Dulaglutide

Dulaglutide is a synthetic GLP-1 receptor agonist consisting of two identical, disulfide-linked chains, each containing a GLP-1 analogue sequence covalently joined to a modified human immunoglobulin G4 (IgG4) heavy chain via a small peptide linker. Its amino acid sequence shares approximately 90% homology with endogenous human GLP-1 (7-37). A key structural modification is the substitution of alanine with glycine at position 8 (Ala8Gly), which renders the molecule resistant to cleavage by dipeptidyl peptidase-4 (DPP-4). This substitution, combined with the large IgG4 scaffold, slows renal clearance and extends the plasma half-life to approximately five days, enabling once-weekly subcutaneous dosing.

Upon injection, dulaglutide binds to and activates the GLP-1 receptor, a membrane-bound G-protein-coupled receptor expressed on pancreatic beta cells, alpha cells, cardiac myocytes, kidney tubular cells, and central nervous system neurons. Receptor activation stimulates adenylyl cyclase, elevating intracellular cyclic AMP (cAMP) and triggering glucose-dependent insulin secretion. Because this pathway requires ambient glucose for activity, the risk of insulin-induced hypoglycemia is substantially lower than with non-glucose-dependent secretagogues.

• Reduces glucagon secretion from pancreatic alpha cells, attenuating post-meal hepatic glucose output • Slows gastric emptying, blunting postprandial glucose excursions and contributing to early satiety • Acts on hypothalamic centers to reduce appetite and caloric intake • Promotes beta-cell survival in preclinical models, though long-term effects on beta-cell mass in humans are not established

Dulaglutide has been evaluated in a large phase 3 program known as the AWARD (Assessment of Weekly AdministRation of LY2189265 in Diabetes) studies, comprising eight randomized controlled trials. Across six core AWARD trials, dulaglutide 1.5 mg once weekly demonstrated superiority over active comparators — including exenatide twice daily, insulin glargine, sitagliptin, and metformin — in five of the six studies, achieving greater proportions of patients reaching HbA1c targets of less than 7.0% and 6.5%. Mean HbA1c reductions from baseline ranged from approximately 0.8% to 1.6% for the 1.5 mg dose and 0.7% to 1.1% for the 0.75 mg dose, depending on the comparator arm and baseline characteristics.

The AWARD-11 trial (n = 1,842) assessed expanded doses of 3.0 mg and 4.5 mg versus the established 1.5 mg dose over 52 weeks in patients with type 2 diabetes inadequately controlled on metformin. At 36 weeks, mean weight change was -3.1 kg for 1.5 mg, -4.0 kg for 3.0 mg, and -4.7 kg for 4.5 mg, with both higher doses statistically superior (p = 0.001 and p less than 0.001, respectively). HbA1c reductions were dose-dependent: 1.5 mg, -1.0 to -2.2%; 3.0 mg, -1.2 to -2.5%; 4.5 mg, -1.2 to -3.2% across baseline HbA1c subgroups. On the basis of these findings, the FDA approved the 3.0 mg and 4.5 mg doses.

The REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial enrolled 9,901 adults aged 50 or older with type 2 diabetes across 24 countries and followed them for a median of 5.4 years. Dulaglutide 1.5 mg significantly reduced the first occurrence of major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke, or CV death) versus placebo: 12.0% versus 13.4% (HR 0.88, 95% CI 0.79-0.99; p = 0.026), yielding a number needed to treat of 71. Importantly, approximately 69% of REWIND participants had no established cardiovascular disease at enrollment, making this the broadest CVD-risk population among GLP-1 RA outcome trials. All-cause mortality did not differ significantly between groups.

AWARD-7 demonstrated that dulaglutide slowed eGFR decline versus insulin glargine in patients with type 2 diabetes and moderate-to-severe CKD. A retrospective Korean cohort study (n = 197 with CKD stages 2-4) found the mean annual eGFR decline was -0.76 mL/min/1.73 m2 during dulaglutide treatment versus -2.41 mL/min/1.73 m2 before treatment (p = 0.003).

Typical dosage: 0.75-4.5 mg (weekly).

Dulaglutide (brand name Trulicity) is administered as a subcutaneous injection once weekly, at any time of day, with or without food. It is injected into the abdomen, thigh, or upper arm via a single-use prefilled autoinjector pen.

Approved adult dosing, per the current FDA label: • Initiation: 0.75 mg once weekly for at least 4 weeks (allows GI tolerability to be established) • Standard dose: 1.5 mg once weekly (the principal dose studied across the AWARD program) • Dose escalation: if additional glycemic control is needed, increase by 1.5 mg increments at intervals of no less than 4 weeks • Maximum approved dose: 4.5 mg once weekly

Approved pediatric dosing (age 10 and older): • Starting dose: 0.75 mg once weekly • Maximum dose: 1.5 mg once weekly after at least 4 weeks

No dose adjustment is required solely for renal impairment, though patients with severe renal disease should be monitored for volume depletion-related complications if GI adverse effects are severe. No hepatic dose adjustment is specified in the label.

Dulaglutide was initially FDA-approved in September 2014 at the 0.75 mg and 1.5 mg doses. The 3.0 mg and 4.5 mg doses received FDA approval based on AWARD-11 data and became available for clinical use in 2020.

This information is provided for educational purposes only and does not constitute medical advice. Dosing decisions must be made by a licensed prescriber with full knowledge of the patient's clinical status, comorbidities, and concomitant medications.

Lyophilized (before reconstitution)

Refrigerate 2–8°C before first use. Do not freeze. Protect from light in the original carton. A room-temperature allowance up to 30°C is permitted for up to 14 days before use only.

Reconstituted

Trulicity is a single-use pen — administer promptly and discard after use; there is no in-use storage period.

For general storage chemistry (bacteriostatic vs sterile water, freeze-thaw, BUD framework), see Storage & handling.

Last reviewed: July 1, 2026

Dulaglutide has been formally studied and is approved for use in combination with several antidiabetic drug classes. These combinations are backed by randomized trial evidence from the AWARD program.

Metformin: The most common clinical combination, serving as a backbone in the majority of AWARD trials. Complementary mechanisms (metformin reduces hepatic glucose output; dulaglutide improves insulin secretion and reduces glucagon) produce additive glycemic lowering with no increased hypoglycemia risk.

SGLT-2 inhibitors: AWARD-10 specifically evaluated dulaglutide added to an SGLT-2 inhibitor with or without metformin. The combination is supported by complementary and largely non-overlapping mechanisms: GLP-1 receptor activation enhances insulin secretion while SGLT-2 inhibition promotes urinary glucose excretion. Real-world observational data from Indian patients (n = 30 dulaglutide arm) showed HbA1c reduction of approximately 1.0% and weight loss of -4.2 kg at 13 weeks with this triple combination, though that study was small and limited in generalizability.

Basal insulin: Studied in AWARD-2 and AWARD-9; the combination of dulaglutide with insulin glargine produced greater HbA1c lowering than insulin glargine alone with a lower risk of hypoglycemia than insulin dose escalation.

DPP-4 inhibitors: Co-administration with DPP-4 inhibitors is not generally recommended, as both drug classes act on the GLP-1 pathway and meaningful additive benefit has not been demonstrated. Evidence for this specific combination is largely anecdotal or based on small observational series.

Dulaglutide is approved by the U.S. Food and Drug Administration for one or more clinical indications. Refer to the prescribing information for full safety and dosing details.

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Reported side effects: Nausea, diarrhea, injection site reactions

Gastrointestinal adverse effects are the most common class of side effects, occurring in 32-41% of treated patients across the AWARD trials. In the REWIND trial, GI events were reported in 47.4% of the dulaglutide group versus 34.1% in the placebo group. Specific rates from registration trials include nausea (8-29%), diarrhea (up to 13%), vomiting (up to 13%), abdominal pain, and decreased appetite. These effects are most pronounced during the initiation and dose-escalation phases and tend to attenuate over weeks to months of continued therapy.

The FDA label carries a boxed warning for thyroid C-cell tumors. Dulaglutide caused dose-dependent and duration-dependent increases in thyroid C-cell tumors (including medullary thyroid carcinoma, MTC) in rodent studies. Whether dulaglutide causes thyroid C-cell tumors, including MTC, in humans is unknown. Dulaglutide is contraindicated in patients with a personal or family history of MTC and in those with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Additional warnings and precautions: • Acute pancreatitis: cases have been reported; discontinue immediately if pancreatitis is suspected and do not restart if confirmed • Hypoglycemia: clinically significant risk only when combined with insulin or insulin secretagogues such as sulfonylureas; dose reduction of those agents should be considered • Acute kidney injury: reported secondary to volume depletion from severe GI adverse effects; monitor renal function when initiating or escalating in patients at risk • Gastroparesis: not recommended in patients with severe gastroparesis or other severe GI motility disorders • Pulmonary aspiration: delayed gastric emptying may increase aspiration risk during general anesthesia or sedation procedures • Hypersensitivity reactions: serious reactions including anaphylaxis reported post-marketing; monitor for signs and discontinue if reaction occurs

Immunogenicity is low; anti-drug antibodies developed in 1-2.8% of patients in clinical trials, and antibody formation was not associated with altered clinical response or adverse events in most cases.