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VOLUME 9 NUMBER 2 • JUNE 2012
77
SA JOURNAL OF DIABETES & VASCULAR DISEASE
CONFERENCE REPORT
P
arkingwas at a premiumduring the recent
SEMDSA congress hosted in Cape Town.
Balmy autumn weather and spectacular
Atlantic views marginally compensated for
the trudge up a steep incline. However,
the congress itself proved to be most
worthwhile. Many interesting local studies
were presented. Two topics appeared to
dominate the chit chat during tea times:
evidence that has emerged on the use of
incretin-based therapies in the treatment of
diabetes, and the role that vitamin D plays in
the general health of humans.
Incretin-based therapies
The incretins are among the many hormones
responsible for glucose homeostasis.
Incretins, including glucagon-like peptide-1
(GLP-1), are released by intestinal entero-
endocrine cells in response to a meal. GLP-1
elicits glucose-dependent insulin secretion;
suppresses glucagon secretion, appetite and
food intake; slows gastric emptying, and
stimulates beta-cell proliferation in pre-clinical
models. Circulating GLP-1 is short-lived,
80% is degraded within two minutes by the
enzyme dipeptidyl peptidase-4 (DPP-4).
GLP-1 secretion is diminished in patients
with type 2 diabetes mellitus (T2DM); how-
ever its insulinotropic activity is maintained,
resulting in the targeting of this hormone for
diabetic therapy. Incretin agents include GLP-1
receptor agonists and DPP-4 inhibitors. GLP-1
receptor agonists produce effects similar to
native GLP-1 and are resistant to degrada-
tion by DPP-4. DPP-4 inhibitors inactivate the
enzyme responsible for GLP-1 degradation.
Exenatide, a synthetic formulation on exend-
in-4, has similar effects to native GLP-1.
1
Undoubtedly the highlight of the meeting,
a lunchtime professorial debate between
the eminent opinion leaders David Nathan
(MGH Diabetes Centre, Harvard Medical
School, Boston, USA) and Edward Gale
(Diabetes and Metabolism Unit, University of
Bristol, UK) provided an excellent platform
to summarise currently known advantages
and disadvantages of incretin therapy. I am
uncertain as to how the decision was made
(who made it up that steep hill the fastest?),
but David Nathan was in the position of
defending the integrity of incretin therapy
whereas Edward Gale raised some of the
concerns surrounding these agents. In
introducing these speakers, it was stated that
even though they will fight vociferously to
47th SEMDSA congress 2012
get their points across, it doesn’t necessarily
mean that they agree with everything they
say.
In support of incretin therapy, Prof Nathan
explored value judgements on available data.
Among the main points under consideration
was that of an increased body mass index
(BMI) indicating an increased risk for the
development of diabetes. Those with a BMI
> 35 kg/m
2
face a hundred times greater
risk of T2DM. Obesity and other lifestyle
considerations (falling activity levels) are
contributing to the current global diabetes
pandemic.
The undesirability of therapeutic weight
gain with some anti-diabetic agents may also
increase cardiovascular disease risk. Another
consideration is that of the microvascular
complications of diabetes. Glycaemic status
has a significant effect on microvascular
complications; risk reduction has been
equated to a lowered HbA
1c
level.
Referring to the LEAD studies, Prof
Nathan noted that liraglutide was superior
to comparators in HbA
1c
level reduction. He
added that GLP-1 agonists have the value-
add of weight loss; no hypoglycaemia (unless
in combination with other agents); and the
cardiovascular benefits of decreased systolic
blood pressure, decreased triglycerides and
being high-density lipoprotein (HDL) and
low-density lipoprotein (LDL) neutral.
The GLP-1 agonists also display anti-
inflammatory effects and improvement
of beta-cell function. He added that it has
not yet been demonstrated in humans that
GLP-1 analogues improve beta-cell mass. In
the concluding statements of his argument,
Prof Nathan raised the question of how to
weight composite outcomes in trials for
clinical importance or effect.
Prof Gale’s turn at the podium began with
an amusing anecdote from his student days.
He referred to the wise words of one of his
own mentors; that there are three phases in
the use of any new pharmaceutical agent:
‘the best thing since sliced bread’, ‘I wouldn’t
use it on my dog’, and finally, ‘it is appropriate
for use in certain sub-populations’.
With any new agent, problems emerge
over time. He stated that all diabetes
agents are equally effective for HbA
1c
level
reduction. In terms of incretin therapy, we
are ‘optimism rich and data poor’.
Generally, there is insufficient outcome
data for DPP-4 inhibitors, with a significantly
more expensive cost to be factored in. A
cost comparison made revealed a ratio
of 35 metformin to one liraglutide for
equivalent treatment costs. In dealing with
the advantages espoused by Prof Nathan,
Prof Gale questioned whether the weight
loss observed with GLP-1 agonists could
be sustained over the long term. He also
mentioned adverse events, quoting a 20%
discontinuation within three months, with
7% of patients immediately unable to
tolerate GLP-1 agonists.
Heexaminedthesideeffectsofpancreatitis,
renal failure and anaphylaxis. GLP-1 receptors
are profusely expressed in pancreatic exocrine
ducts and there is evidence that GLP-1 has a
proliferative effect on the duct cells, resulting
in a thickening of the lining. Low-grade
inflammation occurs, which could result in
sub-clinical pancreatitis, although there are
currently no data on pancreatic enzyme levels
in humans. Prof Gale also raised the issue
of a highly significant excess of pancreatitis
with the use of exenatide and sitagliptin.
This is consistently reported within the class
of GLP-1 agonists, but not with other anti-
diabetic agents.
Another consideration was that of
beta-cell mass. Proliferation of beta-cells in
humans decreases as they age, therefore we
can’t increase beta-cell mass, according to
Prof Gale. His final concerns were increased
risk of pancreatic cancer and fluid depletion
syndromes with the use of GLP-1 agonists.
Two other interesting presentations exam-
ined the potentially cardioprotective effects
of GLP-1 agonists and DPP-4 inhibitors.
DPP-4 inhibition is cardioprotective
and improves glucose homeostasis
in obese, insulin-resistant rats
B Huisamen, University of Stellenbosch
Faculty of Health Sciences, Department
Biomedical Sciences, Division Medical
Physiology, Cape Town
Currently, therapy based on GLP-1 is one
of the most promising for type 2 diabetes.
Because of the rapid degradation of GLP-1
by DPP-4, a two-pronged pharmaceutical
attack has been developed with the use
of GLP-1 analogues and DPP-4 inhibitors.
Research has focused on the use of DPP-4
inhibitors to raise attenuated levels of GLP-1
observed in type 2 diabetes.