CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012
AFRICA
287
diagnosed, most patients will already have
lost 50% of their beta-cells. Prof Schmidt
underscored that stopping that decline
is a challenge, but that glucagon-like
peptide 1 (GLP-1), an incretin whose
role in diabetes is increasingly being
recognised, could help to achieve some
currently unmet treatment goals. The
so-called ‘incretin effect’ is severely
impaired in type 2 diabetes patients,
which suggests that if the ‘something
missing’ is reconstituted, the condition
could be positively impacted on.
‘The progressive loss of beta-cells starts
early in the disease process, during the
pre-clinical phase’, he said. ‘Even those
who have only impaired fasting glucose
levels experience beta-cell loss, and this
loss is the basis for the deterioration in
glucose control seen in so many studies.
Different drugs have differing effects on
beta-cell apoptosis. Incretin therapy now
gives us the opportunity to intervene by
targeting an aspect of islet cell dysfunction
that other drugs don’t, namely the alpha-
cell dysfunction/hyperactivity that causes
hyperglucagonaemia.’
GLP-1 and 2 were discovered in 1983
and the former’s role in stimulating
insulin secretion was identified in 1985.
‘It’s a player in the pathophysiology
of diabetes as well as a promising
candidate for therapy’, observed Prof
Schmidt. ‘It normalises glucose levels in
poorly controlled type 2 diabetes without
inducing hyperglucagonaemia. Beta-
cells are resensitised to glucose, elevated
glucagon levels 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 secretion and normalisation of
excessive hepatic glucose output. ‘GLP-
1 therapy is a promising option to help
achieve this.’
Incretin-based therapies in
type 2 diabetes: the clinical
evidence
Are all incretin-based therapies
created equal?
Mahomed AK Omar, specialist physi-
cian/endocrinologist/diabetologist,
Parklands Medical Centre, and honorary
professor, Department of Diabetes and
Endocrinology, University of KwaZulu-
Natal, Durban
There are two types of incretin therapy,
namely GLP-1 receptor agonists and
dipeptidyl 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 amodest 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
