Tirzepatide

Also known as: Mounjaro, Zepbound, LY3298176

Evidence: Clinical

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Overview

Dual GIP and GLP-1 receptor agonist; FDA-approved for type 2 diabetes (2022) and obesity (2023). In SURMOUNT-1, 15 mg weekly gave 20.9% weight loss at 72 weeks versus 3.1% with placebo.

Tirzepatide (LY3298176) is a 39-residue peptide based on the GIP sequence with Aib at positions 2 and 13, a C-terminal amide and a C20 fatty diacid on Lys20, giving a half-life of about 5 days (Coskun 2018). In SURMOUNT-1, 5, 10 and 15 mg weekly gave 15.0%, 19.5% and 20.9% weight loss over 72 weeks versus 3.1% (Jastreboff 2022). It lowered HbA1c more than semaglutide 1 mg in SURPASS-2 (Frías 2021) and gave 20.2% versus 13.7% weight loss against semaglutide 2.4 mg in SURMOUNT-5 (Aronne 2025). FDA approved Mounjaro for type 2 diabetes in 2022 and Zepbound for weight in 2023, with obstructive sleep apnea added later; both are marketed.

Benefits

Weight loss (human RCTs; 20.9% at 15 mg), lower HbA1c in type 2 diabetes (human RCTs), greater weight and HbA1c reduction than semaglutide (head-to-head RCTs), obstructive sleep apnea (FDA indication)

Dosing reference

Research dose: 2.5-15mg weekly
Range: 2500 to 15000 mcg, 1x weekly
Reconstitution: 1.5 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg, 15 mg

Subcutaneous, once weekly. Label titration starts at 2.5 mg weekly for 4 weeks and rises in 2.5 mg steps at least 4 weeks apart to a maintenance dose of 5, 10 or 15 mg (Zepbound label). Coadministration with other GLP-1 receptor agonists is not recommended by the label.

Mechanism

Tirzepatide activates both the GIP and GLP-1 receptors. Together these raise glucose-dependent insulin secretion, lower glucagon, slow gastric emptying and reduce food intake (Zepbound label). In obese mice it lowered weight more than a selective GLP-1 agonist, which the discovery team attributes to combined receptor activation (Coskun 2018). A C20 fatty diacid on Lys20 binds albumin (99% bound), supporting weekly dosing (Coskun 2018; label). The term 'twincretin' and claims of synergy beyond GLP-1 agonists in humans rest on the head-to-head trials, not on a defined mechanism.

Evidence

Clinical: at least one published human trial or an approved drug

SURMOUNT-1 (n=2539, 72 weeks): 15.0%, 19.5% and 20.9% weight loss at 5, 10 and 15 mg versus 3.1% with placebo (Jastreboff et al., 2022)
SURPASS-1 (n=478, 40 weeks, type 2 diabetes): HbA1c fell 1.87 to 2.07 percentage points versus +0.04 with placebo (Rosenstock et al., 2021)
SURPASS-2 (type 2 diabetes): greater HbA1c reduction than semaglutide 1 mg at all doses (Frías et al., 2021)
SURMOUNT-5 (n=751, 72 weeks): 20.2% weight loss versus 13.7% with semaglutide 2.4 mg (Aronne et al., 2025)
Status: FDA-approved and marketed. Mounjaro (type 2 diabetes, 2022), Zepbound (weight, 2023; obstructive sleep apnea added)

References

Side effects

Nausea, vomiting, diarrhea, and constipation dominate, particularly during titration. Reported serious risks include pancreatitis, gallbladder disease, severe gastroparesis, and aspiration risk during anesthesia from delayed gastric emptying. Contraindicated with a personal or family history of medullary thyroid carcinoma or MEN2; rodent studies showed thyroid C-cell tumors.

Storage

Storage: Refrigerated (2-8°C)
Lyophilized: 24+ months refrigerated
Reconstituted: 30 days refrigerated

Pharmacology

Half-life: ~5 days (116.7 h in phase 1; 5 to 6 days in adults with overweight or obesity, subcutaneous; Zepbound label)
Bioavailability: Subcutaneous: ~80%
Molecular weight: 4813.45 Da
Sequence: Y[Aib]EGTFTSDYSI[Aib]LDKIAQK[linker-C20 diacid]AFVQWLIAGGPSSGAPPPS[NH2]