Dipeptidyl peptidase4 inhibitors in the treatment of type 2 diabetes: a ...

review

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Diabetes, Obesity and Metabolism 13: 7–18, 2011.© 2010 Blackwell Publishing Ltdreview article

Dipeptidyl peptidase-4 inhibitors in the treatment of type 2diabetes: a comparative reviewC. F. DeaconDepartment of Biomedical Sciences, University of Copenhagen, Panum Institute, Copenhagen N, Denmark

The dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antihyperglycaemic agents which were developed for the treatment of type 2diabetes by rational drug design, based on an understanding of the underlying mechanism of action and knowledge of the structure of thetarget enzyme. Although they differ in terms of their chemistry, they are all small molecules which are orally available. There are somedifferences between them in terms of their absorption, distribution, metabolism and elimination, as well as in their potency and duration ofaction, but their efficacy, both in terms of inhibiting plasma DPP-4 activity and as antidiabetic agents, appears to be similar. They improveglycaemic control, reducing both fasting and postprandial glucose levels to lower HbA1c levels, without weight gain and with an apparentlybenign adverse event profile. At present, there seems to be little to distinguish between the different inhibitors in terms of their efficacy asantidiabetic agents and their safety. Long-term accumulated clinical experience will reveal whether compound-related characteristics lead toany clinically relevant differences.Keywords: alogliptin, antidiabetic drug, diabetes mellitus, DPP-4, GLP-1, glycaemic control, incretin, linagliptin, saxagliptin, sitagliptin, vildagliptin

Date submitted 14 July 2010; date of first decision 8 September 2010; date of final acceptance 14 September 2010

IntroductionTherapies for type 2 diabetes (T2DM) based on the actionsof the incretin hormone, glucagon-like peptide-1 (GLP-1),were first introduced in 2005. GLP-1 is an intestinal hormone,which has been shown to play an important role in the normalregulation of glucose homeostasis. It has a number of effectsthat contribute to the maintenance of glucose tolerance, such asimprovements in α- and β-cell function, including the glucose-dependent stimulation of insulin and suppression of glucagonsecretion, as well as non-pancreatic effects such as delayinggastric emptying and suppression of appetite [1]. These actionsare preserved in patients with T2DM, and the first clinical-proof-of-concept study, published in 2002, showed that GLP-1could reduce HbA1c levels in T2DM patients when given bycontinuous subcutaneous infusion [2].

GLP-1 is, however, a labile peptide and is rapidly removedfrom the circulation by a combination of degradation andrenal clearance. The enzyme that is responsible for the initialcleavage of GLP-1 (whereby it loses its insulinotropic action)in vivo is the serine protease dipeptidyl peptidase (DPP)-4. Theidentification of its key role in the metabolic clearance of GLP-1in humans provided the rationale for inhibiting the enzyme (inorder to increase the levels of endogenous intact GLP-1) as atherapy of T2DM [3]. Preclinical studies showing that DPP-4inhibition could prevent the degradation of GLP-1 in vivo,leading to increased insulinotropic activity [4], were followed

Correspondence to: Carolyn F. Deacon, Department of Biomedical Sciences, University ofCopenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.E-mail: [email protected]

by the first demonstration in humans, that a DPP-4 inhibitorcould improve glycaemic control in subjects with T2DM [5].

The principle of using DPP-4 inhibitors as therapy ofT2DM [1,6] is now firmly established, and numerous inhibitorsare in varying stages of clinical development, with fouralready approved: sitagliptin in 2006, vildagliptin in 2007and more recently, saxagliptin in 2009 and alogliptin in2010 (presently only in Japan). The purpose of this articleis to review briefly the five leading compounds in the DPP-4inhibitor class (sitagliptin, vildagliptin, saxagliptin, alogliptinand linagliptin, currently in phase 3 clinical development), withspecial emphasis on any features which may help to distinguishbetween them.

ChemistryAs a therapeutic class, the DPP-4 inhibitors comprise adiverse group of compounds, which can be broadly dividedinto those that mimic the dipeptide structure of DPP-4substrates and those which are non-peptidomimetic. Com-pounds such as sitagliptin (β-amino acid based) [7–9], andvildagliptin [10–12] and saxagliptin [13,14], which are nitrile-containing inhibitors, belong to the former class, whereasalogliptin (modified pyrimidinedione) [15,16] and linagliptin(xanthine-based) [17,18] are members of the latter (figure 1,Table 1).

The compounds which have been developed for therapeuticuse are all competitive reversible inhibitors, which displayhigh affinity for DPP-4, resulting in inhibition constants (Ki)in the low nanomolar range [13,19–21]. There are, however,differences in the way in which they interact with the enzyme.

review article DIABETES, OBESITY AND METABOLISM

Figure 1. Structures of dipeptidyl peptidase (DPP)-4 inhibitors approved or in late stage clinical development.

Thus, sitagliptin, alogliptin and linagliptin form non-covalentinteractions with residues in the catalytic site [7,15,17]. Incontrast, inhibition of DPP-4 by vildagliptin and saxagliptinhas been described as a two-step process that involves theformation of a reversible covalent enzyme–inhibitor complexin which there is a slow rate of inhibitor binding and a slowrate of inhibitor dissociation, resulting in the enzyme slowlyequilibrating between the active and inactive forms [22–24].This means that the catalytic activity will be inhibited evenafter the free drug has been cleared from the circulation andmay help to explain why vildagliptin and saxagliptin inhibitDPP-4 activity for longer than their relatively short half-liveswould suggest. This may have repercussions in terms of theirdurations of action and dosing frequencies (see below).

Potency and DPP-4 Inhibitory EfficacyAlthough the described DPP-4 inhibitors are all competitivereversible inhibitors, it can be difficult to compare themusing data reported in individual studies, because these are

influenced by differences in the assay conditions used toestimate the extent of DPP-4 inhibition. However, one studyin which the inhibitors were directly compared under identicalexperimental conditions reported that all five inhibitors showedsimilar efficacy (i.e. maximal effect) for inhibition of DPP-4in vitro, but that there were differences in potency (i.e. amountof compound needed; IC50 = ∼1 nM for linagliptin vs. 19,62, 50 and 24 nM, for sitagliptin, vildagliptin, saxagliptinand alogliptin, respectively) [19]. With regard to half-life,there are also differences between the various inhibitors.Vildagliptin [12,25] and saxagliptin [14,26] are cleared fromthe plasma relatively quickly, whereas sitagliptin [9,27],alogliptin [28] and linagliptin [29] have much longer survivaltimes (Table 2, figure 2). These differences are reflected inthe therapeutic doses, which range from 5 mg for saxagliptinto 100 mg for sitagliptin, and in the dosing frequency (oncedaily for most of them, twice daily for vildagliptin; Table 2).Nevertheless, despite the differences in potency, when usedat their therapeutic doses, the effects of the inhibitors, interms of the extent of DPP-4 inhibition in vivo, are broadly

Table 1. Chemistry, metabolism and elimination of dipeptidyl peptidase (DPP)-4 inhibitors.

Inhibitor Chemistry Metabolism Elimination route

Sitagliptin [7–9] β-amino acid-based Not appreciably metabolized Renal (∼80% unchanged as parent)Vildagliptin [10–12] Cyanopyrrolidine Hydrolysed to inactive metabolite (P450

enzyme independent)Renal (22% as parent, 55% as primary metabolite)

Saxagliptin [13,14] Cyanopyrrolidine Hepatically metabolized to active metabolite(via P450 3A4/5)

Renal (12–29% as parent, 21–52% as metabolite)

Alogliptin [15,16] Modified pyrimidinedione Not appreciably metabolized Renal (>70% unchanged as parent)Linagliptin [17,18] Xanthine-based Not appreciably metabolized Biliary (>70% unchanged as parent); <6% via kidney

8 Deacon Volume 13 No. 1 January 2011

DIABETES, OBESITY AND METABOLISM review articleTable 2. Half-life, potency (dose) and dipeptidyl peptidase (DPP)-4 inhibitory efficacy of DPP-4 inhibitors.

Inhibitor Compound t1/2 (h) Dosing DPP-4 inhibition∗

Sitagliptin [9,27] 8–24 100 mg qd Max ∼97%; >80% 24 h postdoseVildagliptin [12,25] 1 1/2–4 1/2 50 mg bid Max ∼95%; >80% 12 h postdoseSaxagliptin [14,26] 2–4 (parent) 3–7 (metabolite) 5 mg qd Max ∼80%; ∼70% 24 h postdoseAlogliptin [28] 12–21 25 mg qd Max ∼90%; ∼75% 24 h postdoseLinagliptin [29] 10–40 5 mg qd (anticipated) Max ∼80%; ∼70% 24 h postdose

∗DPP-4 activity measured in human plasma ex vivo; not corrected for sample dilution in the assay.

similar. Over 90% inhibition is attained within 15 min ofinhibitor administration, with around 70–90% inhibitionbeing sustained at 24 h postdose (Table 2, figure 2); forvildagliptin, although the extent of plasma DPP-4 inhibitiondrops to around 50% after 24 h with the 50 mg dose, the twicedaily therapeutic dosing regimen maintains plasma DPP-4inhibition at >80% over the full 24-h period. However, itshould be pointed out that plasma DPP-4 activity is assessedex vivo (i.e. in plasma samples taken after in vivo dosing) and isgenerally not corrected for the inherent dilution of the samplein the assay. Hence, the true extent of DPP-4 inhibition in vivois probably higher than the measured values suggest.

SelectivityDPP-4 is a member of a family of proteases, two of which(DPP-8 and -9) have been implicated in preclinical toxicitiesand suppression of T-cell activation and proliferation insome [30,31], but not all [20] studies; in order to minimizeany potential off-target side effects, the inhibitors intended tobe used therapeutically have, therefore, been chosen with this inmind (Table 3). Thus, in this respect, sitagliptin and alogliptincan both be described as being highly selective; they essentiallyshow no inhibitory activity against other members of the DPP-4family when tested in vitro [7,15]. Vildagliptin and saxagliptinare somewhat less selective with regard to inhibition of DPP-8/9in vitro [20,21], although whether this has any significance invivo is questionable because DPP-8/9 are located intracellularly.Linagliptin, while being selective with regard to DPP-8/9, isless selective with regard to fibroblast activation protein-α(FAPα)/seprase [19]. FAPα is an extracellular enzyme whichis not generally present in normal adult tissue (although it isexpressed in stromal fibroblasts and upregulated during tissueremodelling) [32]. However, the extent of any FAPα inhibitionin vivo with the therapeutic dose of linagliptin in humans hasnot been reported.

Figure 2. Extent of plasma dipeptidyl peptidase (DPP)-4 activity inhumans after DPP-4 inhibitor administration. (A) Vildagliptin, modifiedfrom He et al. [25]; (B) saxagliptin, modified from Boulton et al. [26];(C) sitagliptin, modified from Bergman et al. [27]; (D) alogliptin, modifiedfrom Covington et al. [28] and (E) linagliptin, modified from Heiseet al. [29].

None of the inhibitors have been reported to have anysignificant inhibitory activity on a panel of different enzymes,including the CYP450 enzymes (sitagliptin [7]; vildagliptin [12];saxagliptin [14]; alogliptin [15] and linagliptin [19]), althoughlinagliptin was reported to inhibit CYP3A4 activity weakly ina competitive manner (Ki = 115 μM) and to be a poor-to-moderate mechanism-based inhibitor of CYP3A4 [18].

Table 3. In vitro selectivity of dipeptidyl peptidase (DPP)-4 inhibitors (fold selectivity for DPP-4 vs. other enzymes).

Inhibitor Selectivity QPP/DPP-2 PEP FAPα DPP-8 DPP-9

Sitagliptin [7] High >5550 >5550 >5550 >2660 >5550Vildagliptin [10,20] Moderate >100 000 60 000 285 270 32Saxagliptin [21] Moderate >50 000 Not reported >4000 390 77Alogliptin [15] High >14 000 >14 000 >14 000 >14 000 >14 000Linagliptin [19] Moderate >100 000 >100 000 89 40 000 >10 000

QPP, quiescent cell proline dipeptidase; PEP, prolyl endopeptidase; FAPα, fibroblast activation protein-α.

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AbsorptionThe DPP-4 inhibitors are all orally available and are rapidlyabsorbed (figure 2), with significant inhibition of plasma DPP-4activity being seen within 5 min of administration. Oral biovail-ability in humans is generally high (∼87% for sitagliptin [33],85% for vildagliptin [34] and ∼67% for saxagliptin [35]),although somewhat lower for linagliptin (∼30%) [36].

DistributionWhere available, data indicate that the volume of distributionof the various inhibitors in humans is greater than the totalbody water (∼70 l for vildagliptin [12], 198 l for sitagliptin [9],300 l for alogliptin [28] and ∼2.7 l/kg for saxagliptin [35]),suggesting that these compounds distribute widely into thetissues. However, although their chemistries suggest thatthey are unlikely to diffuse freely over the cell membrane,whether or not they actually cross the cell membrane hasnot been studied in detail and no information is available forsitagliptin, alogliptin or linagliptin. The intrinsic membranepermeability of saxagliptin is reported to be very low, andneither saxagliptin nor its major metabolite (BMS-510849) isa prominent substrate for multidrug resistance P-glycoprotein(Pgp) transporters or for cellular uptake transporters [26].There is some indirect evidence that vildagliptin may be able tocross the cell membrane. Thus, it has been reported that at veryhigh doses (>600 times the human dose), vildagliptin inhibitsDPP-8/9 in vivo in rats [20]; because DPP-8/9 are locatedin the cytosol, this would suggest that vildagliptin does havesome access to the intracellular compartment, but it is unclearwhether this occurs in humans with the therapeutic dose.

In the plasma, most of the inhibitors display low,reversible protein binding (38% for sitagliptin [33], 10% forvildagliptin [11,12] and negligible for saxagliptin [14]). Incontrast, linagliptin binds extensively to plasma proteins ina concentration-dependent manner and it has been calculatedthat at the therapeutic dose (5 mg) most of the drug will beprotein bound (primarily to DPP-4) [37].

Preclinical studies have revealed that the highest concen-trations of the drugs are found in the intestines, kidney andliver [9,12,14,38], which, notably, are also the tissues with thehighest expression of DPP-4. Available information indicatesthat very low levels of the inhibitors are found in the brain(saxagliptin and its primary metabolite [35], vildagliptin [12]and linagliptin [38]), suggesting that the compounds maynot cross the blood–brain barrier. However, they do appearto be able to cross the placenta freely (saxagliptin [14],vildagliptin [12] and sitagliptin [9]).

MetabolismSitagliptin, alogliptin and linagliptin do not undergo apprecia-ble metabolism in vivo in humans; around 80% of the doseis eliminated unchanged as the parent compound (Table 1).For sitagliptin, the limited metabolism produces six metabo-lites in trace amounts (each accounting for <1% to 7% ofsitagliptin-related material in plasma), with in vitro studiesindicating that the primary enzyme responsible is CYP3A4

with a lesser contribution from CYP2C8 [8]. Three of thesemetabolites (M1, M2 and M5) are active, but are not expectedto contribute to the pharmacodynamic profile of sitagliptinbecause of the combination of low plasma concentration andlow affinity for DPP-4 [8,9]. For alogliptin, the parent moleculeaccounts for >80% of alogliptin-related material in plasma andtwo minor metabolites have been identified, N-demethylated(active) and N-acetylated (inactive) alogliptin, accounting forless than 1% and approximately 5%, respectively [16]. In thecase of linagliptin, the parent compound made up around 70%of drug-related material in plasma, while exposure to the majormetabolite (CD1790, identified as S-3-hydroxypiperidinylderivative of linagliptin) was around 18% of that of the parentcompound. Formation of CD1790, which is pharmacologicallyinactive, is dependent upon CYP3A4. In addition, seven minormetabolites (each accounting for 0.3 to <5% of linagliptin-related material in plasma) were identified [18].

In contrast, both vildagliptin and saxagliptin undergoextensive metabolism in humans (Table 1). The majormetabolic pathway for vildagliptin is hydrolysis at its cyanomoiety, which occurs in the liver and other tissues viaa CYP450-independent mechanism, to produce a carboxylicacid metabolite (M20.7/LAY151) and four minor metabolites.The parent molecule and the major metabolite, whichis pharmacologically inactive, account for the majority ofvildagliptin-related material in the plasma (approximately22 and 55%, respectively) [11,12]. Saxagliptin is hepaticallymetabolized by CYP 3A4/5 to produce a major metabolite (5-hydroxy saxagliptin; BMS-510849), which is also a competitive,reversible inhibitor of DPP-4 with approximately 50% ofthe potency of the parent drug. Systemic exposure tosaxagliptin-related material is accounted for by the parentmolecule (22%) and BMS-510849 plus other unidentifiedminor monohydroxylated metabolites (76%) [14].

ExcretionGenerally, the DPP-4 inhibitors are eliminated primarily viathe kidney, with the rate of renal clearance exceeding glomeru-lar filtration, suggesting that active transport is involved. Forsitagliptin, around 70% of the dose is excreted as the parentmolecule and active transport has been shown to account foraround 50% of its clearance [39]; the human organic aniontransporter (OAT)-3, organic anion transporting polypeptide(OATP)-4C1 and Pgp transporters in the proximal tubule havebeen indicated to be involved [40]. Alogliptin (and its minormetabolites) is renally eliminated, with around 60–70% of thedose appearing in the urine as the parent compound [28,41].Clearance of alogliptin is greater than normal glomerular fil-tration, but the renal transporters involved have not beenidentified, although drug-interaction studies suggest that Pgpis unlikely to be involved [28]. Similarly, both saxagliptin andits primary metabolite (BMS-510849) are primarily renallyeliminated, accounting for 24 and 36% of the dose, respec-tively [14]. Again, renal clearance of the parent compoundis greater than the glomerular filtration rate, indicating theinvolvement of active renal secretion, but the mechanism isunknown; saxagliptin is reported not to be a substrate for OAT1,OAT3, OATPA, OATPC, OATP8, organic cation transporter


DIABETES, OBESITY AND METABOLISM review article(OCT)-1, OCT2, sodium taurocholate co-transporting peptideor peptide transporters (PepT1 and PepT2) [14]. In contrast,clearance of BMS-510849 is similar to the glomerular filtra-tion, suggesting that this is a main mechanism involved in itselimination [14]. Data for vildagliptin also indicate the kidneysto be the predominant route of elimination, with 22% of thedose appearing in the urine unchanged and 50% appearingas the major metabolite (M20.7); active transport in additionto glomerular filtration was indicated to be involved in theelimination of both compounds [11].

Linagliptin is the exception, with <6% of the dose beingexcreted in the urine [29]. This may be, at least in part,because of the high degree of protein binding [37], meaningthat the drug escapes glomerular filtration. Rather, linagliptinhas a hepatic route of elimination, with 78% appearing in thefaeces unchanged. Renal excretion of the primary metabolite(CD1790) is negligible; this undergoes further metabolism andis also eliminated in the faeces [18].

Potential for Drug–Drug InteractionsIn general, the DPP-4 inhibitors have not been reportedto result in any meaningful activation or inhibition ofthe CYP enzyme system, suggesting that they are unlikelyto be involved in clinically meaningful drug interactionsinvolving these systems. There are data suggesting thatthere is no great propensity for the DPP-4 inhibitors to beinvolved in any clinically relevant drug–drug interactions withother commonly prescribed medications [9,12,14], includingmetformin [42–45], pioglitazone [46–48], rosiglitazone [49],glyburide [46,47,50] and simvastatin [51–53], suggesting thatthese agents can be co-administered with the DPP-4 inhibitorswithout the need for dose adjustment of either drug.

As mentioned, CYP3A4/5 is involved in the conversion ofsaxagliptin to the active metabolite (BMS-510849), and stronginhibitors of CYP3A4/5, such as ketoconazole, increase theexposure to the parent compound. For this reason, dose reduc-tion by half (2.5 mg qd) is recommended when saxagliptinis co-administered with strong CYP3A4/5 inhibitors [54].Linagliptin is also a substrate for CYP3A4, and ketoconazoleprevents the generation of the metabolite, CD1790. However,because this is of only minor importance in the clearance oflinagliptin, inhibition or induction of CYP3A4 by concomi-tantly administered drugs was not considered likely to alter theoverall exposure to linagliptin [18]. Additionally, linagliptinhas been identified as a weak competitive and a poor-to-moderate mechanism-based inhibitor of CYP3A4, resulting ina decrease in the clearance of other compounds metabolizedby this pathway by less than twofold; linagliptin was thereforeconsidered to have only a weak potential for clinically relevantinteractions with drugs metabolized by this system [18].

Safety/TolerabilitySome differences between the different DPP-4 inhibitors havearisen from preclinical safety studies and observations madeduring the course of the clinical trial programmes.

Thus, vildagliptin and saxagliptin, but not sitagliptin oralogliptin, were reported to be associated with adverse skin

toxicology in monkeys. However, this may be a findingwhich is specific to monkeys, as it has not been observedin other preclinical species, and importantly, there have beenno reports of skin problems in the clinical trials with any of theinhibitors [12,14,55–57].

For saxagliptin, small, reversible, dose-dependent reductionsin absolute lymphocyte count have been noted in some of theclinical trials, but this has not been reported for the otherDPP-4 inhibitors. The effect was more apparent at saxagliptindoses ≥20 mg (which is greater than the therapeutic dose),but values still remained within normal limits [14,58]. Therewas no effect on white blood cell or neutrophil count and noevidence of altered immune function. At present, the clinicalsignificance of this (if any) remains unknown.

At the time of initial registration of vildagliptin (in EU), ameta-analysis of the clinical trial data revealed that the 100 mgqd dose was associated with small numerical elevations inliver transaminases compared to placebo or 50 mg bid. Forthis reason, the recommended therapeutic dose was changed to50 mg bid, with the recommendation that liver function tests beperformed before initiation and at three monthly intervals forthe first year of treatment and periodically thereafter [12,59].Subsequently, the trend for mild increases (greater than threetimes the upper limit of normal) in liver enzymes was confirmedin the larger pooled safety analysis, but notably, this wasnot associated with any increased incidence of actual hepaticadverse events [56]. Nevertheless, liver function tests are stillrecommended and vildagliptin is not approved for use inpatients with hepatic insufficiency (see later).

Despite the above observations, overall, the DPP-4 inhibitorsas a class appear to be very well tolerated, and rates ofadverse effects have been low, and generally not differentto placebo or comparator. An early meta-analysis of incretin-based therapies (in which inhibitor data were available onlyfor sitagliptin and vildagliptin) did, however, suggest thatthere was an increased risk of some infections (urinary tractinfections with both inhibitors and nasopharyngitis moreevident with sitagliptin) and headache (more evident withvildagliptin) [60,61]. Since then, updated safety analyses (each>10 000 patients, exposed for up to 2 years) of the sitagliptinand vildagliptin clinical trials have been published, showingno increased risk for urinary tract or respiratory infections orheadache (and indeed, no increased risk of any other adverseeffect) with the DPP-4 inhibitors compared to placebo orcomparator [55,56]. Notably, recent debate over potential linksbetween some antidiabetic medications and cancer [62] or bonefracture [63] does not seem to extend to the DPP-4 inhibitors,with no evidence for increased signals being observed in thesafety analyses [55,56]. Cardiovascular safety of new drugs,including antihyperglycaemic agents, has also been the focusof concern, with the FDA requiring pharmaceutical companiesto show that new agents to not increase the risk of adversecardiovascular events. Retrospective analyses of data from theclinical development programmes of sitagliptin, vildagliptinand saxagliptin do not appear to indicate any increasedcardiovascular risk with the DPP-4 inhibitors relative tocomparators [55,64,65], but large prospective trials, designedspecifically to evaluate the effect of sitagliptin, saxagliptin and



Table 4. Prescribing characteristics of dipeptidyl peptidase (DPP)-4 inhibitors.

Renal insufficiency∗ Hepatic insufficiency

InhibitorMild (CrCl≥50 ml/min)

Moderate (CrCl≥30–<50 ml/min)

Severe/ESRD (CrCl<30 ml/min) Mild/moderate Severe

Sitagliptin(launched EU, USA)

√Presently not

recommended (EU)1/2 dose (USA)†

Presently notrecommended (EU)1/4 dose (USA)†

√Presently not

recommended†

Vildagliptin‡

(launched EU)

√Presently not

recommended†Presently not

recommended†Not recommended Not recommended

Saxagliptin§

(launched EU, USA)

√Presently not

recommended (EU)1/2 dose (USA)†

Presently notrecommended (EU)1/2 dose (USA)†

√(Moderate: use withcaution)

Presently notrecommended†

Alogliptin(launched Japan)

√1/2 dose 1/4 dose

√Presently not

recommended†

Linagliptin(not yet approved)

√(likely)

√(likely)

√(likely) Unknown

Dose adjustment? / notrecommended?

UnknownDose adjustment? /not recommended?

CrCl, creatinine clearance; ESRD, end-stage renal disease.∗Assessment of renal function recommended prior to initiation of treatment and periodically thereafter.†Not studied/no clinical experience.‡Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter.§Dose reduction (2.5 mg) when saxagliptin co-administered with strong cytochrome P450 3A4/5 inhibitors (e.g. ketoconazole).

alogliptin on cardiovascular outcomes are underway. There hasalso been some debate over whether incretin-based therapies,including the DPP-4 inhibitors, are associated with elevated riskof pancreatitis [66]. This does not seem to be borne out by thepooled safety analyses [56,67] or retrospective analyses of largehealthcare data bases [68,69]. Continued vigilance and longerterm reports are still needed to confirm these observations.

Use in Patient SubpopulationsRenal Insufficiency

Because most of the described DPP-4 inhibitors are eliminatedrenally, it might be expected that their pharmacokinetic profilewould be influenced by impairments in renal function. In linewith this, exposure to sitagliptin increased proportionately tothe degree of renal failure, but the drug was well tolerated,even in patients with end-stage renal disease (ESRD), includingthose on dialysis; the fraction removed by dialysis was small(∼13% for haemodialysis started at 4 h postdose) [70]. Basedon this study, it was concluded that no dose adjustment wasnecessary in subjects with mild renal insufficiency [creatinineclearance (CrCl) 50–80 ml/min]. However, in order to main-tain plasma sitagliptin exposure comparable to that in subjectswith normal renal function, in subjects with moderate renalinsufficiency (CrCl 30–50 ml/min) or severe renal insufficiency(CrCl <30 ml/min)/ESRD, dose reductions of 50 and 75%,respectively, are required [70]. In T2DM patients with moder-ate or severe chronic renal insufficiency (including those withESRD on dialysis), sitagliptin provided effective glycaemic con-trol over 1 year and was generally well tolerated [71]. Exposureto vildagliptin and saxagliptin is also similarly increased in sub-jects with impaired renal function [12,14], and as for sitagliptin,vildagliptin is reported to be well tolerated in patients with mildrenal insufficiency, with the rate of adverse events being similar

to comparators [56]; no data are yet available in patients withmoderate or severe renal impairment (Table 4).

On the bais of these observations, sitagliptin, vildagliptin andsaxagliptin have been approved for use in subjects with mildrenal insufficiency without dose adjustment, and where theindication is approved, sitagliptin and saxagliptin can be usedin patients with moderate or severe renal insufficiency/ESRDwith appropriate dose adjustment (Table 4). Alogliptin is alsoeliminated renally and can be used in subjects with moderateor severe renal impairment with dose reduction (Table 4).Because linagliptin is not predominantly eliminated via thekidneys, it could be anticipated that this drug might be ableto be used in renal disease patients, including those withsevere renal insufficiency/ESRD without the need for any doseadjustment [72].

Hepatic Insufficiency

The DPP-4 inhibitors generally appear to be well tolerated inpatients with hepatic impairment and there seems to be noclinically meaningful impact of hepatic insufficiency on theirpharmacokinetics. Thus, in subjects with moderate hepaticimpairment, exposure to sitagliptin was slightly, but non-significantly increased [73], whereas exposure to alogliptin wasslightly decreased [74]. For vildagliptin, exposure to the parentdrug showed non-significant trends to decrease in patientswith mild or moderate hepatic impairment and to increasein patients with severe hepatic impairment, whereas exposureto the primary (inactive) metabolite (M20.7) increased non-significantly in all groups, compared with healthy subjects [75].In line with its hepatic metabolism, saxagliptin exposureincreased and that of the active metabolite (BMS-510849)decreased in subjects with hepatic impairment [14].

Overall, these studies suggested that no dose adjustment willbe necessary in patients with hepatic impairment. Vildagliptin


DIABETES, OBESITY AND METABOLISM review articleis, however, not recommended for use in patients with hepaticinsufficiency or those with pretreatment alanine aminotrans-ferase or aspartate aminotransferase at greater than threetimes the upper limit of normal (because of the associationof vildagliptin with mild increases in hepatic transaminases; seeabove). The other DPP-4 inhibitors which have been approvedcan be used in patients with mild/moderate hepatic insuf-ficiency without dose adjustment (Table 4), although becausehepatic impairment increases exposure to saxagliptin (in accordwith its hepatic metabolism; see above), caution is required ifused in subjects with moderate hepatic insufficiency [14]. Atpresent, limited data in subjects with severe hepatic impairmentmean that the DPP-4 inhibitors are currently not recommendedfor use in this patient group. Because the liver is the primaryroute of elimination for linagliptin, it could be anticipatedthat linagliptin may require dose adjustment or may not berecommended for use in subjects with hepatic impairment.

Antidiabetic EfficacyAs might be expected from their similar efficacy in inhibitingDPP-4 activity (see above), broadly speaking, the DPP-4inhibitors all seem to show similar efficacy in lowering HbA1clevels, although it must be stressed that these are observationsmade in different studies and so must be interpreted with somecaution (figure 3). At present, data are available only fromone direct head-to-head comparison between the inhibitors,in which the efficacy of saxagliptin and sitagliptin as add-on therapy in metformin-treated patients was compared [76].This showed non-inferiority of saxagliptin to sitagliptin interms of HbA1c lowering (−0.5 vs. −0.6% from a baselineof ∼7.7%; i.e. from 60 to 55 mmol/mol for saxagliptinvs. from 61 to 54 mmol/mol for sitagliptin) at week 18,

Figure 3. HbA1c lowering efficacy of dipeptidyl peptidase (DPP)-4inhibitors in relation to baseline HbA1c levels, as monotherapy or add-ontherapy (open symbols) or initial combination therapy (closed symbols)in studies of ≥12 weeks duration (see Appendix for references). Triangle,sitagliptin (100 mg qd); circle, vildagliptin (50 mg bid or 100 mg qd);square, saxagliptin (5 mg qd); diamond, alogliptin (25 mg qd) and star,linagliptin (5 mg qd).

with similar proportions of subjects (26 vs. 29%) reachingtarget HbA1c levels of <6.5% (<48 mmol/mol). However,in terms of the reduction in fasting plasma glucose, it didappear that there might be a small difference, with sitagliptinbeing more efficacious (−0.6 vs. −0.9 mmol/l; difference0.30 ± 0.115 mmol/l, 95% confidence interval: 0.08–0.53);this could potentially be related to differences in the half-lifeof the compounds (Table 2, figure 2). In other direct head-to-head studies, the DPP-4 inhibitors have shown similarefficacy to metformin [77,78], the sulphonylureas [79,80], theglitazones [81,82] and the alpha-glucosidase inhibitors [83]. Inline with other antidiabetic agents [84], greater reductions inHbA1c are seen in subjects with higher baseline levels (figure 3).

ConclusionsThe DPP-4 inhibitors are the first new therapeutic class oforal antihyperglycaemic drug for T2DM for many years. Theywere designed for the treatment of the disease based on priorknowledge of the physiology of the incretin hormone GLP-1and an understanding of the target (DPP-4), contrasting withthe development of other antidiabetic agents whose bloodglucose-lowering effects were initially discovered more bychance than by design without fully knowing the underlyingmechanisms (e.g. metformin, sulphonylureas and glitazones).Identification of the 3-dimensional/tertiary structure of theDPP-4 protein allowed the rational design of small moleculeinhibitors which interact only with the catalytic site withoutinterfering in any of the other functions of the DPP-4/CD26molecule. This, together with the understanding of the role ofGLP-1 in glucose homeostasis and its unique susceptibility tocleavage by DPP-4, probably accounts for the remarkable lackof adverse effects so far associated with the therapeutic use ofthe DPP-4 inhibitors.

As a class, the DPP-4 inhibitors comprise of a groupof chemically diverse compounds, which differ in terms oftheir potency to inhibit the DPP-4 enzyme, their durationof action and their metabolism and elimination, as wellas isolated compound-specific characteristics (Table 5). Theyare all apparently well tolerated (side-effect profile resemblesplacebo) and result in clinically meaningful reductions in bloodglucose (fasting and postprandial) and HbA1c levels, withminimal risk of hypoglycaemia and without weight gain—inthis latter respect, they are better than all other agents exceptmetformin and the incretin mimetics. They are used withoutthe need for dose titration and give broadly similar HbA1clowering efficacy to other oral antidiabetic agents; they arecompatible with first-line therapy and they give predictableadditivity to other agents, where they can be used without doseadjustment of either agent.

At present, although there are some practical differencesbetween the different DPP-4 inhibitors with respect to dosingfrequency and their ability to be used in different patientsubpopulations, there seems to be little to distinguish betweenthem in terms of their efficacy as antidiabetic agents and theirsafety. Only long-term accumulated clinical experience willreveal whether compound-related characteristics lead to anyclinically relevant differences.



Table 5. Differences and similarities between dipeptidyl peptidase(DPP)-4 inhibitors.

Differences Similarities

Chemical structures Efficacy (HbA1c lowering)In vitro selectivity TolerabilityMetabolism (changed/unchanged,

active/inactive metabolite)Safety

Elimination (renal/hepatic)Preclinical toxicitiesPotency (therapeutic dose)Dosing frequency (once/twice daily)Use in patient subpopulations (e.g.

impaired renal/hepatic function)

Conflict of InterestAs this is a single author review, C. F. Deacon wasresponsible for all aspects of the manuscript. CFD has receivedconsultancy/lecture fees from companies with an interest indeveloping and marketing incretin-based therapies for thetreatment of type 2 diabetes (Astra Zeneca/BMS, Lilly, Merck,Novartis, Novo Nordisk, Servier). Spouse is employed by Merckand holds stock options in Merck and Novo Nordisk.

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glipizide, in patients with type 2 diabetes inadequately controlled on metformin

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Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacyand safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in

patients with type 2 diabetes mellitus. Diabetologia 2006; 49: 2564–2571.

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