- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- CVD - Cardiovascular disease
- DM - Diabetes mellitus
- FBS - Fasting blood sugar
- GFR - Glomerular filtration rate
- GI - Gastrointestinal
- GLP-1 - Glucagon-like peptide-1
- OSA - Obstructive sleep apnea
- RCT - Randomized controlled trial
- T2DM - Type 2 diabetes mellitus
- Thyroid C-cell tumor = Thyroid medullary tumor
DRUGS IN CLASS
- Dual GLP-1 and GIP agonists
- Tirzepatide (Zepbound®) - marketed for weight loss
- Tirzepatide (Mounjaro®) - marketed for diabetes
MECHANISM OF ACTION
- 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.
- 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
- GLP-1 and GIP suppress hunger
- GLP-1 slows gastric emptying
- Fat tissue
- GIP increases fatty acid and glucose uptake by fat tissue [1,2,3]
- 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.
- Tirzepatide (Zepbound®)
- Tirzepatide (Zepbound®) is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with one of the following:
- BMI ≥ 30
- BMI ≥ 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease)
- The effects of tirzepatide on weight loss were evaluated in the two trials below. In the SURMOUNT-1 trial, 2539 overweight nondiabetics were randomized to tirzepatide (5 mg, 10 mg, 15 mg) or placebo for 72 weeks. In SURMOUNT-2, 938 overweight diabetics received tirzepatide (10 mg, 15 mg) or placebo for 72 weeks.
RCTSURMOUNT-1 trial - Tirzepatide vs Placebo for Weight Loss in Obese Patients Without Diabetes, NEJM (2022) [PubMed abstract]
- The SURMOUNT-1 trial enrolled 2539 adults with a BMI ≥ 30 or a BMI ≥ 27 and at least one weight-related complication
Main inclusion criteria
- Age ≥ 18 years
- History of unsuccessful dieting
- BMI ≥ 30 or ≥ 27 and 1 or more of the following:
Main exclusion criteria
- Previous bariatric surgery
- Other weight loss drug within 90 days
- Average age 45 years
- Female sex - 68%
- Average body weight - 231 lbs (105 kg)
- Average BMI - 38
Randomized treatment groups
- Group 1 (630 patients): Tirzepatide 5 mg once weekly
- Group 2 (636 patients): Tirzepatide 10 mg once weekly
- Group 3 (630 patients): Tirzepatide 15 mg once weekly
- Group 4 (643 patients): Placebo once weekly
- Tirzepatide was initiated at a dose of 2.5 mg once weekly (or matching placebo) and was increased by 2.5 mg every 4 weeks during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20
Primary outcome: The coprimary end points were the percentage change in body weight from baseline to week 72 and a weight reduction of 5% or more at week 72
|Duration: 72 weeks|
|Outcome||Tir 5 mg||Tir 10 mg||Tir 15 mg||Placebo||Comparisons|
|% change in body weight||−15%||−19.5%||−20.9%||−3.1%||Tir (all doses) vs Placebo p<0.001|
|≥ 5% weight loss||85%||89%||91%||35%||Tir (all doses) vs Placebo p<0.001|
|Body weight lost||35.5 lbs (16.1 kg)||48.9 lbs (22.2 kg)||52.0 lbs (23.6 kg)||5.3 lb (2.4 kg)||N/A|
Findings: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight.
- RCTSURMOUNT-2 trial - Tirzepatide vs Placebo for Weight Loss in Diabetes, 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
- 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.
- In SURMOUNT-1, tirzepatide caused impressive weight loss, with patients in the 15-mg group shedding an average of 21% (52 lbs) of their body weight. Weight loss in SURMOUNT-2, which only enrolled diabetics, was less (14.7% at 15 mg) but still significant.
- 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.
|Gastrointestinal Side effects|
|Tir 5 mg
|Tir 10 mg
|Tir 15 mg
|Injection site reactions||2%||6%||8%||8%|
✝ Hair loss in tirzepatide-treated patients was more common in women than men (7.1% vs 0.5%)
‡ Hypotension in tirzepatide-treated patients was more common in those receiving antihypertensives (2.2% vs 1.2%)
- 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. If a patient is found to have an elevated calcitonin level, further evaluation should be performed.
- 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
- Tirzepatide has been associated with an increased risk of gallbladder disease. In trials, cholelithiasis was reported in 1.1% of tirzepatide-treated patients and 1% of placebo-treated patients, and cholecystitis was seen in 0.7% and 0.2%, respectively. It's unclear if these events were directly related to tirzepatide or rapid weight loss, which is another risk factor for gallbladder disease.
- If patients develop symptoms of cholelithiasis (e.g., right upper quadrant pain with nausea and vomiting), gallbladder imaging should be performed.
- Acute pancreatitis has occurred in patients treated with GLP-1 agonists, including tirzepatide. In trials, the incidence of acute pancreatitis was 0.2% in both tirzepatide- and 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.
- Hypersensitivity reactions
- Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients receiving tirzepatide. In trials, serious reactions were reported in 0.1% of tirzepatide-treated and 0% of placebo-treated patients. Patients who experience serious reactions should discontinue tirzepatide. Use caution in patients with a history of reactions to other GLP-1 agonists.
- 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 a trial enrolling overweight diabetics, hypoglycemia occurred in 4.2% of tirzepatide-treated patients and 1.3% of placebo-treated patients, with tirzepatide-treated patients taking insulin secretagogues having the greatest risk (10.3%).
- 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]
- 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. 
- Suicidal behavior and ideation
- Suicidal thoughts and behaviors have been reported in trials with other weight loss treatments. Monitor patients for worsening depression and suicidal behaviors during therapy and discontinue tirzepatide if they occur.
- Increases in amylase and lipase
- In trials, tirzepatide-treated patients had a mean increase from baseline in amylase of 20% to 25% and an increase in lipase of 28% to 35%. Placebo-treated patients had increases in amylase and lipase of 2.1% and 5.8%, respectively.
- The clinical significance of these increases is unknown
- Anti-tirzepatide antibodies
- In trials, 65% of tirzepatide-treated patients developed anti-tirzepatide antibodies. Antibody cross-reactivity with native GIP and GLP-1 was seen in 40% and 16.5%, respectively. Antibody development was not associated with decreased effectiveness, but it was associated with an increase in hypersensitivity and injection site reactions (6.2% and 11.3%, respectively).
- History of hypersensitivity reaction to tirzepatide or any of its excipients
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- 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
- Severe gastrointestinal disease
- Tirzepatide may cause severe gastrointestinal reactions. In trials, severe GI events were more common in tirzepatide-treated patients (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than in those receiving placebo (1%). Tirzepatide has not been studied in patients with severe GI disease, including gastroparesis, and is not recommended in these patients. 
- 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 decreased gastric emptying - see gastric emptying below
- Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of tirzepatide
- 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 the process of gastric emptying, and this may alter 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 require rapid absorption to achieve their desired therapeutic effect
- Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
- Metabolism and clearance
- Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis
- 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
- Starting: 2.5 mg subcutaneously once weekly. After 4 weeks, increase the dose to 5 mg once weekly.
- Maintenance: the recommended maintenance dosages are 5 mg, 10 mg, or 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 chronic weight management.
- Inject subcutaneously in the abdomen, thigh, or upper arm at any time of day, with or without meals. 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.
- 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)
- Store in refrigerator
- Pens can be stored at room temperature for up to 21 days. If stored at room temperature, do not return to refrigerator. 
- Zepbound was FDA-approved in 2023. It does not have long-term safety data.
- 1 - Zepbound 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)