From: Angioedema associated with dipeptidyl peptidase-IV inhibitors
First author (reference) | Patient (sex, age) | Medical history (apart from diabetes mellitus)a | Treatmentsb | Clinical features of angioedema | Information on management and/or outcome of angioedema | Relevant investigations |
---|---|---|---|---|---|---|
Beaudouin [37] | 56-year-old man | Prior acute coronary syndrome Dyslipidemia Seasonal rhinitis (not requiring treatment) Recurrent angioedema 5 years after the start of lisinopril, involving face, uvula and hands, on a yearly basis over 3–4 days, despite use of prednisolone | Sitagliptin 100 mg/day (last year) Lisinopril 10 mg/day (for 15 years) Glibenclamide, metformin, flurbiprofen, atorvastatin | After combination with sitagliptin, increased frequency of attacks (every 6 weeks) and association with abdominal pain | After withdrawal of lisinopril, disappearance of abdominal pain and occurrence of only 3 episodes of facial or foot swelling over 9 months After subsequent withdrawal of sitagliptin, absence of attacks (FU: 19 months) | Normal C1-INH level and function, and serum tryptase levels Sensitization to ragweed and grass pollens Deficiency of ACE, aminopeptidase P and carboxypeptidase N; DPP-IV results not available |
Gabb [38] | 66-year-old man | Hypertension Stable ischaemic heart disease Urolithiasis Benign prostatic hypertrophy Cough related to ramipril | Saxagliptin (last 6 months) Candesartan (for 5 years) Metformin, carvedilol, rosuvastatin | Foreign body sensation in the throat and dysphonia; oedema of the soft palate and uvula | Inefficacy of promethazine Discontinuation of candesartan | Normal complement levels |
Gosmanov [39] | 46-year-old African American woman | Uncomplicated hypertension Obesity Compensated vitamin D deficiency Riedel’s thyroiditis | Sitagliptin 50 mg + metformin 500 mg BID (last week) Losartan 100 mg/day Prednisone for thyroiditis | Upper and lower lip angioedema (concomitant pruritic morbilliform rash) | Discontinuation of sitagliptin, continuation of losartan and metformin monotherapy, and prednisone tapering, without any recurrence of symptoms | – |
Hahn [40] | 83-year-old woman | Hypertension Coronary heart disease | Saxagliptin 5 mg/day Ramipril 5 mg/day (for > 5 years) | Acute swelling of the tongue, followed by hypopharyngeal and supraglottical involvement | Interruption of ramipril but not of saxagliptin. No regression of symptoms within > 30 h despite various sequential treatments. Partial monitoring in an intensive care unit Initial use of IV prednisolone, IV antihistamine, inhalations with epinephrine, and then C1-INH. Subsequent intubation via the nasal route, and use of icatibant (initial improvement only after 8 h) Use of amlodipine instead of ramipril without any further attacks (FU:1.5 years) | Normal concentration of C4 and C1-INH Decreased ACE activity and increased C1-INH activity |
Hermanrud [41] | Middle-aged Caucasian man | Hypertension | Daily use of sitagliptin Ramipril on a daily basis | Numerous episodes (47 in a year) in the head and neck area, occurring a few days after starting sitagliptin therapy Occasional severe lingual and laryngeal involvement | Referral to the ED in case of severe attacks. No effect of IV antihistamines and IV corticosteroids; no or sparse efficacy of epinephrine; some effect of C1-INH used once After ramipril discontinuation, severe oral, hypopharyngeal and laryngeal attacks with no response to high-dose antihistamines, steroids and epinephrine After substitution of sitagliptin with empagliflozin, only two episodes with slight swelling of the upper lip or tongue (FU: 12 months) | Complement and allergy tests with normal results |
Millot [42] | 67-year-old man | Hypertension Pulmonary embolism | Sitagliptin (last 2 months) Perindopril (for 10 years) Metformin, anti-vitamin K medication | Three episodes within 1 month; the third with significant glosso-pharyngo-laryngeal oedema and severe dyspnoea Two similar severe attacks in the following weeks | Regression in < 48 h of the first two attacks after use of antihistamines and corticosteroids Referral to ED for severe attacks For the third episode, supplemental oxygen, epinephrine aerosol, IV dexchlorpheniramine, IV methylprednisolone, without improvement in the next hour. After treatment with a concentrate of 4 coagulation factors used as an anti-vitamin K antagonist, regression of dyspnoea and dysphonia within 20 min, and of all symptoms within 8 h Resolution of the symptoms within 1 h from the use of C1-INH in the fourth episode, and within 30 min after injection of icatibant in the fifth | Histamine, tryptase, C3 and C4 levels, C1-INH level and function with normal results Negative auto-antibodies Low aminopeptidase P activity; no decreased activity of ACE and carboxypeptidase N |
Saisho [43] | 69-year-old man | Dyslipidaemia Gastroesophageal reflux disease | Vildagliptin 50 mg BID Ezetimibe, lansoprazole | Lower lip angioedema episodes occurring the day after starting vildagliptin therapy | Resolution after 1 day from vildagliptin interruption and switching to alogliptin 25 mg/day without recurrence (FU: 6 months) | – |
Skalli [44] | 79-year-old woman | History of major cardiovascular events Gastrointestinal disturbances with metformin | Sitagliptin Irbesartan 150 mg/day Insulin determir, atenolol, lysine acetylsalicylate, clopidogrel, atorvastatin, lansoprazole, clomipramine, hydroxyzine | Swelling of the lips, tongue and mouth, 14 days after starting sitagliptin | Remission within a few days after stopping sitagliptin After 10 days, reintroduction of sitagliptin and occurrence of angioedema with dyspnea 2 days later leading to permanent discontinuation of sitagliptin | – |
Hamasaki [45] | 60-year-old man | – | Anagliptin 200 mg/day | Severe edema of hands and face after a few weeks | Resolution at 2 weeks after the discontinuation of anagliptin | No detection of specific allergens |
Arcani [46] | 59-year-old man | Current cigarette smoking Two episodes of transient lip edema, several years earlier Recurrent angioedema in his daughter | Sitagliptin 50 mg/day (last 3 months) Metformin | Involvement of tongue, mouth floor, lower lip, right side of the face and neck, moderate dyspnea and dysphagia with sialorrhea | Referral to ED. 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. Resolution over the next days following discontinuation of alogliptin In the last episode (after re-treatment), referral to ED. Gradual improvement with IV antihistamines and steroids, with resolution over the next 2 days No attacks after permanent discontinuation of alogliptin (FU: 6 months) | C4, C1-INH, and C1q binding assays within normal range |