Tirzepatide is a novel medication that is FDA approved for the treatment of type 2 diabetes mellitus. Given its potent weight loss properties, tirzepatide be used off-label for obesity treatment. It works as a dual GLP-1 agonist and GIP agonist to maximize similar benefits that are seen with GLP-1 medications such as semaglutide. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications, and given as a once-a-week subcutaneous injectable. The FDA approved Tirzepatide in May 2022. The most commonly reported adverse effects are gastrointestinal, such as nausea or diarrhea. This activity reviews the indications, mechanism of action, adverse effects and contraindications, and important pearls for the use of tirzepatide. In addition, it highlights the administration, monitoring, and toxicity associated with tirzepatide for all clinicians.

Indications

Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist, which is FDA-approved for treating type 2 diabetes mellitus. It is important to note that tirzepatide is not approved for treating type-1 diabetes mellitus and has not been studied in patients with pancreatitis. Tirzepatide is a GIP receptor and GLP-1 receptor agonist, leading to significantly improved glycemic control in type 2 diabetics and significant weight reduction.

The FDA approved Tirzepatide in May 2022. Tirzepatide can also be used off-label for treating obesity. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications like semaglutide. It is a once-a-week subcutaneous injectable medication with incremental dose increases. 

Current clinical data has demonstrated that tirzepatide is superior to placebo in improving hemoglobin A1C levels. The SURPASS-5 clinical trial showed a -2.11% reduction in hemoglobin A1C levels at 5mg per week dosing, compared to -0.86% with placebo. At the highest dose of 15 mg per week, tirzepatide led to a -2.34% reduction in hemoglobin A1C. This was demonstrated over 40 weeks. A weight reduction of 5.4 kg was seen with 5mg of tirzepatide dosing, and a 10.5 kg reduction was seen with 15 mg dosing. This dose-dependent correlation with weight loss is similar to semaglutide, a common GLP-1 medication utilized for weight loss management.

Comparatively, tirzepatide has been shown to work similarly to GLP-1 medications but with greater efficacy. Given its weight loss properties and lack of liver toxicity, it is likely to play an indirect role in the treatment of nonalcoholic fatty liver disease (NAFLD) as well; however, further research is needed before it is approved for NAFLD.

Mechanism of Action

Tirzepatide is a synthetic peptide; and a dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. It is composed of 39 amino acids and is an analog of the gastric inhibitory polypeptide. Functionally, it stimulates insulin release from the pancreas and leads to a reduction of hyperglycemia. In addition, Tirzepatide also increases the levels of adiponectin. Its dual agonism ability leads to a more significant reduction of hyperglycemia than GLP-1 agonist agents alone and lowers the user’s appetite.

Pharmacokinetics

Absorption: Tirzepatide has a bioavailability of approximately 80%. The time it takes to reach peak serum levels can range from 8 to 72 hours.

Distribution: The mean apparent steady-state volume of distribution(Vd) of tirzepatide is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).

Metabolism: Once injected, the peptide structure undergoes proteolytic cleavage. In addition, the C20 fatty diacid composition undergoes beta-oxidation and amide hydrolysis.

Excretion: Tirzepatide has a half-life of 5 days, allowing once-weekly dosing, and is cleared in urine and feces in the form of metabolites.

Administration

Tirzepatide is administered subcutaneously via an injection. It is not available in oral form at this time.

It is available in various dosages: 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, 15 mg/0.5 mL. Standard dosing is once weekly, with the usual initiation dose being 5 mg/0.5 mL. Prescribed doses can be increased on follow-up visits based on efficacy, as defined by hemoglobin A1C levels and body weight, and adverse effects. The primary adverse drug reactions are largely gastrointestinal related, such as abdominal discomfort and nausea, with variable severity. The patients’ ability to tolerate side effects plays a significant role in the titration of tirzepatide dosing.

Use in Specific Patient Population 

Patients with Hepatic Impairment: According to the manufacturer’s product information, no dosage adjustment of tirzepatide is suggested for patients with hepatic impairment.

Patients with Renal Impairment: No dosage adjustment of tirzepatide is suggested for patients with hepatic impairment. However, tirzepatide is associated with gastrointestinal ADRs, including nausea, vomiting, and diarrhea leading to dehydration, which can cause acute kidney injury. Use with caution in patients prone to dehydration. 

Pregnancy Considerations: Available information on tirzepatide use in pregnant women is inadequate to evaluate for a drug-related risk of congenital disabilities and adverse maternal or fetal outcomes. A risk to the mother and fetus is associated with poorly controlled diabetes in pregnancy. In addition, increased incidences of external, visceral, and skeletal malformations have been observed in animal reproduction studies. Therefore, there may be risks to the fetus from exposure to tirzepatide during pregnancy.

Consequently, tirzepatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Patients of childbearing age should be prescribed tirzepatide after discussing the possible teratogenic effects. Physicians should also discuss the initiation of contraception before prescribing tirzepatide. In addition, the efficacy of oral hormonal contraception declines while on tirzepatide therapy.

There should be shared decision-making on possibly changing the method of contraception to a non-oral route or utilizing barrier contraception for at least four weeks after initiation of tirzepatide therapy.

Breastfeeding Considerations: There is no information on tirzepatide in animal or human milk or its effects on the breastfed infant. Therefore, clinicians should consider the developmental and health benefits of breastfeeding, the mother’s clinical need for tirzepatide, and potential adverse impacts on the breastfed infant from tirzepatide.

Tirzepatide is a large molecule with high molecular weight. Accordingly, the milk concentration is likely to be less, and absorption is unlikely because it is presumably partially destroyed in the infant’s gastrointestinal tract. Therefore, until more clinical data become available, tirzepatide should be used cautiously during breastfeeding, especially in newborn or preterm infants.

Adverse Effects

Based on available data, most users do not experience significant adverse drug reactions. The primary adverse effects reported are gastrointestinal, but other side effects have also been infrequently reported. Decreased appetite is frequently reported, though this is a potential contributory etiology of intentional weight loss. Below are the adverse drug reactions reported by System Organ Class (SOC).

Gastrointestinal: Decreased appetite is often reported. Nausea and diarrhea may occur in up to 10% of patients, in addition to some infrequent reports of vomiting and acid reflux. Constipation has also been reported in some users.

Delayed gastric emptying hinders the absorption of other oral medications. This is particularly significant in those with preexisting delayed gastric emptying as it can exacerbate their symptoms. It is important to note that the efficacy of oral hormonal contraceptives is decreased, so patients should be advised to use non-oral contraceptive methods.

Cardiovascular: Sinus tachycardia has been reported but may be blunted by concurrent medication use.

Renal: Infrequent cases of acute kidney injury have been reported, likely secondary to dehydration from gastrointestinal losses. These may occur in healthy and preexisting chronic renal disease patients. Monitoring for signs of dehydration is likely to prevent renal injury.

Dermatologic: Hypersensitivity reactions have been infrequently reported at the injection site. The prevalence is not higher than those reported by patients using GLP-1 agonists. Such events should be discussed with a physician and may warrant medication discontinuation.

Pancreatitis: GLP-1 medications are a known risk factor for acute pancreatitis. The risk level for tirzepatide is similar to GLP-1 agonist medications. Patients should be advised to seek care at the local emergency department if they develop severe abdominal pain while on tirzepatide therapy. Asymptomatic elevation of lipase and amylase may also be seen in some patients.

Hepatobiliary: There have been reports of cholelithiasis and cholecystitis occurring in patients on tirzepatide therapy.

Ocular: Patients with preexisting diabetic retinopathy should be advised that those symptoms may temporarily worsen if their glycemic control quickly improves. Any vision changes while using tirzepatide(GLP-1 receptor agonist) should be immediately discussed with a physician.

Endocrine: There is a small risk of hypoglycemia and dose-dependent. This risk is more significant for those on insulin therapy and/or those utilizing sulfonylureas. Patients should be advised on the potential symptoms of hypoglycemia.

Contraindications

Boxed Warning: Data in animal studies has demonstrated the potential of developing medullary thyroid carcinoma. It is unknown whether this would also occur in humans at this time. Given the theoretical risk, tirzepatide should be avoided in those with a personal or family history of medullary thyroid carcinoma. Patients with a history of MEN 2 (multiple endocrine neoplasia syndrome type-2) should also avoid tirzepatide.

Patients with other thyroid cancer-related risk factors should be advised of the theoretical risks. Furthermore, patients who experience a hypersensitivity reaction should avoid using tirzepatide any further. Other relative contraindications also exist, such as gallbladder disease or diabetic retinopathy.

Tirzepatide is only approved for those with type 2 diabetes mellitus and should not be used in those with type 1 diabetes mellitus. It is also not directly approved for other forms of diabetes, such as latent autoimmune diabetes in adults.

Patients who are currently using other GLP-1 agents, such as semaglutide or liraglutide, should not be prescribed tirzepatide. Patients on insulin therapy can be initiated on tirzepatide therapy and cautiously have their insulin dose decreased to minimize the risk of hypoglycemia.

Monitoring

Patients should have their hemoglobin A1c and body weight monitored during scheduled follow-up visits. Follow-up intervals will vary depending on the local standard of care for diabetes management and/or obesity treatment. Hemoglobin A1C monitoring can be done as soon as every three months, depending on the patient and their A1C goal.

It is important to note that hemolytic anemia, G6PD deficiency, and pregnancy) can lead to discrepancies between the A1C result and the patient’s true glycemic status. Given the significantly improved insulin sensitivity while on tirzepatide, patients who also use insulin should be instructed to monitor their blood sugars more closely.

It is important to note that hemolytic anemia, G6PD deficiency, and pregnancy) can lead to discrepancies between the A1C result and the patient’s true glycemic status.

Monitoring for side effects, such as gastrointestinal-related symptoms, may also be necessary, especially as the prescribed doses increase. In addition, the asymptomatic elevation of lipase and amylase levels can be seen in patients using tirzepatide. Still, no clinical data suggests any utility in monitoring these markers without symptoms. 

Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of medullary carcinoma of the thyroid in patients treated with tirzepatide. In addition, such monitoring may increase the risk of unnecessary procedures. However, monitor for the thyroid nodules on physical examination, and if serum calcitonin >50 ng/L, then further diagnostic assessment of the patient for medullary carcinoma of the thyroid is required. Patients with a personal or family history of medullary thyroid carcinoma or MEN 2 should not be prescribed tirzepatide.

Integration of quality of life(QOL) assessment into routine care provides the optimum clinical care for patients with DM-2. Monitoring of  Diabetes-Dependent Quality of Life (ADDQoL), Diabetes Quality of Life (DQoL), and Short Form-12 (SF-12) help monitor the QOL in patients with type 2 diabetes mellitus.

Toxicity

Patients who overdose on tirzepatide should be monitored for any changes in clinical status. As this medication has a long half-life, patients may require prolonged monitoring. Clinicians should contact poison control, and consultation with a toxicologist may be necessary. There is no current antidote for tirzepatide overdose, but supportive care for symptom control would be consistent with the usual standard of care.

Patients with acute pancreatitis usually present with abdominal pain, serum lipase>3 ULN, and evidence of acute pancreatitis on imaging. American Gastroenterological Association guidelines recommend goal-directed fluid management for patients with acute pancreatitis.

Enhancing Healthcare Team Outcomes

Tirzepatide is a novel medication approved for treating type 2 diabetes mellitus with the additional benefit of weight loss. Clinicians are likely to be prescribing it in the setting of uncontrolled diabetes after first-line treatment. Current clinical data has shown tirzepatide to be highly efficacious in improving hemoglobin A1C levels and reducing body weight in a dose-dependent manner.

According to The American Diabetes Association (ADA) 2021 guidelines, an HbA1c goal for many nonpregnant adults of <7% is appropriate. According to guidelines, if the HbA1c target is not achieved after three months of metformin monotherapy, metformin can be combined with a GLP-1 receptor agonist (preferred in patients with a compelling need for weight loss) or other agents based on comorbidities and shared decision-making.

After initiating therapy with tirzepatide, clinicians are likely to follow up with patients in set intervals as early as four weeks or as late as 12 weeks, depending on the dosage and the local standard of care for diabetes management. Pharmacists are likely to play a key role for patients on tirzepatide. Their roles would include dispensing the medication, further counseling patients on adverse effects, and in some cases, they may be monitoring the patients’ hemoglobin A1Cs.

Certain care teams incorporate clinical pharmacists into their diabetes management. Given that tirzepatide can potentially lead to a few adverse effects, it is likely that nurses will have first-line contact with patients regarding these side effects. Knowledge and understanding of the medication’s adverse effects can be beneficial in counseling patients on when to seek further help.  Clinicians should also educate patients about warning symptoms of hypoglycemia, such as irritability, tremors, and confusion.

Tirzepatide is also likely to be prescribed in weight loss clinics, similar to GLP-1 medications. Obesity management clinics often incorporate multidisciplinary care that includes dietitians or social workers to help maximize patient outcomes. Given the popularity of semaglutide in weight loss clinics, it is likely that tirzepatide will gain similar popularity among physicians and patients, given the high levels of reported efficacy. However, as the clinical data has shown that weight reduction appears to be dose-dependent, Weight loss management may likely be limited by the ability of the patient to tolerate higher doses of tirzepatide.

A recent systematic review and meta-analysis reported that interprofessional collaboration between specialists, clinicians, nurses, and other healthcare providers could significantly improve Patient-Reported Outcomes (PROs) in patients with type-2 diabetes mellitus. [Level 1] Meticulous record keeping in the patient’s medical record is also crucial so that all interprofessional team members have the same updated and accurate patient data from which to operate and make decisions regarding patient care.