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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
70
VOLUME 8 NUMBER 2 • JUNE 2011
inhibitors (sitagliptin, vildagliptin and saxagliptin). Key features of
the currently licensed GLP-1 receptor agonists and DPP-4 inhibitors
are summarised in Table 3. Clinical studies have shown that
incretin-based therapies not only improve glycaemic control in type
2 diabetes patients, but additionally favour weight management.
However, it must be noted that incretin-based therapies are only
licensed for the treatment of type 2 diabetes, and their effect on
body weight is an additional benefit.
45–49
Interestingly, both GLP-1
receptor agonists, liraglutide and exenatide, are currently being
investigated for the treatment of obesity.
50,51
Of note, due to their
combined beneficial effect on glycaemic control and body weight,
incretin therapies may be a cost-effective treatment option for
selected obese patients with type 2 diabetes.
52–54
GLP-1 receptor agonists
Exenatide
Exenatide is a synthetic form of exendin-4, a peptide originally
isolated from the saliva of the Gila monster (53% homology with
human GLP-1).
45,55
Exenatide can be administered by subcutaneous
injection twice daily at any time within an hour before the morning
and evening meal (Table 3).
45
Exenatide, added to various oral
anti-diabetic agents, significantly reduces HbA
1C
levels (0.8–1.0%
reduction compared with placebo) and induces weight loss
of 2–3 kg from baseline, in the majority of phase III studies.
56–59
Hence, exenatide is currently recommended for use in the UK in
combination with metformin and/or SU in inadequately controlled
type 2 diabetes patients with a BMI
≥
35 kg/m
2
and obesity-related
problems.
60
In patients with BMI
<
35 kg/m
2
exenatide treatment
can be considered if the patient is not suitable for insulin therapy
or would benefit significantly from weight loss.
60
Importantly,
exenatide-induced weight loss seems to be maintained during
follow up, while improvements are also noted in surrogate
markers of beta-cell function.
59,61,62
The most common side effects
of exenatide are nausea and vomiting, probably associated with
inhibition of gastric emptying.
63
However, the weight-loss effect of
exenatide appears to be independent of nausea. The incidence of
hypoglycaemia is low with exenatide, but may be increased when
the drug is combined with SUs (Table 3). In clinical practice, there
have been rare cases of acute pancreatitis in exenatide-treated
patients.
45
Liraglutide
Liraglutide is a once-daily human GLP-1 analogue (97% sequence
identity to human GLP-1).
46
Its current European licence states
Table 3.
Key features of incretin-based therapies licensed in Europe for management of hyperglycaemia
45–49
Glucagon-like peptide-1 (GLP-1) receptor agonists
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Exenatide
45
Liraglutide
46
Sitagliptin
47
Vildagliptin
48
Saxagliptin
49
Administration,
dose
• bd sc within 60 min
before breakfast and
dinner
• 5
μ
g bd increased to 10
μ
g bd after at least 1
month
• od sc independent of
meal times
• 0.6 mg od increased
to 1.2 mg od after at
least 1 week, further
increased to 1.8 mg if
required
• 100 mg od as add-on to
MTF; SU; TZD; MTF
+
SU;
MTF
+
TZD; insulin (with
or without MTF)
• With or without food
• 50 mg od with SU
• 50 mg bd with MTF
• 50 mg bd with TZD
• With or without food
• 5 mg od with MTF
• 5 mg od with SU
(lower SU dose can be
considered)
• 5 mg od with TZD
• With or without food
Indication
In combination with
MTF and/or SU in T2DM
patients with suboptimal
glycaemic control
In combination with MTF
and/or SU or MTF and
TZD in T2DM patients
with suboptimal glycaemic
control
As monotherapy or in
combination with MTF;
SU; TZD; MTF
+
SU; MTF
+
TZD or insulin (with or
without MTF) in T2DM
patients with suboptimal
glycaemic control
In combination with
MTF; SU or TZD in T2DM
patients with suboptimal
glycaemic control
In combination with
MTF; SU or TZD in T2DM
patients with suboptimal
glycaemic control
Very common
(
≥
1/10) side
effects*
Hypoglycaemia (with
MTF
+
SU or SU), nausea,
vomiting, diarrhoea
Hypoglycaemia, nausea,
diarrhoea, headache,
vomiting
Hypoglycaemia (with
MTF
+
SU or SU)
None reported in Summary
of Product Characteristics
Hypoglycaemia (with SU)
Hypoglycaemia
risk
Low – increases when
used in combination with
SU
Low – increases when
used in combination with
SU
Low – increases when
used in combination with
SU
Incidence was common
with SU or MTF,
uncommon with TZD
Low – increases when
used in combination with
SU
Clinical practice
points
Only recommended in
patients with normal
kidney function or mild
renal impairment
Inform patients on
pancreatitis symptoms
Once-daily dosing
Independent of meal time
Only recommended in
patients with normal
kidney function or mild
renal impairment
Inform patients on
pancreatitis symptoms
Not recommended for
patients with moderate or
severe renal insufficiency
Inform patients on
pancreatitis symptoms
Monitor liver function
before treatment, every 3
months for the first year
and periodically thereafter
Not recommended for
patients with moderate
to severe renal or hepatic
impairment
*Side effects rated as very common (
≥
1/10) in Summary of Product Characteristics.
For full details please refer to Summary of Product Characteristics.
bd
=
twice daily; MTF
=
metformin; od
=
once daily; sc
=
subcutaneous; SU
=
sulphonylurea; T2DM
=
type 2 diabetes mellitus; TZD = thiazolidinedione/glitazone.
