Tirzepatide: Difference between revisions

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| generic = Tirzepatide

| brand = Mounjaro (T2DM), Zepbound (obesity, OSA)

| structure = 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.<ref name="coskun2018">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</ref>

| structure =

| classes = [[GLP-1 receptor agonist]] · [[GIP receptor agonist]] · [[Antidiabetic medicines|Antidiabetic]] · [[Anti-obesity medicines|Anti-obesity]] · "Twincretin"

| mechanism = ~~Activates both~~ [[GIP receptor~~|GIP~~]] and [[GLP-1 receptor~~|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.<ref name="coskun2018"/><ref name="~~surpass2~~"~~>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</ref>~~

| mechanism = Dual agonist of the [[GIP receptor]] and [[GLP-1 receptor]] ("twincretin").

| uses = [[Type 2 diabetes mellitus]] · [[Obesity]] · [[Obstructive sleep apnea]] in obesity

| starting_dose = 2.5 mg SC weekly × 4 wk (non-therapeutic ramp)<ref name="mounjaro-label">US FDA. ''Mounjaro (tirzepatide) prescribing information.'' Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf</ref>

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| halflife = ~5 days (~120 h)<ref name="mounjaro-label"/>

| bioavailability = SC ~80%{{Citation needed}}

| pregnancy = Avoid. Discontinue ≥1 month ~~before planned pregnancy due to long half~~-~~life~~. ~~Animal data show embryofetal harm.<ref name="mounjaro-label"/>~~ May reduce efficacy ~~of oral contraceptives (delayed gastric emptying) — non-oral or barrier contraception advised, particularly~~ during ~~dose escalation~~.<ref name="mounjaro-label"/>

| pregnancy = Avoid. Discontinue ≥1 month pre-conception. May reduce oral contraceptive efficacy during titration.<ref name="mounjaro-label"/>

| legal = Rx-only;<ref name="mounjaro-label"/> not a controlled substance

| intro = 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)<ref name="mounjaro-label"/> and '''[[Zepbound]]''' (for [[obesity]], November 2023;<ref name="zepbound-label"/> later expanded to [[obstructive sleep apnea]] in obesity in December 2024<ref name="surmount-osa">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</ref>).

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In direct comparison, tirzepatide produced greater HbA1c reduction and greater weight loss than [[semaglutide]] at maximum approved doses (SURPASS-2),<ref name="surpass2"/> 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).<ref name="surmount1"/>

| pharmacokinetics = 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.<ref name="coskun2018"/><ref name="mounjaro-label"/> Cleared predominantly by proteolytic catabolism; no CYP-mediated metabolism. Renal and hepatic impairment do not require dose adjustment.<ref name="mounjaro-label"/>

| 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.<ref name="coskun2018">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</ref>

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.<ref name="coskun2018"/><ref name="mounjaro-label"/> Cleared predominantly by proteolytic catabolism; no CYP-mediated metabolism. Renal and hepatic impairment do not require dose adjustment.<ref name="mounjaro-label"/>

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.<ref name="mounjaro-label"/>

| pharmacodynamics = At the 15 mg/wk maintenance dose:

| pharmacodynamics = '''Receptor pharmacology'''. Activates both [[GIP receptor|GIP]] and [[GLP-1 receptor|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.<ref name="coskun2018"/><ref name="surpass2">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</ref>

At the 15 mg/wk maintenance dose:

* HbA1c reduction of ~2.0–2.3 percentage points in T2DM<ref name="surpass2"/>

* Weight loss of ~22.5% body weight at 72 wk in obesity without T2DM (SURMOUNT-1)<ref name="surmount1"/>

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