November/December 2009
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A Review of Incretin-Based
Therapies for Type 2
Diabetes Treatment
Continuous, subcutaneous administration of native GLP-1 to type 2 diabetes patients
has been shown to lower fasting and postprandial glucose and A1C,
as well as promote satiety and weight loss.
By Julie A. Lovshin, MD; and Daniel J. Drucker, MD
Glucagon-like peptide 1 (GLP-1), an incretin
hormone, stimulates insulin release1 and
plays a major role in glucose metabolism.2,3
Unlike the other incretin hormone, glucosedependent
insulinotropic polypeptide (GIP), GLP-1
retains its glucose-regulatory actions in patients with
diabetes. According to a report in Nature Reviews
Endocrinology (2009;5:262–269), these findings led to
the creation of distinct GLP-1 receptor (GLP-1R) agonists,
which mimic the actions of GLP-1 in vivo in
humans.2-4 When investigators were able to elucidate
the role of dipeptidyl peptidase 4 (DPP-4) in the inactivation
of bioactive GLP-1 and GIP5,6 orally available
DPP-4 inhibitors were developed. DPP-4 stabilizes both
incretin hormones at physiologically active levels. The
following is a summary of Drs. Lovshin and Drucker’s
original review.
INTRODUCTION
GLP-1 is secreted at low basal rates in the fasting state
and increases after eating. GLP-1 binds to GLP-1R, a receptor
expressed on pancreatic beta cells, increasing beta cells’
sensitivity to glucose. GLP has been shown to protect
rodent and human pancreatic beta cells from apoptotic
cell death, and in other animal experiments, triggers proliferative
pathways that lead to expansion of beta-cell mass.
GLP-1 also suppresses glucagon from pancreatic alpha cells,
resulting in a decrease in hepatic glucose production and a
delay in nutrients traveling from the stomach to the duo
denum through inhibition of gastric emptying.7 GLP-1 promotes
satiety, often resulting in weight loss. In healthy individuals,
glucose-dependent insulinotropic peptide (GIP)
exerts incretin-like effects on beta-cells, however, its actions
are impaired in type 2 diabetes patients thus limiting its
potential as a clinical therapy.8,9
Continuous, subcutaneous administration of native
GLP-1 to type 2 diabetes patients with type 2 diabetes
has been shown to lower fasting and postprandial glucose
and A1C, as well as promote weight loss.10 Based
these findings, two drug classes have emerged: peptidebased,
degradation-resistant GLP-1R agonists (administered
by subcutaneous injection) and oral DPP-4
inhibitors.4 The glucose regulatory effects of both classes
of agents occur through GLP-1, but there are differences
in their mechanisms of action. Both act on pancreatic
islets to stimulate insulin secretion and inhibit glucagon
secretion. GLP-1R agonists, however, also inhibit gastric
emptying and promote satiety. DPP-4 inhibitors stabilize
bioactive GIP levels, so these agents may lower glucose
levels in part through GIP-mediated stimulation of
insulin secretion.9
The first GLP-1R agonist to be introduced was exenatide
(Byetta, Eli Lilly and Amylin) and the first DPP-4
inhibitor was sitagliptin (Januvia, Merck). Now several of
these drugs are either commercially available or have
reached late stages of clinical development.
GLP-1R AGONISTS
Exenatide. Exenatide is a synthetic form of the naturally
occurring Heloderma suspectum peptide exendin. It
exhibits about 50% amino acid identity with human GLP-
1 and is a potent agonist of human GLP-1R. It is resistant
to degradation by DPP-4 and therefore has increased circulating
half-life in vivo. Three 30-week, pivotal, phase 3
clinical trials examined the efficacy of twice-daily injections
of 5 or 10 µg exenatide in patients with type 2 diabetes
who were inadequately controlled with a sulfonylurea
and/or metformin.11-13 Substantial benefits on A1C
levels and modest reductions in body weight were
observed. Exenatide lowered fasting (FPG) and postprandial
glucose (PPG) concentrations, and was generally well
tolerated; mild nausea and vomiting were the most common
adverse effects. Nausea dissipated over time in most
patients.
The US Food and Drug Administration approved exenatide
in 2005, and the European Medicines Agency granted
subsequent approval in November 2006. Exenatide is
indicated an adjunct to metformin, sulfonylurea, or both,
in patients with type 2 diabetes. A 16-week study examining
the efficacy of exenatide plus thiazolidinediones
(TZDs) found that exenatide-treated patients had substantial
reductions in FPG (about 1.69 mmol/L), A1C (0.98%)
and weight (1.5 kg).14 Exenatide was then approved for
use with a TZD, with or without metformin.
Exenatide’s efficacy has been assessed in head-to-head
comparison trials with insulin glargine in combination
with metformin or a sulfonylurea. An open-label study
revealed similar improvements in blood glucose control
in both treatment groups. Insulin therapy, however, generally
led to gain weight, whereas exenatide was associated
with weight loss. The incidence of hypoglycemia was
comparable between the two groups, but gastrointestinal
malaise and drop-out rates were higher among
patients taking exenatide.15 Similar results were observed
in a 52-week, open-label study.16 Exenatide represents a
reasonable alternative to insulin therapy in patients suboptimally
controlled with oral agents, particularly with
regard to weight-gain concerns, based on these studies.
Liraglutide. Liraglutide (Victoza, Novo Nordisk) is a
modified form of human GLP-1 that has a prolonged
half-life in vivo. Liraglutide has been shown to mimic the
expected actions of GLP-1, and nausea and diarrhea are
the most commonly reported adverse events.17 Several
phase 3 clinical trials have investigated liraglutide’s efficacy—
as monotherapy or in combination—compared with
oral agents, exenatide, or insulin. Liraglutide was found to
be at least as efficacious in lowering A1C as comparator
treatments and was often associated with weight loss.
Add-on therapy with liraglutide among patients inadequately
controlled with metformin and rosiglitazone
caused a mean A1C reduction of 1.5%, from a baseline
value of 8.6%, as well as weight loss of about 2 kg and a
reduction in systolic blood pressure.18 Nausea, vomiting
and diarrhea were the most common adverse events and
the principal reasons for withdrawal from the study. A
52-week study that compared monotherapy with
glimepiride or liraglutide showed that liraglutide was
more effective for A1C lowering. Liraglutide-treated
patients also experienced weight loss and blood pressure
reduction, whereas glimepiride-treated patients gained
weight.19 Liraglutide was also more effective than rosiglitazone
in producing additional reductions in FPG and
A1C over 26 weeks. Rosiglitazone was associated with
weight gain and liraglutide was not.20
Additive glimepiride was compared with liraglutide in
a 26-week study of patients inadequately controlled with
metformin.21 Liraglutide was as effective as glimepiride in
reducing A1C, was associated with fewer episodes of
minor hypoglycemia, a slight reduction in blood pressure,
and an increase in heart rate, and more nausea versus
glimepiride. Body weight decreased in liraglutide-treated
patients but increased with glimepiride.21 Liraglutide produced
a greater reduction in A1C and body weight versus insulin glargine on a background
therapy of metformin and glimepiride. Liraglutide
also improved the proinsulin:C-peptide ratio and reduced
systolic blood pressure; however, some liraglutide
patients had episodes of major hypoglycemia (n = 5),
whereas no episodes were seen in the insulin patients.22
A US new drug application was filed for liraglutide in
May 2008. Liraglutide is also being investigated obesity
treatment in nondiabetic patients at doses of up to 3 mg
daily.
Modified exenatide. Ave0010 (Sanofi-Aventis) is a
modified exendin-4 molecule. A dose-ranging, placebocontrolled
phase 2b study looked at 542 type 2 diabetes
patients inadequately controlled with metformin
monotherapy.23 After 13-week treatment with escalating
doses of Ave0010 (5 µg, 10 µg, 20 µg, or 30 µg). Patients
had reductions in A1C from baseline with once-daily
(0.28–0.57%) and twice-daily (0.47–0.69%) Ave0010, as
well as decreases in body weight. This agent is in phase 3
clinical trials.
A long-acting, once-weekly formulation of exenatide
was evaluated at two doses, 0.8 mg and 2 mg, in type 2
diabetes patients who were also treated with diet and
exercise and/or metformin for 15 weeks. Both groups
had marked reductions in A1C, however, only the 2-mg
exenatide-treated patients lots weight.24 A clinical trial
compared the efficacy of 10 µg exenatide twice daily with
2 mg exenatide once weekly in 300 patients who were either not treated with oral agents or who were receiving
one or two oral agents for 30 weeks.24 Both groups
experienced significant reductions in A1C. More patients
assigned to once-weekly exenatide achieved target A1C
<7% versus those who received twice-daily exenatide
(77% versus 61%, respectively). Weight loss was similar in
both treatment groups (3.6–3.9 kg). Once-weekly treatment
was associated with a greater reduction in plasma
glucagon and FPG versus the twice-daily dose. Twicedaily
exenatide was a more potent suppressor of postprandial
glycemic excursions, the investigators noted.
Nausea and vomiting were the most commonly reported
adverse effects.
Albiglutide. Albiglutide (Syncria, GlaxoSmithKline) is a
long-acting, recombinant GLP-1R agonist. It allows sustained
action and once-weekly administration. Preclinical
rodent studies showed that it activates GLP-1R and
reproduces many GLP-1 actions, including inhibition of
gastric emptying and satiety following acute administration.
25 This agent entered phase 3 clinical studies in the
first quarter of 2009.
Taspoglutide. Taspoglutide (Roche/Ipsen) is a GLP-1-
based molecule that is resistant to DPP-4 degradation. A
zinc-based formulation of taspoglutide allows onceweekly
dosing. A randomized, placebo-controlled, phase
2 trial investigated the efficacy and safety of weekly or
biweekly taspoglutide in 306 type 2 diabetes patients
inadequately controlled with metformin.26 Both taspoglutide
regimens reduced A1C after 8 weeks, and dosedependent
reductions in body weight were observed in
both groups. Taspoglutide therapy was associated with
nausea and vomiting, and some patients developed
antipeptide antibodies. A second phase 2 study examined
taspoglutide dosing regimens in 133 metformintreated
patients who were randomized to placebo or 20
mg taspoglutide once weekly for 4 weeks, followed by a
second 4-week treatment period with 20 mg, 30 mg or
40 mg once weekly. All patients had improved glucose
control, and nausea was the most commonly reported
adverse event.27 This drug is being evaluated in phase 3
studies.
Other long-acting GLP-1R agonists. CJC1134
(ConjuChem) was shown to exert a broad range of GLP-
1-receptor-dependent glucose-regulatory actions in preclinical
studies.28 Several once-weekly GLP-1 therapies
are under clinical investigation in phase 1 or 2 studies
(Table 1.)
Adverse effects of GLP-1R agonists. Nausea and vomiting are the most commonly reported dverse events associated
with GLP-1R agonists. Incidence and severity seems
to be related to maximum doses and the time taken to
reach this concentration. Although nausea and vomiting
are usually mild, transient, and diminish over time, some
patients will not be able to tolerate the therapy.
Exenatide is linked to induction of antiexenatide antibodies.
29 Antiexenatide antibodies do not seem to
impact the agents effectiveness for most patients, however,
a small subset of individuals with high titers of antibodies
(>1:625) may have diminished benefits.
Pancreatitis has been reported in some exenatide
patients30 and in several participants during the liraglutide
clinical trials.19 Concerns are emerging surrounding
new onset or possible exacerbation of pancreatitis, but
data are limited regarding pancreatitis among exenatidetreated
patients versus those using other therapies. It is
known that GLP-1 or exendin-4 alone can cause or exacerbate
pancreatitis, and many patients who are treated
with GLP-1R agonists have occasional abdominal discomfort.
This complicates the diagnosis of pancreatitis.
Nevertheless, understanding the potential relationship
between these therapies and pancreatic inflammation is
clinically important.
DPP-4 INHIBITORS
Sitagliptin and vildagliptin. Sitagliptin was approved
for US use in October 2006, followed by approval in
other countries. Vildagliptin (Galvus, Novartis) was subsequently
approved for use in Europe and other countries
but not in the United States. DPP-4 inhibitors may
be administered orally, once daily (sitagliptin) or twice
daily (vildagliptin), they do not influence body weight,
and are well tolerated.
Sitagliptin has been approved for US use as monotherapy
or in combination with metformin, a sulfonylurea, or
a TZD.31-36 DPP-4 inhibitors are approved for use in combination
with metformin for patients with early type 2
diabetes who are assigned combination therapy. Many
patients treated with this combination achieved target
A1C. Similar results have been observed with
vildagliptin.37-39
Alogliptin and saxagliptin. Alogliptin (Takeda) has
been studied in phase 3 trials as monotherapy or in combination
with other oral antidiabetic agents (metformin,
sulfonylurea, or TZD). It has also been evaluated as
monotherapy for 26 weeks in patients with poorly controlled
diabetes at doses of 12.5 mg or 25 mg daily.
Patients experienced reductions in A1C, and the agent
appeared to be well tolerated.40 Alogliptin, at doses of
12.5 mg and 25 mg once daily, also reduced blood glucose
levels when added to existing therapy in patients
responding inadequately to metformin monotherapy.41
Alogliptin and vildagliptin have been successfully used in
combination with insulin.42 An NDA for alogliptin was
filed December 2007. In June 2008, an NDA was filed for
saxagliptin, a once-daily selective DPP-4 inhibitor investigated
in phase 3 trials. It is not know to what extent
alogliptin or saxagliptin will exhibit unique antidiabetic
properties or if the safety profile will be different from
that seen with other DPP-4 inhibitors. Additional DPP-4
inhibitors in late-stage testing (Table 1) include linagliptin
(BI-1356, Boehringer Ingelheim) and dutogliptin tartrate
(PHX1149, Phenomix).43
UNANSWERED QUESTIONS
Preclinical study evidence shows that GLP-1R activation,
and, to a lesser extent, GIP-receptor activation, promotes
expansion of beta-cell mass through cell proliferation
and apoptosis inhibition. Incretin-based therapies
have disease-modifying biological potential due to their
effects on the beta cell,3 however clinical studies have not
shown much evidence suggesting a regenerative or protective
effect of these agents on beta-cell function in diabetes
patients. Exenatide has been suggested as a possible
treatment for patients with type 1 diabetes following
islet transplantation.44,45
Cardiovascular safety of antidiabetic agents is of great
interest, however, information is limited about the cardiovascular
actions of GLP-1R agonists in humans. They
may be associated with weight loss, blood pressure
reductions, and improvements in plasma lipid profiles.
These agents are not likely to increase CVD risk in diabetes
patients.46 Preliminary data indicate that native
GLP-1 may have beneficial effects on heart failure47 or following
myocardial infarction.48 Less is known about the
actions of DPP-4 on the cardiovascular system, and DPP-
4-inhibitor therapy is not associated with significant
reduction in body weight or blood pressure.
CONCLUSIONS
New diabetes treatments are increasing important due
to the rising prevalence of type 2 diabetes around the
world. Emerging incretin-based therapies are expensive,
and physician and patient experience with these new agents is limited. As incretin therapies gain wider acceptance
and new agents come to market, interest will continue
to increase. There are several advantages associated
with the use of incretin drugs, such as their glucosedependent
mechanism of action and no risk of weight
gain, their long-term efficacy, safety, and durability of
effect continues to be elucidated. Incretin-based agents
represent an important option in the fight against diabetes,
but they should be fully scrutinized.
Julie A. Lovshin, MD, and Daniel J, Drucker, MD, are in
the Department of Medicine, Samuel Lunenfeld Research
Institute, Mt Sinai Hospital, University of Toronto. Dr.
Drucker may be reached at d.drucker@utoronto.ca.
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