Trulicity Side Effects: Delayed-Onset Adverse Events You Need to Know

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Does Trulicity cause side effects that appear late?

The label's main adverse reaction table comes from placebo-controlled trials with a mean exposure of 23.8 weeks: 568 patients on placebo, 836 on 0.75 mg and 834 on 1.5 mg [1]. Nausea, diarrhea and vomiting are the most frequent reactions in it [1]. The serious risks, such as kidney injury, gallbladder disease, pancreatitis and hypersensitivity, are described in the Warnings and Precautions section, which gives no typical time of onset [1].

Gastrointestinal reactions during treatment, and higher doses

In the placebo-controlled pool, the rates at 0.75 mg and 1.5 mg were: nausea 12.4% and 21.1%, diarrhea 8.9% and 12.6%, vomiting 6.0% and 12.7%, abdominal pain 6.5% and 9.4%, decreased appetite 4.9% and 8.6%, dyspepsia 4.1% and 5.8%, and fatigue 4.2% and 5.6%, against 5.3%, 6.7%, 2.3%, 4.9%, 1.6%, 2.3% and 2.6% on placebo [1]. Constipation was 3.9% on 0.75 mg and 3.7% on 1.5 mg versus 0.7% on placebo, and reflux 1.7% and 2.0% versus 0.5% [1].

Investigators graded most gastrointestinal events as mild or moderate; severe events accounted for 7% of cases at 0.75 mg and 11% at 1.5 mg [1]. Severe GI reactions were more frequent on drug than placebo: 2.2% on 0.75 mg and 4.3% on 1.5 mg versus 1.4% [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's dosing schedule is to start at 0.75 mg and wait at least 4 weeks before each increase, and it says to follow this escalation to reduce the risk of gastrointestinal adverse reactions [1].

In AWARD-11, 1,842 adults on metformin were followed for 36 weeks on 1.5, 3 or 4.5 mg weekly. Nausea was 13.4%, 15.6% and 16.4%; diarrhea 7.0%, 11.4% and 10.7%; vomiting 5.6%, 8.3% and 9.3% [1]. The label cautions that adverse reaction rates from different clinical studies cannot be directly compared, so these should not be set against the placebo-controlled pool [1].

Over a longer horizon, REWIND followed 9,901 adults with type 2 diabetes and cardiovascular disease or risk factors for a median of 5.4 years on dulaglutide 1.5 mg or placebo; 47.4% of dulaglutide patients and 34.1% of placebo patients reported a gastrointestinal adverse event during that follow-up [2]. These figures do not show how long individual symptoms lasted.

The label says Trulicity is not recommended in patients with severe gastroparesis [1].

Acute kidney injury: the label ties it to dehydration

The label warns about acute kidney injury due to volume depletion and describes postmarketing reports, some requiring hemodialysis [1]. The majority of 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 dose initiation and escalation [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 describes what to watch for: persistent or severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by nausea or vomiting [1]. If pancreatitis is suspected, the label says to discontinue Trulicity and begin appropriate management [1].

Acute gallbladder disease

Acute gallbladder disease is a labeled warning. If cholelithiasis or cholecystitis is suspected, the label says gallbladder studies are indicated [1].

Thyroid C-cell tumors: what the boxed warning covers

The boxed warning rests on animal data. In male and female rats, dulaglutide caused a dose-related, treatment-duration-dependent increase in thyroid C-cell adenomas and carcinomas after lifetime exposure, and the label states that human relevance has not been determined [1].

Human data are case-level, not a rate. The label reports one case of medullary thyroid carcinoma in a patient treated with Trulicity in a clinical trial, a patient whose pretreatment calcitonin was about 8 times the upper limit of normal, and one case of C-cell hyperplasia with elevated calcitonin following treatment in the cardiovascular outcomes trial REWIND [1].

Trulicity is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or with Multiple Endocrine Neoplasia syndrome type 2 [1]. The label asks that patients be told the symptoms of thyroid tumors (a mass in the neck, dysphagia, dyspnea, persistent hoarseness). It states that routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection, and that such monitoring may increase the risk of unnecessary procedures because of low test specificity and a high background incidence of thyroid disease [1].

Hypersensitivity reactions

Postmarketing reports include anaphylactic reactions and angioedema [1]. The label directs that Trulicity be discontinued if a hypersensitivity reaction occurs, that it be treated promptly per standard of care, and that the patient be monitored until signs and symptoms resolve [1]. A previous serious hypersensitivity reaction to dulaglutide or a product component is a contraindication, and the label advises caution in patients with a history of angioedema or anaphylaxis to another GLP-1 receptor agonist [1].

Other labeled risks

Diabetic retinopathy complications were reported in a cardiovascular outcomes trial, and the label says to monitor patients with a history of diabetic retinopathy [1]. Pulmonary aspiration during general anesthesia or deep sedation has been reported with GLP-1 receptor agonists, and the label instructs that patients inform healthcare providers of any planned surgery or procedure [1].

Hypoglycemia risk depends on what Trulicity is combined with. With insulin glargine, glucose below 54 mg/dL occurred in 14.7% on 1.5 mg versus 9.3% on placebo; with glimepiride, 3.3% versus 0% [1]. The label says to consider reducing the insulin or sulfonylurea dose when starting Trulicity [1].

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