TIRZEPATIDE (MOUNJARO®)

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• Dual GLP-1 and GIP agonists
• Tirzepatide (Mounjaro®) - marketed for diabetes
• Tirzepatide (Zepbound®) - marketed for weight loss

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• GLP-1 and GIP
• GLP-1 stands for "glucagon-like peptide-1," and GIP stands for "glucose-dependent insulinotropic polypeptide." GIP is also sometimes referred to as "gastric inhibitory polypeptide."
• GLP-1 and GIP are hormones secreted by specialized cells in the small intestine in response to food consumption. The actions of GLP-1 and GIP on different tissues are described below. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1 and GIP, rendering them inactive.
• Pancreas
• GLP-1 and GIP stimulate insulin secretion
• GLP-1 suppresses glucagon secretion during hyperglycemia
• GIP suppresses glucagon secretion during hyperglycemia and stimulates secretion during euglycemia and hypoglycemia
• Brain
• GLP-1 and GIP suppress hunger
• Stomach
• GLP-1 slows gastric emptying
• Fat tissue
• GIP increases fatty acid and glucose uptake by fat tissue [1,2,3]


• Tirzepatide
• Tirzepatide is a dual GLP-1 / GIP receptor agonist that mimics the actions of GLP-1 and GIP. It has been modified so that DPP-4 cannot metabolize it.
• GLP-1 / GIP therapies illustration

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• Tirzepatide (Mounjaro®)
• Type 2 diabetes - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

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• RCT
  SURMOUNT-2 trial - Tirzepatide vs Placebo for Weight Loss in DM, Lancet (2023) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=938 | length = 72 weeks) in overweight diabetics (mean BMI 36 | mean A1C 8.02%)
• Treatment: Tirzepatide 10 mg once weekly vs Tirzepatide 15 mg once weekly vs Placebo
• Primary outcome: Coprimary endpoints were the percent change in body weight from baseline and body weight reduction of 5% or higher
• Results:
• Primary outcome (% reduction in weight): Tirzepatide 10 mg - 12.8%, Tirzepatide 15 mg - 14.7%, Placebo - 3.2% (p<0.0001 for tirzepatide vs placebo)
• Primary outcome (weight loss ≥ 5%): Tirzepatide 10 mg - 79%, Tirzepatide 15 mg - 83%, Placebo - 32%
• Findings: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in body weight, with a safety profile that was similar to other incretin-based therapies for weight management.

• ADA recommendations
• See type 2 diabetes treatment recommendations

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• Gastrointestinal side effects
• Gastrointestinal side effects are the most common type of adverse reaction seen with tirzepatide. The table below gives the incidence of GI complaints from placebo-controlled trials.

• Hypoglycemia
• Tirzepatide by itself does not pose a significant risk of hypoglycemia. When it is combined with other diabetes medications, particularly insulin and insulin secretagogues, hypoglycemia can occur. In the SURPASS-2 trial where tirzepatide was added to metformin, hypoglycemia (< 54 mg/dl) occurred in 0.6%, 0.2%, and 1.7% of patients treated with tirzepatide 5 mg, 10 mg, and 15 mg, respectively.
• Patients taking concomitant diabetes medications should monitor their blood sugars closely and be prepared to treat hypoglycemia if needed (see hypoglycemia for more). When adding tirzepatide to insulin or insulin secretagogue therapy, consider reducing the dose of these medications. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. In a similar study, patients with an A1C ≥ 7.5% reduced their insulin glargine dose by 30% when beginning tirzepatide. [1,3,5]

• Heart rate increase
• In trials, tirzepatide-treated patients had an average increase in heart rate of 2 - 4 bpm compared to 1 bpm in placebo-treated patients. Sinus tachycardia, defined as ≥ 15 bmp increase over baseline, was reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo, tirzepatide 5 mg, 10 mg, and 15 mg, respectively.
• The clinical significance of these increases is unknown

• Injection site reactions
• In trials, injection site reactions were reported in 3.2% of tirzepatide-treated patients and 0.4% of placebo-treated patients

• Increases in amylase and lipase
• In trials, tirzepatide-treated patients had a mean increase from baseline in amylase of 33% to 38% and an increase in lipase of 31% to 42%. Placebo-treated patients had an increase in amylase of 4% and no change in lipase.
• The clinical significance of these increases is unknown

• Hypersensitivity reactions
• Serious hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and eczema, have occurred in patients receiving tirzepatide. In trials, reactions were reported in 3.2% of tirzepatide-treated and 1.7% of placebo-treated patients. Patients who develop anti-tirzepatide antibodies are at greater risk.

• Severe GI adverse reactions
• Severe GI adverse reactions have been reported in patients receiving tirzepatide. In placebo-controlled trials, severe GI reactions were reported in 1.3% (5 mg), 0.4% (10 mg), and 1.2% (15 mg) of Mounjaro-treated patients compared to 0.9% of placebo-treated patients.

• Anti-tirzepatide antibodies
• In trials, 51% of tirzepatide-treated patients developed anti-tirzepatide antibodies. Antibody cross-reactivity with native GIP and GLP-1 was seen in 34% and 14%, respectively. Antibody development was not associated with decreased effectiveness, but it was associated with an increase in hypersensitivity and injection site reactions.

• Pancreatitis
• Acute pancreatitis has occurred in patients treated with GLP-1 agonists. In trials, the incidence of acute pancreatitis in tirzepatide-treated patients was 0.23 cases per 100 patient-years compared to 0.11 cases per 100 patient-years in placebo-treated patients. Patients who develop symptoms of pancreatitis (e.g., upper abdominal pain radiating to the back, nausea, vomiting) should be evaluated promptly.
• Patients with a history of pancreatitis were excluded from trials, so it is unknown if they are at greater risk.

• Acute kidney injury
• Tirzepatide may cause nausea, vomiting, and diarrhea that can lead to dehydration and, if severe, acute kidney injury. There have been case reports of acute kidney injury and worsening of chronic renal failure in patients receiving GLP-1 analogs. In most cases, symptoms of nausea, vomiting, and diarrhea were present.
• Use caution when prescribing tirzepatide to patients with renal impairment and those taking medications that may affect kidney function (e.g. ACE inhibitors, NSAIDs, diuretics). Monitor renal function closely in patients with chronic kidney disease who are experiencing significant gastrointestinal reactions.

• Gallbladder disease
• GLP-1 analogs have been associated with an increased risk of gallbladder disease. Rapid weight loss is also a risk factor. In trials, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was seen in 0.6% of tirzepatide-treated patients and 0% of placebo-treated patients.
• If patients develop symptoms of cholelithiasis (e.g. right upper quadrant pain with nausea and vomiting), gallbladder imaging should be performed.

• Thyroid cancer
• In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats treated with clinically relevant doses of tirzepatide. It is unknown if tirzepatide increases the risk of tumors in humans as the incidence of these events is too low to establish causality.
• Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer
• Routine monitoring with serum calcitonin or thyroid ultrasound is of uncertain value and will likely lead to many incidental findings and unnecessary procedures. Patients with medullary thyroid carcinoma usually have calcitonin levels > 50 ng/L. In the SURPASS-2 trial, tirzepatide did not cause relevant changes in mean calcitonin levels.

• Diabetic retinopathy
• Rapid improvements in glucose control have been associated with a temporary worsening of diabetic retinopathy. Patients with significant diabetic retinopathy were excluded from tirzepatide trials. Use caution when initiating tirzepatide in patients with diabetic retinopathy. [1]

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• History of hypersensitivity reaction to tirzepatide
• Personal or family history of medullary thyroid carcinoma (MTC)
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

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• Kidney disease
• No dose adjustment is recommended in patients with any degree of renal impairment

• Liver disease
• No dose adjustment is recommended in patients with any degree of liver disease

• Stomach disorders
• Tirzepatide slows gastric emptying and is not recommended in patients with significant stomach disorders, including diabetic gastroparesis

• General anesthesia or deep sedation
• GLP-1 therapies, like tirzepatide, slow gastric emptying, possibly increasing the risk of residual gastric contents and pulmonary aspiration in patients receiving anesthesia or deep sedation for procedures. Rare postmarketing cases of pulmonary aspiration from retained stomach contents have been reported in GLP-1-treated patients, even after following the recommended preoperative fast. Recommendations from the American Society of Anesthesiologists for managing GLP-1 therapies perioperatively are available here - GLP-1 therapy perioperative management recommendations.

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• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).

• Insulin and insulin secretagogues - Adding tirzepatide to insulin or insulin secretagogues (e.g., sulfonylureas, meglitinides) increases the risk of hypoglycemia. Consider decreasing the dose of these medications when starting tirzepatide. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. In a similar study, patients with an A1C ≥ 7.5% reduced their insulin glargine dose by 30% when beginning tirzepatide. Monitor blood sugars closely after initiation and adjust medications as needed. Patients should be aware of the signs and symptoms of hypoglycemia (see hypoglycemia). [1,3,5]
• Oral contraceptives - in a pharmacokinetic study, ethinyl estradiol, norgestimate, and norelgestromin absorption was reduced by tirzepatide. The manufacturer recommends that patients using oral hormonal contraceptives switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after tirzepatide initiation and for 4 weeks after each dose escalation.
• Drugs affected by gastric emptying
• Medications are partially digested in the stomach before being emptied into the small intestine, where most drugs are absorbed. Tirzepatide slows gastric emptying, possibly altering the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
• Antibiotics: Antibiotics require rapid absorption to achieve their desired therapeutic effect
• Drugs with a narrow therapeutic index: Drugs with a narrow therapeutic index may have their steady state altered by delayed gastric emptying. Examples include:
• Carbamazepine (Tegretol®)
• Cyclosporine (Neoral®)
• Digoxin
• Levothyroxine (Synthroid®)
• Lithium
• Phenytoin (Dilantin®)
• Tacrolimus (Prograf®)
• Theophylline (Theo-24®)
• Warfarin (Coumadin®) [4]
• Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of tirzepatide. Examples include anticholinergic medications and opioid pain medications (e.g., hydrocodone, morphine)

• Metabolism and clearance
• Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis

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• Dosage forms
• Single-dose pen
• 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
• Comes in carton with 4 pens
• No generic: $$$$ for 4 pens

• Dosing
• Starting: 2.5 mg subcutaneously once weekly. After 4 weeks, increase the dose to 5 mg once weekly.
• Maintenance: 5 - 15 mg once weekly
• Maximum: 15 mg once weekly
• Dose may be increased in increments of 2.5 mg every 4 weeks as needed. The 2.5 mg dose is not intended for glycemic control.
• Inject subcutaneously in the abdomen, thigh, or upper arm. Rotate injection sites.
• Missed doses: administer tirzepatide as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
• Patients taking insulin and insulin secretagogues: consider decreasing the dose of these medications when starting tirzepatide. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. In a similar study, patients with an A1C ≥ 7.5% reduced their insulin glargine dose by 30% when beginning tirzepatide. [3,5]
• The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours) [1]

• Storage
• Store in refrigerator
• Pens can be stored at room temperature for up to 21 days [1]

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• Tirzepatide was FDA-approved in 2022. It does not have long-term safety data.

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• 1 - Tirzepatide PI
• 2 - PMID 34170647 - Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes, NEJM (2021)
• 3 - PMID 35133415 - Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial, JAMA (2022)
• 4 - North Carolina Pharmacy Practice Act. Article 4A. 90-85.28(b1).
• 5 - PMID 37786396 - Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial, JAMA (2023)