Case Presentation: We present a case of angioedema following initiation of empagliflozin in a patient with a history of ARB- and NSAID-induced angioedema and ACE-I-induced cough. A 68-year-old woman with heart failure with mildly reduced ejection fraction (40-45%), non-ischemic cardiomyopathy, asthma, hypertension, hyperlipidemia presented to the emergency department (ED) with one hour of lip and tongue swelling, dysphagia, muffled voice, and a pruritic rash that started twelve hours after taking her first dose of empagliflozin 10 mg. Chart review confirmed prior angioedema from ibuprofen, hymenoptera venom, and losartan, and a prior ACE-I-induced cough. Her family history was notable for a daughter with NSAID-induced angioedema. She denied recent exposure to new foods, products, or medications other than empagliflozin. On arrival, she was hemodynamically stable (BP: 129/69, Pulse: 79, Respiratory Rate: 18, SpO2: 100%) with clear lungs and no evidence of respiratory distress, wheeze, or stridor. Examination revealed urticaria on the back and legs and significant swelling of the lips, tongue, soft palate, and uvula. Direct laryngoscopy demonstrated oropharyngeal edema. She received 0.3 mg IM epinephrine, 50 mg IV diphenhydramine, 20 mg IV famotidine, 60 mg IV methylprednisolone, and 1,000 mg IV tranexamic acid. Laboratory studies revealed WbC 1.24 and metabolic alkalosis. Complement C4 (411) and C1 esterase inhibitor (28) were normal, excluding hereditary angioedema. The patient was admitted to the ICU for airway monitoring. Over 24 hours, her swelling improved and the rash resolved. Recurrence of facial swelling after initial treatment caused a plan for a longer course of steroids. She was discharged on cetirizine 10 mg daily, a prednisone taper, and an epinephrine auto-injector.
Discussion: Angioedema is a rare and potentially life-threatening adverse reaction that is mediated by histamine or bradykinin. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin, are widely used in heart failure and diabetes but are not commonly associated with angioedema. The patient’s clinical features of urticaria, pruritus, and subsequent rapid improvement with antihistamines and corticosteroids strongly point to histamine-mediated angioedema. Although SGLT2 inhibitors are not widely recognized as causes of angioedema, there have been reports of rare hypersensitivity reactions. The strong temporal association with empagliflozin initiation and absence of alternative triggers support a probable drug reaction. The mechanism of SGLT2 inhibitor-induced angioedema has not been well defined; however, based on the clinical features in this case, it is most consistent with a histamine- rather than bradykinin-mediated. Further, as SGLT2 inhibitors are not known to affect bradykinin pathways, this supports a histamine-mediated angioedema reaction with empagliflozin as the likely trigger.
Conclusions: Empagliflozin may rarely cause histamine-mediated angioedema. Clinicians should consider SGLT2 inhibitors in the differential diagnosis of new-onset angioedema, especially in patients with prior drug-induced hypersensitivity.