Are GLP-1 RAs safe to administer in T2DM with a history of acute pancreatitis and alcohol-use disorder?

Comment by InpharmD Researcher

Limited data suggest that the use of GLP-1 RAs in patients with prior history of pancreatitis may not increase the risk of subsequent pancreatic complications. A recent case-control study, published as a poster abstract, did not find alcohol use or prior history of pancreatitis to be a risk factor for new-onset acute pancreatitis after GLP-1 RA initiation for obesity; risk factors for pancreatitis included diabetes, tobacco use, and CKD. Another study in heavy alcohol consumers reported comparable rates of serious adverse events between exenatide and placebo. Notably, the majority of clinical trials involving GLP-1RAs typically excluded individuals with a history of pancreatitis. Additionally, there is a lack of data comparing specific agents, as most data looked at GLP-1 RAs as a whole or just one specific agent.

Background

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-1RA 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. [1]

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). [2], [3]

A 2022 article investigates the possible mechanism for which GLP-1RAs can be used as a potential anti-addiction treatment. GLP-1RAs have been tested in male rats and non-human primates to demonstrate their effect on alcohol consumption in acute and subchronic settings. One study observed exenatide decreasing or abolishing the rewarding effects of systemically injected alcohol. However, since GLP-1RAs are known to suppress appetite, it is possible the effect is due to the caloric component within alcohol. In non-human primates, exenatide was administered for 5 weeks while liraglutide was administered for 2 weeks before reintroduction of alcohol while on treatment. Both GLP-1RAs reported reduced alcohol consumption without emetic events. However, a human genetics study suggests the GLP-1 receptor variant may increase alcohol self-administration via changes in brain response and rewards, but the precise mechanism of action on addiction-related endpoints remains under investigation. A few human studies have been initiated since the publication of the article, and further data remains limited. [4]

A 2022 exploratory randomized, controlled trial investigated the use of exenatide once weekly in patients with alcohol use disorder to determine the effect on alcohol consumption. A total of 127 patients with characteristics of heavy drinking were included to receive either exenatide 2 mg subQ Qweekly (same dose for diabetes care) or placebo. The results demonstrated no significant reduction in the number of heavy drinking days versus placebo, but new data regarding pharmacokinetics and effect on brain transmissions were identified. For safety, the rates of serious adverse events were similar between exenatide and placebo (24.2% vs 18.5%, respectively). There were no cases of pancreatic enzyme elevation. Common adverse events include gastrointestinal symptoms, body weight loss, fatigue, and injection site reaction. However, one patient in the exenatide group committed suicide 7 weeks later after withdrawal from trial. [5]

Relevant Prescribing Information

Neither manufacturer label discusses use in patients with alcohol use disorder.

Mounjaro:
Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists.

In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 MOUNJARO-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). MOUNJARO has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO.

After initiation of MOUNJARO, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue MOUNJARO and initiate appropriate management.

Ozempic:
In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo-treated patients (0.33 cases per 100 patient years), both on a background of standard of care.

After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management initiated; if confirmed, OZEMPIC should not be restarted.

Literature Review

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

What GLP-1 medication that is safe to administer in T2D with acute pancreatitis and alcohol-use disorder? Is Mounjaro or Ozempic safe to use?

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