What are the side effects of Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide (Byetta), liraglutide (Victoza), and semaglutide (Ozempic)?

Side Effects of GLP-1 Receptor Agonists

The most common side effects of GLP-1 receptor agonists are gastrointestinal, including nausea, vomiting, diarrhea, and abdominal pain, which are dose-dependent and occur more frequently with short-acting than long-acting formulations. 1, 2

Common Gastrointestinal Side Effects

• Nausea and vomiting are the most frequently reported adverse effects, occurring in up to 44% (nausea) and 13% (vomiting) of patients, with higher rates seen with semaglutide compared to other GLP-1 RAs 1, 3
• Abdominal pain is extremely common, affecting up to 57.6% of patients in real-world studies 4
• Diarrhea occurs in approximately 13-33% of patients and is more common with long-acting GLP-1 RAs 3, 4, 5
• Constipation affects about 30% of patients and is more common with dulaglutide and liraglutide compared to semaglutide and exenatide 4, 6
• Dyspepsia (indigestion) occurs in 6-7% of patients 3
• Gastroesophageal reflux disease (GERD) is reported in 2-3% of patients 3, 2

Mechanism of Gastrointestinal Side Effects

• Delayed gastric emptying is the primary mechanism causing gastrointestinal symptoms, leading to prolonged gastric retention 2
• Central effects on appetite regulation through action on the hypothalamus and medulla contribute to gastrointestinal symptoms 2
• Effects on vagal nerve endings in the intestinal mucosa generate signals that can contribute to symptoms 2

Serious Adverse Effects

• Acute pancreatitis is a rare but serious complication linked particularly to exenatide and liraglutide use, with liraglutide showing the highest risk (ROR 32.67) in some studies 2, 3, 6
• Gallbladder disorders including cholelithiasis and cholecystitis have been reported, particularly with liraglutide 2, 3
• Renal impairment can occur, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea 3, 7
• Pulmonary aspiration has been reported in patients undergoing elective surgeries requiring general anesthesia 3

Other Side Effects

• Cardiac arrhythmia/tachycardia, with heart rate increases of 3-10 beats/minute 8
• Injection site reactions 3
• Headache (9% of patients) 3
• Feeling jittery (9% of patients) 3
• Dizziness (9% of patients) 3
• Asthenia (weakness) (4-5% of patients) 3
• Hyperhidrosis (excessive sweating) (3% of patients) 3
• Decreased appetite 3

Differences Between GLP-1 Receptor Agonists

• Short-acting agents (exenatide BID, lixisenatide) have more pronounced effects on gastric emptying but less effect on fasting glucose 9
• Long-acting agents (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, semaglutide) have stronger effects on fasting glucose and HbA1c but develop tachyphylaxis to the gastric emptying effect 9
• Semaglutide has shown the greatest risk of nausea (ROR 7.41), diarrhea (ROR 3.55), vomiting (ROR 6.67), and constipation (ROR 6.17) in some studies 6
• Liraglutide has shown the highest risk of upper abdominal pain (ROR 4.63) and pancreatitis in some analyses 6
• Exenatide appears to have a better GI safety profile than other GLP-1 RAs in some real-world studies, except for gastroparesis 4

Management of Side Effects

• Starting at a low dose and titrating slowly significantly improves gastrointestinal tolerability 1, 2
• Gastrointestinal symptoms are typically transient and decrease over time with continued therapy, especially for longer-acting GLP-1 RAs 3, 2
• Reducing meal size, limiting alcohol and carbonated drinks, and avoiding high-fat diets may help minimize symptoms 2
• Consider avoiding GLP-1 receptor agonists in patients with pre-existing gastroparesis 2
• Monitor for signs of pancreatitis, especially in patients with risk factors or history of pancreatitis 2, 3
• Consider temporary discontinuation before elective surgery requiring general anesthesia due to aspiration risk 2, 3

Drug Interactions

• GLP-1 RAs can slow gastric emptying, potentially reducing the extent and rate of absorption of orally administered drugs 3
• For oral medications with narrow therapeutic index or requiring rapid gastrointestinal absorption, advise taking them at least 1 hour before GLP-1 RA injection 3
• Consider reducing the dose of concomitantly administered insulin secretagogues (sulfonylureas) or insulin to reduce hypoglycemia risk 3
• Monitor prothrombin time more frequently when initiating GLP-1 RAs in patients taking warfarin, as there are reports of increased INR sometimes associated with bleeding 3