What are the risks and side effects of Glucagon-like peptide-1 (GLP-1) receptor agonists?

From the Guidelines

GLP-1 agonists like semaglutide, liraglutide, and dulaglutide can cause several side effects and carry some risks, including common side effects such as nausea, vomiting, diarrhea, constipation, abdominal pain, headache, and injection site reactions, as well as more serious but less common risks like pancreatitis, gallbladder problems, hypoglycemia, kidney problems, allergic reactions, and possible increased risk of thyroid tumors. To minimize side effects, start at a low dose and gradually increase as tolerated, take with food and stay hydrated, and monitor for signs of pancreatitis like severe abdominal pain 1. The most recent and highest quality study, published in 2024, highlights the importance of cautious use of GLP-1 receptor agonists in patients with kidney disease due to potential risk of acute kidney injury, and the need to discontinue the medication if pancreatitis is suspected 1. Some key points to consider when prescribing GLP-1 agonists include:

• Common side effects: nausea, vomiting, diarrhea, constipation, abdominal pain, headache, and injection site reactions
• More serious but less common risks: pancreatitis, gallbladder problems, hypoglycemia, kidney problems, allergic reactions, and possible increased risk of thyroid tumors
• Precautions: use caution in people with kidney disease, discontinue if pancreatitis is suspected, and avoid in patients with personal/family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2
• Benefits: generally safe and effective for diabetes and weight loss, with cardiovascular benefits demonstrated in several trials, including the LEADER and SUSTAIN-6 trials 1. Overall, while GLP-1 agonists can be effective for diabetes and weight loss, it is essential to carefully weigh the potential benefits and risks, and to closely monitor patients for any adverse effects, particularly when initiating or increasing the dose of these medications 1.

From the FDA Drug Label

The following additional adverse reactions have been reported during post-approval use of VICTOZA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure • Gastrointestinal: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus • General Disorders and Administration Site Conditions: Allergic reactions: rash and pruritus • Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Immune system: Angioedema and anaphylactic reactions • Metabolism and nutrition: Dehydration resulting from nausea, vomiting and diarrhea • Neoplasms: Medullary thyroid carcinoma • Nervous system: Dysgeusia, dizziness • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation • Renal and urinary: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. • Skin and subcutaneous tissue: Cutaneous amyloidosis

The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure Gastrointestinal: ileus Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy, cholestasis, elevation of liver enzymes, hepatitis Hypersensitivity: anaphylactic reactions, angioedema Nervous System Disorders: dysgeusia Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis

The risks and side effects of GLP-1 receptor agonists include:

• Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis, ileus
• Hepatobiliary: elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis
• Hypersensitivity: anaphylactic reactions, angioedema
• Neoplasms: medullary thyroid carcinoma
• Nervous system: dysgeusia, dizziness
• Pulmonary: pulmonary aspiration
• Renal and urinary: increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis
• Skin and subcutaneous tissue: cutaneous amyloidosis 2 3

From the Research

Risks and Side Effects of GLP-1 Receptor Agonists

The use of Glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with several risks and side effects, including:

• Gastrointestinal adverse events such as abdominal pain, constipation, diarrhea, nausea, and vomiting 4, 5
• Increased risk of pancreatitis, with liraglutide having the greatest risk 4, 5
• Gastroparesis, with dulaglutide and liraglutide having higher odds of gastroparesis than semaglutide 4
• Gastroesophageal reflux disease, gastritis, bezoar, breath odor, intra-abdominal hematoma, and other gastrointestinal system disorders 5
• Hypoglycemia, although the risk is relatively low compared to other diabetes medications 6
• Increased risk of gastrointestinal bleeding, although no significant differences were found between different GLP-1 receptor agonists 4

Comparison of GLP-1 Receptor Agonists

Different GLP-1 receptor agonists have been compared in terms of their efficacy and safety profiles, with some agents having a higher risk of certain side effects:

• Semaglutide has been associated with a higher risk of nausea, diarrhea, vomiting, constipation, and pancreatitis compared to other GLP-1 receptor agonists 4, 5
• Liraglutide has been associated with a higher risk of abdominal pain, upper abdominal pain, and pancreatitis compared to other GLP-1 receptor agonists 4, 5
• Dulaglutide has been associated with a higher risk of abdominal pain, constipation, diarrhea, and nausea compared to semaglutide and exenatide 4
• Exenatide has been associated with a lower risk of gastrointestinal adverse events compared to other GLP-1 receptor agonists, except for gastroparesis 4

Patient Considerations

When selecting a GLP-1 receptor agonist, patient considerations such as individual risk factors, comorbidities, and preferences should be taken into account:

• Patients with a history of gastrointestinal disease or pancreatitis may need to be monitored more closely when taking GLP-1 receptor agonists 4, 5
• Patients who are at risk of hypoglycemia may need to be cautious when taking GLP-1 receptor agonists, although the risk is relatively low compared to other diabetes medications 6
• Patients who are concerned about weight loss or gain may want to consider the efficacy and safety profiles of different GLP-1 receptor agonists, as some agents may be more effective for weight loss than others 6, 7