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Table 1 Case reports of angioedema related to DPP-IV inhibitors [37,38,39,40,41,42,43,44,45,46,47,48]

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

  1. ACE angiotensin converting enzyme, ACEI angiotensin converting enzyme inhibitor, BID twice daily, C1-INH C1-esterase inhibitor, DPP-IV dipeptidyl peptidase‐IV, ED emergency department, FU follow-up period, IV intravenous
  2. aAll patients had type 2 diabetes mellitus; in the case described by Gosmanov and Fontenot diabetes was induced by corticosteroid therapy
  3. bDose and duration of treatment were reported for DPP-IV inhibitors and renin-angiotensin system inhibitors when information was available