Home' Australian Pharmacist : Australian Pharmacist October 2015 Contents Australian Pharmacist October 2015 I ©Pharmaceutical Society of Australia Ltd.
CONTINUING PROFESSIONAL DEVELOPMENT
Angus Thompson is a Lecturer in Therapeutics
and Pharmacy Practice and PhD candidate at the
University of Tasmania, Hobart and a part-time HMR
After reading this article, pharmacists should be
• Describe the class of antidiabetic agent and
mechanism of action of GLP-1 agonists
• Discuss the indications for GLP-1 agonists and
current place in therapy relative to existing
• Explain when GLP-1 agonists should be and
should not be used.
Competency standards (2010) addressed: 1.3, 4.2,
6.1, 6.2, 7.1, 7.3 .
Accreditation number: CAP151010C
BY ANGUS THOMPSON
It is estimated that 1.7 million Australians currently have diabetes, a third
of whom are living with the condition yet to be diagnosed.
Around 280 people develop diabetes
each day and whilst all forms of the
disease are increasing, 85% of cases
are type 2 diabetes.
This is mirrored
in many countries around the world
and diabetes has been described as
the pandemic of the 21st century.
It poses major challenges to health
Although a range of drugs to manage
hyperglycaemia have existed for many
years, the progressive nature of type
2 diabetes means that it inevitably
becomes harder to maintain glycaemic
control, and especially tight glycaemic
control, over time. This, coupled with
the limitations of established treatment
options, has led to significant interest
in new approaches for reducing blood
glucose levels (BGLs). One of the
outcomes of this research has been
the emergence of the glucagon-like
peptide-1 (GLP-1) receptor agonists,
which may also be referred to as GLP-1
analogues, or incretin mimetics.
It is now around eight years since the first
GLP-1 agonist, exenatide, was launched
in Australia and since that time, both
here and overseas, this class of drug
has become established in the modern
management of type 2 diabetes.
Glucagon-like peptide-1 (GLP-1) and
polypeptide (GIP) are the main incretin
hormones present in humans.2
Secreted by the L cells in the ileum
and colon, and the duodenal K cells
respectively, these incretins play a
fundamental role in lowering BGLs.
The discovery of these peptides followed
the recognition that the spike in blood
insulin levels was greater following an
oral glucose load, than with a similar
intravenous glucose load.
All the available GLP-1 agonists
share a common mode of action,
in that they replicate the effect of
endogenous GLP-1. They have a range
of properties, all of which contribute
to improved glycaemic control, and
other effects desirable for people with
type 2 diabetes. These effects include:
• stimulating a glucose-dependent
increase in insulin synthesis and
secretion by beta cells in the pancreas
• suppressing the inappropriately high
level of glucagon present in people
with type 2 diabetes
• delaying of gastric emptying and
thereby slowing the rate the at which
food-derived glucose is delivered to
• decreasing appetite, increasing satiety
and reducing food intake.
The glucose-dependent effect of
GLP-1 agonists to stimulate insulin
secretion contrasts sharply with older
treatments for type 2 diabetes such
as the sulfonylureas, which are less
discriminate secretagogues. The more
selective effect of GLP-1 agonists means
that as the BGLs fall, the stimulation
of insulin secretion decreases
correspondingly. In addition to this,
the normal physiological glucagon
response to hypoglycaemia is not
impaired. These effects explain why the
risk of hypoglycaemia for patients using
GLP-1 agonists is low when they are not
combined with other drugs that increase
this risk. Effectively the GLP-1 agonists
only reduce BGLs when it is necessary.
The effects of GLP-1 and GIP are
normally terminated by the enzyme
dipeptidyl peptidase-4 (DPP-4).
Consequently, it was recognised
that GLP-1 agonists might not only
have a therapeutic role, but so might
modulators of DPP-4. This led to
development of the DPP-4 inhibitors
(e.g. sitagliptin, linagliptin, vildagliptin),
sometimes referred to as incretin
enhancers, as another treatment option
for type 2 diabetes.
Exenatide, the first GLP-1 agonist to
be marketed, is synthetic version of a
39-amino acid peptide (exendin) first
isolated from the saliva of the lizard
Heloderma suspectum, commonly known
as the Gila monster. Exenatide shares
around half the amino acid sequence of
human GLP-1, but is more resistant to
degradation and exerts a physiological
effect three to four times more potent
than the endogenous hormone.
The second GLP-1 agonist, liraglutide,
is synthesised by recombinant DNA
technology and shares over 95% of the
amino acid sequence of human GLP-1.
The molecular structure of liraglutide
facilitates plasma protein binding that
results in a longer duration of action
compared to exenatide.
In addition, a number of other GLP-1
agonists are available overseas or under
development, e.g. albiglutide, dulaglutide
and lixisenatide.3 These alternatives have
undergone molecular modification to
further increase resistance to degradation
by DPP-4, resulting in an extended
duration of action and a corresponding
need for less frequent administration.
A summary of the key features of the
GLP-1 agonists available in Australia and
overseas is provided in Table 1.
All the GLP-1 agonists exhibit
dose-dependent therapeutic and adverse
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