What is the mechanism of action of Tirezepatide (GIP/GLP-1 receptor agonist)?

From the Guidelines

Tirzepatide is a highly effective treatment for obesity and type 2 diabetes, with a significant reduction in weight loss and improvement in glycemic control, as evidenced by a recent study published in JAMA in 2023 1.

Key Points

• Tirzepatide is a dual GIP/GLP-1 receptor agonist that mimics the effects of natural hormones to regulate blood sugar and appetite.
• The standard dosing of tirzepatide starts at 2.5 mg weekly, but the most effective dose for weight loss is 15 mg weekly, as shown in a study published in JAMA in 2023 1.
• Common side effects of tirzepatide include nausea, vomiting, diarrhea, and stomach pain, which often improve over time.
• Tirzepatide should be injected subcutaneously in the abdomen, thigh, or upper arm, rotating injection sites each week.
• The medication works by slowing stomach emptying, reducing appetite, increasing insulin secretion when blood sugar is high, and decreasing glucagon production, making it effective for both weight management and blood sugar control.

Evidence

• A recent meta-analysis published in Annals of Internal Medicine in 2024 found that tirzepatide was associated with greater weight loss compared to other medications, such as semaglutide and liraglutide 1.
• The study published in JAMA in 2023 found that tirzepatide resulted in a mean weight loss of 20.9% at 72 weeks, compared to 3.1% with placebo 1.

Recommendations

• Tirzepatide should be considered as a first-line treatment for obesity and type 2 diabetes, due to its significant efficacy and safety profile, as evidenced by recent studies 1.
• Patients should maintain healthy eating habits and regular physical activity while using tirzepatide for optimal results.
• Healthcare providers should closely monitor patients for potential side effects and adjust the dose as needed to minimize adverse effects.

From the FDA Drug Label

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 MOUNJARO [see Drug Interactions (7.2) and Clinical Pharmacology (12.2,12.3)]. The main concern with Tirezepatide is its potential interaction with oral hormonal contraceptives.

• Patients using oral hormonal contraceptives should 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 MOUNJARO 2. This is due to the potential for reduced contraceptive efficacy. Key points:
• Contraception: Patients should use alternative methods of contraception.
• Dose escalation: Patients should use alternative methods of contraception for 4 weeks after each dose escalation.
• Interaction: Tirezepatide may interact with oral hormonal contraceptives, reducing their efficacy.

From the Research

Overview of Tirzepatide

• Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM) 3, 4, 5, 6.
• It is administered via subcutaneous injection once weekly and is available in single-dose prefilled pens and single-dose vials 3.

Efficacy of Tirzepatide

• Tirzepatide has been shown to be effective in improving glycemic control and promoting weight loss in adults with T2DM 3, 4, 5, 6.
• In phase III SURPASS trials, tirzepatide demonstrated superior glycemic and body weight control compared to placebo and active comparators, including GLP-1 receptor agonists such as dulaglutide and semaglutide 3, 4, 6.
• Tirzepatide has been associated with significant reductions in hemoglobin A1c (HbA1c) and body weight, with absolute reductions in HbA1c of up to 3.02% and relative reductions ranging from 0.44% to 2.11% compared to placebo and active comparators 5.

Safety Profile of Tirzepatide

• Tirzepatide has been generally well tolerated, with a safety profile consistent with that of GLP-1 receptor agonists 3, 4, 5.
• The most common adverse events associated with tirzepatide are gastrointestinal events, including nausea, diarrhea, decreased appetite, and vomiting 3, 4, 5.
• Tirzepatide has been associated with a low risk of clinically significant or severe hypoglycemia and no increased risk of major adverse cardiovascular events 3, 4, 5, 6.

Comparison to Other GLP-1 Receptor Agonists

• Tirzepatide has been compared to other GLP-1 receptor agonists, including semaglutide, and has been shown to have a similar or superior efficacy and safety profile 4, 5, 7.
• GLP-1 receptor agonists, including tirzepatide, have been recommended as the preferred first injectable glucose-lowering therapy for T2DM due to their effectiveness in reducing HbA1c and body weight, as well as their potential to prevent cardiovascular events 7.