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DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
48
VOLUME 9 NUMBER 1 • MARCH 2012
Fig. 3.
Change in weight.
Fig. 4.
Change in systolic blood pressure.
cal significance. It has been shown to
improve left ventricular heart function
in patients with myocardial infarction,
improve endothelial function and reduce
systolic blood pressure.
In the pancreas: proven to preserve
•
β
-cells
(in rodents) by having anti-apoptotic
properties and cause
β
-cell regeneration.
This is of course a difficult phenomenon
to prove in humans, but would make
GLP-1 ideal in the very early stages of
dysglycaemia (pre-diabetes). GLP-1 also
inhibits glucagon release from cells,
responsible for maintaining hepatic glu-
cose output by promoting glycogenolysis
and gluconeogenesis, thereby causing
fasting hyperglycaemia.
Type 2 diabetes is regarded as an incretin-
deficient state and therefore restoration of
hormonal levels to normal would be one of
the physiological means of controlling dys-
glycaemia, with the advantages mentioned
above.
Liraglutide
Liraglutide is a GLP-1 analogue with 97%
linear amino acid sequence homology to
human GLP-1, and a fatty acid side chain for
binding to albumin. It has a half-life of 13
hours, making it ideal for once-daily subcu-
taneous injection. Produced by recombinant
DNA technology in yeasts, liraglutide has
been available in Europe since 2009 and in
the USA and Japan since January 2010. In
South Africa, we are currently awaiting reg-
istration.
In a series of phase III clinical studies
called the LEAD program (with more than
4 400 patients), liraglutide was used as
monotherapy and in combination with one
or two oral antidiabetic agents, in different
dosages (0.6, 1.2 or 1.8 mg). Liraglutide
was measured against active comparators,
including insulin, and against placebo. The
results of these studies are summarised in
Figs 1–4.
Blood pressure reduction was independ-
ent of weight loss. There was no statisti-
cal difference in diastolic blood pressure
changes. There was an increase in pulse rate
of about two to four beats per minute in the
liraglutide group; the clinical significance
of this finding is not yet known. There was
also a reduction in fasting and postprandial
blood glucose, as well as improvement in
β
-cell function (HOMA-B).
Type 2 diabetes is a known risk factor
for Alzheimer’s disease and in a small study
using mice, liraglutide was shown to cross
the blood–brain barrier, where it prevented
memory loss, loss of synapses and deteriora-
tion of synaptic plasticity in the hippocam-
pus. There was also an overall reduction in
the
β
-amyloid plaque count in the cortex
and a reduction in inflammatory response,
as measured by activated microglia. These
are some of the key neurodegenerative
developments found in Alzheimer’s disease,
suggesting liraglutide as a possible treat-
ment in the future.
Common side effects of liraglutide
were mainly gastrointestinal (diarrhoea,
nausea, vomiting, constipation) occurring
within the first four weeks of treatment,
and mostly transient. There was also an
increase in episodes of pharyngitis. There
was no associated increase in the incidence
of pancreatitis or thyroid malignancies, or
any other biochemical, haematological or
fundoscopical changes.
My recommendatons for liraglutide
positioning
It makes physiological sense to start liraglu-
tide very early in the dysglycaemic course
(pre-diabetes). The next alternative would
be to add it to those who are failing with
metformin treatment, instead of adding
sulphonylurea, especially in obese patients.
Price unfortunately will always be a factor.
The other alternatives are:
Obese insulin-resistant patients on high
•
dosages of insulin who, by adding GLP-1
analog, will get weight loss and reduc-
tion in insulin dosage.
Patients with very low glomerular filtra-
•
tion rate < 30 ml/min where metformin is
contraindicated.
As third-line treatment for patients on
•
metformin and sulphonylurea, with a
body mass index > 35 kg/m
2
and HbA
1c
level < 7.5%.
Anybody with co-morbid disease where
•
other drugs are contraindicated.
Conclusion
An ultimate antidiabetic drug should be effi-
cacious in terms of reducing HbA
1c
levels,
with no hypoglycaemia, no weight gain,
and preferably weight loss. Ideally it should
be a tablet. I believe we are slowly moving
towards this goal.
Dr Duma Khutsoane, specialist endocrinologist,
Bloemfontein Mediclinic.