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CONTINUING PROFESSIONAL DEVELOPMENT
The SGLT2 inhibitors are the newest class
of medicines developed for T2DM and
Forxiga (dapagliflozin) was one of the first
medicines in the class to be approved by
the Therapeutic Goods Administration
(TGA) in 2012.
was developed from phlorizin, a
compound that inhibited SGLT1 and
SGLT2.3 However, phlorizin was not
useful as a medicine as it is metabolically
unstable, and poorly absorbed. Its clinical
usefulness was also limited because
of its effects at inhibiting SGLT1 in the
intestines, which caused diarrhoea.
Phlorizin also inhibited facilitative glucose
transporters (GLUTs) to interfere with
glucose uptake into other tissues, leading
to severe hyperglycaemia.
modifications to the chemical structure of
phlorizin, dapagliflozin was developed as
a stable compound that was highly potent
and selective at inhibiting SGLT2.
Place in therapy relative to
The rationale behind the use of
antidiabetic agents in T2DM is to
control BGLs to help control symptoms
of hyperglycaemia (e.g. polyuria,
Adequate control of BGLs
also help prevent and treat long-term
microvascular complications associated
with diabetes, e.g. nephropathy,
neuropathy, and retinopathy.
While there has been debate around the
role of controlling BGLs in macrovascular
complications (e.g. coronary heart,
cerebrovascular, and peripheral vascular
disease), evidence is emerging to suggest
that early control of BGLs may reduce
Before starting pharmacotherapy to
manage BGLs, patients are encouraged
to try to achieve glycaemic control via
lifestyle modifications for 2–3 months,
e.g. healthy eating and exercise/
• when adequate blood glucose control
is not achieved after a 3-month trial of
• when symptoms of hyperglycaemia
are present, or BGLs remain
• in people who are unlikely to achieve
adequate blood glucose control with
lifestyle modifications alone.
Metformin is generally recommended as
first-line therapy for all patients, and it is
the only antidiabetic agent that possibly
reduces cardiovascular mortality.2
Sulfonylureas are recommended
as first line only when metformin is
contraindicated or not tolerated.
Metformin – reduces hepatic glucose
production and increases peripheral
utilisation of glucose.
If blood glucose control remains
inadequate despite metformin
monotherapy, then another antidiabetic
agent is added for a ‘two-drug regimen’.
The first-line options for an additional
antidiabetic agent to be added to
metformin are a sulfonylurea, or a
dipeptidyl peptidase-4 (DPP-4), or a
glucagon-like peptide-1 (GLP-1)
analogue, or basal insulin.2
Sulfonylureas (e.g. glibenclamide,
gliclazide) – increase pancreatic insulin
Most drug-drug combinations will
produce similar glucose lowering
Therefore, choice of treatment
will be guided by patient-centred factors
such as patient preference, the patient’s
clinical picture, and risks versus benefits,
particularly considerations around
hypoglycaemia and weight gain.
For instance, the risk of hypoglycaemia
and weight gain with a sulfonylurea
may be acceptable if the patient does
not wish to administer injections,
as would be required for insulin or
a GLP-1 inhibitor. Other factors to
consider include the cost-effectiveness,
and the evidence and long-term safety
data as this information is more readily
available for some agents than others.
For instance, apart from metformin,
some sulfonylureas and some insulins,
the cardiovascular risks or benefits have
not been well established for other
DPP-4 inhibitors (e.g. sitagliptin,
vildagliptin) – inhibit DPP-4,
which increases incretin hormones
such as glucagon-like peptide-1 and
polypeptide. This leads to an increase
in glucose-dependent insulin secretion,
and reduced glucagon production.
GLP-1 analogues (e.g. exenatide,
liraglutide) – increase glucose-dependent
insulin secretion and reduce
inappropriate glucagon secretion.
It also delays gastric emptying,
which slows glucose absorption and
Insulin (basal insulin regime, e.g. insulin
glargine, insulin detemir, injected
subcutaneously usually at bedtime)
– increases or restores the ability to
metabolise glucose by enhancing
cellular glucose uptake, and also
inhibits endogenous glucose output
Second-line options for an additional
antidiabetic agent to be added to
metformin are an alpha-glucosidase
inhibitor, or a thiazolidinedione, or a
(e.g. acarbose) – delays intestinal
absorption of carbohydrates by
inhibiting alpha-glucosidase enzymes
in the small intestine, and reduces
However, this medicine plays a limited
role in therapy as it is less effective
than sulfonylureas or metformin.
generally usually used when patients
cannot meet glycaemic targets with
other non-insulin antidiabetic agents.
Thiazolidinediones (e.g. pioglitazone,
rosiglitazone) – agonists of peroxisome
proliferator-activated receptor gamma,
which regulates genes involved in lipid
and glucose metabolism; increases the
sensitivity of peripheral tissues to insulin,
and decreases hepatic glucose output.
The usefulness of thiazolidinediones
is limited by their adverse effects
(i.e. increased risk of cardiovascular
adverse events), so the preference is to
use other antidiabetic agents.
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