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Dulaglutide

Also known as Trulicity, LY2189265

Once-weekly GLP-1 receptor agonist for type 2 diabetes with proven cardiovascular benefit.

clinically proven Metabolic & weight approved drug

At a glance

Category
Metabolic & weight
Status
approved drug
Made from
recombinant A GLP-1-Fc fusion protein produced in Chinese hamster ovary (CHO) cell culture by recombinant DNA technology.
Route
subcutaneous, once weekly
Half-life
approximately 5 days in humans per the US prescribing information 6; steady state after 2-4 weekly doses
Onset
glucose lowering within the first week; maximum HbA1c effect after roughly 8-12 weeks
Molecular weight
approximately 63 kDa according to the US prescribing information 6
Sequence
Recombinant fusion protein: two identical chains, each an analogue of human GLP-1(7-37) with Gly8, Glu22 and Gly36 substitutions, joined by a small peptide linker to a modified human IgG4 Fc fragment

Approved by the FDA in September 2014 and by the EMA in November 2014 for type 2 diabetes. The 3.0 mg and 4.5 mg strengths were added in 2020. Also approved to reduce major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease or multiple risk factors 6. Not approved for obesity in the absence of diabetes. Prescription only 6.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Dulaglutide is a GLP-1 receptor agonist built on a completely different life-extension strategy from the acylated peptides. Rather than binding albumin via a fatty acid chain, it is covalently fused to an IgG4 Fc fragment. The large size slows renal filtration and the Fc region engages the neonatal Fc receptor recycling pathway, together producing a half-life of roughly 4.7 days.

Three amino acid substitutions in the GLP-1 portion do specific jobs. Ala8 is replaced by Gly to block dipeptidyl peptidase-4 cleavage. Gly22 becomes Glu to reduce aggregation. Arg36 becomes Gly to improve solubility. The IgG4 Fc itself is modified to prevent half-antibody exchange and to minimise immune effector function, which keeps immunogenicity low.

Pharmacologically the result is a conventional GLP-1 agonist profile: glucose-dependent insulin secretion, suppression of glucagon, slowed gastric emptying and central appetite reduction. Because exposure is continuous and relatively flat, the effect falls more on fasting than on postprandial glucose.

Weight loss with dulaglutide is real but modest, roughly 3-5 kg at the higher doses, and clearly less than with semaglutide 2.4 mg or tirzepatide. Dulaglutide's distinguishing clinical feature is not weight but the cardiovascular outcome data from REWIND, which included a majority of participants without prior cardiovascular events — a primary-prevention population that most other GLP-1 outcome trials did not study.

What the research shows

Dulaglutide is supported by a large phase 3 programme (the AWARD trials, more than a dozen randomised studies) and by REWIND, a cardiovascular outcome trial with nearly 10,000 participants and a median follow-up of over five years. The glycaemic evidence is strong and the cardiovascular signal is one of the better-established in the class. The evidence for weight reduction is real but the effect size is modest by contemporary standards.

Research in humans

REWIND (Lancet 2019, n=9,901, median follow-up 5.4 years) reported a significant reduction in the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death with dulaglutide 1.5 mg weekly compared with placebo, hazard ratio 0.88 1. Notably, about 69% of participants had no prior cardiovascular event, so the benefit extended into a primary-prevention population. The AWARD programme established HbA1c reductions of roughly 0.8-1.5 percentage points depending on dose and background therapy, with dulaglutide non-inferior or superior to metformin, sitagliptin, exenatide twice daily and insulin glargine in the respective comparisons. AWARD-11 showed that escalating to 3.0 mg and 4.5 mg gave further HbA1c and weight reduction beyond 1.5 mg, at the cost of more gastrointestinal adverse events. In SUSTAIN 7, semaglutide produced greater HbA1c and weight reduction than dulaglutide in a head-to-head comparison.

Animal and lab research

In two-year carcinogenicity studies dulaglutide caused a dose-related and treatment-duration-related increase in thyroid C-cell adenomas and carcinomas in rats. This is the basis of the boxed warning. Whether the finding translates to humans has not been established; post-marketing surveillance has not so far shown a clear excess of medullary thyroid carcinoma, but follow-up remains limited relative to the latency of such tumours.

Caveats. The AWARD programme and REWIND were funded and conducted by Eli Lilly. REWIND used an open-label insulin comparator strategy for glycaemic rescue, and the absolute risk reduction, while significant, was small (2.4 events per 100 person-years versus 2.7). The weight effect is modest and dulaglutide has largely been displaced for weight-focused indications by semaglutide and tirzepatide. Long-term thyroid, pancreatic and biliary safety rests on registry data rather than randomised evidence.

What it is used for

  • Type 2 diabetes mellitus, as an adjunct to diet and exercise, alone or combined with metformin, sulfonylureas, SGLT2 inhibitors or insulin 6
  • Reduction of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors 6
  • Approved in the United States for type 2 diabetes in children aged 10 years and older, where the maximum dose is 1.5 mg once weekly 6
  • Used off-label for weight reduction, though not approved for obesity and less effective for that purpose than semaglutide or tirzepatide

Dosing

Dose
0.75 mg to 4.5 mg once weekly
Frequency
once weekly, on the same day each week, at any time of day, with or without food
Route
Subcutaneous injection into the abdomen, thigh or upper arm, rotating sites
Duration
Chronic
  • Standard schedule from the prescribing information: start at 0.75 mg once weekly. Increase to 1.5 mg once weekly for additional glycaemic control 6.
  • If further control is needed, increase to 3.0 mg once weekly after at least 4 weeks on 1.5 mg, and then to a maximum of 4.5 mg once weekly after at least a further 4 weeks. Each escalation step requires at least 4 weeks at the preceding dose 6.
  • The maximum recommended dose is 4.5 mg once weekly 6.
  • The day of the week may be changed provided the last dose was given at least 3 days (72 hours) earlier 6.
  • A missed dose can be taken as soon as possible if at least 3 days remain until the next scheduled dose; otherwise the missed dose is skipped 6.
  • No dose adjustment is required for renal or hepatic impairment, but renal function should be monitored in patients reporting severe gastrointestinal reactions 6.
  • This is the official approved schedule reproduced as reference information, not treatment advice.
  • Separately from this approved schedule, dulaglutide is used off-label for weight loss in people without diabetes. That circulating pattern is described under Protocols; it has no published basis for use outside diabetes and diverges from the label, which escalates the dose toward a glycaemic target.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Trulicity titration (type 2 diabetes)

approved product information

Source: FDA prescribing information for Trulicity (DailyMed)

Weeks 1-40.75 mg subcutaneously once weekly
After 4 weeks1.5 mg once weekly, for additional glycaemic control
Each further stepincrease by 1.5 mg after at least 4 weeks on the current dose (3 mg, then 4.5 mg)
Ceiling4.5 mg once weekly

Unlike semaglutide and tirzepatide, the starting dose here is also a usable maintenance dose, so escalation is conditional on needing more glycaemic control rather than being the expected path.

Off-label weight-loss use of the licensed pen (user-reported)

user protocol — not validated

Source: User weight-loss and GLP-1 forum reports, and off-label telehealth prescribing

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Reported starting pattern0.75 mg once weekly, as on the label, but taken for weight loss by people without diabetes
Commonly reportedheld at 0.75-1.5 mg as a low 'microdose', or the interval stretched to every 10-14 days to cut cost and nausea
Reported ceilingup to 4.5 mg once weekly, the label maximum, among those chasing more weight loss

The label directs escalation toward a glycaemic target in diagnosed diabetes; off-label users take the same licensed pen purely for weight loss, and many deliberately stay at the low starting dose or lengthen the interval rather than escalate. Two things make dulaglutide diverge from the semaglutide-style grey market. First, Trulicity is a sealed single-use fixed-dose pen, so it cannot be part-dosed the way a semaglutide vial can, and genuine microdosing is impractical. Second, dulaglutide is a roughly 63 kDa Fc-fusion protein that garage labs do not reproduce, so the research-chemical powder scene around semaglutide and tirzepatide barely touches it — what circulates is the licensed pen used off-label, obtained by telehealth prescription or diverted supply. None of this has a published basis for non-diabetic weight management, and interval-stretching simply lowers exposure. Users in these communities widely rate dulaglutide the weakest of the injectable GLP-1s and frequently report switching to semaglutide or tirzepatide.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Storage
Store unused pens at 2-8 °C, do not freeze, protect from light in the original carton. A pen that has been frozen must be discarded. Individual pens may be kept at up to 30 °C for a maximum of 14 days if refrigeration is unavailable.

Worked example

Not applicable. Dulaglutide is supplied only as a ready-to-use sterile solution in a single-dose prefilled pen or prefilled syringe, with a hidden pre-attached needle. Nothing is dissolved, diluted or mixed by the user, and there is no lyophilised presentation of the licensed product.

Because dulaglutide is a 60 kDa fusion protein rather than a small peptide, it is considerably more fragile than compounds such as BPC-157: freezing, shaking and heat all risk aggregation, and aggregated material cannot be visually distinguished with confidence. Do not use if the solution is cloudy, discoloured or contains particles.

Safety

Side effects

  • Nausea, vomiting, diarrhoea, abdominal pain and decreased appetite — the most common adverse reactions in the trials, reported at 21.1%, 12.7%, 12.6%, 9.4% and 8.6% respectively; dose-dependent and generally worst in the first weeks after starting or escalating 6
  • Dyspepsia, eructation, flatulence and constipation
  • Fatigue and headache
  • Injection-site reactions (less common than with microsphere formulations)
  • Hypoglycaemia when combined with insulin or a sulfonylurea
  • Acute pancreatitis (uncommon) 6
  • Gallstones and cholecystitis, particularly with rapid weight loss 6
  • Acute kidney injury, usually in the context of volume depletion from vomiting or diarrhoea 6
  • Increase in heart rate of roughly 2-4 beats per minute and first-degree AV block or sinus tachycardia in a small number of patients
  • Worsening of diabetic retinopathy with rapid improvement in glycaemic control 6
  • Delayed gastric emptying with a corresponding risk of retained gastric contents and pulmonary aspiration under general anaesthesia or deep sedation 6
  • Hypersensitivity reactions including anaphylaxis and angioedema (rare) 6
  • Loss of fat-free mass alongside fat mass during weight reduction

Do not use if

  • Personal or family history of medullary thyroid carcinoma (MTC) — a labelled contraindication 6
  • Multiple endocrine neoplasia syndrome type 2 (MEN 2) — a labelled contraindication 6
  • Known serious hypersensitivity to dulaglutide or any excipient — a labelled contraindication 6
  • Boxed warning (FDA): dulaglutide causes thyroid C-cell tumours in rats, and it is unknown whether it causes thyroid C-cell tumours including medullary thyroid carcinoma in humans 6
  • Type 1 diabetes and diabetic ketoacidosis — dulaglutide is not a substitute for insulin
  • History of pancreatitis — a relative contraindication; discontinue permanently if pancreatitis is confirmed
  • Severe gastrointestinal disease including gastroparesis — not studied and not recommended
  • Pregnancy and breastfeeding — human data are inadequate; discontinuation at least 4 weeks before a planned pregnancy is generally advised given the long half-life
  • Pre-existing severe diabetic retinopathy warrants ophthalmological monitoring rather than absolute avoidance

Interactions

Dulaglutide delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medicines 6. Clinical pharmacology studies found the effect on most oral drugs to be small, but the label advises monitoring for narrow-therapeutic-index agents such as warfarin 6 and with drugs requiring rapid onset. Combination with insulin or a sulfonylurea markedly increases hypoglycaemia risk and generally requires reducing the dose of those agents. Dulaglutide should not be combined with another GLP-1 receptor agonist or with a DPP-4 inhibitor, since the mechanisms overlap without demonstrated added benefit. Anaesthesia societies now recommend modified preoperative fasting or gastric ultrasound assessment for patients on GLP-1 receptor agonists because of the aspiration risk from delayed gastric emptying; because dulaglutide has a half-life of several days, simply skipping one dose does not eliminate the effect.

Sources