Trulicity Side Effects: Which Ones Could Be Permanent?

Which Trulicity side effects could be permanent?

Serious reactions described for Trulicity include thyroid C-cell tumors, acute pancreatitis, severe gastrointestinal reactions, acute kidney injury from volume depletion, diabetic retinopathy complications, acute gallbladder disease and serious hypersensitivity [1]. In the placebo-controlled pool, gastrointestinal adverse reactions at 1.5 mg were graded mild in 48% of cases, moderate in 42% and severe in 11% [1].

Thyroid C-cell tumors: the boxed warning

In male and female rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in thyroid C-cell adenomas and carcinomas after lifetime exposure [1]. The label states that it is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rodent findings has not been determined [1].

The label describes two individual cases. One patient treated with Trulicity in a clinical trial developed MTC, and that patient had pretreatment calcitonin levels about 8 times the upper limit of normal. A second case, C-cell hyperplasia with elevated calcitonin levels, was reported in the cardiovascular outcomes trial REWIND [1].

Trulicity is contraindicated in patients with a personal or family history of MTC or with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [1]. According to the label, routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of MTC, and may raise the risk of unnecessary procedures given the low specificity of calcitonin testing and the high background incidence of thyroid disease. The label adds that significantly elevated calcitonin may indicate MTC, that patients with MTC usually have values above 50 ng/L, and that elevated values call for further evaluation [1]. The label says patients should be counseled about symptoms of thyroid tumors: a mass in the neck, dysphagia, dyspnea and persistent hoarseness [1].

Acute pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists including Trulicity [1]. The label directs prescribers to watch for persistent or severe abdominal pain, sometimes radiating to the back and sometimes accompanied by nausea or vomiting, and to discontinue Trulicity and begin appropriate management if pancreatitis is suspected [1].

Severe GI reactions and gastroparesis

In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions were reported in 2.2% of patients on 0.75 mg and 4.3% on 1.5 mg, compared with 1.4% on placebo [1]. The label says Trulicity is not recommended in patients with severe gastroparesis, and that severe gastrointestinal reactions have also been reported postmarketing with GLP-1 receptor agonists [1].

In the longer REWIND trial, 47.4% of patients assigned dulaglutide reported a gastrointestinal adverse event during follow-up, compared with 34.1% on placebo, over a median 5.4 years [2]. Dulaglutide also slows gastric emptying [1].

Acute kidney injury from dehydration

The label describes postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists including Trulicity. Most reported events occurred in patients who had gastrointestinal reactions leading to dehydration, such as nausea, vomiting or diarrhea [1]. The label directs monitoring of renal function in patients reporting reactions that could lead to volume depletion, especially during initiation and dose escalation [1].

Diabetic retinopathy complications

Diabetic retinopathy complications were reported in a Trulicity cardiovascular outcomes trial. The label calls for monitoring patients with a history of diabetic retinopathy [1].

Acute gallbladder disease

Acute gallbladder disease is a listed warning [1]. The label says that if cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated [1].

Hypersensitivity reactions

Anaphylactic reactions and angioedema have been reported in postmarketing use of Trulicity [1]. The label says to discontinue Trulicity if a hypersensitivity reaction occurs, treat promptly per standard of care, and monitor until signs and symptoms resolve [1]. Trulicity is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or any product component, and the label advises caution in patients with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist [1].

Nausea, vomiting and diarrhea: the common reactions

In the adult placebo-controlled pool (placebo 568 patients, 0.75 mg 836, 1.5 mg 834; mean exposure 23.8 weeks), the rates for placebo, 0.75 mg and 1.5 mg were: nausea 5.3%, 12.4% and 21.1%; diarrhea 6.7%, 8.9% and 12.6%; vomiting 2.3%, 6.0% and 12.7%; abdominal pain 4.9%, 6.5% and 9.4%; decreased appetite 1.6%, 4.9% and 8.6% [1]. Treatment was stopped for GI reasons by 0.2% of placebo patients, 1.3% on 0.75 mg and 3.5% on 1.5 mg [1].

The label says to start at 0.75 mg once weekly, increase to 1.5 mg after 4 weeks if more glycemic control is needed, then increase in 1.5 mg steps after at least 4 weeks on the current dose, to a maximum of 4.5 mg weekly in adults. It says to follow this escalation to reduce the risk of gastrointestinal adverse reactions [1]. In AWARD-11 (1,842 adults across three arms, 36 weeks), nausea was reported by 13.4% on 1.5 mg, 15.6% on 3 mg and 16.4% on 4.5 mg; diarrhea by 7.0%, 11.4% and 10.7%; and vomiting by 5.6%, 8.3% and 9.3% [1].

Low blood sugar can be serious, particularly when Trulicity is used with insulin or a sulfonylurea. With insulin glargine, glucose below 54 mg/dL occurred in 14.7% of patients on 1.5 mg versus 9.3% on placebo; with glimepiride, the rates were 3.3% versus 0% [1]. The label says to consider reducing the insulin or sulfonylurea dose when Trulicity is started [1].

Injection-site reactions

In pediatric patients aged 10 and older (150 treated, mean 41.3 weeks), the safety profile was consistent with adults except for injection-site reactions, which were reported in 3.9% of patients on 0.75 mg, 3.8% on 1.5 mg and 2.0% on placebo [1]. The label says to rotate injection sites among the abdomen, thigh and upper arm [1].