Is there newer data to support the possibility of giving a GLP-1 agonist to a patient with DM and obesity with a history of acute pancreatitis (due to a known cause such as hypertriglyceridemia)?

Is there newer data to support the possibility of giving a GLP-1 agonist to a patient with DM and obesity with a history of acute pancreatitis (due to a known cause such as hypertriglyceridemia)?

Comment by InpharmD Researcher

Although the majority of clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs) typically exclude individuals with a history of pancreatitis, limited data has suggested GLP-1 RAs may be used in patients with diabetes and a history of pancreatitis without significant risk of recurrence. GLP-1 RAs may be considered in tandem with vigilant monitoring if the known cause of pancreatitis is currently well-managed and a discussion of risks versus benefits has taken place.

Background

As noted in a 2020 meta-analysis, clinical trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have historically excluded patients with a history of pancreatitis or pancreatic cancer. While GLP-1 RAs are generally not reported increasing 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 2). [1], [2]

Per a poster abstract on pancreatitis risk with GLP-1 receptor agonists at the American College of Gastroenterology’s Annual Scientific Meeting in 2022, risk factors are type 2 diabetes mellitus, tobacco use, and advanced chronic kidney disease (stage 3 or greater). The retrospective, single-center, observational, case-control study involved 2,245 patients prescribed GLP-1 RAs for obesity between 2015 and 2021; patients were not required to have concomitant diabetes. Results found alcohol use, prior history of acute pancreatitis, and gallstone disease were not associated with an increased risk of acute pancreatitis after GLP-1 RA initiation. Higher body mass index (BMI) also appeared to be protective against pancreatitis. These results are based on one observational study conducted in Texas, with a need for other data to confirm the findings. Additionally, the GLP-1 RAs were used for obesity, not diabetes. [3]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there newer data to support the possibility of giving a GLP-1 agonist to a patient with DM and obesity with a history of acute pancreatitis (due to a known cause such as hypertriglyceridemia)?

Level of evidence

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

Please see Tables 1-4 for your response.

Decreased risk of recurrent acute pancreatitis with semaglutide and tirzepatide in people with type 2 diabetes or obesity with a history of acute pancreatitis: A propensity matched global federated TriNetX database-based retrospective cohort study
Design	Retrospective cohort study N= 258,238
Objective	To evaluate and compare the risk of recurrent acute pancreatitis among individuals with type 2 diabetes or obesity with a history of acute pancreatitis taking GLP-1 receptor agonists, particularly semaglutide and tirzepatide
Study Groups	Study cohort (N= 258,238)
Inclusion Criteria	Patients aged 18 years and older with type 2 diabetes or obesity and a history of acute pancreatitis, identified through ICD-10-CM code K85
Exclusion Criteria	Patients who alternated between different GLP-1 RA medications or were concurrently taking dipeptidyl peptidase 4 inhibitors (DPP-4i) or sodium-glucose cotransporter 2 inhibitors (SGLT2i)
Methods	The study analyzed the recurrence of AP over a 5-year period, comparing different GLP-1 RA treatments. Patients were divided into two analyzed categories: category 1, comprised of subjects with a history of AP, and category 2, subjects with a history of AP after excluding known risk factors (e.g., alcohol-related disorders, cholelithiasis, tobacco use, and hypertriglyceridemia). Propensity score matching was used to account for potential confounders. Statistical analyses included z-tests, risk ratios, and odds ratios.
Duration	5-year follow-up
Outcome Measures	Recurrence of acute pancreatitis, comparative risk assessments among different GLP-1 RA treatments
Baseline Characteristics	Not provided
Results	Comparison	Cohort	Sample size after match	People with recurrent AP	Risk	Risk difference	95% confidence interval (CI)	p-value
	GLP-1 RA vs. No GLP-1 RA (No risk factor)	GLP-1 RA	4,996	689	13.8%	-0.271	-0.288 to -0.255	<0.001
	Semaglutide vs. Exenatide	Semaglutide	159	16	10.1%	-0.17	-0.253 to -0.086	<0.001
	Semaglutide vs. Liraglutide	Semaglutide	874	95	10.9%	-0.079	-0.112 to -0.046	<0.001
	Semaglutide vs. Dulaglutide	Semaglutide	182	182	13.6%	-0.018	-0.045 to 0.009	0.188
	Semaglutide vs. Tirzepatide	Semaglutide	47	47	11.7%	0.055	0.015 to 0.094	0.007
Adverse Events	Not specifically reported
Study Author Conclusions	GLP-1 RAs, particularly semaglutide and tirzepatide, are associated with a reduced risk of recurrent acute pancreatitis in people with type 2 diabetes or obesity. Tirzepatide showed the lowest risk of recurrence, highlighting the importance of personalized treatment choices.
InpharmD Researcher Critique	Limitations include potential inaccuracies in electronic health records, lack of dose consideration, and possible selection bias due to data predominantly from affiliated institutions. Residual confounding may still exist despite propensity score matching.

References:

Nassar M, Nassar O, Abosheaishaa H, Misra A. Decreased risk of recurrent acute pancreatitis with semaglutide and tirzepatide in people with type 2 diabetes or obesity with a history of acute pancreatitis: A propensity matched global federated TriNetX database-based retrospective cohort study. Diabetes Metab Syndr. Published online September 19, 2024. doi:10.1016/j.dsx.2024.103116

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

The incidence of acute pancreatitis with GLP-1 receptor agonist therapy in individuals with a known history of pancreatitis
Design	Retrospective, observational, single-center, chart review N= 161
Objective	To determine whether a higher frequency of acute pancreatitis (AP) is associated with glucagon-like peptide-1 receptor agonist (GLP-1 RA) exposure in adults with type 2 diabetes (T2D) and a prior history of AP
Study Groups	Study cohort (N= 161)
Inclusion Criteria	Adult patients, history of AP and a subsequent encounter diagnosis of acute pancreatitis (ICD-9/ ICD-10 codes), exposure to a GLP-1 RA
Exclusion Criteria	Not disclosed
Methods	Data were taken from the electronic health record (EHR) system at Cleveland Clinic for adults meeting inclusion criteria. Exposure was defined as a documented prescription for GLP-1 RAs. Patients were followed until the date of recurrent acute pancreatitis (RAP) or censoring of data.
Duration	2010 to 2019 Mean follow-up: 28.2 months
Outcome Measures	Development of AP
Baseline Characteristics		Study cohort (N= 161)
	Age, years	54 ± 13
	Female	82 (50.9%)
	White	91 (56.5%)
	Medical history T2D Hypertension Obesity Hyperlipidemia	153 (95%)* 139 (86.3%) 119 (73.9%) 129 (80.1%)
	* Of the other 8 patients, 5 were treated for obesity, 2 were off-label for Type 1 diabetes, and 1 was unclear
Results	Endpoint	Study cohort (N= 161)
	Development of RAP	9.9%
	RAP attributed to GLP-1 RA exposure	6 (4%)
Adverse Events	N/A
Study Author Conclusions	While caution certainly needs to be exercised, and future studies are needed, this report would support the use of GLP-1RA in patients with a history of AP, on an individualized basis, particularly among patients where the etiology of the prior episode of AP has been treated and/or no longer exists and where a shared medical decision process between provider and patient has determined that the benefits are considered to outweigh the risks.
InpharmD Researcher Critique	Due to the retrospective nature of the study, data may be missing or inaccurate, such as reported prescriptions via the EHR. Report of RAP associated with GLP-1 RA exposure may have been impacted by confounding variables not adequately captured via clinical documentation, and conversely, RAP considered not associated with GLP-1 RA exposure and which were idiopathic in nature may have been due to GLP-1 RA use. History of acute pancreatitis prior to GLP-1 RA exposure was not documented.

References:

Lomeli LD, Kodali AM, Tsushima Y, Mehta AE, Pantalone KM. The incidence of acute pancreatitis with GLP-1 receptor agonist therapy in individuals with a known history of pancreatitis. Diabetes Res Clin Pract. 2024;215:111806. doi:10.1016/j.diabres.2024.111806

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