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]
A 2022 systematic review and meta-analysis analyzed 76 randomized control trials involving 103,371 patients to determine the risk of gallbladder and biliary diseases with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Biliary disease was defined as the presence of bile duct stone, bile duct obstruction, bile duct stenosis, biliary colic, biliary fistula, biliary cyst, or cholangitis. The pooled analysis indicates that treatment with GLP-1RAs was associated with a significantly increased risk of gallbladder or biliary diseases (risk ratio [RR] 1.37; 95% confidence interval [CI] 1.23 to 1.52) compared with controls. GLP-1 RAs were also associated with increased risks of cholelithiasis (RR 1.27; 95% CI 1.10 to 1.47), cholecystitis (RR 1.36; 95% CI 1.14 to 1.62), and biliary disease (RR 1.55; 95% CI 1.08 to 2.22) compared with controls. When examining the incidence of biliary disease stratified by GLP-1RA agent, liraglutide (RR 1.79; 95% CI, 1.45 to 2.25) and dulaglutide (RR 1.35; 95% CI, 1.06 to 1.73) were associated with an increased risk. Additionally, higher doses of subcutaneous semaglutide (≥1.0 mg) were associated with increased gallbladder or biliary diseases (RR 1.58; 95% CI 1.13 to 2.22). However, it should be noted that the studies were not powered for the subgroup analyses performed in the meta-analysis. [3]
A 2022 commentary provided clinical recommendations for managing the gastrointestinal (GI) side effects associated with GLP-1RAs in patients with overweight or obesity. Drawing on both published evidence and collective clinical expertise, the article emphasized that nausea, vomiting, diarrhea, and constipation are the most frequently reported adverse events with GLP-1RAs, often occurring during initiation and dose escalation. A stepwise approach for managing these side effects was proposed, encapsulated by the "three E’s": education and explanation, escalation to an appropriate dose, and effective management of GI symptoms. If patients present with symptoms indicating pancreatitis, the authors suggest stopping the GLP-1RA and initiating appropriate management for suspected pancreatitis. They recommend against restarting the GLP-1RA if pancreatitis is confirmed and suggest appropriate gallbladder studies and clinical follow-up if cholelithiasis is suspected. [4]
A 2024 case series analyzed 39 patients to characterize and evaluate acute pancreatitis (AP) associated with different GLP-1RAs. Using the Naranjo scale (N= 39), 33 cases (84.6%) were deemed to have a probable causal relationship between GLP-1 RAs and AP, while 4 cases (10.3%) were classified as possible. Two cases involved cholelithiasis; however, none of the patients from the case series were rechallenged with GLP-1RAs due to safety concerns. [5]
A 2025 Cleveland Clinic Journal of Medicine review concluded that, although early GLP-1 receptor agonist trials raised concern for a slight increase in acute pancreatitis, more recent large meta-analyses do not support a class-wide pancreatitis risk, and FDA labels warn to discontinue therapy if pancreatitis is suspected but do not directly contraindicate GLP-1 receptor agonist use in patients with a prior history of pancreatitis. The review does not provide a specific directive on restarting tirzepatide/Mounjaro or switching to another GLP-1 agent after gallstone pancreatitis; however, it states that in patients with prior pancreatitis, the etiology of the prior episode should be determined and preventable or reversible causes should be corrected, noting that gallstones resolved by cholecystectomy may no longer represent an ongoing risk factor. In a retrospective review of 161 patients with prior pancreatitis who subsequently received GLP-1 receptor agonist therapy, 16 patients (10%) developed recurrent acute pancreatitis, with 6 cases clinically attributed to the GLP-1 receptor agonist and the remainder attributed to other causes or idiopathic. The authors recommend screening for pancreatitis risk factors before GLP-1 receptor agonist therapy, discussing cholecystectomy or ursodeoxycholic acid in patients with established gallbladder disease, counseling patients on risks and benefits, regulating the rate of weight loss through dose adjustment and meal content/frequency, and monitoring closely for symptoms or signs of pancreatitis during treatment. [6]
A 2025 review article examined the potential association between GLP-1RAs and gallbladder disease, highlighting several proposed mechanisms including suppression of cholecystokinin (CCK), alterations in bile acid receptor signaling (FXR and TGR5), and changes in gut-brain pathways that may impair gallbladder motility, promote bile stasis, and increase gallstone formation. While GLP-1RAs are effective for the management of type 2 diabetes mellitus and obesity, systematic reviews and meta-analyses cited in the article suggest an increased relative risk of gallbladder-related events, particularly with higher doses, longer treatment durations, and substantial weight loss. The review noted that established risk factors for gallbladder disease—including female sex, advanced age, obesity, insulin resistance, type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease (MASLD), rapid weight loss, high-fat diets, low fiber intake, physical inactivity, prior gallbladder disease, and genetic predisposition—may further increase susceptibility in patients receiving GLP-1RAs. To mitigate risk, the authors recommend individualized risk stratification, patient education regarding symptoms of biliary disease, gradual weight loss, healthy dietary and lifestyle practices, and closer monitoring of patients with multiple risk factors. High-risk patients, particularly those with type 2 diabetes mellitus, MASLD, rapid weight loss, or a history of gallbladder disease, may require periodic biochemical and imaging follow-up, with consideration of prophylactic ursodeoxycholic acid to reduce the risk of gallstone formation. In symptomatic patients, prompt evaluation with liver function testing and gallbladder imaging is advised, and a multidisciplinary approach may help optimize the metabolic benefits of GLP-1RA therapy while minimizing gallbladder-related complications. [7]