100
VOLUME 11 NUMBER 3 • SEPTEMBER 2014
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Incretins: harmful to the pancreas or not?
Nikash Ramsunder
Introduction
Naturally occurring incretins are intestinal hormones that are released in
response to food ingestion in order to potentiate the glucose-induced
insulin response, and account for 50 to 70% of the total insulin
secretion after meal ingestion. Their effects are mediated through
binding with specific receptors as well as neural modulation.
GIP and GLP-1 are both rapidly degraded into their inactive
metabolites by the enzyme dipeptidyl dipeptidase 4.
1
Their physio-
logical actions include:
• stimulation of glucose-induced insulin secretion
• regulation of metabolism in the adipocytes
• promotion of
β
-cell proliferation
• stimulation of insulin gene transcription and hence biosynthesis
• suppression of glucagon secretion in the pancreatic islets
• exertion of trophic effects on pancreatic
β
-cell mass, with
β
-cell
proliferation and
β
-cell neogenesis
• inhibition of gastrointestinal secretion and motility, particularly
gastric emptying
• enhancement of satiety
• stimulate somatostatin secretion
• improvement of endothelial dysfunction in patients with stable
coronary artery disease.
The incretin mimetics GIP and GLP-1, and dipeptidyl peptidase
4 (DPP-4) inhibitors are a new class of antidiabetic agents first
introduced in 2005 (exenatide) and 2007 (sitagliptin), respectively.
The most significant of these benefits that is not found with other
antidiabetic treatments are the glucose-dependant nature of
their insulinotropic effects and that they are associated with very
low rates of hypoglycaemia.
2
They have also shown the ability to
preserve the remaining
β
-cells in diabetes and this at one stage
provided hope that enhancing GLP-1 could potentially alter the
natural progression of diabetes.
3
There is no doubt that incretin-based therapies have been shown
to be effective as glucose-lowering agents, as GLP-1 receptor
agonists demonstrate an efficacy comparable to that of insulin
treatment. This was demonstrated in the AMIGO studies where,
in a comparison of exenatide and insulin glargine, the lowering of
HbA
1c
levels did not differ between the groups during six and 12
months of treatment.
2
However, there is controversy regarding the potential regenerative
effects of incretin therapy on pancreatic
β
-cells, as shown by a
study on pancreases from age-matched donors with diabetes
mellitus (DM) and treated with incretins, those treated with other
therapeutic agents, and non-diabetic control subjects. This study
revealed an average increase in pancreatic mass of around 40% in
those treated with incretins, showing a marked expansion of the
exocrine and endocrine pancreas. The former was accompanied
by increased proliferation and dysplasia and the latter by
β
-cell
hyperplasia with the potential for evolution into neuroendocrine
tumours.
4
This has created concern as to the long-term consequences of
using such therapies. Some of these concerns include the potential
of these drugs to cause acute pancreatitis and to initiate histological
changes to suggest chronic pancreatitis and pancreatic cancer.
Type 2 diabetes mellitus and obesity are known risk factors
for acute and chronic pancreatitis and pancreatic cancer, and
patients are more prone to developing these compared to the non-
diabetic population. Therefore one can assume that there would
be an increased incidence of pre-malignant pancreatic lesions. It
is therefore important to establish whether these pre-malignant
lesions undergo proliferation in response to GLP-1 mimetic therapy
and whether such an effect could explain the early reporting of
pancreatic cancer observed here.
5,6
In animal studies performed on three different species, including
mice, rats and monkeys, the GLP-1 agonist liraglutide did not induce
pancreatitis macroscopically or microscopically in any of the species
when dosed for up to two years and with exposure levels up to 60
times higher than in humans.
7
In another study, however, low-grade
chronic pancreatitis was noted in most rats treated with exenatide,
6
and this is of concern since chronic pancreatitis increases the risk of
pancreatic cancer. There have been reports of acute pancreatitis in
humans with the use of exenetide, the first of which was in 2006.
8,9
Assessment of the US Food and Drug Administration (FDA)
adverse events database (AERS) in 2011
6
showed a six- to 10-fold
increase in pancreatitis in patients treated with the DPP-4 inhibitor
sitagliptin (131 events) and GLP-1 receptor agonist exenatide (971
events), respectively, in comparison to patients treated with the
control drugs rosiglitazone, nateglinide, repaglinide and glipizide
(43 events). The reported event rate for pancreatic cancer was
2.9 times higher for exenatide (81 events) and 2.7 times greater
for sitagliptin (16 events) when compared with control therapies
(13 events).
10
A German adverse-events database showed a high incidence of
reporting of pancreatic cancer in association with exenatide (11
cases in four years with 15 000–25 000 patients treated annually),
with a mean treatment duration of about 12 months. There was no
significant increase for the DPP-4 inhibitors.
10
As these drugs have been around for a relatively short period of
time, these findings must be reviewed with caution. This time period
seems too short to induce tumour development, given the observed
10-year interval between tumour induction, growth and clinical
diagnosis.
9,10
It is also important to consider the limitations of the
FDA AERS database, including incomplete data and reporting bias
introduced by potential confounders, which influenced the choice
of drug therapy, e.g. cigarette smoking, obesity and gender.
11
The above analysis shows an increased reporting of pancreatic
cancer in association with exenatide, compared with other
Correspondence to: Dr Nikash Ramsunder
Department of Internal Medicine, Tygerberg
Hospital, Cape Town
e-mail:
S Afr J Diabetes Vasc Dis
2014;
11
: 100–101
