In an otherwise healthy adult on tirzepatide for type 2 diabetes or obesity who develops a new or worsening skin rash after starting or increasing the dose, is the rash likely drug‑related and how should it be managed?

Tirzepatide-Associated Rash: Assessment and Management

A new or worsening rash after starting or increasing tirzepatide is likely drug-related and should be managed with immediate discontinuation of the medication, topical corticosteroids, and oral antihistamines for mild cases, while severe reactions require emergency evaluation. 1

Likelihood of Drug-Related Rash

Tirzepatide can cause injection site reactions and systemic rashes, though the overall incidence is not well-characterized in large trials. 2 A documented case report confirms tirzepatide-induced injection site rash occurring even in patients who previously tolerated other GLP-1 receptor agonists without issue. 2 Given the temporal relationship with drug initiation or dose escalation, a new rash should be presumed drug-related until proven otherwise. 1

Immediate Severity Assessment

Grade the reaction immediately to determine appropriate management:

• Grade 1 (mild): Isolated rash, itching, or flushing confined to skin without systemic symptoms 1
• Grade 2 (moderate): Urticaria, nausea, vomiting, or throat tightness indicating systemic involvement 1
• Grade 3-4 (severe): Blistering, skin sloughing, mucosal involvement (eyes, mouth, genitals), facial/tongue swelling, respiratory symptoms, or fever—these mandate immediate emergency care for possible Stevens-Johnson syndrome, toxic epidermal necrolysis, or anaphylaxis 1, 3

Management Algorithm for Mild Reactions (Grade 1)

Stop tirzepatide immediately and do not resume without specialist consultation. 1

Initiate topical therapy:

• Apply moderate-potency topical corticosteroid (triamcinolone 0.1% twice daily) to trunk and extremities 1
• Use low-potency hydrocortisone (1-2.5%) for facial involvement 1, 3
• Apply emollients liberally at least once daily to maintain skin barrier and prevent secondary eczema 1, 3

Add oral antihistamine therapy:

• Non-sedating H1-antihistamine (cetirizine 10 mg daily, loratadine, or fexofenadine) for daytime use 1, 3
• Sedating antihistamine (diphenhydramine at bedtime) if nighttime pruritus is severe 1, 3

Management of Moderate to Severe Reactions (Grade 2-4)

Discontinue tirzepatide permanently and obtain urgent medical evaluation. 1

Systemic corticosteroids (prednisone 0.5-2 mg/kg/day equivalent) with taper over 4-6 weeks for widespread or severe cutaneous involvement 1

Laboratory assessment including CBC with differential, comprehensive metabolic panel, and liver function tests to exclude DRESS syndrome (drug rash with eosinophilia and systemic symptoms) 1

Emergency hospitalization for Grade 3-4 reactions with IV methylprednisolone 1-2 mg/kg; burn unit admission may be necessary for extensive skin sloughing 3

Critical Pitfalls to Avoid

• Do not use greasy creams for skin care, as they promote folliculitis 1, 3
• Avoid hot showers and excessive soap, which exacerbate dryness and irritation 1, 3
• Do not apply topical acne medications or retinoids, which increase irritation 1, 3
• Do not attempt dose reduction or rechallenge without allergy/immunology consultation for severe reactions 1

Specialist Referral Criteria

Dermatology referral is indicated when:

• Rash persists >2 weeks despite appropriate topical therapy 1
• Rash involves >30% of body surface area 1
• Diagnosis remains uncertain 1
• Signs of secondary infection develop (warmth, purulent drainage, expanding erythema) 1

Allergy/Immunology referral is advised for:

• Severe (Grade 3-4) reactions 1
• Consideration of future use of related GLP-1 or GIP receptor agonists 1

Alternative Diabetes/Obesity Management

Given tirzepatide's superior efficacy for weight loss (15-21% at 72 weeks) compared to other agents, alternative GLP-1 receptor agonists like semaglutide may be considered after specialist evaluation, though cross-reactivity risk exists. 4 Gastrointestinal adverse events are the most common side effects of tirzepatide (39-49% depending on dose), not dermatologic reactions, making true drug-induced rash a less frequent but important consideration. 5