Is there a place for incretin therapiesin obesity and prediabetes?Jens Juul Holst and Carolyn F. Deacon

The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, The Panum Institute, University of

Copenhagen, DK-2200 Copenhagen N, Denmark

Review

Incretin-based therapies exploit the insulinotropicactions of the gut hormones gastric inhibitory peptide(GIP) and glucagon-like peptide-1 (GLP-1) for the treat-ment of diabetes and include GLP-1 receptor agonistsand inhibitors of dipeptidyl peptidase-4 (DPP-4), theenzyme that inactivates the incretin hormones in thebody. Both drug classes improve metabolic control intype 2 diabetes (T2DM), with GLP-1 receptor agonistsalso lowering body weight. Pharmacotherapy usingDPP-4 inhibitors has few side effects and is weightneutral. Animal studies support their use in prediabetes;however, human data are scarce. GLP-1 receptor agonisteffects are also apparent in non-diabetic obese individu-als. Therefore, incretin-based therapies, if safe, may beeffective in preventing progression of prediabetes; andGLP-1 receptor agonists may have potential for use inthe treatment of obesity.

Incretin biologyIncretins are gastrointestinal hormones that increase in-sulin secretion from pancreatic b cells following food in-gestion. They do so with increasing efficacy as plasmaglucose rises [1]. Two main incretin hormones exist inhumans: gastric inhibitory peptide (GIP; also known asglucose-dependent insulinotropic peptide) and glucagon-like peptide-1 (GLP-1) [2]. Both are secreted by endocrinecells in the small intestinal mucosa, and are rapidly inac-tivated by the ubiquitous enzyme dipeptidyl peptidase-4(DPP-4) [3]. Incretin hormone release is stimulated by foodingestion and the underlying molecular mechanisms arecurrently being investigated [4], with glucose being beststudied. Once released, incretins are carried to the b cellswhere they augment glucose-stimulated insulin secretion[5] although their action is limited because of degradationby DPP-4 (Figure 1).

Incretin-based therapiesThe term encompasses therapies that seek to exploitthe actions of the incretin hormones GLP-1 and GIP.The incretin-mediated amplification of insulin secretion(the so-called incretin effect) is related to the amountof glucose ingested [6], and may account for up to70–80% of the total insulin response to oral glucose ad-ministration; thus, the incretin hormones are clearly

Corresponding authors: Holst, J.J. (jjholst@sund.ku.dk); Deacon, C.F.(deacon@sund.ku.dk).Keywords: DPP-4 inhibitors; GLP-1 receptor agonists; glucose-dependentinsulinotropic polypeptide; GIP; type 2 diabetes; appetite regulation; glucagon.

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potent and powerful stimulators of postprandial insulinsecretion. Given that the incretin effect is severely im-paired in T2DM [6,7], mechanisms that boost the incretinaxis might help to improve the inappropriately low insulinsecretion, which characterizes T2DM. Indeed, patientsrespond well to GLP-1 administration, whereas the effectof GIP is almost completely lost [8,9]. Incretin-based ther-apies are, therefore, mainly focused on GLP-1.

The main hurdle for pharmaceutical development ofGLP-1 therapies was the extreme sensitivity of the mole-cule to digestion by DPP-4, which cleaves and inactivatesGLP-1 (7-36) amide to GLP-1 (9-36) [10] within 1–2 min.GIP is cleaved more slowly, but still has a DPP-4-relatedhalf-life of only 7 min [11,12]. In addition, because there isno ‘memory effect’ of previous exposure to the incretins[13], GLP-1 receptor activation should be maintained for aslong as possible (>24 h) to have full effect. However, therapid renal elimination of incretin hormones does notpermit this. Therapeutic strategies, therefore, relied uponthe development of injectable DPP-4-resistant analogs ofGLP-1 or activators of the GLP-1 receptor, together desig-nated GLP-1 receptor agonists (GLP-1 RAs) [14]. Anotheroption was to block the activity of DPP-4 using orallyavailable inhibitors, thereby protecting the endogenousincretin hormones [15]. Both approaches were followedand proved fruitful: the first marketed drug was theGLP-1 RA exenatide isolated from the saliva of the Gilamonster [16], which has a half-life of 2–3 h after subcuta-neous administration, and thus requires two daily injec-tions. Recently, a slow release formulation of exenatide,suitable for once weekly administration, was approved[17,18]. The next GLP-1 RA to be marketed was liraglu-tide, an acylated form of human GLP-1, which owes itsDPP-4 resistance and long half-life (12 h) to albuminbinding [19]. The first of the DPP-4 inhibitors, whichare now designated ‘gliptins’, sitagliptin, was launchedin 2006; it is suitable for once daily administrationand causes a 2–3-fold elevation of GLP-1 and GIP concen-trations [20,21]. Subsequent years brought a number ofadditional inhibitors (with broadly similar pharmacody-namic properties) to the market such as saxagliptin,vildagliptin, and linagliptin [3]. Together, these makeup the incretin-based therapies.

Should incretin therapy be considered for obesity and/or prediabetes intervention?Current concepts about the pathogenesis of T2DM centeraround two pathogenetic traits: (i) insulin resistance, in

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Incre �ns: GLP -1, GIP

Gut nutrie nts

DPP-4 enzymeCapillary wall

LiverBlood

S�mulates insulin release

Lower blood glucose

Inac�ve GLP-1 andGIP metabolites

DPP-4 inhibitor

TRENDS in Endocrinology & Metabolism

Figure 1. The incretin system and its regulation by DPP-4. A schematic of the

incretin system is shown. Glucagon-like peptide-1 (GLP-1) and glucose-dependent

insulinotropic polypeptide (GIP) stimulate insulin release and help to lower blood

glucose. Dipeptidyl peptidase-4 (DPP-4) degrades GLP-1 and GIP to inactive

metabolites. Blue arrows: without DPP-4 inhibitors. Red arrows: with DPP-4

inhibitors.

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general secondary to obesity [22]; and (ii) failure of the b

cells to respond appropriately to insulin resistance byincreasing insulin secretion, probably an inheritable trait,aggravated by dysmetabolic factors including gluco- andlipo-toxicity [23]. The etiology/pathogenesis of obesity islikely to be found in a combination of genetic and environ-mental factors including sedentary lifestyle and easy avail-ability of high energy density food stuffs. This then raisesthe question regarding what incretin physiology looks likein obesity.

GLP-1 and GIP physiology/pathophysiology

The two incretin hormones are secreted from epithelialendocrine cells in the gut mucosa in response to mealingestion. Classically, the cells producing GIP are de-scribed as K cells and are located in the upper smallintestine, whereas L cells, mainly located in the distalsmall intestine and colon, produce GLP-1. Interestingly,some upper intestinal cells have been found to produceboth hormones [24]. Furthermore, the gut endocrine cellsshow considerable plasticity and may express a variety ofgut hormones, perhaps dependent on factors like matura-tion as a function of time and/or location along the villousaxis [25,26]. The main documented activity for GIP isstimulation of insulin secretion, but GIP receptors arelocated in numerous additional tissues including brain,adrenal glands, and adipose tissue. Mice with global dele-tions of the GIP receptor do not become obese upon high fatfeeding, suggesting that GIP may have a role in fat depo-sition [27]. The role of its adipogenic action in humans is,however, uncertain [28]. GIP appears to have pronouncedeffects on bone resorption in rodents [29] and may be one ofthe gastrointestinal factors responsible for the markedpostprandial inhibition of bone resorption, althoughantiosteoporotic effects of GIP in humans have not yetbeen demonstrated. GIP secretion, which is stimulated

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by dietary fat and other macronutrients, is often increasedin obesity [2]. By contrast, GIP secretion is not particularlyaffected by the progression of obesity-induced glucose in-tolerance, and is generally similar in patients with T2DMand in weight-, gender-, and age-matched controls [30].The physiologic actions of GLP-1 appear much more di-verse. Important tools for physiologic studies include ani-mals with deletions of the incretin receptors, either aloneor in combination. Such studies clearly support the notionthat both hormones are involved in the incretin effect [31],but GLP-1 receptor knockout animals do not become obese[32]. The availability of the GLP-1 receptor antagonist,exendin 9-39, made it possible to analyze the physiologicactions of GLP-1 in more detail. Again, the effect on insulinsecretion can be nicely demonstrated, but it is also clearthat inhibition of glucagon secretion, a known action ofGLP-1, has an important role in the glucose-lowering effectof the hormone [33]. However, under normal physiologicconditions, it may not be the pancreatic effects of GLP-1that are most important. Rather, its function as an appe-tite suppressor and enterogastrone hormone(i.e., one of theileal hormones that inhibit upper gastrointestinal motilityand secretion postprandially) may be the major role [5].Thus, gastric emptying rates, and gastrointestinal (GI)tract motility in general, are strongly inhibited by GLP-1 agonists, and GLP-1 receptor antagonism acceleratesgastric emptying [34]. GLP-1 also powerfully suppressesfood intake, presumably via its action on appetite-regulat-ing centers in the brain [35], and conversely GLP-1 recep-tor antagonists increase food intake in experimentalanimals [36]. Thus, GLP-1 may be a physiologically impor-tant regulator of appetite and food intake. It should benoted that GLP-1 is also produced in certain neurons of thebrain stem, projecting to the hypothalamus where it mayfunction as a transmitter mediating the inhibition of foodintake, but its relevance of this regarding the effects ofperipheral GLP-1 is unclear [35]. GLP-1 (and DPP-4 inhi-bitors) may also delay post-absorptive lipid absorption [37],but the physiologic relevance of this is unclear and malab-sorption of lipids during chronic GLP-1 agonist therapy hasnot been reported. In contrast to GIP, secretion of GLP-1 isgenerally impaired in obesity [5]. GLP-1 secretion is stim-ulated by absorption of digested nutrients [5] with themagnitude of the response depending on the amount ofnutrient consumed [5,38–41]. Nevertheless, it has beenclearly shown that circulating GLP-1 levels are reducedin obese patients [42–48]. GLP-1 responses to oral stimu-lation have been negatively correlated to BMI [5,47], andweight loss was associated with increasing GLP-1responses to meal ingestion [42]. It has been suggestedthat the decrease may be related to the insulin resistancethat accompanies weight gain, and/or reduced L -cell re-sponsiveness to carbohydrates, secondary to increasedlevels of circulating fatty acids [5,49]. Interestingly, moder-ate and intense exercise are associated with increased GLP-1 levels and decreased hunger; and elevations in GLP-1 wereinversely correlated with energy intake post-exercise [50].Overall, individuals who have lost weight following changesin diet or exercise have increased GLP-1 [5]. Theseincreases, and their resulting effect on satiation signaling,may contribute to the weight reductions/maintenance

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observed with these interventions. Nevertheless, it is prob-ably too early to assign an important pathogenetic role forimpaired GLP-1 secretion in obesity.

Another interesting set of recent observations supportthe notion that GLP-1 has potential in prevention of obe-sity and diabetes. Bariatric surgery, particularly gastricbypass surgery, is associated with the greatest weight lossthat can be obtained therapeutically and, notably, this isoften associated with resolution of T2DM, present in aboutone-third of those admitted for bariatric surgery [51].Gastric bypass surgery is associated with dramaticallyincreased postprandial levels of GLP-1, whereas GIP levelsshow only minor and inconsistent changes [52]. The GLP-1increase seems to be secondary to increased exposure of thedistal small intestine, which contains a larger number ofGLP-1-producing cells, to digested nutrients. This wasclearly illustrated in studies of patients with a bypass inwhom it was possible to switch, on 2 consecutive days,between normal passage of nutrients via the stomach(using a gastrostomy catheter) and passage through thebypass. The exaggerated response was only observedafter bypass feeding [53,54]. The post-operative GLP-1responses, which can be increased by 30-fold, are associat-ed with: (i) increased insulin secretion, which in turnexplains much of the diabetes resolution – this conclusionis supported by studies in which the actions of GLP-1 wereblocked using the GLP-1 receptor antagonist exendin 9-39[55,56]; and (ii) inhibition of appetite and food intake [57].Further evidence for the latter includes observations thatpost-operative weight loss was significantly correlated tothe magnitude of the GLP-1 response [57]. These resultssupport the concept that GLP-1 has a major role in post-prandial regulation of glucose metabolism and appetite/food intake, and support speculations regarding possiblepreventive use of GLP-1 in obesity and prediabetes.

Clinical effects of GLP-1 RAAs mentioned, GIP has little effect on insulin secretion andglucose turnover/tolerance in patients with overt T2DM[9]. It also appears that GIP has no effect on appetite/foodintake in humans, although it might still influence glucosetolerance in prediabetes and well-controlled diabetes [58].The interest in the field, therefore, has focused on GLP-1.

Exenatide and liraglutide have well-documented effectsin overt T2DM, as demonstrated in the registration studiesand supported by postmarketing studies [3]. In manystudies, it has been possible to reach a recommendedtreatment target [e.g., a fraction of glycated hemoglobin(HbA1c) below 7%] in 50–60% of those treated, which isequal to or even better than results obtained with insulintherapy [59]. Importantly, and in contrast to insulin, GLP-1 RA therapy is generally associated with significantweight loss, as well as absence of hypoglycemia, a conse-quence of the GLP-1 mechanism of action on pancreatic b

cells, which is to augment glucose-induced insulin secre-tion. Together, these findings are consistent with theproposed antidiabetic actions of GLP-1 after gastric bypasssurgery [60]. The weight loss is also consistent with theactions of GLP-1 on appetite and food intake outlinedabove. As mentioned, GLP-1 must be considered a physio-logic regulator of appetite and food intake; therefore,

amplifying this signal by exogenous administrationmight also lower appetite and food intake in non-diabeticsubjects.

Recent clinical trials in obese patients without diabeteshave indicated that GLP-1 RA treatment does decreasebody weight in this group. In one study, obese subjects [n =152; mean BMI = 39.6 kg/m2; 25% with impaired glucosetolerance (IGT) or impaired fasting glucose (IFG)] wererandomized to receive exenatide or placebo along withlifestyle intervention for 24 weeks. Exenatide-treated sub-jects lost 5.1 kg from baseline versus 1.6 kg with placebo[61]. Another recent double-blind, placebo-controlled, 20-week trial enrolled 564 individuals (18–65 years of age,BMI = 30–40 kg/m2) who were randomized to liraglutide(1.2, 1.8, 2.4, or 3.0 mg/day, n = 90–95 per group), placebo (n= 98), or the lipase inhibitor orlistat (120 mg, n = 95). Allsubjects had a 2093 kJ (500 kcal) per day, energy-deficitdiet, and increased their physical activity as measured by apedometer throughout the trial. Mean weight losses withliraglutide (1.2, 1.8, 2.4, and 3.0 mg) were 4.8, 5.5, 6.3, and7.2 kg, respectively, compared with 2.8 kg with placeboand 4.1 kg with orlistat [62]. Recently reported resultsindicate that the efficacy of liraglutide on weight loss issustained for at least 2 years [63,64]. It should be notedthat these studies employed doses considerably higherthan those recommended for diabetes therapy, althoughthe latter (1.2 mg) was chosen on the basis of acceptablylow rates of mainly gastrointestinal side effects (nauseaand vomiting). However, in the obesity studies, the highdoses were administered to heavy individuals and, whenexpressed per kg body weight, they were not too dissimilar.It is also possible, but still unexplored, that overweightindividuals might tolerate higher doses (per kg) thannormal weight individuals. Side effects may also be mini-mized by gradual dose escalation, and therefore it is cur-rently being investigated whether T2DM patients may alsotolerate larger doses, perhaps with additional antidiabeticbenefit. Moreover, in obese individuals with IGT (aboutone-third of the subjects investigated by Astrup et al.)glucose tolerance was normalized in the majority duringtherapy [63]. This important observation suggests thatGLP-1 RA therapy may actually protect against T2DMin this high-risk population. A number of clinical trials arecurrently investigating this possibility.

Can protection of endogenous incretins delayprogression to T2DM or reduce body weight?Although the effects of exogenously administered GLP-1have been extensively studied, few studies have investi-gated the actions of DPP-4 inhibitors in prediabetes andobesity. However, there are some data in animal modelssuggesting that protection of endogenous GLP-1 mightinfluence the progression of prediabetes to overt T2DM.In one of the earliest studies, a long-acting prototype DPP-4 inhibitor (FE 999-011) not only normalized the glucoseexcursion after oral glucose administration but, intrigu-ingly, also delayed the development of hyperglycemia ininsulin-resistant Zucker obese rats [65]. Similarly, in pre-diabetic db/db mice increased intact GLP-1 levels wereassociated with b cell preservation and delayed progres-sion to diabetes following treatment with alogliptin, and

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the effect was more pronounced after combination treat-ment with alogliptin and pioglitazone, an agonist for theinsulin sensitizer peroxisome proliferator-activated recep-tor gamma (PPARg) [66]. Recent studies also reported thatthe experimental DPP-4 inhibitor DA-1229 improved b cellfunction, and slowed the onset of diabetes in young db/dbmice [67]. In a more mechanistic study, the insulinotropicand glucagonostatic effects of sitagliptin were preserved inthe spontaneously hypertensive obese (SHROB) rat, amodel displaying many of the characteristics of humanmetabolic syndrome [68].

Regarding clinical studies, it appears that the mecha-nism of action of DPP-4 inhibitors (i.e., increased intactincretin levels and actions) is operative in subjects withoutovert diabetes [69–72]. In a study in patients with IFGthere were improvements in b cell function and postpran-dial glycemia after 6 weeks of vildagliptin treatment,although fasting glucose levels themselves were unaltered[69]. In another study, sitagliptin treatment for 8 weekswas associated with modest improvements in b cell func-tion (according to the Disposition Index) in IFG subjects,although this was not sufficient to alter endogenous glu-cose production or glucose uptake, and neither fasting norpostprandial glucose levels were altered [70]. These find-ings were corroborated in yet another study, which showedthat 4 weeks of sitagliptin administration enhanced incre-tin concentrations and decreased fasting glucose concen-tration in IFG and normal glucose tolerance (NGT)subjects, without changing whole body or hepatic insulinsensitivity or indices of b cell function [71]. Thus far, only asingle study has investigated the effects of DPP-4 inhibi-tion in subjects with IGT, showing that vildagliptin ad-ministration for 12 weeks reduced postprandial glucoseexcursions and improved islet function. This was associat-ed with a small but significant reduction in HbA1c levels(�0.15%, from a baseline of 5.9%) [72].

Taken together, these studies provide some evidencethat the enhancement of endogenous incretin hormonelevels by DPP-4 inhibition is possible in subjects at elevat-ed risk of progressing to overt T2DM, and that DPP-4inhibitor administration in prediabetic individuals mayhave some modest benefit on glucose homeostasis. Howev-er, although animal studies suggest that elevating endog-enous incretin hormone concentrations in prediabetes maydelay the transition to diabetes, it remains unproven inhumans (several clinical trials investigating this possibili-ty are listed on clinicaltrials.gov). Numerous clinical trialshave indicated that islet cell dysfunction does improve withDPP-4 inhibitor therapy in T2DM patients, but there ispresently no evidence that this is associated with actualincreases in b cell mass. In an indirect attempt to assessthis a few studies have examined whether the beneficialeffects of DPP-4 inhibition persist after treatment discon-tinuation, and it was noted that all parameters returnedrapidly to pre-treatment values. Thus, beneficial effects onb cell function were reversed within 2 weeks of stoppingvildagliptin, after a 6-week treatment period in IGF sub-jects [69]. However, although 6 weeks may not have beenlong enough for any potential b cell preservation effects tobecome evident, there was some suggestion that DPP-4inhibition was associated with an attenuation of the loss of

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glycemic control in drug-naive patients with T2DM andmild hyperglycemia given vildagliptin therapy for 2 years[73]. Thus, the rate of increase in HbA1c levels tended to beslower with vildagliptin compared with placebo, and b cellfunction, as reflected by the insulin secretory rate to glu-cose (ISR:G) ratio appeared to improve with time, showinga tendency to be greater in the second compared with thefirst year of treatment.

Thus, DPP-4 inhibition might have the potential toimprove glucose homeostasis in people with prediabetes.However, long-term studies are needed to reveal whetheraugmenting endogenous incretin hormones can halt orreverse the loss of functional b cell mass that underliesthe development and progression of T2DM.

With respect to body weight, DPP-4 inhibitors are gen-erally described as being body-weight neutral, althoughmodest weight reduction has been seen in some clinicaltrials, particularly when DPP-4 inhibitors are used incombination with metformin [74,75]. In direct compari-sons, greater weight loss is seen with GLP-1 receptoragonists than with DPP-4 inhibitors: up to �3.7 kg withliraglutide versus �1.2 kg with sitagliptin [76]; �2.0 kgwith exenatide once weekly versus �0.8 kg with sitagliptin[17], and it has been suggested that the greater agonistconcentrations seen with the injectable GLP-1 analogs arerequired to obtain the desired effects on body weight [77].As mentioned, the weight-reducing effects of GLP-1 RAsinvolve interaction with central appetite/satiety centers toreduce food intake, whereas DPP-4 inhibition has not beenshown to affect satiety in obese patients with T2DM, atleast in the short-term (10 days treatment with vildaglip-tin) [78]. Nevertheless, the mere fact that DPP-4 inhibitionis not associated with the weight gain that typically accom-panies improved glycemic control in patients with T2DM[79] does suggest that DPP-4 inhibitors may not becompletely neutral in this respect. Although they maynot be a candidate for obesity therapy, the fact that theyare weight neutral is clearly advantageous in the context oftreating T2DM. Interestingly, a recent study reported that,although DPP-4 inhibition with linagliptin did not preventweight gain in rats given a high-fat cafeteria diet, it didreduce weight regain in animals previously treated withexenatide if they were switched to linagliptin rather thanplacebo [80]. Although presently untested in humans, thisraises the intriguing possibility of using injectable GLP-1RAs to induce weight loss, followed by introduction of anoral DPP-4 inhibitor for weight maintenance.

SafetyA prerequisite for every intervention given to apparentlyhealthy individuals for prevention of a development thatmay only strike few of the members of the group (diabetes)or to ameliorate a physical characteristic of the group thatis not associated with an immediate health threat (obesity)is that it must have an acceptable safety profile. In general,incretin-based therapies are well tolerated [81]. For theGLP-1 RAs the most frequent side effects are gastrointes-tinal, and include nausea and in some cases vomiting [18].Both are usually mild and occur early during treatment,maybe only a few times, and then subside. Few patientsdropped out of the clinical studies because of these side

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effects and, given a promise of weight loss, it seems that abit of nausea was acceptable for most. The same applies tothe mode of administration – subcutaneous injections donot seem to represent a major obstacle. More serious arereports of acute pancreatitis in conjunction with incretin-based therapies [82]. During the registration studies, nei-ther liraglutide nor exenatide therapies were associatedwith increased incidences of pancreatitis, but a number ofpost-marketing reports [83,84] elicited a black box warningagainst this risk for exenatide and subsequently also lir-aglutide and the DPP-4 inhibitors. In the subsequentfollow-up, it became evident that the risk of pancreatitisis increased approximately 3-fold in people with T2DMcompared with the non-diabetic background population[85]. However, it has not been possible to identify a mech-anism for a GLP-1-induced pancreatitis and, in preclinicalstudies examining GLP-1 therapies in experimentally in-duced pancreatitis, there was amelioration rather thanaggravation [86,87]. In toxicology studies, where hugedoses of GLP-1 agonists were administered to experimen-tal animals for their lifetime, there were no signs of pan-creatitis [88]. Additional, careful experiments in largegroups of animals, including diabetic animals, revealedno evidence of pancreatitis or ductal abnormalitites[87,89,90]. Furthermore, analyses of very large (>1 millionindividuals) health-claim databases have been negative[91,92]. A recent review of clinical studies discussed the11 cases observed with liraglutide to date, but provided nonew evidence supporting increased risk of pancreatitis[93]. A single report claiming increased risk of pancreatitisand cancer with GLP-1-based therapies, inspired by stud-ies in transgenic animal models [94,95], stands out [96].The data in this report were collected from the FDAAdverse Event Reporting System (FAERS) database,which is open for reporting to everybody, and where report-ing frequency, therefore, is strongly influenced by publicawareness. After the FDA pancreatitis warning, thereporting frequency to the FAERS also increased. TheFDA therefore specifically warns against using the FAERSdatabase for risk calculation. In the same study [96], theauthors reported increased risk of certain cancers includingpancreatic cancer. Again, neither toxicology nor registrationand postmarketing studies have supported increases inpancreatic cancer risk. In toxicology studies for liraglutideincreased occurrence of thyroid C cell cancers was noted inmice and rats [97]. Subsequent studies revealed muchhigher GLP-1 receptor expression in C cells from rodentsthan in humans and non-human primates, and a sequence ofevents encompassing dose-dependent stimulation of secre-tion (calcitonin), hyperplasia, adenoma, and, in a few cases,cancer formation could be demonstrated. In human cellslines there was no similar development. Similar findingswere made with other GLP-1 receptor agonists, suggestingthat the rodent phenomenon is probably a class effect [97]. Inthe clinical studies, calcitonin levels have therefore beencarefully followed. This has in itself provided interestingdata on calcitonin levels and secretion in large numbers ofT2DM patients and controls, but a relationship betweensecretion and liraglutide therapy could not be established[98]. Neither registration studies nor postmarketing sur-veys have identified any increased risk for C cell carcinoma

(medullary thyroid carcinoma), and the US and Europeanhealth authorities have accepted that this risk is likely to besmall [99] and, therefore, acceptable in light of the benefits ofthe therapy. Although it is impossible on the basis of theexisting data to exclude the possibility that GLP-1-basedtherapies may increase the risk of pancreatitis and pancre-atic cancer, it can be concluded that the risk is so small that itescapes detection from even very large databases.

Postmarketing reports regarding renal failure in con-junction with exenatide therapy have also appeared, andled to a warning against this complication. Although theeffect may possibly be less during chronic treatment, GLP-1 RAs are known to cause natriuresis [100]. If this issuperimposed on electrolyte disturbances of other genesis,perhaps in combination with existing renal insufficiency(and possibly, in some individuals, mild dehydration due toprolonged vomiting and/or diarrhea), a mechanism relat-ing therapy and renal failure may actually exist. It is,therefore, relevant to exert particular care in such cases.The cardiovascular risk associated with GLP-1 receptoragonists was reviewed recently [101]. Rather than increas-ing cardiovascular risk, therapy seems to be associatedwith decreased risk. In fact, in a recent study of nearly 40000 patients treated with exenatide the risk of a cardio-vascular event was significantly reduced compared withother glucose-lowering therapies [102].

For the oral DPP-4 inhibitors the side effect profileresembles that of placebo [103]. Careful analysis of allthe data collected during the clinical development pro-grams and postmarketing period have revealed no in-creased incidence of adverse effects relative to placebo oractive comparator; the most commonly reported sideeffects have been headache and nasopharyngitis [104–106]. Importantly, given that the incretin-based therapieswere developed for T2DM therapy, it is relevant thathypoglycemia does not pose a risk, even in subjects withnormal glucose homeostasis, because of the glucose depen-dency of their islet effects. Cardiovascular risk has alsobeen assessed but, rather than increasing this risk, itseems from controlled clinical trials that GLP-1-basedtherapies may actually decrease cardiovascular risk[101]. Similar findings were reported from a meta-analysisof 43 clinical trials involving more than 20 000 patientstreated with DPP-4 inhibitors [104]. Currently, a numberof very large, long-term outcome studies of cardiovascularrisk associated with incretin-based therapies are beingcarried out and results are expected from 2014 onward.

Concluding remarksObesity and prediabetes are generally looked upon asbeing inflicted by an unhealthy lifestyle, and the logicalapproach to their prevention and therapy, therefore, islifestyle changes. Although this approach can be effective[107], its application on a larger scale is generally disap-pointing and, because the problem is enormous and al-ready imposing a heavy burden on societal healthexpenses, it may be relevant to look for medical/pharma-ceutical solutions. Recent studies have documented thatGLP-1 agonist therapy brings about significant weightloss, not only in individuals with T2DM but also in non-diabetic obese individuals. Simultaneously, the therapy is

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associated with improved metabolism and glucose toler-ance, suggesting that GLP-1 agonists may indeed be usefulfor diabetes prevention. The weight loss with higher dosesmay amount to 5–10% of body weight and may thereforesatisfy criteria set up for successful antiobesity therapy.The effect of the DPP-4 inhibitors on body weight is mini-mal, but they do have beneficial effects on glucose metabo-lism and possibly also lipid metabolism, therefore having a(as yet poorly explored) potential for diabetes prevention inhigh risk groups. The GLP-1 agonists require subcutane-ous injections, but this seems acceptable for most subjectswho seek to lose weight. This promising potential should,however, be weighed against the risk of side effects. It mustbe recognized that obesity and prediabetes are themselvesassociated with a not inconsiderable increased health risk;if treatment of the condition reduces this risk, even ifassociated with new treatment-related risks in a minorityof subjects, this must be considered beneficial. Currently, itis impossible to obtain precise estimates of the risk of themore serious adverse effects (i.e., pancreatitis and cancer)that have been claimed by some to be associated with GLP-1-based therapies. This is because they are so rare thatthey are difficult to distinguish from the spontaneousoccurrence rates in the (obese) background population.In the coming few years, the results of very large, long-lasting outcome studies, including those evaluating car-diovascular safety or risk benefit, that are currently ongo-ing will be known and will provide a background for adecision on whether to engage in preventive therapeuticstudies of lifestyle diseases.

Disclaimer statementThe authors have not received any fees or other forms of support from anypharmaceutical agency for the preparation of this review.J.J.H. has consulted for NovoNordisk and is an advisory board memberfor NovoNordisk, MSD, and Eli Lilly, and has received lecture fees fromthem. C.F.D. has consulted for Eli Lilly and MSD, and has receivedlecture fees from BMS, MSD, Boehringer Ingelheim, Eli Lilly, andNovoNordisk.

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