diabetes mellitus. the incretin effect

23
The incretin hormones glucagon-like-peptide-l (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP) are releasedfrom the intestine following oral ingestion of nutrients. Incretins promote insulin secretion, while GLP-I also inhibits glucagon releaseand gastric emptying minimizing postprandial glucose excursions. The incretins share similar effects on the pancreatic F .elt howwer, there aÍe anumber of differences in e:rtrapancreatic actions. Type 2 diabetes (T2DM) is associatedwith abnormal incretin physiology, and although treatmentwith GIP is ineffective GLP-I effects Íre preserved. The current incretin-based approaches to T2DM indude the GLP-I agonists that are resistant to the serine protease dipeptidylpeptidase-4 (DPP4), which normally rapidly degrades the incretins, flrid DPP4 inhibitors (DPP4i). Incretin-based treatments have provoked much interest due to use-associated weight loss (GLP-I agonists), minimal h1'poglycemia, and potential for positive effects on pancreatic B cell biology and the cardiovascular system. Howwer, the long-term safety of these agents has yet to be established- This review outlines the current understanding of incretin biology, available data pertaining to incretin-based treatment in T2DM, and differences between GLP-f and DPP4i therapy. Keywords: incretin; GLP-I; GIP Introduction The incretin effect describesthe observation that oral glucose inducesa greaterinsulin response com- pared with an equivalent intravenous challenge.l'2 The incretins, of which glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) appear the most important in humans, are released from the intestine following nutrient ingestion.3-s Both GLP-I and GIP are in- sulinotropic; however, incretins alsomodulate po st- prandial glucose disposal, through inhibition of glucagonsecretion (GLP-1),6 delayed gastricempty- ing (GLP-1),7 andpotentiallyalsothrough increased peripheratinsutin sensitivity (GLP- I and GIP).3 The incretin response accounts for approximately 70o/o of the total insulin secreted following the adminis- tration of oral glucose.3 GLP-I and GIP are rapidly degraded by dipeptidylpeptidase-4 (DPP4);8 however,the GLP- I metabolites may also have specific effects of clin- ical relevance. The appreciation that the incretin response is defective itt tfp. 2 diabetes (T2DM)e led to the development of incretin-based therapies, the first ofwhich wasapprovedin 2005.Therapeutic strategies arebased on GLP-I (GLP-1agonists), be- cause while GLP-I retains efficacy in T2DM, there is resistance to the insulinotropic effects of GIP.rO The two classes of incretin-baseddrugs available in- cludethe GLP-1 agonists (short and long acting) and the DPP4 inhibitors (DPP4i), which inhibit DPP4, the enzfme responsiblefor the short half-life of en- dogenousGLP-I (< two minutes). Incretin-based therapies have provoked great interest, in part due to the associated weight loss with GLP-I agonists, and the weight neutrality of DPP4i.a Furthermore, when GLP-I agonists or DPP4i are used outside the setting of concomitant insulin secretagogue or insulin therapy, the risk of hypoglycemia is low. There have been a number of nonglucose lower- ing effectsof incretins reported, including pancre- atic B cell trophism, cardioprotection, neuropro tec- tion, and effects on bone. However, while some of these off-target effects mayprove to be of signifi.cant doi: 1 0. 111 1 1j.17 49-6632.2012.06491 .x Ann. N.Y. Acad. Sci. 00 (2012) 1-20O 2012 New York Academy of Sciences.

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The incretin hormones glucagon-like-peptide-l (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP)

are released from the intestine following oral ingestion of nutrients. Incretins promote insulin secretion, while GLP-I

also inhibits glucagon release and gastric emptying minimizing postprandial glucose excursions. The incretins share

similar effects on the pancreatic F .elt howwer, there aÍe anumber of differences in e:rtrapancreatic actions. Type

2 diabetes (T2DM) is associated with abnormal incretin physiology, and although treatmentwith GIP is ineffective

GLP-I effects Íre preserved. The current incretin-based approaches to T2DM indude the GLP-I agonists that are

resistant to the serine protease dipeptidylpeptidase-4 (DPP4), which normally rapidly degrades the incretins, flrid

DPP4 inhibitors (DPP4i). Incretin-based treatments have provoked much interest due to use-associated weight loss

(GLP-I agonists), minimal h1'poglycemia, and potential for positive effects on pancreatic B cell biology and the

cardiovascular system. Howwer, the long-term safety of these agents has yet to be established- This review outlines

the current understanding of incretin biology, available data pertaining to incretin-based treatment in T2DM, and

differences between GLP-f and DPP4i therapy.

Keywords: incretin; GLP-I; GIP

Introduction

The incretin effect describes the observation thatoral glucose induces a greater insulin response com-pared with an equivalent intravenous challenge.l'2The incretins, of which glucagon-like-peptide-1(GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP) appear the most important inhumans, are released from the intestine followingnutrient ingestion.3-s Both GLP-I and GIP are in-sulinotropic; however, incretins also modulate po st-prandial glucose disposal, through inhibition ofglucagon secretion (GLP- 1),6 delayed gastric empty-ing (GLP- 1),7 andpotentiallyalso through increasedperipherat insutin sensitivity (GLP- I and GIP).3 Theincretin response accounts for approximately 70o/oof the total insulin secreted following the adminis-tration of oral glucose.3

GLP- I and GIP are rapidly degraded bydipeptidylpeptidase-4 (DPP4);8 however, the GLP-I metabolites may also have specific effects of clin-ical relevance. The appreciation that the incretin

response is defective itt tfp. 2 diabetes (T2DM)eled to the development of incretin-based therapies,the first ofwhich was approved in 2005. Therapeuticstrategies are based on GLP-I (GLP-1 agonists), be-cause while GLP- I retains efficacy in T2DM, thereis resistance to the insulinotropic effects of GIP.rOThe two classes of incretin-based drugs available in-clude the GLP- 1 agonists (short and long acting) andthe DPP4 inhibitors (DPP4i), which inhibit DPP4,the enzfme responsible for the short half-life of en-dogenous GLP-I (< two minutes). Incretin-basedtherapies have provoked great interest, in part dueto the associated weight loss with GLP-I agonists,and the weight neutrality of DPP4i.a Furthermore,when GLP-I agonists or DPP4i are used outsidethe setting of concomitant insulin secretagogue orinsulin therapy, the risk of hypoglycemia is low.There have been a number of nonglucose lower-ing effects of incretins reported, including pancre-atic B cell trophism, cardiop ro tectio n, neurop ro tec-tion, and effects on bone. However, while some ofthese off-target effects mayprove to be of signifi.cant

doi: 1 0. 1 1 1 1 1j.17 49-6632.2012.06491 .x

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences.

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tuin. N.Y. Aced. Sd.lSSt{ Wn-glgaF---

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESlssue: The Yar in Diabetes and Obsity

Update on incretin honnotres

Lllza K, Phillipst and Jofranrps B. PrinslslMater t\,ledi€l Research lnsùtute, Brfsbarp, Ausúalla. 2Unilrursttyof Queensland, Brisbane, Austalia

Address fo conwpondefìos: Johann* B. Prins, Mater li,fedical Researcfr Insilitute, [.evd 3, Ar.rbigrry Place, Rq/mmdTenace. Sorlth Brisbane QLD 4101. Ausùafra irrinúnrnri.mater.org.au

Update on incretin hormones

clinical benefit, their clinical relevance remains to beproven in large-scale clinical trials. Clinical experi-ence to date has been positive, and there have beenfew safety concerns; however, there are many as-pects of the incretin system that remain to be fullyexplored.

This review will outline the pathophysiology ofthe incretin system, relevance to T2DM, and theavailable pharmaceutical approaches. Recent stud-ies reviewing these agents in the treatment of T2DMwill be discussed, Ímd specific areas of differencebetween GLP-I agonists and DPP4i will be high-Iighted.

Biology of incretins

GLP-I is secreted in a number of forms, derivedfrom tissue-specifi c posttranslational processing ofthe proglucagon gene (long arm of chromosome2),11 while the gene for the GIP gene has been lo-calized to the long arm of chromosome 17.3 AI-though cells capable of secreting incretins are scat-tered throughout the entire small intestine, GIP isprimarily released from K cells in the duodenumwhile GLP- I is primarily released from L cells inthe ileum.l2 The mechanism underlying the en-teric regulation of incretin release is not entirelyclear. G-protein coupled receptors that sense chem-ical components of food (such as are found on thetongue) have been identified in the human duo-denum, colocalizing with GLP-1.13'la In vitro andrecent in vivo work in humans has shown that in-hibition of components of these taste-signating G-protein coupled receptors (the sweet taste receptorTlR2/TlR3 or the G protein gustducin) reduces se-cretion of GLP-l.I4'ls Nthough this recent work isof interest, there are likely to be other importantpathways mediating incretin release. GLP-I is se-creted in a number of forms; howeveS only GLP-I(7-37) and GLP- t (7-36)amide are biologically ac-tive; GLP-\L-37) and GLP-I(1-36)amide are inac-tive.3 GLP-1(7-37) is amidated to form GLP-l(7-36)amide and is the major active circulating formof GLP-1.3 Lipids and carbohydrates are the mostpotent macronutrient stimuli of incretin release,I6which occurs within minutes of meal ingestion, re-turning to baseline levels by approximately threehours.17 Basal and peak concentrations of bioactiveGLP-I are 5-10 pmoVl and2540 pmol/L, respec-tively.3'18'te 1tt contrast, basal concentrations of GIPare approximately 10 pmoVl, and, depending on

Phillips & Prins

assay characteristics, peak levels range between I50and 300 pmoVl.2o It has been proposed that GIP isthe major incretin in health;2l however, others havereported a similar contribution from GLP- 1 andGIP.I8 The enzfme DPP4 (also known as the T cellantigen CD26) metabolizes both GLP-I (half-Iife of2 minutes) and GIP (half-life of 7 minutes) to theirmetabolites GLP-1(9-36) and GIP(342), respec-tively (Fig. I).e,zz GLP-1(9-36) may be biologicallyactive (hatf-life of 5 minutes); however, GIP(3-42)is not.3 In addition, a substantial proportion of cir-culating GLP- I may undergo C-terminal cleavageby neutral endopeptidase 24.11 (NEP-24.11). Theincretin metabolites are primarily renally cleared.3

GLP-| and GIP receptorsGLP- I and GIP bind to their respective G-proteincoupled receptors, GLP-1 receptor (GLP-lR) andGIP receptor (GIPR), on pancreatic B cells andmediate insulin release.23 Following GLP- I bind-ing to the G-protein coupled receptor, adenosine3' ,5' -cychc monophosphate (cAMP)-protein kinaseA (PKA) is the major effector pathway, althougha PKA-independent pathway also exists'24'25 simi-lar pathways are activated following GIP bindingto its respective receptor.3 Song et aI. recently re-ported that the phosphorylation of snapin is anintegral link in the PKA-dependent pathway, pro-viding a greater understanding of the downstreameffectors of GlP-l-mediated insulin exocytosis andproviding another potential therapeutic approachin T2DM.26

A recent large meta-analysis of nine pooledgenome-wide association scans identified variantsat the GIP-R locus that were associated with de-creased insulin secretion, reduced incretin effect,and an increase in 2-hour glucose levels (0. 1 I + 0.0 1mmoVl).27 This study implicated the GIP-R and in-cretin response in early pathophysiologic pathwaysinvolved in impaired glucose tolerance in humans;however, the GIP-R variants were not associatedwith T2DM in collaborating studies.2T

In addition to pancreatic B cells, GLP-IR is alsoexpressed in pancreatic islets, heart, central nervoussystem, kidney, lung, pituitary skin, nodose gan-glion of the vagus nerve, and gastrointestinal tract.3A recent small study consistently identified GLP-IRexpression in human medullary cancer and C cellhyperplasia; receptor expression was also present in18olo of papillary thyroid cancer and33o/o of control

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences

INCRETIN EFFECT

GLP-r(7"3ó!amÉ€GrF{l-{2'

3if;111f)'m,deFigure 1. Oral intake (particularly carbohydrate and lipid) induces release of the incretins GLP-I (glucagon-like-peptide-l) andGIP (glucose-dependent insulinotropic polypeptide) from the gastrointestinal tract (GIT). GLP-I and GIP promote insulin re-lease in a glucose-dependent fashion, accounting for up to 7Ùo/o of the insulin release observed following oral glucose. GLP-I and

GIP have short haH-lives (2 minutes andT minutes, respectively) and are degraded by the serine protease dipeptidylpeptidase-4(DPP4) to their metabolites (GLP-I(9-36)amide (possible active metabolite) and GIP(HT) (inactive metabolite). Current thera-peutic strategies focus on prolonging GLP-I effects through DPP4-resistant GLP-I analogs and the DPP4 inhibitors.

Ptifps & Prins

Food ntate

thyroid lobes.28 Although primarily a(pressed in thepancreatic islet and B cell, the GIPR is also present inthe stomach, small intestine, adipose tissue, adrenalcortex, pituitary, heart, testis, endothelial cells, bone,trachea, spleen, thymus, lung, kidney, thyroid, andthe central nervous qystem.3

Manipulation of GLP-IR and GIPR in murineknockout models results in impaired glucose toler-ance and decreased glucose-stimulated insulin se-cretion.2e'3o The metabolic phenotype, however, ismodest, suggesting a degree of adaption in the en-teroinsular axis.3l N et al.recently observed signifi-cant plasti.itf i" the incretin axis in their evaluationof glucose homeostasis in glucagon receptor andGLP- lR dual knockout mice.32

Effects of GLP-| and GIPGLP-1 and GIP share a number of effects; in partic-ular, their effects on the pancreatic B cell are similar.However, th.y differ in a number of extra pancreaticp cell effects, as outlined below and summarvedtnTàble l.

Pancreatic effects. GLP-I and GIP promoteglucose-dependent insulin secretion and insulinbio synthesis, acting to regulate po stp randial gluco sedisposal.3 '24'33

In vitro and in preclinical models, GLP-I andGIP promote pancreatic p-cell proliferation anddecrease B cetl apoptosis.34-36 Researchers investi-

gating treatment with GLP- I agonists and DPP4ihave orplored putative effects on pancreatic B cellfunction; however, long-term pancreatic effects ofincretin-based therapyfor T2DM in humans remainto be fully explored.

Henry et a1.37 recently investigated the effect of aDPP4i (saxagliptin) on pancreatic p cell function.In this study, a similar enhancement in insulin se-cretion in both postprandial and basat states wasobserved following 12 weeks of treatment. Vardarliet a1.38 similarly reported a lack of classical incretineffect following treatment with vildagliptin; the in-sulin, C-peptide concentrations, and insulin secre-tion rates measured after oral and intravenous glu-cose testing did not differ between vildagliptin andplacebo. It has been proposed that subtle alterationsin basal incretin concentrations, prolonged effectson pancreatic B cell function, or off-target DPP4effects may explain these findings.3s

In contradistinaion to GIR GLP-I inhibits the re-lease ofboth somatostatin and glucagon. Inhibitionof somatostatin is mediated through direct effectson the pancreatic ò cell.3e The GLP-l antagonist ex-endin 9-39 increases glucagon secretion;a0 however,the mechanistic pathway by which glucagon releaseis inhibited is less clear.3 The importance of basallevels of GLP- 1 inducing a tonic inhibitory effect onglucagon secretion is suggested by the mild fastinghyperglycemia observed in GLP-1x*/- mice.ar

Update on incretin hormones

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences.

Update on incretin hormones

Table 1. GLP-I and GIP effects

Phil l ips & Prins

GLP-I GIP

Pancreatic B cell

Pancreatic cr and ò cell

Gastric emptying

Appetite and weight

Neuroprotection

Cardiac effects

Bone effects

Adipose tissue

f insulin release(glucose dependent)

î I cell proliferation and

.,1 apoptosis

.L glucagon(-glucose-dependent)

f somatostatin

l. gastric emptying

*L appetite and promotes weight loss

Evidence in preclinical studies

Improved CV risk factors: BP, lipids,

inflammatory markers;

evidence of cardioprotection in preclinical and

early clinical trials

î bone formation

J bone resorption

Likely no direct effect

f insulin release(glucose dependent)

f B cell proliferation and

l. apoptosis

<)

e

+>

Evidence in preclinical studies

f bone formation

J bone resorption

f lipogenesis

BR blood pressure; CV, cardiovascular.

Central and peúpheral nervous system effects.

GLP-IR are expressed in the hypothalamus, thala-

mus, hippocampus, and brainstem.42'43 Ivvhile pe-

ripheral GLP-I appears to cross the blood-òrainbarrier,3'e GLP-I is also produced within the cen-tral nervous system (nucleus of the solitary tractin the caudal brainstem), functioning as a neuro-

transmitteL4s'46 It appears that many of GLP-I ef-

fects are mediated through both peripheral and cen-tral pathways, including control of food intake and

satíety.a7'a8Both centrally and peripherally administered

GLP-1 regulates feeding and satiety in animal mod-

.1r.4e-s4 A peripherally administered recombinantGlP-l-albumin protein, which does not cross theblood-brain barrier, had preserved effects on sati-ety in animal models.ss A recent study explored theintracellular mechanisms mediating the inhibitionof food intake induced by GLP- I R activation in

the nucleus tractus solitarius in rats. Hayes et al.report that a centrally administered GLP-I agonist(exendin-4) activated GLP- lR in the hindbrain and

reduced meal number through PKA-mediated sup-pression of 5' adenosine monophosphate-activatedprotein kinase (AMPK) and activation of mitogen-activated protein kinase (MAPK).56

Central and peripheral nervous system effects ofGLP-I also modulate glucose homeostasis. GLP-Ireceptors have been identified in the nodose gan-glion of the afferentvagal nerve, andportal infusionof GLP- I in rats activates both hepatic vagal afferentand pancreatic vagal efferent pathways.sT In mice,inhibition of the sensory afferent pathways abol-ishes GLP- I R agonist-mediated insulin secretion,s8while central nervous system GLP-1 signaling in thesetting of hlperglycemia promotes insulin secretionand activates peripheral neural pathways inhibit-ing glucose uptake in muscle and promote hepaticglycogen storage.se

GLP- lR agonists may also play an important rolein regulating the hypothalamic pituitary axis. GLP- Iagonists increased cortisol levels in healthy subjectsand in those with tfpe 1 diabetes. An increase inACTH suggests a central effect of GLP-I; however,this pathway has yet to be confirmed.60

A number of preclinical studies have suggestedthat GLP-1 has neuroprotective effects.a6'61{s prrt-

ing et al. demonstrated that centrdly expressedGLP- lR facilitates learning and plays a neuroprotec-tive role in mice; however, results should be taken incontext ofthe use of a nonapeptide, considered to beinactive.6l In other animal models, GLP-I reduces

Ann. N.Y. Acad. Sci.00 (2012) 1-20 O 2012 New York Academy of Sciences.

Phill ips & Prins

Table 2. Comparison of GLP-I analogs and DPP4inhibitors

Update on incretin hormones

GLP-I analogs DPP4 inhibitors

Administration

Clearance

GLP-1 concentrations

Increased GIP

DPP4 substrates other thanincretins

HbAlc reduction

Postprandial hlperglycemia

Weight loss

CV risk factors

GIT adverse events

Potential safety concerns

Subcutaneous

Twice daily: exenatide

Daily: liraglutideWeekly: enenatide

Renat exenatide

Extrarenal liraglutide

Supraphysiologic

No

No effect

0.5{.8olo

Reduced: increased insulin secretion,glucagon inhibition, aod slowing ofgastric emptying

1.4-3 kg

Improvement in lipid profile;

greater evidence for reduction in

blood pressure, cardioprotection

versus DPP4 inhibitors

3V50o/o experience GIT adverse effects,

but <5olo cease treatment due to sideeffects; generally transient

Pancreatitis;

medullary thyroid cancer

Oral

Twice daily: vildagliptin

Daily: sitagliptin, saxagliptin,linagliptin, alogliptin

Renal sitagliptin, vildagliptin,saxagliptin, alogliptin

Extraren al: linagliptin

Physiologic

Yes

Increased, including SDF- la(potentially cardioprotective )

O.Gl.9o/o

Reduced: increased insulin secretion,glucagon inhibition

Weight neutral

Improvement in lipid profile

Minimal or nonsignifi cant

Pancreatitis;

infection

in vivo amyloid-beta deposition, decreases amyloidprecursor protein in cultured neuronal cells, andprotects neuronal cells from death induced by ox-idative insult.66 Other studies have also suggested arole for GLP-I in modifting Alzheimer's disease inanimal models.63{s In addition, therapywith GLP- Imodified the course of Parkinronrr6T-6e and Hunt-ington sio diseases in animal models, preserved cor-tical neurons in a rodent model of stroke,6e and wasneuroprotective in an animal model of peripheralneuropathy.Tl

GIPR are expressed in the cerebral cortex, olfac-tory bulb ,72 andhippocampus.3 Animal studies em-ployrng exogenous GIP administration and manip-ulation of GIPR orpression suggest that,like GLP-I,GIP plays a role in neuroprotection and cognitivefunction.3'73'74

Bone effects. GIPR have been identified on os-teoblasts,Ts osteoclasts,T6 and bone marrow stromal

cells,77 while GLP- lR have been found on immatureosteoblastsT8 and bone marrow stromal cells,Te butnot on mature osteoblasts.80 In addition, a func-tional GLP-I receptor, distinct from the pancreaticcAMP-linked GLPI, has recently been identified inosteoblastic cells in rats.8l

GIPR activation increases osteoblastic activityand number,Ts and inhibits osteoclast activity;pulsatile exposure may be an important factor.8zGIPR-/- mice have decreased bone mass and sizeand poor trabecular architecture;83 this defect inbone appears to be mitigated as mice mature, aneffect potenúally mediated by leptin.83 Overexpres-sion of GIPR in transgenic mice was associated withincreased bone mass.84

GLP-IR activation promotes proliferation inmesenchymal stem cells and inhibits differentiationto adipo cyîes.7e GLPIR-/- mice demonstrate de-creased cortical bone mass associated with in-

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences.

Update on incretin hormones

creased osteoclast number and activity in con-junction with decreased calcitonin secretion fromthyroid C cells.so

There has been no evidence of adverse bone ef-fects in preclinical trials, including studies evaluat-ing transgenic murine models. GLP-l administeredfor three days had an anabolic effect in diabetic ratmodels,8s while treatment of wild-tfpe mice withthe DPP4i sitagliptin was associated with improvedbone mineral density.86 A study in postmenopausalwomen did not identifr any acute effect ofparenteralGLP-I or GIP on markers of bone resorption,sT anda recent report demonstrated no adverse effects onbone mineral density or senrn markers of calciumhomeostasis in patients treated with exenatide for44 weeks;88 however, further data on long-term ef-fects of incretin-based therapies on bone dynamicsare needed.

The cardiovascular system and GLP-I. There hasbeen a great deal of interest in GLP-I and itspotential effects on the cardiovascular system. Todate, there is no evidence that GLP-I agonists orDPP4i are associated with adverse cardiovascularoutcomes. Indeed, animal and early human studieshave demonstrated improved cardiovascular pro-fi.les in the setting of GLP-I agonists and DPP4i,and a number of these agents are currently underformal, long-term cardiovascular study.

There is conflicting evidence regarding GLP-Ieffects on blood pressure in animal studies. Infu-sion of GLP-1 was associated with an antihyperten-sive effect due to diuretic and natriuretic effects inDahl salt-sensitive rats,se while Yamamoto et al.eoreported a hypertensive, tachycardic effect, poten-tiully due to activation of the autonomic nervoussystem in rats treated with GLP-IR agonists.

When used in the clinical setting, exenatide ap-pears to mediate a reduction in systolic blood Pres-sure. Okerson et al.er recently published a meta-analysis of six trials of exenatide versus placebo orinsulin tn2,I7I patients; change in blood pressurewas a secondary endpoint in these studies. Over-all, treatment with exenatide was associated with a2.8 mmHg and 3.7 mmHg reduction in systolicblood pressure compared with placebo and insulin,respectively; there was no change in diastolic bloodpressure. The authors found a weak correlation be-tween weight loss and blood pressure reduction,suggesting that other mechanisms mediated the

Phillips & Prins

observed hypotensive effect of exenatide. Indeed,Gutzwiller et al.ez have identified a natriuretic eflecto f GLP- I in both healthy and ob ese, insulin- resistantmen. GLP- t has also been shown to have vasodila-tory effects.e3'e4

The Liraglutide Effea and Aaion in Diabetes(LEAD) studies have enrolled over 4,456 patientsfrom more than 600 sites in 40 countries; the sixstudies (LEAD-1 to LEAD-6)rs-tot have all involvedactive comparator treatments and individual studiesare discussed in more detail below. The investigatorsof the LEAD studies observed a 2.1-7.7 mmHg re-duction in systolic blood pressuree6-e8'100'l0l associ-ated with liraglutide therapy. In these studies therewas no significant change in diastolic bloodpressureand blood pressure reductions occurred within twoweeks, prior to significant weight loss. Liraglutidetreatment was also associated with a mild increasein heart rate, the mechanisrn that is poorly under-stood, but may represent a reflex tachycardia to theblood pressure fall.

GLP- lR is upressed in human cardiomy-ocytes,lO2 and murine GLP-IR knockout modelsdemonstrate impaired left ventricular (LV) con-tractiliry low resting heart rate, increased LVthickness, md diastolic dysfunction.l03 Infusion ofGLP- I l0't-106 or DPP4il07 improves cardiac firnctionand ischemic reperfusion in animal models. Benefi-cial cardiac effects of GLP-1 are observed in GLP-lRknockout models, suggesting the presence of a sec-ond GLP-l receptor.tos

In humans, GLP-I agonists decrease markers ofatherosclerosislos and inflammationlOe and havealso been associated with improved endothelialfunction,e3'e{ ?n effect abrogated by the concomi-tant use of glyburide.e3 Similarly, GLP-I acutelyimproves the postprandial lipid profile,rt0 whilechronic treatment (26 weeks) with liraglutide wasassociated with significant reductions in LDL,triglycerides, and free fatty acids compared withplacebo.ior The effect of GLP-I agonists and DPP4ito reduce postprandial free fatty acids may,in addi-tion to cardiac benefit, also mediate a reduction inlipotoxicrf to tissues, notably pancreatic B cells.

The effects of GLP-I have also been associatedwith improvement in myocardial metabolism andLV function.llt-tl3 Slikolaidis et al.rrr observed asignificant improvement in LV function following a7}-hour GLP-l infusion in subjects (n - 10) com-pared with placebo (r: 11) following successfirl

Ann. N.Y. Acad. Sci.00 (2012) 1-20 O 2012 New York Academy of Sciences

Phillips & Prins

primary angioplasty for acute myocardial infarc-tion. Another small study demonstrated a signifi-cant improvement in LV function, functional status,and quality of life in a five-week infusion of GLP- Iin subjects with severe heart failure.Il3 Read et al.recently performed a randomized crossover study(n - 14) in patients with coronary artery disease,demonstrating that intravenous infusion of GLP-I protected the heart from ischemic LV dysfunc-tion induced by dobutamine stress,ll2 while Lon-berg et al. demonstrated increased myocardial sal-vage in patients given exenatide at the time of pri-mary percutaneous coronary intervention for ST-segment elevation myocardial infarction. I I a

There is currently a greater wealth of data regard-ing possible cardioprotection from GLP-l agonistscompared with DPP4 inhibition. However, a num-ber of these benefi cial cardiovascular effects are diffi -

cult to definitively ascribe to a GLP- I effect indepen-dent from changes in glycemic control and weightloss. At least some of the cardioprotective actionsof GLP-1 are likely to reflect improved transport ofglucose into cardiomyocytes, and improvement of"metabolic inflexibility" of the diabetic heart. For-mal cardiovascular trials with hard end points areneeded to clarifr this intriguing aspect of GLP1 inclinicalpractice, and such studies are underwaywithboth GLP-I agonists and DPP4i.

GlP-l-specific effects on the gastrointestinaltract. GLP-I slows gastric emptying and inhibitspentagastrin and meal-stimulated gastric acid se-cretion.lrs-rr7 The inhibition of gastric emptying isan important mechanistic pathway through whichGLP-1 agonists control postprandial glucose excur-sions,lts and may be one of the reasons why GLP-1agonists demonstrate better glucose control and in-duce more nausea and weight loss, compared withthe DPP4i. A postoperative increase in GLP-1 con-centrations, has been implicated in the metabolicimprovements seen following Roux-en-Y bypass fortreatment of obesity. I re, r2o

GIP and adipose tissue. GIPR are expressed inadipose tissuet2l and GIP is involved in lipidmetabolism, promoting lipid storage.3 Consistentwith this, GIPRT- mice were protected againstdiet-induced obesity, and have reduced adipocytemass.122 GIPR-/- mice maintained on a normalchow diet are glucose intolerant30 while a GIP an-tagonist impaired glucose tolerance in wild-type

Update on incretin hormones

mice.123 However, the research to date in animalmodels has not provided a complete understandingwith regards to GIP effects on glucose tolerance andadipose tissue biology. Szalowska et al.rza recentlyidentified that subchronic administration of a GIPanalog inhibited lipoprotein lipase activity and pro-moted weight loss in both high-fat, diet-inducedobesity and lean mice, directly opposing anothergroup's observations performed under similar ex-perimental conditions. t 25

GlP-l(9-36)amide. GlP-1(9-36)amide is themain GLP-I metabolite in vivo; however, its bio-logical activity is unclear.3 Brownlee suggests thatthis compound has significant antioxidant activity(U.S. patent applications 111297808 & 10/582116).Deacon et al. first demonstrated glucose-loweringeffects of GLP-I(9-36)amide in aporcine model;r26metabolic effects were not subsequently replicatedin mice.r27 Infirsion of GlP-1(9-36)amide inhealthy men reduced postprandial glycemia,ascribed to direct effects on glucose disposal aschanges in glucose were independent of gastricemptying, insulin, and glucagon secretion; theeffects of GLP- I (9-36) amide were significantly less,however, than the intact GLP- I(7-36)arcride.r28A GlP-1(9-36)amide infusion in a canine modelof cardiomyopathy demonstrated positive cardiaceffects of the metabolite, similar to those observedwith native GLP-1 treatmentl2e and positivemetabolic effects have also been demonstrated inmurinel3O and porcinet26 models. More recently,the cardioprotective effects of GLP-1(9-36)amidewere identified in GLP-1Rt- mice, suggesting thepresence of an alternative receptor.l3l

DPP4 substrates, including stromal-derivedfactor l-c. The clinical use of DPP4i to augmentincretin action for the treatment of T2DM has ne-cessitated scrutiny of other potential targets of thisenzfme. DPPA, also known as CD26, is a ubiqui-tous serine protease found in the liver, kidney, lung,intestine, testis, CNS, and adrenal glands, as wellas in endothelial cells and free in the plasma.3 Fur-thermore, DPP4/CD26 is expressed on the surfaceof macrophages and lymphocytes and plays a rolein T-cell costimulation and proliferation.3 At thisstage, there is no evidence to suggest that DPP4ihave clinically relevant effects on T-cell function.

Substrates include growth-hormone releasinghormone, insulin-like-growth factor I (IGF-l),

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences.

Update on incretín hormones

substance P, bradykinin, ffid stromal-derived fac-tor l-a (SDFl-a).s The biological relevance ofDPP4 effects on other potential substrates in vivois not clear; however, no significant adverse is-sues have been identified in clinical trials todate.

There has been particular interest in SDFI-c,a secreted signaling protein that activates the cell-survival factor protein kinase B (PKB/Atft) via theG protein-coupled receptor CXCR4.I32 SDFl-a isexpressed in cardiomyocytes and fibroblasts and isupregulated in the setting of hypoxia.r32 Potentialbeneficial cardiovascular effects of SDFl-ct includea tissue-protective and regenerative role in the set-ting of hypoxial32-r3s in animd models, while afour-week trial of DPP4 inhibition with sitagliptinincreased circulating vasculoprotective endothelialprogenitor cells in patients with T2DM.136

Incretins in diabetes

T2DM is characterized by "

reduced incretin re-sponse.76' 137 16ir was originally ascribed to a GLP- Isecretory defectl38'13e *4 GIP resistance.4 Concen-trations of GIP are preserved or even increased inT2DM,r4o'taI while the incretin effect of GIP is ab-sent, even in supraphysiotogical doses.lO Althoughthe pathophysiology underpinning the absent GIPresponse is unclear, it has been proposed this is sec-ondary to a postreceptor defect or a blunted p-cell

response to glucos e.r42'r43Overall, it appears that GLP-I secretion is often

impaired in T2DM. The largest study assessing dif-ferences in GLP-1 concentrations between subjectswith T2DM (n - 5a) and normal subjects (n -- 33)observed a 53o/o reduction in GLP-I secretion fol-towing a mixed meal.laa However, concentrationsof GLP- I were not reduced in T2DM in later stud-i.r.138'13e There are a number of factors that mayexplain these observed differences.l45 For example,T2DM of longer duration and greater severity aswell as higher BMI ere associated with a greaterGLP-1 secretory defect.tas Furthermore, postpran-dial GLP-I concentrations will vary depending onthe meal stimulus, rates of gastric emptying, andconcomitant treatment (e.g., metformin augmentsGLP-1 secretion).ras Importantly, GLP-I does retaineffrcaq in T2DM '2e'r46 however, as physiologicalconcentrations appear to have little insulinotropicactivirylo'r47'r48 supraphysiologic doses of GLP-Iare required.a

Phillips & Prins

The therapeutic approach to incretin-based ther-apy in T2DM has necessarily focused on GLP- l.As the peptide is rapidly degraded by DPP4, the twotherapeutic classes currently available are the DPP4-resistant GLP- 1 agonists (e.9., exenatide and liraglu-tide), which require parenteral administration, andthe DPP4i (e. 9., sitagliptin, saxagliptin, vildagliptin,linagliptin), which are orally administered. The twoclasses of incretin-based therapies have a number ofcornmon effects; however, there are distinct differ-ences between these therapeutic classes.

GLP-I agonists and DPP4I in the treatmentOf T2DM

GLP-| agonistsExenatide was derived from exendin-4, a peptideidentified in the Gila monster (Hebderma suspec-tum). While the first 30 amino acids of exenatidehave 53o/o sequence identity with native humanGLP-I, the nine amino acid extension has no ho-mology in humans.3 Exenatide is relatively resistantto DPP4 degradation (half-life following subcuta-neous injection is2.4hours) and is given twice duily.Exenatide gained U.S. Food and D*g Administra-tion (FDA) approval in 2005. A new formulation ofexenatide involves a matrix of poly [o,r-lactic-co-glycolic acidl (PGL) microspheresto extend release.This formulation is given once weekly (exenatide

QW), and although it has not yet been FDA ap-proved, the formulation has European MedicinesAgency (EMA) approval. Exenatide is cleared byglomerular filtration and while no dose adjustmentis needed for mild renal impairment, exenatideshould not be used in patients with a creatinineclearance less than 30 ml/min or on dialysis.

Liraglutide, approved by the FDA in 2010, has afaW acid side chain that promotes albumin bindingand it is resistant to DPP4 degradation (half-life isl1-13 hours). Liraglutide has a 97o/o homology tohuman native GLP- I and it is administered daily.Liraglutide, in contrast to exenatide, does not un-dergo significant renal clearance, although cautionwith use in patients with renal impairment is ad-uira4.la9,1s0

Other long-acting GLP-IR agonists under de-velopment include albiglutide and lixisenatide,LY2I89265, and VRS-859.151 Studies with the once-weekly taspoglutide ceased in 2010 due to higherthan expected gastrointestinal adverse events and

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 O 2012 New York Academy of Sciences.

Phillips & Prins

hypersensitivity reactions associated with antibodydevelopment.

Studies eval uating exenatideMonotherapy with twice-daily therapy orenatide re-ducedHbA(lc) by 0.7o/o (5 pugbid) and 0.9o/o (10 pr,gbid) in drug-naive patients (baseline HbA(lc) of7.8o/o) over 24 weel.s.ls2 Adding exenatide (5-10 pg bid) to existing therapy (metformin, sul-fonylurea, or thiazolidinedione) in patients withT2DM with suboptimal glycemic control (base-line HbA(lc) 7.9-8.6o/o),was associated with a 0.5-17o reduction in HbA(1c).1s3-1s6 A recent studylsTdemonstrated noninferiorrty of twice-daily exe-natide (, - 181) compared with premixed insulinaspart 70130 (n - I73) npatients treated with met-formin over 26 weeks. C,onsistent with earlier re-ports,Iss exenatide treatment was associated withlower rates of hlpoglycemia and significant im-provements in weight profile (-4.1 kg with exenatidevs. 1.0 kg weight gain with insulin).Is7

The DIJMIION-5 trial, a 24-week random-ized open-label study, compared once-weekly ex-enatide with twice-daily exenatide in 252 patientswith T2DM that were d*g naive (l9o/o) or previ-ously treated with one (47o/o) or multiple (35o/o) oralantidiabeúc drugs (baseline HbA(lc) of 8.4o/o).rseExenatide QW lowered HbA(lc) to a greater de-gree than twice-daily exenatide (1.60/o vs. 0.9%o, re-spectively), with similar degrees of weight loss (2.3kg vs. 1.4 kg, respectively). Fewer patients orperi-enced mild-to-moderate nausea with weekly treat-ment (14o/o) compared with twice-daily admin-istration of exenatide (35o/o). Injection site reac-tions were uncommon but seen more often withexenatide QW. An earlier study (DURATION-I)also found exenatide QW was associated withsuperior glycemic control and better tolerabilirywith similar weight loss compared with twice-dailyexenatide.l6o

It has been suggested that short-acting agents maybe less susceptible to tachyphylaxis of GLP-I effectson gastric emptying and thus may have superiorpostprandial glucose control compared with long-acting agents;Isl however, a recent study demon-strated the presence of rapid tachyphylaxis of theGLP- l-induced inhibition of gastric emptying inshort-acting formulations in lean subjects.l6l Po-tential limitations of once-weekly exenatide includethe longer time to reach steady state (and thus to

Update on incretin hormones

optimize glycemic control) and the higher rate ofantibody formation. I s I

Studies evaluati ng Ii ragl utideThe LEAD-3 Mono trial assessed the efficacy of li-raglutide (L.2 mg ddyr n - 25I), liraglutide (1.8mg daily; n -- 247), and glimepiride (8 mg daily;n - 248) over 52 weeks in patients with eaù T2DM(baseline HbA(lc) 8.2o/o).e6 Both liraglutide I.2 mgand 1.8 mg reduced FIbA(lc) by u greater degreethan glimepiride (0.84olo vs. l.l4o/o vs.0.5lolo, re-spectively). Furthermore, 1.8 mg dose of liraglu-tide had a significantly greater effect on HbA(lc)reduction compared with the 1.2 mg dose. Nau-sea was reported with greater frequency in sub-jects taking liraglutide L.2 mg and 1.8 mg com-pared with glimepiride-treated patients (27 .5o/o, vs.29.3o/o vs. 8.5olo, respectively). Nausea was an earlyadverse event, with less than I0o/o of patients re-ported ongoing nausea in the liraglutide 1.8 mgdoily group by week 4.e6 The LEAD-I, LEAD-2, LEAD-4, and LEAD-5 trials evaluated the effi-cacy of adding liraglutide to existing oral hypo-glycemic therapy, compared with another add-ontherapy.eT'e8'100'l0t In these trials, liraglutide de-creased HbA ( t c) by 0. G- I . 60/o inpatients with base-tine HbA(lc) of 8.2-8.6o/o.e7'e8,100'tor The LEAD-Sstudy randomized patients with T2DM (previouslymanaged with monotherapy or combination ther-apy) to liraglutide 1.8 mg daily (n - 232), placebo(n - 115), or open label glargine (n - 234), allin combination with metformin 1 g twice dailyand glimepiride 4 mg once daily.too In this 26-weektrial, treatment with liraglutide was associatedwith a 0.24o/o greater reduction in HbA(lc) com-pared with glargine and a 1.39 kg greater weight losscompared with placebo. The observed difference inHbA(lc) in this study was within the predefinednoninferiority margin. 100 Liraglutide improved in-dexes of B-cell function, including HOMA-B,proinsulin-insulin ratio, and pro-insulin-C pep-tide ratio, compared with active comparator andplacebo.9T' 98' loo' 1 o I

Exenatide versus liragl utide (LEAD-6)The LEAD-6 study evaluated the relative effective-ness of 26 weeks of treatment with exenatide (10 pgtwice daily; n - 23I) or liraglutide (1.8 mg daily;n - 233) in patients with T2DM who were sub-optimally controlled on metformin + sulfonylurea(baseline HbA( Ic) 8.2o/o).es Liraglutide decreased

Ann. N.Y. Acad. Sci. 00 (2012) 1-20 @ 2012 New York Academy of Sciences.

Update on incretin hormones

mean HbA(lc) to a greater extent than did exe-natide (L.L2o/o vs.0.79o/o). Liraglutide had a greatereffect on fasting blood glucose (-1.61 mmoUl vs.-0.60 mmoVl) but demonstrated decreased post-prandial glucose control compared with exenatide.Tieatments were well tolerated; however, nauseawas less persistent (treatment rate ratio 0.4a8) andminor hypoglycemia less frequent in liraglutidecompared with exenatide treatment. A comparabledegree of weight loss was seen with both drugs (li-

raglutide 3.24kgvs. exenatíde2.87 kg) and a similarreduction in blood pressure was also seen in botharms (Iiraglutide -2.511-1.05 mmHg vs. exenatide-2.001-L98 mmHg).

An extension trial assessed the relative effi-cacy and safety of either switching from twice-duily exenatide to once-daily liraglutide or con-tinuing liraglutide for a total treatment of 40weeks.l62 Patients changing from exenatide to li-raglutide treatment experienced a significant re-duction in HbA(lc) (0.32o/o), fasting plasmaglucose (0.9 mmoVl), body weight (0.9 kg), andsystolic blood pressure (3.8 mmHg).tut Of note, afurther reduction in weight (0.4 kg) and systolicblood pressure (2.2 mmH.s) was also seen itt pu-tients who continued liraglutide therapy.'62 Bothexenatide and liraglutide are associated with anti-body production, although antibodies are signifi-cantly less common in liraglutide compared withtwice-daily exenatide treatment.ló3 Antibody for-mation related to GLP-I agonists can be separatedinto those based on human GLP- I and the moreimmunogenic antibodies based on exendin 4. InLEAD-6, liraglutide-treated patients had antibodyrates of 8.7o/o (1.2 mg) and8.3o/o (1.8 mg) at26weeksthat were not associated with an attenuation of theglycemic effect ofliraglutide.163 In comparison, 610/oof patients originally treated with exenatide hadantiexenatide antibodies at week 26.163 High lev-els of antiexenatide antibodies were correlated withsignificantly smaller original HbA(lc) reductions;however, the p resence of antib o dies did not comp ro -

mise the subsequent glycemic response to liraglu-tide.r63 The clinical implication of antibody devel-opment remains to be frrlly elucidated and may becompound- and/or antibody-specific. Not surpris-ingly, analogs with lower homology to wild-t1peGLP-1 (e.g., exenatide, taspoglutide, lixisenatide)appear to be associated with greater rates of antibodydevelopment.

Phill ips & Prins

GLP-I agonists and basal insulinThe use of a GLP- I agonist in conjunction with in-sulin has some appeal, particularly with regard to thepotential for mitigating the weight gain seen with in-sulin treatment. There have been a number of smallprospective and retrospective studies evaluating ex-enatide as an add-on to insulin treatmen1.164-t6e 16.majority of these studies have used glargine as thebasal insulin, and most of them reported an im-provement in glycemic control, in association withweight loss, and no major increase in rates of hypo-glycemia.

Although these results are promising, longer-term studies are required to assess whether com-bination therapy translates into improved clinicalendpoints and whether the relatively high costsof these newer agents are feasible for widespreaduse.

Adverse events with exenatide and liraglutideOverall, GLP- I agonists are generally well tolerated.And while gastrointestinal symptoms are common(nausea, vomiting, and diarrhea), they are generallytransient and improve within 4 to 8 weelcs of ther-apy.4 Incidence of hypoglycemia is low and gener-ally mild, in keeping with the glucose dependenceof these medications.a

It is known that patients with T2DM have athreefold higher risk of pancreatitis.tTo However,initial cas€ reportslTl raised concern regarding anexcess of pancreatitis in patients treated with exe-natide, and a warning now is featured in the ex-enatide prescribing information. A claims-basedsafety surveillance report did not identif a greaterrisk of pancreatitis in patients treated with exe-natide, sitagliptin, metformin, or glpuriile.rTz Sim-il"rh in a recent cohort study there was no increasedrisk of pancreatitis in patients treated with exe-natide.lT3 However, Elashoff et aLrTa identified anincreased odds ratio of both pancreatitis and pan-creatic cancer in their review of an FDA databaseof spontaneous- reported adverse events associatedwith exenatide and sitagtitpi". While all of thesestudies are limited by their retrospective design, thesource database used by Elashoff et al.r7a may havebeen particularly prone to bias; lack of informationregarding patient characteristics and adjustment forrisk factors further compound difficulties with thisstudy. However, further studies in this area areneeded.lTs

Ann. N.Y. Acad. Sci.00 (2012) 1-20 @ 2012 New York Academy of Sciences.

Phillios & Prins

A recent meta-analysis of the cardiovascularsafety of exenatide did not identr& an increasednumber of cardiovascular events.l76 However, thatstudy contrasts with a recent retrospective analysisof a large insurance database that reported a re-duction in cardiovascular events in patients takingnnice-daily exenatide.rTT 7o help address the issue,a number of cardiovascular safety studies are cur-rently underway, including the LEAD: Evaluation ofcardiovascular outcome Results (LEADER; clinical-trials.gov identifier NCTO1 179048) and SitagliptittCardiovascular Outcome Study (TECOS; clinical-trials. gov identifier NCT00790205) .

GLP-IR is expressed on thyroid C cells, andalthough not seen in nonhuman primates, benignand malignant thyroid C-cell tumors have been ob-served with GlP-I-based therapies in rats and micetreated long term with high doses of liraglutide.aWhile no specific monitoring with regard to thyroidcell cancer has been proposed, the American Associ-ation of CLinical Endocrinologists suggests that useof liraglutide be avoided in patients with multipleendocrine neoplasia type 2 (MEN2) and in thosewith a personal or family history of medullary thy-roid cancer.l78

DDP4 inhibitorsThe DPP4i currently available include sitagliptin,vildagliptin, and saxagliptin; linagliptin has recentlybeen approved by the FDA, while alogliptin has beenapproved in |apan only.t A number of other DPP4iare in clinical development, including dutogliptin.

DPP4i are selective for DPP4/CD26; however, asoutlined previously, DPPa is a widely e4pressed ser-ine protease with a nurnber of substrates, includingboth GIP and GLP-I. Therefore, in contrastto GLP-lR agonists, DPP4i increase circulating concentra-tions of both GIP and GLP-I. Inhibition of DPP4with these agents typically results in near-completeinhibition of DPP4 over 24 hours, raising GIP andGLP-I concentrations two- to threefolil.rte Anotherpoint of difference between DPP4i and GLP-IRanalogs is that while the latter results in supraphysi-ologic concentrations of incretins, DPP4 inhibitioninduces physiologic concentrations. DPP4i restorethe enteroinsular gradient of GLP-1,t80 pot tttiailyexplaining why DPP4i are effective despite inducingonly modest increases in systemic incretin concen-trations.Isl

Update on incretin hormones

Sitagliptin, linagliptin, saxagliptin, and alogliptinare given once dailOtaz while vildagliptin is giventwice daily.tez't83 11t. DPP4i are all oral agents,in contrast to the GLP-IR agonists, which re-quire parenteral administration. With the excep-tion of linagliptin, which is eliminated extrarenally(biliary excretion), DPP4i are not recommendedfor use in patients with creatinine clearance of<50 ml/min.l8z

DPP4| as mono- and add-on therapyThe DPP4i induce an HbA(lc) reduction of ap-proximately 0.5-0.8olo, whether as mono- or add-on therapy.4'184'18s The more modest glycemic re-duction compared with the GLP-IR agonists islikely due to the lower concentrations of GLP-I achieved. Sitagliptin as monotherapy reducedHbA(lc) by 0.794.940/o from a baseline HbA(lc)of 8.00lo,186 while sacaglipin reduced HbA(lc) by0.4H.63% from a baseline HbA(lc) of 7.9o/o tndrug-naive patients (tolerability in this study wassimilar to placebo).t8t Vildagliptin achieved similarreductions in HbA(lc) compared with glimepirideas add-on therapy to metformin: 0.44o/o reduc-tion with vildagliptin and 0.53o/o with glimepiridefrom a baseline HbA(lc) of 7.3o/o.r8a 1t this study,vildagliptin significantly reduced body weight rel-ative to glimepiride (-I.79 kg) and resulted in alO-fold lower incidence of hypoglycemia.rsa

In comparison with GLP-I agonists, which areassociated with weight loss, the DPP4i are generallyweight neutral.a The reason underlying the differ-ential effects on weight seen in these two incretin-based therapies are not clear, but the difference maybe due to lower concentrations of GLP-I, lack of ef-fect on gastric emptying in DPP4 inhibition, or therelatively anabolic effects of GIP.3'a6

DPP4i appear to have minimal effect on bloodpressure.4'186-1el However, DPP4 inhibition in-creases a number of peptides in addition to GLP-Iand GIR such as the vasoconstrictors neuropeptideY and peptide YY, raising the possibility that theseagents could have hypertensive effects-an hypoth-esis supported in a preclinical study.le2 However,a modest reduction in systolic blood pressure (1.8mmHg) was observed in a small trial of short dura-tion of sitagliptin in subjects with T2DM and mild-to-moderate hypertension. t e3

DPP4 inhibition with sitagliptin and vildagliptinhas been associated with improved indexes of B-cell

Ann. N.Y. Acad. Sci. O0 (201 4 tn @ 2012 New York Academy of Sciences.

Update on incretin hormones

function,l88' 189' 194,195 although a meta-analysis didnot show sitagliptin to have a beneficial effect onHOMA-p and proinsulin/insulin ratio comparedwith active comparator drugs.1e6

Ahren et al.re7 evaluated changes in meal-relatedglucagon responses over the course ofa Z-year studyin patients treated with vildagliptin or glimepirideas add - on therapy to meformin. Although HbA ( I c)and prandial glucose exqusions were similar inthe two groups, vildagliptin was associated witha greater glucagon suppression compared withglimepiride. T2DM is associated with both ct- andp-pancreatic cell dysfunction, and therefore the im-provement in glucagon suppression seen with DPP4inhibition may be of significant clinical interest, al-though the longer-term effects of treatment remainunclear.

Comparisons between DPP4|The DPP4i appear to be similar in efficacy; on aver-age, sitaglipin reduced HbA(lc) by I.0o/o follow-ng 52 weeks of treatment, a I.4o/o reduction inHbA(lc) was observed following vildagliptin treat-ment, while saxagliptin treatment was associatedwith reductions of HbA(lc) between 0.43olo and1.17o6.re8,ree

An l8-week noninferiority study compared theeffrcary and safety of add-on saragliptin 5 mg d"ity(n - 403) or sitagliptin 100 mg daily ( n - 398) itt P"-tients whose glycemia was inadequately controlledwith metformin.2oo Tieatment with saxagliptin andsitagliptin reduced HbA(lc) to a similar extent(0.52o/o vs. 0.620/o, respectively) from a baselineHbA(lc) of 7.7o/o. Both treatments were similarlywell tolerated; mild hypogly.emic events were ob-served in approximately 3o/o of each treatmentgroup, while nausea was reported in l-2.3o/o of pa-tients in the study. Body weight declined by a meanof 0.4 kg itt both groups.2oo

Adverse events DPP4IOverall, the DPP4i are well tolerated, with a low inci-dence of hypoglycemia and gastrointestinal upset.a'sThere is a theoretical concern regarding the poten-tial for DPP4 inhibition to interfere with immunefunction and early reports suggested an increase inupper respiratory tract infection in patients treatedwith DPP4i.4 A recent pooled analysis of.10,246 pa-tients treated with sitagliptin did not identt&

"tt itt-

creased risk of infection, concluding that sitagliptin

Phillips & Prins

was well tolerated in clinical trials of up to 2 yearsin duration.2ol

There have been reports of pancreatitis followingsitagliptin treatment;202 however, a recent surveil-lance repottlTz and a meta-analysis of 19 con-trolled clinical trials, comprising 10,246 patientswith T2DM treated for up to 2 years,202 did notidentify an increased risk of pancreatitis in pa-tients receiving sitagliptin. As in the case of GLP-lR agonists, ongoing postmarketing surveillance isrequired.

Comparison between GLP-| agonists andDPP4iBergenstal et aI. evaluated once-weekly exenatide(n - 170) versus manimum approved doses ofsitagliptin (n - I72) or pioglitazone (n - 172),in patients treated with metformin (DURATION-2).zot In this 26-week study, weekly exenatidereduced HbA(lc) significantly more than eithersitagliptin or pioglitazone (I.5o/o vs. 0.97o vs.l.2o/o),respectively, from a baseline HbA(lc) of 8.5%. Exe-natide treatment was asso ciated with a 2. 3 -kg weightloss, a 1.5 kg and 5.1 kg greater weight loss com-pared with the sitagliptin and pioglitazone arms,respectively. Nausea was seen in 24o/o and l0olo ofexenatide- and sitagliptin-treated patients, while di-arrhea was reported in 18% and t0olo patients, re-spectively.2o3

The efficacy of liraglutide (L.2 mg daily; n - 225and 1.8 mgdaily; n-221) versus sitagliptin (100 mg.ddyt n - 219) as add-on therapy to patients withT2DM inadequately controlled with metforminwas assessed in a 26-week open-label trial.ee Bothdoses of liraglutide were associated with a greaterreduction in HbA(lc) compared with sitagliptin(4.5o/o vs. -1.24olo vs. 4.9o/o, respectively); base-Iine HbA(lc) was 8.5o/o. Nausea was more commonwith liraglutide (2|o/o patients on I.2 mg and 27o/opatients on 1.8 mg) compared with sitagliptin treat-ment (5o/o), and minor hypoglycemia was recordedin about 5o/o of participants in each treatment group.

Overall, the GLP-I agonists result in superiorglycemic control, but with a greater incidenceof gastrointestinal-adverse events compared withDPP4 therapy. Furthermore, the GLP- I agonists ap-pear to ha're a greater degree of glucagon suppres-sion, and effects on gastric slowing are associatedwith weight loss rather than the weight neutralityseen with DPP4 inhibition.

Ann. N.Y. Acad. Sci. m (2012) 1-20 O 2012 New York Academy of Sciences.

Phillips & Prins

A recent meta-analysis of the cardiovascularsafety of exenatide did not identf ut increasednumber of cardiovascular events.l76 However, thatstudy contrasts with a recent retrospective analysisof a large insurance database that reported a re-duction in cardiovascular events in patients takingtwice-daily exenatide .r77 7o help address the issue,a number of cardiovascular safety studies are cur-rently underway, including the LEAD: Evaluation ofcardiovascular outcome Results ( LEADER; clinical-trials.gov identifier NCTOI 179048) and SitagliptittCardiovascular Outcome Study (TECOS; clinical-trials. gov identifier NCT00790205) .

GLP-IR is expressed on thyroid C cells, andalthough not seen in nonhuman primates, benignand malignant thyroid C-cell tumors have been ob-served with GlP-l-based therapies in rats and micetreated long term with high doses of liraglutide.aWhile no specific monitoring with regard to thyroidcell cancer has been proposed, the American Associ-ation of Clinical Endocrinologists suggests that useof liraglutide be avoided in patients with multipleendocrine neoplasia type 2 (MEN2) and in thosewith a personal or family history of medullary thy-roid cancer.l78

DDP4 inhibitorsThe DPP4i currently available include sitagliptin,vildagliptin, and saxagliptin; linagliptin has recentlybeen approved by the FDA, while alogliptin has beenapproved in |apan only.t A number of other DPP4iare in clinical development, including dutogliptin.

DPP4i are selective for DPP4/CD26; however, asoutlined previously, DPPa is a widely eripressed ser-ine protease with a number of substrates, includingboth GIP and GLP-I. Therefore, in contrastto GLP-lR agonists, DPP4i increase circulating concentra-tions of both GIP and GLP-I. Inhibition of DPP4with these agents typicalty results in near-completeinhibition of DPP4 over 24 hours, raising GIP andGLP-I concentrations two- to threefol6.rzs Anotherpoint of difference between DPP4i and GLP-IRanalogs is that while the latter results in supraphysi-ologic concentrations of incretins, DPP4 inhibitioninduces physiologic concentrations. DPP4i restorethe enteroinsular gradient of GLP-1,t80 pot ttti"tlyexplaining why DPP4i are effective despite inducingonly modest increases in systemic incretin concen-trations.l8l

Update on incretin hormones

Sitagliptin, linagliptin, saxagliptin, and alogliptinare given once dailntaz while vildagliptin is giventwice daily.182't8r 11t. DPP4i are all oral agents,in contrast to the GLP-IR agonists, which re-quire parenteral administration. With the excep-tion of linagliptin, which is eliminated extrarenally(biliury excretion), DPP4i are not reconunendedfor use in patients with creatinine clearance of<50 ml/min.l8z

DPP4| as mono- and add-on therapyThe DPP4i induce an HbA(lc) reduction of ap-proximately 0.5-0.8olo, whether as mono- or add-on therapy.4'184'l8s The more modest glycemic re-duction compared with the GLP-IR agonists islikely due to the lower concentrations of GLP-I achieved. Sitagliptin as monotherapy reducedHbA(lc) by 0.794.94olo from a baseline HbA(lc)of 8.00lo,186 while saxaglitpin reduced HbA(lc) by0.4H.63olo from a baseline HbA(lc) of 7.9o/o indrug-naive patients (tolerability in this study wassimilar to placebo).r8s Vildagtiptin achieved similarreductions in HbA(lc) compared with glimepirideas add-on therapy to metformin: 0.44o/o reduc-tion with vildagliptin and 0.53o/o with glimepiridefrom a baseline HbA(lc) of 7.3o/o.t$a In this study,vildagliptin significantly reduced body weight rel-ative to glimepiride (-I.79 kg) and resulted in af 0-fold lower incidence of hypoglycemia.r8a

In comparison with GLP-I agonists, which areassociated with weight loss, the DPP4i are generallyweight neutral.a The reason underlying the differ-ential effects on weight seen in these two incretin-based therapies are not clear, but the difference maybe due to lower concentrations of GLP-I,lack of ef-fect on gastric emptying in DPP4 inhibition, or therelatively anabolic effects of GIP.3'a6

DPP4i appear to have minimal effect on bloodpressure.4'186-lel However, DPP4 inhibition in-creases a number of peptides in addition to GLP-Iand GIR such as the vasoconstrictors neuropeptideY and peptide YY, raising the possibility that theseagents could have hypertensive effects-an hypoth-esis supported in a preclinical study.le2 However,a modest reduction in systolic blood pressure (1.8mmHg) was observed in a small trial of short dura-tion of sitagliptin in subjects with T2DM and mild-to-moderate hypertension. I e3

DPP4 inhibition with sitagliptin and vildagliptinhas been associated with improved indexes of B-cell

Ann. N.Y. Acad. Sci. O0 (201 2) 1-20 @ nlZ New York Academy of Sciences.

Update on incretin hormones

function, 188' I 89' r94'res although a meta-analysis didnot show sitagliptin to have a beneficial effect onHOMA-B and proinsulin/insulin ratio comparedwith active comparator drugs.1e6

Ahren et al.re7 evaluated changes in meal-relatedglucagon responses over the course of a 2-year studyin patients treated with vildagliptin or glimepirideas add-o n therapy to meúormin. Although HbA ( I c )and prandial glucose excursions were similar inthe two groups, vildagliptin was associated witha greater glucagon suppression compared withglimepiride. T2DM is associated with both a- and

B-pancreatic cell dysfuncúon, and therefore the im-provement in glucagon suppression seen with DPP4inhibition may be of significant clinical interest, al-though the longer-term effects of treatment remainunclear.

Comparisons between DPP4|The DPP4i appear to be similar in efficacy; on aver-age, sitaglitpin reduced HbA(lc) by l.0o/o follow-tng 52 weela of treatment, a l.4o/o reduction inHbA(lc) was observed following vildagliptin treat-ment, while saxagliptin treatment was associatedwith reductions of HbA(lc) between 0.437o and1.17o7o.198,199

An l8-week noninferiority study compared theefficacy and safety of add-on saxagliptin 5 mg doily(n -403) or sitagliptin 100 mg daily ( n - 398) itt p"-tients whose glycemia was inadequately controlledwith metformin.2oO Tbeatment with saxagliptin andsitagliptin reduced HbA(tc) to a similar extent(0.52o/o vs. 0.620/u respectively) from a baselineHbA(lc) of 7.7o/o. Both treatments were similarlywell tolerated; mild hypogly.emic events were ob-served in approximately 3o/o of each treatmentgroup, while nausea was reported in l-2.3o/o of pa-tients in the study. Body weight declined by a meanof 0.4 kg itt both groups.2oo

Adverse events DPP4|Overall, the DPP4i are well tolerated, with a low inci-dence of hpo glycemia and gastrointestinal up set. a' s

There is a theoretical concern regarding the poten-tial for DPP4 inhibition to interfere with immunefunction and early reports suggested an increase inupper respiratory tract infection in patients treatedwith DPP4i.4 A recent pooled analysis of 10,246 pa-tients treated with sitagliptin did not identifr an in-creased risk of infection, concluding that sitagliptin

Phillips & Prins

was well tolerated in clinical trials of up to 2 yearsin duration.2ot

There have been reports of pancreatitis followingsitagliptin treatment;2o2 however, a recent surveil-lance reportrTz and a meta-analysis of 19 con-trolled clinical trials, comprising L0,246 patientswith T2DM treated for up to 2 years,202 did notidentify an increased risk of pancreatitis in pa-tients receiving sitagliptin. As in the case of GLP-lR agonists, ongoing postmarketing surveillance isrequired.

Comparison between GLP-I agonists andDPP4iBergenstal et aI. evaluated once-weekly exenatide(n - 170) versus maximum approved doses ofsitagliptin (, - 172) or pioglitazone (n - 172),in patients treated with metformin (DITRATION-

Z).zot In this 26-week study, weekly exenatidereduced HbA(lc) significantly more than eithersitagliptin or pioglituLone (1.5o/o vs. 0.9olo vs.l.2o/o),respectively, from a baseline HbA(lc) of 8.5olo. Exe-natide treatment was associated with aL.3-kgweightloss, a 1.5 kg and 5.1 kg greater weight loss com-pared with the sitagliptin and pioglitazone arms,respectively. Nausea was seen in 24o/o and l0olo ofexenatide- and sitagliptin-treated patients, while di-arrhea was reported in l8olo and 10olo patients, re-spectively.2o3

The efficacy of liraglutide ( 1.2 mg daily; n - 225and 1 .8 mg daily; n - 221) versus sitagliptin ( 100 mgdaily; n - 219) as add-on therapy to patients withT2DM inadequately controlled with metforminwas assessed in a 26-week open-label trial.ee Bothdoses of liraglutide were associated with a greaterreduction in HbA(lc) compared with sitagliptin(-I.5o/o vs. -L.24olo vs. 4.9o/o, respectively); base-line HbA(lc) was 8.5o/o. Nausea was more commonwith liraglutide (2|o/o patients on I .2 mg and 27o/opatients on 1.8 mg) comparedwith sitagliptin treat-ment (5o/o), and minor hypoglycemia was recordedin about 5o/o of participants in each treatment group.

Overall, the GLP-I agonists result in superiorglycemic control, but with a greater incidenceof gastrointestinal-adverse events compared withDPP4 therapy. Furthermore, the GLP-I agonists ap-pear to have a greater degree of glucagon suppres-sion, and effects on gastric slowing are associatedwith weight loss rather than the weight neutralityseen with DPP4 inhibition.

Ann. N.Y. Acad. Sci. m (2012) 1-20 @ 2012 New York Academy of Sciences.

Phil l ips & Prins

There is a proportion of patients who do not re-spond to therapy-up to 30o/o for those treated withvildaglip6tt20+ (a similar percentage of patients arereported to be resistant to thiazolidinedione treat-ment).2os It is not clear whether this phenomenon isclass-related and whether there are clinically usefulpredictors of response.

Clinical guidelines for incretin-based therapyThe 2009 consensus algorithm for initiation andadjustment of therapy from the American DiabetesAssociation and EuropeanAssociation for the Studyof Diabetes classifies the GLP-1 agonists in "tier 2"category (less well-validated therapies) and suggestthat GLP-I agonists should be considered whenweight gain or hypoglycemia are particular con-cerns.206 The DPP4i were not included in the pre-ferred two tiers oftherapybut instead were classifiedas "other potential therapy" along with cr glucosi-dase inhibitors, glinides, and pramlintide. The con-sensus notes that long-term data regarding safetyare lacking for incretin-based therapies.

The use of GLP-I agonists should be avoided inpatients with inflammatorybowel disease or gastro-paresis. Exenatide should be avoided in the settingof severe renal dysfunctiort,2l7 while liraglutide doesnot require dose adjustment in the setting of renalimp airment. 208 Vildagtiptin and saxagliptin shouldbe avoided, and the dose of sitagliptin reduced,in patients with creatinine clearance <50 ml/min;linagliptin does not need dose adjustment in thesetting of renal dysfunction.l82 Given the ongoingconcerns regarding pancreatitis, these agents shouldnot be used in patientswith a historyof pancreatitisor severe hypertriglyceridemia. The NICE guide-lines suggest that treatment with GLP-I agonistsbe ceased after 6 months if HbA(lc) and weighthave not decreased by at least Io/o and 3ol0, respec-tively.2oe

Conclusions

GLP-I and GIP mediate a nutrient-dependent in-sulinotropic effect through actions on the pancreatic

B cell, while GLP-1 also inhibits glucagon secretion.GLP-I and GIP promote pancreatic B-cell prolif-eration and inhibit apoptosis in preclinical trials.There is expanding research investigating the po-tential role for GLP-1 and GIP in neuroprotection;both incretin hormones may mediate effects on thebony skeleton. GLP-I has a known effect on gastric

Update on incretin hormones

emptying, md there is emerging evidence that GLP-1 mayplaya cardioprotective role. However, furtherresearch is needed in this aulea.

GLP-I agonists are associated with supraphysi-ologic concentrations of GLP-I, superior glycemiccontrol, and a greater degree of weight loss com-pared with DPP4i. However, gastrointestinal sideeffects are more corrunon and parenteral adminis-tration is required for GLP-I agonists, while DPP4iare well tolerated and can be taken orally. Althoughyet to be established, it is hoped that these incretin-based therapies may alter the course of T2DMthrough positive effects on the pancreatic B cell.

Ongoing studies are evaluating the cardiovascu-lar safety of GLP- I agonists and DPP4i. Althoughresearch to date suggests that an incretin-based ap-proach may have beneficial cardiovascular effects,trials with hard end points are needed.

The incretin-based therapies offer an excitingnew therapeutic approach in T2DM. These ther-apies are effective, generallywell tolerated, md offerthe tantalizing possibility of modiffing a numberof aspects of the pathophysiology associated withT2DM. However, ongoing research, clinical trials,and surveillance are required to confum an ac-ceptable ongoing risk-benefit ratio of these noveltreatments.

Conflicts of interest

I.B.P. received lecture/consultancy fees from Merck,Novartis, Novo Nordisk, Eli Lilly, Sanofi-Aventis,and Boehringer-Ingelheim, and investigator-initiated study support from Merck

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