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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
Trmaaa©
E-mail address
002-9343/$ -see foi:10.1016/j.amjm
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
tctoalDopngtsnmbo
tswramema
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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S13Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
�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
100 mg qd 180200 mg qd 184Placebo 184
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)‡
(P �0.001)§ 85.0 �0.2 (P �.01)�
(P �0.001)§ 83.7 �0.1 (P �.01)�
85.0 �1.1
(P �0.001)‡ — �0.6(P �0.01)‡ — �0.2
— �0.7
(P �0.001)† 91.4 �0.3 (P �0.17)†
or the Study of Diabetes,20 Diabetologia,22 and Diabet
Med.23
rapeut
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S14 The American Journal of Medicine, Vol 122, No 6A, June
2009
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
Ch
an
ge in
Hb
A1
c(%
)
+2.0
+1.5
+1.0
+0.5
0
-0.5
-1.0
-1.5
Baseline A1c %
-2
placeboexenatide¶(BID)
exenatide LA(once weekly
8.6 8.37.8 8.37.9
5 µg
10 µg
7.8
0.8 mg
2.0 mg
dosage
-0.7-0.9
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S15Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
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-
+2.0
+1.5
+1.0
+0.5
0
-0.5
-1.0
-1.5
Baseline A1c %
-2
placeboexenatide (BID) liraglutid
8.48.2 8.38.3
5 µg
10 µg
8.2
0.6 mg
1.2 mgdosage
-0.4
-0.8
8.4
+0.1
-1.0-0.7
-1.0
1.8mg
Ch
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Hb
A1
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significanceP
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S16 The American Journal of Medicine, Vol 122, No 6A, June
2009
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-
Table 2 Fasting Glucose and Weight Reduction of Incretin The
gentBaseline FastingSerum Glucose (mg/dL)*
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
50 mg qd 175100 mg qd 178Placebo 182
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
Table 3 Fasting Glucose and Weight Reduction of Incretin The
gentBaseline FastingSerum Glucose (mg/dL)*
� FGlu
xenatide30
5 �g bid 18010 �g bid 178 �Placebo 195
iraglutide29
0.6 mg qd 180 �1.2 mg qd 177 �1.8 mg qd 175 �Placebo 171 �
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
ics in Combination with Metformin
Fasting Serumlucose (mg/dL)*
BaselineWeight (kg) � Weight (kg)
7 (P �0.005)† 100 �1.6 (P �0.001)†
10 (P � 0.0001)† 101 �2.8 (P �0.001)†
14 100 �0.3
20 (P �0.0001)† — �1.8 (P �0.0001)‡
29 (P �0.0001)† — �2.6 (P �0.0001)‡
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
2 (P � 0.0003)† 92.5 �0.418 (P �0.001)† 95.3 �0.213 94.8
�1.0
ics in Combination with Sulfonylurea
Serumg/dL)*
BaselineWeight (kg) � Weight (kg)
95.0 �0.9�0.05)† 95.0 �1.6 (P �0.05)†
99.0 �0.6
�0.0001)† 82.6 �0.7�0.0001)† 80.0 �0.3�0.0001)† 83.0 �0.2 (P
�0.0001)‡
81.9 �0.1
�0.001)† 86.5 �0.8 (P �0.0001)†
85.9 �0.4
91.5 �0.1 (P � 0.409)†
87.3 �1.3 (P �0.0001)†
89.4 �0.4
rapeut
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S17Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
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;
Ch
an
ge in
Hb
A1
c(%
)
+2.0
+1.5
+1.0
+0.5
0
-0.5
-1.0
-1.5
Baseline A1c %
-2
placeboexenatide (BID)
8.48.68.5
5 µg
10 µg
8.7
dosage
-0.5
-0.9
+0.1
8.5
0.6 mg
1.m
-0.6-1.1
significance P
-
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S18 The American Journal of Medicine, Vol 122, No 6A, June
2009
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
-
he
Ho
esft
er, a
A
E
S
V
.
S19Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
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
Table 4 Fasting Glucose and Weight Reduction of Incretin The
gentBaseline FastingSerum Glucose (mg/dL)*
xenatide33
10 �g bid 165Placebo 159
itagliptin34
100 mg qd 168Placebo 165
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)
ics in Combination with Thiazolidinedione
Fasting Serumlucose (mg/dL)*
BaselineWeight (kg) � Weight (kg)
29 (P �0.001)† 97.53 �1.75 (P �0.001)‡
�1.8 96.75 �0.24
16.7 (P �0.001)‡ 90.9 �1.8�1 86.4 �1.5
14 — �1.5 (P � 0.849)†
20 — �2.7 (P � 0.003)†
�9 — �1.4
erapeuappro
nifican34
rapeut
�G
�
�
��
35,36
hose patients treated with premixed insulin gained weight,
-
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S20 The American Journal of Medicine, Vol 122, No 6A, June
2009
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-
+2.0
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exenatide (BID) + Met and SU
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S21Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
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
Table 5 Fasting Glucose and Weight Reduction of Incretin The
gentBaseline FastingSerum Glucose (mg/dL)*
� FaGluc
xenatide37
5 �g bid 182 �910 �g bid 178 �11Placebo 180 �14
xenatide38
10 �g bid 198 �32xenatide39
10 �g bid 182 �26iraglutide40
1.8 mg qd 164 �28Placebo 169 �9
iraglutide41
1.2 mg qd 178 �401.8 mg qd 182 �43Placebo 180 �7
*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
Serumg/dL)*
BaselineWeight (kg) � Weight (kg)
.0001)†‡ 97 �1.6 (P �0.01)‡
0.0001)†‡ 98 �1.6 (P �0.01)‡
99 �0.9
0.001)§ 85.5 �2.5 (P �0.001)�
87.5 �2.3 (P �0.0001)†�
0.0001)‡ 85.5 �1.8 (P �0.0001)‡
85.7 �0.4
0.0001)‡ 94.9 �1.0 (P �0.0001)‡
0.0001)‡ 95.3 �2.0 (P �0.0001)‡
98.5 �0.6
rapeut
stingose (m
(P�0(P �
(P �
(P �.6
(P �(P �
39,40
hen exenatide 10 �g bid was used with metformin (45%
-
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S22 The American Journal of Medicine, Vol 122, No 6A, June
2009
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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S23Gilbert and Pratley Efficacy and Safety of Incretin-Based
Therapies in Type 2 Diabetes
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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