Farmacologia Dibetului

Diabetes, Obesity and Metabolism 13: 99117, 2011.
2010 Blackwell Publishing Ltd
Pharmacological management of type 2 diabetes:

the potential of incretin-based therapies
B. Charbonnel & B. Cariou
Department of Endocrinology and Diabetes, University Hospital, Nantes, France
Management guidelines recommend metformin as the rst-line therapy for most patients with type 2 diabetes uncontrolled by diet and
exercise. Efcacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral
agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy
has been associated with gastrointestinal side effects (20% of treated patients in randomized studies) and is contraindicated in patients with
renal insufciency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight
gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain
and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efcacious add-on agent after initial-therapy
failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully
achieve glycaemic targets and potentially provide cardiovascular and -cell-function benets. This review will examine current approaches for
treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.
Keywords: diabetes complications, dipeptidyl peptidase-4 inhibitors, DPP-4 inhibitor, exenatide, GLP-1 analogue, glucagon-like peptide-1
receptor agonists, incretin-based therapies, incretin therapy, liraglutide, metformin, saxagliptin, sitagliptin, type 2 diabetes, type 2 diabetes
management, vildagliptin
Date submitted 30 April 2010; date of first decision 23 June 2010; date of final acceptance 17 September 2010
Introduction
Treatment Intensication in Type 2 Diabetes
Type 2 diabetes is a progressive disease, characterized by a

gradual deterioration in glycaemic control because of the continuing loss of -cell function [1]. Thus, combinations of
glucose-lowering drugs are often needed to maintain blood
glucose at target values: glycated hemoglobin (HbA1c) per
Diabetes Control and Complications Trial (DCCT) <7% or
per International Federation of Clinical Chemistry and Laboratory Medicine <53 mmol/mol [2]. The development and
commercialization of new classes of drugs for diabetes has
increased the treatment options and made the management
of hyperglycaemia more complex. The selection of glucoselowering treatments should take into account patient-specific
factors (e.g. age, duration of diabetes, body weight, waist circumference, associated cardiovascular risk factors), as well as
mechanistic effects of various drugs on the main target organs
involved in the pathogenesis of type 2 diabetes (e.g. liver, skeletal
muscle, adipose tissue, -cell, intestine, kidney). In this review,
we specifically focus on the place of the new incretin therapies,
glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl
peptidase (DPP)-4 inhibitors, in type 2 diabetes treatment.
Metformin: the First Choice at the First Step
Correspondence to: Prof. Bernard Charbonnel, Clinique dEndocrinologie, Maladies

Metaboliques et Nutrition, Hopital G & R Laennec, Boulevard Jacques Monod, 44093
Nantes Cedex 1, France.
E-mail: bernard.charbonnel@univ-nantes.fr
The choice of initial pharmacotherapy when lifestyle changes

alone do not get patients to HbA1c target is relatively simple.
Treatment guidelines [35] (Figure 1) agree in designating
metformin, a biguanide acting as an insulin-sensitizer on the
liver, as the preferred first therapy for most patients, barring
contraindications such as renal disease or chronic hypoxemic conditions that may lead to lactic acidosis. Metformin
is cost-effective, safe, with an extensive clinical experience
with this drug. In addition, metformin does not cause weight
gain and may even be associated with weight loss. In United
Kingdom Prospective Diabetes Study (UKPDS), intensive treatment with metformin in a relatively small group of overweight
patients with newly diagnosed type 2 diabetes reduced the rate
of macrovascular complications vs. conventional treatment.
A significant benefit vs. sulphonylureas or insulin was seen
for all causes of death [6]. Moreover, observational analyses
have also shown reduced rates of all-cause and cardiovascular mortality among patients with type 2 diabetes newly
treated with metformin monotherapy, relative to sulphonylurea monotherapy [7,8]. Recently, the use of metformin was
found to be significantly associated with a reduced mortality
rate in patients with established atherothrombosis who were
included in the Reduction of Atherothrombosis for Continued
Health registry [9]. Metformin use has also been reported to
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DIABETES, OBESITY AND METABOLISM
Tier 1: Well-validated core therapies
At
diagnosis:
Lifestyle + Metformin
+
Basal Insulin
Lifestyle
+
Metformin
+
Sulfonylurea*
STEP 1
STEP 2
+
Intensive Insulin
STEP 3
Tier 2: Less well-validated therapies

+
Pioglitazone
No hypoglycemia
Weight loss
Nausea/vomiting
+
GLP-1 agonist
No hypoglycemia
Weight loss
Nausea/vomiting
+
Pioglitazone
+
Sulfonylurea*
+
Basal Insulin
Figure 1. ADA/EASD (American Diabetes Association/European Association of the Study of Diabetes) algorithm. (Adapted with permission from
Ref. [2]. Copyright 2009 American Diabetes Association). Sulphonylureas other than glibenclamide (glyburide) or chlorpropamide. Insufficient clinical
use to be confident regarding safety.
be associated with a lower rate of different types of cancer in

patients with type 2 diabetes [10].
In patients with intolerance to metformin (20% experienced gastrointestinal disorders and 5% needed to stop
the treatment), sulphonylurea should be an option, especially
when a rapid drop of blood glucose levels is suitable. Alternatively, thiazolidinedione (TZD) should be considered in
subjects with insulin resistance and/or non-alcoholic fatty liver
disease (NAFLD) [11].
Which Adjunctive Therapy to Metformin? The Debate

is Still Open at Step 2
Longitudinal studiesincluding the A Diabetes Outcome
Progression Trial (ADOPT) [12], UKPDS [13] and an analysis of data from the UK General Practice Research
Database [14]have shown that initial pharmacologic
monotherapy (with metformin, a sulphonylurea, or a TZD)
fails to maintain glycaemic control and/or -cell function
over time. However, the rate of deterioration appears to differ between agents; ADOPT indicated that the incidence of
monotherapy failure [defined as fasting plasma glucose (FPG)
>10 mmol/l] at 5 years was lowest (15%) with the TZD rosiglitazone, greater (21%) with metformin, and highest (34%) with
the sulphonylurea glyburide [12].
The failure of initial pharmacotherapy necessitates the introduction of additional treatment. The American Diabetes Association (ADA)/European Association of the Study of Diabetes
(EASD) consensus statement mandates the introduction of
a sulphonylurea (excluding glibenclamide [i.e. glyburide]) or
100 Charbonnel and Cariou
basal insulin as well-validated adjuncts. Alternatively, this

expert consensus suggests that some less well-validated addon treatments could be used in addition to metformin, such as
the TZD pioglitazone or a GLP-1 receptor agonist, especially
in patients at risk of hypoglycaemia [3]. However, this preference for sulphonylurea as a step-1 therapy has been recently
criticized [15], and alternative algorithms have been suggested.
For instance, the UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend the addition of a
sulphonylurea, TZD or DPP-4 inhibitor after step 1 [16]. Alternatively, the Canadian Diabetes Association (CDA) calls for
augmenting initial pharmacotherapy with a second agent suited
to the individual needs of the patient; drug choice is described
as less important than the need to reach glycaemic target [5].
Oral Agents
Sulphonylureas. Sulphonylureas are commonly added to metformin to improve glucose control and can be expected
to decrease HbA1c by 12% (1122 mmol/mol) [3]. Given
that sulphonylureas stimulate insulin secretion regardless of
blood glucose level, these reductions are accompanied by a
substantial risk of hypoglycaemia. In UKPDS, the mean proportion of patients experiencing one or more hypoglycaemic
episodes per year was 11% for those taking chlorpropamide
monotherapy and 17.7% for those taking glibenclamide
monotherapy [6]. In ADOPT, 38.7% of patients taking
glyburide monotherapy experienced at least one minor hypoglycaemia episode throughout the study, while 0.6% of patients
required a hospitalization for severe hypoglycaemia [12].
Volume 13 No. 2 February 2011
Clinical studies have suggested that long-acting sulphonylureas (e.g. glibenclamide, glimepiride) are associated with
greater risk of hypoglycaemia than short-acting sulphonylureas
(e.g. gliclazide, glipizide) [17,18]. Therefore, glibenclamide (i.e.
glyburide) and chlorpropamide, which are not specific to the cell receptor and can alter ischemic preconditioning protective
effect at the heart level [19], should be avoided in the management of type 2 diabetes [3]. In parallel to hypoglycaemic
events, the use of sulphonylureas is associated with weight gain.
In ADOPT, a 1.6-kg gain in the first year of sulphonylurea
monotherapy was reported [12].
Another consideration in the use of sulphonylureas is the
hypothesis that, as insulin secretagogues, they may accelerate
disease progression by inducing -cell exhaustion. It should be
noted that some, but not all, relevant data support this hypothesis. Although sulphonylureas were found to induce apoptosis
in pancreatic -cells in some preclinical studies [2022], such
an effect was not observed in a subsequent study [23]. Nevertheless, in all clinical studies, the rate of disease progression
appears to be higher with sulphonylureas. ADOPT showed
a faster annual rate of decline in homeostasis model assessment (HOMA)-B with glibenclamide (i.e. glyburide) (6.1%)
than with metformin (3.1%) or rosiglitazone (2.0%) [12]. This
decrease followed an initial 6-month increase in HOMA-B
with each therapy. As noted above and logical considering
the HOMA-B data, the incidence of monotherapy failure was
highest with glyburide in ADOPT [12]. Similar data were
shown on shorter durations of treatment in the Quartet
studies comparing glicazide, metformin and pioglitazone [24].
UKPDS is difficult to interpret in this regard because of the
small subgroup of patients on metformin. Although the rates
of HOMA-B decline were similar among diet/exercise, metformin and sulphonylurea, the slope of HbA1c deterioration
was higher with sulphonylurea [1]. Finally, the assignment for
5 years to nateglinide, a short-acting insulin secretagogue close
to the sulphonylurea family, fails to reduce the incidence of
diabetes in patients with impaired glucose tolerance [25]. In
summary, sulphonylureas appear to act very quickly, with a
fast initial blood glucose decrease but with a poor durability of
action. In spite of promising preclinical data on -cell function (see Section -Cell Function), no good long-term clinical
studies are yet available concerning the glycaemic durability of
either DPP-4 inhibitors or GLP-1 receptor agonists.
Thiazolidinediones. TZDs, which act as insulin sensitizers at
many different sites, have glucose-lowering potency similar
to metformin or sulphonylureas, with 0.51.4% decrease of
HbA1c (615 mmol/mol) [3]. In contrast to sulphonylureas,
TZDs have been hypothesized to preserve -cell function,
based on an apparent long-term decrease in type 2 diabetes
incidence or progression in patients with prediabetes (Diabetes REduction Assessment with ramipril and rosiglitazone
Medication and Actos Now for the prevention of diabetes
trials) [12,2629]. However, this protective effect was not
maintained after a wash-out period [30]. At step 1, a better
durability of glycaemic control was shown with rosiglitazone
(ADOPT) [12], compared with sulphonylureas or metformin.
A similar good durability profile combined with metformin was
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also shown at step 2 with pioglitazone (Quartet) [31] or rosiglitazone [Rosiglitazone Evaluated for Cardiac Outcomes and
Regulation of glycemia in Diabetes (RECORD)] [32]. From a
clinical viewpoint, the occurrence of weight gain with TZDs is a
significant barrier to their wider use. Weight gain on TZD treatment is due in part to fluid retention but mainly to increased fat
mass [33,34]. In ADOPT, rosiglitazone monotherapy resulted
in an average 4.8-kg increase at 5 years [12].
The TZD-dependent fluid retention can induce or worsen
congestive heart failure [35,36]. This side effect is specifically sustained through the peroxisome proliferator-activated
receptor (PPAR)- stimulation of epithelial sodium channelmediated renal salt absorption [37] and could be counterbalanced by the use of amiloride or spironolactone [38].
Following the publication of several meta-analyses, rosiglitazone labelling was amended to carry a warning on a potential
increased risk of myocardial ischemic events [36]. Data on this
possible association are mixed. The results of the RECORD
study of rosiglitazone found no increase in the primary
endpoint of cardiovascular hospitalization or cardiovascular death [hazard ratio (HR) 0.99; 95% confidence interval
(CI) 0.851.16] or myocardial infarction (MI; HR 1.14; 95%
CI 0.801.63) [32]. More recently, the results of the Bypass
Angioplasty Revascularization Investigation 2 Diabetes study
have yielded a cardiovascular benefit from an insulin-sensitising
therapy (with metformin and/or rosiglitazone) compared with
an insulin-providing strategy (with sulphonylureas and/or
insulin) in patients with type 2 diabetes who underwent coronary artery bypass grafting [39]. By contrast, a meta-analysis of
42 randomized, controlled trials has yielded odds ratios of 1.43
(p = 0.03) for MI and 1.64 (p = 0.06) for death from cardiovascular causes with rosiglitazone-treated patients compared
with controls [40].
These data were recently updated with 56 randomized controlled trials of rosiglitazone at least 24 weeks in duration
that reported cardiovascular events [41], including the largest
RECORD trial (32). This meta-analysis confirmed a relative
risk (RR) of 1.28 (p = 0.04), but no increase in risk for cardiovascular mortality. In addition, a retrospective observational
analysis from a cohort of 227 571 patients older than 65 years
indicates that the prescription of rosiglitazone was associated
with an increased risk of stroke, heart failure and all-cause mortality, when compared with prescription of pioglitazone [42].
In the PROspective PioglitAzone Clinical Trial In macroVascular Events, which evaluated the secondary prevention of
macrovascular events in patients with type 2 diabetes, no significant difference was found between pioglitazone and placebo
in the primary composite endpoint of death from any cause,
non-fatal MI, stroke, acute coronary syndrome, leg amputation and coronary or leg revascularization [43]. Significant
improvement was reported with pioglitazone vs. placebo in
a secondary endpoint of all-cause mortality, MI or stroke,
whereas the rates of oedema and heart failure were increased
in the pioglitazone-treated group.
Of note, several trials have reported that rosiglitazone and
pioglitazone may exert clinically relevant differential effects on
lipids. These studies indicate that pioglitazone treatment results
in increased high-density lipoprotein cholesterol (HDL-C)
doi:10.1111/j.1463-1326.2010.01317.x 101
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and reduced levels of total low-density lipoprotein cholesterol
(LDL-C), atherogenic small, dense lipid particles and triglycerides compared with rosiglitazone [4446]. The underlying
molecular mechanism that sustains the clinical differences
between rosiglitazone and pioglitazone is the selective PPAR
modulator concept [47]. Altogether, these data strongly suggest
that the cardiovascular safety profile of pioglitazone is superior
to that of rosiglitazone and that pioglitazone should be the first
choice when prescribing a TZD.
Additionally, data from several studies suggest that women
with diabetes [12,48,49], and probably men [50,51], treated
with a TZD, either rosiglitazone and pioglitazone, may be at
greater risk of fracture and reduced bone mass. This effect is
related to PPAR- activation that inhibits bone formation by
diverting mesenchymal stem cells to the adipocytic rather
than to the osteogenic lineage and by directly increasing
osteoclastic activity [52]. The fracture sites linked to TZDs were
located in the distal upper and lower limb, locations different
from those typically found in postmenopausal osteoporosis.
A clinical study specifically powered to assess fracture risk
in postmenopausal women using pioglitazone is ongoing
(ClinicalTrial.gov identifier NCT00708175).
Given the potential risks associated with this class of drug,
pioglitazone should be used with caution in the treatment of
type 2 diabetes [3], with the greatest expected benefit in patients
with an insulin-resistant profile (severe abdominal obesity, low
HDL-C, liver steatosis and/or NAFLD).
Other Oral Agents (Excluding Incretin-based Therapies). Other
oral agents, such as -glucosidase inhibitors or glinides, have
been available for some time, but their use is limited by
weak glucose-lowering potency and the need for multiple daily
administrations. -Glucosidase inhibitors are associated with
gastrointestinal symptoms that lead to frequent discontinuation (2545% of patients in clinical trials) [3]. Frequent dosing
is necessary with glinides because of short circulating halflives [3], and weight gain and hypoglycaemia are associated
with their use [53].
Insulin and the Need for an Early Intensification of Treatment.
When metformin monotherapy fails, the introduction of
insulin is another option [4,5]. Insulin is the most effective
glucose-lowering medication, given that there is no maximum
dose beyond which reduction in glycaemia will not occur
(except in some very insulin-resistant patients), the reason
why insulin is often recommended when HbA1c values are
very high (>9% or >75 mmol/mol) [3]. Drug intolerance or
existing contraindications for any of the oral glucose-lowering
agents are also indications for insulin therapy. In spite of the
rapid and efficacious action provided by insulin therapy, there
is substantial reluctance to initiate insulin after oral antidiabetic
drug (OAD) failure, at least after monotherapy failure at step 2.
Moreover, the ability of patients to monitor their blood glucose
and adjust the insulin dose must be taken into account.
Weight gain and hypoglycaemia are well-known adverse
effects of exogenous insulin. In UKPDS [6], patients assigned
insulin therapy experienced a significantly greater HbA1c
decrease over 10 years compared with those receiving dietbased therapy [6]. Compared with diet-based therapy, however,
insulin therapy was associated with a greater weight increase

of 4.0 kg [6]. The mean proportion of patients per year with
hypoglycaemic episodes was 1.2% for diet and 36.5% for
insulin [6]. Newer insulin analogues are associated with less
weight gain and incidence of hypoglycaemia [5456].
Finally, retrospective studies employing flawed statistical
analyses have found an association between insulin and insulin
secretagogues such as sulphonylureas with an increased risk of
various types of cancer [57]. Better-designed studies addressing
this important issue are ongoing.
The natural progression of type 2 diabetes suggests that
insulin should be initiated earlier in many patients. Patients
often cite fear of weight gain and hypoglycaemic episodes
as reasons for reluctance to initiate insulin [58]. Such attitudes may contribute to clinical inertia among providers, in
which treatment intensification is delayed in spite of elevated
HbA1c [59]. The extent of such delay was made apparent in
a retrospective database study, which evaluated time to initiation of insulin among 2501 UK general practice patients with
type 2 diabetes who had failed oral polytherapy [HbA1c
8.0% (64 mmol/mol)] [60]. It was estimated that only 25%
of patients started insulin by 1.8 years after failure of oral therapy, and only 50% started insulin by 4.9 years after failure [60].
The consequences of this postponed treatment intensification are clear. Increased time with elevated HbA1c has been
strongly correlated to the likelihood of developing devastating
microvascular and macrovascular complications [61,62]. Even
if elevated blood glucose levels following loss of treatment
efficacy are subsequently brought down again, vascular stresses
may persist after glucose normalization, a phenomenon known
as metabolic legacy [63].
The concept of metabolic legacy argues strongly for early
aggressive treatment of type 2 diabetes to minimize the longterm effects of uncontrolled glycaemia. Two 10-year observational studies have shown a reduction in risk for macrovascular
and microvascular complications with intensive glycaemic control vs. conventional therapy. The DCCT/Epidemiology of Diabetes Interventions and Complications in type 1 diabetes [64]
and a UKPDS post-trial follow-up in type 2 diabetes [65] found
that an initial intensive therapy was associated with a persistently reduced risk of microvascular and macrovascular complications, even after the cessation of the interventional period.
Insulin Therapy Initiation and/or Intensication at

Step 3
When glucose control with two agents is inadequate, most
patients may benefit from the initiation or intensification of
insulin therapy to achieve target glycaemia [HbA1c < 7% (<53
mmol/mol)].
The addition of a third oral agent may be considered as an
alternative for those with glycaemia not too far from target [3].
For instance, rosiglitazone combined with metformin and a
sulphonylurea resulted in similar HbA1c improvements except
when baseline HbA1c was 9.5% (80 mmol/mol) [66],
compared with insulin glargine patients in whom insulin was
more effective. The NICE guidelines indicate that, at step 3,
insulin, an OAD, or a GLP-1 receptor agonist may be selected,
based on individual patient needs [16]. The CDA recommends

the addition of another oral agent, introduction of bedtime
basal insulin, or intensification of existing insulin therapy [5].
However, the application of guideline recommendations is not
always straightforward or simple. Actually, the complexity level
is rapidly increasing as a result of the growing emergence of
new classes of blood glucose-lowering drugs.
GLP-1 Receptor Agonists and DPP-4

Inhibitors in the Management of Type 2
Diabetes
In view of their generally limited efficacy over time, potential
adverse effects associated with established OADs and reluctance
to intensify therapy, prescribers may consider two recently
introduced drug classes, based on the incretin physiology: the
GLP-1 receptor agonists and DPP-4 inhibitors.
Physiology of the Incretins and Implications

for Treatment
The native human GLP-1 hormone plays a key role in glucose
homeostasis. Secreted from L-cells of the intestinal mucosa
following food ingestion [67], GLP-1 decreases postmeal
glycaemia via several pathways. First, GLP-1 stimulates insulin
production and secretion by pancreatic -cells. This effect
is glucose-dependent, that is, occurs only in the presence
of elevated blood glucose levels [68]. The glucose-dependent
character of this mechanism provides a rationale for the low
potential of GLP-1-based therapies to induce hypoglycaemia.
Second, GLP-1 decreases glucagon secretion by pancreatic
-cells, thereby reducing hepatic glucose release. As with the
effect of GLP-1 on -cells, this activity decreases in the presence
of low blood glucose, allowing the normal counter-regulatory
response to hypoglycaemia to occur [69,70]. GLP-1 also slows
gastric emptying, delaying nutrient absorption [71,72], and
promotes the feeling of satiety, thereby decreasing food
intake [73,74]. Animal data suggest that the effects of GLP-1
on satiety may be via direct effects on the brain [75].
It is well established that the incretin effect is diminished
in patients with type 2 diabetes [76]. While initial studies
have suggested that GLP-1 concentrations are reduced in
patients with type 2 diabetes [77], there is actually little evidence
sustaining the hypothesis that impairment in incretin secretion
plays a role in the pathogenesis of type 2 diabetes [78]. The
diminution of incretin effect in patients with type 2 diabetes
is probably as a result of global -cell dysfunction linked
to chronic hyperglycaemia rather than a primary defect in
glucose-dependent insulinotropic polypeptide (GIP) or GLP-1
action [78]. However, it seems that GLP-1 retains significantly
more efficacy than GIP, another incretin hormone, in type 2
diabetes [79]. Unlike GLP-1 [80], raising GIP doses even to
highly supraphysiologic concentrations fails to compensate the
insulinotropic activity in patients with type 2 diabetes [81].
GLP-1, therefore, provided a more logical target than GIP for
incretin-based therapies. The brief half-life of native GLP-1 in
humans (2 min) [82] would necessitate constant exogenous
infusion to be used as a type 2 diabetes therapy; drug
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development has focused on augmenting or extending the
action of native GLP-1.
GLP-1 receptor agonists provide pharmacologic levels of
GLP-1 receptor stimulation beyond those that would occur
from the action of the native hormone alone, and DPP-4
inhibitors preserve endogenous GLP-1 by decreasing its degradation by the DPP-4 enzyme. Indeed, the doses of GLP-1
receptor agonists, like exenatide and liraglutide, result in levels
of the active agent that are fivefold higher compared with
physiologic levels of GLP-1, even when considering the peak
concentrations after meal. By contrast, DPP-4 inhibition only
results in about a twofold increase in GLP-1, within the physiologic range. Both classes of agents have shown glycaemic benefits, with GLP-1 receptor agonists typically associated with more
robust antiglycaemic effects [83]. Clinically, there are other differences as well. DPP-4 inhibitors do not inhibit gastric emptying in humans [84,85], but GLP-1 receptor agonists do [86,87].
GLP-1 agonists, but not DPP-4 inhibitors, have been observed
to increase satiety in animal models. Treatment with the GLP-1
receptor agonist liraglutide was associated with decreased food
intake and a reduced preference for fat/simple carbohydrates in
rats. These effects were not observed with the DPP-4 inhibitor
sitagliptin [88]. As an expected clinical consequence, DPP-4
inhibitors are weight neutral in clinical trials, compared with the
weight loss seen with GLP-1 receptor agonists. Adverse events
profiles also differ, with more frequent gastrointestinal adverse
events in GLP-1 receptor agonist-treated patients [8997].
GLP-1 Receptor Agonists

GLP-1 agonists may represent an option for patients who experience inadequate glycaemic control with metformin alone or
with dual oral therapy. These agents may be preferred for
patients in whom a substantial HbA1c reduction and/or weight
loss is desirable or when hypoglycaemia is a concern [3]. The
NICE guidelines recommend exenatide or liraglutide only at
step 3, in patients who fail two oral drugs and in whom weight
gain or potential drawbacks of insulin are a concern, and propose a pragmatic approach to evaluate the usefulness of GLP-1
agonists as a third-line therapy after metformin and sulphonylurea failure. In this way, continued therapy with GLP-1 agonists is only endorsed in the presence of a beneficial metabolic
response, defined as a 1% (11 mmol/mol) decrease in HbA1c
and 3% reduction in weight from baseline at 6 months [16].
Exenatide and Liraglutide: Blood

Glucose-lowering Efcacy, Weight Loss,
Hypoglycaemia and Tolerability
The following sections review data on available GLP-1 receptor agonists (exenatide twice daily, liraglutide once daily)
when used early in the type 2 diabetes disease course,
whether as an add-on to one oral agent or as monotherapy
(Table 1) [89127].
GLP-1 as Alternative Options After Monotherapy

Failure (at Step 2)
Exenatide. At a dosage of 510 g twice daily, exenatide monotherapy decreased HbA1c by 0.70.9% (810
doi:10.1111/j.1463-1326.2010.01317.x 103
review article
Table 1. Changes in glycaemic and weight parameters with incretin therapies in randomized, controlled trials (changes are from baseline).
Regimen
Monotherapy
Exenatide 510 g BID
Liraglutide 1.21.8 mg OD
Sitagliptin 25200 mg/day
Vildagliptin
50100 mg/day
Saxagliptin 2.510 mg/OD

Combined with 1 OAD
Exenatide 510 g BID
Sitagliptin 100 mg OD
Vildagliptin
50100 mg/day
Saxagliptin 2.510 mg OD
Combined with two OADs
Exenatide 510 g BID
Sitagliptin 100 mg OD
Study
HbA1c, % (mmol/mol)
FPG, mmol/l
Weight, kg
Hypoglycaemia
incidence, %
Moretto et al. [89]

Garber et al. [121]
Aschner et al. [92], Hanefeld
et al. [93], Raz et al. [94]
Foley et al. [102], Pi-Sunyer
et al. [113], Rosenstock
et al. [114], Schweizer
et al. [115]
Rosenstock et al. [105]
0.7 to 0.9 (8 to 10)

0.8 to 1.1 (9 to 12)
0.3 to 0.8 (3 to 9)
1.0
0.8 to 1.4
0.6 to 0.9
2.8 to 3.1
2.0 to 2.4
0.1 to 0.8
4 to 5
8 to 12
0.8 to 1.8
0.5 to 1.1 (5 to 12)
0.2 to 1.3
+0.8 to 0.4
0 to 0.7
0.4 to 0.5 (4 to 5)
0.5 to 0.9
0.1 to 1.2
5.2
DeFronzo et al. [90], Buse

et al. [91]
Marre et al. [103], Nauck
et al. [104]
Charbonnel et al. [95], Raz
et al. [96], Rosenstock
et al. [97]
Ferraninni et al. [101], Garber
et al. [110], Bosi et al. [111],
Garber et al. [112]
Chacra et al. [99], DeFronzo
et al. [100], Allen et al. [108]
0.4 to 0.9 (4 to 10)
0.3 to 0.6
0.9 to 2.8
4.5 to 36
0.6 to 1.1 (7 to 12)
0.7 to 1.7
+0.7 to 2.8
3 to 9.2
0.7 to 1.0 (8 to 11)
0.9 to 1.6
+1.8 to 0.7
1.0 to 1.3
0.4 to 1.0 (4 to 11)
0.1 to 1.1
+2.7 to 0.4
0 to 1.7
0.5 to 0.9 (5 to 10)
0.4 to 1.2
+0.8 to 1.4
0.5 to 14.6
Buse et al. [98], Drucker

et al. [109], Zinman
et al. [116], Kendall
et al. [117], Heine et al. [118]
Buse et al. [98], Russell-Jones
et al. [106], Zinman et al. [107]
Hermansen et al. [127]
0.6 to 1.5 (7 to 16)
0.5 to 1.6
1.6 to 3.6
5.7 to 33.6
1.1 to 1.5 (12 to 16)
1.6 to 2.4
1.0 to 3.2
8 to 27
0.4 (4)
0.2
+0.8
12
BID, twice daily; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; OAD, oral antidiabetic drugs; OD, once daily.
Included one episode that required the assistance of another person.
Included one severe episode as judged by the study investigator.
Included three episodes that required the assistance of another person. Range does not include hypoglycaemia incidence from the study comparing
exenatide with insulin glargine. In that study, hypoglycaemia was reported as events per patient-year (7.3 for exenatide and 6.3 for insulin glargine), not as
a percentage.
Included five episodes that required the assistance of another person.
mmol/mol) from baseline at 24 weeks in drug-nave patients.

Weight decreased from baseline by 2.83.1 kg, and the incidence of minor hypoglycaemia was 45%, with no severe
episodes, validating glucose dependence when the GLP-1 receptor agonists are used alone. The incidence of gastrointestinal
symptoms was 313% for nausea, 4% for vomiting and 03%
for diarrhoea [89].
Exenatide 510 g twice daily lowered HbA1c from baseline
by 0.40.8% (49 mmol/mol) in combination with metformin and 0.50.9% (510 mmol/mol) in combination with
a sulphonylurea [90,91]. Weight loss in the two studies ranged
from 0.9 to 2.8 kg. The incidence of mild-to-moderate hypoglycaemia was 4.55.3% with exenatide in combination with
metformin and, as would be expected, was higher in the study
with a concomitant sulphonylurea (1436%). However, no
severe episodes were reported. Rates of gastrointestinal adverse
events in both studies were 3651% for nausea. Nausea was
most common in the first 8 weeks of treatment and subsided
thereafter [90,91]. The dropout rate linked to nausea was 6%

in randomized studies with exenatide [128].
Patients enrolled in randomized controlled studies of
exenatide added to metformin and/or a sulphonylurea entered
into an open-label extension study of exenatide 10 g twice
daily, yielding data on 3 years of exposure. At 3 years, a 1%
(11 mmol/mol) HbA1c reduction was maintained and weight
loss increased progressively to 5.3 kg from baseline to the end
of the extension period [119].
Liraglutide. Liraglutide was assessed in a program of six phase
III trials [Liraglutide Effect and Action in Diabetes (LEAD)]
designed to validate its efficacy both as monotherapy and
in combination with commonly used OADs [120]. In LEAD
3, a 52-week monotherapy study of liraglutide 1.21.8 mg
once daily, HbA1c decreased by 0.81.1% (912 mmol/mol).
Moreover, in drug-nave patients, a significantly greater reduction in HbA1c was observed with liraglutide 1.8 mg compared
with glimepiride at 52 weeks (1.6 vs. 0.88% [17 vs.

10 mmol/mol], p < 0.0001). Weight decreased by 2.02.4 kg
(both from baseline). The incidence of minor hypoglycaemia
was 812%, with no major episodes, and the incidences of
gastrointestinal adverse events ranged from 28 to 29% for
transient nausea, 9 to 12% for vomiting and 16 to 19% for
diarrhoea [121].
Subjects continued to receive liraglutide 1.21.8 mg once
daily during a 1-year extension phase. HbA1c reduction
[0.9 to1.1% (10 to 12 mmol/mol)] and weight loss
(2.12.7 kg) vs. baseline were sustained at the end of year
2 [122].
In addition, two 26-week studies evaluated liraglutide
0.61.8 mg once daily added to metformin (LEAD 2) [104]
or a sulphonylurea (LEAD 1) [103]. HbA1c reductions from
baseline were 0.61.1% (712 mmol/mol) in the two trials. In
a subgroup of patients previously treated with prestudy oral
antihyperglycaemic monotherapy (35% of treated patients),
and thus representing a true monotherapy cohort, the addition of liraglutide to metformin reduced HbA1c as effectively
as glimepiride (1.3 to 1.2% [14 to 13 mmol/mol],
p = NS) [85]. Weight decreased from baseline by 1.82.8 kg
in the metformin combination study, whereas weight change
was negligible (<1 kg) with liraglutide in combination with
sulphonylurea therapy, which is known to increase weight.
Minor hypoglycaemia was somewhat more frequent when
liraglutide was used in combination with sulphonylurea therapy (5.29.2%) than with metformin (3%). To minimize the
risk of hypoglycaemia, it is recommended to reduce by half
the dose of sulphonylurea when initiating a treatment with a
GLP-1 receptor agonist. Across the two studies, the occurrence
of nausea was 1119% and generally subsided after 4 weeks of
treatment [103,104]. The dropout rate because of severe nausea was 2.8% in the LEAD studies [98,103,104,106,107,121],
compared with a 4.1% discontinuation rate because of gastrointestinal side effects with metformin 1500 mg/day in a
24-week trial [129]. It should be stressed that in the LEAD
studies, all patients were subjected to a forced-dose titration to
attain 1.8 mg once daily. In clinical practice, patients experiencing nausea could down-titrate if necessary. One possible way
to reduce the incidence of nausea is to ask for the patients to
reduce their food intake during the initiation of the treatment.
Use of GLP-1 Receptor Agonists in Patients

With Inadequate Response to Two Oral Therapies
(at Step 3)
The treatment of combination failure is even more complex
than addressing inadequate pharmacologic monotherapy. As
the number of co-morbidities and concomitant medications
can be expected to increase in more advanced diabetes,
clinicians need to consider how to address overweight and
obesity, cardiovascular risk and potential drug interactions
most effectively.
Exenatide. Exenatide 10 g twice daily added to a TZD, with or
without metformin, was associated with a 0.9% (10 mmol/mol)
decrease in HbA1c and a 1.75-kg decrease in weight at 16
weeks. Hypoglycaemia occurred in 10.7% of patients, with
review article
no severe episodes [116]. In a 30-week study of exenatide
510 g twice daily added to metformin and a sulphonylurea,
reductions were 0.60.8% (79 mmol/mol) for HbA1c and
1.6 kg for weight. Hypoglycaemia was reported in 19.027.8%
of patients in the exenatide group (including one episode of
severe hypoglycaemia). Gastrointestinal adverse events were
the most common [117]. A 30-week study evaluated exenatide
10 g twice daily as monotherapy, added to one OAD, or
added to two OADs. HbA1c decreased by 1.5% (16 mmol/mol),
weight loss was 3.6 kg, and hypoglycaemia episodes (all minor)
occurred in 5.7% of patients. Rates of nausea (34%), vomiting
(19%) and diarrhoea (13%) were similar to those seen in
other studies of exenatide [109]. In a 26-week randomized
study, both exenatide and insulin glargine similarly reduced
HbA1c levels by 1.1% (12 mmol/mol) in patients with type 2
diabetes inadequately controlled with combination metformin
and sulphonylurea therapy [118]. However, patients receiving
exenatide had fewer postprandial glucose (PPG) excursions
compared with those taking insulin glargine. Change in weight
was significantly better with exenatide (2.3 vs. +1.8 kg with
insulin glargine). Similar rates of symptomatic hypoglycaemia
were observed between the two groups. Patients in the exenatide
group reported more nausea (57.1 vs. 8.6%), vomiting (17.4
vs. 3.7%) and diarrhoea (8.5 vs. 3.0%) compared with those in
the insulin glargine group.
Liraglutide. Liraglutide 1.21.8 mg once daily, combined with
metformin and a TZD for 26 weeks (LEAD 4), was associated with an HbA1c decrease of 1.5% (16 mmol/mol) and
weight loss of 1.0 to 2.0 kg. Rates of minor hypoglycaemia
were 8.09.0%, with no major episodes. Nausea occurred
in 2940% of patients, and vomiting occurred in 717%.
Most gastrointestinal adverse events were transient, occurring
within the first month of the treatment [107]. Use of liraglutide 1.8 mg once daily, in combination with metformin and
a sulphonylurea, resulted in an HbA1c reduction of 1.33%
(14 mmol/mol) at 26 weeks. Most important, this decrease was
significantly greater than that observed with insulin glargine
(1%; 11 mmol/mol), when used as a trial comparator.
Moreover, the extent of the decrease in FPG was similar between
the two arms (1.6 vs. 1.8 mmol/l, liraglutide 1.8 mg vs.
glargine, respectively). Weight decreased significantly by 1.4 kg
vs. placebo and by 3.4 kg vs. glargine. Minor hypoglycaemia
was reported by 27% of patients, and five patients experienced
a major episode. Transient nausea occurred in 14%, vomiting
in 6% and diarrhoea in 10% [106].
A head-to-head trial compared liraglutide 1.8 mg once daily
and exenatide 10 g twice daily (LEAD 6), each added to metformin and/or a sulphonylurea for 26 weeks. HbA1c decreased
significantly more with liraglutide (1.12%; 11 mmol/mol) compared with exenatide (0.79%; 9 mmol/mol), even though the
incidence of minor hypoglycaemia (blood glucose <3.1 mmol/l
and no necessity for assistance from another person) was significantly lower with liraglutide (26 vs. 34%). As previously
shown in the LEAD 5 study, liraglutide was more effective in
controlling FPG than was exenatide (1.61 vs.0.60 mmol/l,
respectively), because of a more prolonged pharmacokinetics.
By contrast, weight loss was similar with liraglutide (3.2 kg)
and exenatide (2.9 kg) [98].
doi:10.1111/j.1463-1326.2010.01317.x 105
review article
DPP-4 Inhibitors
DPP-4 Inhibitors: Blood Glucose-lowering Efficacy, Weight Loss,
Hypoglycaemia and Tolerability. DPP-4 inhibitors are not a
homogeneous chemical class, but these different chemical products share the same mechanisms of action: DPP-4 inhibition
over 24 h, after oral intake once daily (sitagliptin, saxagliptin),
or twice daily (vildagliptin). While DPP-4 inhibitors are
not included among preferred antidiabetes agents in the
ADA/EASD algorithm [3], the NICE guidelines recommend
the consideration of DPP-4 inhibitors as an add-on therapy
following metformin failure, or as a third-line triple oral therapy option, when sulphonylurea therapy is contraindicated or
not tolerated or when risk of hypoglycaemia is a major concern [12]. Data from trials of DPP-4 inhibitors as monotherapy
or added to one OAD indicate that this class exerts moderate HbA1c reductions, is weight neutral, and does not induce
hypoglycaemia (Table 1).
A DPP-4 inhibitor must be given at a dose which inhibits
DPP-4 >80% for 24 h to get its full efficacy, while increasing
the dose above will do not add more efficacy. It appears that
all the commercially available DPP-4 inhibitors share similar
blood glucose-lowering efficacy. The small differences between
studies came from the differences in the patient populations. To
date, however, it cannot be excluded that each DPP-4 inhibitor
might have different safety profiles, because of differences in
chemistry profile or DPP-4 inhibition selectivity.
Sitagliptin. Twelve to twenty-four weeks of monotherapy
with sitagliptin 25200 mg/day (the recommended dose is
100 mg/day) decreased HbA1c by 0.30.8% (39 mmol/mol)
and decreased weight by 0.10.8 kg from baseline. The incidence of hypoglycaemia was low (0.81.8%), and common
adverse events included nasopharyngitis (2.99.1%) and upper
respiratory tract infection (2.98.8%) [9294], which have
not been confirmed in a larger meta-analysis of the phase
III trials [130]. Sitagliptin 100 mg once daily added to an
OAD (metformin or a TZD) for 2430 weeks resulted in
HbA1c reduction of 0.71.0% (811 mmol/mol) and weight
changes of 0.7 to +1.8 kg from baseline. The incidence of
hypoglycaemia ranged from 1.0 to 1.3%, and incidences were
4.07.3% for nasopharyngitis and 07.3% for respiratory tract
infection [9597].
Longer-term pooled clinical trial data are available for
sitagliptin used as monotherapy or added to metformin. In the
monotherapy pooled data analysis, from which data subsequent
to glycaemic rescue were excluded, the 2-year reduction from
baseline in HbA1c was 1.6% (17 mmol/mol) for sitagliptin
monotherapy. Pooled analysis of two trials in which sitagliptin
was added to metformin showed that the combination reduced
HbA1c by 1.1% (12 mmol/mol) [123].
A 2-week, cross-over study has evaluated the effect of exenatide (510 g BID) vs. sitagliptin (100 mg/day) on 2-h PPG
in type 2 diabetes patients treated with metformin. While the
reduction in FPG was similar between the two groups, 2-h PPG
was lower with exenatide than sitagliptin (133 6 vs. 208
6 mg/dl, p < 0.0001). This effect was associated with slowed
gastric emptying and reduced food intake in the exenatide
group [124]. A liraglutide vs. sitagliptine head-to-head 26-week
randomized study in patients with type 2 diabetes inadequately

controlled by metformin has been recently published [83].
The HbA1c reduction was significantly greater with liraglutide 1.2 mg (1.24%; 13 mmol/mol) and 1.8 mg (1.50%;
16 mmol/mol) once daily than with sitagliptin [0.90%
(10 mmol/mol), p < 0.0001 for both comparisons], showing
the superiority of GLP-1 agonism (high pharmacologic circulating levels of the drug) vs. DPP-4 inhibition (doubling of
endogenous circulating GLP-1 levels). Mean weight loss was
significantly greater with liraglutide than with sitagliptin after
26 weeks: 3.38 kg for 1.8 mg liraglutide, 2.86 kg for liraglutide 1.2 mg and 0.96 kg for sitagliptin. But nauseas were more
common with liraglutide (21 and 27% patients for 1.2 mg and
1.8 mg, respectively) than with sitagliptin (5% patients).
Vildagliptin. Owing to a shorter half-life than sitagliptin,
vildagliptin has to be given twice a day to fully inhibit DPP-4,
even though the clinical differences in blood glucose-lowering
efficacy between 100 mg once a day or 50 mg twice a day are
small.
Vildagliptin 50100 mg/day as monotherapy for 2452
weeks yielded HbA1c reductions of 0.51.1% (612
mmol/mol) from baseline, weight change of 0.4 to
+0.3 kg from baseline, and hypoglycaemia incidence of
00.6%. Adverse events included headache (4.910.0%) and
nasopharyngitis (3.513.2%) [113115]. A 2-year study of
vildagliptin 100 mg/day in previously drug-nave patients with
type 2 diabetes found a 0.5% (6 mmol/mol) decrease in HbA1c
and a 0.8-kg increase in body weight from baseline, with a 0.7%
incidence of hypoglycaemia. The most common adverse events
were nasopharyngitis (8.8%), influenza (8.4%) and headache
(7.7%) [102].
At the end of a 1-year extension to a 1-year randomized
controlled study [115], vildagliptin 100 mg monotherapy was
associated with a 1.0% (11 mmol/mol) reduction in HbA1c
and a 0.5 kg increase in weight from baseline [125]. Two-year
extension data from patients enrolled in a 24-week, randomized, controlled monotherapy study [114] reported a 0.82%
(9 mmol/mol) reduction in HbA1c and unchanged weight
(0.002 kg) from baseline [126].
Added to an OAD (metformin, a sulphonylurea or a TZD)
for 2452 weeks, vildagliptin 50100 mg/day reduced HbA1c
by 0.41.0% (411 mmol/mol). Change in weight was 0.4
to +2.7 kg. Hypoglycaemia incidence was low (03.6%), and
common adverse events included nasopharyngitis (4.711.3%)
and headache (3.27.6%) [101,110112].
Saxagliptin. Saxagliptin inhibits DPP-4 over 24 h because of a
long-acting active metabolite. The standard dose of saxagliptin
is 5 mg once daily, which inhibits DPP-4 >70% for 24 h.
Saxagliptin 2.510 mg/day monotherapy in previously drugnave patients with type 2 diabetes was associated with
a decrease in HbA1c of 0.40.5% (45 mmol/mol) and a
reduction in weight of 0.11.2 kg at 24 weeks. Hypoglycaemia
occurred in 5.2% of saxagliptin-treated patients, and common
adverse events were dermatologic changes (13.7%), upper
respiratory tract infection (8.8%) and headache (8.2%) [105].
In three 24-week studies of saxagliptin 2.510 mg once
daily added to an OAD (metformin, a sulphonylurea or a
review article
TZD), HbA1c decreased by 0.50.9% (510 mmol/mol) from

baseline. Change in weight from baseline ranged from 1.4 to
+0.8 kg. The incidence of hypoglycaemia was 0.50.6% in the
study of saxagliptin added to metformin, 2.74.1% in the study
of saxagliptin added to a TZD, and 13.314.6% in the study of
saxagliptin added to a sulphonylurea. Common adverse events
included urinary tract infection (5.010.7%), nasopharyngitis
(5.69.9%) and headache (5.89.4%) [99,100,108].
Additional Benecial Effects of Incretin-based

Therapies
Cardiovascular Parameters. Of potential cardioprotective
interest, GLP-1 receptor agonists have been shown to impact
other cardiovascular risk factors such as blood pressure and
plasma lipid profiles. Because the GLP-1 receptor is expressed
in the heart and the vasculature, a direct effect of GLP-1
receptor activation on the vascular tone could be hypothesized. However, the cardiovascular actions of GLP-1 remain
to be further investigated in humans [131]. Alternatively, the
natriuretic effect of GLP-1 could explain the antihypertensive
properties of the incretins [132]. Moreover, promising data
have emerged about a cardioprotective role for GLP-1 agonists
following MI in mice [133] and humans [134].
Exenatide. Although long-term outcomes studies are lacking, exenatide does improve markers of cardiovascular risk
(Table 2) [89101,103,104,106117,121]. Blood pressure and
lipid data were reported in a monotherapy study. A 3.7-mm
Hg decrease in systolic blood pressure (SBP) from baseline occurred with both exenatide 5 and 10 g twice daily.
Decreases from baseline in diastolic blood pressure (DBP)
were 0.8 mm Hg for 5 g and 2.3 mm Hg for 10 g. No
significant changes in lipid parameters occurred [89]. A study
of exenatide added to a sulphonylurea found no significant
change in total cholesterol or triglycerides but showed a significant (but unspecified) reduction in LDL-C from baseline [91].
Cardiovascular parameters improved at 3 years of follow-up
in patients originally enrolled in three 30-week, double-blind

trials. Significant improvements from baseline were observed
in lipids (44.4 mg/dl for triglycerides, 10.8 mg/dl for total
cholesterol, +8.5 mg/dl for HDL-C, and 11.8 mg/dl in LDLC) and blood pressure (3.5 mm Hg for SBP and 3.3 mm
Hg for DBP) [119]. In a study of exenatide as monotherapy
or added to one or two OADs, DBP decreased from baseline (1.7 mm Hg) and no significant effect on SBP was
observed. Triglycerides significantly decreased from baseline
(11%), but beneficial HDL-C also significantly decreased
(0.03 mmol/l) [109]. Exenatide was associated with a reduction in C-reactive protein (CRP) from baseline in an analysis
of extension data [135].
Liraglutide. Liraglutide has also been shown to improve cardiovascular parameters, although long-term outcomes data are
as yet lacking. Across clinical studies, liraglutide 0.61.8 mg
once daily consistently decreased SBP relative to baseline,
by 0.66.7 mm Hg (Table 2) [98,103,104,106,107,121]. Blood
pressure decreased in the first 2 weeks of treatment, prior
to weight loss, suggesting that the improvement in blood
pressure was not dependent on the weight loss [136,137].
Liraglutide significantly improved lipid parameters (total
cholesterol 0.13 mmol/l, triglycerides 0.20 mmol/l, and
LDL-C 0.20 mmol/l) and cardiovascular biomarkers [B-type
natriuretic peptide 11.9%, high-sensitivity CRP (hsCRP)
23.1%] from baseline in a meta-analysis of six clinical
studies [138].
DPP-4 Inhibitors. Data are scarce on the potential impact
of DPP-4 inhibitors on blood pressure or lipid parameters
across clinical studies (Table 2) [9297,101,102,105,110115].
A trial of saxagliptin 2.5 to 5.0 mg/day yielded reductions of
3.23.9 mm Hg in SBP and 1.83.3 mm Hg in DBP [99], but
effects on blood pressure are not reported in other clinical
trials [100,108]. In the recent liraglutide vs. sitagliptin headto-head study, lowering of DBP was significantly greater with
sitagliptin 100 mg/day (1.78 mm Hg) than with liraglutide
Table 2. Incretin therapies and markers of cardiovascular risk: evidence from randomized, controlled trials.
Agent
Study
Reductions in blood pressure

( mm Hg from baseline)
Significantly improved lipids and

other CV markers (vs. comparators)
Exenatide
Moretto [89], DeFronzo [90], Buse [91], Buse et al. [98],

Drucker et al. [109], Zinman [116], Kendall [117]
2.5 to 3.7 SBP

0.8 to 2.3 DBP
LDL-C
Liraglutide
Buse et al. [98], Marre et al. [103], Nauck et al. [104],

Russell-Jones et al. [106], Zinman et al. [107],
Garber et al. [121]
0.6 to 6.7 SBP
LDL-C, VLDL-C, TG, FFA
Sitagliptin
Aschner et al. [92], Hanefeld et al. [93], Raz et al. [94],

Charbonnel et al. [95], Raz et al. [96], Rosenstock
et al. [97], Foley [102], Hermansen et al. [127]
Ferrannini et al. [101], Garber et al. [110], Bosi et al. [111],
Garber et al. [112], Pi-Sunyer et al. [113],
Rosenstock et al. [114], Schweizer et al. [115]
Not reported
TG, TC, LDL-C, non-HDL-C,

HDL-C, TG-to-HDL-C
No major changes
in vital signs
across studies
TG, TC, VLDL-C, non-HDL-C
Chacra et al. [99], DeFronzo et al. [100], Allen et al. [108]
3.2 to 3.9 SBP

1.8 to 3.3 DBP
None reported
Vildagliptin
Saxagliptin
CV, cardiovascular; DBP, diastolic blood pressure; FFA, free fatty acids; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol.
The listed improvements occurred in at least one of the studies cited.
doi:10.1111/j.1463-1326.2010.01317.x 107
review article
1.8 mg/day (+0.07 mg Hg) [83]. However, the reduction of
SBP and DBP was similar between sitagliptin 100 mm Hg
and liraglutide 1.2 mg/day. Of note, heart rate increased with
liraglutide and decreased slightly with sitagliptin. Concerning
the other cardiovascular biomarkers, saxagliptin did not affect
the levels of hsCRP, platelet activation factor-1, fibrinogen or
interleukin-6 in one trial [105].
Large, long-term cardiovascular outcome studies are
planned with liraglutide (LEAD: Evaluation of Cardiovascular Outcome Results; ClinicalTrial.gov identifier NCT01179048)
and with DPP-4 inhibitors. The most advanced of the DPP4 studies is the Trial to Evaluate Cardiovascular Outcomes
after treatment with Sitagliptin (ClinicalTrial.gov identifier
NCT00790205). The primary end point of these studies is
to validate the cardiovascular safety of these drugs, but cardiovascular benefit may be prespecified as a secondary end point.
-Cell Function. Preclinical studies are encouraging, but clinical data are limited to surrogate parameters of -cell function,
the most controversial being HOMA-B which may simply
reflect the ability of a drug to stimulate insulin. Clearly, a good
glycaemic clinical durability study (like ADOPT for the TZDs)
is lacking in this field.
Exenatide. Exenatide appears to exert a beneficial effect on
-cells, which could have implications for disease progression,
although long-term outcomes research is needed. -cell mass
increased in insulin-resistant obese fa/fa Zucker rats treated
with exenatide [139]. In vitro and in mice, exenatide inhibited
-cell apoptosis [140], and exposure to exenatide promoted
replication and neogenesis of -cells in a rat model of type
2 diabetes [141]. Exenatide-protected islet allografts against
rejection and increased insulin secretion post-transplant in
diabetic non-human primates (Macaca fascicularis) [142].
Although changes in -cell mass cannot be evaluated
in humans, exenatide achieved significant improvements
vs. placebo in indices of -cell function: HOMA-B (1932%) [89,116] and proinsulin:insulin ratio [90,91]. An analysis
of pooled data indicated that exenatide improved the postprandial -cell response [143]. Patients with type 2 diabetes
who received exenatide for 1 year experienced improvement
in indices of -cell function, vs. baseline and compared with
insulin glargine (for a similar HbA1c reduction), although it
should be noted that these benefits were not sustained after a
12-week washout period [144]. Exenatide has been observed
to increase insulin secretion following islet transplantation in
type 1 diabetes [145].
Liraglutide. Liraglutide has also been shown to increase
-cell mass in diabetic mice [146] and Zucker diabetic fatty
rats [147], to inhibit -cell apoptosis by cytokines and free
fatty acids in rat islet cells [148], and to improve engraftment and function of islet transplants in diabetic mice [149]
and in a porcine marginal mass islet autograft transplant
model [150]. In humans, liraglutide exerted beneficial effects
vs. comparators on measures of -cell function, including HOMA-B (2743%) [87,103,107,151], proinsulin:insulin
ratio [103,104,107,151] and proinsulin : C-peptide ratio [106].
Other improvements with liraglutide therapy included
increased first-phase insulin secretion and maximum -cell

insulin secretory capacity [152]. Liraglutide was associated with
significant improvement in -cell function head to head compared with sitagliptin, with no treatment-related differences
recorded for markers of insulin resistance (i.e. HOMA-IR) [83].
DPP-4 Inhibitors. Similar to the GLP-1 receptor agonists, the
DPP-4 inhibitors exert beneficial effects on -cells in preclinical and clinical studies. A sitagliptin analogue increased -cell
mass and function in a murine model of type 2 diabetes [153].
Sitagliptin achieved improvements in HOMA-B (1020%) and
proinsulin:insulin ratio compared with placebo in clinical trials [9297,127,154]. A meta-analysis of data from randomized,
placebo- or active-controlled trials found that sitagliptin significantly improved HOMA-B and proinsulin:insulin ratio relative
to placebo. Proinsulin:insulin ratio did not differ between
sitagliptin-treated patients and patients receiving active control
medication, however, and sitagliptin was significantly inferior
to active control on HOMA-B [155], which may simply indicate a difference in the ability to secrete insulin more than a
true effect on -cell health, when the active control is sulphonylurea. Saxagliptin also significantly improved HOMA-2 vs.
placebo in several trials [100,105,108].
Vildagliptin was associated with improvements in proinsulin:insulin ratio [102,110] and insulin secretory rate area
under the curve (AUC) : glucose AUC ratio vs. placebo
in clinical studies [110112]. A 52-week study found that
vildagliptin increased meal-related insulin secretion independently of changes in insulin sensitivity [156]. Improvements in
-cell function with vildagliptin have not been sustained after
washout [157,158].
Safety of Incretin-based Therapies

Tolerability issues (e.g. gastrointestinal disorders, hypoglycemia) with GLP-1 receptor agonists and DPP-4 inhibitors
had been reviewed in previous sections.
Acute Pancreatitis. Acute pancreatitis has been reported in
patients treated with both GLP-1 receptor agonists and DPP-4
inhibitors; exenatide and sitagliptin labels recommend vigilance
for signs and symptoms of acute pancreatitis [159,160]. A
claims-based safety surveillance system that assessed risk
for acute pancreatitis with either exenatide or sitagliptin
found no difference in risk between those patients receiving
either of the incretin-based therapies vs. those who were on
metformin or glyburide [161]. Incidence of acute pancreatitis
among patients using either liraglutide or a comparator
in clinical trials is similar to that expected in a type 2
diabetes population [98,103,104,107,121], but the incidence
of pancreatitis was found to be increased in the liraglutide
group in LEAD-6 study [98]. One potential explanation is
that patients with type 2 diabetes have a threefold greater
risk of developing pancreatitis compared with the general
population [162]. Thus, the increasing number of cases of
pancreatitis following incretin-based therapies published or
reported to the US Food and Drug Administration (FDA) could
be a consequence of increased awareness of the potential link.
Alternatively, some animal studies suggest that treatments with
GLP-1 agonist or DPP-4 inhibitors may favour the development

of histologically proven low-grade pancreatitis [163,164].
Exenatide [163] and sitagliptin [164] seem to induce pancreatic
ductal cell replication, a critical step in the pathogenesis
of low-grade pancreatitis and also a well-established factor
for pancreatic adenocarcinoma [165]. Interestingly, metformin
counterbalances the positive effect of sitagliptin on pancreatic
ductal replication [164], suggesting that GLP-1-based therapies
should be preferentially used in combination with metformin in
clinical practice. Thus, an accurate postmarketing surveillance
is needed to further assess the effect of GLP-1-based therapies
on exocrine pancreas function.
Antibodies to GLP-1 Agonists. One safety consideration with
GLP-1 agonists is the potential to induce antibodies, as has
been reported for other protein-based therapies. Antiexenatide antibody formation was common in clinical studies,
with a 2748% incidence [8991,109,116,117]. The presence of antibodies had little apparent effect on efficacy or
safety [90,91,116,117], although the prescribing information
for exenatide notes that, among a small proportion (6%)
of patients who developed high-titre blocking antibody levels in clinical trials, approximately half had no glycaemic
response [159]. Liraglutide exhibited a low potential to induce
antibodies (413%) in clinical trials, compared with the incidence reported for exenatide [103,106,107]. This is probably
because of the greater amino acid sequence homology of
liraglutide (97%) as compared with exenatide (50%) to
native human GLP-1 [166,167]. Unfortunately, no data are
available concerning the prevalence of antibodies following
either exenatide or liraglutide treatments in the LEAD-6
head-to-head study [98]. It should be mentioned here, that
during phase III studies with the not yet approved long-acting
GLP-1 receptor agonist taspoglutide, a potential association
between hypersensitivity reactions (mainly skin reactions and
gastrointestinal symptoms) and antitaspoglutide antibodies
was identified [168]. Similar hypersensitivity reactions were
not reported with either exenatide or liraglutide in clinical
trials. However, postmarketing hypersensitivity reactions were
reported at very low rate for exenatide [159].
Given that DPP-4 inhibitors, unlike GLP-1 receptor agonists, are not protein-based therapies, no antibody formation
is expected. Nonetheless, the expression of DPP-4 on lymphocytes [169] suggests the need for vigilance regarding possible
immune system effects. A first meta-analysis of clinical studies
data found a significantly increased risk of all-cause infection
(e.g. nasopharyngitis, upper respiratory tract infection, urinary
tract infection) associated with sitagliptin (RR 1.15; 95% CI
1.021.31, p = 0.03), but not with vildagliptin (RR 1.04; 95%
CI 0.871.24, p = 0.05) [169]. This finding was not confirmed
for sitagliptin in a subsequent meta-analysis of a larger pool of
data [130].
Kidney Function and Pharmacological Interactions. Kidney
function is frequently compromised in patients with
long-standing type 2 diabetes. Pharmacokinetics study indicates that exenatide is eliminated renally, with a reduction
of mean clearance of the compound and a poor tolerance in
subjects with end-stage renal disease (ESRD) [170,171]. Thus,
review article
use of exenatide is not recommended in patients with severe
renal impairment [creatinine clearance (CrCl) <30 ml/min]
or ESRD. Dose escalation from 5 to 10 g should proceed conservatively in patients with moderate renal impairment (CrCl:
3050 ml/min) [158]. Exenatide has not exhibited clinically
significant interactions with other medications (e.g. statins,
warfarin, digoxin, paracetamol) in clinical studies [172175],
although postmarketing reports have been made of increased
international normalized ratio in patients taking exenatide and
warfarin [158]. Caution is accordingly warranted in patients
taking this combination.
Liraglutide half-life was not found to be increased, and
clearance was not found to be decreased in subjects with
renal impairment, including ESRD, supporting the observation
that the kidneys are not a major site for the elimination
and degradation of liraglutide [176,177]. However, the
liraglutide-prescribing information does not recommend use
in patients with moderate (CrCl 3059 ml/min) or worse renal
dysfunction because of limited therapeutic experience [178].
Clinical data indicate only minor pharmacokinetic interactions
between liraglutide and a range of drugs (e.g. atorvastatin,
lisinopril, digoxin, griseofulvin, paracetamol or an oral
contraceptive) and no need for dosage adjustment [179181].
Elimination of sitagliptin occurs primarily via renal excretion. Given the limited experience of sitagliptin use in moderate
or greater renal impairment (i.e. CrCl <50 ml/min), sitagliptin
is not recommended for use in such patients. In the United
States, but not in Europe, sitagliptin at dose of 50 mg once
daily is recommended instead of 100 mg in such patients. No
clinically meaningful pharmacokinetic interaction has been
found between sitagliptin and metformin, glyburide, simvastatin, rosiglitazone, warfarin or oral contraceptives [182].
Vildagliptin should not be used in patients with moderate or
greater renal impairment or in those with hepatic impairment,
including those with alanine aminotransferase or aspartate
aminotransferase threefold greater than the upper limit of
normal. The increase of liver enzymes in some patients on
vildagliptin 100 mg once daily has resulted in approval of
vildagliptin 50 mg once or twice daily in Europe (vildagliptin
is not approved in the United States). No clinically significant interactions have been found with a range of medications,
including metformin, glyburide, digoxin, amlodipine, ramipril,
valsartan or simvastatin [183].
The US product information for saxagliptin recommends
dosage reduction in patients with moderate or greater renal
impairment; the EU summary of product characteristics warns
against use in these patients owing to the lack of clinical data [184,185]. Saxagliptin has exhibited pharmacokinetic
interactions with strong inhibitors of hepatic cytochrome P450
3A4/5 enzymes. US labelling recommends dosage reduction
of saxagliptin when used concomitantly with such inhibitors,
such as ketoconazole, atazanavir, telithromycin or nefazodone;
the EU label states that clinical data suggest a low risk of interaction with these drugs and recommends careful monitoring of
glucose control when saxagliptin is used with them concomitantly [184,185].
Calcitonin-producing C-cell Hyperplasia. The GLP-1 receptor
was found to be expressed in thyroid C-cell lines of several
doi:10.1111/j.1463-1326.2010.01317.x 109
review article
species, including mice, rats, monkeys and humans, with no
expression in other thyroid cell types [186]. However, the
expression level of GLP-1 receptor was 22-fold higher in mouse
cell line than in human line, and in situ hybridization experiments failed to detect GLP-1 receptor mRNA in sections
from human thyroid gland [186]. Moreover, GLP-1 agonists
increase cyclic adenosine monophosphate (cAMP) and calcitonin release in rat, but not in human, C-cell lines. Liraglutide
induced C-cell hyperplasia, C-cell adenoma, and, at the highest
doses, C-cell carcinoma in preclinical rodent studies. Similar
findings did not occur in non-human primates (who express
similar levels of GLP-1 receptor to human) exposed to 60 times
the human dose of 1.8 mg, confirming that rodent C-cells are
sensitive to GLP-1-agonist activation, yet human and nonhuman primate C-cells are not [186]. More important, there
were no cases of medullary thyroid carcinoma in the LEAD
studies, and calcitonin levels, the biomarker of medullary thyroid carcinoma, were not increased after 2 years of clinical exposure to liraglutide. FDA requires the establishment of a cancer
registry to monitor the annual incidence of medullary thyroid
carcinoma over the next 15 years but does not encourage checking calctinonin levels for patients receiving liraglutide [187].
The Place of Incretin-based Therapies in Clinical

Practice
In view of the data presented here, some practical principles can
be formulated for the clinical use of GLP-1 receptor agonists
and DPP-4 inhibitors (Figure 2 [2]).
1. At step 1, most newly diagnosed patients with type 2 diabetes
will be initiated on metformin pharmacotherapy. Longterm clinical studies are lacking to promote the utilization
of incretin-based therapy at this initial step, and metformin
remains the most cost-effective drug.
2. At step 2 of treatment intensification, incretin-based therapies are currently recommended as add-on therapy, when
metformin alone is not adequate to reach the HbA1c target,
by both the ADA/EASD (which suggest GLP-1 receptor
agonists) and the NICE (which suggests DPP-4 inhibitors)
guidelines, mainly in patients at risk for hypoglycaemia
or who are obese [3,16]. Early DPP-4 inhibitor initiation
appears to be a good option, facilitating early intensification
and reducing clinical inertia. The stopping rules proposed
in the NICE guidelines [to switch to another option if HbA1c
has not decreased by 0.5% (5 mmol/mol)] could allow differentiation between good and bad responders, because
no baseline characteristics are predictive of response.
Beyond the lack of hypoglycaemia and weight gain, there are
other benefits in prescribing incretin-based therapies over
other available antidiabetic agents. Poor durability over time
of sulphonylureas makes incretin-based therapies theoretically preferable, even though the precise durability of DPP-4
inhibitors or GLP-1 agonists is not known. Adverse effects
associated with TZDs also make incretin-based therapies
preferable, although the long-term safety of the newer drugs
remains to be confirmed. Finally, the only disadvantage to
prescribing these drugs at step 2, compared with the other
available options, is their cost.
The choice of incretin therapy has to be individualized:

DPP-4 inhibitors are easy to use and well tolerated, although
this advantage must be weighed against the expectations
about HbA1c reductions. Indeed, compared with TZDs,
HbA1c decrease with DDP-4 inhibitors is on an average
similar (in non-inferiority trials) or slightly less (in clinical practice). DPP-4 inhibitors have a slower onset of
action compared with sulphonylureas, but HbA1c decrease
with DPP-4 inhibitors is similar (in non-inferiority trials)
or slightly less (in clinical practice) after 1 year of treatment. Compared with the GLP-1 agonist liraglutide, DPP-4
inhibitors are less potent, do not result in weight loss and
are not associated with nausea. GLP-1 receptor agonists
are injectable drugs and therefore perhaps less easily taken
than DPP-4 inhibitors. Nausea, at least when starting treatment, also has to be considered. Weight loss, however, at
least in those patients who lose >5 kg, is of considerable
interest.
3. At step 3 of treatment intensification, NICE Guidelines [16]
recommend GLP-1 agonists in very obese patients with body
mass index (BMI) >35 kg/m2 . Alternatives to liraglutide at
step 3 are insulin, which is the preferred option by NICE, or
adding a third agent. In the case of failure of a dual oral treatment, adding a third oral drug may provide a good choice,
if the prospect of injection with insulin results in a delay in
intensification of treatment or clinical inertia. Pioglitazone
is primarily indicated for initiation after dual therapy failure.
It may also be a good indication for DPP-4 inhibitors, especially in patients on a metforminTZD combination. DPP-4
inhibitorsulfonylurea combination is not optimal, even
though efficacy has beenshown. Combining two insulin secretagogues, even though acting through different pathways,
is not ideal, and the benefits of DPP-4 inhibitors (e.g. weight
neutral, no hypogycaemia) are lost in this combination with
durability of effect which appears to be uncertain.
Basal insulin is generally recommended at step 3, for
robust reasons. Insulin is the most effective glucose-lowering
medication, given that there is no maximum dose beyond
which reduction in glycaemia will not occur, it is a wellvalidated option (ADA/EASD), and the natural progressive
history of the disease suggests that most patients will eventually require it.
GLP-1 receptor agonists appear to be an alternative to
insulin: a single injection without need for titration, weight
loss instead of weight gain, no hypoglycemia (if sulphonylureas are reduced or stopped), a similar or even better blood
glucose-lowering efficacy, at least in the clinical studies.
It may be anticipated, if the cost is not the priority, that
this option will become the recommended intensification of
treatment at step 3; insulin may then become step 4 in the
case of GLP-1 receptor agonist failure. In this scenario, the
change from GLP-1 receptor agonists to insulin may occur
early, if HbA1c does not decrease by 1% (11 mmol/mol) in
the stopping rules proposed in the NICE guidelines [16].
If the choice of a GLP-1 receptor agonist is made at step 3 in
patients on a combined DPP-4 inhibitormetformin treatment not adequately controlling glycemia, it seems logical
to stop the DPP-4 inhibitor.
OAD tritherapy
Met/SU/PIO
Met/DPP-4 Inh/PIO
MET/SU/DPP-4 Inh
Metformin
Metformin +
DPP-4
DPP 4 iinhibitors
hibit
++ lack of hypoglycaemia
+ weight neutral
+ tolerability
-- cost
? durability
? pancreatitis
++ cost efficacy
++ long-term safety
- GI disorders
Metformin/OAD +
Insulin (bed-time)
Met/SU/insulin
Met/PIO/insulin
++ cost efficacy
+ no upper limit dose
-- hypoglycaemia
-weight gain (PIO>SU)
- fluid retention (PIO)
et o
Metformin
+
GLP-1 agonists
++ lack of hypoglycaemia
++ weight loss
-- cost
--nausea
? durability
? pancreatitis
titi
y
++ cost efficacy
++ no upper limit dose
-hypoglycaemia
- weight gain
Metformin +
Insulin multi-injections
(premix twice daily,
basal-bolus regimens)
Metformin +
Insulin
I
li
(bed-time regimen)
++ cost efficacy
+ no upper limit dose
-- hypoglycaemia
-weight gain
Figure 2. Pharmacological management of type 2 diabetes. Therapeutic options at each of three steps of treatment intensification are shown. + and indicate the benefits and disadvantages of each options,
respectively. For more details, see the text. DPP-4 inh, DPP-4 inhibitors; GI, gastrointestinal; GLP-1, GLP-1 receptor agonists; MET, metformin; NAFLD, non-alcoholic fatty liver disease; OAD, oral antidiabetic
drug; PIO, pioglitazone; SU, sulphonylureas.
OAD bitherapy + GLP-1

GLP-1/Met
GLP-1/MET/SU
GLP-1/Met/PIO
++ weight loss
+lack of hypoglycaemia (PIO)
-hypoglycaemia (SU)
-- nauseas
-- cost
Metformin +
Pioglitazone
++ durability
++ insulin-sensitization
+ NAFLD
-- weigth gain
-- fluid retention
-- fractures
+ efficacy for HbA1C 9%

-- clinical inertia for HbA1c > 9%
Step 3
Metformin
M
tf
i +
Sulphonylureas
++ cost efficacy
+ long-term safety
-- durability
-- hypoglycaemia
- weight gain
Step 2
Step 1
HbA1C target < 7% (53 mmol/mol)

Life style changes associated at each step
Maximum 6 months delay between each step
review article
doi:10.1111/j.1463-1326.2010.01317.x 111
review article
Conclusions
Disease progression in patients with type 2 diabetes inevitably
necessitates treatment intensification to cope with declining
-cell function. Although guidelines differ on when to
consider the introduction of incretin therapies, clinical data
support the glycaemic efficacy and extraglycaemic benefits
of the GLP-1 receptor agonists and DPP-4 inhibitors. The
differing mechanisms of action of GLP-1 receptor agonists
and DPP-4 inhibitors appear to result in differing therapeutic
profiles. Both agents significantly reduce HbA1c, although the
effect is consistently more pronounced with GLP-1 receptor
agonists. The low risk of hypoglycaemia associated with these
agents provides an advantage relative to the introduction of
sulphonylurea or insulin therapy. Weight loss (GLP-1 receptor
agonists) or weight neutrality (DPP-4 inhibitors) support the
use of incretin therapies in patients for whom overweight
or obesity is a concern. The lack of clinically significant
drug interactions suggests the utility of incretin therapies
in patients receiving treatment for co-morbid conditions.
Incretin therapies improve -cell function, but there is
currently no evidence of a long-term, disease-modifying
effect. GLP-1 receptor agonists merit further investigation
to determine if improvements in markers of cardiovascular
function (e.g. blood pressure, lipids) correlate with better
long-term cardiovascular outcomes.
Acknowledgements
The authors thank Andrew Horgan, PhD, and Patricia Abramo
of AdelphiEden Health Communications for providing medical
writing and editorial services. Funding for the preparation of
this review was provided by Novo Nordisk, Inc.
Conict of Interest
B. Charbonnel has received fees for consultancy, speaking,
travel or accommodation from Takeda, GlaxoSmithKline,
Merck Sharpe & Dohme, AstraZeneca, Bristol Myers Squibb,
Boehringer Ingelheim, Novo Nordisk, Roche, Sanofi-Aventis
and Novartis.
B. Cariou has acted as an investigator for Roche, Boehringer
Ingelheim, Novo Nordisk, Eli Lilly & Co, Genfit, Johnson
& Johnson and has received fees for consultancy, speaking,
travel or accommodation from Novo Nordisk, Eli Lilly & Co,
Sanofi-Aventis, Merck & Co Inc, Pierre Fabre, Takeda, Genfit,
GlaxoSmithKline, Novartis and Servier.
Prof. B. Charbonnel and Prof. B. Cariou received no
honorarium or payment for authorship of this review.
The authors report that they have made substantial
contributions to the conception and design of the study,
acquisition of data, analysis and interpretation of data, drafting
the article and final approval of the version to be submitted.
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Diabetes, Obesity and Metabolism 13: 99117, 2011.

2010 Blackwell Publishing Ltd

Pharmacological management of type 2 diabetes:

Treatment Intensication in Type 2 Diabetes

Type 2 diabetes is a progressive disease, characterized by a

Metformin: the First Choice at the First Step

Correspondence to: Prof. Bernard Charbonnel, Clinique dEndocrinologie, Maladies

The choice of initial pharmacotherapy when lifestyle changes

DIABETES, OBESITY AND METABOLISM

Tier 1: Well-validated core therapies

Tier 2: Less well-validated therapies

be associated with a lower rate of different types of cancer in

Which Adjunctive Therapy to Metformin? The Debate

100 Charbonnel and Cariou

basal insulin as well-validated adjuncts. Alternatively, this

Volume 13 No. 2 February 2011

DIABETES, OBESITY AND METABOLISM

Volume 13 No. 2 February 2011

102 Charbonnel and Cariou

DIABETES, OBESITY AND METABOLISM

insulin therapy was associated with a greater weight increase

Insulin Therapy Initiation and/or Intensication at

Volume 13 No. 2 February 2011

DIABETES, OBESITY AND METABOLISM

based on individual patient needs [16]. The CDA recommends

GLP-1 Receptor Agonists and DPP-4

Physiology of the Incretins and Implications

Volume 13 No. 2 February 2011

GLP-1 Receptor Agonists

Exenatide and Liraglutide: Blood

GLP-1 as Alternative Options After Monotherapy

DIABETES, OBESITY AND METABOLISM

Saxagliptin 2.510 mg/OD

Moretto et al. [89]

0.7 to 0.9 (8 to 10)

0.5 to 1.1 (5 to 12)

DeFronzo et al. [90], Buse

0.4 to 0.9 (4 to 10)

0.6 to 1.1 (7 to 12)

0.7 to 1.0 (8 to 11)

0.4 to 1.0 (4 to 11)

0.5 to 0.9 (5 to 10)

Buse et al. [98], Drucker

0.6 to 1.5 (7 to 16)

1.1 to 1.5 (12 to 16)

mmol/mol) from baseline at 24 weeks in drug-nave patients.

104 Charbonnel and Cariou

thereafter [90,91]. The dropout rate linked to nausea was 6%

Volume 13 No. 2 February 2011

DIABETES, OBESITY AND METABOLISM

with glimepiride at 52 weeks (1.6 vs. 0.88% [17 vs.

Use of GLP-1 Receptor Agonists in Patients

Volume 13 No. 2 February 2011

106 Charbonnel and Cariou

DIABETES, OBESITY AND METABOLISM

randomized study in patients with type 2 diabetes inadequately

Volume 13 No. 2 February 2011

DIABETES, OBESITY AND METABOLISM

TZD), HbA1c decreased by 0.50.9% (510 mmol/mol) from

Additional Benecial Effects of Incretin-based

in patients originally enrolled in three 30-week, double-blind

Reductions in blood pressure

Significantly improved lipids and