REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
30
VOLUME 11 NUMBER 1 • MARCH 2014
However, the major limitation of that study is a lack of information
about confounding factors, such as obesity, smoking, alcohol
consumption and other medication use; hence, the results must be
interpreted with caution. A population-based case control study of
adults with type 2 diabetes shows that treatment with sitagliptin or
exenatide is associated with a two-fold risk of acute pancreatitis,
after adjusting for confounding factors
55
; however, pooled analysis
of multiple randomised controlled trials did not show an increased
incidence of pancreatitis with DPP-4 inhibitors.
56,57
Similarly, meta-
analyses of longitudinal studies did not show an increased risk of
pancreatitis with exenatide nor liraglutide.
58,59
Animal studies showing dysplasia and pancreatitic changes in
histology used toxicological dosages of gliptins (up to 200 times the
amount recommended for man) or very high doses of exanitide,
and so their relevance to clinical practice has been challenged.
60,61
Examination of pancreata from a small number of human organ
donors whom were treated with GLP-1 analogues (
n
= 8) and
matched control subjects with and without diabetes (
n
= 12 and
n
= 14, respectively), shows increased dysplastic changes in the
exocrine compartments of the donor group.
62
This autopsy data
is difficult to interpret, because of the difficulties in controlling
for autolysis and confounding variables in the controls; however,
a large retrospective insurance database analysis does not show
an increased risk of pancreatic cancer with the use of exenatide.
63
There is no longitudinal data to date from studies or post-marketing
surveillance that suggests an increased risk of pancreatic cancer is
associated with GLP-1 based therapies in humans.
Much larger studies are required to determine whether there
is a definite link between GLP-1 based therapies and pancreatitis;
however, it is apparent that if there is a risk, it is very low. It seems
prudent, because the concern was raised, that these agents should
be used with caution in patients with risk factors for pancreatitis,
such as a previous history of pancreatitis, alcohol abuse or severe
hypertriglyceridaemia.
There is no convincing evidence that GLP-1-based drugs induce
pancreatic cancer in humans; however, it is prudent that careful
monitoring of these agents over the longer term be carried out, and
the long-term cardiovascular outcome studies underway, especially
for many of the gliptins and GLP-1s, as pooled data should provide
more information as to their safety.
GLP-1 therapies and pancreatic beta-cell function
In a rat model, exenatide administration for eight weeks increased
first phase glucose-stimulated insulin secretion and expanded beta-
cell mass, by increasing cell proliferation and reducing apoptosis.
62
A similar effect is noted in liraglutide-treated rats, the beneficial
effect resulting from altered cell kinetics and amelioration of gluco-
lipotoxicity.
65
In clinical studies of humans with type 2 diabetes,
exenatide may improve beta-cell function; however, there is no
evidence of beta-cell regeneration.
66
Ongoing human studies
are investigating whether GLP-1 based therapies can preserve
pancreatic beta cells.
Thyroid C-cell hyperplasia and GLP-1
Long-term treatment of rodents with liraglutide is associated with
thyroid C-cell hyperplasia and tumours. The GLP-1 receptor is highly
expressed in the C-cells of rats and mice, whereas the expression of
this receptor is low in humans.
67
In a recent study, serum calcitonin
levels were measured at three-month intervals, for up to two years,
in 5 000 subjects receiving liraglutide or alternative therapy. There
was no evidence of an increase in calcitonin due to the GLP-1
receptor agonist.
68
There are no reported cases of medullary thyroid
cancer following initiation of GLP-1-based therapy; however,
caution is warranted in the use of these agents in patients with a
history of thyroid cancer.
GLP-1 analogues and cholesterol
It was shown in human trials that treatment with exenatide reduced
fasting and post-prandial triglycerides, VLDL cholesterol and free
fatty acid levels, in addition to improving markers of oxidative
stress. Following cessation of treatment, lipid levels reverted to
their pre-treatment values, indicating that ongoing treatment may
be necessary to maintain beneficial effects.
69,70
The improvement in
post-prandial lipaemia may be a result of delayed gastric emptying
and insulin-mediated inhibition of lipolysis.
71
GLP-1, metabolic rate and body composition
Treatment with liraglutide does not influence basal metabolic
rate nor 24-hour energy expenditure.
72,73
GLP-1 infusion reduces
diet-induced energy expenditure, primarily through lowering
carbohydrate oxidation, without any effect on protein or lipid
oxidation
74
; hence, the body weight lowering effect of GLP-1
analogues is likely to be due to reduced energy intake, rather than
increased energy expenditure.
It has been noted that treatment with exenatide for one
year reduced body weight by 6% from baseline, whereas the
reduction in total fat mass (measured by DEXA – dual energy X-ray
absorptiometry) was significantly greater, at 11%.
69
Short-term
treatment with liraglutide for eight weeks has shown conflicting
effects on body composition.
73,75
However, long-term treatment with
liraglutide significantly reduced visceral and subcutaneous fat.
76
As
a result of the reduction in abdominal obesity, GLP-1 analogues are
likely to have a favourable impact on cardiovascular risk.
77
Conclusion
GLP-1 was first identified in the 1970s, when it was thought to
be a mediator of the ‘entero-insular’ axis with no other significant
effects.
78
The advent and success of GLP-1-based therapies renewed
interest in its other actions. It is clear that GLP-1-based therapies
have significant beneficial effects on blood pressure, lipid profile,
induction of satiety, and body weight and composition in addition
to glycaemic control. It is unclear whether GLP-1-based therapies
have adverse effects on the exocrine pancreas.Hence, they should
be used with caution in patients who are at risk for pancreatic
diseases.
Key messages
GLP-1 based drugs have a favourable effect on
•
cardiovascular risk factors
GLP-1 based drugs should be used with caution in patients
•
at risk of pancreatitis
Animal studies suggest GLP-1 based drugs improve
•
microvascular complications of diabetes
