Early clinical trials suggested that patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists had a slightly increased risk of acute pancreatitis. Consequently, clinicians have avoided using GLP-1 receptor agonists in patients with a history of acute pancreatitis. However, recent large meta-analyses of clinical trial data do not support a class-wide risk. Denying these valuable therapeutic medications to patients with a history of pancreatitis seems unwarranted.
Incretin-based drug therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic peptide and GLP-1 receptor agonists are rapidly becoming first-line options for treating type 2 diabetes. These agents have a beneficial effect on pancreatic islet function by facilitating the secretion of insulin in response to ambient blood glucose levels and inhibiting glucagon secretion both directly and indirectly.
The remarkably low incidence of hypoglycemia and significant weight loss associated with these agents have contributed to their increased use. However, the effect of GLP-1 receptor agonists on the exocrine pancreas and the risk of acute pancreatitis has remained a cause for concern.
There are many known acute pancreatitis risk factors. Most of these are not aggravated or caused by GLP-1 receptor agonists, except possibly gallbladder disease.
Obesity increases the incidence and severity of acute pancreatitis. Visceral fat in the abdomen, regardless of body mass index, has the greatest impact on the development of acute pancreatitis.
Rapid weight loss (i.e., more than 1.5 kg per week) or excessive weight reduction (i.e., > 25% body weight) increases the risk of developing gallstones. During rapid weight loss, hepatic cholesterol synthesis and secretion increase, altering the ratio of cholesterol to bile salts. Notably, GLP-1 receptor agonists also slow biliary motility, which can contribute to the development of bile duct–blocking sludge and stones.
| Table 1: Common Causes of Pancreatitis | ||
|---|---|---|
| Mechanical | Toxic and Metabolic | Other |
| Gallstones Pancreatic duct obstruction Ampullary stenosis Trauma Surgery (includes bariatric) Congenital malformations |
Alcohol use Smoking Obesity Weight loss Hypertriglyceridemia Hypercalcemia Drug induced Scorpion envenomation Organophosphate poisoning |
Ischemia due to vascular compromise Iatrogenic injury Infection Hereditary Autoimmune Cystic fibrosis |
Overall, numerous meta-analyses to date have failed to find a statistically significant increase in pancreatitis incidence associated with GLP-1 receptor agonist therapy. The relationship seems to be between pancreatitis and weight loss, rather than the GLP-1 receptor agonist.
The US Food and Drug Administration drug labels include a warning that acute pancreatitis has been observed and treatment should be discontinued if suspected. However, labels do not directly contraindicate use in patients with a history of pancreatitis.
A retrospective chart review identified 161 patients with a documented history of pancreatitis who were prescribed a GLP-1 receptor agonist.
This study showed that the risk of recurrent pancreatitis in this cohort was likely no greater than what is observed in the general population.
Because patients being considered for GLP-1 receptor agonist therapy are already at risk due to type 2 diabetes, obesity, or both, screening for other potential risk factors before starting treatment is recommended.
| Table 2: Screening for Risk Factors Before Starting Therapy | |
|---|---|
| Hypertriglyceridemia | Excess alcohol use |
| Metabolic dysfunction–associated fatty liver disease (MAFLD) | Current smoker |
| High normal or mildly elevated liver enzymes (ALP, ALT, AST, GGT, Bilirubin) | History of pancreatitis |
| Symptoms of gallbladder disease | Hypercalcemia |
During GLP-1 receptor agonist therapy, monitor patients for the following signs or symptoms of acute pancreatitis:
Recommendation: Weight loss of more than 1.5 kg per week is associated with prolonged periods of fasting or anorexia. Patients experiencing rapid weight loss should undergo gallbladder ultrasonography. The GLP-1 receptor agonist dose should be lowered, and patients should be encouraged to increase meal size and frequency. A diet that is 19% to 30% fat is recommended to promote bile flow.
GLP-1 receptor agonists have great therapeutic potential for treating diabetes and obesity; preserving cardiovascular, cerebrovascular, and renal function; reversing MAFLD; and potentially slowing the progression of dementia. Clinicians should not limit the use of GLP-1 receptor agonists and deny potential medical benefits to patients because of a history of pancreatitis or a likelihood of developing pancreatitis.
Patients can be counseled about potential risks and benefits and allowed to participate in informed decision-making. The risk of pancreatitis can be minimized by addressing and mitigating risk factors from previous episodes, regulating the rate of weight loss, closely monitoring patients, and implementing appropriate precautionary measures.