GLP-1 agonist · type 2 diabetes
Dulaglutide is a long-acting GLP-1 receptor agonist used to treat type 2 diabetes. It is a large fusion protein: two identical chains, each joining a modified GLP-1 sequence to the Fc portion of a human antibody, which keeps it in the body far longer than the natural hormone. It is injected under the skin and marketed as Trulicity.
GLP-1 is a gut hormone released after meals. Dulaglutide's GLP-1 portion, about 90% identical to the natural hormone, activates GLP-1 receptors on pancreatic beta cells, raising cyclic AMP and increasing insulin release in a glucose-dependent way, so the push on insulin fades as blood sugar falls. It also lowers glucagon and slows stomach emptying. Natural GLP-1 is quickly cut by the enzyme DPP-4; dulaglutide carries changes at that cutting site, and its fusion to a modified IgG4 Fc segment makes a molecule of about 63 kilodaltons with a much longer life in the body. Other changes were made to reduce immune recognition and Fc-receptor binding.
Dulaglutide's evidence comes from large human trials. In AWARD-1, adults with type 2 diabetes already taking metformin and pioglitazone lowered HbA1c more with dulaglutide than with placebo or exenatide over 26 weeks, with nausea, vomiting and diarrhea as the main side effects1.
In REWIND, 9,901 people aged 50 or older with type 2 diabetes and either prior cardiovascular disease or risk factors were followed for a median 5.4 years: heart attack, stroke or cardiovascular death occurred in 12.0% on dulaglutide versus 13.4% on placebo (hazard ratio 0.88), all-cause death did not differ significantly, and gastrointestinal side effects were more common (47% vs 34%)2.
In a 26-week trial of 154 youths aged 10 to 17, HbA1c fell on dulaglutide and rose on placebo3. These trials underpin the label's indications4.
The FDA approved dulaglutide as Trulicity in 2014. Its label indications are, as an adjunct to diet and exercise, improving glycemic control in adults and in children aged 10 and older with type 2 diabetes, and reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors4.
The label carries a boxed warning: dulaglutide caused thyroid C-cell tumors in rats, and it is contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2. The most common reactions are nausea, diarrhea, vomiting, abdominal pain and decreased appetite. Warnings cover pancreatitis, low blood sugar when combined with insulin or insulin secretagogues, serious allergic reactions, kidney injury from fluid loss, severe gastrointestinal reactions, diabetic retinopathy complications, gallbladder disease, and aspiration during anesthesia or deep sedation.
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