Tirzepatide: Difference between revisions
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| 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>). | | 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>). | ||
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 | 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 = '''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> | | 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> | ||
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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"/> | 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 | 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 = '''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> | | 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> | ||
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<problem ref="osa-obesity" author="MDElliottMD"/> | <problem ref="osa-obesity" author="MDElliottMD"/> | ||
| dosing = <titration slug="mounjaro-standard" author="MDElliottMD" title="Mounjaro | | dosing = <titration slug="mounjaro-standard" author="MDElliottMD" title="Mounjaro, standard T2DM titration"> | ||
2.5 mg SC weekly × 4 weeks (non-therapeutic ramp) | 2.5 mg SC weekly × 4 weeks (non-therapeutic ramp) | ||
→ 5 mg SC weekly × ≥4 weeks | → 5 mg SC weekly × ≥4 weeks | ||
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→ 15 mg weekly (max)<ref name="mounjaro-label"/> | → 15 mg weekly (max)<ref name="mounjaro-label"/> | ||
Hold at any tolerated dose if response is adequate. Slow titration is preferred in any patient with significant GI symptoms | 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. | ||
</titration> | </titration> | ||
<titration slug="zepbound-standard" author="MDElliottMD" title="Zepbound | <titration slug="zepbound-standard" author="MDElliottMD" title="Zepbound, standard obesity titration"> | ||
2.5 mg SC weekly × 4 weeks (non-therapeutic ramp) | 2.5 mg SC weekly × 4 weeks (non-therapeutic ramp) | ||
→ 5 mg SC weekly × ≥4 weeks | → 5 mg SC weekly × ≥4 weeks | ||
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| effects = * '''Early satiety''' and reduced food intake<ref name="surmount1"/> | | effects = * '''Early satiety''' and reduced food intake<ref name="surmount1"/> | ||
* '''Food noise quieting''' (also reported with semaglutide){{Citation needed}} | * '''Food noise quieting''' (also reported with semaglutide){{Citation needed}} | ||
* '''Nausea''' | * '''Nausea''', dose-dependent, worst during titration steps<ref name="mounjaro-label"/> | ||
* '''Constipation or diarrhea''' (variable)<ref name="mounjaro-label"/> | * '''Constipation or diarrhea''' (variable)<ref name="mounjaro-label"/> | ||
* '''Decreased appetite''' (clinically the desired effect)<ref name="mounjaro-label"/> | * '''Decreased appetite''' (clinically the desired effect)<ref name="mounjaro-label"/> | ||
* '''Injection-site reactions''' | * '''Injection-site reactions''', uncommon, generally mild<ref name="mounjaro-label"/> | ||
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. | 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. | ||
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| interactions = <pharmaInteractions/> | | interactions = <pharmaInteractions/> | ||
| pregnancy_details = Avoid. Animal embryofetal toxicity is documented.<ref name="mounjaro-label"/> Discontinue ≥1 month before planned conception. Clinically important interaction: tirzepatide reduces absorption of oral contraceptives during initiation and dose escalation | | pregnancy_details = Avoid. Animal embryofetal toxicity is documented.<ref name="mounjaro-label"/> 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.<ref name="mounjaro-label"/> | ||
| monitoring = * Baseline: HbA1c, weight, BP, renal function, lipid panel | | monitoring = * Baseline: HbA1c, weight, BP, renal function, lipid panel | ||
* Personal or family history of MTC or [[MEN2]] | * Personal or family history of MTC or [[MEN2]], '''contraindicated''', do not start<ref name="mounjaro-label"/> | ||
* Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]]<ref name="mounjaro-label"/> | * Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]]<ref name="mounjaro-label"/> | ||
* Annual: renal function, lipids | * Annual: renal function, lipids | ||
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}} | }} | ||
[[Category:GLP-1 receptor agonists]] | [[Category:GLP-1 receptor agonists]] | ||
[[Category:GIP receptor agonists]] | [[Category:GIP receptor agonists]] | ||