Defining the role ofGLP-1 receptor agonists forindividualized treatment oftype 2 diabetesExpert Rev. Endocrinol. Metab. Early online, 1–12 (2014)

Daisuke Yabe*1–3

and Yutaka Seino1

1Center for Diabetes, Endocrinology

and Metabolism, Kansai Electric Power

Hospital, Osaka, Japan2Center for Metabolism and Clinical

Nutrition, Kansai Electric Power

Hospital, Osaka, Japan3Division of Molecular and Metabolic

Medicine, Kobe University Graduate

School of Medicine, Kobe, Japan

*Author for correspondence:

Tel.: +81 664 585 821

Fax: +81 664 586 994

ydaisuke-kyoto@umin.ac.jp

With the advent of dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptoragonists (GLP-1 RAs) over the past decade, incretin therapy has become established as animportant treatment strategy for type 2 diabetes mellitus (T2DM), with an efficacy and safetyprofile distinct from that of other anti-hyperglycemic agents. However, our understanding ofthe optimal clinical use of incretins remains incomplete. This review focuses on the use ofGLP-1 RAs in the treatment of T2DM, with reference to the differing dominant mechanismsof action between short- and long-acting GLP-1 RAs and the clinical implications of thisdifference. The role of GLP-1 and the effects of GLP-1 RAs in various organs other than thepancreas will also be discussed.

KEYWORDS: albiglutide • DPP-4 inhibitor • dulaglutide • exenatide • exenatide LAR • GLP-1 receptor agonist • incretin

• liraglutide • lixisenatide • type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a progres-sive metabolic disorder characterized by deteri-oration of pancreatic b-cell function andinsulin resistance in the liver and peripheraltissues. These factors combine and result inoverproduction of hepatic blood glucose andelevations in plasma glucose (FPG) in the fast-ing state, and insufficient glucose uptake bymuscle cells and elevated postprandial plasmaglucose (PPG) following a meal [1]. In additionto the b-cell, liver and muscle, dysfunction ofthe pancreatic a-cell (hyperglucagonemia), thefat cell (accelerated lipolysis), kidney (increasedglucose reabsorption), brain (insulin resistance)and gastrointestinal tract (incretin system) canall play an important role in the developmentand progression of T2DM [1].

The incretin system consists of two gut hor-mones, glucose-dependent insulinotropic poly-peptide and glucagon-like peptide-1 (GLP-1),which are released by gastrointestinal endocrinecells following food intake to stimulate insulinsecretion from b-cells glucose dependently [2,3].GLP-1 is also associated with suppression ofglucagon secretion from a-cells and a delayingeffect of gastric emptying that reduces therate of glucose absorption from the small

intestine [4], and has an inhibitory neurologicalinfluence on appetite and glucose ingestion[2,3,5–7]. Together, the incretin effects in responseto glucose intake ensure that PPG excursionsare limited, regardless of carbohydrate loadfrom a meal [8].

Patients with T2DM demonstrate animpaired capability to regulate their incretineffect, which may contribute to the exagger-ated PPG excursions [9]. Efforts to correct thisdysfunction with exogenous GLP-1 have beenhampered by the short half-life of the peptidein the body [10]. Human GLP-1 is rapidly bro-ken down by the DPP-4 enzyme and metabo-lized in the liver in a matter of minutes, withonly a small percentage of the intact hormonecirculating systemically [11]. The advent ofDPP-4 inhibitors and GLP-1 receptor agonists(GLP-1 RAs) over the past decade has seenincretin therapy become established as animportant treatment strategy for T2DM, withan efficacy and safety profile distinct fromother anti-diabetic agents [12,13]. However, ourunderstanding of the optimal clinical use ofincretins remains incomplete. This review willfocus on the GLP-1 RAs and their use in thetreatment of T2DM, with reference to the

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differing dominant mechanisms of action between GLP-1 RAs.The role played by GLP-1 and the effects of GLP-1 RAs invarious organs other than the pancreas will also be discussed.

Classification & comparison of GLP-1 RAs in bothclinical & basic researchThere are currently five different GLP-1 RAs approved for usein patients with poorly controlled T2DM (TABLE 1). From a clin-ical perspective, these five agents can be divided into two broadcategories according to their relative half-lives: twice-daily exe-natide and once-daily lixisenatide are short-acting GLP-1 RAs,while once-daily liraglutide, once-weekly exenatide long-actingrelease (LAR) and albiglutide are long-acting GLP-1 RAs. Thedifference in the half-lives of these two classes appears to affectthe mechanistic action by which they exert their glucose-lowering effects. Short-acting GLP-1 RAs have limited effectson insulin secretion but strongly inhibit postprandial glucagonsecretion [14], which may aid PPG control [15]. They also have adelaying effect on gastric emptying, which results in pro-nounced reductions in PPG levels by reducing the rate of glu-cose absorption from the small intestine [5,16,17]. In contrast,long-acting GLP-1 RAs have a limited gastric emptying effect,and a consequently more modest effect on PPG excur-sions [18,19]. Instead, long-acting GLP-1 RAs provide reductionsin both FPG and PPG through stimulation of insulin secretionand inhibition of glucagon secretion [20].

Short-acting GLP-1 RAs

The first GLP-1 RA to be developed was exenatide, a syntheticversion of the 39-residue exendin-4 peptide originally isolatedfrom Gila monster lizard salivary secretions [21]. Exendin-4shares approximately 50% sequence homology with mammalianGLP-1 and is a potent agonist of the GLP-1 receptor [22]. Cru-cially, however, exendin-4 is resistant to proteolytic cleavage bythe DPP-4 enzyme, and so has a half-life of approximately 2.5 hin plasma, making it clinically viable for therapeutic use [21].Exenatide 10 mg is administered twice daily (b.i.d.) within60 min prior to the breakfast and evening meal [23,24]. In the piv-otal clinical studies of exenatide, glycated hemoglobin (HbA1c)levels were reduced by 0.8–0.9% over a period of 30 weeks,with relatively modest reductions in FPG (-0.6 mmol/l[-10.1 mg/dl]) indicating that the predominant glucose-loweringeffect was via reductions in PPG levels [25–27]. Blood glucosemeasurements confirmed that exenatide provides significantreductions in PPG after breakfast and after the evening meal [28].

The structure of the once-daily short-acting GLP-1 RA lixi-senatide is also based on the exendin-4 peptide, with modifica-tions to the C-terminal end. The binding affinity oflixisenatide for the human GLP-1 receptor is approximatelyfourfold greater than that of human GLP-1 in vitro [29,30].Like exenatide, the structure of lixisenatide is resistantto DPP-4 metabolism, and it has a half-life in plasma of2–4 h [20,31]. A dose-ranging study comparing once- versustwice-daily lixisenatide administration showed comparablereductions in HbA1c over 13 weeks, with a dose of 20 mg once

daily (q.d.) selected for Phase III studies on the basis that itprovided the best tolerability profile while conferring glycemiccontrol [32]. In the Phase III clinical study program, addition oflixisenatide to existing oral therapy resulted in significant reduc-tion in HbA1c of 0.7–0.9% over 24 weeks [33–36]. As with exe-natide, reductions in FPG were modest, although statisticallysignificant; however, reductions in PPG of 4.5–6.2 mmol/l(82–113 mg/dl) were much more marked [37]. Although thelargest reductions in PPG are generally seen post-breakfast, anunsurprising observation given the half-life of lixisenatide andit’s usual timing of administration, a pharmacologic study ofonce-daily lixisenatide administered before breakfast revealed asignificant reduction in PPG versus placebo after breakfast(p < 0.0001), lunch (p < 0.001) and dinner (p < 0.05) [16],demonstrating a significant effect on plasma glucose levelsthroughout the day. Furthermore, the effect of lixisenatide onPPG was correlated with a reduction in the rate of gastric emp-tying [16]. A recent study demonstrated that lixisenatide wasequally effective and well tolerated when administered q.d.before the main meal of the day versus before-breakfastadministration [38].

A head-to-head study of once-daily lixisenatide versus twice-daily exenatide showed statistically non-inferior reductions inHbA1c over 24 weeks (-0.8 vs -1.0%; treatment difference0.17% [95% CI: 0.033–0.297]) despite the different dosingregimens [36]. Although PPG levels were not recorded in thisstudy, both lixisenatide and exenatide showed moderate reduc-tions in FPG (-1.22 vs -1.45 mmol/l [-22 vs -26.1 mg/dl]), inline with the predominant PPG-lowering effects associated withshort-acting GLP-1 RAs.

Long-acting GLP-1 RAs

A LAR formulation of exenatide was subsequently developed toprovide consistent availability in plasma with once-weekly dos-ing. The LAR formulation consists of injectable microspheres ofexenatide and a biodegradable polymer that provides sustainedexenatide release into plasma with a half-life of approximately2 weeks [39]. In Phase III clinical studies, once-weekly exenatideLAR was associated with reduction in HbA1c of 1.3–1.9% over30 weeks of treatment [40,41]. In the DURATION-1 study,which compared once-weekly exenatide LAR with twice-dailyexenatide, HbA1c reductions were significantly greater withthe long-acting versus regular formulation after 30 weeksof treatment (-1.9 vs -1.5%; treatment difference -0.33 [95%CI: -0.54 to -0.12]; p = 0.0023) [41]. Reductions in FPG weresignificantly greater with exenatide LAR versus exenatide(-2.3 vs -1.4 [-42 vs -25 mg/dl]; p < 0.0001), while changes in2-h PPG were significantly lower in patients treated with exena-tide b.i.d. (-5.3 vs -6.9 mmol/l [-96 vs -126 mg/dl];p = 0.0124) [41]. Consistent with these observations, delay ingastric emptying was markedly less pronounced with exenatideLAR than with exenatide [41].

Liraglutide is a second long-acting GLP-1 RA and the firstanalog of human GLP-1 RA, which is administered q.d. Theliraglutide structure includes modifications for attachment of a

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16-carbon free fatty acid chain that promotes reversible bindingwith plasma proteins, increasing resistance to DPP-4 cleavage,inhibiting renal clearance and extending its half-life to approxi-mately 12 h [42]. The Phase III clinical studies showed a reduc-tion in HbA1c levels of 1.1–1.8% [18,43–46]. Similar to exenatideLAR, head-to-head comparison of once-daily liraglutide versustwice-daily regular exenatide over 26 weeks revealed

significantly greater reductions in HbA1c (-1.12 vs -0.79%;treatment difference -0.33 [95% CI: -0.47 to -0.18]) and FPG(-1.61 vs -0.60 mmol/l [29 vs 11 mg/dl]; p < 0.0001), but sig-nificantly lower reductions in PPG after breakfast and din-ner [18]. Two recent meta-analyses revealed that exenatide LARand liraglutide showed similar reductions in HbA1c levels, butthat these reductions were superior to those seen with twice-

Table 1. Summary of approved short- and long-acting glucagon-like peptide-1 receptor agonists for thetreatment of type 2 diabetes.

Peptideorigin

Modifications Half-life Dosingregimen

Glucose-loweringeffect and changein body weight

Ref.

Short-acting GLP-1 receptor agonists

Exenatide Exendin-4 Synthetic Exendin-4:

39-amino acids with

53% homology to

human GLP-1. An

Ala2Gly substitution

(relative to human

GLP-1) gives resistance

to DPP-mediated

inactivation

~2.5 h b.i.d. HbA1c

reduction: 0.8–0.9%,

body weight

reduction:

1.6–2.8 kg, over

30 weeks

[25–27]

Lixisenatide Exendin-4 Pro38 removed and

C-terminus modified

with six additional Lys

residues

2–4 h q.d. HbA1c

reduction: 0.7–0.9%,

body weight

reduction:

1.6–3.0 kg, over

24 weeks

[37]

Long-acting GLP-1 receptor agonists

Exenatide

long-acting release

Exendin-4 Exendin-4

administered in a

matrix of

biodegradable polymer

(poly-D,L-lactide-co-

glycolide), resulting in

a release over time

after administration

~2 weeks Once weekly HbA1c

reduction: 1.3–1.9%,

body weight

reduction:

2.3–3.7 kg, over

30 weeks

[40,41,118,119]

Liraglutide GLP-1 Lys34Arg substitution,

and addition of a

C-16 fatty acid

(palmitoyl) at Lys26,

attached by a

glutamate linker

12 h q.d. HbA1c reduction:

1.1–1.8%, body

weight reduction:

0.2–3.2 kg, over

26 week

[18,43–46]

Albiglutide GLP-1 Dimer of a 30 amino

acid peptide, with an

Ala2Glu substitution to

increase resistance to

DPP-4, and fused to

human albumin

6–7 days Once weekly HbA1c

reduction:0.8%,

body weight

reduction: 0.6 kg,

over 32 weeks

[51]

Dulaglutide GLP-1 Covalently linked to an

Fc fragment of human

IgG4

90 h Once weekly HbA1c reduction:

0.8–1.1%, body

weight reduction:

2.6–3.0 kg, over

52 weeks

[120]

b.i.d.: Twice daily; DDP-4: Dipeptidyl peptidase 4; FPG: Fasting plasma glucose; GLP-1: Glucagon-like peptide-1; PPG: Postprandial plasma glucose; q.d.: Once daily.

Defining the role of GLP-1 RAs for individualized treatment of type 2 diabetes Review

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daily exenatide [47,48]. However, a head-to-head trial of liraglu-tide and exenatide LAR found that while both resulted inimprovements in glycemic control, greater reductions inHbA1c, reduced persistence of nausea and fewer occurrences ofhypoglycemia were seen with once-daily liraglutide [49].

The most recent GLP-RA to be approved is albiglutide.Albiglutide is a fusion peptide composed of two DPP-4-resist-ant GLP-1 analogs non-reversibly bound to human serumalbumin, resulting in a half-life of 6–7 days [50]. Data wererecently published from a 32-week Phase III study comparingonce-weekly albiglutide with once-daily liraglutide, whichshowed a reduction in HbA1c of -0.78 versus -0.99%, respec-tively (treatment difference 0.21% [95% CI: 0.08–0.34];p = 0.0846 for non-inferiority) [51]. However, while patientswho received once-daily liraglutide had greater reductions inHbA1c, they also experienced more gastrointestinal side effects,though fewer injection site reactions, than patients whoreceived once-weekly albiglutide [51].

Safety issues associated with the use of GLP-1 RAsOne of the principal attractive features of GLP-1 RAs, in addi-tion to their glucose-lowering benefits, is the relatively low riskof hypoglycemia associated with these agents. GLP-1-inducedstimulation of insulin is glucose-dependent and is negligibleunder conditions of hypoglycemia [52]. Consequently, hypogly-cemia associated with GLP-1 RAs is markedly lower than withsome other anti-diabetic therapies [53,54]. A meta-analysis of27 randomized controlled studies of non-insulin anti-diabeticagents added to metformin therapy showed that GLP-1 RAswere associated with levels of hypoglycemia comparable withplacebo [53]. In contrast, treatment with thiazolidinediones, sul-fonylureas (SUs) and glinides resulted in an increase in hypo-glycemia 2, 2.6- and 7-fold greater than placebo, respectively.As GLP-1 receptor activation by the GLP-1 RA exenatide hasbeen shown to ameliorate ATP production in pancreatic b-cellsand enhance sensitivity to SU [55,56], caution needs to takenwith respect to the potential for hypoglycemia whenGLP-1 RAs are used in combination with SU.

The most common class of adverse events (AEs) experiencedby patients receiving GLP-1 RAs are gastrointestinal AEs. In ameta-analysis of clinical studies of GLP-1 RAs versus insulin, asignificantly greater proportion of patients treated withGLP-1 RAs experienced gastrointestinal AEs compared withthose treated with insulin (Mantel–Haenszel odds ratio 15.00[5.44, 41.35]; p < 0.01) [57]. A review and meta-analysis ofGLP-1 RAs and DPP-4 inhibitors as an add-on to metforminby Deacon et al. found that while AEs were rare overall, theincidence of nausea and vomiting increased with GLP-1 RAtreatment [48]. However, it should also be noted that these gas-trointestinal side effects were mild to moderate in intensity,rarely resulting in treatment withdrawal, were transient in themajority of cases [37,58–60] and the frequency of events appearedto decline over the first few weeks of treatment [61]. The risk ofgastrointestinal side effects may also be influenced by dosingtitration, meal size, meal frequency and BMI.

While short-acting GLP-1 RAs, such as exenatide and lixise-natide, have been associated with a small or non-significanteffect, or even a reduction in resting heart rate, several long-acting GLP-1 RAs, including dulaglutide, liraglutide and LARexenatide, have been shown to be associated with a significantincrease in resting heart rate [62,63]. A significant effect ofGLP-1 RAs on electrocardiogram QT intervals has not beendemonstrated [64–66]. Administration of liraglutide 0.6, 1.2 or1.8 mg q.d. over 7 days found no concentration–exposuredependency on QTc intervals compared with placebo, and noQTc thresholds 500 ms or increases over >60 ms [64], andsingle-dose exenatide 10 mg was not found to be associatedwith clinically meaningful prolongation of the QTc interval,compared with placebo, in healthy subjects [66]. Analysis ofcardiovascular events from Phase II and Phase III liraglutidestudies demonstrated that the overall risk of cardiovascularevents was low, meeting the US FDA criteria for ruling outunacceptable increases in cardiovascular risk [67]. Data fromongoing long-term large-scale cardiovascular outcomes studiesare needed to confirm the lack of cardiovascular risk withGLP-1 RAs [68,69].

Acute pancreatitis is another rare but potentially serioussafety issue with regard to use of GLP-RAs and DPP-4 inhibi-tors. Concerns were raised initially on the basis of individualcase reports in exenatide- and liraglutide-treated patients [70],and retrospective analyses of medical databases [71]. However,both of these sources of information can be unrepresentative ofthe clinical reality and subject to potential bias. Evidence fromrandomized clinical studies of GLP-1 RAs provides a more rig-orous assessment and has not identified a link, although thestatistical power of individual studies is limited for detectingsuch a rare event [72]. More recently, a meta-analysis of 41 ran-domized clinical studies with GLP-1 RAs showed no increasein the risk of pancreatitis with the use of GLP-1 RAs [73], andrecent incretin pancreatic safety reviews by both the FDA andEMA found no evidence of a causal relationship [74]. Concernshave also been raised regarding a potential increased risk ofmedullary thyroid cancer with GLP-1 RAs based on evidenceof thyroid C-cell hyperplasia and tumors associated with long-term liraglutide exposure in rodents [75]. However, large-scalemonitoring during clinical studies has not identified any indica-tors of cancer development, and no increased incidence of C-cell cancer was identified during the clinical studies of otherGLP-1 RAs [76]. An analysis of data reported to the FDAadverse event reporting system did seem to show an increasedrisk of pancreatic and thyroid cancer with incretin therapies,although the data were not consistent and have been discred-ited on the basis of a bias in reporting of events [77,78].

Predictors of efficacy for GLP-1 RAsBaseline HbA1c

A meta-analysis that included seven studies relating to short-acting GLP-1 RAs and seven studies relating to long-actingGLP-1 RAs identified a linear significant negative correlationbetween baseline HbA1c and reduction in HbA1c in both

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groups over the course of the studies, with a significantlygreater reduction seen in the long-acting GLP-1 RA group [48].Similarly, Kawata et al. identified HbA1c at baseline as the sin-gle largest predictive factor for reduction in HbA1c with liraglu-tide, with significant associations seen at 12 weeks after thestart of liraglutide (b = -0.854, p = 0.001) and at 24 weeks(b = -0.602, p = 0.013) [79]. The authors concluded that base-line HbA1c may be a predictive factor for HbA1c reduction forall incretin therapies, and this could explain why increasedbaseline HbA1c is associated with a greater degree of HbA1c

reduction on treatment with liraglutide.

Ethnicity

Accumulating evidence suggests that GLP-1RAs exert a greatereffect on glycemic control in Asian patients than in non-Asianpatients [80]. In a study comparing the efficacy of lixisenatide inJapanese and Caucasian patients with T2DM insufficiently con-trolled with SU with or without metformin, Japanese patientsexperienced a greater benefit in terms of reduction in PPG excur-sions compared with Caucasian patients [81]. In Japanese patients,the LS mean difference versus placebo in PPG AUC[0:29–4:30 h]

after a standardized breakfast was -406.7 (36.7) h•mg/dl for thelixisenatide q.d. group and -346.3 (35.1) h•mg/dl for the lixise-natide b.i.d. group compared with -260.1 (39.5) h•mg/dl and-231.3 (38.6) h•mg/dl, respectively, in Caucasian patients [81].The authors suggest that greater efficacy of GLP-1 RAs in Asianpatients may be attributable to lower insulin secretory capacity [82]

along with little enhancement of meal-induced GLP-1 secretionin Japanese subjects [83,84].

Residual b-cell function

Pancreatic b-cells are critical for regulation of glucose homeosta-sis, and their progressive loss is a cardinal symptom of T2DMthat underlies the progression of deteriorating glucose control.Long-acting GLP-RAs significantly improve glycemic controlpartly by stimulating insulin release from pancreatic b-cells,unlike short-acting GLP-RAs, which act primarily througheffects on gastric motility. This difference in mechanism ofaction suggests that a certain amount of residual b-cell functionis required for optimal efficacy of long-acting GLP-1 RAs, whileresidual b-cell function is less important for the efficacy ofshort-acting GLP-1 RAs, such as exenatide and lixisenatide. Evi-dence in support of this hypothesis comes from an analysis ofdata from the Phase III studies of liraglutide, which showed asignificantly greater beneficial effect on HbA1c, with liraglutideversus exenatide in patients with high-estimated b-cell mass butno difference in patients with low-estimated b-cell mass [85]. Incontrast, a similar pooled analysis of data from two Phase IIIstudies of short-acting lixisenatide showed that HbA1c reduc-tions were consistent regardless of patients’ b-cell function, andthat PPG reductions were actually significantly greater inpatients with low- versus high-residual b-cell function [17].

The clinical importance of b-cell function for the efficacy oflong-acting GLP-1 RAs has been shown in a recent analysis ofpatients with T2DM switching from insulin to liraglutide

therapy [86]. Patients whose hyperglycemia was uncontrolledafter 12 weeks of liraglutide therapy had a longer duration ofdiabetes, higher baseline insulin doses and lower b-cell functioncompared with responders, indicating a more advanced stageof disease.

Gender

Treatment of T2DM with twice-daily exenatide 10 mg as anadd-on to oral therapy (metformin or metformin ± SU) hasbeen shown to result in better glycemic control in male patientsthan in female patients after 12 months of treatment, withHbA1c £7% achieved in a significantly greater proportion ofmales than females (38 vs 27%). With regard to safety, nosignificant gender difference regarding gastrointestinal AEs hasbeen reported; for example, 60 and 63 cases of nausea werereported with exenatide therapy in males and females,respectively [87].

Predictors of achieving therapeutic glycemic response (HbA1c

£7%) at 1 year among males were found to be inversely relatedto a longer duration of disease and baseline HcA1c. In females,baseline therapy with metformin was related to a positive glyce-mic outcome at 1 year, and baseline SU treatment or combina-tion treatment was associated with a negative effect onachievement of glycemic targets. In females only, an increase inbaseline homeostatic model assessment-b was also associatedwith a positive glycemic response [87].

Expectations beyond glycemic controlThe benefit of improved glycemic control with a low risk ofhypoglycemia makes the GLP-1 RAs an attractive treatmentoption in T2DM. However, the multiple physiologicaleffects of GLP-1 indicate that the clinical benefits ofGLP-1 RAs are likely to extend further (FIGURE 1). Preclinicalstudies of animal models indicate that incretins play a role ina range of diverse biological activities, with potential implica-tions for improvements in diabetes-related microvascularcomplications (e.g., retinopathy, nephropathy and neuropa-thy) and macrovascular complications (e.g., coronary arterydisease, peripheral artery disease and cerebrovascular disease),as well as diabetes-related comorbidities (e.g., obesity,non-alcoholic fatty liver disease, bone fracture and cognitivedysfunction) [88–90].

GLP-1 RAs have a clinically demonstrable benefit in termsof weight, which can be helpful in ameliorating early T2DMand the effects of weight gain from other anti-diabetictherapies [91–93]. A meta-analysis of 25 randomized controlledstudies of GLP-1 RAs of at least 20 weeks’ duration showedthat weight decrease was a consistent phenomenon, with areduction in body weight of approximately 2.9 kg per study [94].Another meta-analysis that included 29 randomized controlledstudies of GLP-1 RAs of at least 24 weeks’ duration reported areduction in BMI at 6 months of -1.0 kg/m2

[95]. Comparablereductions in weight were seen with short- and long-actingGLP-1 RAs. Weight decrease with GLP-1 RAs is thought tooccur through delayed gastric emptying and neurological

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suppression of appetite by increasing the perception of fullnessand satiety [96]. As the effects of long-acting GLP-1 RAs ongastric emptying could be lost with sustained dosing, as dis-cussed above, the fact that weight reduction with GLP-1 RAsis independent of the duration of action highlights the impor-tance of GLP-1 RA-mediated suppression of appetite via thebrain [20]. The potential for weight decrease with GLP-1 RAs isan attractive feature, particularly for patients with considerableobesity and for those needing intensified therapy with a treat-ment option that may contribute to an increase body weight,such as insulin.

Studies in animals show that GLP-1 RAs may have potentialcardioprotective effects [88,90,97]. In patients with acute myocar-dial infarction and left ventricular ejection fraction dysfunction,GLP-1 infused over 72 h significantly improved left ventricularejection fraction, and other measures of cardiac function,including global wall motion indices and regional wallmotion [98]. More recently, it was reported that GLP-1 infusionprotects the heart from ischemic left ventricle dysfunctioninduced by dobutamine stress in patients with coronary arterydisease [99]. Exenatide has also been shown to reduce reperfu-sion injury and final infarct size in patients with ST-segmentelevated myocardial infarction [100,101].

GLP-1 RAs also have well-documented benefits against riskfactors for cardiovascular disease, including hypertension anddyslipidemia. The anti-hypertensive effects of GLP-1 have consis-tently been shown in several clinical studies. A meta-analysis of

16 randomized controlled studies of GLP-1 RAs in patients withT2DM revealed that GLP-1 RAs reduced systolic blood pressureand diastolic blood pressure by 1–5 mmHg compared with someother anti-diabetic drugs including insulin, glimepiride and pla-cebo [102]. A pooled analysis of six Phase III clinical trials with lir-aglutide also found significantly greater systolic blood pressurereductions from baseline with liraglutide 1.2 mg q.d. (2.7 [0.8]mmHg) and 1.8 mg (2.9 [0.7] mmHg) than with placebo (0.5[0.9] mmHg) (p = 0.0029 and p = 0.0004, respectively), after26 weeks [103]. Measurement of flow-mediated vasodilatation ofthe brachial artery in patients with T2DM has shown a signifi-cantly greater increase in flow-mediated vasodilatation with exe-natide versus glimepiride [104]. In mice, activation of GLP-1receptors expressed in cardiac atria has been shown to stimulateatrial natriuretic peptide production, a powerful vasodilator [105],indicating that GLP-1 RAs exert their anti-hypertensive effectsthrough a vasodilatory action.

GLP-1 infusion inhibits postprandial elevation of triglyceridesand free fatty acids in healthy individuals [106]. A single subcuta-neous injection of exenatide in patients with newly diagnosedT2DM was also associated with a marked reduction in postpran-dial triacylglycerol, as well as in apolipoprotein B48 [107].Whether these effects on triglycerides and free fatty acids are aresult of delayed gastric emptying or some other mechanism hasyet to be determined. Nevertheless, the data show thatGLP-1 receptor activation ameliorates postprandial lipidemia,which is likely to be beneficial for patients with T2DM.

Extrapancreatic actions Macrovascular Microvascular Co-morbidities

Cerebrovasculardisease

GLP-1: Prevent

Cardiovasculardisease

GLP-1: Prevent

RetinopathyGLP-1: Prevent

DementiaGLP-1: Improve

Fatty liverGLP-1: Improve

ObesityGLP-1: Improve

Bone fractureGLP-1: Prevent

NephropathyGLP-1: Prevent

NeuropathyGLP-1: Prevent

HypertensionGLP-1: Improve

DyslipidemiaGLP-1: Improve

InflammationGLP-1: Prevent

Peripheral arterydisease

GLP-1: Prevent

Intrapancreatic actions

Insulin secretionGLP-1: Stimulate

Glucagon secretionGLP-1: Suppress

β cell massGLP-1: Increase

Figure 1. Intra- and extrapancreatic function of glucagon-like peptide-1 and expected effects on diabetic complications andco-morbidities.GLP-1: Glucagon-like peptide-1.Adapted with permission from [90] � Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd (2013).

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GLP-1 RAs as add-on therapies in clinical useMeta-analyses comparing multiple different add-on therapies tometformin for treatment of T2DM have reported that treat-ment with add-on GLP-1 RAs was as effective as basal orbiphasic insulin in terms of glycemic control [54] and resultedin a greater decrease in HbA1c compared with adjunctive SU,glinides, thiazolidinediones, a-glucosidase inhibitors andDPP-4 inhibitors [48,54]. In a meta-analysis comparing metfor-min in combination with either DPP-4 inhibitors orGLP-1 RAs, both were found to significantly reduce HbA1c,but long-term concomitant treatment with metformin andlong-acting GLP-1 RAs (liraglutide or exenatide once weekly)were associated with significantly greater reductions in FPGthan add-on treatment with short-acting exenatide (b.i.d.) orDPP-4 inhibitors [48]. The addition of short-acting agents tobasal insulin has been shown to be effective in achievingHbA1c targets in patients with T2DM insufficiently controlledwith basal insulin alone [91,108–111]. In particular, the additionof short-acting GLP-1 RAs to basal insulin is a favorableoption for treatment intensification in patients with T2DMdue to complementary effects on PPG and FPG, respectively,and can result in improved overall glycemic control versus basalinsulin alone [112–114]. The efficacy of long-acting GLP-1 RAsto basal insulin still needs to be compared with that of short-acting GLP-1 RAs in clinical trials in the future.

Some T2DM therapy combinations are associated withweight increase. While add-on treatment with DPP-4 inhibitorsis reported to be weight-neutral, [48,53,54,115], SU, glinides, thiazo-lidinediones, basal insulin and biphasic insulin add-on therapiesare associated with weight increase. By contrast, botha-glucosidase inhibitors [53,54] and GLP-1 RAs as add-on thera-pies have been associated with weight decrease [48,53,54,115].The addition of GLP-1 RAs to basal insulin is associated withsignificant weight reduction compared with placebo plus basalinsulin [114,116], which may be of particular clinical importanceand relevance to patients.

A final important consideration for add-on therapy regimensis the risk of hypoglycemia. Neither DPP-4 inhibitors norGLP-1 RAs in combination with metformin were associatedwith an increase in the risk of hypoglycemia [54,117]. Additionof GLP-1 RAs to basal insulin was not associated withincreased risk of hypoglycemia compared with basal insulinalone [114,116].

ConclusionIncretin-based therapy, specifically GLP-1 RAs, represent avaluable addition to treatment options for T2DM. A variety ofGLP-1 RAs are available which, due to differing mechanismsof action, provide different clinical profiles. Long-actingGLP-1 RAs help patients reach glycemic targets through FPGand PPG control as a result of insulinotropic effects, whereasshort-acting GLP-1 RAs confer overall glycemic controlthrough pronounced effects on PPG, mainly as a result ofdelayed gastric emptying. Safety and tolerability profiles alsodiffer somewhat between agents, although gastrointestinal

events remain the most common type of AE with this class ofdrug. Beyond the glycemic control actions of GLP-1 RAs, thesedrugs are also associated with multiple physiological effects,with potential implications for improvements in diabetes-related microvascular and macrovascular complications, as wellas diabetes-related comorbidities. GLP-1 RAs are associatedwith reduced weight increase or even weight decrease. Finally,GLP-1 RAs represent an attractive option as add-on therapyfor patients who may not have adequate glycemic control withtheir existing treatment regimen. In particular, the addition ofshort-acting GLP-1 RAs to basal insulin represents a clinicallyuseful treatment option for patients with inadequate PPG con-trol despite well-controlled FPG.

In summary, GLP-1 RAs represent an effective and well-tolerated treatment option for many different types of patientswith T2DM.

Expert commentaryIt has been thought that GLP-1 RAs improve glycemia by bothameliorating impaired secretion of insulin and glucagon, andby delaying gastric emptying. Accumulating evidence showsthat the primary mode of action is different among differentGLP-1 RAs; long-acting GLP-1 RAs acting preferentially viapancreatic b-cells, while short-acting GLP-1 RAs do so mainlyvia delayed gastric emptying. Such differences are reflected bydifferential effects of long- and short-acting GLP-1 RAs onfasting and postprandial glucose levels, although effects arecomparable on body weight changes. Although it remains to betested in clinical trials, our current knowledge strongly suggeststhat long-acting GLP-1 RAs ameliorate glycemia more effi-ciently in patients with sufficient b-cell function, while short-acting GLP-1 RAs, possibly combined with basal insulin, couldimprove postprandial glucose excursions even in patients withlow b-cell function.

Five-year viewWhile long-term efficacy of GLP-1 RAs in glucose loweringand body weight reduction have been documented over theyears, beneficial effects on diabetes complications (e.g., micro-and macroangiopathies) need to be assessed through large-scalerandomized clinical trials, along with any potential AE risks (e.g., pancreatic diseases). Meanwhile, development of once-weekly or once-monthly GLP-1 RAs, as well as oral or nasalGLP-1 RAs, should be continued to improve the quality of lifeof patients with T2DM.

Financial & competing interests disclosure

D Yabe has taken part in advisory panels for Sanofi, Novo Nordisk, Inc.

and Novartis Pharma AG, and has taken part in speaker’ s bureaux for

Sanofi, Novo Nordisk Inc., Merck Sharp & Dohme Limited, Takeda

Pharmaceuticals USA, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.,

Eli Lilly and Company and Bristol-Myers Squibb Company. Y Seino

has acted as medical advisor for Eli Lilly, Sanoi, Novo Nordisk,

GlaxoSmithKline, Taisho Pharmaceuticals, Astellas Pharmaceuticals,

Becton, Dickinson & Company, Boerhringer Ingelheim, Johnson &

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Johnson, Takeda Pharmaceuticals and Otsuka Pharmaceuticals. The

authors have no other relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript apart

from those disclosed. Writing and editorial assistance was provided by

A Shepherd of Caudex Medical, funded by Sanofi.

Key issues

• Patients with type 2 diabetes mellitus (T2DM) demonstrate an impaired capability to regulate their incretin effect, and correction of this

dysfunction with exogenous glucagon-like peptide-1, GLP-1 receptor agonists (GLP-1 RAs), has become established as an important

treatment strategy for T2DM, with an efficacy and safety profile distinct from that of other anti-diabetic agents.

• The different GLP-1 RAs approved for use in patients with poorly controlled T2DM can be divided into two broad categories according

to their relative half-lives as short- and long-acting GLP-1 RAs, which exert their glucose-lowering effects through different dominant

mechanistic actions: delayed gastric emptying and enhanced insulin secretion.

• Short-acting GLP-1 RAs have limited effects on insulin and glucagon secretion, but have a delaying effect on gastric emptying, which

results in pronounced reductions in postprandial plasma glucose (PPG) levels by reducing the rate of glucose absorption from the

small intestine.

• Long-acting GLP-1 RAs have a limited effect on gastric emptying, but provide reductions in fasting plasma glucose (FPG) and PPG – the

latter less robustly than short-acting GLP-1RAs – through amelioration of insulin and glucagon secretion.

• The clinical implication of these mechanistic differences is that short-acting GLP-RAs are better suited to improve control of PPG

excursions, even in patients with limited residual b-cell function, while long-acting GLP-1 RAs are more appropriate for patients needing

control of FPG, in addition to PPG, but require a certain amount of residual b-cell function.• Compared with thiazolidinediones, sulfonylureas and glinides, GLP-1 RAs are associated with a relatively low risk of hypoglycemia, as

GLP-1-induced stimulation of insulin is glucose-dependent and is negligible under conditions of hypoglycemia, although caution is

advised if GLP-1 RAs are used in combination with sulfonylureas, as they may enhance b-cell sensitivity to this agent.

• Both short- and long-acting GLP-1 RAs have a clinically demonstrable benefit in terms of weight, which can be helpful in ameliorating

early T2DM and the effects of weight gain from other anti-diabetic therapies, such as insulin.

• GLP-1 RAs also have well-documented benefits against risk factors for cardiovascular disease, including hypertension and dyslipidemia.

• The most common class of adverse events experienced by patients receiving GLP-1 RAs are gastrointestinal adverse events, and

although concerns have been raised about a potential increased risk of acute pancreatitis, thyroid C-cell hyperplasia and tumors, no

increased risk has been identified.

• GLP-1 RAs represent an attractive option as add-on therapy for patients who may not have adequate glycemic control with their

existing treatment regimen, and in particular, the addition of GLP-1 RAs to basal insulin represents a clinically useful treatment option

for patients with inadequate PPG control and body weight gain despite well-controlled FPG.

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