Tirzepatide
Also known as: Mounjaro, Zepbound, LY3298176
At a Glance
Tirzepatide is a first-in-class dual agonist developed by Eli Lilly that activates both GIP and GLP-1 receptors. It is FDA-approved as:
- Mounjaro (for type 2 diabetes)
- Zepbound (for chronic weight management)
Tirzepatide has demonstrated greater weight loss and glycemic control than semaglutide in head-to-head trials.
[PMID: 34170647] [PMID: 40353578]⚠️ Prescription Medication: Tirzepatide is an FDA-approved prescription drug. This dossier summarizes published research only.
Mechanism of Action
Tirzepatide is a synthetic peptide that activates two incretin receptors:
GIP Receptor Agonism
- Enhances insulin secretion in a glucose-dependent manner
- May improve β-cell function
- Potentially enhances fat oxidation
- May reduce GLP-1-associated nausea
GLP-1 Receptor Agonism
- Reduces appetite via central nervous system effects
- Slows gastric emptying
- Enhances insulin secretion
- Suppresses glucagon release
Design Note: Tirzepatide is a single molecule with dual agonism, not a combination of two drugs. It has greater affinity for GIP than GLP-1 receptors.
Evidence Summary
Weight Loss (SURMOUNT Trials)
High Confidence RCT ≤3 YearsSURMOUNT-1 (N=2,539):
| Dose | Mean Weight Loss at 72 Weeks |
|---|---|
| 5 mg | -15.0% |
| 10 mg | -19.5% |
| 15 mg | -20.9% |
| Placebo | -3.1% |
- 91% achieved ≥5% weight loss (15 mg)
- 57% achieved ≥20% weight loss (15 mg)
- Greater efficacy than any approved anti-obesity medication
Head-to-Head vs. Semaglutide (SURPASS-2)
High Confidence RCT ≤3 YearsIn patients with T2D:
- Tirzepatide 15 mg: -2.46% HbA1c vs. semaglutide 1 mg: -1.86%
- Tirzepatide 15 mg: -12.4 kg weight loss vs. semaglutide: -6.2 kg
- All tirzepatide doses were statistically superior to semaglutide
Type 2 Diabetes (SURPASS Program)
High Confidence RCT ≤3 Years- HbA1c reductions of 2.0–2.6% across trials
- Up to 95% of patients achieved HbA1c <7%
- Superior to insulin degludec, semaglutide, and insulin glargine
Safety & Unknowns
Common Adverse Events
| Event | Incidence (15 mg) |
|---|---|
| Nausea | 24–31% |
| Diarrhea | 18–23% |
| Vomiting | 9–13% |
| Constipation | 6–11% |
| Decreased appetite | 8–11% |
- GI effects decrease with continued treatment
- Dose escalation reduces severity
Warnings & Precautions
- Thyroid C-cell tumors: Boxed warning (same as GLP-1 agonists)
- Pancreatitis: Rare; monitor for symptoms
- Gallbladder disease: Increased cholelithiasis risk
- Hypoglycemia: Risk with insulin or sulfonylureas
Unknowns
- Cardiovascular outcomes: SURPASS-CVOT ongoing; no definitive MACE data yet
- Long-term safety: Limited data beyond 2 years
- Muscle mass effects: Some studies suggest fat-preferential loss
Regulatory Status
| Region | Status |
|---|---|
| FDA | Approved (Mounjaro 2022, Zepbound 2023) |
| EMA | Approved |
| WADA | Not prohibited |
Key Studies
| Year | Trial | Finding |
|---|---|---|
| 2022 | SURMOUNT-1 | 20.9% weight loss at 72 weeks |
| 2021 | SURPASS-2 | Superior to semaglutide 1 mg |
| 2024 | SURMOUNT-OSA | Reduced sleep apnea severity |
Primary sources: [PMID: 35658024] [PMID: 34170647] [PMID: 40353578]
Related Compounds
- Semaglutide: GLP-1 only agonist
- Retatrutide: Triple agonist (investigational)
- Orforglipron: Oral GLP-1 agonist (investigational)
Changelog
| Date | Change |
|---|---|
| 2026-01-21 | Initial dossier created |