VOLUME 11 NUMBER 3 • SEPTEMBER 2014
101
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
treatments. It may suggest that the apparent increase in pancreatic
cancer with GLP-1 mimetic therapy is through the mechanism of
chronic inflammation and increased cell turnover.
6
A cohort study that included patients without claims of
prior pancreatic disease, which initiated exenatide or other
antihyperglycaemic drugs between 2005 and 2007, showed that
with exenatide (
n
= 25 719), 40 confirmed cases of acute pancreatitis
were found, compared to 254 among the other antihyperglycaemic
agents (
n
= 234 536). The conclusion reached was that exenatide
was not associated with an increased risk of pancreatitis when
compared with other antihyperglycaemic medications.
12
Other retrospective cohort studies of a large medical and
pharmacy claims database of 786 656 patients have shown that
the incidence of acute pancreatitis in the non-diabetic group, the
diabetic group, the exenatide group and the sitagliptin group were
1.9, 5.6, 5.7 and 5.6 cases per 1 000 patient years, respectively. The
risk of acute pancreatitis was significantly higher in the combined
diabetic group than in the non-diabetic group.
13
The risk of acute pancreatitis was similar in the exenatide versus
the diabetic control group, and the sitagliptin versus the diabetic
control group. No association was found between the use of
exenatide or sitagliptin and acute pancreatitis.
12,13
Noel
et al.
also
examined the risk for pancreatitis in subjects with type 2 diabetes
and they reported a similar increased risk for acute pancreatitis
(4.22 cases per 1 000 patient years).
14
Pancreas-related events after authorisation of DPP-4 inhibitors
have also raised early concerns about their possible association
with pancreatitis. Events of acute pancreatitis, including fatal
haemorrhagic or necrotising pancreatitis, have been reported in
patients receiving sitagliptin, vildagliptin or saxagliptin. In addition,
a case–control study suggests an association of sitagliptin with an
increased odds ratio of hospitalisation for acute pancreatitis.
15-18
These findings need to be looked at with caution in the light
of data from randomised, controlled trials that did not verify an
association of sitagliptin with acute pancreatitis (
n
= 1 event per
4 709 patient years) compared with a control group (
n
= 4 events per
3 942 patient years).
19
The incidence of acute or chronic pancreatitis
was similar however between patients receiving alogliptin and
those on placebo in a randomised control trial of 18 weeks.
20,21
Linagliptin was associated with an increased number of cases
of pancreatitis compared to placebo. The study showed 11 cases
of pancreatitis among patients treated with linagliptin in a dataset
of 4 687 patients. There were 15.2 cases of pancreatitis per
10 000 patient-year exposure in patients treated with linagliptin as
opposed to 3.7 cases per 1 000 patient-year exposure in patients
receiving placebo.
22,23
Furthermore, therewere 11 reports of pancreatitis
out of 5 902 patients treated with allogliptin and five out of 5 183
patients in the control group during the drug’s clinical programme.
22
Conclusion
There are conflicting data surrounding the latest therapies for
diabetes mellitus, which include the GLP-1 mimetics and the DPP-4
antagonists, with some reports suggesting that there is a link
between incretin use and pancreatic adverse events. Others suggest
that there is no relationship between the two. Current evidence is
insufficient to define a causative relationship between the DPP-4
inhibitors and GLP-1 agonists and pancreatic adverse events. There
is a need for trials of sufficient size and duration with well-defined
parameters, as well as close pharmaco vigilance to evaluate their
effects on the durability of glycaemic control, the durability and
magnitude of weight regulation, their effects on cardiovascular
outcomes and long-term trials on safety.
Acknowledgement
Dr F Mahomed, head of Department of Internal Medicine, Grey’s
Hospital, assisted with this article.
References
1. Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-I) and
abnormalities in type 2 diabetes.
Diabetes Metab
2008;
34
: S65–S72.
2. Nauck AM, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies,
viewpoints on the way to consensus.
Diabetes care
2009;
32
(2): S223–S231.
3. Lamont BJ, Andrikopoulos S. Hope and fear for a new class of type 2 diabetes
drugs: Is there preclinical evidence that incretin-based therapies alter pancreatic
morphology? J Endocrinol 2014;
221
(1): T43–T61.
4. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler
PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy
in humans with increased exocrine pancreas dysplasia and the potential for
glucagon-producing neuroendocrine tumors.
Diabetes
2013;
62
: 2595–2604.
5. Cefalu WT. A critical analysis of the clinical use of incretin-based therapies.
Diabetes Care
2013;
36
: 2126–2132.
6. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler P. Pancreatitis, pancreatic
and thyroid cancer with glucagon like peptide I-based therapies.
Gastroenterology
2011;
141
: 150–156.
7. Niels NCB, Molck AM, Lars MW, Lotte BK. The human GLP I analog liraglutide and
the pancreas. Evidence for the absence of structural pancreatic changes in three
species.
Diabetes
2012;
61
: 1243–1249.
8. Denker SP, Demarco PE. Exenatide (exendin-4)-induced pancreatitis. A case
report.
Diabetes Care
2006;
29
(2): 471.
9. Spranger J, Stammschulte UGT. GLP-I based therapies: The dilemma of uncertainty.
J Gastroenterol 2011;
141
: 20–23.
10. Vangoitsenhoven R, Mathieu C, Schueren B. GLP-I and cancer: friend or foe.
Endocrine Related Cancer
2012;
19
: F77–F88.
11. Phillips LK, Prins BJ. Update on incretin hormones.
A New York Acad Sci
2012:
1–20.
12. Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn SG,
et al
. A
cohort study of acute pancreatitis in relation to exenatide use.
Diabetes Obesity
Metab
2011;
13
(6): 559–566.
13. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated
with exenatide or sitagliptin, a retrospective observational pharmacy claims
analysis.
Diabetes Care
2010;
33
(11): 2349–2354.
14. Olansky L. Do incretin-based therapies cause acute pancreatitis.
J Diabetes Sci
Technol
2010;
4
(1): 228–229.
15. Girgis C, Champion B. Vildagliptin induced acute pancreatitis.
Endocrine Pract
2011;
17
: e48–e50.
16. Saraogi R, Mallik R, Ghosh S. Mid acute pancreatitis with vildagliptin use.
Indian
J Endocrinol Metab
2012;
16
: S480–S482.
17. Kunjathaya P, Ramaswami P, Krishnamurthy A, Bhat N. Acute necrotizing
pancreatitis associated with vildagliptin.
J Oncol Pract
2013;
14
: 81–84.
18. Singh S, Chang H, Richards T, Weiner J, Clark J, Segal J. Glucagon-like peptide-
I-based therapies and the risk of hospitalization for acute pancreatitis in type 2
diabetes mellitus: a population-based matched case-control study.
J Am Med
Assoc Int Med
2013;
173
: 534–539.
19. Engel S, Williams HD, Golm G, Clay R, Machotka S, Kaufman K,
et al.
Sitagliptin:
review of preclinical and clinical data regarding the incidence of pancreatitis.
Int J
Clin Pract
2010;
64
: 984–990.
20. Ligueros MS, Foley J, Schweizer A, Couturier A, Kothny W. An assessment of
adverse effects of vildagliptin versus comparators on the liver, spleen, the pancreas,
the immune system, the skin and in patients with impaired renal function from
a large pooled database of phase II and phase III clinical trials.
Diabetes Obesity
Metab
2010;
12
: 495–509.
21. White W, Cannon C, Heller S, Nissen S, Bergenstal R, Bakris G,
et al
. Alogliptin
after acute coronary syndrome in patients with type 2 diabetes.
New Engl J Med
2013;
369
: 1327–1335.
22. Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a
perspective review.
Ther Adv Drug Safety
2014;
5
: 138–146.
23. Linagliptin assessment report.
Eur Med Agency
(updated 20 September
2012, Cited 5 June 2014). Available from
en_GB/document_library/EPAR_-_public_assessment_report/human/000771/
WC500115748.pdf
