Tirzepatide (Zepbound, Mounjaro)

What Is Tirzepatide?

Tirzepatide is a once-weekly injectable medication that activates both the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. This dual action boosts insulin secretion, reduces appetite, and leads to substantial weight loss and glycemic control improvements. It was first approved in the U.S. in 2022 (Mounjaro) and later for obesity in 2023 (Zepbound).

Mechanism of Action

  • GLP-1 activity: Enhances glucose-dependent insulin release, suppresses glucagon, slows gastric emptying, and reduces appetite
  • GIP activity: Improves insulin sensitivity, supports fat metabolism, and may enhance GLP-1’s weight loss effects
  • The combination results in superior glycemic control and greater weight reduction than GLP-1 agonists alone

Indications

  • Mounjaro: Type 2 diabetes in adults (monotherapy or with other antidiabetic agents)
  • Zepbound: Chronic weight management in adults with a BMI ≥30 kg/m2 or ≥27 kg/m2 with a weight-related condition (e.g., hypertension, type 2 diabetes, dyslipidemia)

Dosage & Administration

  • Once-weekly subcutaneous injection
  • Start at 2.5 mg once weekly and increase every 4 weeks to 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg
  • Administer in abdomen, thigh, or upper arm

Benefits

  • HbA1c reductions of up to 2.0–2.4%
  • Average weight loss up to 22.5% in clinical trials (SURMOUNT-1)
  • Improved cardiometabolic markers (blood pressure, triglycerides, insulin sensitivity)
  • Potential benefits in NAFLD, PCOS, and other metabolic disorders under investigation

Side Effects

  • Common: Nausea, diarrhea, vomiting, constipation, abdominal pain
  • Less common: Hair thinning, injection site reactions, fatigue
  • Rare: Pancreatitis, gallbladder disease, kidney injury
  • Monitor for severe GI side effects during dose escalation

Contraindications & Warnings

  • Personal or family history of medullary thyroid carcinoma (MTC)
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
  • Use with caution in patients with a history of pancreatitis or severe GI disease

Clinical Evidence

  • SURPASS Trials (Mounjaro): Showed superior HbA1c reduction vs. insulin, GLP-1s, and SGLT2 inhibitors
  • SURMOUNT Trials (Zepbound): Demonstrated record-setting weight loss (15–22%) in people with and without diabetes
  • Ongoing studies on cardiovascular outcomes, fatty liver disease, and reproductive health

Comparison to GLP-1 Agonists

  • Greater weight loss than semaglutide (Wegovy)
  • More potent HbA1c reduction than GLP-1 monotherapy
  • Dual agonism may produce additional metabolic benefits (e.g., lipid metabolism, fat oxidation)

Cost & Access

  • Generally more expensive than GLP-1 monotherapies
  • Covered by insurance for type 2 diabetes (Mounjaro)
  • Coverage for weight loss (Zepbound) may require prior authorization
  • Lilly offers savings cards and patient support programs

Summary

Tirzepatide, under the names Mounjaro and Zepbound, represents the next generation of incretin-based therapies. With unmatched weight loss and metabolic improvements, it is reshaping the treatment landscape for both type 2 diabetes and obesity.

References

  1. Jastreboff AM, et al. “Tirzepatide once weekly for the treatment of obesity.” NEJM. 2022.
  2. Frias JP, et al. “Tirzepatide versus Semaglutide once weekly in patients with type 2 diabetes.” NEJM. 2021.
  3. Zepbound Prescribing Information. U.S. FDA. 2023.
  4. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care.