Angioedema following initiation of glecaprevir/pibrentasvir while on sitagliptin

Angioedema associated with dipeptidyl peptidase-IV inhibitors

“…No improvement after use of epinephrine aerosol, IV methylprednisolone, IV antihistamine, and then IV epinephrine. Subsequent IV administration of C1-INH and tranexamic acid with gradual improvement and resolution after 36 h No other episodes after discontinuation of sitagliptin (FU: 4 years) Normal C1-INH levels and function, ACE levels, and aminopeptidase P activity Normal DPP-IV activity 1 week after stopping sitagliptin Reduced carboxypeptidase N activity Heterozygous Thr328Lys mutation in the coagulation factor XII gene Schneider [ 47 ] 67-year-old Hispanic woman Hypertension Hepatitis C virus infection Chronic renal failure Schizophrenia Sitagliptin 100 mg/day Amlodipine, carvedilol, mirtazapine, olanzapine, insulin detemir (no changes to all these drugs in the past year) Glecaprevir/pibrentasvir started 2 weeks before her first attack Two episodes separated by 1 month, involving the tongue with drooling and dyspnea In the second event, also edema of the lingual surface of the epiglottitis Use of epinephrine and diphenhydramine in the first episode with resolution within a day. For the second event, referral to ED and use of epinephrine, dexamethasone, and diphenhydramine with slow improvement No further episodes after the discontinuation of sitagliptin (FU: 1 year), while remaining on glecaprevir/pibrentasvir for other 2 months Normal C4 level during the event Yeddi [ 48 ] 67-year-old African American man – Alogliptin 12.5 mg BID Metformin Two weeks after starting alogliptin, facial, lip and tongue swelling on 4 consecutive mornings Few months later, re-treatment with alogliptin, and development of lip and face swelling within hours of ingestion of the first pill Partial improvement with antihistamine for the initial episodes.…”

“…In the recent publication written by Schneider and Ramesh [ 47 ], angioedema took place in the setting of co-administration of glecaprevir/pibrentasvir for hepatitis C and sitagliptin. Because sitagliptin is a substrate of p-glycoprotein/ABCB1, which is inhibited by glecaprevir/pibrentasvir, the authors hypothesized that this drug interaction could give rise to increased serum concentrations of sitagliptin, thus inducing a more pronounced effect on DPP-IV inhibition and on the resulting mechanisms responsible for angioedema [ 47 ]. The temporal relationship of starting glecaprevir/pibrentasvir followed by the development of angioedema and the permanent recovery of symptoms after sitagliptin withdrawal might be hints supportive of the possible relevance of this drug interaction.…”

“…In the reported clinical cases, the influence of specific factors on the risk of angioedema cannot be ruled out, such as ethnicity [ 39 , 47 , 48 ], smoking [ 46 ], seasonal rhinitis [ 37 ], history of ACEI-related cough [ 38 ], use of prednisone for thyroiditis [ 39 ], flurbiprofen [ 37 ] or lysine acetylsalicylate [ 44 ]. Anyway, the limited number of case reports does not allow to gather sufficient information.…”

“…The histaminergic nature of angioedema was also excluded in some reports on the basis of the lack of response to medications conventionally employed for the control of histamine-mediated and anaphylactic responses, including antihistamines, corticosteroids and/or epinephrine [ 38 , 40 – 42 , 46 ]. A gradual and slow improvement of symptoms following the use of similar medications was sometimes outlined [ 47 , 48 ].…”

“…Some patients had severe symptoms, with hypopharyngeal and/or laryngeal oedema and dyspnea [ 40 – 42 , 46 , 47 ], and a few of them were ACEI users [ 40 – 42 ].…”