Bottom line
Dulaglutide is a once-weekly GLP-1 receptor agonist engineered as a fusion protein of a GLP-1 analog dimer linked to a modified human IgG4 Fc fragment. Approved as Trulicity for T2D (2014), the REWIND trial (N=9,901) demonstrated a 12% reduction in MACE, notably including a large proportion of participants without established CVD. Higher doses (3.0 and 4.5 mg) were approved in 2020, and pediatric approval for T2D followed in 2022. Dulaglutide is not approved for weight management.
Identity and composition
| Field | Verified information |
|---|---|
| Preferred name | Dulaglutide |
| Key aliases | Trulicity, LY 2189265, GLP-1-Fc |
| Molecular/sequence identity | Disulfide-linked homodimer of two identical 275-amino-acid chains. Each chain contains a human GLP-1(7-37) analog with Ala8→Gly, Gly22→Glu, and Arg36→Gly substitutions, joined through a (Gly4-Ser)3-Ala peptide linker to a modified human IgG4 Fc hinge-CH2-CH3 fragment. |
| Modifications/form | The GLP-1 Ala8→Gly substitution confers DPP-4 resistance. The IgG4 Fc contains S228P to limit half-antibody formation and F234A/L235A to reduce Fcγ-receptor interactions; the terminal Fc lysine is removed. Fc fusion extends half-life and reduces renal clearance; produced in CHO cells. |
| Stable identifiers | CAS: 923950-08-7; DrugBank: DB09045; UNII: WTT295HSY5. No unambiguous exact-name PubChem compound was selected in this review. |
| Identity caveats | Structurally unique among GLP-1 RAs — it is not a small peptide but a fusion protein (approximately 63 kDa in the FDA label). Not interchangeable with other GLP-1 RAs. Not approved for chronic weight management |
Development and approval status
| Jurisdiction | Status and indication | Product/source | As of |
|---|---|---|---|
| US (FDA) | Approved Sep 2014 for T2D glycemic control | Trulicity (BLA 125469) | 2026-08-06 |
| US (FDA) | CV risk reduction label expansion Jan 2020 (adults with T2D + established CVD or multiple CV risk factors) | Trulicity label update (based on REWIND) | 2026-08-06 |
| US (FDA) | Higher doses (3.0 mg, 4.5 mg) approved Sep 2020 | Trulicity label update (AWARD-11) | 2026-08-06 |
| US (FDA) | Pediatric T2D approval Jun 2022 (age 10–17) | Trulicity | 2026-08-06 |
| EU (EMA) | Approved Nov 2014 (0.75 mg, 1.5 mg); higher doses approved 2021 | Trulicity | 2026-08-06 |
Mechanism and pharmacology
Dulaglutide is a GLP-1 receptor agonist with a molecular weight of approximately 63 kDa in the FDA label due to the Fc fusion. Relative to native GLP-1(7-37), its peptide component contains Gly⁸, Glu²², and Gly³⁶ substitutions; Gly⁸ reduces susceptibility to DPP-4 cleavage and Gly³⁶ helps reduce a predicted T-cell epitope at the linker junction. The modified IgG4 Fc moiety extends systemic residence through FcRn recycling, supporting once-weekly dosing. Fc substitutions S228P, F234A, and L235A reduce half-antibody formation and Fc-receptor-mediated effector activity. Dulaglutide enhances glucose-dependent insulin secretion, suppresses glucagon secretion, and delays gastric emptying.
Evidence by claim
| Claim/indication | Stage | Grade | Best human evidence | Main result | Important limitations |
|---|---|---|---|---|---|
| Glycemic control (T2D) | Approved | A | AWARD program (6 phase 3 trials; >5,000 pts) | HbA1c reduction 0.7–1.6%; dose-dependent | More pronounced with higher doses; efficacy vs comparators (metformin, sitagliptin, exenatide, insulin glargine) |
| CV risk reduction (T2D ± CVD) | Approved | A | REWIND (N=9,901; median 5.4 yr) | 3-point MACE HR 0.88 (0.79–0.99); 24% stroke reduction | Included primary prevention (69% no prior CVD); longest follow-up of any GLP-1 RA CVOT |
| T2D in pediatric (10–17 yr) | Approved | A | AWARD-PEDS (N=154; 26 wk) | HbA1c reduction −0.6% vs +0.4% placebo; 44% vs 7% achieved HbA1c below 7% | Small N; short duration |
| Weight management | Not approved | — | AWARD program (weight was secondary endpoint) | Modest weight loss (1–3 kg at 1.5 mg dose) | Not studied at higher doses for weight loss; no dedicated obesity trial |
Key studies
| Study | Design/population | Exposure studied | Endpoints and result | Limitations |
|---|---|---|---|---|
| REWIND; Gerstein et al., Lancet 2019; PMID: 31189511 | CVOT; N=9,901 T2D (69% no prior CVD); median 5.4 yr | Dulaglutide 1.5 mg SC qwk vs placebo | MACE HR 0.88 (0.79–0.99); nonfatal stroke HR 0.76 (0.62–0.93); CV death 0.91 (0.78–1.06) | Included broader CV risk population (not exclusively secondary prevention); absolute risk reduction modest (1.5%) |
| AWARD-1; Wysham et al., Diabetes Care 2014; PMID: 24879836 | RCT phase 3; N=978 T2D (on metformin + pioglitazone); 52 wk | Dulaglutide 0.75/1.5 mg vs exenatide BID vs placebo | HbA1c Δ −1.51% (1.5 mg) vs −0.99% (exenatide); 58% achieved HbA1c below 7% at 1.5 mg | Exenatide BID as comparator (not QW); limited to pio + metformin background |
| AWARD-11; Frias et al., Diabetes Care 2021; PMID: 33741356 | RCT; N=1,842 T2D on metformin; 36 wk | Dulaglutide 3.0 or 4.5 mg vs 1.5 mg | HbA1c −1.41%/−1.60%/−1.71% for 1.5/3.0/4.5 mg; dose-dependent weight change | No placebo or external active comparator; all groups received dulaglutide |
| AWARD-PEDS; Arslanian et al., NEJM 2022; PMID: 35658022 | RCT; N=154 pediatric T2D (10–17 yr); 26 wk + 26 wk extension | Fixed dulaglutide 0.75 or 1.5 mg once weekly vs placebo | HbA1c Δ −0.6% vs +0.4% (difference −1.0%); 44% vs 7% achieved HbA1c below 7% | Small sample; short placebo-controlled phase; high placebo HbA1c increase from baseline |
Dose and administration evidence
Approved labeled regimen
The label summary below is product-, indication-, and jurisdiction-specific; consult the full current label and a licensed clinician/pharmacist.
The entries summarize the cited US FDA Trulicity label for type 2 diabetes.
Initiate 0.75 mg SC once weekly; may increase to 1.5 mg for additional glycemic control.
Higher doses (3.0 mg, 4.5 mg SC qwk) approved Sep 2020 for adults requiring additional glycemic control beyond 1.5 mg.
Pediatric patients aged 10 years and older: 0.75 mg once weekly; if additional glycemic control is needed, the US label permits an increase to a maximum of 1.5 mg once weekly after at least 4 weeks. This is not weight-based.
No dose adjustment needed for renal or hepatic impairment.
Studied regimens (not recommendations)
AWARD-11 established dose-dependent efficacy for 3.0 mg and 4.5 mg weekly; these doses resulted in greater HbA1c reduction and modest additional weight loss vs 1.5 mg.
What is not established
Use of higher doses (3.0/4.5 mg) for weight management in the absence of T2D.
Use in combination with tirzepatide or other incretin-based therapies.
Long-term safety >6 years (REWIND median 5.4 yr).
CV outcomes in patients without T2D.
Safety
Established label risks
Boxed warning: Thyroid C-cell tumors. Rodent studies demonstrated C-cell neoplasia; human risk not excluded.
Gastrointestinal: Nausea (29%), vomiting (17%), diarrhea (14%), abdominal pain; dose-dependent.
Pancreatitis: Postmarketing reports of acute pancreatitis; discontinue if suspected.
Acute kidney injury: Reported in context of severe GI adverse events.
Gallbladder disease: Cholelithiasis reported, particularly with rapid glycemic improvement.
Hypoglycemia: Low risk with monotherapy; increased with sulfonylurea or insulin coadministration.
Hypersensitivity: Angioedema, anaphylaxis reported (very rare); recipients with history of serious hypersensitivity to other GLP-1 RAs should be treated with caution.
Human-study signals
REWIND: No imbalance in pancreatitis (0.7% vs 0.8%), pancreatic cancer (0.1% vs 0.2%), or thyroid cancer (0.1% vs 0.1%).
REWIND: Gallbladder-related AEs higher with dulaglutide (2.8% vs 2.0%); numerically more cholecystectomies.
Injection-site reactions rare (<1%), comparable to placebo.
Unknowns and product-quality risks
Immunogenicity: Anti-drug antibodies (~1–3%) lower than exenatide or lixisenatide due to the Fc structure.
Long-term effects of chronic GLP-1 receptor activation on pancreatic, renal, and thyroid tissue are not fully characterized.
No approved generic; product is a biologic — any follow-on product would be a biosimilar, not a generic.
Interactions and special populations
Gastric emptying delay may reduce absorption rate of oral medications (clinically meaningful for narrow-therapeutic-index drugs).
Insulin and sulfonylurea coadministration: Increased hypoglycemia risk; consider dose reduction.
Moderate/severe renal impairment (eGFR 15–59): No dose adjustment per label. Very limited data below eGFR 15.
Hepatic impairment: No dose adjustment; limited data in Child-Pugh C.
Pregnancy: human data are insufficient; the US label says dulaglutide should be used during pregnancy only if the potential benefit justifies the potential fetal risk. Pregnancy is not listed as a formal contraindication.
Regulatory, compounding, and sport notes
Boxed warning for thyroid C-cell tumors per class requirement.
Trulicity is a biologic (BLA, not NDA); no FDA-approved biosimilars or generics as of 2026.
Compounded dulaglutide is not FDA-approved and presents risks of impurity and potency variation due to the complexity of Fc-fusion protein manufacture.
WADA: GLP-1 receptor agonists are not prohibited. Not listed on the WADA Prohibited List.
Evidence gaps
Dedicated obesity trial (not T2D) for higher doses
CV outcomes in persons without T2D
Long-term pediatric safety beyond 1 year
Comparative effectiveness against semaglutide 2.0 mg and tirzepatide
Safety in pregnancy beyond animal data
Immunogenicity data from long-term use and impact on efficacy
Search notes
Databases and registries: PubMed, FDA Drugs@FDA, ClinicalTrials.gov, DailyMed, EMA EPAR
Search terms: "dulaglutide", "Trulicity", "REWIND", "AWARD program", "AWARD-11", "GLP-1-Fc", "LY 2189265"
Last searched: 2026-08-06
Inclusion emphasis: CVOT publication, phase 3 registration trials, FDA labeling documents, pediatric data
Sources
Gerstein HC et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394(10193):121-130. PMID: 31189511. https://doi.org/10.1016/S0140-6736(19)31149-3
Wysham C et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37(8):2159-2167. PMID: 24879836. https://doi.org/10.2337/dc13-2760
Frias JP et al. Efficacy and safety of once-weekly dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in patients with type 2 diabetes (AWARD-11). Diabetes Care. 2021;44(3):765-773. PMID: 33741356. https://doi.org/10.2337/dc20-1473
Arslanian SA et al. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes (AWARD-PEDS). N Engl J Med. 2022;387(5):433-443. PMID: 35658022. https://doi.org/10.1056/NEJMoa2204601
FDA. Trulicity (dulaglutide) injection label. BLA 125469. DailyMed. Accessed 2026-08-06. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=463050bd-2b1c-40f5-b3c3-0a04bb433309
Glaesner W et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287-296. PMID: 20503261. https://doi.org/10.1002/dmrr.1080
Gerstein HC et al. Design and baseline characteristics of participants in the REWIND trial. Diabetes Obes Metab. 2018;20(1):42-49. PMID: 28573765. https://doi.org/10.1111/dom.13028
FDA. Trulicity (dulaglutide) BLA 125469 pharmacology review; chemical designation specifies [Gly8,Glu22,Gly36] human GLP-1(7-37), the linker, and modified IgG4 Fc. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125469Orig1s000PharmR.pdf
FDA GSRS. Dulaglutide (UNII WTT295HSY5); complete protein record contains two identical 275-residue subunits. https://precision.fda.gov/uniisearch/srs/unii/wtt295hsy5