What are the side effects of a Glucagon-like peptide-1 (GLP-1) patch?

Side Effects of GLP-1 Patch

GLP-1 receptor agonists cause primarily gastrointestinal side effects that are dose-dependent and usually transient, with nausea being the most common, occurring alongside risks of pancreatitis, gallbladder disease, and injection site reactions. 1, 2

Gastrointestinal Side Effects (Most Common)

Primary GI Symptoms

• Nausea and vomiting are the most frequent adverse effects, occurring in a dose-dependent manner and significantly more with short-acting formulations (exenatide, lixisenatide) compared to long-acting agents (semaglutide, dulaglutide). 2, 3
• Diarrhea occurs commonly and is actually more frequent with long-acting GLP-1 receptor agonists than short-acting ones. 4
• Abdominal pain was reported in 57.6% of patients in real-world data, making it the most commonly reported GI complaint. 5
• Dyspepsia and gastroesophageal reflux develop due to delayed gastric emptying, a primary mechanism of action of these medications. 2
• Constipation affects approximately 30% of patients in real-world cohorts. 5

Mitigation Strategy

• Start at the lowest dose and up-titrate gradually every few weeks to minimize nausea and vomiting. 1, 3
• These symptoms typically occur during initial treatment and gradually diminish within a few weeks, particularly with longer-acting formulations. 3
• Advise patients to reduce meal size, limit alcohol and carbonated drinks, and avoid high-fat diets. 2, 3

Serious Gastrointestinal Complications

Pancreatitis

• Acute pancreatitis is a rare but serious complication, with post-marketing reports including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, particularly with exenatide. 2, 6
• Discontinue the medication promptly if pancreatitis is suspected and do not restart if confirmed. 1, 6
• Use with caution in patients with a history of pancreatitis. 1, 2

Gallbladder Disease

• GLP-1 receptor agonists increase the risk of cholelithiasis and cholecystitis. 2, 6
• The FDA has reported these complications in patients using liraglutide and semaglutide. 2
• If gallbladder disease is suspected, gallbladder studies are indicated. 6

Gastroparesis Risk

• Avoid GLP-1 receptor agonists in patients with pre-existing gastroparesis due to their effect of delaying gastric emptying. 2
• Care should be taken in patients with prior gastric surgery, including bariatric surgery. 1

Hypoglycemia Risk

• GLP-1 receptor agonists do not cause hypoglycemia when used alone or with metformin or thiazolidinediones. 7
• Risk increases significantly when combined with insulin secretagogues (sulfonylureas, glinides) or insulin. 1, 3
• Consider discontinuing any sulfonylurea or glinide when starting therapy, and reduce total daily insulin dose by up to 20%. 3
• Instruct patients to monitor glucose more closely at home for the first 4 weeks of therapy. 3

Renal Complications

• Acute kidney injury has been reported post-marketing, sometimes requiring hemodialysis and kidney transplantation. 6
• This primarily occurs through hemodynamic derangement due to severe nausea, vomiting, and diarrhea causing volume depletion. 7
• Check renal function in the first several weeks of therapy, especially in patients with impaired baseline renal function. 3
• Watch for signs of volume depletion such as orthostatic lightheadedness. 3
• Exenatide should not be used in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease. 1, 6

Injection Site and Hypersensitivity Reactions

• Injection site reactions (pruritus, erythema, inflammation, induration, irritation) occur in approximately 1.4% of patients. 8
• Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported. 8, 6
• Rash and urticaria were reported in 3% of pediatric patients treated with semaglutide. 8
• Discontinue immediately if serious hypersensitivity occurs. 6

Thyroid and Endocrine Concerns

• FDA Black Box Warning for thyroid C-cell tumors: GLP-1 receptor agonists are contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2). 1, 3

Ophthalmologic Complications

• Diabetic retinopathy complications were reported with semaglutide, predominantly in patients with prior history of proliferative retinopathy. 1, 3
• Ensure patients undergo appropriate eye examinations before starting therapy if not done within the last 12 months. 3
• Monitor patients with a history of diabetic retinopathy for progression. 3

Other Notable Side Effects

Cardiovascular and Hemodynamic

• First-time administration or dose escalation increases the risk of transient blood pressure elevation. 3
• Assess for symptoms of hypertensive urgency including severe headache, visual disturbances, and chest pain. 3

Musculoskeletal

• More fractures of the hip and pelvis were reported in female patients (1% vs 0.2%) and patients aged 75 years and older (2.4% vs 0.6%) on semaglutide compared to placebo. 8

Urologic

• Urolithiasis occurred in 1.2% of semaglutide-treated patients versus 0.8% on placebo, with serious reactions more frequent (0.6% vs 0.4%). 8

Perioperative Risk

• Pulmonary aspiration during general anesthesia or deep sedation has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries. 2, 6
• Temporary discontinuation before elective surgery requiring general anesthesia may be necessary. 2

Laboratory Abnormalities

• Amylase and lipase elevations: Mean increases of 15-16% for amylase and 39% for lipase, though clinical significance is unknown without other signs of pancreatitis. 8
• Liver enzyme elevations: ALT increases ≥5 times upper limit of normal occurred in 3% of pediatric patients on semaglutide. 8
• Bilirubin elevations: Total bilirubin ≥3 times upper limit of normal in 0.3% of semaglutide-treated adults. 8

Drug-Specific Differences

• Dulaglutide and liraglutide have higher rates of abdominal pain, constipation, diarrhea, nausea, vomiting, and gastroparesis compared to semaglutide. 5
• Liraglutide and exenatide have the highest pancreatitis rates (4.0% and 3.8%, respectively). 5
• Long-acting agents are associated with less nausea and vomiting but more diarrhea than short-acting agents. 4
• Lixisenatide causes less nausea and diarrhea compared to exenatide twice daily. 4

Contraindications

• History of serious hypersensitivity reaction to the drug. 1
• Pregnancy or breastfeeding. 1
• Personal or family history of medullary thyroid cancer or MEN2. 1
• Severe renal impairment or end-stage renal disease (for exenatide and lixisenatide). 1
• History of drug-induced immune-mediated thrombocytopenia from exenatide products. 6