When tirzepatide was used as monotherapy for diabetes, none of the patients in the trials reported hypoglycemia (blood glucose less than 54 mg/dL) or severe hypoglycemia. When tirzepatide was added to basal insulin with or without metformin, hypoglycemia occurred in 16%, 19%, and 14%, and severe hypoglycemia occurred in 0%, 2%, and 1% of patients treated with tirzepatide 5 mg, 10 mg, and 15 mg, respectively. Hypoglycemia was more frequent when tirzepatide was used in combination with a sulfonylurea. In a clinical trial up to 104 weeks of treatment, when administered with a sulfonylurea, hypoglycemia occurred in 13.8%, 9.9%, and 12.8%, and severe hypoglycemia occurred in 0.5%, 0%, and 0.6% of patients treated with tirzepatide 5 mg, 10 mg, and 15 mg, respectively.[67631] In clinical trials of tirzepatide for weight management, patients with type 2 diabetes mellitus (T2DM) and a BMI of 27 kg/m² or greater, hypoglycemia (plasma glucose less than 54 mg/dL) was reported in 4.2% of tirzepatide-treated patients versus 1.3% of placebo-treated patients. In a trial of tirzepatide in adults with obesity/overweight without T2DM, there was no systematic capturing of hypoglycemia, but plasma glucose less than 54 mg/dL was reported in 0.3% of tirzepatide-treated patients versus no placebo-treated patients.[69808]

Gastrointestinal (GI) side effects are among the most common adverse events associated with tirzepatide and are sometimes severe. In the pool of placebo-controlled trials of tirzepatide for diabetes, GI adverse reactions occurred more frequently among patients receiving tirzepatide than placebo (placebo 20.4%, tirzepatide 5 mg 37.1%, tirzepatide 10 mg 39.6%, tirzepatide 15 mg 43.6%). More patients receiving tirzepatide 5 mg (3%), tirzepatide 10 mg (5.4%), and tirzepatide 15 mg (6.6%) discontinued treatment due to GI events than patients receiving placebo (0.4%). The following GI side effects were reported in 5% or more of patients receiving tirzepatide for diabetes treatment: anorexia (5% to 11%), nausea (12% to 18%), diarrhea (12% to 17%), vomiting (5% to 9%), constipation (6% to 7%), dyspepsia (5% to 8%), and abdominal pain (5% to 6%). In patients with renal disease, diarrhea, nausea, and vomiting may cause dehydration; severe dehydration could cause acute kidney injury. Tirzepatide therapy commonly resulted in significant weight loss; patients treated with tirzepatide for diabetes lost between 12 pounds (5 mg) and 25 pounds (15 mg) on average. Ileus has been reported with tirzepatide in postmarketing surveillance.[67631] In clinical trials of tirzepatide for weight management, GI adverse reactions occurred more frequently among patients receiving tirzepatide than placebo. More patients receiving tirzepatide discontinued treatment due to GI adverse reactions than patients receiving placebo. Nausea (25% to 29%), vomiting (8% to 13%), and diarrhea (19% to 23%) occurred during dose escalation and decreased over time. Constipation (11% to 17%), abdominal pain (9% to 10%), dyspepsia (9% to 10%), gastroesophageal reflux disease (4% to 5%), flatulence (3% to 4%), eructation (4% to 5%), and abdominal distention (3% to 4%) were reported in patients receiving tirzepatide for weight management. Dysgeusia was reported in 0.4% of tirzepatide patients compared to none in placebo-treated patients. Xerostomia or dry throat was reported in 1% of tirzepatide patients compared to 0.1% of placebo patients.[69808]

Acute gallbladder disease has been reported during clinical trials with GLP-1 receptor agonists. In tirzepatide placebo-controlled clinical trials for diabetes, acute gallbladder disease (cholelithiasis, biliary colic, cholecystitis, and cholecystectomy) was reported by 0.6% of patients treated with tirzepatide patients and 0% of placebo-treated patients. In clinical trials of tirzepatide for weight management, cholelithiasis (1.1%), cholecystitis (0.7%), and cholecystectomy (0.2%) were reported in tirzepatide-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.[67631] [69808]

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists. In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 patients treated with tirzepatide (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure).[67631] In the pool of placebo-controlled clinical trials, treatment with tirzepatide resulted in hyperamylasemia, with mean increases from baseline in serum pancreatic amylase concentrations of 33% to 38% and serum lipase concentrations of 31% to 42%. Placebo treated patients had a mean increase from baseline in pancreatic amylase of 4% and no changes were observed in lipase. The clinical significance of elevations in lipase or amylase with tirzepatide is unknown in the absence of other signs and symptoms of pancreatitis.[67631] Treatment with tirzepatide for weight management resulted in mean increases from baseline in serum pancreatic amylase concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with tirzepatide is unknown in the absence of other signs and symptoms of pancreatitis.[69808] Patients should be instructed to seek prompt medical attention if they experience unexplained persistent severe abdominal pain, which may or may not be accompanied by vomiting. If pancreatitis is suspected, tirzepatide should be discontinued. If pancreatitis is confirmed, tirzepatide should not be restarted unless an alternative etiology is identified.[67631] [69808]

Hypersensitivity reactions (e.g., rash, urticaria, pruritus, and eczema/atopic dermatitis) have been reported with tirzepatide in clinical trials and were sometimes severe. Hypersensitivity reactions were reported in 3.2% of patients treated with tirzepatide for diabetes and 5% of patients receiving tirzepatide for weight management. Serious hypersensitivity reactions, including anaphylaxis, anaphylactoid reactions, and angioedema, have been reported in patients treated with tirzepatide in postmarketing surveillance. In clinical trials of tirzepatide for weight management, immediate hypersensitivity reactions (within 1 day after drug administration) occurred in 2.1% of patients receiving tirzepatide compared to 0.4% of patients receiving placebo, while non-immediate hypersensitivity reactions occurred in 3.5% of patients receiving tirzepatide compared to 2.7% of patients receiving placebo. It is unknown whether patients with a history of anaphylactoid reactions or angioedema with another GLP-1 receptor agonist will be predisposed to anaphylaxis with tirzepatide.[67631] [69808]

In the pool of placebo-controlled trials of tirzepatide for diabetes, injection site reactions were reported in 3.2% of patients treated with tirzepatide compared to 0.4% of placebo-treated patients. In the pool of 7 clinical trials, injection site reactions occurred in 119/2,570 (4.6%) of tirzepatide-treated patients with anti-tirzepatide antibodies and in 18/2,455 (0.7%) of tirzepatide-treated patients who did not develop anti-tirzepatide antibodies.[67631] In clinical trials of tirzepatide for weight management, injection site reactions, including localized bruising (ecchymosis), erythema, pruritus, pain, and rash were reported in 6% to 8% of patients. Injection site reactions occurred more frequent in those with anti-tirzepatide antibodies (11.3%) compared to patients who did not develop anti-tirzepatide antibodies.[69808]

Tirzepatide, like other GLP-1 receptor agonists, may be associated with acute kidney injury. In clinical trials of tirzepatide for weight management, acute kidney injury was reported in 0.5% of tirzepatide-treated patients and 0.2% of patients receiving placebo. There are postmarketing reports of acute kidney injury in patients treated with GLP-1 receptor agonists. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. The reports have included increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure (unspecified), sometimes requiring hemodialysis. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors (ACE inhibitors), nonsteroidal anti-inflammatory drugs (NSAIDs), or diuretics. Altered renal function was reversible in many cases with supportive treatment and discontinuation of potentially causative agents. Advise patients of the potential risks of dehydration due to GI adverse reactions and to take precautions to avoid fluid depletion while taking tirzepatide. Monitor renal function when initiating or escalating doses of tirzepatide in patients with renal impairment who report severe gastrointestinal adverse reactions. Tirzepatide has not been found to be directly nephrotoxic in preclinical or clinical studies.[67631] [69808]

In the pool of placebo-controlled trials of tirzepatide for diabetes, treatment with tirzepatide resulted in a mean increase in heart rate of 2 to 4 beats per minute compared to a mean increase of 1 beat per minute in placebo-treated patients. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of 15 or more beats per minute, also were reported in 4.3% to 7%, 4.6% to 7.1%, 5.9% to 9.3% and 10% to 23% of subjects treated with placebo, tirzepatide 5 mg, 10 mg, and 15 mg, respectively. The clinical relevance of heart rate increases is uncertain.[67631] In clinical trials of tirzepatide for weight management, hypotension (including orthostatic hypotension) occurred more frequently among patients receiving tirzepatide (1% to 2%) than patients receiving placebo (0.1%). Hypotension was more frequently seen in tirzepatide-treated patients on concomitant antihypertensive therapy (2.2%) compared to tirzepatide-treated patients not on antihypertensive therapy (1.2%). Hypotension also occurred in association with gastrointestinal adverse events and dehydration. Treatment with tirzepatide for weight management resulted in a mean increase in heart rate of 1 to 3 beats per minute compared to no increase in placebo-treated patients.[69808]

In clinical trials of tirzepatide for weight management, general symptoms of fatigue (including asthenia, lethargy, and malaise) were reported in 5% to 7% of tirzepatide-treated patients. Dizziness was reported in 4% to 5% of patients receiving tirzepatide. Dysesthesia occurred in 0.2% of patients treated with tirzepatide 5 mg and 10 mg, and 0.4% of patients treated with tirzepatide 15 mg, compared to 0.1% of placebo-treated patients in clinical trials for weight management.[69808]

In clinical trials of tirzepatide for weight management, hair loss (alopecia) adverse reactions were associated with weight reduction. In clinical trials, hair loss was reported at higher incidences than with placebo and in 4% to 5% of tirzepatide-treated patients, and more frequently in female than male patients in the tirzepatide (7.1% female versus 0.5% male). No tirzepatide-treated patients discontinued study treatment due to hair loss.[69808]

Anti-tirzepatide antibody formation is possible during treatment with tirzepatide. During the 40- to 104-week treatment periods with anti-drug antibody (ADA) sampling conducted up to 44 to 108 weeks in 7 clinical trials for diabetes, 51% (2,570/5,025) of tirzepatide-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 34% and 14% of patients treated with tirzepatide showed cross-reactivity to native GIP or native GLP-1, respectively. Of the 2,570 tirzepatide-treated patients who developed anti-tirzepatide antibodies during the treatment periods in these 7 trials, 2% and 2% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.9% and 0.4% developed neutralizing antibodies against native GIP or GLP-1, respectively.[67631] During the 72-week treatment period with ADA sampling in the weight management studies, 64.5% (1591/2467) of tirzepatide-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 40% and 16.5% of tirzepatide-treated patients showed cross-reactivity to native GIP or native GLP-1, respectively. Of the tirzepatide-treated patients, 2.8% and 2.7% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.8% and 0.1% developed neutralizing antibodies against native GIP or GLP-1, respectively.[69808] There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of tirzepatide. More tirzepatide-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies.[67631] [69808]

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Retinopathy complications have been reported with other GLP-1 receptor agonists. Monitor for visual changes in patients with a history of diabetic retinopathy. Inform patients to contact their prescriber if changes in vision are experienced during treatment with tirzepatide.[67631] [69808]

Tirzepatide may be associated with the development of a new primary malignancy. Tirzepatide has been shown to cause dose-dependent and treatment duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant exposures in both genders of rats. A statistically significant increase in thyroid C-cell adenomas was observed in males (0.5 mg/kg or greater) and females (0.15 mg/kg or greater), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females at all doses examined. The potential of tirzepatide to induce C-cell tumors in mice has not been evaluated. It is unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. It is not known whether monitoring serum calcitonin or performing thyroid ultrasounds will diminish human risk of thyroid C-cell tumors. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with tirzepatide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.[67631] [69808]

Suicidal behavior and suicidal ideation have been reported in clinical trials with other incretin mimetics indicated for weight management. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in moods or behaviors. Discontinue tirzepatide in patients who develop suicidal thoughts or behaviors.[69808] In January 2024, the FDA announced that they have not found evidence that use of GLP-1 RAs for type 2 diabetes or weight management causes suicidal thoughts or actions. During their preliminary evaluation, they conducted detailed reviews of reports of suicidal thoughts or actions received in the FDA Adverse Event Reporting System (FAERS) and reviews of clinical trials, including large outcome studies and observational studies. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, they cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue. Further evaluations include a meta-analysis of clinical trials across all GLP-1 RA products and an analysis of postmarketing data in the Sentinel System; final conclusions and recommendations will be communicated once more information is known.[70130]

There have been postmarketing reports of perioperative pulmonary aspiration in patients receiving GLP-1 receptor agonists who underwent elective surgery or procedures requiring general anesthesia or deep sedation. Despite adherence to preoperative fasting guidelines, these patients were found to have residual gastric contents. The available data is insufficient to give recommendations on mitigating the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking tirzepatide, including whether to modify preoperative fasting recommendations or temporarily discontinue tirzepatide.[69808]

Tirzepatide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Tirzepatide has been shown to cause dose-dependent and treatment duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant exposures in both genders of rats. A statistically significant increase in thyroid C-cell adenomas was observed in males (0.5 mg/kg or greater) and females (0.15 mg/kg or greater), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females at all doses examined. The potential of tirzepatide to induce C-cell tumors in mice has not been evaluated. It is unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. It is not known whether monitoring serum calcitonin or performing thyroid ultrasounds will diminish human risk of thyroid C-cell tumors. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with tirzepatide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.[67631] [69808]

Tirzepatide is contraindicated in any patient who has exhibited tirzepatide hypersensitivity or hypersensitivity to any of its inactive ingredients. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with tirzepatide. It is unknown whether patients with a history of angioedema or anaphylaxis with another glucagon-like peptide-1 (GLP-1) receptor agonist will be predisposed to anaphylaxis with tirzepatide. Monitor these patients closely when starting tirzepatide. If hypersensitivity reactions occur, discontinue use of tirzepatide; treat promptly per standard of care, and monitor until signs and symptoms resolve.[67631] [69808]

Tirzepatide is not indicated for use in patients with type 1 diabetes mellitus.[67631]

Hypoglycemia should be monitored by the patient and clinician when tirzepatide treatment is initiated and continued for type 2 diabetes mellitus (T2DM) and when used for weight reduction and maintenance. The risk of hypoglycemia, including severe hypoglycemia, is increased when tirzepatide is used in combination with insulin secretagogues (e.g., sulfonylureas, "glinides") or with insulin. Although specific dose recommendations are not available for most agents, the clinician should consider a dose reduction of the insulin secretagogue or insulin when used in combination with tirzepatide.[67631] In a trial of tirzepatide in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose less than 54 mg/dL was reported in 0.3% of tirzepatide-treated patients versus no placebo-treated patients.[69808] Adequate blood glucose monitoring should be continued and followed. Patient and family education regarding hypoglycemia management is crucial; the patient and patient's family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes (where deficiencies in the release or response to counter-regulatory hormones exist), with autonomic neuropathy, intensified diabetes control, or taking medications such as beta-blockers, guanethidine, or reserpine. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or another carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to prevent an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia in a patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.[64926]

Tirzepatide has not been studied in patients with severe gastrointestinal (GI) disease, including gastroparesis. Because tirzepatide is commonly associated with GI adverse reactions, including slowed gastric emptying, nausea, vomiting, and diarrhea, the use of tirzepatide is not recommended in patients with severe GI disease (e.g., severe gastroparesis, inflammatory bowel disease such as Crohn disease or ulcerative colitis).[67631] [69808]

Use caution when initiating or increasing doses of tirzepatide in patients with renal impairment; however, no dose adjustments are needed based on renal function. There have been postmarketing reports of acute kidney injury, and worsening of chronic renal failure, which sometimes has required hemodialysis, in patients treated with GLP-1 receptor agonists. Some of these events have been reported in patients without known underlying renal disease. In many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of tirzepatide in patients reporting severe adverse gastrointestinal reactions.[67631] [69808]

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists. In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 patients treated with tirzepatide (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). Tirzepatide has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on tirzepatide. After initiation of tirzepatide, and after dose increases, observe patients for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue tirzepatide and initiate appropriate management.[67631] [69808] In 2014, the FDA and EMA agencies stated that while they have not reached any new conclusions about safety risks of the incretin mimetics, the totality of the reviewed data (clinical and animal studies) provides reassurance that the data do not support an increased risk of pancreatitis or pancreatic cancer in patients receiving incretin mimetics. Continue to consider precautions related to pancreatic risk until more data are available.[53573] [56778]

Use tirzepatide with caution in patients with a history of gallbladder disease. Acute events of gallbladder disease have been reported in GLP-1 receptor agonist trials. In tirzepatide placebo-controlled clinical trials for diabetes, acute gallbladder disease (cholelithiasis, colic, and cholecystectomy) was reported by 0.6% of patients treated with tirzepatide patients and 0% of placebo-treated patients. In clinical trials of tirzepatide for weight loss, cholelithiasis (1.1%), cholecystitis (0.7%), and cholecystectomy (0.2%) were reported in tirzepatide-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.[67631] [69808]

Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. Fever, thyroid disease, infection, emesis, recent trauma or surgery, and certain medications can affect the response to antidiabetic agents. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring when acute illness is present. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever).[64926]

Tirzepatide should be used with caution in patients who will undergo elective surgery or procedures requiring general anesthesia or deep sedation. Tirzepatide delays gastric emptying. There have been postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists who underwent elective surgery or procedures requiring general anesthesia or deep sedation. Despite adherence to preoperative fasting guidelines, these patients were found to have residual gastric contents. The available data is insufficient to give recommendations on mitigating the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking tirzepatide, including whether to modify preoperative fasting recommendations or temporarily discontinue tirzepatide.[69808]

Monitor for visual changes in patients with a history of diabetic retinopathy. Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Inform patients to contact their prescriber if changes in vision are experienced during treatment.[67631] [69808]

Tirzepatide (Zepbound) for the treatment of obesity or weight management should not be used during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus. There is a pregnancy exposure registry for women who are exposed to tirzepatide intended for weight management (Zepbound) during pregnancy. Contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) for more information.[69808] According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy; these guidelines recommend contraception requirements for patients of childbearing potential; those receiving tirzepatide for weight reduction should use adequate contraception and discontinue tirzepatide if pregnancy occurs.[62881] Counsel female patients about the potential risk to the fetus during pregnancy and regarding contraception requirements during tirzepatide treatment for any indication. Use of tirzepatide may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with tirzepatide.[67631] [69808] There are no adequate data or clinical studies of tirzepatide use for the treatment of type 2 diabetes mellitus (T2DM) in pregnant women to inform a drug-associated risk for adverse developmental outcomes; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption.[67631] The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.[64926] [62358]

Use tirzepatide with caution during breast-feeding. There is no information regarding the presence of tirzepatide in human milk, the effects of tirzepatide on the breastfed infant, or the effects of the drug on milk production.[67631] [69808] If tirzepatide for the management of type 2 diabetes mellitus (T2DM) is discontinued and blood glucose is not controlled on diet and exercise alone, the clinician may consider insulin therapy. Oral hypoglycemics may also be considered. Metformin monotherapy may be appropriate for some patients as available studies indicate low excretion in milk and that maternal use during breast-feeding is not expected to result in side effects to a healthy nursing infant. Some experts recommend using metformin with caution if the patient is breastfeeding a newborn or a premature neonate with reduced renal function.[31407] [31408] [31409] [32459] [70364] Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected; therefore, this agent may be an alternative if postprandial glucose control is needed.[46303] Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide.[31568] If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.[46104]

During clinical trials the safety and efficacy of tirzepatide were not different in geriatric versus younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.[67631] [69808] Geriatric adults with diabetes mellitus are especially at risk for hypoglycemic episodes, especially if other risk factors are present, such as intensive insulin therapy, use of an excessive insulin dose, improper timing of insulin with regard to meals, injection of the wrong type of insulin, decreased renal function, severe liver disease, alcohol ingestion, defective counter-regulatory hormone release, missing meals/fasting, or gastroparesis.[30444] Because hypoglycemic events may be difficult to recognize in some older adults, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals.[64926]

Monitor blood glucose for needed dosage adjustments with tirzepatide in diabetic patients whenever a change in either nicotine intake or tobacco smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose or an increase in absorption of subcutaneous absorption of injections.

Suicidal behavior and ideation have been reported in clinical trials with other incretin mimetics indicated for weight management. Therefore, administer tirzepatide (a dual GIP/ GLP-1 agonist) with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation; monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in moods or behaviors. Discontinue tirzepatide in patients who develop suicidal thoughts or behaviors.[67631] [69808] In January 2024, the FDA announced that they have not found evidence that use of GLP-1 RAs for type 2 diabetes or weight management causes suicidal thoughts or actions. During their preliminary evaluation, they conducted detailed reviews of reports of suicidal thoughts or actions received in the FDA Adverse Event Reporting System (FAERS) and reviews of clinical trials, including large outcome studies and observational studies. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, they cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue. Further evaluations include a meta-analysis of clinical trials across all GLP-1 RA products and an analysis of postmarketing data in the Sentinel System; final conclusions and recommendations will be communicated once more information is known.[70130] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all patients undergoing weight loss therapy should be monitored for mood disorders, depression, and suicidal ideation. Caution is recommended in patients with a psychotic disorder (e.g., schizophrenia) due to insufficient data. Patients receiving an antipsychotic should be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; these guidelines suggest that metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]