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SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS
VOLUME 9 NUMBER 1 • MARCH 2012 47
In 2000 there was an estimated 171 million
people worldwide living with diabetes,
and this number is predicted to increase
by the year 2030 to 366 million people. It
is estimated there will be a 162% increase
in the incidence of diabetes in Africa, which
sadly, will further erode already depleted
financial and human resources.
Type 2 diabetes mellitus is a complex
metabolic disease, which is characterised
by hyperglycaemia (due to defective insulin
secretion, insulin action or both) and also
hyperglucagonaemia, with resultant dis-
turbances in carbohydrate, fat and protein
metabolism. The exact aetiology of this dis-
ease is unknown, however interplay between
genetics and environmental factors (obesity,
sedentary lifestyle) are considered to play a
critical role in its pathogenesis.
Type 2 diabetes accounts for 90% of
the diabetic population, and the majority
of these individuals die of cardiovascular
disease. The underlying reason for this pan-
demic is obesity, which accounts for 80 to
95% of type 2 diabetes. Obesity also exacer-
bates hypertension and atherogenic dyslipi-
daemia. Therefore, management of weight
gain in diabetes is paramount.
The United Kingdom Prospective Diabe-
tes Study (UKPDS) clearly demonstrated that
over time, most of the currently available
antidiabetic drugs (including insulin) are
associated with weight gain, which further
Drug Trends
Liraglutide, an incretin mimetic
increases the cardiovascular risk. This may
also serve as a deterrent for tight glycaemic
control.
Another impediment to intensive gly-
caemic control is hypogylcaemia, which
although seldom occurring in type 2 diabe-
tes patients, still remains a major concern.
The 2010 National Health and Nutrition
Examination survey (NHANES 111) revealed
that only 44.6% of diabetics have reached
target HbA1c levels below 7%.
By nature, type 2 diabetes is a progressive
disease, which is characterised by declining
β-cell function, with a resultant reduction in
production of insulin. As most antidiabetic
drugs rely on endogenous insulin production,
they ultimately become ineffective, except for
insulin therapy, which needs intensification.
It is against this background that newer
therapies are being developed. These target-
specific pathogenic mechanisms with a
potential of halting or delaying progression
of the disease, providing glycaemic control
with reduced or no risk of hypoglycaemia,
and are weight neutral or, better still, lead
to weight reduction.
Incretin physiology
Incretin hormones, glucagon-like peptide-1
(GLP-1) and glucose-dependent insulino-
tropic polypeptide (GIP) are naturally occur-
ring hormones. GLP-1 and GIP are secreted
by the L cells in the distal part of the small
intestine and colon, and the K cells in the
duodenum and upper jejunum, in response
to oral glucose ingestion. They then bind to
a G-protein-coupled receptor on the pan-
creatic β-cells, where they lead to insulin
release and glucagon suppression in a glu-
cose-dependent manner.
This accounts for up to 70% of insulin
production (the so-called incretin effect).
This then primarily restores first-phase insu-
lin secretion (deficient in type 2 diabetes)
and targets postprandial hyperglycaemia, an
independent cardiovascular risk (DECODE
study).
Incretin hormones have a very short half-
life of one to two minutes as they are quickly
degraded by the enzyme dipeptidyl pepti-
dase-4 (DPP-4). Incretin receptors are ubiq-
uitous and found in many organs, including
the heart, brain, kidneys, gut, lung, nerves
and endothelial cells, where GLP-1 exerts
different effects as described below:
In the brain: promotes satiety and alters •
food preference to healthier food.
In the gut via the vagus nerve: leads to •
delayed gastrointestinal motility, associ-
ated with marked weight loss (average
of 3 kg).
In the kidneys: a natriuretic effect by •
modulating NA+/H + exchange, which has
a hypotensive effect.
In the heart: causes an increase in pulse •
rate, a condition of as yet unproven clini-
Fig. 1. Change in HbA1c level. Fig. 2. Proportion reaching HbA1c level < 7%.