Dpp4 beta cell preservation

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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: [email protected]

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

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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

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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”

14

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

15

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.

16

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

17

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

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.

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

21 2002 HFD-induced diabetic

C57BL/6J mice 8 wk NVP DPP728 (0.12 μmol/g/day), orally

In vivo: Improved oral glucose disposal Ex vivo: Increased pancreatic insulin secretion

Increased GLUT-2 expression 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 Increased insulin sensitivity

No difference in β-cell area or islet size

Ex vivo: Increased pancreatic insulin secretion

24 2003 STZ-induced diabetic Wistar rats

7 wk P32/98 (20 mg/kg/day), orally

In vivo: Improved oral glucose disposal Increased insulin levels Ex vivo: Increased pancreatic insulin secretion

Increased pancreatic insulin content Increased number of β-cells

25 2006 HFD- and/or STZ-induced

diabetic mice 2-3 months des-fluoro-sitagliptin (43, 208 and 576 mg/kg/day) or glipizide (20 mg/kg/day), orally

In vivo: Improved oral glucose disposal Decreased glucagon secretion. Ex vivo: Increased pancreatic insulin secretion

Restored β-cell mass & number Restored β-cell/α-cell distribution pattern Increased pancreatic insulin content

→ No such effect of glipizide

26 2007 DIRKO & wild type mice on HFD

8 wk vildagliptin (1 μmol/ml drinking water ad libitum), orally

In vivo: Improved oral glucose disposal in wild type mice → No such effect in DIRKO-mice

n/a

27 2007 Mice with beta-cell

hIAPP-overexpression 8-9 wk vildagliptin (3μmol/day), orally In vivo: Improved iv glucose tolerance and insulin response

Improved insulin response to gastric glucose Restored pancreatic insulin content

Restored β-cell/α-cell distribution pattern Ex vivo: Increased pancreatic insulin secretion

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

tolerance Slighty increased glucose responsiveness of the

β-cell

29 2008 Diabetic C57BL/KSJ db/db mice

8 wk vildagliptin (1mg/kg/day) and/or valsartan (10mg/kg/day), orally

In vivo: Improved glucose tolerance Increased pancreatic β-cell area Increased β-cell proliferation

Reduced apoptosis → Greater effect in combination with valsartan

30 2008 STZ-induced diabetic mice

Islet transplantation plus 4 wk sitagliptin (added to ad libitum diet), orally

In vivo: Improved glucose disposal Increased insulin levels

Sustained islet graft preservation (measured by Positron Emission Tomography [PET] imaging)

Decreased glucagon levels

31 2009 Diabetic Lepob/Lepob mice 4-5 wk alogliptin (45.7 mg/kg/day) and/or pioglitazon (4.0 mg/kg/day), orally

In vivo: Improved HbA1c, fasting & non-fasting glucose Increased insulin levels Decreased glucagon levels

Increased pancreatic insulin content → Greater effect in combination with pioglitazon

32 2009 HFD- and STZ-induced

diabetic mice 10 wk sitagliptin (280 mg/kg/day) or glipizide (20 mg/kg/day), orally

In vivo: Improved oral glucose disposal Ex vivo: Increased pancreatic insulin secretion

Restored β-cell/α-cell distribution pattern 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), orally

In vivo: Improved oral glucose disposal Increased insulin levels

No difference in islet number and area 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 voglibose (1.8 mg/kg/day), orally

In vivo: Improved fasting glucose and HbA1c Increased insulin levels; decreased glucagon levels

Increased pancreatic insulin content 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), orally

In vivo: Small increase in insulin levels No effect on non-fasting glucose

Enhanced β-cell replication Reduced apoptosis

→ Durable effects after 12-days drug washout

18

Table 2. DPP-4 inhibitors and static measures of beta-cell function: clinical studies, monotherapy

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.

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

42 2006 sitagliptin 100 mg QD (107) 18 wk +12.1 n/a +11.2 <0.05 -0.050 n/a -0.120 <0.05 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

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

sitagliptin 50 mg QD (n/a) +11.3-15.2 <0.05

sitagliptin 100 mg QD (n/a) +11.3-15.2 <0.05

sitagliptin 50 mg BID (n/a) +11.3-15.2 <0.05

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 vildagliptin 50 mg QD (53) +6.4 +10.7 0.282 vildagliptin 100 mg QD (63) +22.5 +26.8 0.007 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 saxagliptin 10 mg QD (63) +24.7 +25.4 sign saxagliptin 20 mg QD (54) +20.8 +21.5 sign saxagliptin 40 mg QD (52) +18.3 +19.0 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 saxagliptin 5 mg QD (106) +13.2 +5.1 sign saxagliptin 10 mg QD (98) +15.5 +7.4 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

19

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

52 2006 sitagliptin 100 mg QD (453) 24 wk +19.5 n/a +16.0 <0.001 -0.030 n/a -0.050 <0.01 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

20

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

Δ IGI (%) Δ AUCinsulin/AUCglucose (%) Δ AUCGlucagon (%)

Ref Year Intervention (N) Duration vs BL P vs COM P vs BL P vs

COM P vs BL P vs COM P

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

42 2006 sitagliptin 100 mg QD (107) 18 wk +28.6 n/a +38.6 <0.001 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


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 placebo (25) crossover

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

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.

21

Table 5. DPP-4 inhibitors and dynamic, postprandial, measures of islet cell function: clinical studies, combination therapy

Δ IGI (%) Δ AUCinsulin/AUCglucose (%) Δ AUCGlucagon (%)

Ref Year Intervention (N) Duration vs BL P vs COM P vs BL P vs

COM P vs BL P vs COM P

Sitagliptin as add-on to metformin


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)

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

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.

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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 inhibitor

HOMA-B PI/I ratio IGI AUCinsulin/glucose Modelling IVGTT

Hyperglycaemic Clamp

Effect after 1 year treatment

Effect after ≥ 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.

23

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Conflict of interest details: van Genugten: writing manuscript van Raalte: writing manuscript Diamant: writing manuscript Authorship details: 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.

Dpp4 beta cell preservation

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