ACHIEVING BEST PRACTICE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
160
VOLUME 7 NUMBER 4 • NOVEMBER 2010
Incretin mimetics: where will they make a difference?
ADRI KOK
T
he incretin mimetics have recently been added to our available
choice of anti-hyperglycaemic agents in South Africa. As our
targets for diabetes control tighten, our available choices of
treatment, by necessity, will need to be expanded. The benefits that
the incretin mimetics afford include weight loss that is sustained,
possible beta-cell sparing and of course significant lowering of the
blood glucose level.
These agents address both fasting and post-prandial glucose
levels, reduce the risk of hypoglycaemia and avoid the weight gain
seen with sulphonylurea drugs and insulin. They exert their effect
through a glucose-dependant stimulation of insulin secretion,
inhibition of glucagon secretion, slowing of gastric emptying, and
by a reduction in appetite.
1
The first in this class of incretin mimetics is the glucagon-like
peptide-1 (GLP-1) receptor agonists, of which exenatide (Byetta)
has been the first to be introduced to our market. The second,
liraglutide (Victoza), is in the process of registration.
2
The dipeptidyl
peptidase 4 (DPP-4) inhibitors act as incretin enhancers, that is
by slowing the inactivation of the incretin hormone (GLP-1) and
glucose-dependant insulinotropic peptide.
The incretins are released by the gastrointestinal tract in response
to food. They are involved with the process of glucose-dependant
insulin secretion and if their inactivation is inhibited, will prolong
their effect and so slow glucose absorption. Several of these agents
are in the process of registration at the Medicines Control Council
(MCC) and are not yet available in South Africa (Fig. 1).
3
Although the GLP-1 agonists were initially introduced for use
at the time of oral agent failure (metformin, sulphonylureas,
repaglinide, TZDs) before the use of insulin, more and more
studies have been done using these agents in type 2 diabetic
patients (T2DM) on various regimens of insulin therapy. At present,
exenatide is approved as adjunctive therapy in T2DM for those
patients on metformin, sulphonylurea, or a combination of these.
It can also be used with a thiazolidinedione. Monotherapy with
exenatide is presently under review by the FDA. It would be logical
to use this agent earlier in the progressive decline of beta-cell
function in T2DM but the cost prevents us from doing so. With the
much cheaper generic alternatives of metformin and the various
sulphonylureas on the South African market, the cost of GLP-1
agonists is prohibitive.
However, the use of the GLP-1 agonists in patients already on
combined oral therapy (metformin) and various insulin regimens
is a great possibility. In one study by Bunck
et al
.,
4
they assessed
β
-cell function, comparing exenatide subcutaneously twice a day
with insulin glargine once daily, titrated to a pres-specified regimen
to control blood sugars to between 4.5 and 5.5 mmol/l. Beta-cell
function was assessed using an arginine-stimulated hyperglycaemic
clamp at weeks zero and 52 and after a four-week off-drug period.
All the patients were on metformin treatment.
The authors found a significant improvement of
β
-cell function
in the exenatide group at 52 weeks compared to insulin glargine. It
also became clear that ongoing treatment is necessary to maintain
this benefit, as both
β
-cell function and glycaemic control returned
to pre-treatment values when these agents were stopped.
4
It is not possible to review here all the studies where exenatide
was compared to various insulin therapies, but all of these
concluded that exenatide was not inferior to or better than the
insulin regimen. At the same time, exenatide-treated patients did
not suffer hypoglycaemia or weight loss, and improved their post-
prandial glucose levels while achieving the same or better HbA
1c
levels (Figs 2, 3).
4
Correspondence to: Dr Adri Kok, physician, private practice,
Johannesburg
e-mail:
S Afr J Diabetes Vasc Dis
2010;
7
: 160–162.
Dr Adri Kok
Figure 1.
The incretin concept.
Mixed meal
Intestinal release of:
GLP-1 from L-cells
GIP from K-cells
↑
Glucose-dependent
insulin secretion
↓
Glucagon secretion
↓
Gastric emptying
↓
Appetite
Active plasma
GLP-1 and GIP
Inactive plasma
GLP-1 and GIP
Rapid inactivation
(
>
80% of pool)
↑
Glucose-dependent
Insulin secretion
↓
Glucagon secretion
DPP-4
GLP-1
actions
GIP
actions
Adapted from Mudaciar & Henry.
2
