What are the symptoms of an allergic reaction to Glucagon-like peptide-1 (GLP-1)?

Allergic Reactions to GLP-1 Receptor Agonists: Clinical Presentation

Allergic reactions to GLP-1 receptor agonists typically manifest as injection site reactions, but can progress to serious systemic hypersensitivity including anaphylaxis, which occurs at a rate of approximately 37-41 per 100,000 person-years. 1

Spectrum of Allergic Manifestations

Local Reactions

• Injection site reactions are among the most commonly reported adverse effects, presenting as erythema, pruritus, or localized swelling at the subcutaneous injection site 2
• These local reactions should be distinguished from the more common gastrointestinal side effects (nausea, vomiting, diarrhea) which are not allergic in nature 2

Dermatologic Hypersensitivity

• Dermatologic disorders represent a significant category of adverse reactions, with 14 cases documented in systematic reviews of case reports 3
• Skin manifestations can include rash, urticaria, and pruritus extending beyond the injection site 3

Systemic Allergic Reactions

• Angioedema has been reported in 3 documented cases, representing a serious allergic manifestation 3
• Anaphylactic reactions occur at an increased rate compared to other diabetes medications, with GLP-1 receptor agonists showing a 38% increased risk versus SGLT-2 inhibitors (HR 1.38,95% CI: 1.02-1.87) 1
• The absolute incidence of anaphylaxis is 36.9-40.7 per 100,000 person-years, which is modestly elevated compared to DPP-4 inhibitors (32.1 per 100,000 person-years) 1

Immunologic Complications

• Immunologic adverse reactions have been documented in 13 cases across systematic reviews, indicating true hypersensitivity responses 3
• These reactions are distinct from the medication's intended immunomodulatory effects and represent genuine allergic phenomena 3

Clinical Recognition Algorithm

Immediate Assessment (Within Minutes to Hours)

Look for signs of anaphylaxis: difficulty breathing, wheezing, throat tightness, hypotension, tachycardia, diffuse urticaria, or facial/tongue swelling 1

Early Phase (First Few Doses)

Monitor for injection site reactions: localized erythema, swelling, warmth, or pruritus that persists beyond 24-48 hours or worsens with subsequent injections 2

Delayed Reactions (Days to Weeks)

Watch for dermatologic manifestations: generalized rash, urticaria appearing distant from injection sites, or progressive skin symptoms 3

Critical Distinction from Common Side Effects

Do not confuse allergic reactions with the expected gastrointestinal adverse effects (nausea, vomiting, dyspepsia, diarrhea), which occur commonly but are pharmacologic effects related to delayed gastric emptying rather than immune-mediated hypersensitivity 2, 4. These GI symptoms are dose-dependent, occur more frequently with short-acting formulations, and typically diminish over time with continued use 4.

Contraindications Based on Allergy History

History of serious hypersensitivity reaction to any GLP-1 receptor agonist is an absolute contraindication to using any medication in this class 2. Cross-reactivity between different GLP-1 receptor agonists is possible given their structural similarities 5.

Management Implications

When true allergic reactions occur, immediate discontinuation is required 2. For anaphylaxis, standard emergency protocols apply with epinephrine as first-line treatment 1. The risk appears consistent across the class, with liraglutide and exenatide having the most documented cases, though this may reflect their longer market presence 3.