Elevated Pancreatic Enzymes and Acute Pancreatitis in Subjects with Type 2 Diabetes Mellitus Treated with Exenatide _Juniper Publishers
Authored by Udaya M Kabadi
Abstract
Background: Acute pancreatitis
is listed as an adverse effect of exenatide [EX] by the regulatory
agencies. However, the prevalence of acute pancreatitis is reported to
be variable in multiple clinical trials and Meta analyses.
Methods: Retrospective comparative
analysis was conducted for incidence of acute pancreatitis in 164
subjects with type 2 Diabetes Mellitus administered Exenatide and age
and weight matched 150 subjects receiving Metformin and SU glipizide.
Results: In 50 subjects, EX was
discontinued, one because of persistent chest pain and 49 because of
onset of severe nausea or/and vomiting. Thirty nine subjects also
complained of abdominal pain. In 35 of these, serum amylase and lipase
were elevated. However, abdominal CT scan confirmed presence of acute
pancreatitis in14 subjects (8.5%) with no apparent pancreatic
abnormality being noted in the remaining 21 subjects (12.8%). Acute
pancreatitis as established by the same diagnostic criteria occurred in 4
subjects (2.7%) treated with Metformin and Glipizide (p< 0.01).
Abdominal pain, nausea and vomiting resolved with simultaneous
normalization of pancreatic enzymes in all subjects following treatment
recommended for acute pancreatitis.
Conclusion: Therefore, the
incidence of acute pancreatitis confirmed by abdominal CT scan is
increased > 3 fold in subjects with type 2 Diabetes Mellitus
administered exenatide when compared with subjects treated with
Metformin and Glipizide. Moreover, elevated pancreatic enzymes without
diagnostic abdominal CT findings in many subjects administered exenatide
may indicate presence of pancreatitis in the early stage of the
disorder although requiring further examination.
Introduction
Regulatory agencies worldwide including FDA have
continued to list acute pancreatitis as an adverse effect of GLP 1
analogs including exenatide despite post marketing studies and Meta
analyses indicating variable incidence [1-5]. However, in many of the
initial clinical trials, data regarding serum concentrations of
pancreatic enzymes in subjects on onset of abdominal pain, nausea and
vomiting was not provided thus possibly missing the diagnosis of acute
pancreatitis. Moreover, a plausible mechanism of occurrence of acute
pancreatitis following administration of these agents has not been
discussed. Therefore, retrospective analysis was conducted for examining
the incidence of acute pancreatitis in subjects administered GLP1
analog exenatide and compared with its incidence in subjects treated
with Metformin and SU Glipizide.
Subjects and Methods
This retrospective analysis examined the incidence of
acute pancreatitis on administration of exenatide in subjects with type
2 diabetes Mellitus. 164 consecutive obese (BMI levels >30kg/m2)
adult subjects, 126 men and 38 women (ages 34- 76 years) with history of
type 2 Diabetes Mellitus and HbA1c levels, 7.5-9.5% and desirable
fasting plasma glucose concentration, 80-130 mg/dl while receiving
metformin, glipizide and insulin glargine between January 2011 and
December 2013 and initiated on sc. exenatide 5mcg twice daily to attain
and maintain postprandial glycemic control are included in this
analysis. The diagnosis of type 2 diabetes was confirmed by fasting
serum C-peptide concentration > 1ng/dl.
The dose of sc. exenatide was increased to 10mcg twice daily
after 4 weeks if subjects tolerated the initial dose. The incidence
of acute pancreatitis in age and weight matched subjects with
type 2 Diabetes Mellitus treated with metformin and glipizide
was used for comparison. The duration of therapy in both
groups of at least 6 months was deemed to be appropriate for
comparison. Exclusion criteria of our study were prior history
of acute pancreatitis, gall bladder disease, gastroparesis and
allergic reaction to any GLP1 analog. Subjects with creatinine
> 1.5mg/dl, liver enzymes > 2.5 time’s upper limit of normal,
serum triglycerides > 500mg/dl and pregnant women were
excluded as well.
All the subjects in both groups were being treated with
either ACE inhibitor Lisinopril or ARB Losartan for management
of hypertension and/or for renal protection as well as a statin,
Atorvastatin or Rosuvastatin for dyslipidemia and/or cardio
protection. Subjects over 50 years of age were also administered
aspirin 81 mg daily in absence of contraindications, e.g. history
of bleeding or a bleeding disorder. Laboratory tests were
determined using well established commercial kits by the
local laboratory at the medical center where the study was
conducted. The statistical comparison between the incidence
of acute pancreatitis in subjects with type 2 diabetes mellitus
administered exenatide on one hand and subjects treated
with metformin and Glipizide on the other was conducted by
multivariate analysis with determination of the relative risk
odds ratio.
Results
In 42 subjects, exenatide was discontinued within 1-3 weeks
after initiation with 5 mcg twice daily, one because of persistent
chest pain and 41 because of onset of severe nausea or/and
vomiting. Exenatide was discontinued in another 8 subjects due
to onset of the same symptoms within a week after increasing the
dose to 10mcg twice daily. Thirty nine of these 49 subjects also
complained of abdominal pain and In 35 of these, serum amylase
and lipase were elevated > 2 x highest normal concentration
indicative of pancreatitis whereas in the remaining 14 subjects,
these enzyme concentrations were normal.
However, abdominal CT scan confirmed presence of acute
pancreatitis in14 subjects (8.5%) with no apparent pancreatic
abnormality being noted on CT scan in the remaining 21 subjects
(12.8%). Acute pancreatitis as established by onset of acute
abdominal pain, elevated pancreatic enzymes and abdominal
CT scan occurred in 4 of 150 subjects (2.7%) treated with
metformin and glipizide (RR 3.2, confidence interval, 2-13- 4.37;
p<0.01vs. exenatide). The relative risk remained significant
(3.0, confidence interval, 1.82-4.16; p<0.01) after elimination
of other factors namely, HbA1c, age, duration of diabetes, serum
triglycerides and liver enzymes by multivariate analysis.
Serum pancreatic enzymes were not determined in any
remaining subjects treated with metformin and glipizide because of lack symptoms, e.g. nausea, vomiting and/ or abdominal pain.
All subjects were treated with therapy recommended for acute
pancreatitis including discontinuation of oral intake, intravenous
infusion of normal saline as well as dextrose and parenteral
administration of drugs for relief of pain. Abdominal pain,
nausea and vomiting resolved within 3-5 days and normalization
of pancreatic enzymes ensued within 7-10 days.
Discussion
Acute pancreatitis in subjects in this study was attributed
to exenetide since other known causative factors, e.g. alcohol,
gall bladder disease, trauma, tumour, peptic ulcer disease,
hyperparathyroidism etc. were excluded. Moreover, the study
also demonstrates 3 fold increase in the incidence of acute
pancreatitis confirmed by history, physical examination and
elevated serum pancreatic enzymes in subjects with type 2
diabetes treated with exenatide in comparison to subjects
administered metformin and glipizide. The incidence is further
exaggerated if the subjects with elevated serum amylase and
lipase concentrations with symptoms diagnostic are included in
the analysis.
Lack of acute pancreatitis diagnostic evidence on abdominal
CT scan may be attributed to the presentation in the early stage
of the disorder. This finding is consistent with several case
reports as well as documentation in some clinical trials and Meta
analyses and animals [6-18]. However, other Meta analyses and
another animal study refute this conclusion [1-5,19-22].
The discrepancy and variability of these conclusions
may be attributed to the differences in the documentation of
concentrations of serum pancreatic enzyme in these reports.
In many clinical trials, serum pancreatic enzymes were not
reported probably because of lack of assessment despite onset
and persistence of characteristic symptoms of acute pancreatitis,
e. g abdominal pain, nausea and vomiting. We believe that
Meta analyses describing lack of increase in incidence of acute
pancreatitis may have included these same clinical trials to
ARGHive at the discrepant conclusion. Finally, the rise in pancreatic
enzymes is well documented in several clinical trials and animal
studies [23,24].
Despite the variability of conclusions by individual
reports, many regulatory agencies continue to mention acute
pancreatitis as a major adverse event in the ‘prescription
information’ document for all GLP1 analogs including exenatide
[1-5]. This alert regarding these drugs may be attributed to
several case reports in the literature describing serious nature
of the presentation of acute pancreatitis as well as the data in
animals [6-18], thus, the occurrence of acute pancreatitis on
administration of GLP1 analogs including exenatide is adequately
established as documented in this report.
However, the data regarding the pathophysiology of the
disorder is sparse. Delay in pancreatic ductal empting similar to the gastric empting, a well established effect induced by GLP1
analogs including exenatide may contribute to stagnation of
pancreatic secretions leading to inflammation. Moreover, this
mechanism is likely to be exacerbated in subjects with type 2
diabetes manifesting autonomic neuropathy involving pancreas
causing asynchronicity between the sphincter of Oddie and
pancreatic ductal musculature similar to gastro paresis [25-29].
The rise in pancreatic enzymes may be attributed to the same
mechanism as well. However, none of the clinical trials or case
reports describes presence of autonomic dysfunction or even
peripheral neuropathy in subjects manifesting acute pancreatitis.
Unfortunately, testing for autonomic dysfunction was not
conducted in subjects in our study as subjects with symptoms of
gastroparesis were excluded. Thus, acute pancreatitis following
administration of these drugs may be consistent with ‘acalculus
pancreatitis known to occur in subjects with diabetes mellitus
and elderly.
Therefore, in conclusion, subjects manifestation abdominal
pain, nausea and vomiting on administration of GLP1 analogs
including exenatide must be evaluated by appropriate testing
for presence of acute pancreatitis and then managed by
recommended therapy as per the alert issued by regulatory
agencies. Moreover, future exposure to any GLP1 analogs must
be avoided in these subjects.
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