperglycaemia in T2DM, since glucagon stimulates hepatic glucose production [5]. Hence,
in patients with T2DM, functional pancreatic islet-cell balance is impaired resulting in
chronic hyperglycaemia. A major challenge in the treatment of T2DM is to identify a
therapeutic agent that can alter the course of the disease by preventing this gradual decline in
pancreatic islet-cell function and diminution of beta-cell mass. Current T2DM treatment
options, most notably metformin and the sulfonylurea derivatives, fail in this regard, since
glycaemic control deteriorates over time despite treatment with these drugs [3,6]. Eventually,
almost all patients with T2DM will require insulin replacement therapy.
In recent years, a new class of glucose-lowering medication based on incretin
hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide
(GIP), has been introduced for the treatment of T2DM. These compounds enhance the so-
called incretin effect, i.e. the phenomenon that following oral ingestion of glucose, due to the
secretion of the gut-derived incretin hormones, the increase in plasma insulin response is two
to three fold greater than is the case when the same level of hyperglycaemia is produced by

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intravenous administration of glucose [7]. Incretin-enhancers or dipeptidyl peptidase (DPP)-4
inhibitors inhibit the incretin-degrading enzyme DPP-4 that is ubiquitously present, thereby
increasing the bio-availability of active GLP-1 and GIP which results in enhanced meal-
related insulin secretion. In addition, DPP-4 inhibitors lower postprandial glucagon responses
and thus may restore functional islet cell balance. In this review we will discuss the evidence
that DPP-4 inhibitors improve both beta-cell and alpha-cell function. We will discuss
preclinical data and subsequently address the effects of all currently-available DPP-4
inhibitors on fasting and dynamic measures of islet cell function as reported in randomised
clinical trials in humans (last PUBMED search 1-Apr-2011). Finally, based on the current
evidence, we will discuss the potential of these agents to durably enhance islet-cell function in
patients with T2DM and modify the progressive course of the disease.

DPP-4 inhibitors: mode of action and clinical efficacy
The incretin hormones GLP-1 and GIP are secreted from the small intestine directly in
response to food intake and stimulate postprandial glucose-dependent insulin secretion. In
recent years several studies have unravelled the pathways via which GLP-1 and GIP increase
postprandial insulin secretion [8]. GLP-1 and GIP receptors are present on pancreatic beta
cells via which the incretin hormones directly enhance insulin secretion from insulin
containing granules. However, the most important contributor may be GLP-1’s effect on
afferent nerves in the intestinal mucosa or portal vein [9,10], since less than 25% of the active
metabolite eventually reaches the pancreatic islets, due to direct cleavage by the enzyme DPP-
4 upon secretion from the L-cells located in the gut [11]. Furthermore GLP-1 lowers glucagon
secretion mainly indirectly via somatostatin, in addition to a proposed direct inhibition
through GLP-1 receptors on the alpha cells. Although GLP-1-stimulated insulin secretion
from the beta-cell is also believed to contribute to the indirect route by which GLP-1
decreases glucagon, studies in T1DM patients who had no residual beta-cell function also
showed decreased (postprandial) glucagon secretion [12,13], arguing against an important
role of insulin secretion in GLP-1’s effect on glucagon. GIP, however, exerts a
glucagonotropic effect in the euglycaemic state [14]. In addition, evidence exists from
preclinical studies that incretins also replenish insulin stores and may promote beta-cell mass
by increasing beta-cell proliferation and reducing apoptosis [8,15].
Endogenous GLP-1 and GIP are not suitable for therapeutic use in humans, since
directly upon secretion, both GLP-1 and GIP are cleaved by the enzyme DPP-4, resulting in
an active plasma half-life time of just several minutes and thus necessitating continuous

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parenteral administration [16]. DPP-4 inhibitors increase endogenous circulating levels of
active GLP-1 and GIP by blocking the incretin-degrading enzyme DPP-4 and thereby
approximately double postprandial active, i.e. non-degraded, incretin levels [17]. The extent
to which other DPP-4 substrates, such as glucagon-like peptide-2, peptide YY [18], gastrin
releasing peptide or pituitary adenylate cyclase activating polypeptide (PACAP) [19],
contribute to the glucose-lowering effect in vivo remains at present unclear.
Treatment of patients with T2DM with DPP-4 inhibitors as monotherapy has shown
beneficial effects on glycaemic control as measured by haemoglobin A1c (HbA1c) levels,
compared to placebo: mean change in HbA1c as compared to placebo ranged from -0.67% to
-0.79% (-9 to -7 mmol/mol); P <0.001 [20]. DPP-4 inhibitors can be administered orally, once
or twice daily. Currently, the DPP-4 inhibitors sitagliptin and saxagliptin are approved by
both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)
for use as monotherapy (sitagliptin only) or as add-on to other glucose-lowering medication in
the treatment of T2DM. Vildagliptin is approved for the European market only as add-on and
alogliptin is currently approved for the Japanese market and awaiting approval by EMA and
FDA. The approval of linagliptin is currently pending, while several other companies have
DPP-4 inhibitors still under development.

DPP-4 inhibition improves pancreatic islet-cell function: preclinical data
Administration of DPP-4 inhibitors to several rodent models of diabetes (e.g. high-fat diet-
induced and/or streptozotocin (STZ)-induced diabetes) resulted in improved fasting and non-
fasting glucose control, together with enhanced plasma insulin levels, reduced plasma
glucagon levels and increased pancreatic insulin content (summarised in Table 1) [21-35].
However, in addition to the use of different rodent models, these studies use diverse methods
in order to describe glucose metabolism and pancreatic function, which potentially hampers
comparison.
Flock et al. demonstrated the necessity of the presence of functional incretin receptors on islet
cells for the glucoregulatory effect of DPP-4 inhibitors in dual incretin-receptor knock-out
(DIRKO) mice. In these mice, DPP-4 inhibitor treatment did not exert any favourable effect,
whereas in wild type mice DPP-4 inhibition resulted in improved glycaemic control [26]. The
beneficial effects of DPP-4 treatment on fasting and non-fasting glycaemic control remained
present during chronic treatment (up to three months) (Table 1). Moreover, when compared to
conventional therapy, the sulphonylurea (SU) agent glipizide, DPP-4 inhibitor treatment
resulted in prolonged improvement in glycaemic control over ten weeks, whereas in the

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glipizide-treated mice glycaemic control deteriorated after approximately five weeks despite
ongoing treatment [25,32].
Several studies have assessed the effects of acute and chronic treatment with DPP-4
inhibitors on pancreatic islet morphology and beta-cell mass in rodents (Table 1). Chronic
DPP-4 inhibitor treatment (two to three months) was demonstrated to increase beta-cell mass
by promoting cell proliferation and reducing apoptosis [24,25,29]. Interestingly, after a
twelve-day drug washout period, durable beneficial effects on beta-cell mass, i.e. enhanced
beta-cell replication and reduced apoptosis, were seen in neonatal rats treated with a DPP-4
inhibitor for nineteen days [35]. In contrast, other studies showed no effect of treatment with
DPP-4 inhibitors on total beta-cell mass [21,23,28,34], however in various studies a beneficial
effect on the intra-islet distribution pattern of alpha and beta cells was shown [27,32]. In
addition, DPP-4 inhibition demonstrated durable effects on pancreatic islet mass and/or
insulin content while this effect was not seen by SU [32]. Furthermore, combination treatment
of a DPP-4 inhibitor with either the thiazolidinedione (TZD) pioglitazone [31] or the alpha-
glucosidase inhibitor voglibose [34], resulted in increased pancreatic insulin content,
compared to either agent alone.
To summarise, in various animal models, DPP-4 inhibitors improved glucose
tolerance, by enhancing insulin secretion and reducing glucagon secretion and this effect
outlasted the action of the presently used blood-glucose lowering agents, most particularly
SU. Since DPP-4 inhibitors also stimulated insulin production, increased beta-cell mass and
restored pancreatic islet topography in these rodent models, DPP-4 inhibition holds a promise
as therapeutical option with regard to preservation of beta-cell function also in humans with
T2DM.

DPP-4 inhibition and pancreatic beta-cell function: clinical data
Measures of beta-cell function in humans
Pancreatic beta-cell function involves many different aspects, including glucose and nutrient
sensing, insulin secretion and production following stimulation by different secretagogues and
pro-insulin to insulin processing. Therefore, any test performed, and any variable derived
thereof, has limitations and should be regarded as mere surrogate estimate. Also, irrespective
of the actual test performed it is always important to keep in mind that insulin secretion
responses should be interpreted in the context of prevailing insulin sensitivity and glucose
level [2]. As such, an identical insulin response before and following an intervention that
reduces blood glucose and body weight, may still designate an improvement when taking into

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account the glucose and body weight changes.
In humans, the various aspects of beta-cell function can be assessed by several
methods including static and dynamic measurements. The most widely used estimates are the
static or fasting measures, including the homeostatic model assessment beta-cell function
index (HOMA-B) [36] and the pro-insulin to insulin (PI/I) ratio [37]. However, the value of
fasting measures of beta-cell function is limited, since beta cells are mostly active in the
postprandial and hyperglycaemic state. Dynamic measures may therefore be more appropriate
to quantify beta-cell function. As such, many studies have calculated parameters of beta-cell
function from intravenous glucose challenge tests, oral glucose tolerance tests or standardized
mixed meal tests. Typical beta-cell measurements derived from oral glucose load tests include
the postprandial insulin area under the curve (AUC) corrected for glucose AUC
(AUCinsulin/glucose), which measures insulin secretion during the total postprandial period, and
the insulinogenic index (IGI), a measure of early phase insulin secretion (i.e. insulin secretion
during the first 30 minutes after meal ingestion corrected for glucose). In addition,
mathematical models have been developed to describe postprandial beta-cell function
[38,38,39]. These models describe different aspects of the insulin secretory function.
Furthermore, dynamic measures of beta-cell function may be assessed from the
intravenous glucose tolerance test (IVGTT) or the hyperglycaemic (arginine-stimulated)
clamp method. Although the hyperglycaemic clamp test, due to its high reproducibility, is
currently regarded as the gold standard for assessing pancreatic beta-cell function, it is a non-
physiological test since glucose consumption does not normally occur via the intravenous
route, and additionally, its use is limited for routine measurements due to the demands
imposed on the patient and the associated high cost.
In the sections below, we will present the results of clinical trials using DPP-4
inhibition in patients with T2DM and subjects with pre-diabetes, i.e. impaired glucose
metabolism, with regard to aforementioned static and dynamic parameters of beta-cell
function.

Effect of DPP-4 inhibitors on static measures of beta-cell function
DPP-4 inhibitor monotherapy was shown to improve fasting measures of beta-cell function,
including HOMA-B and PI/I ratio, in clinical trials in (drug-naïve) patients with T2DM
(Table 2) [40-50]. Concerning HOMA-B, trials of 12 to 26 week duration demonstrated an
increase within the range of 5.1% to 26.8 % following monotherapy with either sitagliptin,
vildagliptin, alogliptin, saxagliptin or linagliptin compared to placebo treatment (Table 2).

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Furthermore, PI/I ratio improved by treatment with all DPP-4 inhibitors given as
monotherapy relative to placebo: 24-26 week active treatment with either sitagliptin,
vildagliptin, alogliptin or linagliptin resulted in a decrease of PI/I ratio ranging from 0.04 to
0.12 (Table 2) [40,41,46,47,50].
When used as add-on therapy to other oral blood glucose-lowering agents such as
metformin, SU derivates or TZDs, DPP-4 inhibition exerted an additional beneficial effect on
these fasting parameters of beta-cell function in most studies (Table 3) [43,51-64]. DPP-4
inhibition as add-on to metformin improved static measures of beta-cell function comparable
to other glucose lowering agents as add-on to metformin, e.g. TZD [55] and SU, the latter
with regard to PI/I ratio only [54,56]. DPP-4 inhibitors as add-on to either SU [61], TZDs
[62,64] or metformin/SU combination therapy [60], similarly affected static parameters of
beta-cell function beneficially compared to placebo.

Effect of DPP-4 inhibitors on dynamic measures of beta-cell function
Postprandial parameters of beta-cell function Clinical trials that assessed the effect of DPP-4
inhibitors on beta-cell function measurements derived from standardised mixed-meal tests or
oral glucose tolerance tests are presented in Table 4 (monotherapy) [17,40,41,44,46,49,50,65-
73] and table 5 (combination treatment) [43,51-53,56,59,60,63,64,74-79].
The early beta-cell response, calculated as IGI, was improved by DPP-4 inhibition in
several trials in which monotherapy up to one year was assessed (approximate mean increase
of 38%) [44,46,49,67]. Saxagliptin as add-on to TZD resulted in increased IGI compared to
placebo as add-on to TZD after 24 weeks treatment (up to 150 % increase compared to
placebo) [64]. Postprandial AUCinsulin/glucose, was improved by both sitagliptin [40,41,44] and
vildagliptin [46,66,67,70] with an increase compared to placebo ranging from 15.1% to
38.6%. Drug-naïve diabetic patients with mild hyperglycaemia, i.e. HbA1c < 7.5% (58
mmol/mol), benefited from one year DPP-4 inhibitor treatment as well according to an
increase of 14.4% (P<0.001) in AUCinsulin/glucose [67] (Table 4). In addition, a beneficial effect
was also present in subjects at risk to develop T2DM, i.e. subjects with impaired fasting
glucose (IFG) and/or impaired glucose tolerance (IGT) [72,73]. DPP-4 inhibitors as add-on to
either metformin [51], SU [61] or metformin/SU [60] showed after 24 weeks treatment an
increase in AUCinsulin/glucose ratio within a range of 22.7% to 28.8%. In contrast, Retnakaran et
al., did not show different results for AUCinsulin/glucose (corrected for insulin resistance)
following 48 weeks sitagliptin treatment compared to placebo as add-on to metformin
(decrements in beta-cell function were 16.1 % and 31.7 % respectively; p=0.23). However,

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this intervention was preceded by a four-week intensive insulin treatment period which could
have outweighed the effects of DPP-4 inhibition [53].
Mathematical modelling of postprandial beta-cell function DPP-4 inhibitors improved
several model-derived parameters of beta-cell function. The model-based approach developed
by Mari et al. was used to assess beta-cell function after one year treatment with vildagliptin
50 mg QD in drug-naïve patients with T2DM. Several model-derived parameters of beta-cell
function improved significantly (insulin secretory rate by 17%, P<0.001; glucose sensitivity
of the beta-cell by 40%, P<0.001) [66]. This effect was shown for insulin secretory rate after
both four weeks of treatment (P<0.005) [80] and acute treatment (P<0.04) [81]. Based on
Cobelli’s model, Φtotal increased by 19.1% (P<0.05) and Φs almost doubled (93% increase;
P<0.05) after 24 weeks sitagliptin compared to placebo as add-on to metformin [82]. A
similar positive effect was seen in studies of shorter duration [69,71,83].
Parameters of beta-cell function derived from intravenous glucose studies Aaboe et al. [84]
investigated the effect of sitagliptin 100 mg QD after twelve weeks of treatment on
hyperglycaemic and arginine-stimulated clamp-derived parameters of beta-cell function in 24
patients with T2DM treated with metformin. With blood-glucose targeted at 20 mM, first-
phase insulin secretion, second-phase insulin secretion and arginine-stimulated insulin
secretion were increased, compared to placebo treatment. In accordance, Bunck et al. [85]
reported significantly improved clamp-derived beta-cell function parameters after one year
treatment with vildagliptin 100 mg QD in drug-naïve diabetic patients with mild
hyperglycaemia. Additionally, in patients with T2DM on metformin or diet, 12-week
vildagliptin treatment resulted in an increase in acute insulin response to intravenous glucose
(AIRg) of 50% (P=0.033) [86]. Utzschneider et al. investigated the effect of a six week
vildagliptin treatment during an intravenous glucose tolerance test in IFG subjects at high risk
for developing diabetes, and demonstrated in this population similarly an enhanced acute
insulin secretion (AIRg +27%, P<0.05) [72].

DPP-4 inhibition and pancreatic alpha-cell function: clinical data
Failure to suppress glucagon secretion under hyperglycaemic conditions is an important
feature of T2DM [5]. Several short- and long-term trials showed beneficial effects of DPP-4
inhibitors on postprandial glucagon excursions [49,64,65,69-71,73,77] (Table 4&5). With
regard to other glucose-lowering agents, the significantly reduced postprandial AUCglucagon
resulting from 24-week saxagliptin treatment, tended to surpass that of TZD treatment alone
(P=0.072) [64]. In subjects with impaired glucose metabolism there was no effect on

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postprandial AUCglucagon after a six week treatment with vildagliptin [72], although a twelve-
week treatment in a larger cohort of subjects at risk to develop T2DM did show a small but
significant decrease in glucagon levels (-7.6% compared to placebo, P=0.007) [73].
Furthermore, in a four week cross-over study, comparing vildagliptin 100 mg QD to placebo,
alpha-cell function was assessed both postprandially and during a stepped hyperinsulinaemic-
hypoglycaemic clamp. In accordance with other studies, postprandial AUCglucagon decreased
significantly by 9.7%. Moreover, during hypoglycaemia, the glucagon-lowering effect of
DPP-4 inhibition was attenuated [70]. The finding that DPP-4 inhibitors affect glucagon
levels dependent of prevailing blood glucose levels is clinically important given previous
concerns regarding these agents and their effect on the glucagon response to hypoglycaemia.
In fact, the above-described data suggest that DPP-4 inhibitors may even decrease the risk of
hypoglycaemia [70].

Long-term effects of DPP-4 inhibition on pancreatic islet cell function: clinical data
Since most clinical (registration) trials to date are designed to last up to approximately six
months, there is little information concerning long-term effects of DPP-4 inhibition on
pancreatic islet-cell function in humans. Although the duration of the majority of randomised
clinical trials (RCT) was prolonged by an extension period, mostly up to two years, it is likely
that only those patients who showed response to DPP-4 therapy, or otherwise profited from
the intervention, consented to continue in the trial. Conversely, those who had loss of
glycaemic control were not enrolled in the extension part of the RCT. These patients had
either progression of beta-cell function deterioration or may have already been non-
responders to DPP-4 inhibition at the onset of the study. Therefore, data from extended trials
should be carefully interpreted.
Stable beneficial effects on PI/I ratio [57] or both PI/I ratio and HOMA-B [54] were
shown during a one year treatment with vildagliptin or sitagliptin, respectively, as add-on to
metformin. Also after two years of treatment, beneficial effect of sitagliptin on fasting beta-
cell function was demonstrated; and this effect was larger compared to that reached when SU
was used as add-on to metformin [56]. Accordingly, a beneficial effect on dynamic
parameters of beta-cell function was visible after one year treatment with vildagliptin as add-
on to metformin, demonstrated by a 72.3% increase in AUCinsulin/glucose, whereas this
parameter deteriorated by 24.5% in the placebo-treated group [74]. Moreover, in another
study with treatment duration of two years, vildagliptin did show a stabilization of beta-cell
function, in contrast to the deterioration seen in the placebo-treated group [68]. In addition,

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two years of sitagliptin as add-on to metformin significantly improved beta-cell function
which persisted after a wash-out period of four to seven days (AUCinsulin/glucose +8.9%
compared to baseline) [56]. However, in studies lasting one year, after a four week wash-out
period the beneficial effect on beta-cell function did not sustain [67,74]. Similarly, in studies
that assessed dynamic beta-cell function by intravenous glucose challenge tests, lasting six
weeks [72], twelve weeks [86] or 52 weeks [85], beta-cell function parameters returned back
to baseline values after the washout period of two weeks (for the first two studies) and twelve
weeks (for the latter study). Concerning pancreatic alpha-cell function, two year treatment
with vildagliptin 50 mg BID as add-on to metformin improved postprandial glucagon
suppression compared to the use of a SU as add-on to metformin [77]. No data about
persistence of effects on glucagon secretion following an off-drug period are available.
In conclusion, the available data indicate that DPP-4 inhibitors show stable
improvements in beta-cell function parameters after chronic treatment up to two years in
open-label extension trials, however, there is at present no direct evidence to suggest that
DPP-4 inhibitors have durable effects on beta-cell function after cessation of therapy. Thus, it
is presently unknown whether these agents can modify the progressive course of T2DM.

Summary and discussion
In summary, preclinical studies have demonstrated beneficial effects of DPP-4 inhibition on
pancreatic islet-cell function. This was concluded from studies in different rodent models of
hyperglycaemia and diabetes showing improved insulin secretion, increased beta-cell mass
and proliferation, and suppression of glucagon secretion under hyperglycaemic conditions. In
humans, DPP-4 inhibitors improved fasting and dynamic beta-cell function measures
including HOMA-B, PI/I ratio, IGI, AUCinsulin/glucose ratio and model-derived parameters
obtained during oral glucose challenge tests. Moreover, glucose- and arginine-stimulated
insulin secretion, assessed by the hyperglycaemic clamp method, were improved by DPP-4
inhibition (Table 6). Finally, postprandial glucagon excursion decreased during DPP-4
inhibitor treatment. These improvements in islet-cell function clinically result in HbA1c
reduction, and data from animal studies possibly suggest sustained effects on islet-cell
function. However, several important considerations regarding DPP-4 inhibition and the
effect on pancreatic islet-cell function should be addressed.
Firstly, given the many different tests performed and variables reported to assess
changes in beta-cell function after intervention with incretin-based therapies in the various
human studies, the size of the effects is difficult to compare. In particular, it is impossible to

11

reliably compare the effects of the different agents from data obtained from separate versus
head-to-head comparison studies, however, we attempted to fully outline the currently
available data and to compare when possible.
Secondly, aetiology and course of T2DM in rodents is different from that in humans
and although rodent studies reported improved glycaemic control together with positive
effects on beta-cell mass and morphology, in humans such durable effects have not (yet) been
demonstrated after chronic treatment with DPP-4 inhibitors. Indeed, whether the beneficial
effects that are observed in clinical trials up to two years remain after drug-washout, is still
inconclusive (Table 6) since few studies reported off-drug values of beta-cell function of
which only one showed durable effects measured four to seven days after cessation of therapy
[56], whereas in others after cessation of minimally four weeks, no positive effects were
observed any longer [67,72,74,85,86]. Moreover, most long-term studies were extension
studies from original six-month trials, therefore it is possible that only patients that responded
well to the intervention consented to continue in the trial whereas the non-responders declined
enrollment in the extension. It would be of interest, to compare the (long-term) responders to
those who dropped out due to disease progression in order to identify possible determinants or
predictors of response to incretin-based therapy, such as disease duration at onset of therapy,
baseline beta-cell function or genetic determinants such as GLP-1 receptor polymorphism.
Additionally, since beta-cell function declines gradually over years, the possible beta-cell
sparing effect of a therapeutic agent should be assessed after substantially long-term treatment
of years. Indeed, since in the UKPDS [3] and ADOPT (A Diabetes Outcome Progression
Trial) [87] studies, beta-cell function improved initially but over time a decline was found, too
short observations may yield erroneous results. Therefore longer term studies with a duration
of at least five, but preferably more years using gold-standard methodology for reproducible
repetitive beta-cell function assessment and including a drug-washout period, should be
carried out in order to assess the full potential of DPP-4 inhibitors regarding their ability to
preserve pancreatic islet-cell function.
In recent years, the goal of the treatment of T2DM has been shifted from merely
reducing HbA1c levels alone, to simultaneously addressing several aspects of the more
complex pathophysiologic interplay characterising T2DM, e.g. gluco- and lipotoxicity,
reduced muscle glucose uptake, hepatic insulin resistance, decreased incretin effect, increased
glucagon secretion and decreased insulin secretion, as well as improving cardiovascular risk
factors including weight, blood pressure and lipid profile [88]. Given this complexity and the
heterogeneous phenotype of patients with T2DM, it seems obvious that, in order to achieve

12

these aims, combination of different blood-glucose lowering agents with complementary
mechanisms of action is necessary. Indeed, in addition to addressing the multiple
pathophysiological defects of T2DM, combining agents in the early phase of the disease, may
result in early robust HbA1c lowering, thus minimize the deleterious effect of glucose
toxicity, improve residual beta-cell function and allow to use lower doses of individual agents
in order to reduce side effects [89,90]. Also, initial combination therapy, as opposed to the
step-wise approach advocated in the current guidelines [91] may prevent clinical inertia which
results in significant delays in therapeutic adjustments at the cost of accumulation of
considerable glycaemic burden and late complications [89,92]. Combination therapy that
improves both insulin secretion and peripheral or hepatic insulin sensitivity may be most
effective in preventing the natural decline in glycaemic control. However, in clinical practice,
the use of currently established anti-hyperglycaemic drugs is associated with potential side
effects that may off-set the efficacy, e.g. by adversely affecting cardiovascular risk factors
and/or hamper patient compliance. For example, SU agents lower blood glucose but do not
slow down beta-cell function deterioration [87]. Additionally, SU cause body weight gain and
hypoglycaemia, both of which are associated with increased cardiovascular risk in patients
with T2DM [93], metformin use is associated with gastro-intestinal side-effects and TZDs
cause weight gain and fluid retention, which can progress to peripheral oedema and/or overt
heart failure [91]. Therefore, new drugs such as DPP-4 inhibitors may be of great additive
value, as they not only address multiple pathophysiologic mechanisms underlying T2DM but,
to date, also seem to have a relatively favourable side-effect profile (see below). In this
regard, combining DPP-4 inhibitors with currently employed strategies that improve insulin
sensitivity, i.e. TZD and/or metformin, might be particularly suited. Interestingly, metformin
potentially increases GLP-1 levels and acts as GLP-1 sensitizer [94], resulting in a synergistic
effect when used in combination with the DPP-4 inhibitor sitagliptin as observed in healthy
humans [95]. Indeed, a recent meta-analysis shows that combination therapies are more
efficacious in improving glycaemic control than administering each of the individual drugs
alone [96]. Furthermore, the use of DPP-4 inhibitors alongside insulin replacement therapy
has been reported to be safe. The first trials that assessed the use of DPP-4 inhibitors
compared to placebo in combination with insulin treatment showed better glycaemic control
and less use of insulin despite fewer hypoglycaemic events [97,98].
Concerning implementation of incretin-based therapies, at present, the moment of
initiation in the treatment of T2DM is under debate. Current diabetes treatment-guidelines
recommend a stepwise approach, which by some authors has been termed a “treat-to-failure”

13

approach [99]. Accordingly, a next agent should be added whenever HbA1c rises above a
preset target level [91]. In clinical practice, however, the next therapeutic step is often taken
to late, leading to accumulation of considerable glycaemic burden [92]. In order to achieve
greater efficacy, a more aggressive approach in the early phase of T2DM has been advocated:
initiating a combination of two or more anti-hyperglycaemic agents that collectively address
multiple pathophysiological mechanisms, in order to minimize glycaemic burden over time
[89]. Furthermore, it was demonstrated that early on in the development of T2DM, when
HbA1c is just above the target of 7.0% (53 mmol/mol), postprandial hyperglycaemia mainly
contributes to the progression of the disease [100]. Taking together the findings that DPP-4
inhibition 1) improves postprandial glucose disposal; 2) already exerts a glucose lowering
effect when administered to subjects with IFG and/or IGT [72,73]; 3) does not cause
hypoglycaemia and 4) seems to preserve beta-cell function at least for the first two years of
treatment, one may conclude that early combination therapy consisting of a DPP-4 inhibitor in
addition to a drug with complementary modes of action (e.g. metformin and/or TZD) may be
needed to halt the progressive nature of T2DM.
As stated above, an advantage of DPP-4 inhibition compared to other glucose-
lowering agents, is the fact that DPP-4 inhibitors show generally mild side effects in clinical
use. Importantly, due to the glucose-dependent effect on insulin secretion, hypoglycaemia is
seldom seen during DPP-4 inhibitor monotherapy or when a DPP-4 inhibitor is added to
ongoing metformin therapy [101]. Pooled analyses from clinical trials up to two years, in
which adverse events during sitagliptin and vildagliptin therapy were evaluated, showed no
difference in incidence of adverse events, e.g. hypoglycaemic events, infection rate, skin
reaction, hepatic injury or increased risk of major cardiovascular events, compared to placebo
[102,103]. However, early clinical trials showed a higher incidence rate of infections, mainly
from the upper respiratory tract and urinary tract [104]. Moreover, recent concerns are raised
about incretin-based therapies and incidence of pancreatitis, however incidence of pancreatitis
during sitagliptin treatment was similar to that in placebo [105,106]. Due to the relative short-
term studies conducted with DPP-4 inhibitors and the recent introduction of this group in the
market, side effects need to be monitored carefully in ongoing trials and postmarketing
analysis. Furthermore, the different compounds are of diverse chemical structure and may
therefore theoretically exert different clinical efficacy and side effect profiles [107]. Thus an
aspect that should be monitored closely, is that, besides their role in glucose metabolism,
DPP-4 inhibitors might intervene with other (unknown) metabolic or immunologic pathways,
given the ubiquitous expression of DPP-4 in the human body. Up to now most and longest

14

trials are performed with vildagliptin and sitagliptin. Careful long-term surveillance of all
compounds from this new class of glucose-lowering agents is needed and this can be
effectuated as, according to the FDA and EMA guidance [108], all pharmaceutical companies
with DPP-4 inhibiting agents on the market or about to be launched, have committed
themselves to perform large-sized long-term outcome trials to assess long-term efficacy but in
particular cardiovascular and overall safety of the drugs (TECOS-trial for sitagliptin
NCT00790205; EXAMINE trial for alogliptin NCT 00968708; SAVOR-TIMI 53 trial for
saxagliptin NCT01107886; CAROLINA trial for linagliptin NCT01243424).
A limitation to the clinical use of DPP-4 inhibitors might be the higher cost, compared
to more established compounds such as metformin, SU and insulin. One study assessed the
cost-effectiveness of the DPP-4 inhibitor sitagliptin against the TZD rosiglitazone or SU
derivatives as add-on to metformin treatment, in which equal cost-effectiveness was
concluded [109]. However, when performing cost-effectiveness analyses in the context of
novel drugs for chronic use, it is important that not only direct but also indirect costs are
included, such as those inferred by hospital admission because of hypoglycaemia, costs
related to non-compliance due to a drug’s unfavourable side-effect profile, costs related to
drug-related body weight gain or indirect costs due to sick-leave and loss of work force
related to the disease and/or therapy, therefore more extensive cost-effectiveness analyses
should be conducted for DPP-4 inhibitor therapy.

To conclude, overall, present evidence suggests that DPP-4 inhibitors improve
pancreatic islet cell function in humans based on both static and dynamic parameters as
shown in clinical trials up to two years. However, little data indicate sustained improvements
after drug wash-out, giving doubt to the hypothesis generated in pre-clinical studies that these
agents may durably preserve beta-cell function in humans. Moreover, it is uncertain whether
DPP-4 inhibitor monotherapy may alter the progressive course of the disease by preserving
functional beta-cell mass, in the presence of persistent damaging factors such as
(gluco)lipotoxicity, and the associated oxidative stress and low grade inflammation, or
hepatic insulin resistance. As stated above, DDP-4 inhibitors may be particularly useful in the
early phase when combined with agents addressing complementary pathophysiological
mechanisms. However, long-term trials should be awaited for to assess whether treatment
with DPP-4 inhibitors durably (and equally) improves islet-cell function and whether it may
change the progressive course of T2DM by preserving beta-cell function.

15

List of abbreviations
AUC Area under the curve
BID Twice daily
DPP-4 Dipeptidyl peptidase-4
EMA European Medicines Agency
FDA Food and Drug Administration
GIP Glucose-dependent insulinotropic polypeptide
GLP-1 Glucagon-like peptide 1
IFG Impaired fasting glucose
IGT Impaired glucose tolerance
HbA1c Haemoglobin A1c
HOMA-B Homeostatic model assessment beta-cell function index
IVGTT Intravenous glucose tolerance test
PI/I ratio Pro-insulin to insulin ratio
QD Once daily
RCT Randomised clinical trial
SU Sulfonylurea drugs
T2DM Type 2 diabetes mellitus
TZD Thiazolidinedione

16

Table 1. DPP-4 inhibitors and islet cell function and morphology: preclinical studies

Effect of DPP-4 inhibition
Ref Year Animal model Intervention Islet-cell function Islet morphology

21 2002 HFD-induced diabetic 8 wk NVP DPP728 (0.12 μmol/g/day), In vivo: Improved oral glucose disposal Increased GLUT-2 expression
C57BL/6J mice orally Ex vivo: Increased pancreatic insulin secretion Preserved islet size
No difference β-cell/α-cell distribution pattern

22 2002 VDF Zucker rats 12 wk P32/98 (20 mg/kg/day), orally In vivo: Increased early phase insulin n/a
Improved hepatic and peripheral insulin sensitivity

23 2002 VDF Zucker rats 3 months P32/98 (20 mg/kg/day), orally In vivo: Improved oral glucose disposal No difference in β-cell area or islet size
Increased insulin sensitivity
Ex vivo: Increased pancreatic insulin secretion

24 2003 STZ-induced diabetic 7 wk P32/98 (20 mg/kg/day), orally In vivo: Improved oral glucose disposal Increased pancreatic insulin content
Wistar rats Increased insulin levels Increased number of β-cells

25 2006 HFD- and/or STZ-induced 2-3 months des-fluoro-sitagliptin In vivo: Improved oral glucose disposal Restored β-cell mass & number
diabetic mice (43, 208 and 576 mg/kg/day) or Decreased glucagon secretion. Restored β-cell/α-cell distribution pattern
glipizide (20 mg/kg/day), orally Ex vivo: Increased pancreatic insulin secretion Increased pancreatic insulin content
→ No such effect of glipizide

26 2007 DIRKO & wild type mice 8 wk vildagliptin (1 μmol/ml drinking In vivo: Improved oral glucose disposal in wild type mice n/a
on HFD water ad libitum), orally → No such effect in DIRKO-mice

27 2007 Mice with beta-cell 8-9 wk vildagliptin (3μmol/day), orally In vivo: Improved iv glucose tolerance and insulin response Restored pancreatic insulin content
hIAPP-overexpression Improved insulin response to gastric glucose Restored β-cell/α-cell distribution pattern

28 2008 Fatty Zucker rats with 3-8 wk P32/98 (21.61 mg/kg/day), orally In vivo: Restored non-fasting glucose levels No effect on islet size or β-cell density
impaired glucose Slighty increased glucose responsiveness of the
tolerance β-cell

29 2008 Diabetic C57BL/KSJ 8 wk vildagliptin (1mg/kg/day) In vivo: Improved glucose tolerance Increased pancreatic β-cell area
db/db mice and/or valsartan (10mg/kg/day), orally Increased β-cell proliferation
Reduced apoptosis
→ Greater effect in combination with valsartan

30 2008 STZ-induced diabetic Islet transplantation plus 4 wk sitagliptin In vivo: Improved glucose disposal Sustained islet graft preservation (measured by
mice (added to ad libitum diet), orally Increased insulin levels Positron Emission Tomography [PET] imaging)
Decreased glucagon levels

31 2009 Diabetic Lepob/Lepob mice 4-5 wk alogliptin (45.7 mg/kg/day) In vivo: Improved HbA1c, fasting & non-fasting glucose Increased pancreatic insulin content
and/or pioglitazon (4.0 mg/kg/day), orally Increased insulin levels → Greater effect in combination with
Decreased glucagon levels pioglitazon

32 2009 HFD- and STZ-induced 10 wk sitagliptin (280 mg/kg/day) In vivo: Improved oral glucose disposal Restored β-cell/α-cell distribution pattern
diabetic mice or glipizide (20 mg/kg/day), orally Ex vivo: Increased pancreatic insulin secretion Restored pancreatic insulin content
No effect on proliferation
→ No such effect of glipizide

33 2010 C57BI/6J mice on HFD 12 wk des-fluoro-sitagliptin (4 g/kg), In vivo: Improved oral glucose disposal No difference in islet number and area
orally Increased insulin levels Improved percentage of small islets
Ex vivo: Increased pancreatic insulin secretion Reduced inflammatory cytokine expression

34 2010 Prediabetic db/db mice 4 wk alogliptin (72.8 mg/kg/day) and/or In vivo: Improved fasting glucose and HbA1c Increased pancreatic insulin content
voglibose (1.8 mg/kg/day), orally Increased insulin levels; decreased glucagon levels Increased GLUT-2 and PDX1 expression
→ Greater effect in combination with voglibose → Greater effect in combination with voglibose
No difference in pancreatic glucagon content

35 2011 Neonatal Wistar rats 19 days vildagliptin (60 mg/kg/day), In vivo: Small increase in insulin levels Enhanced β-cell replication
orally No effect on non-fasting glucose Reduced apoptosis
→ Durable effects after 12-days drug washout

Ref: reference; VDF: Vancouver diabetic fatty; STZ: streptozotocin; HFD: high fat diet; DIRKO: dual incretin-
receptor knock-out; hIAPP: human islet amyloid polypeptide; P32/98: isoleucine thiazolidide.

17

Table 2. DPP-4 inhibitors and static measures of beta-cell function: clinical studies, monotherapy
Δ HOMA-B (%) Δ PI/I ratio
Ref Year Intervention (N) Duration vs BL P vs COM P vs BL P vs COM P

Sitagliptin monotherapy

41 2006 sitagliptin 100 mg QD (238) 24 wk +13.2 n/a +12.9 <0.01 -0.080 n/a -0.070 <0.01
sitagliptin 200 mg QD (250) +13.1 n/a +12.8 <0.01 -0.110 n/a -0.100 <0.001
placebo (253) +0.3 n/a -0.010 n/a

sitagliptin 200 mg QD (201) +13.0 n/a +12.0 <0.05 -0.020 n/a -0.090 ns
placebo (202) +1.0 n/a +0.070 n/a

+11.3-
43 2007 sitagliptin 25 mg QD (n/a) 12 wk n/a n/a <0.05
15.2
+11.3-
sitagliptin 50 mg QD (n/a) <0.05
15.2
+11.3-
sitagliptin 100 mg QD (n/a) <0.05
15.2
+11.3-
sitagliptin 50 mg BID (n/a) <0.05
15.2
Placebo (n/a)

44 2007 sitagliptin 5 mg BID (125) 12 wk +8.3 n/a +8.9 ns
sitagliptin 12.5 mg BID (123) +8.2 +8.8 ns
sitagliptin 25 mg BID (123) +6.7 +7.3 ns
sitagliptin 50 mg BID (124) +17.3 +17.8 <0.001
glipizide 5 - 20 mg QD (123) +25.4 +26.0 sign
placebo (125) -0.6

45 2008 sitagliptin 100 mg QD (75) 12 wk +9.5 n/a +12.6 <0.001
placebo (76) -3.1

Vildagliptin monotherapy

46 2005 vildagliptin 25 mg BID (51) 12 wk +16.9 n/a +21.2 0.051
vildagliptin 25 mg QD (54) +2.9 +7.2 0.476
placebo (58) -4.3

47 2008 vildagliptin 100 mg QD (1470) 24 wk +10.3 n/a +11.5 0.01 -0.050 n/a -0.090 <0.001
placebo (182) -1.2 +0.040

Alogliptin monotherapy

48 2008 alogliptin 12,5 mg QD (133) 26 wk +7.5 n/a +7.8 0.279 -0.040 -0.086 0.001
alogliptin 25 mg QD (131) +9.7 +10.0 0.172 -0.038 -0.084 0.002
placebo (65) -0.3 +0.046

Saxagliptin monotherapy

49 2008 saxagliptin 2.5 mg QD (55) 12 wk +23.8 n/a +24.5 sign
saxagliptin 5 mg QD (47) +16.9 +17.6 sign
placebo (67) -0.7

49 2008 saxagliptin 100 mg QD (44) 6 wk +13.8 n/a +11.7 sign
placebo (41) +2.1

50 2009 saxagliptin 2.5 mg QD (120) 24 wk +14.6 n/a +6.5 sign
placebo (95) +8.1

Linagliptin monotherapy

51 2010 linagliptin 5 mg QD (157) 24 wk +5.0 n/a +22.2 0.049 -0.02 n/a -0.04 0.025
placebo (57) -17.2 +0.02

Data are displayed as reported in the cited reference or calculated from reported figures if possible. Ref:
reference; HOMA-B: homeostatic model assessment beta-cell function index; PI/I ratio: Pro-insulin-to-insulin
ratio; vs BL: versus baseline; vs COM: versus comparator (placebo unless otherwise stated); ns: non-significant;
sign: significant, level of significance not reported in reference; n/a: not available. *PI/I ratio measured by using
c-peptide concentrations; † decreased significantly, values not reported in reference.

18

Table 3. DPP-4 inhibitors and static measures of beta-cell function: clinical studies, combination therapy
Δ HOMA-B (%) Δ PI/IR
Ref Year Intervention (N) Duration vs BL P vs COM P vs BL P vs COM P

Sitagliptin as add-on to metformin

placebo (224) +3.5 +0.020

53 2007 sita/met 100mg/1000mg (183) 24 wk +31.0 n/a +27.3 <0.001 -0.140 -0.140 <0.001
sita/met 100mg/2000mg (180) +33.0 +29.3 <0.001 -0.200 -0.200 <0.001
metformin 1000mg QD (179) +11.1 +7.3 ns -0.090 -0.080 <0.05
metformin 2000mg QD (179) +14.3 +10.6 <0.05 -0.120 -0.120 <0.001
sitaglipin 100mg QD (178) +10.8 +7.1 ns -0.080 -0.080 <0.05
placebo (169) +3.7 -0.010

54 2010 sitagliptin 100 mg QD (10) 48 wk +26.1 n/a +39.6 ns -0.001 n/a -0.001 ns
placebo (11) -13.5 n/a 0.000 n/a

55 2007 sitagliptin 100 mg QD (382) 52 wk +3.6 n/a -10.4‡ n/a -0.016 n/a -0.048 n/a
glipizide 5-20 mg QD (411) +14.0 0.033

56 2008 sitagliptin 100 mg QD (94) 18 wk +9.4 n/a +16.3 <0.05 -0.050 n/a -0.020 n/a
rosiglitazon 8 mg QD (87) +8.4 n/a +15.3 n/a -0.040 -0.010
placebo (92) -6.9 n/a -0.030

57 2010 sitagliptin 100 mg QD (248) 2 year +12.9 n/a -6.3‡ n/a -0.050 n/a -0.040 sign
glipizide 20 mg QD (256) +19.2 n/a -0.010 n/a

Vildagliptin as add-on to metformin

58 2007 vildagliptin 50 mg QD (29) 52 wk -0.02* n/a -0.007 0.052
placebo (26) -0.013 n/a

Alogliptin as add-on to metformin

59 2009 alogliptin 12.5 mg QD (213) 26 wk n/a n/a n/a ns n/a n/a n/a <0.011
alogliptin 25 mg QD (210) ns
placebo (104)

Saxagliptin as add-on to metformin

60 2009 saxagliptin 2.5 mg QD (192) 24 wk +16.5 +11.6
saxagliptin 5 mg QD (191) +17.6 +12.7
saxagliptin 10 mg QD (181) +18.1 +13.2
placebo (179) +4.9

Sitagliptin as add-on to metformin and/or
sulfonylurea

61 2007 sitagliptin 100 mg QD (222) 24 wk +11.3 <0.001 +12.0 <0,05 -0.057 <0.05 -0.028 ns
placebo (219) -0.7 -0.029

Vildagliptin as add-on to sulfonylurea

62 2008 vildagliptin 50 mg QD (170) 24 wk n/a n/a † †
vildagliptin 50 mg BID (169) † †
placebo (176)

Sitagliptin as add-on to thiazolidinedione

63 2006 sitagliptin 100 mg QD (175) 24 wk +11.5 n/a +5.7 ns -0.080 n/a -0.070 <0.001
placebo (178) +5.8 0.000

64 2011 sitagliptin 100 mg QD (217) 24 wk +31.0 sign +11.8 0.118 -0.103 sign -0.062 0.056
placebo (208) +19.3 sign -0.041 ns

Saxagliptin as add-on to thiazolidinedione

65 2009 saxagliptin 2.5 mg QD (195) 24 wk +10.0 n/a +7.1 0.0553
saxagliptin 5 mg QD (186) +11.0 +8.1 0.0301
placebo (184) +2.9

Data are displayed as reported in the cited reference or calculated from reported figures if possible. Ref:
reference; HOMA-B: homeostatic model assessment beta-cell function index; PI/I ratio: Pro-insulin-to-insulin
ratio; vs BL: versus baseline; vs COM: versus comparator (placebo unless otherwise stated); ns: non-significant;
sign: significant, level of significance not reported in reference; n/a: not available. *PI/I ratio measured by using
c-peptide concentrations; † decreased significantly, values not reported in reference; ‡ active comparator

19

Table 4. DPP-4 inhibitors and dynamic, postprandial, measures of islet cell function: clinical studies,
monotherapy

Δ IGI (%) Δ AUCinsulin/AUCglucose (%) Δ AUCGlucagon (%)
vs vs vs
Ref Year Intervention (N) Duration vs BL P P vs BL P P vs BL P P
COM COM COM

Sitagliptin monotherapy

66** 2006 sitagliptin 100 mg QD (58) 3 day n/a n/a n/a <0.05
sitagliptin 200 mg QD (58) crossover <0.05
placebo (58)

41 2006 sitagliptin 100 mg QD (238) 24 wk +8.0 n/a +15.1 <0,05
sitagliptin 200 mg QD (250) +27.1 +34.1 <0.001
placebo (253) -7.1

sitagliptin 200 mg QD (201) +26.3 n/a +36.3 <0.01
placebo (202) -10.0 n/a

44 2007 sitagliptin 5 mg BID (125) 12 wk +17.7 n/a +27.4 n/a
sitagliptin 12.5 mg BID (123) +13.2 +22.9
sitagliptin 25 mg BID (123) +16.5 +26.2
sitagliptin 50 mg BID (124) +34.5 +44.2
glipizide 5 - 20 mg QD (123) +90.3 +100
placebo (125) -9.7

placebo (76) -5.0

Vildagliptin monotherapy

17 2004 vildagliptin 50 mg QD (56) 52 wk n/a n/a n/a 0.016
placebo (51)

47 2008 vildagliptin 100 mg QD (1470) 24 wk +26.4 <0.05 +38.2 ns +41.6 n/a +42.7 <0.001
placebo (182) -11.8 n/a -1.1

67 2008 vildagliptin 50mg QD (156) 52 wk +5.4 n/a +20.9 n/a
placebo (150) -15.9

68 2008 vildagliptin 50 mg QD (156) 52 wk n/a n/a n/a 0.003 +8.7 0.05 +4.4 <0.001
placebo (150) -5.7 0.001

69 2008 vildagliptin 50 mg QD (156) 112 wk n/a 0.682 n/a 0.174
placebo (150) 0.134

70 2008 vildagliptin 50 mg BID (16) 6 wk n/a n/a n/a <0.05
placebo (16) crossover

71 2009 vildagliptin 100 mg QD (25) 28 day n/a n/a +9.0 0.037 n/a n/a -9.7 0.005

72 2009 vildagliptin 50 mg BID (14) 10 day -11.8 0.03

Vildagliptin monotherapy in non-diabetic subjects

73 2008 vildagliptin 100mg QD (22) 6 wk +26.2 0.013 n/a n/a

74 2008 vildagliptin 50mg QD (90) 12 wk +8.0 n/a +10.8 0.002 -4.4 n/a -7.6 0.007
placebo (89) -2.8 +3.2

Saxagliptin monotherapy

50** 2009 saxagliptin 2.5 mg QD (120) 24 wk +57.1 n/a +39.7 n/a -26.7 sign -7.4 n/a
saxagliptin 5 mg QD (106) +42.3 n/a +24.9 n/a -26.7 sign -7.4
saxagliptin 10 mg QD (98) +31.0 n/a +13.6 n/a -30.8 sign -11.5
placebo (95) +17.4 n/a -19.3 sign

Linagliptin monotherapy

51 2010 linagliptin 5 mg QD (44) 24 wk +7.3 n/a +24.7 0.11
placebo (10) -17.4

Percentage change as reported in the cited reference or calculated from reported figures if possible. Measures are
derived from mixed meal tolerance tests, unless otherwise stated. Ref: reference; IGI: insulinogenic index; AUC:
area under the curve; vs BL: versus baseline; vs COM: versus comparator (placebo unless otherwise stated);
sign: significant, level of significance not reported in reference; ns: non-significant; n/a: not available. * P-value
for between treatment difference vs. pioglitazone; † P-value for between treatment difference vs. sitagliptin; **
use of oral glucose tolerance test in stead of mixed meal test.

20

Table 5. DPP-4 inhibitors and dynamic, postprandial, measures of islet cell function: clinical studies,
combination therapy
Δ IGI (%) Δ AUCinsulin/AUCglucose (%) Δ AUCGlucagon (%)
vs vs vs
Ref Year Intervention (N) Duration vs BL P P vs BL P P vs BL P P
COM COM COM

Sitagliptin as add-on to metformin

placebo (224) -5.3

53 2007 sita/met 100mg/1000mg (183) 24 wk +50.0 n/a +50.0 <0.001
sita/met 100mg/2000mg (180) +50.0 +50.0 <0.001
metformin 1000mg (179) +25.0 +25.0 <0.001
metformin 2000mg (179) +27.8 +27.8 <0.05
sitagliptin 100mg (178) +36.7 +36.7 <0.05
placebo (169) 0

77 2008 sitagliptin 100 mg QD (95) 2 wk n/a n/a -49‡ 0.02 n/a 0.0017 n/a n/a n/a 0.0011 n/a 0.0011
exenatide 10 μgr BID (95) crossover n/a n/a † † † †

54§ 2010 sitagliptin 100 mg QD (10) 48 wk n/a n/a n/a 0.23 -16.1 n/a +15.6 0.23
placebo (11) -31.7 n/a

57 2010 sitagliptin 100 mg QD (248) 2 year +15.8 n/a +40.2‡ n/a +8.9 n/a +3.0‡ n/a
glipizide 20 mg QD (256) -24.4 +5.9 n/a

Sitagliptin as add-on to metformin and/or
sulfonylurea

61 2007 sitagliptin 100 mg QD (222) 24 wk +14.5 <0,05 +25.8 <0.05
placebo (219) -11.3

Vildagliptin as add-on to metformin

75 2005 vildagliptin 50 mg QD (31) 52 wk +72.3 sign +96.8 sign
placebo (26) -24.5 sign

76 2007 vildagliptin 50 mg QD (177) 24 wk n/a n/a n/a <0.001
vildagliptin 100 mg QD (185) <0.001
placebo (182)

<0.001
78 2010 vildagliptin 50 mg BID 2 year n/a n/a n/a
‡
glimepiride 6 mg QD

Saxagliptin as add-on to metformin

60** 2009 saxagliptin 2.5 mg QD (192) 24 wk n/a ns n/a ns
saxagliptin 5 mg QD (191) n/a ns n/a ns
saxagliptin 10 mg QD (181) n/a ns n/a ns
placebo (179) n/a ns

Vildagliptin as add-on to sulfonylurea

62 2008 vildagliptin 50 mg QD (170) 24 wk +16.6 n/a +22.7 0.024
vildagliptin 50 mg BID (169) +17.5 +23.6 0.014
placebo (176) -6.1

Sitagliptin as add-on to thiazolidinedione

64 2011 sitagliptin 100 mg QD (217) 24 wk +50.0 sign +50.0 <0.001 n/a
placebo (208) 0 ns

Vildagliptin as add-on to thiazolidinedione

79 2007 vildagliptin 100 mg QD (48) 24 wk +37.0 n/a +27.0 <0.01
vildagliptin 50 mg QD (48) +35.0 +25.0 <0.01
placebo (42) +10.0

80 2007 vildagliptin 100 mg QD (154) 24 wk n/a n/a n/a n/a
pioglitazon 30 mg QD (161)
vilda+pio 50/15 mg QD (144) <0.05*
vilda+pio 100/30 mg QD (148)

Saxagliptin as add-on to thiazolidinedione

65** 2009 saxagliptin 2.5 mg QD (195) 24 wk +91.7 n/a +156.7 Sign -4.1 n/a -1.9 0.5482
saxagliptin 5 mg QD (186) +78.6 n/a +143.6 sign -8.1 -5.9 0.0722
placebo (184) -65 n/a -2.2
Percentage change as reported in the cited reference or calculated from reported figures if possible. Measures are
derived from mixed meal tolerance tests, unless otherwise stated. Ref: reference; IGI: insulinogenic index; AUC:
area under the curve; pio: pioglitazone; vs BL: versus baseline; vs COM: versus comparator (placebo unless
otherwise stated); sign: significant, level of significance not reported in reference; ns: non-significant; n/a: not
available. * P-value for between treatment difference vs. pioglitazone; † P-value for between treatment
difference vs. sitagliptin; ** use of oral glucose tolerance test in stead of mixed meal test § IGI and
AUCinsulin/AUCglucose are corrected for insulin resistance; ‡active comparator.

21

Table 6. Clinical effect of DPP-4 inhibitors on pancreatic beta-cell function

Effect of clinical use of DPP-4 inhibitors on pancreatic beta-cell function
Static Dynamic Sustainability
DPP-4 Hyperglycaemic Effect after 1 Effect after ≥
inhibitor HOMA-B PI/I ratio IGI AUCinsulin/glucose Modelling IVGTT Clamp year treatment 4 wk washout

Sitagliptin ↑ ↑ ↑/= ↑/= ↑/= n/a ↑ ↑ =
Vildagliptin ↑ ↑/= ↑/= ↑/= ↑/= ↑ ↑ ↑ =
Saxagliptin ↑ n/a ↑/= n/a n/a n/a n/a n/a n/a
Alogliptin = ↑ n/a n/a n/a n/a n/a n/a n/a
Linagliptin ↑ ↑ n/a = n/a n/a n/a n/a n/a

IGI: insulinogenic index; AUC: area under the curve; HOMA-B: homeostatic model assessment beta-cell
function index; PI/I ratio: pro-insulin-to-insulin ratio; IVGTT: intravenous glucose-tolerance test; ↑: beneficial
effects of DPP-4 inhibitor treatment in all studies; ↑/=: beneficial effects of DPP-4 inhibitor treatment in some
studies, but not all; =: no effect of DPP-4 inhibitor treatment; n/a: data not available.

22

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