Tirzepatide
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Tirzepatide
Mounjaro (T2DM), Zepbound (obesity, OSA)
Tirzepatide is the first dual GIP / GLP-1 receptor agonist ("twincretin") approved for clinical use. Eli Lilly markets it as Mounjaro (for type 2 diabetes mellitus, FDA-approved May 2022)[1] and Zepbound (for obesity, November 2023;[2] later expanded to obstructive sleep apnea in obesity in December 2024[4]).
In direct comparison, tirzepatide produced greater HbA1c reduction and greater weight loss than semaglutide at maximum approved doses (SURPASS-2),[5] and the largest weight loss yet reported with an injectable incretin in obesity without diabetes — up to ~22.5% body weight at 72 weeks (SURMOUNT-1).[3]
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Avoid. Animal embryofetal toxicity is documented.[1] Discontinue ≥1 month before planned conception. Clinically important interaction: tirzepatide reduces absorption of oral contraceptives during initiation and dose escalation — counsel patients to switch to a non-oral or barrier method for at least the first 4 weeks of each new dose level.[1]
GLP-1 receptor agonist · Semaglutide · Liraglutide · Dulaglutide · Exenatide · Type 2 diabetes mellitus · Obesity · Obstructive sleep apnea
Experience
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Problems
Titration strategies
Mounjaro — standard T2DM titration0
2.5 mg SC weekly × 4 weeks (non-therapeutic ramp)
→ 5 mg SC weekly × ≥4 weeks → 7.5 mg weekly × ≥4 weeks if needed → 10 mg weekly × ≥4 weeks if needed → 12.5 mg weekly × ≥4 weeks if needed → 15 mg weekly (max)[1]
Hold at any tolerated dose if response is adequate. Slow titration is preferred in any patient with significant GI symptoms — holding 8–12 weeks before advancing is reasonable.Zepbound — standard obesity titration0
2.5 mg SC weekly × 4 weeks (non-therapeutic ramp)
→ 5 mg SC weekly × ≥4 weeks → 7.5 mg → 10 mg → 12.5 mg → 15 mg weekly (max), each step held ≥4 weeks[2]
Maintenance is generally 5, 10, or 15 mg/wk depending on response and tolerability. The intermediate steps (7.5 / 12.5 mg) exist to ease titration but are not typical maintenance doses.Effects
- Early satiety and reduced food intake[3]
- Food noise quieting (also reported with semaglutide)[citation needed]
- Nausea — dose-dependent, worst during titration steps[1]
- Constipation or diarrhea (variable)[1]
- Decreased appetite (clinically the desired effect)[1]
- Injection-site reactions — uncommon, generally mild[1]
GI tolerability appears modestly better than selective GLP-1 RAs at comparable HbA1c / weight-loss endpoints,[citation needed] possibly reflecting the additional GIP-receptor activity.
Pharmacokinetics
Chemistry. 39-amino-acid synthetic peptide; dual agonist at the GIP receptor and GLP-1 receptor. Acylated with a C20 fatty diacid linked via γGlu-2×AEEA spacer for albumin binding → ~5-day half-life enabling weekly dosing.[6]
Acylation with a C20 fatty diacid drives non-covalent albumin binding, producing a terminal half-life of ~120 hours and supporting once-weekly subcutaneous dosing.[6][1] Cleared predominantly by proteolytic catabolism; no CYP-mediated metabolism. Renal and hepatic impairment do not require dose adjustment.[1]
Delayed gastric emptying is greatest during dose escalation and attenuates over time. This can reduce absorption of co-administered oral medicines, including oral contraceptives — clinically relevant during the first 4 weeks of any new dose level.[1]Pharmacodynamics
Receptor pharmacology. Activates both GIP and GLP-1 receptors. The dual mechanism produces greater glucose-dependent insulin secretion, greater weight loss, and a somewhat improved GI tolerability profile relative to selective GLP-1 RAs in head-to-head comparison.[6][5]
At the 15 mg/wk maintenance dose:
- HbA1c reduction of ~2.0–2.3 percentage points in T2DM[5]
- Weight loss of ~22.5% body weight at 72 wk in obesity without T2DM (SURMOUNT-1)[3]
- In T2DM with obesity, ~15.7% weight loss at 72 wk (SURMOUNT-2)[7]
- In moderate-to-severe OSA with obesity, ~50% reduction in apnea–hypopnea index at 52 wk (SURMOUNT-OSA)[4]
Interactions
No interactions reported yet.
Pregnancy and lactation
Monitoring
- Baseline: HbA1c, weight, BP, renal function, lipid panel
- Personal or family history of MTC or MEN2 — contraindicated, do not start[1]
- Every 3 months for first year: HbA1c, weight, GI tolerability, signs of pancreatitis or gallbladder disease[1]
- Annual: renal function, lipids
- Pre-procedure: hold weekly dose ≥7 days before any planned anesthesia (per ASA 2024 guidance)[8]
Patient counseling
- Slow titration is non-negotiable.
- Inject SC in abdomen, thigh, or upper arm; rotate sites.[1]
- GI side effects peak in the first 2–4 weeks of each new dose level, then attenuate.
- Oral contraceptives: switch to a non-oral / barrier method for at least 4 weeks after starting and after each dose escalation.[1]
- Hydrate aggressively (volume depletion → AKI is a real risk).[1]
- Resistance training during weight loss protects lean mass.[citation needed]
- If a weekly dose is missed: take within 4 days; if >4 days, skip and resume on the next regular day.[1]
- Surgery: hold dose 7 days pre-op and tell every anesthesiologist.[8]
- Pregnancy planning: stop ≥1 month before trying to conceive.[1]
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See also
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 US FDA. Mounjaro (tirzepatide) prescribing information. Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
- ↑ 2.0 2.1 2.2 2.3 US FDA. Zepbound (tirzepatide) prescribing information. Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217806s000lbl.pdf
- ↑ 3.0 3.1 3.2 3.3 Jastreboff AM et al. (2022). Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). NEJM 387:205–16. doi:10.1056/NEJMoa2206038
- ↑ 4.0 4.1 Malhotra A, Grunstein RR, Fietze I et al. (2024). Tirzepatide for the treatment of obstructive sleep apnea and obesity (SURMOUNT-OSA). NEJM 391(13):1193–205. doi:10.1056/NEJMoa2404881
- ↑ 5.0 5.1 5.2 Frías JP et al. (2021). Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). NEJM 385(6):503–15. doi:10.1056/NEJMoa2107519
- ↑ 6.0 6.1 6.2 Coskun T, Sloop KW, Loghin C et al. (2018). LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. Mol Metab 18:3–14. doi:10.1016/j.molmet.2018.09.009
- ↑ Garvey WT, Frias JP, Jastreboff AM et al. (2023). Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2). Lancet 402(10402):613–26. doi:10.1016/S0140-6736(23)01200-X
- ↑ 8.0 8.1 Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. Surg Obes Relat Dis 20(12):1183–8.
Summary
Classes
Pharmacy
Starting dose
2.5 mg SC weekly × 4 wk (non-therapeutic ramp)[1]
Pharmacology
Routes
Subcutaneous (abdomen, thigh, upper arm)[1]
Onset
Glycemic effect within days; full weight effect over months[3]
Duration
~7 days (weekly dosing)[1]
Half-life
~5 days (~120 h)[1]
Bioavailability
SC ~80%[citation needed]
Pregnancy
Avoid. Discontinue ≥1 month pre-conception. May reduce oral contraceptive efficacy during titration.[1]
Legal status
Rx-only;[1] not a controlled substance
Purported mechanism
Dual agonist of the GIP receptor and GLP-1 receptor ("twincretin").