What are the side effects of Tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist)?

From the Guidelines

Tirzepatide can cause several side effects, with gastrointestinal issues being most common, including nausea, vomiting, diarrhea, and constipation, as reported in a 2023 study published in JAMA 1. These side effects typically occur during the initial weeks of treatment and often improve over time. The medication may also cause decreased appetite and weight loss, which is actually part of its intended effect for obesity treatment. Some patients experience injection site reactions like redness or itching. More serious but less common side effects include pancreatitis, gallbladder problems, hypoglycemia (especially when combined with insulin or sulfonylureas), and potential thyroid tumors (based on animal studies).

Key Points to Consider

• Tirzepatide should be started at a low dose (2.5mg weekly) and gradually increased to minimize side effects, as recommended in the JAMA study 1.
• Patients with a history of pancreatitis, medullary thyroid cancer, or Multiple Endocrine Neoplasia syndrome type 2 should avoid this medication, according to the study published in JAMA 1.
• Taking tirzepatide with food and staying well-hydrated can help reduce nausea, as suggested in a narrative review published in Anaesthesia 1.
• The medication works by mimicking gut hormones that regulate blood sugar and appetite, which naturally affect digestive processes and metabolism, as explained in the review published in Anaesthesia 1.

Management of Side Effects

• Nausea and vomiting can be managed by avoiding gastroparesis and starting the medication at a low dose, as recommended in the Anaesthesia review 1.
• Diarrhea can be managed by reducing meal size, as suggested in the same review 1.
• Gastrointestinal reflux can be managed by limiting alcohol and carbonated drinks, as recommended in the review published in Anaesthesia 1.
• Constipation can be managed by avoiding a high-fat diet, as suggested in the same review 1.

Important Considerations

• Tirzepatide has been shown to be effective in reducing body weight and improving glycemic control, as reported in a systematic review and network meta-analysis published in Annals of Internal Medicine 1.
• However, the medication may have potential risks, such as pancreatitis and thyroid tumors, which should be carefully considered and monitored, as discussed in the review published in JAMA 1.

From the FDA Drug Label

5.2 Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists. 5.5 Acute Kidney Injury MOUNJARO has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea [see Adverse Reactions (6. 1)]. 5.6 Severe Gastrointestinal Adverse Reactions Use of MOUNJARO has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions 6.1]. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] Pancreatitis [see Warnings and Precautions (5.2)] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Acute Kidney Injury [see Warnings and Precautions (5.5)] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)]

Tirzepatide side effects include:

• Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis
• Hypoglycemia: Increased risk of hypoglycemia when used with insulin secretagogues or insulin
• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis and angioedema
• Acute kidney injury: Associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea
• Severe gastrointestinal adverse reactions: Sometimes severe, including nausea, vomiting, and diarrhea
• Thyroid C-cell tumors: Risk of thyroid C-cell tumors 2
• Pulmonary aspiration: Rare postmarketing reports of pulmonary aspiration during general anesthesia or deep sedation 2
• Diabetic retinopathy complications: Temporary worsening of diabetic retinopathy with rapid improvement in glucose control 2
• Acute gallbladder disease: Acute events of gallbladder disease, including cholelithiasis or cholecystitis 2

From the Research

Tirzepatide Side Effects

• The most common side effects of tirzepatide include gastrointestinal (GI) symptoms such as nausea, vomiting, decreased appetite, constipation, and diarrhea 3, 4, 5.
• The incidence of these side effects is dose-dependent, with higher doses of tirzepatide associated with a higher risk of GI symptoms 4, 5.
• Compared to placebo, tirzepatide is associated with a significantly higher risk of nausea, vomiting, decreased appetite, constipation, and diarrhea 3, 4, 5.
• Tirzepatide is also associated with a higher risk of GI symptoms compared to insulin, but the risk is comparable to that of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) 5.

Specific Side Effects

• Nausea: The incidence of nausea with tirzepatide is significantly higher than with placebo, with a risk ratio of 2.90 (95% CI, 1.89 to 4.44; P ≤ 0.00001) 3.
• Vomiting: The incidence of vomiting with tirzepatide is significantly higher than with placebo, with a risk ratio of 2.69 (95% CI, 1.67 to 4.36; P ≤ 0.0001) 3.
• Decreased appetite: The incidence of decreased appetite with tirzepatide is significantly higher than with placebo, with a risk ratio of 5.04 (95% CI, 3.01 to 8.45; P ≤ 0.00001) 3.
• Constipation: The incidence of constipation with tirzepatide is significantly higher than with placebo, with a risk ratio of 3.08 (95% CI, 1.83 to 5.20; P ≤ 0.0001) 3.
• Diarrhea: The incidence of diarrhea with tirzepatide is significantly higher than with placebo, with a risk ratio of 2.07 (95% CI, 1.60 to 2.68; P ≤ 0.00001) 3.

Other Safety Considerations

• Pancreatic safety: Tirzepatide has been associated with a low risk of pancreatitis, with a risk ratio comparable to that of placebo and GLP-1 RAs 6.
• Renal safety: Tirzepatide has been associated with a positive effect on urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), with no increase in adverse renal events compared to placebo, insulin, and GLP-1 RAs 7.