Dulaglutide

Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology. It consists of two identical disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to a modified human IgG4 heavy-chain Fc fragment by a small peptide linker. The Fc-fusion architecture prevents receptor-mediated clearance and markedly extends its half-life, enabling once-weekly dosing.

Mechanism of Action

Dulaglutide activates the GLP-1 receptor, a G-protein-coupled receptor expressed on pancreatic beta cells and other tissues. Receptor binding triggers adenylyl cyclase activation, increasing intracellular cAMP and producing:

• Glucose-dependent insulin secretion when blood glucose is elevated.
• Glucagon suppression in a glucose-dependent manner (counter-regulatory glucagon response to hypoglycemia is preserved).
• Slowed gastric emptying, reducing the rate of postprandial glucose appearance.
• Reduced appetite and food intake, supporting modest weight loss.
• Cardiovascular effects: the REWIND trial demonstrated reduced MACE, providing a cardiovascular benefit independent of glycemic control.

Pharmacokinetics

• Bioavailability: 47% (at 1.5 mg dose) to 65% (at 0.75 mg dose) after subcutaneous administration.
• Tmax: 24–48 hours after subcutaneous injection.
• Volume of distribution: apparent Vd ~3.09 L; apparent population peripheral Vd ~6 L.
• Protein binding: specific binding data not available; degraded by general protein catabolism (not CYP-mediated).
• Metabolism: presumed degradation into component amino acids via general protein catabolism pathways; no specific metabolic enzymes identified.
• Half-life: approximately 5 days (~90–120 hours), enabling once-weekly dosing.
• Clearance: apparent population mean clearance ~0.142 L/h.
• Excretion: degraded to amino acids; elimination expected through normal protein catabolism.
• Steady state: achieved after 2–4 weeks of weekly dosing.

In the AWARD clinical trial program for type 2 diabetes, dulaglutide demonstrated:

• HbA1c reduction: typically 1.1–1.5% from baseline.
• Weight loss: approximately 2–3 kg average.
• Cardiovascular outcomes (REWIND trial): 12% reduction in major adverse cardiovascular events; 24% reduction in non-fatal stroke; reduced composite renal outcome.
• Hypoglycemia: low risk when used without insulin or insulin secretagogues.

Dulaglutide is indicated for the treatment of adults with type 2 diabetes mellitus to improve glycemic control:

• Monotherapy when diet and exercise alone are inadequate, or when metformin is inappropriate.
• Combination therapy with other glucose-lowering medications when these, with diet and exercise, are inadequate.
• Cardiovascular risk reduction in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors.

• Hypersensitivity to dulaglutide or any of the excipients.
• Personal or family history of medullary thyroid carcinoma (MTC).
• Multiple endocrine neoplasia syndrome type 2 (MEN 2).
• Type 1 diabetes mellitus.
• Diabetic ketoacidosis.

Not recommended: severe gastrointestinal disease (including severe gastroparesis), inflammatory bowel disease, severe renal impairment (eGFR <15 mL/min/1.73 m²) or end-stage renal disease, severe hepatic impairment, pregnancy and breastfeeding, patients under 18 years.

Very Common (>10%): nausea, diarrhea, vomiting.

Common (1–10%): decreased appetite, abdominal pain, dyspepsia, constipation, flatulence, abdominal distension, gastroesophageal reflux disease, eructation, fatigue, asthenia, hypoglycemia (with insulin or sulfonylureas), injection site reactions, small increase in heart rate, first-degree AV block (usually asymptomatic), increased lipase and amylase.

Uncommon (<1%): acute pancreatitis, severe hypersensitivity reactions, anaphylaxis, angioedema, dehydration secondary to GI symptoms, acute gallbladder disease.

Gastrointestinal effects are most pronounced during the first weeks and generally decrease over time.

• Oral medications: slowed gastric emptying may affect absorption of co-administered oral drugs requiring rapid GI absorption.
• Insulin and insulin secretagogues: increased hypoglycemia risk; reduce dose when initiating dulaglutide.
• Warfarin: monitor INR when initiating or discontinuing.
• Oral contraceptives: no clinically significant effect.

Do not mix dulaglutide with insulin or other injectable medications.

Dulaglutide is administered once weekly by subcutaneous injection (abdomen, thigh, or upper arm) at any time of day, with or without food. The single-dose pen delivers a fixed dose; no dose selection is required. Do not inject intravenously or intramuscularly.

Dosing Regimen

• Starting dose: 0.75 mg once weekly.
• Maintenance dose: 1.5 mg once weekly (after at least 4 weeks at 0.75 mg, if additional control is needed).
• Higher doses: 3 mg once weekly (after ≥4 weeks at 1.5 mg), then 4.5 mg once weekly (after ≥4 weeks at 3 mg).
• Maximum: 4.5 mg once weekly.

Missed Dose

• If ≤3 days (72 hours) until the next scheduled dose: skip the missed dose and resume on the scheduled day.
• If >3 days until the next dose: administer as soon as possible, then resume the usual weekly schedule.

Do not administer two doses within 3 days of each other.

Use with Other Antidiabetic Medications

• Metformin: continue at current dose.
• Sulfonylurea or insulin: consider reducing the dose to minimize hypoglycemia risk; monitor blood glucose when initiating dulaglutide.
• DPP-4 inhibitors: concurrent use is not routinely recommended.

Pancreatitis Warning

Discontinue promptly if pancreatitis is suspected (persistent severe abdominal pain, sometimes radiating to the back, with possible vomiting). Do not restart if pancreatitis is confirmed.

Thyroid C-Cell Tumors

In animal studies, dulaglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors. Counsel patients on symptoms (neck mass, hoarseness, dysphagia, dyspnea). Routine serum calcitonin monitoring is of uncertain value.

Hypoglycemia

Dulaglutide alone does not cause hypoglycemia due to its glucose-dependent mechanism. Risk increases with concomitant insulin or sulfonylureas. Educate patients on recognition and treatment.

Renal Impairment

Use with caution. Gastrointestinal side effects may cause dehydration, acute kidney injury, or worsening of chronic renal failure. Ensure adequate hydration. Dose adjustment is not required, but monitor renal function.

Diabetic Retinopathy

Rapid glucose improvement may transiently worsen diabetic retinopathy. Monitor patients with a history of retinopathy.

Acute Gallbladder Disease

GLP-1 receptor agonists may increase the risk of cholelithiasis and cholecystitis. Inform patients about symptoms (right upper abdominal pain, nausea/vomiting, fever, jaundice).

Heart Rate

May cause small increases in heart rate (average 2–4 beats/min). Monitor at regular intervals.

Pregnancy and Lactation

Discontinue if pregnancy occurs or is planned. Limited data in pregnancy. Excretion in breast milk is not established; not recommended during breastfeeding.

Pediatric Use

Safety and efficacy are not established in patients under 18 years.

Effect on Driving

Unlikely to affect ability to drive. Patients on concomitant insulin or sulfonylureas should be aware of hypoglycemia risk.

Unopened pens: store in a refrigerator at 2–8°C, in the original carton. Do not freeze. Protect from light.

Room temperature storage: may be stored at room temperature (not exceeding 30°C) for up to 14 days. Discard if not used within 14 days.

After cap removal: use immediately. The single-use pen should be discarded after use.

Do not use if the solution is cloudy, discolored, or contains particles. Solution should be clear and colorless.

24 months when stored properly. Do not use after the expiry date.

Prescription required.