Dulaglutide (revision 19)
Old revision·23:59, 11 Nov 2025·ExenatideEzra
| DulaglutideClinical data | |
|---|---|
| INN | dulaglutide |
| Class | GLP-1 receptor agonist |
| Architecture | GLP-1 analogue dimer fused to IgG4 Fc |
| Route | Subcutaneous, weekly |
| Properties | |
| Molar mass | ≈59,670 g·mol⁻¹ |
| Half-life | ≈90 h |
| Bioavailability, SC | ≈47–65% |
| Compound infobox · conventions | |
Dulaglutide is a GLP-1 receptor agonist constructed as a covalent fusion protein: two modified GLP-1(7–37) analogues joined by a peptide linker to the Fc fragment of a human IgG4 antibody. At about 60 kDa it is an order of magnitude larger than the acylated peptide agonists and is properly a biologic rather than a synthetic peptide.[1]
The fusion strategy extends half-life by two independent mechanisms: the conjugate is far too large for glomerular filtration, and the Fc fragment engages the neonatal Fc receptor, which rescues it from lysosomal degradation and recycles it to the circulation. The resulting half-life of about 90 hours supports weekly dosing.[1]
The GLP-1 portion carries three substitutions — Aib at position 8 for DPP-4 resistance, and two further changes that reduce immunogenicity of the junction region. The IgG4 backbone was chosen because it does not appreciably engage complement or Fcγ receptors.[2]
Architecture and its consequences
[edit]Fusion to Fc is a different engineering philosophy from acylation. Acylation leaves a small peptide with a reversible carrier attachment; fusion produces a permanently large molecule. The trade-offs run in both directions.
In favour of fusion: half-life is long without requiring albumin availability, the molecule is a defined single species rather than an equilibrium between bound and free, and manufacture is by cell culture rather than by solid-phase synthesis, which scales differently.
Against it: subcutaneous bioavailability is lower — roughly half, compared with about 89% for semaglutide — because a 60 kDa protein reaches the circulation largely by lymphatic drainage rather than by capillary absorption. Anti-drug antibodies are detectable in a small percentage of recipients, though neutralising antibodies are rare and clinically significant loss of effect has not been demonstrated.[1]
Clinical evidence
[edit]Across the AWARD programme, dulaglutide 0.75–4.5 mg weekly reduced glycated haemoglobin by roughly 0.8–1.6 percentage points depending on dose and background therapy, with weight change of about −1 to −4.7 kg.[2]
The REWIND trial randomised 9,901 people with type 2 diabetes, most of whom did not have established cardiovascular disease, and reported a hazard ratio of 0.88 (95% CI 0.79–0.99) for the primary cardiovascular composite over a median 5.4 years. Its distinctive feature is the predominantly primary-prevention population, which differentiates it from the outcome trials of other agents in the class and makes its result harder to compare with them.[2]
Effect sizes for weight are modest relative to semaglutide and tirzepatide, and dulaglutide does not hold a weight-management indication.
Practical and analytical notes
[edit]Dulaglutide is supplied in a prefilled single-dose device with the needle concealed, which simplifies administration but removes the option of dose adjustment between the fixed presentations available.
Analytically it does not resemble the synthetic peptides that occupy most of this wiki. It is characterised as a protein biologic — by peptide mapping, glycan analysis where relevant, size-exclusion chromatography for aggregates and charge-variant methods — rather than by the reverse-phase area percent determination that dominates peptide certificates.[3] A certificate reporting a single reverse-phase purity figure for a 60 kDa fusion protein would be inadequate on its face.
Dulaglutide is not commonly encountered in research-chemical supply, since it cannot be made by solid-phase synthesis and requires a cell-culture expression system with the associated downstream processing.[4]
See also
References
- ^ a b c Glaesner W, Vick AM, Millican R, et al. "Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265." Diabetes/Metabolism Research and Reviews 26(4):287–296 (2010). PMID 20503261.
- ^ a b c Gerstein HC, Colhoun HM, Dagenais GR, et al. "Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial." The Lancet 394(10193):121–130 (2019). DOI:10.1016/S0140-6736(19)31149-3. PMID 31189511.
- ^ International Council for Harmonisation, Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (1999).
- ^ United States Pharmacopeia, General Chapter <1503>, Quality Attributes of Synthetic Peptide Drug Substances.