Dulaglutide

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GLP-1 receptor agonist · Antidiabetic · Fc-fusion biologic

Dulaglutide

Trulicity

Dulaglutide is a weekly subcutaneous GLP-1 receptor agonist developed by Eli Lilly, marketed as Trulicity since September 2014.^[1] 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.^[2] Dulaglutide's principal clinical distinction is the 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.^[3]

Experience

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Problems

Type 2 diabetes mellitus—

Cardiovascular risk reduction in type 2 diabetes—

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Titration strategies

Trulicity, standard T2DM titration0

0.75 mg SC weekly (starting and minimum effective dose)

→ 1.5 mg SC weekly × ≥4 weeks (most common maintenance) → 3 mg weekly × ≥4 weeks if additional HbA1c reduction needed → 4.5 mg weekly (max)^[1]

The 0.75 mg starting dose is therapeutic (unlike the non-therapeutic ramps with semaglutide and tirzepatide). Most patients escalate to 1.5 mg within the first month.

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Effects

Early satiety (less pronounced than with semaglutide/tirzepatide at equipotent HbA1c reduction)^{[citation needed]}
Nausea, usually mild-to-moderate, peaks in first 2–4 weeks^[1]
Diarrhea / constipation^[1]
Abdominal pain^[1]
Decreased appetite^[1]
Injection-site reactions, uncommon, generally mild^[1]

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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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.^[2]

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.^[2]^[1] Cleared by proteolytic catabolism; no CYP-mediated metabolism. No dose adjustment for renal or hepatic impairment.^[1]

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.^[2]

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^[4]
Weight loss of ~2–5 kg, dose-dependent^[4]
12% relative risk reduction in MACE (REWIND)^[3]
Modest SBP reduction (~1–2 mmHg)^[1]
Interactions

No interactions reported yet.

Pregnancy and lactation

Avoid. Animal embryofetal toxicity is documented.^[1] 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
Personal or family history of MTC or MEN2, contraindicated, do not start^[1]
Every 3 months for first year: HbA1c, weight, GI tolerability, signs of pancreatitis or gallbladder disease
Annual: renal function, lipids
Pre-procedure: hold weekly dose ≥7 days before any planned anesthesia^[5]
Patient 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.^[1]
If a weekly dose is missed: take within 3 days; if >3 days, skip and resume on the next regular day.^[1]
Surgery: hold dose 7 days pre-op.^[5]
Pregnancy planning: stop ≥1 month before trying to conceive.^[1]
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Relevant Literature

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References

↑ ^1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 ^1.15 ^1.16 ^1.17 ^1.18 ^1.19 ^1.20 ^1.21 ^1.22 ^1.23 ^1.24 US FDA. Trulicity (dulaglutide) prescribing information. Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125469s044lbl.pdf
↑ ^2.0 ^2.1 ^2.2 ^2.3 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
↑ ^3.0 ^3.1 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
↑ ^4.0 ^4.1 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
↑ ^5.0 ^5.1 Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. Surg Obes Relat Dis 20(12):1183–8.

Summary

Classes

GLP-1 receptor agonist · Antidiabetic · Fc-fusion biologic

Common uses

Pharmacy

Starting dose

0.75 mg SC weekly^[1]

Preparations

Pre-filled single-dose pen: 0.75 / 1.5 / 3 / 4.5 mg^[1]

US FDA Max

4.5 mg/wk SC^[1]

Pharmacology

Routes

Subcutaneous (abdomen, thigh, upper arm)^[1]

Onset

Glycemic effect within days; near-maximal HbA1c effect by 4 weeks at any given dose^[1]

Duration

~7 days (weekly dosing)^[1]

Half-life

~5 days (~120 h)^[1]

Bioavailability

SC ~47%–65%^[1]

Pregnancy

Avoid. Discontinue at least 1 month before planned pregnancy. Animal data show embryofetal harm.^[1]

Legal status

Rx-only;^[1] not a controlled substance

Purported mechanism

Long-acting agonist of the GLP-1 receptor; Fc-fusion construct.

[trulicity-label-1] 1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 ^1.15 ^1.16 ^1.17 ^1.18 ^1.19 ^1.20 ^1.21 ^1.22 ^1.23 ^1.24 US FDA. Trulicity (dulaglutide) prescribing information. Eli Lilly. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125469s044lbl.pdf

[glaesner2010-2] 2.0 ^2.1 ^2.2 ^2.3 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

[rewind-3] 3.0 ^3.1 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

[award11-4] 4.0 ^4.1 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

[kindel2024-5] 5.0 ^5.1 Kindel TL et al. (2024). Perioperative GLP-1 receptor agonist safety guidance. Surg Obes Relat Dis 20(12):1183–8.

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