Dulaglutide
GLP-1 analog fused to modified IgG4 Fc fragment; once-weekly injectable GLP-1 receptor agonist with proven cardiovascular benefit.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Trulicity, LY2189265 |
| Category | GLP-1 Receptor Agonist / Fc Fusion Protein (Metabolic) |
| Sequence | Modified GLP-1(7-37) analog covalently linked to modified human IgG4 Fc fragment via small peptide linker |
| Molecular Weight | ~63 kDa (fusion protein — significantly larger than traditional peptides) |
| Molecular Formula | Fusion protein (not expressed as simple molecular formula) |
| PubChem CID | N/A (biologic; not in PubChem as small molecule) |
| Administration | SubQ once weekly (single-dose auto-injector pen) |
| Typical Dose Range | 0.75 mg, 1.5 mg, 3.0 mg, or 4.5 mg once weekly |
| Half-Life | ~5 days (120 hours) |
| Storage | Refrigerate 2-8C; may be stored at room temperature (up to 30C) for up to 14 days |
| FDA Status | FDA Approved (2014) — Type 2 diabetes; CV risk reduction (REWIND, 2020 label update) |
| WADA Status | Not listed as prohibited |
Note on Classification: Dulaglutide is technically a GLP-1/Fc fusion protein (~63 kDa), far larger than traditional peptides (<10 kDa). It is included in this vault because (1) its active moiety is a modified GLP-1 peptide, (2) it belongs to the GLP-1 RA class alongside true peptides like semaglutide and exenatide, and (3) practitioners using peptide-based metabolic therapies must understand the full GLP-1 RA landscape. Similar to how the vault includes MK-677 (a non-peptide GH secretagogue), dulaglutide is included for completeness.
Mechanism of Action
Dulaglutide consists of two components: (1) a modified GLP-1(7-37) analog with amino acid substitutions that confer DPP-4 resistance (Ala8Gly substitution) and enhanced potency, and (2) a modified human IgG4 Fc fragment. The two are covalently linked via a small peptide linker. The Fc fusion dramatically extends the half-life to approximately 5 days through three mechanisms: reduced renal clearance (due to the ~63 kDa size exceeding the glomerular filtration threshold), FcRn-mediated recycling from endosomal degradation, and reduced immunogenicity through the IgG4 (vs. IgG1) framework that minimizes complement activation.
Upon subcutaneous injection, dulaglutide activates GLP-1 receptors with the same downstream pharmacology as native GLP-1: glucose-dependent insulin secretion via cAMP/PKA signaling in pancreatic beta cells, suppression of glucagon secretion from alpha cells, delayed gastric emptying, and central satiety signaling through hypothalamic GLP-1R activation. The continuous receptor occupancy from once-weekly dosing provides more stable GLP-1R activation compared to short-acting agents like exenatide BID.
The REWIND trial demonstrated cardiovascular benefit, likely mediated through multiple mechanisms: anti-inflammatory effects on vascular endothelium, reduction in postprandial lipemia, modest blood pressure reduction, and direct GLP-1R-mediated cardioprotection. Dulaglutide showed a unique signal for stroke reduction, possibly through anti-atherosclerotic and anti-inflammatory effects on cerebral vasculature (PMID: 31189511).
Key Research Areas
- Cardiovascular Protection — REWIND demonstrated 12% reduction in 3-point MACE, with significant stroke reduction (HR 0.76) in a predominantly primary prevention population (PMID: 31189511)
- Glycemic Control — Comprehensive AWARD trial program (6+ Phase 3 RCTs) established superiority over multiple comparators (PMID: 31927749)
- Higher-Dose Optimization — AWARD-11 demonstrated dose-response up to 4.5 mg with additional glycemic and weight benefits (PMID: 33397768)
- Cognitive Protection — Exploratory REWIND analysis showed reduced cognitive decline, suggesting neuroprotective properties
- Renal Outcomes — Post-hoc analyses suggest renal-protective effects consistent with GLP-1 RA class
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 25+ | AWARD 1-11, REWIND, multiple Phase 3 |
| Human observational | 15+ | Real-world effectiveness, post-marketing |
| Animal in vivo | 10+ | Preclinical pharmacology, cardioprotection |
| In vitro | 5+ | GLP-1R binding, Fc recycling characterization |
| Systematic reviews | 5+ | Meta-analyses of AWARD program, CV outcomes |
Clinical Applications
- Type 2 Diabetes — FDA-approved first/second-line injectable; superior to multiple comparators
- Weight Management — Modest weight loss (3-4.6 kg depending on dose); not approved for obesity alone
- Metabolic Syndrome — Improvements in glycemia, weight, blood pressure, lipids
Protocols Using This Peptide
- Weight Loss Protocol — Referenced as GLP-1 RA option within metabolic framework
- Metabolic Reset Protocol — Component of comprehensive metabolic optimization
Ageless Peps Products
Dulaglutide is an FDA-approved pharmaceutical (Trulicity) and is NOT sold by Ageless Peps. It is included in this vault for educational reference and comparative understanding of the GLP-1 RA landscape.
Dosing Reference
FDA-Approved Dosing
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ | 0.75 mg (starting) | Once weekly | Ongoing | FDA label |
| SubQ | 1.5 mg (standard) | Once weekly | Ongoing | FDA label |
| SubQ | 3.0 mg (higher dose) | Once weekly | Ongoing | AWARD-11 |
| SubQ | 4.5 mg (maximum) | Once weekly | Ongoing | AWARD-11 |
Cycling
No cycling is applicable. Dulaglutide is prescribed as continuous chronic therapy. Dose escalation from 0.75 mg to 1.5 mg after 4 weeks is recommended; further escalation to 3.0 and 4.5 mg can be considered for additional glycemic/weight benefit.
Contraindications & Safety
- Contraindications: Personal or family history of MTC, MEN2, known hypersensitivity to dulaglutide
- Common side effects: Nausea (12-21%), diarrhea (8-12%), vomiting (6-12%), abdominal pain, decreased appetite; generally mild-moderate and decrease over time
- Drug interactions: Slows gastric emptying — potential impact on oral medication absorption; caution with sulfonylureas/insulin (hypoglycemia risk); may affect warfarin INR monitoring
- Pregnancy/nursing: Not recommended; discontinue at least 2 months before planned pregnancy (long half-life)
- Special populations: No dose adjustment for renal impairment (use caution in severe); no dose adjustment for hepatic impairment; limited data in pediatric populations
Synergistic Combinations
- Metformin (not a peptide) + Dulaglutide — Standard first-line combination for T2D
- SGLT2 inhibitors (not peptides) — Triple pathway approach: GLP-1R + SGLT2 + metformin for comprehensive cardiometabolic management
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 31189511 | Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND) | 2019 | RCT |
| 31927749 | Efficacy and safety of dulaglutide: systematic review and meta-analysis of 21 RCTs | 2020 | Systematic Review |
| 33397768 | Dulaglutide 3.0 mg and 4.5 mg vs. 1.5 mg (AWARD-11) | 2021 | RCT |
References
- PMID 31189511 — REWIND cardiovascular outcomes trial
- PMID 31927749 — Systematic review and meta-analysis of 21 RCTs
- PMID 33397768 — AWARD-11 higher-dose trial
Related
- Peptide Index
- Condition Index
- Protocol Index
- Semaglutide
- Exenatide
- Liraglutide
- Tirzepatide
- GLP-1 (Native)
#peptide #metabolic #fda-approved #not-sold #subq