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VOLUME 9 NUMBER 2 • JUNE 2012
85
SA JOURNAL OF DIABETES & VASCULAR DISEASE
CONFERENCE REPORT
exenatide and liraglutide have been widely
used in clinical practice in the UK since 2008
and 2009, respectively.
15
Improvements in
glycaemic control and body weight in the
clinical setting correlate with that observed
in the trial setting.
With experience from his own practice,
Dr Kumar commented that incretin therapies
were superior to insulin, sulfonylureas and
thiazides forweightadvantageandavoidance
of hypoglycaemia. With an excellent safety
and tolerability profile (nausea usually settles
within a week), incretin therapy has high
acceptability in patients.
Furthermore, Dr Kumar finds incretin
therapy suitable for use in the patient
failing metformin; and has noted efficacy
in combination with almost all other oral
anti-diabetic agents (as well as insulin) at
different stages of the natural history of
disease progression. Cost as a limiting factor
was the only disadvantage highlighted, with
Dr Kumar postulating that he expects this
to also be a disadvantage for use in South
Africa.
Source
Ussher JR, Drucker DJ. Cardiovascular Biology of the
Incretin System.
Endocrine Rev
2012;
33
: 187–215.
Incretins in combination with
insulin
The rationale for using incretin mimetics
with insulin was discussed by Prof Mahomed
Omar (South Africa) and Dr Ajay Kumar
(India) with reference to relevant studies.
Adding incretins to insulin-treated
patients
‘At the outset, this approach should seek
to mitigate the problems associated with
increasing insulin dosages such as weight
gain, hypoglycaemia and complications of
high insulin dose therapy’, Prof Omar said.
He addressed firstly, the addition of DPP-4
inbhibitors, vildagliptin and sitagliptin to
type 2 diabetes patients who are poorly
controlled on insulin.
16,17
‘The reductions in HbA
1c
levels were
modest, about 0.59%, but were sustained
over a year, when these agents were added
to patients on insulin, with or without
metformin. Experience with hypoglycaemia
was mixed, with vildagliptin reducing
hypoglycaemic events and sitagliptin
increasing these events, perhaps due to the
latter study design, which tried to improve
overall glucose control. The weight reduction
effect was neutral in both studies’, Prof
Omar pointed out.
Turning to the incretin mimetics, Prof
Omar cited a proof-of-concept study where
the addition of exenatide to patients on
insulin glargine resulted in a greater decrease
in HbA
1c
level (a reduction of 1.9%), a low
hypoglycaemic event rate and weight loss of
1 to 2 kg in the exenatide arm.
18
In a further study of exenatide, which
was given to patients with diabetes of long
duration (10 years) and an expected low
level of residual beta-cell function, who
were already on insulin, metformin and
pioglitazone, exenatide (bd) resulted in
improved glucose control accompanied by a
very significant reduction in insulin (glargine)
dose.
19
‘The adverse GI events with incretin
mimetics were as expected but did improve
over time’, Prof Omar noted.
A newer concept: patients already on
liraglutide who are then given added
insulin
In a well-conducted study over a year,
20
the addition of insulin detemir to a group
of patients on metformin and liraglutide,
who were not yet at target HbA
1c
level, was
contrasted with the larger primary group,
which had reached optimal control on these
two agents (61% of the 988 patients),
and to a control group within the poorer-
controlled arm without insulin. The patients
receiving insulin were told to self-titrate,
and in this well-controlled therapy reached
the recommended range of 35–40 U/day of
insulin detemir.
Importantly, the addition of insulin
detemir resulted in a further drop of 0.5%
in HbA
1c
level and patients did not gain
weight. The rate of hypoglycaemia was very
low at 0.23 in these insulin-treated patients.
‘If you contrast this to the Treat-To-Target
study, where a rate of three to 3.5 episodes/
patient year was seen, this strategy was very
successful’, Prof Omar noted.
‘In conclusion, it is better to put patients
onto a GLP-1 agonist before using insulin than
using the reverse strategy’, Dr Ajay Kumar.
There have been no studies as yet using
incretin-based therapies in children/
adolescents under the age of 18 years
and clinicians should wait for these
studies before treating this category of
patient –
Prof Juris Meier
Incretins and pancreatitis
Dr Adri Kok and Prof Juris Meier
This session scrutinised the evidence related
to the increased prevalence of acute
pancreatitis in type 2 diabetes patients,
acknowledging that these patients have
a three-fold higher risk of developing
pancreatitis (4.5 cases per 1 000 patient
years). ‘We know that the exocrine pancreas
is also affected in diabetic patients, with
increased fibrosis occuring in both type 1
and type 2 diabetes’, Dr Adri Kok noted.
Prof Meier presented the animal studies
on incretins and the risk of pancreatitis,
noting the difficulty of extrapolating these
findings to humans.
Following the published analysis of the
Adverse Event Reports (AERS) as reported to
the FDA,
21
the EASD has recently published
their expert comment on their website
http://www.easd.org/easd/index.php/easd-
statements. Their evaluation indicates that
at this juncture the AERS evaluation cannot
be considered as robust data on which to
base clinical decisions.
Dr Kok concluded that physicians should
not over-interpret this matter, but should
be cautious. In summary, Prof Ascott-
Evans noted that there is no major signal
of concern about either incretin mimetics
or DDP-4 inhibitors and the causation of
pancreatitis.
Practical advice
Adding liraglutide therapy to a sulpho-
nylurea (SU) plus metformin therapy,
clinicians can halve the SU dose and
then monitor glucose levels to decrease
the risk of hypoglycaemia.
When adding liraglutide to insulin-
treated patients, one can pragmatically
reduce the insulin units by 20–25%, and
then monitor –
Dr Mahomed AK Omar
‘There is no value in doing HOMA tests
prior to using these incretin-based
therapies, as they have been shown to
be effective across the diabetes spectrum
–
Prof Juris Meier