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Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
Dpp4 beta cell preservation
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Dpp4 beta cell preservation

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DPP4 I AND BETA CELL

DPP4 I AND BETA CELL

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  • 1. Dipeptidyl Peptidase-4 Inhibitors and Preservation of Pancreatic Islet-Cell Function: ACritical Appraisal of the EvidenceR.E. van Genugten, D.H. van Raalte, M. DiamantDiabetes Center, Department of Internal Medicine, VU University Medical Center,Amsterdam, The NetherlandsCorresponding 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.nlManuscript word count: 5305Abstract word count: 220Number of tables: 6Keywords type 2 diabetes, incretins, GLP-1, GIP, beta cell, beta-cell mass, alpha cell,sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptinDisclosure statement RvG and DvR declare no conflict of interest. Through MD, the VUUniversity Medical Center received research grants from Amylin, Eli Lilly, Glaxo SmithKline, Merck, Novartis, Novo Nordisk, Sanofi Aventis and Takeda, consultancy fee from EliLilly, Merck, Novo Nordisk, Sanofi Aventis and speaker fee from Eli Lilly, Merck and NovoNordisk.Acknowledgements RvG is supported by the EFSD/MSD clinical research programme 2008and 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 thisarticle as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01473.x 1
  • 2. AbstractType 2 diabetes mellitus (T2DM) develops as a consequence of progressive beta-celldysfunction in the presence of insulin resistance. None of the currently-available T2DMtherapies is able to change the course of the disease by halting the relentless decline inpancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretinenhancers, have been introduced in the treatment of T2DM. This class of glucose-loweringagents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependentinsulinotropic 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 rodentstudies, DPP-4 inhibitors demonstrated beneficial effects on (functional) beta-cell mass andpancreatic insulin content. Studies in humans with T2DM have indicated improvement ofislet-cell function, both in the fasted state and under postprandial conditions and thesebeneficial effects were sustained in studies with a duration up to two years. However, there isat present no evidence in humans to suggest that DPP-4 inhibitors have durable effects onbeta-cell function after cessation of therapy. Long-term, large-sized trials using an activeblood glucose lowering comparator followed by a sufficiently long washout period afterdiscontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durablypreserve pancreatic islet-cell function in patients with T2DM. 2
  • 3. IntroductionPrevention and treatment of type 2 diabetes mellitus (T2DM) and its complications areworldwide major health care issues given the alarming global increase in the prevalence ofT2DM due to the obesity pandemic [1]. Abdominal obesity and hepatic steatosis decreaseperipheral and hepatic insulin sensitivity. Under normal circumstances, pancreatic beta cellscompensate for this reduced insulin sensitivity by enhancing insulin secretion. However, insusceptible individuals, this compensatory response is hampered by incipient beta-celldysfunction resulting in a gradual rise in blood glucose concentrations and finally, thedevelopment of T2DM [2]. Beta-cell dysfunction is not only a prerequisite for thedevelopment of T2DM, but, due to its progressive nature, it additionally determines theprogressive course of the disease. Accordingly, T2DM is characterised by progressive loss ofglycaemic control and increased need for multiple therapies to sustain normoglycaemia [3]. Inthe United Kingdom Prospective Diabetes Study (UKPDS) the decline of pancreatic beta-cellfunction in newly diagnosed patients with T2DM was estimated to occur at an annual rate ofapproximately 4% [3]. In addition to loss of beta-cell function, autopsy studies have shownthat 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-cellsand impaired beta-cell function, leading to a diminished functional islet mass, contribute tothe development and subsequently, the progressive course of T2DM. More recently, reducedinhibition of glucagon-secreting alpha-cells has also been identified to contribute tohyperglycaemia in T2DM, since glucagon stimulates hepatic glucose production [5]. Hence,in patients with T2DM, functional pancreatic islet-cell balance is impaired resulting inchronic hyperglycaemia. A major challenge in the treatment of T2DM is to identify atherapeutic agent that can alter the course of the disease by preventing this gradual decline inpancreatic islet-cell function and diminution of beta-cell mass. Current T2DM treatmentoptions, most notably metformin and the sulfonylurea derivatives, fail in this regard, sinceglycaemic 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 incretinhormones, 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 thesecretion of the gut-derived incretin hormones, the increase in plasma insulin response is twoto three fold greater than is the case when the same level of hyperglycaemia is produced by 3
  • 4. intravenous administration of glucose [7]. Incretin-enhancers or dipeptidyl peptidase (DPP)-4inhibitors inhibit the incretin-degrading enzyme DPP-4 that is ubiquitously present, therebyincreasing 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 responsesand thus may restore functional islet cell balance. In this review we will discuss the evidencethat DPP-4 inhibitors improve both beta-cell and alpha-cell function. We will discusspreclinical data and subsequently address the effects of all currently-available DPP-4inhibitors on fasting and dynamic measures of islet cell function as reported in randomisedclinical trials in humans (last PUBMED search 1-Apr-2011). Finally, based on the currentevidence, we will discuss the potential of these agents to durably enhance islet-cell function inpatients with T2DM and modify the progressive course of the disease.DPP-4 inhibitors: mode of action and clinical efficacyThe incretin hormones GLP-1 and GIP are secreted from the small intestine directly inresponse to food intake and stimulate postprandial glucose-dependent insulin secretion. Inrecent years several studies have unravelled the pathways via which GLP-1 and GIP increasepostprandial insulin secretion [8]. GLP-1 and GIP receptors are present on pancreatic betacells via which the incretin hormones directly enhance insulin secretion from insulincontaining granules. However, the most important contributor may be GLP-1’s effect onafferent nerves in the intestinal mucosa or portal vein [9,10], since less than 25% of the activemetabolite 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 glucagonsecretion mainly indirectly via somatostatin, in addition to a proposed direct inhibitionthrough GLP-1 receptors on the alpha cells. Although GLP-1-stimulated insulin secretionfrom the beta-cell is also believed to contribute to the indirect route by which GLP-1decreases glucagon, studies in T1DM patients who had no residual beta-cell function alsoshowed decreased (postprandial) glucagon secretion [12,13], arguing against an importantrole of insulin secretion in GLP-1’s effect on glucagon. GIP, however, exerts aglucagonotropic effect in the euglycaemic state [14]. In addition, evidence exists frompreclinical studies that incretins also replenish insulin stores and may promote beta-cell massby increasing beta-cell proliferation and reducing apoptosis [8,15]. Endogenous GLP-1 and GIP are not suitable for therapeutic use in humans, sincedirectly upon secretion, both GLP-1 and GIP are cleaved by the enzyme DPP-4, resulting inan active plasma half-life time of just several minutes and thus necessitating continuous 4
  • 5. parenteral administration [16]. DPP-4 inhibitors increase endogenous circulating levels ofactive GLP-1 and GIP by blocking the incretin-degrading enzyme DPP-4 and therebyapproximately double postprandial active, i.e. non-degraded, incretin levels [17]. The extentto which other DPP-4 substrates, such as glucagon-like peptide-2, peptide YY [18], gastrinreleasing 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 shownbeneficial 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, onceor twice daily. Currently, the DPP-4 inhibitors sitagliptin and saxagliptin are approved byboth 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 inthe treatment of T2DM. Vildagliptin is approved for the European market only as add-on andalogliptin is currently approved for the Japanese market and awaiting approval by EMA andFDA. The approval of linagliptin is currently pending, while several other companies haveDPP-4 inhibitors still under development.DPP-4 inhibition improves pancreatic islet-cell function: preclinical dataAdministration 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 plasmaglucagon 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 methodsin order to describe glucose metabolism and pancreatic function, which potentially hamperscomparison.Flock et al. demonstrated the necessity of the presence of functional incretin receptors on isletcells 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]. Thebeneficial effects of DPP-4 treatment on fasting and non-fasting glycaemic control remainedpresent during chronic treatment (up to three months) (Table 1). Moreover, when compared toconventional therapy, the sulphonylurea (SU) agent glipizide, DPP-4 inhibitor treatmentresulted in prolonged improvement in glycaemic control over ten weeks, whereas in the 5
  • 6. glipizide-treated mice glycaemic control deteriorated after approximately five weeks despiteongoing treatment [25,32]. Several studies have assessed the effects of acute and chronic treatment with DPP-4inhibitors on pancreatic islet morphology and beta-cell mass in rodents (Table 1). ChronicDPP-4 inhibitor treatment (two to three months) was demonstrated to increase beta-cell massby promoting cell proliferation and reducing apoptosis [24,25,29]. Interestingly, after atwelve-day drug washout period, durable beneficial effects on beta-cell mass, i.e. enhancedbeta-cell replication and reduced apoptosis, were seen in neonatal rats treated with a DPP-4inhibitor for nineteen days [35]. In contrast, other studies showed no effect of treatment withDPP-4 inhibitors on total beta-cell mass [21,23,28,34], however in various studies a beneficialeffect on the intra-islet distribution pattern of alpha and beta cells was shown [27,32]. Inaddition, DPP-4 inhibition demonstrated durable effects on pancreatic islet mass and/orinsulin content while this effect was not seen by SU [32]. Furthermore, combination treatmentof 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 glucosetolerance, by enhancing insulin secretion and reducing glucagon secretion and this effectoutlasted the action of the presently used blood-glucose lowering agents, most particularlySU. Since DPP-4 inhibitors also stimulated insulin production, increased beta-cell mass andrestored pancreatic islet topography in these rodent models, DPP-4 inhibition holds a promiseas therapeutical option with regard to preservation of beta-cell function also in humans withT2DM.DPP-4 inhibition and pancreatic beta-cell function: clinical dataMeasures of beta-cell function in humansPancreatic beta-cell function involves many different aspects, including glucose and nutrientsensing, insulin secretion and production following stimulation by different secretagogues andpro-insulin to insulin processing. Therefore, any test performed, and any variable derivedthereof, has limitations and should be regarded as mere surrogate estimate. Also, irrespectiveof the actual test performed it is always important to keep in mind that insulin secretionresponses should be interpreted in the context of prevailing insulin sensitivity and glucoselevel [2]. As such, an identical insulin response before and following an intervention thatreduces blood glucose and body weight, may still designate an improvement when taking into 6
  • 7. account the glucose and body weight changes. In humans, the various aspects of beta-cell function can be assessed by severalmethods including static and dynamic measurements. The most widely used estimates are thestatic or fasting measures, including the homeostatic model assessment beta-cell functionindex (HOMA-B) [36] and the pro-insulin to insulin (PI/I) ratio [37]. However, the value offasting measures of beta-cell function is limited, since beta cells are mostly active in thepostprandial and hyperglycaemic state. Dynamic measures may therefore be more appropriateto quantify beta-cell function. As such, many studies have calculated parameters of beta-cellfunction from intravenous glucose challenge tests, oral glucose tolerance tests or standardizedmixed meal tests. Typical beta-cell measurements derived from oral glucose load tests includethe postprandial insulin area under the curve (AUC) corrected for glucose AUC(AUCinsulin/glucose), which measures insulin secretion during the total postprandial period, andthe insulinogenic index (IGI), a measure of early phase insulin secretion (i.e. insulin secretionduring 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 theintravenous glucose tolerance test (IVGTT) or the hyperglycaemic (arginine-stimulated)clamp method. Although the hyperglycaemic clamp test, due to its high reproducibility, iscurrently 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 intravenousroute, and additionally, its use is limited for routine measurements due to the demandsimposed on the patient and the associated high cost. In the sections below, we will present the results of clinical trials using DPP-4inhibition in patients with T2DM and subjects with pre-diabetes, i.e. impaired glucosemetabolism, with regard to aforementioned static and dynamic parameters of beta-cellfunction.Effect of DPP-4 inhibitors on static measures of beta-cell functionDPP-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 anincrease 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). 7
  • 8. Furthermore, PI/I ratio improved by treatment with all DPP-4 inhibitors given asmonotherapy 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 to0.12 (Table 2) [40,41,46,47,50]. When used as add-on therapy to other oral blood glucose-lowering agents such asmetformin, SU derivates or TZDs, DPP-4 inhibition exerted an additional beneficial effect onthese fasting parameters of beta-cell function in most studies (Table 3) [43,51-64]. DPP-4inhibition as add-on to metformin improved static measures of beta-cell function comparableto other glucose lowering agents as add-on to metformin, e.g. TZD [55] and SU, the latterwith 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 ofbeta-cell function beneficially compared to placebo.Effect of DPP-4 inhibitors on dynamic measures of beta-cell functionPostprandial parameters of beta-cell function Clinical trials that assessed the effect of DPP-4inhibitors on beta-cell function measurements derived from standardised mixed-meal tests ororal 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 inseveral trials in which monotherapy up to one year was assessed (approximate mean increaseof 38%) [44,46,49,67]. Saxagliptin as add-on to TZD resulted in increased IGI compared toplacebo as add-on to TZD after 24 weeks treatment (up to 150 % increase compared toplacebo) [64]. Postprandial AUCinsulin/glucose, was improved by both sitagliptin [40,41,44] andvildagliptin [46,66,67,70] with an increase compared to placebo ranging from 15.1% to38.6%. Drug-naïve diabetic patients with mild hyperglycaemia, i.e. HbA1c < 7.5% (58mmol/mol), benefited from one year DPP-4 inhibitor treatment as well according to anincrease of 14.4% (P<0.001) in AUCinsulin/glucose [67] (Table 4). In addition, a beneficial effectwas also present in subjects at risk to develop T2DM, i.e. subjects with impaired fastingglucose (IFG) and/or impaired glucose tolerance (IGT) [72,73]. DPP-4 inhibitors as add-on toeither metformin [51], SU [61] or metformin/SU [60] showed after 24 weeks treatment anincrease in AUCinsulin/glucose ratio within a range of 22.7% to 28.8%. In contrast, Retnakaran etal., 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, 8
  • 9. this intervention was preceded by a four-week intensive insulin treatment period which couldhave outweighed the effects of DPP-4 inhibition [53].Mathematical modelling of postprandial beta-cell function DPP-4 inhibitors improvedseveral model-derived parameters of beta-cell function. The model-based approach developedby Mari et al. was used to assess beta-cell function after one year treatment with vildagliptin50 mg QD in drug-naïve patients with T2DM. Several model-derived parameters of beta-cellfunction improved significantly (insulin secretory rate by 17%, P<0.001; glucose sensitivityof the beta-cell by 40%, P<0.001) [66]. This effect was shown for insulin secretory rate afterboth four weeks of treatment (P<0.005) [80] and acute treatment (P<0.04) [81]. Based onCobelli’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]. Asimilar 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 onhyperglycaemic and arginine-stimulated clamp-derived parameters of beta-cell function in 24patients with T2DM treated with metformin. With blood-glucose targeted at 20 mM, first-phase insulin secretion, second-phase insulin secretion and arginine-stimulated insulinsecretion were increased, compared to placebo treatment. In accordance, Bunck et al. [85]reported significantly improved clamp-derived beta-cell function parameters after one yeartreatment with vildagliptin 100 mg QD in drug-naïve diabetic patients with mildhyperglycaemia. Additionally, in patients with T2DM on metformin or diet, 12-weekvildagliptin 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 weekvildagliptin treatment during an intravenous glucose tolerance test in IFG subjects at high riskfor developing diabetes, and demonstrated in this population similarly an enhanced acuteinsulin secretion (AIRg +27%, P<0.05) [72].DPP-4 inhibition and pancreatic alpha-cell function: clinical dataFailure to suppress glucagon secretion under hyperglycaemic conditions is an importantfeature of T2DM [5]. Several short- and long-term trials showed beneficial effects of DPP-4inhibitors on postprandial glucagon excursions [49,64,65,69-71,73,77] (Table 4&5). Withregard to other glucose-lowering agents, the significantly reduced postprandial AUCglucagonresulting 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 9
  • 10. 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 butsignificant 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 decreasedsignificantly by 9.7%. Moreover, during hypoglycaemia, the glucagon-lowering effect ofDPP-4 inhibition was attenuated [70]. The finding that DPP-4 inhibitors affect glucagonlevels dependent of prevailing blood glucose levels is clinically important given previousconcerns 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 ofhypoglycaemia [70].Long-term effects of DPP-4 inhibition on pancreatic islet cell function: clinical dataSince most clinical (registration) trials to date are designed to last up to approximately sixmonths, there is little information concerning long-term effects of DPP-4 inhibition onpancreatic islet-cell function in humans. Although the duration of the majority of randomisedclinical trials (RCT) was prolonged by an extension period, mostly up to two years, it is likelythat only those patients who showed response to DPP-4 therapy, or otherwise profited fromthe intervention, consented to continue in the trial. Conversely, those who had loss ofglycaemic control were not enrolled in the extension part of the RCT. These patients hadeither 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 trialsshould be carefully interpreted. Stable beneficial effects on PI/I ratio [57] or both PI/I ratio and HOMA-B [54] wereshown during a one year treatment with vildagliptin or sitagliptin, respectively, as add-on tometformin. 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 SUwas used as add-on to metformin [56]. Accordingly, a beneficial effect on dynamicparameters 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 thisparameter deteriorated by 24.5% in the placebo-treated group [74]. Moreover, in anotherstudy with treatment duration of two years, vildagliptin did show a stabilization of beta-cellfunction, in contrast to the deterioration seen in the placebo-treated group [68]. In addition, 10
  • 11. two years of sitagliptin as add-on to metformin significantly improved beta-cell functionwhich 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-outperiod the beneficial effect on beta-cell function did not sustain [67,74]. Similarly, in studiesthat assessed dynamic beta-cell function by intravenous glucose challenge tests, lasting sixweeks [72], twelve weeks [86] or 52 weeks [85], beta-cell function parameters returned backto baseline values after the washout period of two weeks (for the first two studies) and twelveweeks (for the latter study). Concerning pancreatic alpha-cell function, two year treatmentwith vildagliptin 50 mg BID as add-on to metformin improved postprandial glucagonsuppression compared to the use of a SU as add-on to metformin [77]. No data aboutpersistence of effects on glucagon secretion following an off-drug period are available. In conclusion, the available data indicate that DPP-4 inhibitors show stableimprovements in beta-cell function parameters after chronic treatment up to two years inopen-label extension trials, however, there is at present no direct evidence to suggest thatDPP-4 inhibitors have durable effects on beta-cell function after cessation of therapy. Thus, itis presently unknown whether these agents can modify the progressive course of T2DM.Summary and discussionIn summary, preclinical studies have demonstrated beneficial effects of DPP-4 inhibition onpancreatic islet-cell function. This was concluded from studies in different rodent models ofhyperglycaemia and diabetes showing improved insulin secretion, increased beta-cell massand proliferation, and suppression of glucagon secretion under hyperglycaemic conditions. Inhumans, DPP-4 inhibitors improved fasting and dynamic beta-cell function measuresincluding HOMA-B, PI/I ratio, IGI, AUCinsulin/glucose ratio and model-derived parametersobtained during oral glucose challenge tests. Moreover, glucose- and arginine-stimulatedinsulin secretion, assessed by the hyperglycaemic clamp method, were improved by DPP-4inhibition (Table 6). Finally, postprandial glucagon excursion decreased during DPP-4inhibitor treatment. These improvements in islet-cell function clinically result in HbA1creduction, and data from animal studies possibly suggest sustained effects on islet-cellfunction. However, several important considerations regarding DPP-4 inhibition and theeffect on pancreatic islet-cell function should be addressed. Firstly, given the many different tests performed and variables reported to assesschanges in beta-cell function after intervention with incretin-based therapies in the varioushuman studies, the size of the effects is difficult to compare. In particular, it is impossible to 11
  • 12. reliably compare the effects of the different agents from data obtained from separate versushead-to-head comparison studies, however, we attempted to fully outline the currentlyavailable data and to compare when possible. Secondly, aetiology and course of T2DM in rodents is different from that in humansand although rodent studies reported improved glycaemic control together with positiveeffects on beta-cell mass and morphology, in humans such durable effects have not (yet) beendemonstrated after chronic treatment with DPP-4 inhibitors. Indeed, whether the beneficialeffects that are observed in clinical trials up to two years remain after drug-washout, is stillinconclusive (Table 6) since few studies reported off-drug values of beta-cell function ofwhich 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 wereobserved any longer [67,72,74,85,86]. Moreover, most long-term studies were extensionstudies from original six-month trials, therefore it is possible that only patients that respondedwell to the intervention consented to continue in the trial whereas the non-responders declinedenrollment in the extension. It would be of interest, to compare the (long-term) responders tothose who dropped out due to disease progression in order to identify possible determinants orpredictors 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-cellsparing effect of a therapeutic agent should be assessed after substantially long-term treatmentof years. Indeed, since in the UKPDS [3] and ADOPT (A Diabetes Outcome ProgressionTrial) [87] studies, beta-cell function improved initially but over time a decline was found, tooshort observations may yield erroneous results. Therefore longer term studies with a durationof at least five, but preferably more years using gold-standard methodology for reproduciblerepetitive beta-cell function assessment and including a drug-washout period, should becarried out in order to assess the full potential of DPP-4 inhibitors regarding their ability topreserve pancreatic islet-cell function. In recent years, the goal of the treatment of T2DM has been shifted from merelyreducing HbA1c levels alone, to simultaneously addressing several aspects of the morecomplex pathophysiologic interplay characterising T2DM, e.g. gluco- and lipotoxicity,reduced muscle glucose uptake, hepatic insulin resistance, decreased incretin effect, increasedglucagon secretion and decreased insulin secretion, as well as improving cardiovascular riskfactors including weight, blood pressure and lipid profile [88]. Given this complexity and theheterogeneous phenotype of patients with T2DM, it seems obvious that, in order to achieve 12
  • 13. these aims, combination of different blood-glucose lowering agents with complementarymechanisms of action is necessary. Indeed, in addition to addressing the multiplepathophysiological defects of T2DM, combining agents in the early phase of the disease, mayresult in early robust HbA1c lowering, thus minimize the deleterious effect of glucosetoxicity, improve residual beta-cell function and allow to use lower doses of individual agentsin order to reduce side effects [89,90]. Also, initial combination therapy, as opposed to thestep-wise approach advocated in the current guidelines [91] may prevent clinical inertia whichresults in significant delays in therapeutic adjustments at the cost of accumulation ofconsiderable glycaemic burden and late complications [89,92]. Combination therapy thatimproves both insulin secretion and peripheral or hepatic insulin sensitivity may be mosteffective in preventing the natural decline in glycaemic control. However, in clinical practice,the use of currently established anti-hyperglycaemic drugs is associated with potential sideeffects that may off-set the efficacy, e.g. by adversely affecting cardiovascular risk factorsand/or hamper patient compliance. For example, SU agents lower blood glucose but do notslow down beta-cell function deterioration [87]. Additionally, SU cause body weight gain andhypoglycaemia, both of which are associated with increased cardiovascular risk in patientswith T2DM [93], metformin use is associated with gastro-intestinal side-effects and TZDscause weight gain and fluid retention, which can progress to peripheral oedema and/or overtheart failure [91]. Therefore, new drugs such as DPP-4 inhibitors may be of great additivevalue, 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 thisregard, combining DPP-4 inhibitors with currently employed strategies that improve insulinsensitivity, i.e. TZD and/or metformin, might be particularly suited. Interestingly, metforminpotentially increases GLP-1 levels and acts as GLP-1 sensitizer [94], resulting in a synergisticeffect when used in combination with the DPP-4 inhibitor sitagliptin as observed in healthyhumans [95]. Indeed, a recent meta-analysis shows that combination therapies are moreefficacious in improving glycaemic control than administering each of the individual drugsalone [96]. Furthermore, the use of DPP-4 inhibitors alongside insulin replacement therapyhas been reported to be safe. The first trials that assessed the use of DPP-4 inhibitorscompared to placebo in combination with insulin treatment showed better glycaemic controland less use of insulin despite fewer hypoglycaemic events [97,98]. Concerning implementation of incretin-based therapies, at present, the moment ofinitiation in the treatment of T2DM is under debate. Current diabetes treatment-guidelinesrecommend a stepwise approach, which by some authors has been termed a “treat-to-failure” 13
  • 14. approach [99]. Accordingly, a next agent should be added whenever HbA1c rises above apreset target level [91]. In clinical practice, however, the next therapeutic step is often takento late, leading to accumulation of considerable glycaemic burden [92]. In order to achievegreater 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 addressmultiple pathophysiological mechanisms, in order to minimize glycaemic burden over time[89]. Furthermore, it was demonstrated that early on in the development of T2DM, whenHbA1c is just above the target of 7.0% (53 mmol/mol), postprandial hyperglycaemia mainlycontributes to the progression of the disease [100]. Taking together the findings that DPP-4inhibition 1) improves postprandial glucose disposal; 2) already exerts a glucose loweringeffect when administered to subjects with IFG and/or IGT [72,73]; 3) does not causehypoglycaemia and 4) seems to preserve beta-cell function at least for the first two years oftreatment, one may conclude that early combination therapy consisting of a DPP-4 inhibitor inaddition to a drug with complementary modes of action (e.g. metformin and/or TZD) may beneeded 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 clinicaluse. Importantly, due to the glucose-dependent effect on insulin secretion, hypoglycaemia isseldom seen during DPP-4 inhibitor monotherapy or when a DPP-4 inhibitor is added toongoing metformin therapy [101]. Pooled analyses from clinical trials up to two years, inwhich adverse events during sitagliptin and vildagliptin therapy were evaluated, showed nodifference in incidence of adverse events, e.g. hypoglycaemic events, infection rate, skinreaction, 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, mainlyfrom the upper respiratory tract and urinary tract [104]. Moreover, recent concerns are raisedabout incretin-based therapies and incidence of pancreatitis, however incidence of pancreatitisduring 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 themarket, side effects need to be monitored carefully in ongoing trials and postmarketinganalysis. Furthermore, the different compounds are of diverse chemical structure and maytherefore theoretically exert different clinical efficacy and side effect profiles [107]. Thus anaspect 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
  • 15. trials are performed with vildagliptin and sitagliptin. Careful long-term surveillance of allcompounds from this new class of glucose-lowering agents is needed and this can beeffectuated as, according to the FDA and EMA guidance [108], all pharmaceutical companieswith DPP-4 inhibiting agents on the market or about to be launched, have committedthemselves to perform large-sized long-term outcome trials to assess long-term efficacy but inparticular cardiovascular and overall safety of the drugs (TECOS-trial for sitagliptinNCT00790205; EXAMINE trial for alogliptin NCT 00968708; SAVOR-TIMI 53 trial forsaxagliptin NCT01107886; CAROLINA trial for linagliptin NCT01243424). A limitation to the clinical use of DPP-4 inhibitors might be the higher cost, comparedto more established compounds such as metformin, SU and insulin. One study assessed thecost-effectiveness of the DPP-4 inhibitor sitagliptin against the TZD rosiglitazone or SUderivatives as add-on to metformin treatment, in which equal cost-effectiveness wasconcluded [109]. However, when performing cost-effectiveness analyses in the context ofnovel drugs for chronic use, it is important that not only direct but also indirect costs areincluded, such as those inferred by hospital admission because of hypoglycaemia, costsrelated to non-compliance due to a drug’s unfavourable side-effect profile, costs related todrug-related body weight gain or indirect costs due to sick-leave and loss of work forcerelated to the disease and/or therapy, therefore more extensive cost-effectiveness analysesshould be conducted for DPP-4 inhibitor therapy. To conclude, overall, present evidence suggests that DPP-4 inhibitors improvepancreatic islet cell function in humans based on both static and dynamic parameters asshown in clinical trials up to two years. However, little data indicate sustained improvementsafter drug wash-out, giving doubt to the hypothesis generated in pre-clinical studies that theseagents may durably preserve beta-cell function in humans. Moreover, it is uncertain whetherDPP-4 inhibitor monotherapy may alter the progressive course of the disease by preservingfunctional beta-cell mass, in the presence of persistent damaging factors such as(gluco)lipotoxicity, and the associated oxidative stress and low grade inflammation, orhepatic insulin resistance. As stated above, DDP-4 inhibitors may be particularly useful in theearly phase when combined with agents addressing complementary pathophysiologicalmechanisms. However, long-term trials should be awaited for to assess whether treatmentwith DPP-4 inhibitors durably (and equally) improves islet-cell function and whether it maychange the progressive course of T2DM by preserving beta-cell function. 15
  • 16. List of abbreviationsAUC Area under the curveBID Twice dailyDPP-4 Dipeptidyl peptidase-4EMA European Medicines AgencyFDA Food and Drug AdministrationGIP Glucose-dependent insulinotropic polypeptideGLP-1 Glucagon-like peptide 1IFG Impaired fasting glucoseIGT Impaired glucose toleranceHbA1c Haemoglobin A1cHOMA-B Homeostatic model assessment beta-cell function indexIVGTT Intravenous glucose tolerance testPI/I ratio Pro-insulin to insulin ratioQD Once dailyRCT Randomised clinical trialSU Sulfonylurea drugsT2DM Type 2 diabetes mellitusTZD Thiazolidinedione 16
  • 17. Table 1. DPP-4 inhibitors and islet cell function and morphology: preclinical studies Effect of DPP-4 inhibitionRef Year Animal model Intervention Islet-cell function Islet morphology21 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 pattern22 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 sensitivity23 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 secretion24 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 Ex vivo: Increased pancreatic insulin secretion25 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 glipizide26 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-mice27 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 Ex vivo: Increased pancreatic insulin secretion28 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-cell29 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 valsartan30 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 levels31 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 pioglitazon32 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 glipizide33 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 expression34 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 content35 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
  • 18. Table 2. DPP-4 inhibitors and static measures of beta-cell function: clinical studies, monotherapy Δ HOMA-B (%) Δ PI/I ratioRef Year Intervention (N) Duration vs BL P vs COM P vs BL P vs COM PSitagliptin 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 +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) -3.1Vildagliptin 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 +0.040Alogliptin 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 +0.046Saxagliptin 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) +8.1Linagliptin 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 +0.02Data 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-insulinratio; 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 usingc-peptide concentrations; † decreased significantly, values not reported in reference. 18
  • 19. Table 3. DPP-4 inhibitors and static measures of beta-cell function: clinical studies, combination therapy Δ HOMA-B (%) Δ PI/IRRef Year Intervention (N) Duration vs BL P vs COM P vs BL P vs COM PSitagliptin 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/aVildagliptin 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/aAlogliptin 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) +4.9Sitagliptin as add-on to metformin and/orsulfonylurea 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 -0.029Vildagliptin 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 nsSaxagliptin 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) +2.9Data 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-insulinratio; 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 usingc-peptide concentrations; † decreased significantly, values not reported in reference; ‡ active comparator 19
  • 20. 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 COMSitagliptin monotherapy66** 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 45 2008 sitagliptin 100 mg QD (75) 12 wk +68.0 n/a +73.0 <0.001 placebo (76) -5.0Vildagliptin 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) crossoverVildagliptin 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 +3.2Saxagliptin monotherapy50** 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 signLinagliptin 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
  • 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 (%) vs vs vs Ref Year Intervention (N) Duration vs BL P P vs BL P P vs BL P P COM COM COMSitagliptin as add-on to metformin 52 2006 sitagliptin 100 mg QD (453) 24 wk +23.5 n/a +28.8 <0.001 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/aSitagliptin as add-on to metformin and/orsulfonylurea 61 2007 sitagliptin 100 mg QD (222) 24 wk +14.5 <0,05 +25.8 <0.05 placebo (219) -11.3Vildagliptin 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 QDSaxagliptin as add-on to metformin60** 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 nsVildagliptin 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) -6.1Sitagliptin 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 nsVildagliptin 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 thiazolidinedione65** 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
  • 22. 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 washoutSitagliptin ↑ ↑ ↑/= ↑/= ↑/= 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/aLinagliptin ↑ ↑ n/a = n/a n/a n/a n/a n/aIGI: insulinogenic index; AUC: area under the curve; HOMA-B: homeostatic model assessment beta-cellfunction index; PI/I ratio: pro-insulin-to-insulin ratio; IVGTT: intravenous glucose-tolerance test; ↑: beneficialeffects of DPP-4 inhibitor treatment in all studies; ↑/=: beneficial effects of DPP-4 inhibitor treatment in somestudies, but not all; =: no effect of DPP-4 inhibitor treatment; n/a: data not available. 22
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  • 32. Conflict of interest details: van Genugten: writing manuscript van Raalte: writingmanuscript Diamant: writing manuscriptAuthorship details: RvG and DvR declare no conflict of interest. Through MD, the VUUniversity Medical Center received research grants from Amylin, Eli Lilly, Glaxo SmithKline, Merck, Novartis, Novo Nordisk, Sanofi Aventis and Takeda, consultancy fee from EliLilly, Merck, Novo Nordisk, Sanofi Aventis and speaker fee from Eli Lilly, Merck and NovoNordisk. 32

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