Dulaglutide: Difference between revisions
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MDElliottMD (talk | contribs) Create Dulaglutide page (initial draft, MedTemplate, full inline cites) |
MDElliottMD (talk | contribs) Fix Cargo VARCHAR(300) overflow: blank structure, shorten mechanism, move chemistry/mechanism prose to PK/PD |
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| generic = Dulaglutide | | generic = Dulaglutide | ||
| brand = Trulicity | | brand = Trulicity | ||
| structure = | | structure = | ||
| classes = [[GLP-1 receptor agonist]] · [[Antidiabetic medicines|Antidiabetic]] · Fc-fusion biologic | | classes = [[GLP-1 receptor agonist]] · [[Antidiabetic medicines|Antidiabetic]] · Fc-fusion biologic | ||
| mechanism = | | mechanism = Long-acting agonist of the [[GLP-1 receptor]]; Fc-fusion construct. | ||
| uses = [[Type 2 diabetes mellitus]] · [[Cardiovascular risk reduction]] in T2DM | | uses = [[Type 2 diabetes mellitus]] · [[Cardiovascular risk reduction]] in T2DM | ||
| starting_dose = 0.75 mg SC weekly<ref name="trulicity-label">US FDA. ''Trulicity (dulaglutide) prescribing information.'' Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125469s044lbl.pdf</ref> | | starting_dose = 0.75 mg SC weekly<ref name="trulicity-label">US FDA. ''Trulicity (dulaglutide) prescribing information.'' Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125469s044lbl.pdf</ref> | ||
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Dulaglutide's principal clinical distinction is the [[REWIND trial|REWIND trial]], in which dulaglutide reduced major adverse cardiovascular events by 12% in T2DM patients ''including a majority with no prior cardiovascular disease'' — making it the first GLP-1 RA to demonstrate cardiovascular benefit in ''primary'' prevention.<ref name="rewind">Gerstein HC et al. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). ''Lancet'' 394(10193):121–30. doi:10.1016/S0140-6736(19)31149-3</ref> | Dulaglutide's principal clinical distinction is the [[REWIND trial|REWIND trial]], in which dulaglutide reduced major adverse cardiovascular events by 12% in T2DM patients ''including a majority with no prior cardiovascular disease'' — making it the first GLP-1 RA to demonstrate cardiovascular benefit in ''primary'' prevention.<ref name="rewind">Gerstein HC et al. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). ''Lancet'' 394(10193):121–30. doi:10.1016/S0140-6736(19)31149-3</ref> | ||
| pharmacokinetics = The Fc-IgG4 fusion confers protection from renal filtration (~63 kDa, well above the glomerular cutoff) and triggers FcRn-mediated recycling, producing a terminal half-life of ~120 hours.<ref name="glaesner2010"/><ref name="trulicity-label"/> Cleared by proteolytic catabolism; no CYP-mediated metabolism. No dose adjustment for renal or hepatic impairment.<ref name="trulicity-label"/> | | pharmacokinetics = '''Chemistry'''. '''Fc-fusion construct''': two identical GLP-1 analog peptides (each modified at positions 8, 22, 36 for DPP-4 resistance and reduced immunogenicity) linked to a human IgG4 Fc fragment via a small glycine-rich peptide linker. The Fc tail drives the long half-life through FcRn recycling.<ref name="glaesner2010">Glaesner W, Vick AM, Millican R et al. (2010). Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. ''Diabetes Metab Res Rev'' 26(4):287–96. doi:10.1002/dmrr.1080</ref> | ||
The Fc-IgG4 fusion confers protection from renal filtration (~63 kDa, well above the glomerular cutoff) and triggers FcRn-mediated recycling, producing a terminal half-life of ~120 hours.<ref name="glaesner2010"/><ref name="trulicity-label"/> Cleared by proteolytic catabolism; no CYP-mediated metabolism. No dose adjustment for renal or hepatic impairment.<ref name="trulicity-label"/> | |||
The large molecular size limits both injection-site dispersion and oral bioavailability — dulaglutide cannot be formulated for oral use. | The large molecular size limits both injection-site dispersion and oral bioavailability — dulaglutide cannot be formulated for oral use. | ||
| pharmacodynamics = At maintenance doses: | | pharmacodynamics = '''Receptor pharmacology'''. Selective long-acting agonist of the [[GLP-1 receptor]]. The Fc-IgG4 structure differentiates it pharmacokinetically (large protein cleared by FcRn-mediated recycling rather than albumin binding) but the receptor pharmacology is the standard GLP-1 RA profile.<ref name="glaesner2010"/> | ||
At maintenance doses: | |||
* HbA1c reduction of ~0.8–1.5 percentage points (1.5 mg/wk) and ~1.6–1.9 (4.5 mg/wk) in T2DM<ref name="award11">Frias JP, Bonora E, Nevarez Ruiz L et al. (2021). Efficacy and safety of dulaglutide 3 and 4.5 mg versus 1.5 mg in metformin-treated patients with type 2 diabetes (AWARD-11). ''Diabetes Care'' 44(3):765–73. doi:10.2337/dc20-1473</ref> | * HbA1c reduction of ~0.8–1.5 percentage points (1.5 mg/wk) and ~1.6–1.9 (4.5 mg/wk) in T2DM<ref name="award11">Frias JP, Bonora E, Nevarez Ruiz L et al. (2021). Efficacy and safety of dulaglutide 3 and 4.5 mg versus 1.5 mg in metformin-treated patients with type 2 diabetes (AWARD-11). ''Diabetes Care'' 44(3):765–73. doi:10.2337/dc20-1473</ref> | ||
* Weight loss of ~2–5 kg, dose-dependent<ref name="award11"/> | * Weight loss of ~2–5 kg, dose-dependent<ref name="award11"/> | ||