Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes.

Abstract

Lixisenatide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist mimicking several favorable actions of endogenous GLP-1 that result in improved glycemic control with little or no hypoglycemia and weight loss. Phase II trials have shown that lixisenatide 20 μg once daily restores first-phase insulin release in patients with type 2 diabetes and improves the second-phase insulin response. Administered once or twice daily for 4 weeks, it significantly reduced postprandial and fasting blood glucose levels, and glycosylated hemoglobin (HbA(1c)). The efficacy and safety of lixisenatide once daily is being assessed in the GETGOAL Phase III clinical trial program. Results have shown beneficial effects on HbA(1c) compared with placebo in combination with commonly used antidiabetes agents, with no increased risk of hypoglycemia and with beneficial weight reduction. Adverse effects were similar to those observed for available GLP-1 receptor agonists, the most frequent being gastrointestinal. Both GLP-1 receptor agonists and long-acting insulin analogs have demonstrated protective effects on beta cells in preclinical studies. This, along with the pronounced effect of lixisenatide on postprandial plasma glucose, provides a rationale for combining it with long-acting basal insulin analogs, in the hope that the additive effects on glycemic control combined with a potential benefit on islet cells may lead to a new treatment approach to control blood glucose better and prevent long-term complications in patients with type 2 diabetes.

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which permits unrestricted noncommercial use, provided the original work is properly cited.
Core Evidence 2011:6 67–79
Core Evidence
Lixisenatide: evidence for its potential use in the
treatment of type 2 diabetes
Anthony H Barnett
University of Birmingham and
BioMedical Research Centre, Heart
of England National Health Service
Foundation Trust, Birmingham, UK
Correspondence: Anthony H Barnett
Diabetes Centre, Birmingham Heartlands
Hospital, Bordesley Green East,
Birmingham, B9 5SS, UK
Tel +44 012 1424 3587
Fax +44 012 1424 0593
Email anthony.barnett@heartofengland.
nhs.uk
Abstract: Lixisenatide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist
mimicking several favorable actions of endogenous GLP-1 that result in improved glycemic
control with little or no hypoglycemia and weight loss. Phase II trials have shown that lixisenatide
20 µg once daily restores first-phase insulin release in patients with type 2 diabetes and improves
the second-phase insulin response. Administered once or twice daily for 4 weeks, it significantly
reduced postprandial and fasting blood glucose levels, and glycosylated hemoglobin (HbA1c).
The efficacy and safety of lixisenatide once daily is being assessed in the GETGOAL Phase III
clinical trial program. Results have shown beneficial effects on HbA1c compared with placebo in
combination with commonly used antidiabetes agents, with no increased risk of hypoglycemia
and with beneficial weight reduction. Adverse effects were similar to those observed for available
GLP-1 receptor agonists, the most frequent being gastrointestinal. Both GLP-1 receptor agonists
and long-acting insulin analogs have demonstrated protective effects on beta cells in preclinical
studies. This, along with the pronounced effect of lixisenatide on postprandial plasma glucose,
provides a rationale for combining it with long-acting basal insulin analogs, in the hope that the
additive effects on glycemic control combined with a potential benefit on islet cells may lead to
a new treatment approach to control blood glucose better and prevent long-term complications
in patients with type 2 diabetes.
Keywords: GLP-1 receptor agonist, combination therapy, GETGOAL program, insulin,
lixisenatide, postprandial plasma glucose, type 2 diabetes
Core Evidence clinical impact summary for lixisenatide in type 2 diabetes
Outcome measureEvidenceImplications
Disease-oriented
evidence
Demonstrates all the beneficial
effects associated with
glucagon-like peptide 1
receptor agonists: improved
glycemic control, increased meal-
related and glucose-stimulated
insulin secretion, suppression of
glucagon, weight loss, delayed
gastric emptying, appetite
suppression, and enhanced
beta cell function
Lixisenatide has a pronounced
effect on postprandial
plasma glucose levels
Provides another
therapeutic choice
for a large patient
population
Provides a rationale for
combining with long-
acting insulin analogs
for additive effects on
glycemic control
(Continued)
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Core Evidence 2011:6
Introduction
Worldwide, the type 2 diabetes epidemic continues to expand
and exert socioeconomic strain on national health care systems.1
Statistics from the UK indicate that around 10% of National
Health Service spending is on diabetes and its complications,
which equates to £9 billion.2 Although there is a wide variation
in prevalence by European country, the total number of adults
with diabetes in the region was predicted to reach 55.2 million
by 2010, accounting for 8.5% of the adult population.3
In the UK, as in other countries, the prevalence of type 2
diabetes is increasing and varies with factors including age,
ethnic group, and social deprivation. Quality and Outcomes
Framework data, which provide information on people
17 years of age and older with type 2 diabetes registered
with general practices, indicate that during the period April
2009 to March 2010, the number of people diagnosed in
England increased by more than 125,000 on the previous
year, resulting in a UK prevalence of 5.4%.4 The true
prevalence will be far higher than this because this figure
does not include the estimated 1.1 million people in the UK
with undiagnosed type 2 diabetes. These disturbing figures
illustrate the importance of preventing type 2 diabetes, and
helping those who do have the disease to manage it to prevent
serious complications, such as renal failure, diabetic retin-
opathy, amputation, and cardiovascular disease.
The past decade has seen considerable progress in our
understanding of the pathogenetic mechanisms involved
in the progression of the disease. The treatment of type 2
diabetes has taken advantage of these scientific advances
and resulted in several new therapies coming to the market.
Some of the most important developments in this area sur-
round glucagon-like peptide 1 (GLP-1), a naturally occur-
ring peptide that is released from the gut within minutes
of eating a meal.5 GLP-1 possesses a number of properties
that make it a potentially ideal antidiabetes agent, including
glucose-dependent insulin secretion, inhibition of glucagon
secretion, delayed gastric emptying, and promotion of satiety.
In addition, direct effects on beta-cell growth and survival
have been identified.5
Two therapeutic strategies have been developed to take
advantage of these actions. The first is to use GLP-1 receptor
agonists, which have a substantially longer half-life than GLP-1
due to reduced degradation by the dipeptidyl peptidase 4 (DPP-4)
enzyme. Exenatide and liraglutide are the two currently avail-
able GLP-1 receptor agonists. The second strategy is to inhibit
DPP-4, which prolongs the half-life of endogenously released
GLP-1 and has led to the development of the DPP-4 inhibitors.
Both strategies have proved very successful and the use of these
agents as add-on treatment for type 2 diabetes is endorsed by
the National Institute for Health and Clinical Excellence,6
the European Association for the Study of Diabetes,7 and the
American Diabetes Association,8 among others.
GLP-1 also has a number of favorable effects for patients
with type 2 diabetes beyond its benefits on glucose control.
For example, agents that activate the GLP-1 receptor improve
glucose tolerance alongside a low risk of hypoglycemia,
beneficial weight loss, and have the potential to modify disease
progression.5 The diverse actions of this class, and their novel
and complementary mechanism of action, make them an
appealing addition to the current therapeutic options for treating
type 2 diabetes and significant research is ongoing in this field.
The latest agent to reach Phase III clinical trials is the GLP-1
receptor agonist, lixisenatide. To provide the most up to date
information on this agent, the Clinicaltrials.gov registry was first
searched to identify all relevant clinical trials, then conference
abstracts, and Medline were searched to obtain all published
articles. This review summarizes all the available published
evidence for lixisenatide up to the end of June 2011.
Lixisenatide: a new GLP-1 receptor
agonist
The very short half-life of endogenous GLP-19 has
led to extensive research to find new compounds with
pharmacokinetic properties suitable for development of a
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Barnett
(Continued)
Outcome measureEvidenceImplications
Patient-oriented evidence
HypoglycemiaLow risk of hypoglycemia in
combination with insulin
Nausea is the most frequent
adverse event similar to
other glucagon-like peptide 1
receptor agonists
Beneficial weight loss has been
observed with lixisenatide
if approved, lixisenatide may
offer an alternative in patients
in whom hypoglycemia must
be avoided or weight loss is
important
Gastrointestinal adverse events
weight loss

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Core Evidence 2011:6
pharmaceutical agent. Exendin-4 was first isolated from the
salivary gland of the Gila monster (Heloderma suspectum),
and characterization showed that the peptide was structurally
related to but distinct from GLP-1, with a sequence homology
of 53%.9 Exendin-4 is a potent agonist for the mammalian
GLP-1 receptor with a longer in vivo half-life, prolonged
duration of action, and GLP-mimetic actions.
Lixisenatide (also known as AVE0010 and ZP10) is a
GLP-1 receptor agonist in late-stage development. In 2003,
Zealand Pharma outlicensed lixisenatide to Sanofi-Aventis
who is now responsible for all further clinical development.
Like exenatide, lixisenatide is a synthetic version of
exendin−4. It is able to withstand physiological degradation
by DPP-4 as a result of C-terminal modification with six lysine
residues and deletion of one proline (Figure 1). The half-life
of lixisenatide is 2−4 hours, and it is classed as a short-acting
GLP-1-receptor agonist, compared with the long-acting
GLP-1-based peptides, liraglutide and albiglutide. Despite its
relatively short half-life, lixisenatide is intended for once-daily
dosing as a result of its strong binding affinity to the GLP-1
receptor. Receptor binding studies have shown that the median
inhibitory concentration (IC50) of lixisenatide for the human
GLP-1 receptor is 1.4 nM, which is approximately four-fold
greater than the affinity of GLP-1.10 In contrast, liraglutide
has been shown to displace radiolabeled GLP-1 from human
GLP-1 receptors with an IC50 of 0.11 nM, compared with
values of 0.35 nM for GLP-1 and 0.55 nM for exenatide.
Preclinical findings
The preclinical pharmacological profile of lixisenatide
demonstrates a number of important acute and longer-term
actions that are highly relevant to the maintenance of glucose
homeostasis. A detailed review of the preclinical pharmaco-
logical profile of lixisenatide is provided by Werner et al11
and is only briefly summarized here.
Effects on glucose-stimulated insulin
secretion
The beneficial effects of lixisenatide on glycemic control
have been demonstrated in both healthy animals and in
animal models of type 2 diabetes. In isolated pancreas from
healthy Wistar rats, lixisenatide significantly improved
glucose-stimulated insulin secretion compared with saline
control after a switch to high glucose concentrations. The
effect of lixisenatide on insulin secretion was greater than
that observed with GLP-1, consistent with the greater affinity
reported for lixisenatide at the GLP-1 receptor.12
When fed a lipid-rich diet, the inherited obesity gene
mutation of the Zucker Diabetic Fatty (ZDF) rat provides us
with an animal model that mimics human adult onset type
2 diabetes and its related complications. A continuous sub-
cutaneous infusion of lixisenatide 50 µg/kg/day for 6 weeks
to ZDF rats preserved both first-phase and second-phase
glucose-stimulated insulin secretion and total insulin secre-
tion, whereas untreated rats showed a progressive impairment
of insulin secretion and loss of the biphasic pattern of insulin
secretion during the development of type 2 diabetes.12 Treated
ZDF rats also demonstrated a suppression of glucagon secre-
tion in response to high glucose concentrations.
Effects on blood glucose levels
In healthy normoglycemic dogs, single subcutaneous injections
of lixisenatide produced dose-dependent reductions in plasma
glucose after an oral glucose challenge and significantly
reduced postprandial glucose excursions by 67% compared
with placebo without increasing insulin concentrations.13
Using absorption of paracetamol as a measure of gastric
emptying, the researchers observed that lixisenatide signifi-
cantly reduced arterial plasma paracetamol concentration by
53% versus placebo, suggesting that the effect of lixisenatide
on postprandial blood glucose excursions in dogs is, at least
in part, related to inhibition of gastric emptying and delayed
intestinal glucose absorption.13
Dose-dependent reductions in plasma glucose after an
oral glucose challenge have been demonstrated in both the
db/db mouse and ZDF rat,10,14 two rodent models of diabetes
in which mutations in the leptin receptor gene result in
obesity and insulin resistance. Importantly, this activity was
glucose-dependent with no effect at physiological glucose
concentrations. Although the lack of effective leptin signaling
GLP-1 (7–37)
GLP-1 (7–36) amide
Exendin-4
Lixisenatide
H2N–H
H2N–H
H2N–H
H2N–H
–COOH
–CONH2
P
PSS
–CONH2
K K K K K K
–CONH2
A
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Figure 1 Structure of lixisenatide. The amino acid sequence of lixisenatide is shown alongside that of exendin-4 and pharmacologically active forms of human glucagon-like
peptide 1. Amino acids highlighted in black show elements of lixisenatide or exendin-4 that differ from human glucagon-like peptide 1. Amino acids highlighted in gray show
elements unique to lixisenatide.11
Abbreviation: GLP-1, glucagon-like peptide 1.
Note: Reprinted from Regulatory Peptides, Vol 164, U Werner, H Haschke, AW Herling, W Kramer, Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist
for the treatment of type 2 diabetes, Pages 58–64, Copyright 2010, with permission from Elsevier.
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Lixisenatide in type 2 diabetes

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Core Evidence 2011:6
in db/db mice and ZDF rats promotes the development of
diabetes via mechanisms that do not commonly occur in most
human patients with type 2 diabetes, these animal models
have contributed substantially to our understanding of the
pathophysiology and treatment of type 2 diabetes and its com-
plications. In db/db mice, chronic lixisenatide administration
prevented the progressive deterioration in glucose tolerance
observed in control animals and was associated with signifi-
cant dose-dependent reductions in glycosylated hemoglobin
(HbA1c).10 In ZDF rats, a continuous subcutaneous infusion
of lixisenatide 50 µg/kg/day for 12 weeks significantly
decreased basal blood glucose and improved oral glucose
tolerance compared with control animals.14 At the end of the
study, there was also a significant 1.7% reduction in HbA1c
compared with controls. Lixisenatide had no hypoglycemic
effect and did not change HbA1c in normoglycemic rats.
Effects on beta cell function
There is also evidence from animal studies that lixisenatide
can maintain beta cell mass and function through stimulation
of islet cell proliferation and neogenesis, and inhibition of
islet cell apoptosis. In two experiments in the db/db mouse
model of diabetes in which animals were treated chroni-
cally with intraperitoneal administration of lixisenatide up
to 500 µg/kg or control, lixisenatide preserved pancreatic
insulin mRNA expression and was associated with a dose-
dependent increase in beta cell mass.10
The effects of lixisenatide on beta cell function have also
been evaluated using pancreatic islets isolated from eight post
mortem subjects who did not have type 2 diabetes.15 The islets
were cultured either acutely (1 hour) under physiological
conditions at low (2.8 mmol/L) or high (20 mmol/L)
glucose concentrations, or chronically (48 hours) under
lipotoxic conditions, followed by a 1-hour incubation at
low or high glucose concentrations. Under physiological
conditions, lixisenatide dose-dependently increased glucose-
stimulated insulin secretion in human islets to a greater
degree than GLP-1. Chronic lipotoxic stress conditions led
to increases in triglyceride content, decreases in insulin con-
tent, and reductions in glucose-stimulated insulin secretion
in untreated human islets. Although lixisenatide and GLP-1
had no effect on triglyceride content, both peptides were
able to prevent lipid-induced insulin depletion. Moreover,
lixisenatide and GLP-1 were able to preserve the beta-cell
response to glucose in human islets.
In vitro studies using the INS-1 rat pancreatic beta cell
line have shown that lixisenatide protects beta cells against
lipid-induced and cytokine-induced apoptosis in the order
of 50%−60%.16 Similar findings have been observed when
beta cells are pretreated with several different rapid-acting
or long-acting insulin analogs, and combined treatment of
cells with lixisenatide and the long-acting analog, insulin
glargine, has revealed additive activity and the prevention of
both cytokine-induced and free fatty acid-induced apoptosis
by up to 80%. These early findings are now being evaluated
in clinical trials to determine whether the combination of
a GLP-1 receptor agonist, such as lixisenatide, and insulin
glargine might represent an effective strategy for preserving
beta cell mass in patients with type 2 diabetes.
Pharmacokinetic and
pharmacodynamic studies
Two lixisenatide trials have determined the dose-response
effect and successfully demonstrated the restoration of insulin
release in patients with type 2 diabetes taking oral anti-
diabetes agents.17,18 In a 4-week study, the pharmacokinetics
and pharmacodynamics of stepwise increasing doses of lix-
isenatide were examined in 64 patients with type 2 diabetes
(HbA1c $ 7.0% to # 10.0%).17 Patients were randomized to
one of three treatment arms, ie, lixisenatide once daily (5 µg
in the morning with volume-matched placebo in the evening),
lixisenatide twice daily (5 µg in the morning and 5 µg in the
evening), or volume-matched placebo in the morning and
evening. The lixisenatide treatment was increased, based
on tolerability, every fifth day in increments of 2.5 µg to a
maximum dose of 20 µg per injection (ie, 20 µg in the once-
daily arm and 40 µg in the twice-daily arm). Patients were
on a stable treatment with metformin and/or sulfonylurea,
which was maintained throughout the study.
Lixisenatide concentrations increased in a dose- dependent
manner, reaching peak concentrations between one and two
hours (Table 1).17 At each dose level (5 µg, 10 µg, and 20 µg)
the morning steady-state plasma concentration profiles were
similar for the once-daily and twice-daily lixisenatide treatment
groups. Mean area under the concentration-time curve (AUC)
and peak plasma concentration (Cmax) increased according to the
dose and dose frequency of lixisenatide (Table 1). Comparisons
of lixisenatide doses (5 µg, 10 µg, and 20 µg) demonstrated
significantly greater AUC h.pg/mL values for the 20 µg group
compared with all other treatment groups (Table 1).
At doses of 5–20 µg, both the once-daily and twice-daily
lixisenatide treatment regimens were associated with statisti-
cally significant improvements in the primary endpoint of
change in the AUC for postprandial blood glucose after a
standardized test meal on day 28. The greatest reductions in
postprandial blood glucose compared with placebo were seen
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Core Evidence 2011:6
after the breakfast test meal; there were no significant dif-
ferences between the two treatment regimens in the primary
endpoint. As observed with other GLP-1 peptide agonists,
five patients did form antibodies to lixisenatide, and pharma-
cokinetic data were reported only for those individuals who
were antibody-negative (n = 59) due to a potential interaction
between anti-lixisenatide antibodies and the assay to deter-
mine lixisenatide plasma concentrations. In this study, the
half-life of lixisenatide was 2.7–4.3 hours and was slightly
longer in the groups that received twice-daily dosing.
In a two-way crossover study, 22 patients with type 2
diabetes were randomized to a single subcutaneous injec-
tion of lixisenatide 20 µg or placebo.18 Two hours after
the lixisenatide or placebo injection, patients received an
intravenous bolus of glucose 0.3 g/kg body weight over a
period of 30 seconds. Lixisenatide enhanced the first-phase
insulin response to intravenous glucose by more than
six-fold and second-phase insulin response by approximately
three-fold compared with placebo (Figure 2). In this study,
lixisenatide did not affect glucagon suppression. Maximum
plasma concentrations were achieved 2 hours after the
single injection.
To determine the pharmacokinetics and safety of
l ixisenatide in patients with renal impairment, a single
5 µg subcutaneous injection was administered to eight
healthy subjects with normal renal function (creatinine
clearance .80 mL/minute), and eight each with mild
(50–80 mL/minute), moderate (30–50 mL/minute), or
severe renal impairment (,30 mL/minute, but not requiring
dialysis).19 AUC and Cmax values observed in patients with
mild to moderate renal impairment did not differ significantly
from those observed in healthy subjects. In patients with
severe renal impairment, drug exposure was increased,
suggesting that dosage adjustment may be required.
To characterize the dose-response effect of lixisenatide
fully, a total of eight regimens (5, 10, 20, or 30 µg) each
administered once daily or twice daily, were compared with
placebo in a 13-week, randomized, placebo-controlled,
parallel-group study of 542 patients with type 2 diabetes
(HbA1c $7.0% to ,9.0%) who were inadequately controlled
on metformin monotherapy.20 The lixisenatide 20 µg and
30 µg doses were administered in escalating doses during the
first 4 weeks of the study, with the dose initiated at 10 µg for
1 week and increased by 5 µg per week up to the target dose.
At week 13, statistically significant reductions in the primary
endpoint (change in HbA1c from baseline to endpoint) were
observed for all lixisenatide treatment groups compared
with placebo (all P , 0.01 versus placebo). A dose-response
relationship for HbA1c level was observed for both the once-
daily and twice-daily lixisenatide dosing regimens. Mean
HbA1c reductions from the mildly hyperglycemic baseline
HbA1c of 7.6% were 0.47%, 0.50%, 0.69%, and 0.76% for
the once-daily lixisenatide regimens, and 0.65%, 0.78%,
0.75% and 0.87% for the twice-daily regimens, respectively,
compared with 0.18% for placebo (Figure 3). A target
Table 1 Pharmacokinetic results from a study of 64 patients with type 2 diabetes randomized to lixisenatide once-daily or twice-daily,
or placebo for 28 days. Results are for the 24-hour measurement period performed on days 4, 12, and 2817
Variable
Day 4 (5 μg)
Lixisenatide
1×/day (n = 8)
267.6 ± 130
Day 12 (10 μg)
Lixisenatide
1×/day (n = 9)
420.5 ± 178
Day 28 (20 μg)
Lixisenatide
1×/day (n = 9)
847.8 ± 337
Lixisenatide
2×/day (n = 11)
512.6 ± 152
Lixisenatide
2×/day (n = 11)
916.0 ± 249
Lixisenatide
2×/day (n = 11)
1788.6 ± 709AUC h⋅pg/mL
(mean ± SD)
Cmax, pg/mL
(mean ± SD)
tmax, h (median)
T½, h (median)
Abbreviations: AUC, area under the concentration-time curve; SD, standard deviation; tmax, time to peak plasma concentration; t1/2, elimination half-life.
37.3 ± 12 50.9 ± 17 82.7 ± 37108.6 ± 24187.2 ± 70234.4 ± 90
1.25
3.4
2.25
4.3
1.25
2.7
2.25
3.1
1.25
2.8
1.25
3.2
0
100110120 130
Time (min)
IV glucose
1st phase
insulin release
Insulin secretion rate (pg·kg−1·min−1)
140 150
Placebo
Lixisenatide
160
5
10
15
20
Figure 2 Mean insulin secretion rate after an intravenous glucose challenge following
injection of lixisenatide 20 µg or placebo.18
Note: Data compiled from ClinicalTrials.gov.
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Lixisenatide in type 2 diabetes