Tirzepatide: Difference between revisions

Line 21:

| 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 — up to ~22.5% body weight at 72 weeks (SURMOUNT-1).<ref name="surmount1"/>

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>

Line 27:

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"/>

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>

Line 41:

| dosing = <titration slug="mounjaro-standard" author="MDElliottMD" title="Mounjaro — standard T2DM titration">

| dosing = <titration slug="mounjaro-standard" author="MDElliottMD" title="Mounjaro, standard T2DM titration">

2.5 mg SC weekly × 4 weeks (non-therapeutic ramp)

→ 5 mg SC weekly × ≥4 weeks

Line 49:

→ 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 — holding 8–12 weeks before advancing is reasonable.

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>

2.5 mg SC weekly × 4 weeks (non-therapeutic ramp)

→ 5 mg SC weekly × ≥4 weeks

Line 62:

| effects = * '''Early satiety''' and reduced food intake<ref name="surmount1"/>

* '''Food noise quieting''' (also reported with semaglutide){{Citation needed}}

* '''Nausea''' — dose-dependent, worst during titration steps<ref name="mounjaro-label"/>

* '''Nausea''', dose-dependent, worst during titration steps<ref name="mounjaro-label"/>

* '''Constipation or diarrhea''' (variable)<ref name="mounjaro-label"/>

* '''Decreased appetite''' (clinically the desired effect)<ref name="mounjaro-label"/>

* '''Injection-site reactions''' — uncommon, generally mild<ref name="mounjaro-label"/>

* '''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.

Line 71:

| 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 — 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"/>

| 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

* Personal or family history of MTC or [[MEN2]] — '''contraindicated''', do not start<ref name="mounjaro-label"/>

* 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"/>

* Annual: renal function, lipids

MDElliottMD (talk | contribs)