What are the side effects of Glucagon-like peptide-1 (GLP-1) medications, such as exenatide, liraglutide, and semaglutide?

Side Effects of GLP-1 Receptor Agonist Medications

The most common side effects of GLP-1 medications are gastrointestinal disturbances—particularly nausea (occurring in 18-44% of patients), vomiting (4-18%), and diarrhea (6-18%)—which are typically dose-dependent, transient, and can be mitigated through slow dose titration and reduced meal sizes. 1

Most Common Gastrointestinal Side Effects

The gastrointestinal adverse events represent the primary tolerability concern with GLP-1 receptor agonists:

• Nausea is the most frequently reported side effect, occurring in 18-44% of patients with exenatide and up to 44% with liraglutide 1, 2
• Vomiting affects 4-18% of patients, with higher rates seen with semaglutide (18%) compared to exenatide (13%) 1, 2
• Diarrhea occurs in 6-18% of patients across different agents 1, 2
• Constipation affects 10-30% of patients 3
• Dyspepsia and gastroesophageal reflux disease occur in 3-7% of patients 1, 2
• Abdominal pain was reported in 57.6% of real-world users in one large cohort study 4

These gastrointestinal symptoms are more frequent with short-acting than long-acting formulations and typically decrease in frequency and severity with continued therapy 1. The American College of Cardiology guidelines emphasize that these symptoms are usually transient for longer-acting GLP-1 receptor agonists 1.

Serious Gastrointestinal Complications

Beyond common GI disturbances, several serious complications warrant attention:

• Gallbladder disease including acute cholecystitis and cholelithiasis requiring cholecystectomy can occur 1
• Pancreatitis has been reported, though causality remains unestablished; the FDA and European Medicines Agency have not identified a definitive causal link 1. Liraglutide showed the highest pancreatitis risk (32.67 ROR) in real-world data 5
• Severe gastroparesis and small bowel obstruction/ileus progression have been documented 1
• Pulmonary aspiration during surgery or procedures requiring anesthesia due to delayed gastric emptying 2

The 2024 Anaesthesia guidelines recommend discontinuing GLP-1 receptor agonists if pancreatitis is suspected 1.

Cardiovascular and Metabolic Effects

• Elevated heart rate can occur with all GLP-1 receptor agonists 1
• Cardiac arrhythmia/tachycardia may develop; if symptomatic, monitoring and beta blockers should be considered 1
• Hypoglycemia is unlikely when GLP-1 receptor agonists are used alone, but risk increases significantly when combined with insulin or sulfonylureas 1, 2

The American College of Cardiology recommends reducing doses of concomitant insulin secretagogues or insulin when initiating GLP-1 receptor agonist therapy 1.

Renal Complications

• Acute kidney injury can occur, particularly in the setting of severe gastrointestinal fluid losses from nausea, vomiting, or diarrhea 2
• Worsened chronic renal failure and cases requiring hemodialysis have been reported 2
• Liraglutide and semaglutide should be used with caution in patients with severe renal impairment or end-stage renal disease 1

Ophthalmologic Concerns

• Diabetic retinopathy complications increased with semaglutide in the SUSTAIN-6 trial, hypothesized to relate to rapid glucose reduction 1
• The American College of Cardiology recommends appropriate eye examinations before starting therapy if not completed within the last 12 months 1

Hematologic and Immunologic Reactions

• Drug-induced thrombocytopenia with reduced platelet counts can lead to serious bleeding 2
• Injection-site reactions including generalized pruritus, urticaria, macular or papular rash 2
• Anaphylactic reactions and angioedema have been reported 2

Thyroid Safety Concerns

• Black box warning exists for risk of thyroid C-cell tumors in rodents, though human relevance has not been determined 1
• Absolute contraindication in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2) 3

Other Notable Side Effects

• Alopecia (hair loss) has been reported in post-marketing surveillance 2
• Headache occurs in 6-14% of patients 1, 2
• Dizziness affects 6-9% of patients 1, 2
• Asthenia (weakness) in 2-5% of patients 1, 2

Comparative Safety Between Agents

Real-world evidence suggests differences in GI adverse event profiles between specific agents:

• Semaglutide has the greatest risk of nausea (ROR 7.41), vomiting (ROR 6.67), constipation (ROR 6.17), and diarrhea (ROR 3.55) 5
• Liraglutide has the greatest risk of upper abdominal pain (ROR 4.63) and pancreatitis (ROR 32.67), with the highest severe rate of gastrointestinal adverse events at 23.31% 5
• Dulaglutide and liraglutide had higher odds of abdominal pain, nausea, vomiting, and gastroparesis compared to semaglutide 4
• Exenatide appears to have a relatively safer GI profile except for gastroparesis 4

Management Strategies

To minimize adverse effects, the following approach should be implemented:

• Start at low doses and titrate slowly to increase gastrointestinal tolerability 1
• Reduce meal sizes to help manage nausea and other GI symptoms 1
• Limit alcohol and carbonated drinks to reduce reflux 1
• Avoid high-fat diets to minimize GI distress 1
• Avoid use in gastroparesis as these agents delay gastric emptying 1
• Take oral medications with narrow therapeutic index at least 1 hour before GLP-1 injection 2

Critical Pitfalls to Avoid

• Do not overlook the need to reduce insulin or sulfonylurea doses when initiating GLP-1 therapy to prevent hypoglycemia 1, 2
• Do not dismiss persistent nausea, vomiting, or diarrhea—these can lead to dehydration and acute kidney injury requiring immediate intervention 2
• Do not prescribe to patients with personal or family history of medullary thyroid carcinoma or MEN2 3
• Do not forget to counsel patients about continuing GLP-1 therapy before elective surgery due to aspiration risk 2
• Monitor INR more frequently in patients taking warfarin after initiating or changing GLP-1 doses 2