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VOLUME 9 NUMBER 2 • JUNE 2012
CONFERENCE REPORT
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Mahomed AK Omar,
specialist physician/
endocrinologist/
diabetologist, Parklands
Medical Centre, and
honorary professor,
Department of Diabetes
and Endocrinology, University of
KwaZulu-Natal, Durban.
resensitisedtoglucose,elevatedglucagonlevels
are reduced, and because GLP-1 is glucose
dependent, its effects taper off as glucose
levels normalise, therefore also minimising the
risk of hypoglycaemic episodes.
Because higher doses of GLP-1 improve the
insulin response in type 2 diabetes, elevating
GLP-1 levels is the basis for the therapeutic
concept behind the use of GLP-1 analogues.
One such analogue, liraglutide, has been
shown to improve both phases of insulin
secretion. Its restoration of beta-cell sensitivity
is an immediate effect, and it also works in a
chronic setting, improving metabolic control,
with positive effects on glycaemia, weight
loss, insulin secretion and insulin sensitivity.
‘Liraglutide improves two markers of
beta-cell function, HOMA-B and the pro-
insulin/insulin ratio’, said Prof Schmidt.
‘Animal and
in vitro
studies have shown that
it promotes beta-cell survival, stimulating
proliferation and inhibiting apoptosis and,
as a consequence, increasing mass.’ He
added the rider that while the evidence for
proliferation is currently indirect, it is hoped
that long-running clinical studies will, in
time, confirm this.
Liraglutide’s induction of weight loss, as
seen in the LEAD studies,
3-8
is a key advantage
of the treatment. More than 75%of patients
on liraglutide lost weight, with one-quarter
losing an average of 7.7 kg. ‘Data from
LEAD also support its being used as early
as possible to preserve beta-cell mass and
function, with greatest effectiveness seen in
those with early-stage type 2 diabetes who
still had a relatively high beta-cell mass.’
In conclusion, Prof Schmidt reiterated
that targeting islet cell dysfunction resulted
in preservation of beta-cell function and
mass, with restoration of insulin pulsatility,
normalisation of excessive glucagon secre-
tion and normalisation of excessive hepatic
glucose output. ‘GLP-1 therapy is a promis-
ing option to help achieve this.’
Incretin-based therapies in type 2
diabetes: the clinical evidence
Are all incretin-based therapies created
equal?
There are two types of incretin therapy,
namelyGLP-1 receptor agonists anddipeptidyl
peptidase-4 (DPP-4) inhibitors, each with
differing modes of action and hence differing
efficacy and safety profiles. Prof Omar began
by pointing out that endogenous GLP-1 is
degraded by DPP-4 and rendered inactive
within two minutes. ‘This means we need
to prolong the activity of GLP-1 to achieve
metabolic effects. We can either inhibit DPP-4
to lengthen GLP-1’s action, or we can use a
GLP-1 analogue that acts in the same way as
GLP-1, but is not degraded by DPP-4.’ GLP-1
analogues are given subcutaneously. DPP-4
inhibitors are oral medications.
Liraglutide is a once-daily GLP-1
analogue with a 97% amino acid sequence
similarity to human GLP-1. Its half-life has
been prolonged to 13 hours. By contrast,
the other GLP-1 analogue, exenatide, has
only a 53% sequence homology compared
to native GLP-1. It too is resistant to DPP-4
and has a longer half-life, though not as
long as liraglutide’s. It is also available in an
extended-release delivery system, exenatide
ER, which is administered once a week (not
available in South Africa).
Turning to pharmacodynamics, Prof
Omar said that the concentration of active
liraglutide is significantly higher than the
GLP-1 concentration achievable with a
DPP-4 inhibitor. This is significant in that
small levels have only modest effects and
higher levels are necessary to increase satiety
and reduce weight.
The clinical advantages of liraglutide
have been demonstrated in head-to-head
trials. The 1860 LIRA-DDP-4 trial compared
liraglutide to the DPP-4 inhibitor, sitagliptin.
9
There was a significant drop in HbA
1c
levels
in the liraglutide group, but only a modest
benefit in the sitagliptin-treated patients.
Sixty per cent of those on liraglutide
achieved their target HbA
1c
level of < 7%,
compared with only a quarter of those
taking sitagliptin.’
When it came to body weight, liraglutide
produced a 3- to 3.6-kg loss, where the drop
with sitagliptin was only 1 kg. When it came
to side effects, both agents were associated
with some minor episodes of hypoglycaemia,
while there was also some transient nausea
with liraglutide’, Prof Omar noted.
Patient satisfaction rates were higher
with liraglutide. After a year, some sitagliptin
patients were switched to liraglutide; they
experienced improvements in HbA
1c
level as
well as additional weight loss. ‘It is impressive
that patients rated treatment satisfaction
higher with an injectable therapy that cased
mild gastrointestinal (GI) symptoms than an
oral therapy with fewer GI symptoms.’
In the DURATION-2 study, which
compared exenatide once weekly to
sitagliptin or pioglitazone, superior HbA
1c
levels were achieved with exenatide ER.
10
Sixty per cent of patients reached target on
exenatide ER compared with only 30% on
sitagliptin. ‘As expected, weight loss was
also better with exenatide’, observed Prof
Omar. ‘Side-effect profiles were similar, with
no major hypoglycaemic episodes and only
a low frequency of minor hypoglycaemia.’
So if the GLP-1 analogues are superior to
the DPP-4 inhibitors, how do they compare
against each other? In LEAD-6, exenatide
was compared to liraglutide, with HbA
1c
level as the primary endpoint.
8
Liraglutide
had a significantly greater effect in lowering
HbA
1c
levels than exenatide. Those switched
from the latter to the former at 26 weeks
experienced further improvement. Weight
loss was similar with both agents.
Where side effects were concerned,
there was transient nausea with liraglutide,
but the rates of nausea were higher with
exenatide and persisted for longer. ‘Antibody
formation was also much greater with
exenatide, because of its only having a 53%
homology with human GLP-1, compared
with liraglutide’s 97%’, said Prof Omar. ‘This
is significant because these antibodies may
blunt exenatide’s effectiveness.’
DURATION-1 compared exenatide twice
daily to exenatide ER.
11
The latter was
associated with a significantly greater drop
in HbA
1c
levels, with many more exenatide
ER-treated patients attaining the target of
< 7%. Those switched to the ER formula-
tion after 52 weeks experienced further
improvements in HbA
1c
levels, suggesting
that exenatide ER is more efficacious than
exenatide twice daily. Exenatide ER also had
a superior side-effect profile.
DURATION-6 compared exenatide ER to
liraglutide.
12
Liraglutide performed better,
with 60% of patients reaching their HbA
1c
target level of < 7%, compared with 52%.
Weight-loss results were also better with
liraglutide. When it came to side effects,
liraglutide was associated with higher rates
of nausea and vomiting, while injection site
reactions were more common with exenatide
ER (published at present as an abstract only).
‘In conclusion, there is evidence that HbA
1c
lowering is better with GLP-1 analogues
than with DPP-4 inhibitors, and that of
the former, liraglutide is superior to both
exenatide formulations’, said Prof Omar.
GLP-1 analogues, liraglutide in particular, also