Dulaglutide: Difference between revisions
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| pregnancy = Avoid. Discontinue at least 1 month before planned pregnancy. Animal data show embryofetal harm.<ref name="trulicity-label"/> | | pregnancy = Avoid. Discontinue at least 1 month before planned pregnancy. Animal data show embryofetal harm.<ref name="trulicity-label"/> | ||
| legal = Rx-only;<ref name="trulicity-label"/> not a controlled substance | | legal = Rx-only;<ref name="trulicity-label"/> not a controlled substance | ||
| intro = Dulaglutide is a weekly subcutaneous [[GLP-1 receptor agonist]] developed by Eli Lilly, marketed as '''[[Trulicity]]''' since September 2014.<ref name="trulicity-label"/> Structurally distinct from the acylated peptide GLP-1 RAs ([[semaglutide]], [[liraglutide]]), dulaglutide is an Fc-fusion biologic | | intro = Dulaglutide is a weekly subcutaneous [[GLP-1 receptor agonist]] developed by Eli Lilly, marketed as '''[[Trulicity]]''' since September 2014.<ref name="trulicity-label"/> Structurally distinct from the acylated peptide GLP-1 RAs ([[semaglutide]], [[liraglutide]]), dulaglutide is an Fc-fusion biologic, its long half-life comes from FcRn-mediated recycling rather than albumin binding.<ref name="glaesner2010"/> | ||
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'' | 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 = '''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> | | 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> | ||
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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 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 | The large molecular size limits both injection-site dispersion and oral bioavailability, dulaglutide cannot be formulated for oral use. | ||
| 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"/> | | 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"/> | ||
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<problem ref="cv-risk-t2dm" author="MDElliottMD"/> | <problem ref="cv-risk-t2dm" author="MDElliottMD"/> | ||
| dosing = <titration slug="trulicity-standard" author="MDElliottMD" title="Trulicity | | dosing = <titration slug="trulicity-standard" author="MDElliottMD" title="Trulicity, standard T2DM titration"> | ||
0.75 mg SC weekly (starting and minimum effective dose) | 0.75 mg SC weekly (starting and minimum effective dose) | ||
→ 1.5 mg SC weekly × ≥4 weeks (most common maintenance) | → 1.5 mg SC weekly × ≥4 weeks (most common maintenance) | ||
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| effects = * '''Early satiety''' (less pronounced than with semaglutide/tirzepatide at equipotent HbA1c reduction){{Citation needed}} | | effects = * '''Early satiety''' (less pronounced than with semaglutide/tirzepatide at equipotent HbA1c reduction){{Citation needed}} | ||
* '''Nausea''' | * '''Nausea''', usually mild-to-moderate, peaks in first 2–4 weeks<ref name="trulicity-label"/> | ||
* '''Diarrhea / constipation'''<ref name="trulicity-label"/> | * '''Diarrhea / constipation'''<ref name="trulicity-label"/> | ||
* '''Abdominal pain'''<ref name="trulicity-label"/> | * '''Abdominal pain'''<ref name="trulicity-label"/> | ||
* '''Decreased appetite'''<ref name="trulicity-label"/> | * '''Decreased appetite'''<ref name="trulicity-label"/> | ||
* '''Injection-site reactions''' | * '''Injection-site reactions''', uncommon, generally mild<ref name="trulicity-label"/> | ||
GI tolerability is generally considered modestly better than weekly exenatide and comparable to or slightly better than weekly semaglutide at equivalent glycemic effect.{{Citation needed}} | GI tolerability is generally considered modestly better than weekly exenatide and comparable to or slightly better than weekly semaglutide at equivalent glycemic effect.{{Citation needed}} | ||
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| interactions = <pharmaInteractions/> | | interactions = <pharmaInteractions/> | ||
| pregnancy_details = Avoid. Animal embryofetal toxicity is documented.<ref name="trulicity-label"/> Discontinue at least 1 month before planned conception due to the ~5-day half-life. The pen contains no preservatives | | pregnancy_details = Avoid. Animal embryofetal toxicity is documented.<ref name="trulicity-label"/> Discontinue at least 1 month before planned conception due to the ~5-day half-life. The pen contains no preservatives, single-dose only. | ||
| 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="trulicity-label"/> | ||
* Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]] | * Every 3 months for first year: HbA1c, weight, GI tolerability, signs of [[pancreatitis]] or [[gallbladder disease]] | ||
* Annual: renal function, lipids | * Annual: renal function, lipids | ||
* '''Pre-procedure''': hold weekly dose ≥7 days before any planned anesthesia<ref name="kindel2024">Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. ''Surg Obes Relat Dis'' 20(12):1183–8.</ref> | * '''Pre-procedure''': hold weekly dose ≥7 days before any planned anesthesia<ref name="kindel2024">Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. ''Surg Obes Relat Dis'' 20(12):1183–8.</ref> | ||
| counseling = * Use the pre-filled pen as directed; the needle is hidden | | counseling = * Use the pre-filled pen as directed; the needle is hidden, patients do not see it. This is often the preferred GLP-1 RA for needle-averse patients.{{Citation needed}} | ||
* GI side effects peak in first 2–4 weeks, then attenuate.<ref name="trulicity-label"/> | * GI side effects peak in first 2–4 weeks, then attenuate.<ref name="trulicity-label"/> | ||
* If a weekly dose is missed: take within 3 days; if >3 days, skip and resume on the next regular day.<ref name="trulicity-label"/> | * If a weekly dose is missed: take within 3 days; if >3 days, skip and resume on the next regular day.<ref name="trulicity-label"/> | ||
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}} | }} | ||
[[Category:GLP-1 receptor agonists]] | [[Category:GLP-1 receptor agonists]] | ||
[[Category:Antidiabetic medicines]] | [[Category:Antidiabetic medicines]] | ||
[[Category:Eli Lilly medicines]] | [[Category:Eli Lilly medicines]] | ||