Extending our understanding of exenatide: a rare case of angio-oedema

Abstract

Exenatide is a subcutaneous injectable glucagon-like peptide 1 receptor agonist that has been approved by the Federal Drug Administration for the treatment of type 2 diabetes mellitus. While side effects such as nausea, vomiting and local hypersensitivity reactions are more commonly described, angio-oedema has never been previously reported in the literature. We present the case of a 67-year-old woman who presented to the emergency department with acute-onset tongue swelling, difficulty breathing, dizziness and diffuse itching which began shortly after receiving her first dose of intramuscular extended release (ER) exenatide. This case aims to raise awareness of the potential adverse effect of angio-oedema secondary to exenatide ER and serves as a reminder to clinicians to discuss possible adverse effects of medications and early recognition of symptoms which would prompt further medical attention.

Background

A population-based study published in 2018 found that 8.5% of adults in the USA have been diagnosed with some form of diabetes mellitus, with the vast majority (91.2%) having type 2 diabetes mellitus (T2DM).¹ According to the American Diabetes Association’s (ADA) Standards of Medical Care in Diabetes recommendations from 2015, metformin is the preferred initial pharmacotherapy for the treatment of T2DM; however, for patients who present with HbA1c greater than 7.5% after 3 months of monotherapy, it is recommended to consider the addition of a glucagon-like peptide 1 (GLP-1) receptor agonist, a second oral agent or basal insulin.² Following this, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology published a consensus statement on T2DM management in 2016; confirming the consideration of a GLP-1 receptor agonists as additional therapy for patients who fail to achieve target HbA1c (<7.5%) after 3 months of initial metformin therapy but to also consider sodium–glucose cotransporter-2 inhibitors depending on the patient’s cardiovascular risk.^{3 4}

Exenatide extended release (ER) is a weekly subcutaneous injectable GLP-1 receptor agonist that has been approved by the Federal Drug Administration in the treatment of T2DM as outlined above.⁵ The mechanism of action involves the suppression of glucagon secretion, delay of gastric emptying and enhancement of insulin secretion by the pancreatic beta cells; with commonly reported side effects of nausea, vomiting and local injection site hypersensitivity reactions.^6–8

GLP-1 receptor agonists, such as exenatide, have become more widely used in the treatment of T2DM after they were approved for use as combination therapy to achieve optimal glycaemic control and included as second-line therapy according to the ADA and AACE.² Exenatide is available in two preparations, Byetta and Bydureon. Bydureon is the newly approved ER formulation of exenatide that is dosed once weekly as 2 mg, whereas Byetta is dosed two times per day as 5–10 mcg.⁵

Angio-oedema is a condition resulting from the loss of vasculature tissue integrity with ensuing extravasation of fluid.⁹ There are three known underlying mechanisms causing angio-oedema; mast cell-mediated mechanism, which involves release of mast cell-derived mediators that increase vascular permeability; bradykinin-mediated mechanism, which involves increased bradykinin production leading to increased vascular permeability; and aetiologies of unknown mechanism, which can be caused by vasoactive mediator other than histamine or bradykinin.¹⁰ Angio-oedema due to C1 inhibitor deficiency can be hereditary or acquired. Abnormalities in the level or function of C1 inhibitor leads to increased bradykinin production, which, in turn, causes angio-oedema.⁹ This condition is associated with recurrent attacks of angio-oedema without urticaria. These patients are usually unresponsive to antihistamines or corticosteroids.¹⁰ Mast cell-mediated angio-oedema is due to release of histamine and other mast cell-derived mediators.⁹ Angiotensin-converting enzyme (ACE) inhibitor-induced angio-oedema is associated with ACE inhibitor use history, and typically, there is no urticaria history.¹⁰ Allergic angio-oedema, one of the most common causes of angio-oedema, can be caused by exposure to certain foods (peanuts, shellfish, eggs and milk), drugs (ACE inhibitors, penicillin and sulfa drugs) and insect bites (bees, wasp and yellow jacket).⁹ It can occur without any history of allergic rhinitis, asthma or atopic dermatitis. It is driven by a mast cell-mediated mechanism. Swelling can involve the entire face or particular areas such as lips, eyes, tongue or pharynx.⁹

While angio-oedema has been documented as a potential adverse effect of exenatide by its manufacturer, its incidence remains unknown and cases have not been previously published.⁵ We present the first case of angio-oedema secondary to exenatide ER, to raise awareness of this rare side effect and its clinical significance.

Case presentation

A 67-year-old woman with T2DM presented to our institution with acute complaints of tongue swelling, difficulty breathing, dizziness and diffuse itching that began 15 min after self-administering her first dose of exenatide ER.

She had no previous history of drug allergy, asthma, eczema or adverse reactions to other medications. Her other home medications included hydrochlorothiazide 12.5 mg once daily, levothyroxine 150 mcg once daily, metformin 500 mg two times per day, Lantus 15 units at nighttime and Humalog 2–15 units three times a day with meals (on a sliding scale). She had been taking these medications for greater than 1 year without any noted adverse effects, except for a notable history of not tolerating metformin despite being at a reduced dose of 500 mg two times per day due to its gastrointestinal side effects, resulting in her missing doses frequently. As a result, she continued to have poor control of her diabetes (HbA1c=7.6%, goal <7.0%) despite being compliant with insulin and was ultimately started on exenatide ER. On review of recent lifestyle changes, the patient denied any exposure to new foods, topical or oral creams, laundry detergents, illicit drugs or any other new medications. Surgical history includes thyroidectomy for thyroid cancer, hysterectomy, bladder sling surgery and ganglion cyst removal from feet. The patient is a former smoker who quit smoking 20 years ago, denies illicit drug use and rarely drinks alcohol. Family history is positive for diabetes mellitus in the mother and father. The patient did not report any history of angio-oedema in the family.

On presentation, her blood pressure was 183/114 mm Hg, pulse 90 beats/min, respiratory rate of 20/min, saturating 98% on room air with a temperature of 98ºF. On examination, the patient was in moderate distress, holding her tongue out of her mouth with moderate tongue swelling noted, but was able to talk in full sentences, with no swelling of eyelids or lips noted. Rest of the head, eyes, ears, nose and throat examination was unremarkable. Lung examination demonstrated clear breath sounds without wheezing. She had no rashes on the exposed skin. Cardiac examination showed a regular rate and rhythm with no abnormal heart sounds or murmurs. Abdomen was soft, non-distended and non-tender. The patient had normal affect and mood.

The possibility of exenatide ER induced angio-oedema was considered given the correlation of medication ingestion and onset of symptoms.

Investigations

Complete blood count demonstrated a mild leucocytosis of 11 000 μL and basic metabolic panel demonstrated mild hyponatraemia (131 mmol/L). Routine urine analysis showed no evidence of infectious process. ECG demonstrated sinus tachycardia with a heart rate of 138/min. Due to the severity of her initial presentation, imaging was deferred for quicker medication administration.

Differential diagnosis

Angio-oedema can be caused by one of several different clinical conditions (table 1).¹⁰ Allergic angio-oedema, is usually accompanied by urticaria and the patient may also complain of pruritus. It is preceded by exposure to an allergen or offending agent.⁴ This condition is associated with resolution of symptoms with antihistamines and corticosteroids.¹⁰ Considering our patient’s temporal sequence of symptoms with exenatide ER injection, pruritus and resolution of symptoms with administration of antihistamines and corticosteroids, this is a likely diagnosis.

Table 1.

Differential diagnoses of acute angio-oedema^{11 21 22}

Entity	Frequency of occurrence	Clinical presentation	Comments
Allergen-induced angio-oedema	No clear data	Sudden onset (≤1 hour). Swelling typically localised to area of exposure (eg, food would suggest swelling to oral mucosa). Can be associated with hypotension, urticaria and dyspnoea. Symptoms typically subside in 24–37 hours.	First condition aetiology considered in acute presentations. Food allergens most common culprit, to include shellfish, nuts and flavour enhancers. Can be ruled out with allergy skin testing.
Hereditary angio-oedema	1:50 000 people	Can occur at any age, most common initial presentation is within the first two decades of life; however, in acquired causes, initial symptoms start after the fourth decade. Slow, progressive onset of symptoms over several hours that can last over 72 hours.	Often associated with deficiency in the C1 esterase inhibitor. Mortality rate reported as high as 40% secondary to asphyxiation. Common cause for gastrointestinal angio-oedema.
Medication-induced angio-oedema	0.1%–1.6% of the US population (ACE-I specifically)	Primarily associated with abdominal swelling, peripheral swelling in the extremities as well as genitourinary swelling. Onset over 6–12 hours that can last up to 48 hours.	Commonly associated with ACE-inhibitors. May occur after initial ingestion of medication, or delayed for months after.
Facial cellulitis	No clear data	Will have erythema with associated swelling. Periorbital oedema is commonly seen with cellulitis, rather than acute angio-oedema. Concurrent blisters or vesicles are suggestive of cellulitis rather than angio-oedema.

ACE, angiotensin-converting enzyme.

Hereditary angio-oedema, our patient’s history of urticaria associated with angio-oedema, negative family history and good response to antihistamine and corticosteroids make this a less likely cause of her condition.

ACE inhibitor-induced angio-oedema, our patient did not have history of ACE inhibitor use.

Facial cellulitis should be excluded in patients presenting with angio-oedema.¹⁰ Our patient did not have any history of recent trauma, minor cuts, fever, chills or facial swelling with redness.

Treatment

Due to concern for histamine-associated angio-oedema, our patient immediately received an intramuscular dose of epinephrine 0.3 mg, as well as intravenous doses of dexamethasone 10 mg. The patient was given 25 mg of oral Benadryl and 20 mg of famotidine. Within minutes, she had improvement in her tongue swelling and wheezing. Given the 2-week half-life of exenatide ER, she was placed on sliding scale insulin and was admitted for further evaluation and management. Approximately 24 hours after her admission, she had a repeat episode of tongue swelling and feeling of dyspnoea that resolved after repeat treatment as above with the addition of 1 unit fresh frozen plasma (FFP).¹¹

Outcome and follow-up

She remained symptom-free after the second occurrence and was discharged home on hospital day 3 with planned discontinuation of exenatide ER as an outpatient along with a 10-day course of 40 mg of oral prednisone and a 7-day course of 40 mg oral famotidine. Benadryl 25 mg orally as needed for return of swelling and epinephrine pen 0.3 mg intramuscularly as needed for dyspnoea, pruritus, tongue swelling and wheezing were given for precautionary purposes. The patient was instructed on how to use the epinephrine pen prior to discharge.^11–13 She was also advised to follow-up with her primary care physician within a week of discharge.

A follow-up call placed 2 weeks after discharge revealed that she was doing well after discontinuation of exenatide ER. Her diabetes was well controlled on subcutaneous 15 units of Lantus at night and Humalog 2–15 units three times a day before meals per sliding scale, which was her previous regimen except exenatide ER. She did not report any other episode of difficulty breathing, tongue swelling or pruritus. She had completed medication regimen prescribed at discharge and had not required additional Benadryl or use of the epinephrine.

Discussion

GLP-1 receptor agonists in combination with basal insulin has been shown to achieve strict glycaemic control with no increased risk of hypoglycaemia or weight gain.⁷ In 2016, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial was published which showed that, among patients with T2DM, the rate of first occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke was lower with liraglutide (GLP-1 receptor agonist) than with placebo.¹⁴ As a result, GLP-1 agonists such as exenatide ER are being prescribed at increasing rates in those with T2DM and because of this, providers should understand the various side effects associated with it.

One study after systematic review and network meta-anaylsis found that all GLP-1 receptor agonist dose regimens significantly increased the incidence of gastrointestinal adverse effects, compared with placebo or conventional treatment.⁷ Dehydration, sometimes leading to renal impairment and acute renal failure, has been reported in patients treated with GLP-1 receptor agonists.⁸ Injection site reactions, such as rash, erythema or itching at the injection site, are common with GLP-1 receptor agonists.⁸ The predominant injection site reaction is pruritus. These reactions do not usually lead to the discontinuation of treatment as they are often transient and self-limited.⁸ GLP-1 receptor agonists are synthetic peptides and, like other subcutaneously injected peptides, may lead to antibody formation. The incidence of antibody formation was 44% with exenatide ER, 8.6% with liraglutide, 69.8% with lixisenatide, 4% with albiglutide and 1.6% with dulaglutide.⁸ Other than injection site reactions, anti-exenatide antibodies were not found to cause systemic disease.¹⁵ The development of anti-exenatide antibodies was noted to present clinically as a diminished glycaemic response rather than an anaphylactic reaction. Clinical relevance of these antibodies has yet to be clearly established by literature.^{4 5}

Multiple trials have been performed and studied for the comparison of efficacy of exenatide ER once weekly formulation (Bydureon) versus insulin glargine (Lantus, Basaglar and Toujeo), liraglutide (Victoza) and exenatide two times per day formulations (Byetta).¹⁶ Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions in HbA1c noted with liraglutide compared with once weekly exenatide ER.¹⁷ Another study demonstrated significantly greater improvements in glycaemic control in exenatide ER once weekly versus exenatide two times per day formulation, with no increased risk of hypoglycaemia.¹⁶ Also in a study comparing exenatide ER once weekly versus insulin glargine, the change in baseline HbA1c was significantly greater with exenatide once weekly when compared with insulin glargine.¹⁸

Naranjo Adverse Drug Reaction Probability Scale is used to assess whether there is a causal relationship between an adverse reaction and a drug using a simple questionnaire to assign probability scores.¹⁹ It includes assessing temporal sequence of drug with the adverse event, resolution of symptoms with drug discontinuation and no alternative diagnosis possible based on patient’s history, physical examination and diagnostic tests.¹⁹ Applying Naranjo Scale to our patient, Bydureon was a probable cause of angio-oedema.²⁰ Given the reasonable temporal relationship of angio-oedema and resolution of symptoms after discontinuation of exenatide ER, the FFP was given based on literature published in regards to the role in angio-oedema secondary to ACE with the thought there may be similar underlying pathophysiology.¹¹

There are no reported cases in literature related to Bydureon as a cause of angio-oedema. We report this novel case to guide further research into understanding this adverse effect caused by exenatide formulations and its clinical implications. Although GLP-1 receptor agonists are increasingly being prescribed due to their efficacy, this potential life-threatening adverse effect should be taken into consideration and patients should be counselled regarding it.

Learning points.

• Exenatide extended release (ER) induced angio-oedema is reported in an otherwise healthy adult.

• A patient suspected of exenatide ER-induced angio-oedema should be closely monitored for 3–4 days as this medication has a prolonged half-life (2 weeks).

• Exenatide ER should be discontinued and the patient should be discharged with intramuscular epinephrine pen.

• This severe adverse effect should be taken into consideration when prescribing exenatide ER.