INTRODUCTION

Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly used in the treatment of type 2 diabetes mellitus and obesity because of their ability to improve glycemic control and promote weight loss. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist that has demonstrated significant metabolic benefits and is being used with increasing frequency in clinical practice. The adverse effects most commonly associated with GLP-1 receptor agonists are gastrointestinal, including nausea, vomiting, and diarrhea [1,2]. Cutaneous reactions are reported less often and are typically limited to injection-site reactions or nonspecific dermatologic findings.

Although rare immune-mediated dermatologic reactions such as urticaria and hypersensitivity eruptions have been described with GLP-1 receptor agonists, biopsy-confirmed exanthematous drug eruptions associated with tirzepatide remain uncommon in literature [3,4]. Furthermore, reports describing systemic or diffuse cutaneous reactions beyond localized injection-site involvement are limited. Here, we present a case of a biopsy-confirmed exanthematous drug eruption that developed temporally in association with prolonged watery diarrhea following initiation of tirzepatide, highlighting a broader spectrum of potential adverse effects.

CASE REPORT

A 74-year-old woman with a past medical history of type 2 diabetes mellitus, hypertension, hypothyroidism, hyperlipidemia, gout, chronic kidney disease stage 3, obstructive sleep apnea, rheumatoid arthritis, and obesity presented with three weeks of profuse watery diarrhea and a new pruritic rash involving the bilateral upper extremities.

Three weeks prior to presentation, she had started tirzepatide for weight management. Approximately three days after initiation, she developed watery diarrhea. She discontinued tirzepatide shortly before presentation due to persistent symptoms. During this time, she also developed an intensely pruritic rash on both arms that progressively worsened. She denied fever, nausea, vomiting, or recent sick contacts but reported fatigue, decreased appetite, and intermittent shaking chills.

On presentation to the emergency department, the patient was hypotensive with blood pressure measured at 83/44 mmHg and was clinically volume depleted. She required intravenous fluid resuscitation. Physical examination revealed symmetric erythematous papules and thin scaly plaques in a morbilliform distribution involving the bilateral upper extremities with extension to the proximal lower extremities (Figs 1a and 1b), without facial or mucosal involvement. No features suggestive of severe cutaneous adverse reactions, including DRESS or Stevens-Johnson syndrome, were observed.

	Figure 1: a) Erythematous coalescing macules and papules forming thin plaques on the right upper extremity in a patient with biopsy-confirmed exanthematous drug eruption following tirzepatide initiation. b) Faint symmetric erythematous macules and papules involving the bilateral lower extremities, consistent with a diffuse morbilliform drug eruption.
	Figure 2: Punch biopsy of the left upper arm demonstrating superficial dermal perivascular dermatitis with scattered eosinophils (H&E stain), consistent with a drug-induced exanthematous eruption.

Initial laboratory evaluation demonstrated mild hyperbilirubinemia with otherwise unremarkable inflammatory markers, including normal erythrocyte sedimentation rate and C-reactive protein.

Dermatology was consulted for evaluation of the patient’s pruritic rash. Examination demonstrated erythematous papules and thin scaly plaques involving the bilateral upper extremities with extension to the proximal lower extremities. Punch biopsy of the left upper arm revealed superficial dermal perivascular dermatitis with scattered eosinophils and mild epidermal spongiosis. Findings were most consistent with a drug-induced exanthematous eruption. Periodic acid–Schiff with diastase (PASD) staining was negative for fungal organisms. The patient was treated with topical triamcinolone 0.1% ointment with improvement in pruritus and rash appearance.

Evaluation of the patient’s diarrhea revealed stool testing positive for Clostridioides difficile by PCR but negative for toxin antigen. Given the clinical course, findings favored colonization rather than active infection, making it unlikely to explain the cutaneous manifestations. With supportive management and intravenous hydration, the patient’s diarrhea gradually improved.

The patient’s rash and gastrointestinal symptoms improved prior to discharge, and tirzepatide was documented as a medication allergy. Given the temporal relationship, absence of alternative new medications, supportive histopathologic findings, and clinical improvement following drug discontinuation, a drug-induced exanthematous eruption was considered the most likely diagnosis.

DISCUSSION

In this case, the patient presented with a rash and diarrhea following the initiation of tirzepatide, a dual-acting GIP and GLP-1 receptor agonist. Interest in GLP-1s has risen significantly in recent years and their adverse effects have been studied through extensive clinical trials. The most commonly reported adverse effects include nausea, abdominal pain, diarrhea, and constipation [1]. Likewise, a systematic review and meta-analysis reported gastrointestinal symptoms, notably nausea and diarrhea, as the most commonly reported adverse effect of tirzepatide [2]. While these findings align with the watery diarrhea experienced by the patient in our case, they highlight the scarcity in existing literature on dermatological symptoms associated with GLP-1 medications. In contrast to prior reports limited to injection-site or urticarial reactions, this case demonstrates a diffuse biopsy-confirmed exanthematous eruption.

Cutaneous reactions associated with tirzepatide have been described in a limited number of reports. Most documented reactions involve localized injection-site reactions related to subcutaneous administration. One report described the development of a rash at the injection site following transition from dulaglutide to tirzepatide [3]. Systemic hypersensitivity reactions have also been reported, including a case characterized by generalized urticaria and severe pruritus after tirzepatide exposure [4]. In contrast, the present case demonstrates the development of a diffuse morbilliform eruption not limited to the injection site and without urticarial morphology. Punch biopsy findings were consistent with an exanthematous drug eruption. Although these histopathologic findings are not specific, they support the clinical diagnosis.

While exanthematous drug eruptions are the most common type of cutaneous drug reactions, they have not been well described in association with tirzepatide use. These reactions typically develop within a few weeks of drug administration, presenting with maculopapular lesions that typically spread to the extremities in a symmetrical fashion [5,6]. The exact pathophysiology of exanthematous drug eruption is not fully understood. The current understanding is that the reaction represents a T-cell mediated Type IV delayed hypersensitivity reaction [6,7]. However, it is also thought that the mechanism may differ by the offending drug [8]. Management consists of prompt discontinuation of the offending agent and supportive care with topical corticosteroids and antihistamines; symptoms typically begin to improve within days and resolve within 1–2 weeks following drug withdrawal [9]. In this case, the patient’s pruritus and rash improved during hospitalization with topical corticosteroid therapy, with documented improvement by hospital day 4 and prior to discharge, although complete resolution was not documented.

Given the rapidly increasing use of tirzepatide and other GLP-1 receptor agonists for both diabetes and weight management, recognition of less common adverse effects is increasingly important for clinicians. This case highlights the potential for systemic dermatologic reactions that may not be immediately recognized as related to tirzepatide use. Moreover, drug-induced exanthem can be caused by a wide range of medications and can be difficult to distinguish from viral-induced exanthem [9]. This means that variables such as concurrent medication usage or viral illness can further complicate the processes of diagnosis or identifying the cause. As a result, documentation of rare adverse reactions is important for improving clinical awareness and patient counseling.

CONCLUSION

This report contributes to the growing body of evidence regarding potential immune-mediated cutaneous adverse effects of medications that act as GLP-1 receptor agonists. Clinicians should consider tirzepatide as a potential cause of diffuse morbilliform eruptions, even in the absence of injection-site reactions. Increased recognition of such reactions may facilitate earlier diagnosis and appropriate management.