Zepbound Side Effects: Rare but Serious Adverse Events Explained

What serious risks does the Zepbound label list?

The Zepbound label's warnings and precautions section lists serious risks including thyroid C-cell tumors, severe gastrointestinal adverse reactions, acute kidney injury due to volume depletion, acute gallbladder disease, acute pancreatitis, serious hypersensitivity reactions, hypoglycemia, diabetic retinopathy complications, and pulmonary aspiration during general anesthesia or deep sedation [1]. It also says Zepbound is not recommended in patients with severe gastroparesis [1].

The label gives rates for some of these events. In the pooled weight-management trials, severe GI reactions occurred in 1.7% of patients at 5 mg, 2.5% at 10 mg, and 3.1% at 15 mg vs 1% with placebo [1]. Any GI adverse reaction occurred in 56% on each Zepbound dose vs 30% with placebo [1].

Thyroid C-cell tumors and the boxed warning

The boxed warning is based on a 2-year rat study in which tirzepatide caused dose- and duration-dependent thyroid C-cell tumors, including adenomas and carcinomas, at clinically relevant plasma exposures [1]. The label says it is unknown whether Zepbound causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans because human relevance has not been determined [1].

Zepbound is contraindicated in patients with a personal or family history of MTC or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [1]. The label lists neck mass, dysphagia, dyspnea, and persistent hoarseness as symptoms of thyroid tumors [1]. Routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early MTC detection, and the label notes such monitoring may increase unnecessary procedures [1].

Acute pancreatitis

The label says acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or Zepbound [1]. In the pooled weight-management trials, adjudication-confirmed acute pancreatitis occurred in 0.2% of Zepbound patients and 0.2% of placebo patients, or 0.14 vs 0.15 patients per 100 years of exposure [1]. That pool combines SURMOUNT-1 (2,539 adults with obesity or overweight and no diabetes, 72 weeks) [2] and SURMOUNT-2 (938 adults with a BMI of 27 or higher and type 2 diabetes) [3]. In the pooled OSA trials, the exposure-adjusted rate was 0.84 per 100 years with Zepbound vs 0 with placebo [1].

The label describes persistent or severe abdominal pain, sometimes radiating to the back and possibly with nausea or vomiting, as signs of pancreatitis [1]. It says to discontinue Zepbound if pancreatitis is suspected and start appropriate management [1]. Mean amylase rose 20% to 25% and lipase 28% to 35%; the label says the clinical significance is unknown without signs of pancreatitis [1].

Gallbladder disease

In the pooled weight-management trials, cholelithiasis occurred in 1.1% of Zepbound patients vs 1% of placebo patients, cholecystitis in 0.7% vs 0.2%, and cholecystectomy in 0.2% vs none [1]. The label says acute gallbladder events were associated with weight reduction [1]. If cholecystitis is suspected, the label says gallbladder diagnostic studies and appropriate clinical follow-up are indicated [1].

Acute kidney injury

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

Hypoglycemia with insulin or sulfonylureas

The label warns that concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia, and that reducing the insulin or secretagogue dose may be necessary [1]. In SURMOUNT-2, hypoglycemia below 54 mg/dL occurred in 10.3% of patients taking a sulfonylurea vs 2.1% of those not taking one [1].

Serious allergic reactions

Postmarketing reports include anaphylaxis and angioedema with tirzepatide [1]. In the pooled weight-management trials, severe hypersensitivity reactions occurred in 0.1% of Zepbound patients vs none on placebo [1]. Zepbound is contraindicated in patients with a known serious hypersensitivity to tirzepatide or any excipient [1]. The label says to discontinue Zepbound if a hypersensitivity reaction is suspected [1].

Diabetic retinopathy and aspiration risk

The label includes a warning to monitor patients with a history of diabetic retinopathy for progression [1]. It also warns about pulmonary aspiration during general anesthesia or deep sedation in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures [1].

Is suicidal thinking a listed Zepbound side effect?

The current Zepbound label contains no mention of suicidal behavior or ideation [1].