Is there any data looking at rechallenging with a GLP-1 receptor agonist (GLP-1 RA) in a patient with a previous history of pancreatitis?

Comment by InpharmD Researcher

Limited data suggests that the use of exenatide extended-release (case report) or liraglutide (subgroup analysis) in patients with prior history of pancreatitis did not increase the risk of subsequent pancreatic complications. It should be noted, however, that the majority of clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RAs) typically exclude individuals with a history of pancreatitis. Currently, there is no available data on the rechallenge of GLP-1RAs in patients with prior pancreatitis, though the incidence rate of pancreatic adverse event associated with treatment is rare.

Background

As noted in a 2020 meta-analysis, clinical trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have historically excluded patients with a history of pancreatitis or pancreatic cancer. While GLP-1RAs are generally not reported to increase the risk of acute pancreatitis or pancreatic cancer for treatment of type-2 diabetes mellitus (T2DM), whether these safety findings can be extrapolated to patients with prior pancreatitis remains uncertain. However, the LEADER study included such patients and did not find liraglutide, in particular, to serve as a cumulative risk factor for acute pancreatic adverse events in patients with prior history of acute pancreatitis (See Table 1). [1, 2]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any data looking at rechallenging with a GLP-1 receptor agonist (GLP-1 RA) in a patient with previous history of pancreatitis? Specifically, pancreatitis previously caused by use of GLP-1 RA?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: Results From the LEADER Randomized Trial
Design	Randomized, double-blind, placebo-controlled, multi-center trial N= 9,340
Objective	To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5–5.0 years
Study Groups	Liraglutide (n= 4,668) Placebo (n= 4,672)
Inclusion Criteria	Type 2 diabetes and high risk for cardiovascular events
Exclusion Criteria	Type 1 diabetes; the use of GLP-1–receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, pramlintide, or rapid-acting insulin; a familial or personal history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; and the occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization
Methods	Eligible patients were randomized 1:1 to either subcutaneous liraglutide 1.8 mg daily (or maximum tolerated doses) or placebo. Fasting serum lipase, amylase, and incident of pancreatitis were monitored.
Duration	Treatment period: 3.5 to 5 years Median observation time: 3.84 years Follow-up period: 30 day
Outcome Measures	Primary composite outcome: first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Secondary: acute pancreatitis
Baseline Characteristics		Liraglutide (n=4,668)	Placebo (n=4,672)
	Age, years	64.2	64.4
	Male	64.5%	64.0%
	Diabetes duration, years	12.8 + 8.0	12.9 + 8.1
	Glycated hemoglobin, %	8.7 + 1.6	8.7 + 1.5
	Patient with a history of previous pancreatitis	147	120
Results	Endpoint	Liraglutide (n=4,668)	Placebo (N=4,672)
	Primary composite outcome	608 (13.0%)	694 (14.9%)
	Acute pancreatitis events ^a Patients with a history of previous pancreatitis	18 (0.4%) 2/147 (1.4%)	23 (0.5%) 6/120 (5.05)
	Chronic pancreatitis	0	2 (0.04%)
	Severity of acute pancreatitis Mild Moderate Severe Hospitalization	16/18 (88.95) 0 2/18 (11.1%) 17/18 (94.4%)	21/23 (91.3%) 3/23 (13.0%) 1/23 (4.3%) 19/23 (82.6%)
	Gallstone disease	7/18 (38.9%)	10/23 (43.5%)
	Predictive value of increased lipase or amylase levels for confirmed acute pancreatitis
	Lipase > ULN during trial ^b Subsequent acute pancreatitis	2,604 7 (0.27%)	1,682 11 (0.65%)
	Lipase ≥33 ULN during trial Subsequent acute pancreatitis	339 0	216 2(0.93%)
	Amylase >ULN during trial Subsequent acute pancreatitis	1,382 3 (0.22%)	1,084 5 (0.46%)
	Amylase ≥33 ULN during trial Subsequent acute pancreatitis	38 0	35 0
	^aIn both groups, most cases of acute pancreatitis developed >12 months after beginning the trial. ^bCompared with the placebo group, liraglutide-treated patients had increases in serum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and then remained stable.
Adverse Events	See results.
Study Author Conclusions	In a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardless of previous history of pancreatitis) compared with the placebo group. Liraglutide was associated with increases in serum lipase and amylase, which were not predictive of an event of subsequent acute pancreatitis.
InpharmD Researcher Critique	The population of the trial included patients with type 2 diabetes, the majority being men, with a higher mean age and longer diabetes duration. Therefore, the findings may not be generalizable to other patient populations. Furthermore, since only a small number of patients with a previous history of pancreatitis were included, the recurrent risk cannot be completely ruled out.

References:

[1] Steinberg WM, Buse JB, Ghorbani MLM, et al. Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: Results From the LEADER Randomized Trial. Diabetes Care. 2017;40(7):966-972. doi:10.2337/dc16-2747
[2] Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

GLP-1 Agonist Use in a Patient With an Explainable Cause of Pancreatitis
Design	Case report
Case presentation	A 51-year-old Caucasian male with a history of diabetes, hypertension, and dyslipidemia presented to the emergency department (ED) with back pain, abdominal pain, nausea, and vomiting. Tests showed that he had pancreatitis caused by high levels of triglycerides. He did not have gallstones or a history of alcohol abuse. After being discharged, he was treated with a combination of anti-lipidemia therapy and a glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide extended-release 2 mg SubQ weekly) for his diabetes. He did not experience another episode of pancreatitis during one year of follow-up.
Study Author Conclusions	This case report illustrates the point that the use of a GLP-1 receptor agonist is not absolutely contraindicated in patients with diabetes and a history of pancreatitis. The rare incidence and uncertain causality of pancreatitis associated with GLP-1 receptor agonist use should not automatically preclude the consideration of these agents in a patient with a history of pancreatitis. As seen in this case, healthcare providers may consider GLP-1 receptor agonist therapy for patients with a history of pancreatitis originating from a known cause that has been adequately managed. We recommend that the risks and benefits of therapy be considered and discussed with such patients and that as a precaution, vigilant monitoring for pancreatitis recurrence be conducted in patients subsequently receiving GLP-1 receptor agonist therapy.

References:

Brady SM, Kane MP, Busch RS. Glp-1 agonist use in a patient with an explainable cause of pancreatitis. AACE Clinical Case Reports. 2016;2(2):e82-e85. doi: 10.4158/EP15658.CR