Efficacy and Safety of Incretin-Based Therapies in Patients ......Patients with Type 2 Diabetes Mellitus Matthew P. Gilbert, DO, MPH, Richard E. Pratley, MD Diabetes and Metabolism

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fficacy and Safety of Incretin-Based Therapies inatients with Type 2 Diabetes Mellitus

atthew P. Gilbert, DO, MPH, Richard E. Pratley, MD

iabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine, Burlington, Vermont, USA

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ABSTRACT

his article aims to provide an overview of efficacy and safety data on glucagon-like peptide–1 (GLP-1)eceptor agonists and dipeptidyl peptidase–4 (DPP-4) inhibitors in the treatment of type 2 diabetesellitus. Our goal is to differentiate the clinical profiles of GLP-1 receptor agonists and DPP-4 inhibitors,

s well as the individual agents within each class. Additionally, we examine the utility of GLP-1 receptorgonists and DPP-4 inhibitors as these agents may be applied at different stages of type 2 diabetes therapynd discuss recently published clinical findings and their implications for treatment.

2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, S11–S24

KEYWORDS: DPP-4; exenatide-LAR; GLP-1 receptor agonist; liraglutide; sitagliptin

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he current pandemic of diabetes mellitus and projectionsor future growth in the prevalence of the disease threaten toreate a global health crisis. Findings from clinical trialsrovide clear and compelling evidence that intensive treat-ent of type 2 diabetes can significantly reduce the risk of

isease-associated cardiovascular and renal complications.1

afe and effective treatments for diabetes may mitigate,hough certainly not dispel, the looming public health crisis.lthough many therapies for type 2 diabetes exist, including

nsulin secretagogues and insulin sensitizers, success iniabetes is fleeting. Treatment is characterized by progres-ive diminution of effect, leading almost inevitably to treat-ent failure. As monotherapies fail, additional agents are

dded. Glycemic control is stabilized, but sometimes at theost of side effects such as weight gain or hypoglycemia,hich themselves may undermine therapeutic effect. Even-

ually even combinations of oral agents fail, necessitatinghe introduction of insulin. Clearly there is a continuingeed to add to the armamentarium of safe and effectiventidiabetic remedies, with better risk-benefit ratios andreater patient acceptability.2

Statement of author disclosure: Please see the Author Disclosuresection at the end of this article.

Requests for reprints should be addressed to Richard E. Pratley, MD,iabetes and Metabolism Translational Medicine Unit, University of Ver-ont College of Medicine, Given C33189, Beaumont Avenue, Burlington,ermont 05405.

c: [email protected].

ront matter © 2009 Elsevier Inc. All rights reserved.ed.2009.03.013

Impairment of incretin activity plays an integral part inhe metabolic derangement underlying type 2 diabetes. Glu-agon-like peptide–1 (GLP-1) receptor agonists and dipep-idyl peptidase–4 (DPP-4) inhibitors represent the 2 classesf incretin therapies currently available. GLP-1 receptorgonists enhance incretin activity by providing pharmaco-ogic levels of human GLP-1 receptor stimulation, whereasPP-4 inhibitors exert their effects by slowing the degradationf endogenous GLP-1 and glucose-dependent insulinotropicolypeptide (GIP). Incretin-based therapies enhance endoge-ous insulin secretion without causing hypoglycemia or weightain. This review focuses on the efficacy and safety of incretinherapies, and the utility of their application at differenttages in the progression of diabetes. It must also be recog-ized that diabetes is quite commonly accompanied byultiple comorbid conditions; diabetes agents that would

enefit, or at least not worsen, common comorbidities (e.g.,besity, hypertension, dyslipidemia) are highly desirable.

Exenatide is a synthetic, 39–amino acid peptide form ofhe exendin-4 molecule first isolated from the salivary glandecretions of the Gila monster.3 It shares 53% homologyith mammalian GLP-1 but is resistant to enzymatic deg-

adation by DPP-4.4 It was the first approved therapeuticgent in the incretin class of medications, and acts byimicking the physiologic actions of native GLP-1. Ex-

natide is administered twice daily within 60 minutes oforning and evening meals. Differences in the N-terminal

mino acid sequence of exenatide from that of native GLP-1

onfer resistance to the effects of DPP-4, substantially in-

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S12 The American Journal of Medicine, Vol 122, No 6A, June 2009

reasing its half-life in the circulation (approximately 2.4ours compared with 1 to 2 minutes for native GLP-1). Theuration of effect of exenatide is therefore substantiallyonger than that of native GLP-1, although twice-daily ad-inistration is required.5,6 Exenatide is predominantly elim-

nated by glomerular filtration with subsequent proteolyticegradation; hence it is contraindicated in patients withnd-stage renal disease or severe renal impairment. Ex-natide is not recommended in patients with severe gastro-ntestinal disease. In a small proportion of patients, forma-ion of antibodies at high titers could result in the failure ofxenatide to achieve adequate improvement in glycemicontrol.3 Exenatide is available in the United States; it isndicated for adjunctive therapy to improve glycemic con-rol in patients with type 2 diabetes that is inadequatelyontrolled on metformin, a sulfonylurea, a thiazolidinedi-ne, a combination of metformin and a sulfonylurea, or aombination of metformin and a thiazolidinedione.

Liraglutide is a once-daily human GLP-1 analog with7% homology with human GLP. Modifications to the mol-cule include 1 amino acid substitution and the attachmentf a fatty acid chain with a glutamoyl spacer to a lysineesidue.7 Those adjustments slow the absorption and retardhe degradation of liraglutide by the proteolytic enzymePP-4, prolonging the half-life to 13 hours.8 The route of

limination of liraglutide appears to be by generalized pro-eolysis, with no single organ system having demonstratedajor involvement; hence no dosage adjustment appears to

e necessary in patients with severe renal impairment orepatic insufficiency.9-11 Liraglutide is currently under re-iew by the US Food and Drug Administration (FDA).

DPP-4 inhibitors are oral agents that prolong the bioac-ivity of native GLP-1 (and GIP) by inhibiting the proteo-ytic activity of the DPP-4 enzyme. DPP-4 inhibitors haveeen shown to elevate active GLP-1 levels 2- to 3-fold byroviding up to 90% inhibition of plasma DPP-4 activityver 24 hours in vivo.12,13 Sitagliptin is the only DPP-4nhibitor currently available in the United States. A combi-ation tablet containing sitagliptin and metformin is alsovailable. Approximately 79% of the sitagliptin dose isxcreted unchanged in the urine; metabolism is a minor path-ay of elimination. Dosage adjustment is recommended inatients with moderate or severe renal impairment, and inatients with end-stage renal disease requiring dialysis. Post-arketing reports of serious hypersensitivity reactions, includ-

ng anaphylaxis, angioedema, and Stevens-Johnson syn-rome have been noted in patients on sitagliptin.14

ildagliptin, another DPP-4 inhibitor, has been approvedor use in the European Union and other countries. Vilda-liptin is primarily metabolized by liver hydrolysis and isontraindicated in patients with severe hepatic dysfunc-ion.15 Vildagliptin has been associated with changes iniver enzyme levels and, in animal models, with skin lesionsncluding blistering and ulceration.16 Approval in thenited States is pending additional trials in patients with

enal dysfunction.17 e

FFICACY OF INCRETIN-BASED THERAPIES INATIENTS FAILING DIET OR EXERCISE

randomized, double-blind, 24-week monotherapy trialompared twice-daily exenatide 5 �g, exenatide 10 �g, andlacebo in 232 patients with type 2 diabetes inadequatelyontrolled by diet and exercise alone. Compared with pla-ebo, exenatide 5 �g and 10 �g demonstrated significantlyreater mean reductions in hemoglobin A1c (HbA1c) (P �.003 and P �0.001 for the 5-�g and 10-�g doses, respec-ively), fasting plasma glucose (FPG) (P � 0.029 and P �.016), and body weight (Table 1 and Figure 1).5,18-23 Theroportion of patients achieving HbA1c �7% at study end-oint was 48% in the 5-�g group (P � 0.024) and 46% inhe 10-�g group (P � 0.036) versus 29% in the placeboroup. The incidence of nausea was significantly greater inhe combined exenatide groups (8%) relative to placebo0%; P � 0.010), whereas hypoglycemia rates were slightly,lthough not significantly, higher in patients receiving ex-natide 5 �g (5%) or exenatide 10 �g (4%) relative tolacebo (1%).18

A long-acting–release (LAR) formulation of exenatideonce weekly administration) is currently in phase 3 clinicalevelopment. In a phase 2 study, exenatide-LAR (0.8 or 2.0g) was administered for 15 weeks to patients with type 2

iabetes whose disease was suboptimally controlled withetformin and or/diet and exercise (N � 45). Mean HbA1c

evels were reduced significantly with both exenatide-LARoses compared with placebo (P �0.0001) (Figure 1). Onlyhe 2.0-mg dose was associated with a significant meanody weight reduction versus placebo (P �0.05) (Table 1).ypoglycemia was reported in 25% of patients in the.8-mg dose group (n � 16) and in no patients in the 2.0-mgose group (n � 15). Nausea was reported in 19% and 27%f the patients who received exenatide-LAR at the 0.8 and.0 mg doses, respectively, and in 15% of patients whoeceived placebo. Injection-site bruising was observed in3% and 7% of patients in the 0.8 and 2.0 mg groups,espectively. Exenatide LAR injections were administeredy study site staff.5

In a 14-week phase 2 monotherapy trial, HbA1c reduc-ions observed with liraglutide 1.9 mg and 1.25 mg onceaily were –1.45% and –1.40% versus �0.29 for placeboP �0.0001). The percentage of patients reaching the targetbA1c goal of �7% was 46% with liraglutide 1.9 mg and8% with liraglutide 1.25 mg versus 5% for placebo. Pa-ients on the highest dose of liraglutide realized significanteductions in systolic blood pressure compared with patientsiven placebo, –7.9 mm Hg (P � 0.0023).24 Garber andolleagues19 randomized 746 patients with type 2 diabeteso 52 weeks of double-blind monotherapy with liraglutide.2 mg/day, liraglutide 1.8 mg/day, or glimepiride 8 mg/ay. Patients had previously experienced inadequate glyce-ic control while treated with diet and exercise alone or up

o a half-maximal dose of a single oral agent. Each lira-lutide dose reduced mean HbA1c to a significantly greater

xtent than glimepiride (P � 0.0014 for 1.2 mg and

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�0.0001 for 1.8 mg) (Figure 1). Reductions in FPG andody weight were significantly greater with either dose ofiraglutide versus glimepiride (Table 1). The subgroup pre-iously treated with diet and exercise alone (thus a truerug-naive population) experienced a –1.6% decrease inbA1c with liraglutide 1.8 mg; that reduction was main-

ained for the full 52 weeks of the study. In the overall studyopulation, a significantly greater proportion of patientsreated with liraglutide 1.2 mg (43%) and 1.8 mg (51%)eached target HbA1c �7% compared with those treatedith glimepiride (28%; P �0.001 for both liraglutide dosesersus glimepiride). Nausea was the most frequently expe-ienced adverse event with liraglutide (27.5% incidence for.2 mg and 29.3% for 1.8 mg versus 8.5% for glimepiride),ut was generally transient. Minor hypoglycemia occurredn 12% of patients treated with liraglutide 1.2 mg, 8% ofhose treated with liraglutide 1.8 mg, and 24% of thosereated with glimepiride. There was no incidence of majorypoglycemia.19

The efficacy and safety of DPP-4 inhibitors as mono-herapy have been evaluated in a number of clinical trials. Inhese studies, DPP-4 inhibitors have been well tolerated andave demonstrated weight neutrality rather than weight loss,

Table 1 Fasting Glucose and Weight Reduction of Incretin The

gentBaseline FastingSerum Glucose (mg/dL)*

xenatide18

5 �g bid 16610 �g bid 154Placebo 160

xenatide-LAR5

0.8 mg once weekly 1862.0 mg once weekly 168Placebo 184

iraglutide19,20

1.2 mg qd 1681.8 mg qd 171

itagliptin21

100 mg qd 171200 mg qd 175Placebo 177

itagliptin22


ildagliptin23

100 mg qd 189

LAR � long-acting release.*1 mg/dL � 0.5551 mmol/L.†Significance vs. baseline.‡Significance vs. comparator.�Significance vs. placebo.§Significance with least-squares mean difference vs. placebo.Adapted from Diabetes Care,5,21 Clin Ther,18 Lancet,19 European Assoc

hich has been seen with the GLP-1 receptor agonists. d

Aschner and associates21 conducted a 24-week study ofitagliptin 100 mg or 200 mg monotherapy versus placeboN � 741) in patients with type 2 diabetes not on an oralntidiabetes agent. HbA1c and FPG were reduced signifi-antly versus placebo by both sitagliptin doses (P �0.001or both endpoints) (Figure 1 and Table 1). Sitagliptin alsoncreased the proportion of patients who achieved a goalbA1c �7% (41% for 100 mg and 45% for 200 mg versus7% with placebo, P �0.001). Similarly low rates of hy-oglycemia were observed in all treatment groups. Thereas no change in body weight from baseline with sitaglip-

in.21 Comparable glycemic results were reported in an8-week trial of sitagliptin 100 mg or 200 mg monotherapyersus placebo (N � 521). Patients were either drug-naiver had discontinued oral antidiabetic drugs before a run-ineriod of treatment with diet and exercise alone. The safetyata showed a similarly low incidence of hypoglycemiacross both sitagliptin groups and the placebo group. Thereas no significant reduction in body weight in either sita-liptin treatment group (Figure 1 and Table 1).22

In a 52-week study comparing vildagliptin 50 mg twiceaily and metformin 1,000 mg twice daily in drug-naiveatients, Schweizer and coworkers23 reported that both

ics as Monotherapy

ing Serume (mg/dL)*

BaselineWeight (kg) � Weight (kg)

(P � 0.029)† 85 �2.8 (P � 0.004)†

(P � 0.016)† 86 �3.1 (P � 0.001)†

86 �1.4

(P �0.001)† 107 Negligible(P �0.001)† 110 �3.8 (P �0.05)†

101 Negligible

(P � 0.027)‡ 92.5 �2.05 (P �0.0001)‡

(P � 0.027)‡ 92.8 �2.45 (P �0.0001)‡

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or the Study of Diabetes,20 Diabetologia,22 and Diabet Med.23

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P �0.001 for both endpoints) (Figure 1 and Table 1).owever, statistical noninferiority of vildagliptin 50 mg

wice daily to metformin 1,000 mg twice daily was notstablished. A total of 35% of patients treated with vilda-liptin and 45% of patients treated with metformin reachedoal HbA1c �7%. Patients receiving vildagliptin experi-nced a modest weight gain; there was a modest reductionn body weight among patients given metformin (–1.9 kg)Table 1). The proportion of patients who experienced �1astrointestinal adverse event was twice as high with met-ormin (44%) compared with vildagliptin (22%).23

FFICACY OF INCRETIN-BASED THERAPIESHEN COMBINED WITH METFORMIN

andomized, double-blind, phase 3 clinical trials have dem-nstrated the efficacy and safety of GLP-1 receptor agonistsn patients who fail to meet treatment goals when treatedith metformin alone. In a 30-week trial, treatment with

xenatide 10 �g twice daily, dosed 15 minutes before break-ast and dinner, resulted in significant reductions in HbA1c

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reviously treated with oral agent monotherapy (e.g.,1.30% for the liraglutide 1.8 mg monotherapy group ver-us 0.71% for the liraglutide 1.8 mg combination group).he proportion of patients in the overall study populationho achieved HbA1c �7% was 28% and 42% for lira-lutide 0.6 and 1.8 mg, respectively, 11% for placebo, and6% for glimepiride; all liraglutide doses were significantlyuperior to placebo. Reductions in FPG at all liraglutideoses were significantly superior to placebo (P �0.0001)nd comparable to glimepiride; reduction in body weightas significantly greater with each dose of liraglutide com-ared with glimepiride (P �0.0001), and the 1.2-mg and.8-mg doses were significantly better compared with pla-ebo (P �0.01) (Table 2). Gastrointestinal complaints werehe most frequent adverse effects, with nausea occurring in1% to 19% of patients treated with liraglutide, althoughausea incidence declined to �4% of patients per weekfter 16 weeks. No patient experienced major hypoglyce-ia, and the incidence of minor hypoglycemic events was

.8% and 3.3% for liraglutide 0.6 and 1.8 mg, respectively,

.5% for placebo, and 16.9% for glimepiride.26

In a 24-week study, Charbonnel and colleagues12 eval-ated the addition of sitagliptin 100 mg daily or placebo tohe treatment of 701 patients with type 2 diabetes failingetformin (�1,500 mg/day) monotherapy. Sitagliptin sig-

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he exenatide 10 �g twice-daily group (Table 3).29-32 A sig-ificantly larger percentage of patients reached HbA1c goal of7% in the exenatide groups than in the sulfonylurea plus

lacebo group (27% to 34% vs. 8%). Patients in the exenatide0-�g bid, but not the 5-�g bid group, experienced signifi-



xenatide25

5 �g bid 17610 �g bid 168Placebo 170

iraglutide26

0.6 mg qd 1841.2 mg qd 1781.8 mg qd 182Placebo 180

itagliptin12

100 mg qd (�Met �1,500 mg qd) 169Placebo 173

ildagliptin28


Met � metformin.*1 mg/dL � 0.5551 mmol/L.†Significance vs. placebo.‡Significance vs. comparator.§Significance vs. baseline.Adapted from Diabetes Care.12,25-28



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iraglutide29

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itagliptin31

100 mg qd 181 �Placebo 182 �1

ildagliptin32

50 mg qd 18950 mg bid 189Placebo 186

*1 mg/dL � 0.5551 mmol/L.†P values represent significance vs. placebo.‡P values represent significance vs. comparator.

29 30
Adapted from Diabet Med, Diabetes Care, and Diabetes Obes Metab.
antly greater weight loss from baseline compared with pa-ients in the sulfonylurea plus placebo group (P �0.05) (Table). Common adverse events with exenatide 5 to 10 �g bidncluded nausea (39% to 51%), vomiting (10% to 13%), andild-to-moderate hypoglycemia (14% to 36%).30

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Fasting Serumlucose (mg/dL)*


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10 (P � 0.0001)† 101 �2.8 (P �0.001)†

14 100 �0.3

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31 (P �0.0001)† — �2.8 (P �0.0001)‡

7 — �1.5

16 (P �0.0001)† — �0.6 to �0.7 (P �0.05)§

9 — �0.6 to �0.7

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A 26-week, double-blind study compared the combina-ion of liraglutide (0.6 mg/day, 1.2 mg/day, and 1.8 mg/ay), rosiglitazone (4 mg/day), or placebo with glimepirideherapy in 1,041 patients with type 2 diabetes (Table 3). Alliraglutide doses achieved HbA1c reductions that were sig-ificantly superior to placebo (P �0.0001) (Figure 3); re-uctions observed with liraglutide 1.2 and 1.8 mg wereignificantly superior to rosiglitazone (P �0.0001). Theroportion (42%) of patients in the liraglutide 1.8-mg groupho achieved HbA1c �7% significantly (P �0.0003) ex-

eeded the proportions of rosiglitazone (22%) and placebo8%) patients who achieved this goal. FPG reductions withll doses of liraglutide were significantly superior to placeboP �0.0001) (Table 3), and liraglutide 1.2 and 1.8 mg dosesere significantly superior to rosiglitazone (P �0.006).eight changes in the liraglutide groups were modest, pos-

ibly reflecting background sulfonylurea therapy or the rel-tively low baseline weight of the subjects. Adverse effectsssociated with liraglutide tended to be gastrointestinal;

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ies. In the subgroup of patients whose diabetes remainedncontrolled on both glimepiride and metformin, the addi-ion of sitagliptin resulted in an incremental HbA1c reduc-ion of –0.6% from baseline.31

Garber and colleagues32 investigated the efficacy andolerability of vildagliptin versus placebo in patients withype 2 diabetes that was controlled suboptimally with aulfonylurea drug alone. This randomized, double-blind,ulticenter study (N � 515) was conducted over a 24-week

eriod using vildagliptin 50 mg, given once or twice daily,ersus placebo. The adjusted mean change in HbA1cwasignificantly superior with both vildagliptin doses comparedith placebo (P �0.001) (Figure 3); however, no significantifferences in the adjusted mean change in FPG were ob-erved (Table 3). Significantly greater proportions of pa-ients receiving vildagliptin 50 mg daily (21.2%) and 50 mgwice daily (24.8%) achieved HbA1c �7% compared withlacebo (12%). Body weight increased significantly in pa-ients receiving vildagliptin 50 mg twice daily versus pla-ebo (P �0.001); change in weight was similar for theildagliptin 50-mg daily group and placebo (Table 3). Theverall incidence of adverse events was similar in all treat-ent groups. No dose-related adverse effects were observed

n the vildagliptin-treated patients.32

FFICACY OF INCRETIN-BASED THERAPIES INATIENTS WHEN COMBINED WITH AHIAZOLIDINEDIONEinman and colleagues33 assessed the utility of adding ex-natide to the regimen of patients with type 2 diabetes (N �33) poorly controlled on a thiazolidinedione (with or with-ut metformin) in a placebo run-in, randomized, double-lind, placebo-controlled trial. Patients were randomized towice-daily administration of exenatide 10 �g or placebo.he dosages of thiazolidinedione (rosiglitazone �4 mg/dayr pioglitazone �30 mg/day) and metformin were constanthroughout the study. At 16 weeks, the addition of exenatideo treatment regimens resulted in significant reductions inbA1c, FPG, and body weight compared with placebo

P �0.001 for all endpoints) (Figure 4 and Table 4).33-36 Inhe exenatide-treated cohort, 62% achieved HbA1c �7%,ompared with 16% of patients in the placebo add-on groupP �0.001). The most frequent adverse event was nausea,ccurring in 39.7% of patients treated with exenatide and5.2% of patients in the placebo group. Vomiting occurredore frequently in the treatment group (13.2%) than in

atients who received the placebo injections (0.9%). Thencidence of hypoglycemia was low and similar across bothroups of patients. No cases of severe hypoglycemia wereeported.33

The addition of sitagliptin 100 mg daily to the treatmentf patients with type 2 diabetes failing monotherapy withioglitazone (30 or 45 mg/day) was evaluated in a 24-week,lacebo-controlled trial (N � 353) (Table 4 and Figure 4).itagliptin significantly reduced mean HbA1c, reduced FPG,

nd increased the number of patients who achieved the e

bA1c goal of �7% (45% vs. 23%, P �0.001 for allndpoints) (Figure 4 and Table 4). Incidence of hypoglyce-ia was low and not significantly different across compar-

tor groups. There was no significant change in body weightompared with placebo in patients treated with sitagliptin.34

The combinations of vildagliptin 50 mg–pioglitazone 15g and vildagliptin 100 mg–pioglitazone 30 mg, each ad-inistered once daily, were evaluated in a 24-week, ran-

omized, placebo-controlled trial involving 607 drug-naiveatients with type 2 diabetes. Initial combination therapyas compared with monotherapy with either agent. Both

ombinations were significantly more efficacious at producingbA1c reductions from baseline than pioglitazone mono-

herapy; the higher-dose combination was significantly morefficacious than vildagliptin monotherapy. A significantlyigher proportion of patients treated with vildagliptin 100g–pioglitazone 30 mg (65%) achieved target HbA1c �7%

ompared with those treated with pioglitazone (43%) mono-herapy. Vildagliptin added to pioglitazone produced nodditional weight gain beyond that observed with pioglita-one monotherapy (Table 4).35

Garber and associates36 administered vildagliptin 50 or00 mg daily for 24 weeks to 463 patients inadequatelyontrolled on pioglitazone (45 mg daily). Mean HbA1c val-es were significantly reduced in the vildagliptin plus pio-litazone groups compared with the placebo plus pioglita-one group (P � 0.001 and P �0.001, respectively) (Figure). Mean FPG values after the addition of vildagliptin wereot significantly different from those observed with contin-ation of pioglitazone monotherapy (Table 4). Significantlyore patients receiving vildagliptin 50 mg (29%) or 100 mg

36%) achieved HbA1c �7% compared with patients inhe placebo plus pioglitazone arm (15%) (P �0.001).Thereas also a significant weight gain associated with the ad-ition of vildagliptin 100 mg versus placebo (P � 0.003)Table 4).36

FFICACY OF INCRETIN-BASED THERAPIES INOMBINATION WITH TWO ORAL AGENTS

endall and colleagues37 evaluated the additive effect ofxenatide in a 30-week, double-blind, placebo-controlledtudy performed in 733 patients unable to achieve glycemicontrol with a combination of metformin and a sulfonyl-rea. Participants were randomized to exenatide 5 �g, ex-natide 10 �g, or placebo in addition to their oral agents. At0 weeks, mean adjusted HbA1c, FPG, and body weightere significantly reduced in both exenatide groups relative

o placebo (P �0.0001 for HbA1c and FPG; P �0.01 foreight) (Figure 5 and Table 5).37-41 Exenatide-treated pa-

ients were more likely to achieve a target HbA1c of �7%han were patients given placebo (34% with exenatide 10g and 27% with exenatide 5 �g versus 9% with placebo).ausea was the most common adverse event in the ex-

natide-treated patients. The incidence of mild-to-moderate

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ypoglycemia was 28% with exenatide 10 �g, 19% withxenatide 5 �g, and 13% with placebo.37

A 52-week, open-label, noninferiority trial describedbA1c reductions with exenatide 10 �g similar to those

Figure 4 Glycemic effect of incretin thHbA1c � hemoglobin A1c. *Not currentlyicance in the intent-to-treat sample; ‡sig(Adapted from Ann Intern Med,33 Clin Th



xenatide33

10 �g bid 165Placebo 159

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ildagliptin35

50 mg qd (�PG 45 mg qd) 186100 mg qd (�PG 45 mg qd) 180Placebo 182

PG � pioglitazone.*1 mg/dL � 0.5551 mmol/L.†Significance vs. placebo.‡Significance vs. baseline.Adapted from Ann Intern Med,33 Clin Ther,34 and Diabetes Obes Metab

bserved with biphasic insulin aspart 70/30 (Figure 5). Both t

xenatide- and premixed insulin–treated patients exhibitedignificant reductions in fasting serum blood glucose valuesrom baseline (P �0.001) (Table 5). On average, exenatide-reated patients experienced a decline in body weight, while

tics combined with a thiazolidinedione.ved for use in the United States; †signif-t vs. baseline; §significant vs. placebo.nd Diabetes Obes Metab.35,36)

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29 (P �0.001)† 97.53 �1.75 (P �0.001)‡

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esulting in a statistically significant between-group differ-nce at the 52-week endpoint (P �0.001) (Table 5). Thencidence of gastrointestinal side effects was higher in thexenatide group, with nausea (33%) and vomiting (15%) theost common reported adverse events. The rate of hypo-

lycemia was similar in both treatment groups, and noevere hypoglycemic events were reported.38

Heine and coworkers39 conducted a 26-week, multicenter,andomized trial comparing the addition of exenatide or insulinlargine in 551 patients with type 2 diabetes that was con-rolled suboptimally with metformin and a sulfonylurea drug.t study end, the adjusted mean value of HbA1c was similarly

educed from baseline in both treatment groups. Proportions ofatients achieving HbA1c�7% were also similar (46% forxenatide and 48% for insulin glargine). Reductions in FPGevels were significantly greater in patients treated with insulinlargine (P �0.001). Exenatide was associated with weighteduction, insulin glargine with weight gain; the between-roup weight change was statistically significant (P �0.0001)Table 5). The most common adverse events in the exenatide-

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y liraglutide versus both metformin plus sulfonylurea (P �.0001) or versus insulin glargine in combination with met-ormin plus sulfonylurea (P �0.0001) (Table 5). Gastroin-estinal symptoms were the most frequent adverse events inatients treated with liraglutide; 14% of subjects in thisroup reported nausea. The incidence of nausea in the lira-lutide group was initially 5% to 7% of subjects. Fiveiraglutide-treated patients (2.2%) and no patients in thether groups experienced major hypoglycemic episodes.he incidence of minor hypoglycemia was similar with

iraglutide (27%), glargine (29%), and placebo (17%).40

A 26-week double-blind study evaluated liraglutide inombination with metformin and a thiazolidinedione. Sub-ects (N � 533) were randomized to liraglutide 1.2 mg/day,iraglutide 1.8 mg/day, or placebo in addition to metforminlus rosiglitazone. Liraglutide 1.2 mg and 1.8 mg signifi-antly reduced HbA1c, FPG, and weight compared withlacebo (P �0.0001 for all endpoints) (Figure 5 and Table). The proportion of patients reaching HbA1c �7% wasignificantly greater with 1.2 mg (58%) and 1.8 mg (54%)ompared with placebo (28%) (P �0.0001 for both doses ofiraglutide). Nausea occurred in 29.4% of patients treatedith 1.2 mg and 39.9% of patients treated with liraglutide.8 mg, compared with 8.6% of placebo-treated patients.ausea incidence in the liraglutide groups decreased to the

ame level as placebo by week 16 of the study. No majorypoglycemic episodes were reported. The incidence ofinor hypoglycemia with liraglutide 1.8 mg was signifi-

antly higher than the incidence with placebo, but rates in



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iraglutide41

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*1 mg/dL � 0.5551 mmol/L.†Significance in intent-to-treat population.‡Significance vs. placebo.§Significance vs. baseline.�Significance vs. comparator.Adapted from Diabetes Care,37,41 Diabetologia,38 and Ann Intern Med.

ll groups were low: liraglutide 1.2 mg (0.38 events per w

ear), liraglutide 1.8 mg (0.64 events per year), and placebo0.17 events per year).41

FFICACY OF INCRETIN-BASED THERAPIES INATIENTS TREATED WITH INSULINonseca and colleagues43 assessed the efficacy and tolera-ility of vildagliptin added to insulin therapy in patientsith inadequately controlled type 2 diabetes. In the 24-eek, double-blind, randomized, placebo-controlled trial,atients received vildagliptin 50 mg bid (n � 144) or pla-ebo (n � 152) in addition to insulin. The mean insulin dosen the combined cohort was 82 U/day. In patients receivingildagliptin, the reduction in HbA1c from baseline was sig-ificantly greater than with placebo (P � 0.010). Changes inPG and body weight did not demonstrate statistically sig-ificant between-group differences. Rates of hypoglycemiand severe hypoglycemia were lower in the vildagliptinompared with placebo (P �0.001). The overall frequencyf adverse events was similar in both groups, as was theercentage of serious adverse events: vildagliptin (8.3%)nd placebo (9.2%).43

AFETY OF INCRETIN THERAPIEShe incidence of gastrointestinal side effects has been rel-tively high in studies assessing exenatide, particularly athe higher 10-�g dose. In the sulfonylurea add-on trial,ausea was reported in 51% of patients who received the 10g bid dosage, compared with only 7% of those who re-eived sulfonylurea alone.30 Nausea was more common

ics in Combination with 2 Oral Agents

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s. 23%) as well as when that dose was combined withetformin plus a sulfonylurea (48.5% vs. 20.6%).25,37 In

eneral, the incidence of nausea declined with longer dura-ion of treatment. In phase 3 trials of liraglutide, 1.8-mg/dayosage was associated with nausea rates of between 7% and0%, compared with rates of 2% to 9% in the placebo arms.he incidence of nausea typically declined over the first 4eeks of treatment.19,29,40,41,44

Both exenatide and exenatide-LAR appear to elicit anmmune response. Detectable antibodies to exenatide haveeveloped in a substantial number of clinical trial patientsapproximately 40% to 50%).25,30 Rate of antibody forma-ion appears to be higher with exenatide-LAR, occurring in4% of patients in a recent phase 3 trial,45 and in 67% in ahase 2 trial.4 High-titer (�1/625) antibody levels wereetected in 24% of patients to whom exenatide-LAR wasdministered.45 In the majority of patients, antibodies haveot been shown to influence glycemic response in the ref-renced studies. However, in the proportion of patients�6%) who developed high-titer antibodies, approximatelyalf (3%) showed evidence of attenuated glycemic re-ponse.3 In the exenatide-LAR phase 3 studies referencedbove, glycemic response appeared to be attenuated (HbA1ceduction of –1.4%) in the 24% of patients who developedigh-titer antibodies compared with the response (HbA1ceduction of –1.9%) in patients without antibodies.45 Lira-lutide’s nearly identical homology to native GLP-1 haseant that reports of antibodies in clinical trials have oc-

urred at a much lower rate (0% to 13%) than has beenbserved with exenatide.29,40,41,44

Cases of acute pancreatitis in patients taking exenatideave been reported to the FDA, which prompted a requestor a warning label instructing prescribers to be vigilant forigns and symptoms of pancreatitis.3 During clinical devel-pment, however, the incidence of acute pancreatitis inatients treated with exenatide (1.7 cases per 1,000 subject-ears) was lower than the incidence observed in comparatorroups treated with placebo (3.0 cases per 1,000 subject-ears) or insulin (2.0 cases per 1,000 subject years).46 Givenhat patients with type 2 diabetes have as much as a 3-foldncreased risk of pancreatitis compared with the generalopulation,47 it is not possible to determine at this timehether the reported cases are attributable to exenatide or toreexisting elevated risk.

DPP-4 inhibitors have proved to be generally safe andell tolerated in clinical trials. Sitagliptin is primarily excretedia renal elimination; thus the dosage must be adjusted inatients with moderate-to-severe renal insufficiency or end-tage renal disease. Hypoglycemia and gastrointestinal adversevents appear to be infrequent. A meta-analysis by Amori andolleagues48 reported that DPP-4 inhibitors may be associ-ted with a 1.2-fold increased risk of infection for nasophar-ngitis, a 1.5-fold increased risk for urinary tract infection,nd a 1.4-fold increased risk for frequency of headache.

In postmarketing studies of sitagliptin, severe skin reac-ions, including some cases of Stevens-Johnson syndrome,

ave been reported. As most trials with DPP-4 inhibitors are

f 30 weeks duration, longer follow-up is needed to estab-ish the long-term safety of these agents.

UMMARYoth GLP-1 receptor agonists and DPP-4 inhibitors providenique benefits with different modes of action that comple-ent and extend the present therapeutic armamentarium for

he treatment of type 2 diabetes. DPP-4 inhibitors are ef-ective, well-tolerated, weight-neutral oral agents. Becausef their ease of use for both patients and providers, DPP-4nhibitors will play an increasingly important role in thereatment of type 2 diabetes. While the efficacy of exenatides limited by its relatively short half-life and minor effectsn fasting glucose levels, longer-acting GLP-1 receptorgonists, such as liraglutide, exenatide-LAR, and other mol-cules in development have more robust effects on fastinglucose levels and appear to offer superior efficacy to ex-natide and most oral agents. In addition, an importantttribute of members of this class is their ability to promoteeight loss. Despite their proven benefits, GLP-1 receptor

gonists must be administered subcutaneously; therefore,ealthcare providers should be prepared to address anyotential patient barriers to injection.

CKNOWLEDGMENTe thank AdelphiEden for providing medical editorial

ervices.

UTHOR DISCLOSUREShe authors who contributed to this article have disclosed

he following industry relationships:

atthew P. Gilbert, DO, MPH, reports no relationships todisclose with any manufacturer of a product or devicediscussed in this supplement.

ichard E. Pratley, MD, is a member of the Speakers’Bureau for Merck & Co., Inc., Novartis PharmaceuticalsCorp., Novo Nordisk A/S, and Takeda PharmaceuticalsNorth America, Inc.; has worked as a consultant toGlaxoSmithKline, Hoffman-La Roche Inc., NovartisPharmaceuticals Corp., Novo Nordisk A/S, and TakedaPharmaceuticals North America, Inc.; serves on the ad-visory board of GlaxoSmithKline, Hoffman-La RocheInc., Novartis Pharmaceuticals Corp., Novo NordiskA/S, and Takeda Pharmaceuticals North America, Inc.;has received research/grants support from Eli Lilly andCompany, GlaxoSmithKline, Merck & Co., Inc., Novar-tis Pharmaceuticals Corp., sanofi-aventis, and TakedaPharmaceuticals North America, Inc.; has participatedin clinical trials for Eli Lilly and Company, Glaxo-SmithKline, Merck & Co., Inc., Novartis Pharmaceuti-cals Corp., sanofi-aventis, and Takeda PharmaceuticalsNorth America, Inc.; and owns stock in Novartis Phar-

maceuticals Corp.

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2. Davies M, Lavalle-González F, Storms F, Gomis R; AT.LANTUSStudy Group. Initiation of insulin glargine therapy in type 2 diabetessubjects suboptimally controlled on oral antidiabetic agents: resultsfrom the AT.LANTUS trial. Diabetes Obes Metab. 2008;10:387-399.

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Efficacy and Safety of Incretin-Based Therapies in Patients with Type 2 Diabetes MellitusEFFICACY OF INCRETIN-BASED THERAPIES IN PATIENTS FAILING DIET OR EXERCISEEFFICACY OF INCRETIN-BASED THERAPIES WHEN COMBINED WITH METFORMINEFFICACY OF INCRETIN-BASED THERAPIES WHEN COMBINED WITH A SULFONYLUREAEFFICACY OF INCRETIN-BASED THERAPIES IN PATIENTS WHEN COMBINED WITH A THIAZOLIDINEDIONEEFFICACY OF INCRETIN-BASED THERAPIES IN COMBINATION WITH TWO ORAL AGENTSEFFICACY OF INCRETIN-BASED THERAPIES IN PATIENTS TREATED WITH INSULINSAFETY OF INCRETIN THERAPIESSUMMARYAUTHOR DISCLOSURESACKNOWLEDGMENTReferences

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Efficacy and Safety of Incretin-Based Therapies in Patients ......Patients with Type 2 Diabetes Mellitus Matthew P. Gilbert, DO, MPH, Richard E. Pratley, MD Diabetes and Metabolism