Stephanie Schenck reviewed the risks of acute pancreatitis and pancreatic cancer associated with incretin-based diabetes medications like Januvia and Victoza. She discussed case reports that prompted FDA warnings, potential biological mechanisms, and clinical studies that both supported and disputed a risk. While a mechanism can't be ruled out, most human studies found no increased risk of pancreatitis or cancer. However, the drugs are not recommended for high-risk patients or those with a history of pancreatitis.

1. Stephanie Schenck, Drake University PharmD Candidate 2015
Advanced Pharmacy Practice Experience: HealthPartners
July 2014
Incretin-Based Therapies and the Risk of Acute Pancreatitis
and Pancreatic Cancer
Why this topic?
 Upcoming formulary changes from Januvia to Tradjenta may bring about
more questions from patients on risks of incretin-based therapies
 To understand the case reports that led to the FDA’s warning and clinical
studies that followed
 To review the proposed biological rationale for pancreatic side effects
 To evaluate the clinical significance of the risk of pancreatitis and pancreatic
cancer from these medication classes
Glucagon-like Peptide 1
 Produced in enteroendocrine cells of the gut, secreted into the bloodstream
when glucose enters the duodenum
 Actions at GLP-1 receptors:
o β-cells: enhances insulin secretion
o α-cells: inhibits glucagon secretion
o Stomach: delays gastric emptying
o Brain: enhance satiety
 Degraded by DPP-4 (dipeptidyl peptidase-4) within minutes
Incretin-based therapies
 DPP-4 inhibitors
o Januvia (sitagliptin), Onglyza (saxagliptin), Tradjenta (linagliptin),
Nesina (alogliptin)
 GLP-1 Receptor Agonists
o Byetta/Bydureon (exenatide) and Victoza (liraglutide)
Pancreatitis1
 Common causes
o Gallstones (35-40%)
o Chronic alcohol abuse (30%)
o Idiopathic (20-30%)
 Incidence rate in non-diabetics: 1.49 cases/1,000 patient-years2
 Symptoms & signs
o Hallmark: persistent severe abdominal pain that may radiate to back
o Nausea & vomiting
o Serum amylase and lipase x3 upper limit of normal
o Characteristics findings on CT scan
 Risk factors of pancreatitis
o Type 2 diabetes at 2.83-fold greater risk2

2. o Hypertriglyceridemia (TRG >1000mg/dL)1
o Obesity
o History of acute pancreatitis
FDA warnings:
 Precaution added to Byetta labeling3
o FDA Alert (10/2007)—30 cases of acute pancreatitis
 27 cases had at least one other risk factor
 22 cases improved after discontinuing Byetta
o Alert Update (8/2008)—6 cases, 2 of which were fatal, of
hemorrhagic or necrotizing pancreatitis
 Sitagliptin Drug Safety Communication: 88 cases of acute pancreatitis4
(2009)
o 2 cases of hemorrhagic or necrotizing pancreatitis
o 45 cases had at least one other risk factor
o 47 cases resolved after discontinuing sitagliptin
 Incretin Mimetics Drug Safety Communication (3/2013)5
o Researchers suggest increased risk of pancreatitis and pancreatic
duct metaplasia based on pancreatitis tissue samples6
o No conclusion made by FDA on whether these drugs cause or
contribute to pancreatic cancer development
Possible biologic mechanism for incretin-induced pancreatitis and pancreatic cancer
 Studies that support a mechanism
o 10 weeks of exenatide in rats led to more pancreatic acinar
inflammation & pyknotic nuclei7,8
o 12 weeks of sitagliptin in rats increased pancreatic ductal turnover,
ductal metaplasia, and in 1 rat, pancreatitis9
o Increased exocrine cell proliferation and dysplasia in human
pancreatic tissue of patients who took sitagliptin or exenatide6
 Limitations: incretin group much older and had longer
duration of DM
 Studies that dispute a mechanism
o 1 year of sitagliptin in mice did not increase islet amyloid deposition,
β-cell toxicity, pancreatic ductal proliferation, pancreatitis, or
pancreatic cancer10
o Preclinical trials show that animal concentrations of sitagliptin far
beyond that expected in human exposure demonstrated no evidence
of treatment-related pancreatitis.11
o Exenatide did not predispose to or exacerbate experimental
pancreatitis in mice12
o 13 weeks of high-dose exenatide in rats was not associated with
ductal cell proliferation or apoptosis.13
o Liraglutide inhibited growth and promoted apoptosis in human
pancreatic cancer cell lines in vitro14

3. Studies analyzing the association between incretin-based therapies and pancreatitis
and pancreatic cancer
 Study that found an association
o Population-based case-control study—patients who used exenatide or
sitagliptin were twice as likely to be hospitalized with pancreatitis
compared to non-users15
 Studies that found no association
o 7 retrospective and prospective cohort studies using healthcare
claims found no association between incretin-based therapy use
(exenatide, sitagliptin, liraglutide) and pancreatitis16-22 or pancreatic
cancer19,21
o 4 meta-analyses found no association between incretin-based therapy
and increased risk of pancreatitis or pancreatic cancer 11, 23-25
Clinical implications:
 Despite conflicting evidence, a mechanism for incretin therapies causing
pancreatitis cannot be ruled out at this time. However, the majority human
studies found no increased risk for pancreatitis and pancreatic cancer. The
fact that high-concentrations in animals had no pancreatic side effects is
comforting.
 Patients on these drugs tend to be overweight type 2 diabetics
 Current prescribing information/warnings26-32:
o None have been studied in patients with a history of pancreatitis and
it is unknown whether these patients are at increased risk. Monitor
for signs/symptoms of pancreatitis; discontinue use immediately if
pancreatitis is suspected and initiate appropriate management
o GLP-1 agonists’ prescribing information only: recommends
consideration of alternative therapies if patient has a history
pancreatitis
 Avoid use in higher risk patients: hypertriglyceridemia, alcohol abusers,
history of recurrent gallstones, history of idiopathic pancreatitis.
 If a patient had drug-induced acute pancreatitis in the past, I would still
consider using incretin-based therapies.

4. References
1. Forsmark CE, Baillie J. AGA Institute Technical Review on Acute Pancreatitis.
Gastroenterology. 2007; 123:2022-2044.
2. Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased Risk of Acute
Pancreatitis and Biliary Disease Observed in Patients With Type 2 Diabetes:
A Retrospective Cohort Study. Diabetes Care. 2009; 32:834-838.
3. Information for Healthcare Professionals: Exenatide (marketed as Byetta)
8/2008 Update. FDA. 8/18/2008.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationf
orPatientsandProviders/ucm124713.htm Accessed July 14, 2014.
4. Information for Healthcare Professionals: Acute Pancreatitis and Sitagliptin.
FDA. 9/25/2009.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationf
orPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/u
cm183764.htm Accessed July 14, 2014.
5. FDA Drug Safety Communication: FDA Investigating Reports of Possible
Increased Risk of Pancreatitis and Pre-Cancerous Findings of the Pancreas
from Incretin Mimetic Drugs for Type 2 Diabetes. FDA. 3/14/2014.
http://www.fda.gov/drugs/drugsafety/ucm343187.htm Accessed July 14,
2014.
6. Butler AE, Campbell-Thompson M, Gurlo T, et al. 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.
7. Nachnani JS, Bulchandani DG, Nookala A, et al. Biochemical and histological
effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia. 2010;
53:153-159.
8. Yu X, Tang H, Huang L, et al. Exenatide-Induced Chronic Damage of
Pancreatic Tissue in Rats. Pancreas. 2012; 41(8):1235-1240.
9. Matveyenko AV, Dry S, Cox HI, et al. Beneficial Endocrine but Adverse
Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide
Transgenic Rat Model of Type 2 Diabetes. Diabetes: 2009; 58:1604-1615
10. Aston-Mourney K, Subramanian SL, Zraika S, et al. One Year of Sitagliptin
Treatment Protects Against Islet Amyloid-Associated β-cell Loss and Does
Not Induce Pancreatitis or Pancreatic Neoplasia in Mice. Am J Physiol
Endocrinol Metab. 2013; 305: E475-E484.
11. Engel SS, Williams-Herman DE, Golm GT, et al. Sitagliptin: Review of
Preclinical and Clinical Data Regarding Incidence of Pancreatitis. Int J Clin
Pract. 2010; 64(7):984-990.
12. Koehler JA, Baggio LL, Lamont BJ et al. Glucagon-Like Peptide-1 Receptor
Activation Modulates Pancreatitis-Associated Gene Expression But Does Not
Modify the Susceptibility to Experimental Pancreatitis in Mice. Diabetes.
2009; 58:2148-2161.

5. 13. Tatarkiewicz K, Belanger P, Gu G, et al. No Evidence of Drug-Induced
Pancreatitis in Rats Treated with Exenatide for 13 Weeks. Diabetes, Obesity
and Metabolism. 2013; 25:417-426.
14. Zhao H, Wei R, Wang L, et al. Activation of Glucagon-like Peptide-1 Receptor
Inhibits Growth and Promotes Apoptosis of Human Pancreatic Cancer Cells in
a cAMP-Dependent Manner. Am J Physiol Endorinol Metab. 214; 306: E1431-
E1441.
15. Singh S, Chang HY, Richard TM et al. Glucagonlike Peptide 1-Based Therapies
and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus:
a Population-Based Matched Case-Control Study. JAMA Intern Med. 203 Apr
8; Vol. 173 (7): 534-9.
16. Dore DD, Bloomgren GL, Wenten M, et al. A Cohort Study of Acute
Pancreatitis in Relation to Exenatide Use. Diabetes, Obesity and Metabolism.
2011; 13:559-566.
17. 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; 33:2349-2354.
18. Dore DD. Use of a Claims-Based Active Drug Safety Surveillance System to
Assess the Risk of Acute Pancreatitis with Exenatide or Sitagliptin Compared
to Metformin or Glyburide. Current Medical Research & Opinion. 2009;
25(4):1019-1027.
19. Romley JA, Goldman DP, Solomon M, et al. Exenatide Therapy and the Risk of
Pancreatitis and Pancreatic Cancer in a Privately Insured Population.
Diabetes Technology & Therapeutics. 2012: 14(10)904-911.
20. Wenten M, Gaebler JA, Hussein M, et al. Relative Risk of Acute Pancreatitis in
Initiators of Exenatide Twice Daily Compared With Other Anti-Diabetic
Medication: a Follow-Up Study. Diabet Med. 2012; 29:1412-1418.
21. Funch D, Gydesen H, Tornoe K, et al. A Prospective, Claims-Based Assessment
of the Risk of Pancreatitis and Pancreatic Cancer with Liraglutide Compared
to Other Antidiabetic Drugs. Diabetes, Obesity and Metabolism. 2014; 16:273-
275.
22. Faillie J, Azoulay L, Patenaude V, et al. Incretin Based Drugs and Risk of Acute
Pancreatitis in Patients with Type 2 Diabetes: Cohort Study. BMJ. 2014;
348;g2780.
23. Monami M, Dicembrini I, Mannucci E. Dipeptidyl Peptidase-4 Inhibitors and
Pancreatitis Risk: A Meta-Analysis of Randomized Clinical Trials. Diabetes,
Obesity and Metablism. 2014; 16:48-56.
24. Alves C, Batel-Marques F, Macedo AF. A Meta-Analysis of Serious Adverse
Events Reported with Exenatide and Liraglutide: Acute Pancreatitis and
Cancer. Diabetes Research and Clinical Practice. 2012; 98(2):271-284.
25. Li L, Shen J, Bala MM, et al. Incretin Treatment and Risk of Pancreatitis in
Patients with Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis
of Randomised and Non-Randomised Studies. BMJ. 2014;348:g2366.
26. Byetta [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2013.
http://www1.astrazeneca-us.com/pi/pi_byetta.pdf#page=1 Accessed July
14, 2014.

6. 27. Bydureon [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
2014. http://www1.astrazeneca-us.com/pi/pi_bydureon.pdf#page=1
Accessed July 14, 2014.
28. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc.;2013.
http://www.novo-pi.com/victoza.pdf Accessed July 14, 2014.
29. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.: 2010.
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf
Accessed July 14, 2014.
30. Onglyza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
2009. http://www1.astrazeneca-us.com/pi/pi_onglyza.pdf#page=1 Accessed
July 14, 2014.
31. Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim
Pharmaceuticals, Inc.;2011. http://bidocs.boehringer-
ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath
=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf Accessed July 14,
2014.
32. Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America,
Inc.;2013.
http://general.takedapharm.com/content/file.aspx?applicationcode=66b0b9
42-e82b-46ad-886a-
f4aa59f5f33c&filetypecode=NesinaPi&cacheRandomizer=16a532da-bd7b-
4b3e-ae8e-1a667a48e81e Accessed July 14, 2014.