December 22, 2022

To: Danya H. Wilson, PharmD

From: Samantha Triplett, PharmD
CC: Genevieve Lynn (Ness) Engle, PharmD, BCMAS
Re: Mild epigastric pain and elevated lipase levels with GLP-1 receptor agonists
__________________________________________________________________________

In response to your request regarding the presentation of mild epigastric pain and mildly
elevated lipase levels in patients taking glucagon-like-peptide-1 (GLP-1) receptor agonists, the
following information is provided.

Response and Recommendation:

There is limited evidence regarding the association of GLP-1 receptor agonist treatment with
mild epigastric pain and/or mildly elevated lipase levels.

There is a probable association of GLP-1 receptor agonists (exenatide, liraglutide, albiglutide,

dulaglutide) and pancreatitis.1 The incidence of GLP-1 receptor agonists and pancreatitis is
unknown and the evidence is limited (evidence from nonrandomized clinical trials, prospective
observational studies, cohort studies, retrospective studies, case-control studies, meta-analyses
and/or postmarketing surveillance studies). The concern for pancreatitis in association with
GLP-1 receptor agonists typically presents with severe abdominal pain.2-13

Analysis and Synthesis:

Abdominal pain is a known adverse event associated with GLP-1 receptor agonists.2-19
However, there is a lack of severity grading of abdominal pain associated with GLP-1 receptor
agonists in the literature and is typically referred to as severe abdominal pain or generally as
abdominal pain. The adverse event rate of abdominal pain/discomfort/distension varies by drug
product and can be found in Table 1. Literature describing mild epigastric pain was not found,
however, reports of epigastric discomfort were reported in the Food and Drug Administration
(FDA) Adverse Event Reporting System (FAERS). 20 Data of reported epigastric discomfort
(Figure 1) and upper abdominal pain (Figure 2) from the FAERS database are included in Table
2. There are currently no reports of epigastric discomfort associated with insulin
degludec/liraglutide or insulin glargine/lixisenatide.

An increase in lipase levels has been associated with a few of the GLP-1 receptor agonists
(dulaglutide, insulin degludec/liraglutide, liraglutide, semaglutide) but all GLP-1 receptor
agonists have a risk associated with pancreatitis.2-19 The increase in lipase levels is not well
understood and varies by drug product. Lipase level increases, similar to abdominal pain, are
not generally graded in terms of severity and instead are just referred to as increases in lipase
levels. However, the individual drug monographs do provide a frequency and/or an average
increase from baseline expected based on the clinical trials. The reported frequencies and/or
average anticipated increase in lipase from baseline are included in Table 1. Reports of
increased lipase (Figure 3) and increased amylase (Figure 4) with GLP-1 receptor agonists from
the FAERS database are included in Table 2.20

Table 1. Abdominal pain/discomfort/distension adverse event (ADE) rate and average

anticipated increase in lipase from baseline associated with GLP-1 receptor agonists (RAs) in
Clinical Pharmacology and each drug’s respective package insert.
Average anticipated increase in
GLP-1 RAs Frequency of abdominal ADE
lipase level from baseline
Dulaglutide
Abdominal pain: 6.5% to 9.4%2,14 14% to 20%2,14
Frequency of abdominal pain not
Exenatide Not mentioned3-6,15
defined3-6,15
Abdominal pain: 5.4%7,8,16
Liraglutide Abdominal discomfort: 4.8% 33%7,8,16
Upper abdominal pain: 5.1%
Subcutaneous: 22%9,17
Oral 7 mg: 30%10,17
Semaglutide Abdominal pain: 5.7% to 20%9-11,17
Oral 14 mg: 34%10,17
Weight Management: 39%11,17
Insulin degludec; Frequency of abdominal pain not
33%12,18
liraglutide defined12,18
Insulin glargine; Frequency of abdominal pain not
Not mentioned13,19
lixisenatide defined13,19

Table 2. FAERS reports of epigastric discomfort, upper abdominal pain, and increased lipase
levels with GLP-1 receptor agonists (RAs).20
Insulin Insulin
GLP-1 RAs Dulaglutide Exenatide Liraglutide Semaglutide degludec; glargine;
liraglutide lixisenatide
Epigastric Discomfort
No. of
Reports/Total 10/54,501 15/76,304 2/34,873 12/15,517 0/781 0/1,889
No. of Cases
Outcomes 8 NS 1 DA 2 DA 2H
2 other 4H 2H 8 NS
-- --
8 NS 2 NS 3 other
2 other 2 other
Upper Abdominal Pain
No. of
Reports/Total 1472/54,501 1572/76,304 1200/34,873 627 12/781 25/1,889
No. of Cases
Outcomes 2 X 15 X 6X 4X 2H 6H
 14 DA 27 DA 14 DA 11 DA 7 NS 16 NS
115 H 243 H 140 H 52 H 3 other 6 other
8 LT 19 LT 8 LT 2 LT
1173 NS 208 1147 NS 910 NS 423 NS
other 5 RI 3 RI 4 RI
254 other 175 other 153 other
Increased Lipase Level
No. of
Reports/Total 167/54,501 190/76,304 292/34,873 51/15,517 6/781 6/1,889
No. of Cases
1 DA 2X 1X 1X 4H 1 DA
34 H 1 DA 2 DA 14 H 2 NS 3H
6 LT 63 H 69 H 15 NS 2 NS
Outcomes 66 NS 4 LT 146 NS 24 other 1 other
1 RI 59 NS 2 RI
72 other 1 RI 92 other
87 other
Increased Amylase Level
No. of
Reports/Total 69/54,501 89/76,304 122 23/15,517 1/781 1/1,889
No. of Cases
1X 1X 1 DA 6H 1H 1H
13 H 1 DA 31 H 2 LT 1 other
1 LT 33 H 2 LT 4 NS
Outcomes 31 NS 2 LT 50 NS 13 other
28 other 21 NS 2 RI
1 RI 46 other
40 other
Abbreviations: died (“X”), disabled (“DA”), hospitalized (“H”), life threatening (“LT”), required intervention (“RI”),
non-serious (“NS”), other outcome (“other”)
Disclaimer: all reported adverse drug reactions are current as of September 30, 2022 and were made without
verification that the medication(s) listed were the direct cause of the reactions above.
Overall, there is a lack of literature available describing specifically, mildly elevated lipase levels
and/or mild epigastric pain associated with GLP-1 receptor agonists. Literature currently
available can be found described in Table 3.

Table 3: Literature search results from Medline Ultimate

Reference Description of Reference
21,22
Smits MM, et al. Measured changes in plasma lipase and amylase levels during
(Letter to the Editor intravenous administration of exenatide compared to placebo in 57
regarding the patients with type 2 diabetes.
Randomized, ● Exenatide loading dose: 50 ng/min in 30 minutes
placebo-controlled, ● Exenatide continuous infusion: 25 ng/min
double-blind, acute ● Plasma lipase and amylase levels were measured at baseline
intervention, clinical (approximately 150 minutes prior to administration) and during
trial) intervention in both a fasting state and after consumption of a high-fat
meal.
● Lipase and amylase levels were within normal limits at baseline.
● Both the lipase and amylase levels decreased upon administration of
exenatide (compared to placebo; p<0.005, confidence intervals were not
included in this report).
● At 280 minutes post infusion, amylase levels were significantly higher
compared to placebo (mean difference; 4.5 土 10.57 units/L; p=0.001).
● Amylase levels never exceeded 3x ULN within the 5 hours.
● Neither the exenatide or placebo treatment groups experienced an
increase in lipase levels during the intervention (confidence intervals
and p-values were not included in this report).
Iyer SN, et al.23 A 76-year-old Caucasian female presented with a 7-day history of severe
(Case report) abdominal pain, vomiting, and fever. Patient was admitted to the hospital.
● Exenatide was initiated 3 years prior to presentation. At presentation,
exenatide dose was 5 μg subcutaneously once daily. The case report
 does not describe how long the patient was on this dose or if the dose
of exenatide was recently changed.
● Sitagliptin 100 mg daily was prescribed a few weeks prior to
presentation.
● Upon presentation, Serum amylase: 1,136 units/L; serum lipase: 3,500
units/L
● Exenatide and sitagliptin were discontinued, insulin initiated.
● Hospitalization day 9: serum lipase was normal (15 units/L); serum
amylase levels were not mentioned at this time.
● Patient discharged to a rehabilitation clinic but was readmitted due to
worsening symptoms.
● Computed tomography indicated extensive pancreatic parenchymal
necrosis.
● Autopsy findings: acute necrotizing pancreatitis with complete digestion
of pancreas.
24
Knezevich E, et al. A 53-year-old African American male presented to the emergency
(Case report) department with new onset intolerable abdominal pain in the upper left and
right quadrant for 2 to 3 hours.
● Serum amylase: 3,963 units/L; serum lipase: > 15,000 units/L
● Computed tomography scan indicated peripancreatic inflammation
(differential diagnosis included acute pancreatitis, fluid accumulation, or
gallstones).
● Patient had previously tried exenatide 5 to 10 μg subcutaneously twice
daily but was discontinued a year prior to hospital admission due to
nonadherence.
● Patient was initiated on a one-month trial of sitagliptin 100 mg daily
when liraglutide was initiated (~9 weeks prior to presentation). Two
months prior to the patient's presentation to the emergency department,
the liraglutide dose was increased from 0.6 to 1.2 mg subcutaneously,
after completion of 0.6 mg subcutaneously daily for one week.
● Liraglutide discontinued indefinitely, all orally administered medications
were discontinued. Patient was treated with intravenous fluids,
analgesia for pain, and initiated on insulin detemir 5 to 13 units daily.
● Day 2 of hospital stay; serum amylase was 435 units/L and serum
lipase was 1,424 units/L.
● Days 3 through 7 of hospital stay, serum amylase and lipase levels had
decreased, and the patient no longer had symptoms.
● Day 8 of hospital stay; serum amylase was 133 units/L and serum
lipase was 532 units/L.
● Patient restarted home medications with the exclusion of liraglutide.
Smits MM, et al.25 A total of 56 patients with type 2 diabetes were randomized 1:1:1 to
(Randomized, receive liraglutide 1.8 mg, sitagliptin 100 mg, or placebo. Secondary
placebo-controlled, endpoint measured change in lipase and amylase serum concentrations
double-blind, from baseline to 2, 6, and 12 weeks of treatment.
12-week intervention, ● At 6 weeks: serum lipase levels were significantly higher with liraglutide
clinical trial) compared to placebo (mean difference: 23.5 units/L [95% CI, 2.1 to
 44.8], p=0.03).
● At 6 weeks: serum amylase levels were increased in the liraglutide
group compared to placebo (mean difference: 10.3 units/L [95% CI, -0.2
to 20.9], p=0.06).
● At 12 weeks: no difference found in serum lipase levels in the liraglutide
group compared to placebo.
● At 12 weeks: no difference found in serum amylase levels in the
liraglutide group compared to placebo.
Steinberg WM, et A total of 9,340 patients with type 2 diabetes were randomized 1:1 to
al.26 receive either liraglutide or placebo. Serum lipase and amylase levels were
(Randomized, measured (fasting) at baseline. Multivariable comparison of serum lipase
placebo-controlled, and amylase levels associated with baseline characteristics.
double-blind clinical ● Baseline lipase for n=9,273 patients (mean 土 SD): 47.5 土 43.7 units/L
trial) ● Baseline amylase for n=9,309 patients (mean 土 SD): 66.2 土 36.3
units/L
● Patients with severely reduced eGFR, defined as <30 mL/min/1.73m2,
produced the largest effect on increasing lipase and amylase at
baseline.
● eGFR<30 effect on lipase activity compared to patients with eGFR≥90,
1.54 (95% CI, 1.413 to 1.678), p<0.0001.
● eGFR<30 effect on amylase activity compared to patients with
eGFR≥90, 1.466 (95% CI, 1.368 to 1.572), p<0.0001.
● Additional analyses of history of cardiovascular disease, thyroid
disease, autoimmune disease, pancreatitis, or gallstones at baseline
concluded that they had no effect on either lipase or amylase activity.

Clinical Pharmacology’s Adverse Event Report list and package inserts were used to determine
the frequency and incidence of pancreatitis and abdominal pain for each GLP-1 receptor
agonist.

Medline Ultimate was searched for literature using the following search terms:
● (MH “Glucagon-Like Peptide-1 Receptor”) AND (MH “Lipase”) - 7 results
● (MH “Glucagon-Like Peptide-1 Receptor”) OR (MH “Glucagon-Like Peptide 1”) AND (MH
“Lipase) - 38 results
● (MH “Glucagon-Like Peptide-1 Receptor”) AND (MH “Abdominal Pain”) AND “mild” - no
results
● (MH “Glucagon-Like Peptide-1 Receptor”) AND (MH “Abdominal Pain”) - no results

Thank you for contacting the Christy Houston Foundation Drug Information Center at the
Belmont University College of Pharmacy. Please do not hesitate to contact the Drug Information
Center at 615-460-8382 or [email protected] with any additional questions.

References:
1. Kale-Padhan PB, Wilhelm SM. Pancreatitis. In: Tisdale JE, Miller DA, eds. Drug-Induced
Diseases. 3rd ed. e-Book. American Society of Health-System Pharmacists;
2018:877-904. Accessed December 19, 2022. https://doi.org/10.37573/9781585285310
2. Dulaglutide. Package insert. Eli Lilly and Co.; 2022.
3. Bydureon® (exenatide synthetic). Package insert. Astrazeneca AB.; 2022.
4. Bydureon BCise® (exenatide synthetic). Package insert. Astrazeneca AB.; 2022.
5. Bydureon Pen® (exenatide synthetic). Package insert. Astrazeneca AB.; 2022.
6. Byetta® (exenatide synthetic). Package insert. Astrazeneca AB.; 2022.
7. Insulin degludec; liraglutide. Package insert. Novo; 2022.
8. Insulin glargine/lixisenatide. Package insert. Sanofi-Aventis US; 2022.
9. Saxenda® (liraglutide). Package insert. Novo; 2022.
10. Victoza® (liraglutide). Package insert. Novo Nordisk Inc.; 2022.
11. Ozempic® (semaglutide). Package insert. Novo; 2022.
12. Rybelsus® (semaglutide). Package insert. Novo; 2022.
13. Wegovy® (semaglutide). Package insert. Novo; 2021.
14. Dulaglutide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated November 22, 2022.
Accessed December 19, 2022. https://www.clinicalkey.com/pharmacology/
15. Exenatide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated July 28, 2022. Accessed
December 19, 2022. https://www.clinicalkey.com/pharmacology/
16. Insulin degludec/liraglutide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated
February 27, 2021. Accessed December 19, 2022.
https://www.clinicalkey.com/pharmacology/
17. Insulin glargine/lixisenatide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated June
17, 2022. Accessed December 19, 2022. https://www.clinicalkey.com/pharmacology/
18. Liraglutide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated December 9, 2020.
Accessed December 19, 2022. https://www.clinicalkey.com/pharmacology/
19. Semaglutide. Clinical Pharmacology. Elsevier, Inc.; 2022. Updated June 16, 2022.
Accessed December 19, 2022. https://www.clinicalkey.com/pharmacology/
20. FDA Adverse Event Reporting System (FAERS) public dashboard. U.S. Food & Drug
Administration. Updated September 30, 2022. Accessed December 19, 2022.
https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-
faers/fda-adverse-event-reporting-system-faers-public-dashboard
21. Smits MM, Tonneijck L, Muskiet MHA, et al. Acute plasma amylase increase after
glucagon-like peptide-1 receptor agonist exenatide administration in type 2 diabetes.
Diabet Med. 2017;34(4):591-592. doi:10.1111/dme.13160
22. Smits MM, Tonneijck L, Muskiet MHA, et al. Cardiovascular, renal and gastrointestinal
effects of incretin-based therapies: an acute and 12-week randomised, double-blind,
placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open.
2015;5(11):e009579. doi:10.1136/bmjopen-2015-009579
23. Iyer SN, Drake AJ III, West RL, Mendez CE, Tanenberg RJ. Case report of acute
 necrotizing pancreatitis associated with combination treatment of sitagliptin and
exenatide. Endocr Pract. 2012;18(1):e1-4. doi:10.4158/EP11264.CR
24. Knezevich E, Crnic T, Kershaw S, Drincic A. Liraglutide-associated acute pancreatitis.
Am J Health Syst Pharm. 2012;69(5):386-389. doi:10.2146/ajhp110221
25. Smits MM, Tonneijck L, Muskiet MHA, et al. Pancreatic effects of liraglutide or sitagliptin
in overweight patients with type 2 diabetes: a 12-week randomized, placebo-controlled
trial. Diabetes Care. 2017;40(3):301-308. doi:10.2337/dc16-0836
26. Steinberg WM, Nauck MA, Zinman B, et al. LEADER 3 - lipase and amylase activity in
subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER
trial. Pancreas. 2014;43(8):1223-1231. doi:10.1097/MPA.0000000000000229