Dulaglutide (Trulicity): the antibody-fused weekly GLP-1

Dulaglutide solved the once-weekly problem a different way from semaglutide. Instead of a fatty acid that binds albumin, two GLP-1GLP-1A gut hormone released after eating that raises insulin, slows the stomach and reduces appetite; the medicines copy it and last much longer. analogue chains are fused to a modified antibody Fc fragment, which is large enough to circulate for about a week. It is a large protein, filed as a biologic (a BLA rather than an NDA), and it comes in a single-use pen with a hidden needle that made it the easiest injection in the class for years.

Mechanism and receptor profile

The Trulicity label describes dulaglutide as a human GLP-1 receptor agonist with 90% amino-acid sequence homology to endogenous human GLP-1(7-37). It activates the GLP-1 receptor on pancreatic beta cells, raising cyclic AMP and glucose-dependent insulin release, and it lowers glucagon and slows gastric emptyinggastric emptyingHow quickly food leaves the stomach; these medicines slow it, which is part of why people feel full sooner.. GLP-1 receptor only; no GIPGIPA second gut hormone released after eating; tirzepatide activates its receptor as well as the GLP-1 receptor. or glucagon activity.

FDA approvals, with dates

The cardiovascular indication is unusual in the class because REWIND enrolled mostly people without a prior cardiovascular event, so the label wording covers "multiple cardiovascular risk factors" as well as established disease.

Dosing as the label states it

• Adults: 0.75 mg once weekly to start. After 4 weeks, may increase to 1.5 mg. If more glycemic control is needed, increase in 1.5 mg steps after at least 4 weeks on the current dose, to a maximum of 4.5 mg weekly.
• Patients aged 10 to 17: 0.75 mg once weekly; may increase to 1.5 mg after at least 4 weeks. Maximum 1.5 mg.
• Missed dose: take it if at least 3 days (72 hours) remain before the next scheduled dose; otherwise skip.
• Any time of day, with or without food, in the abdomen, thigh or upper arm.

Pivotal trials and their numbers

In REWIND 47.4% of the dulaglutide group reported a gastrointestinal adverse event during follow-up.

Adverse reactions from the label

Show the data7 rows: Trulicity, label Table 1: pooled placebo-controlled trials in adults (placebo n=568; 0.75 mg n=836; 1.5 mg n=834)

Trulicity, label Table 1: pooled placebo-controlled trials in adults (placebo n=568; 0.75 mg n=836; 1.5 mg n=834)

Adverse reaction	Placebo %	0.75 mg %	1.5 mg %
Nausea	5.3	12.4	21.1
Diarrhea	6.7	8.9	12.6
Vomiting	2.3	6.0	12.7
Abdominal pain	4.9	6.5	9.4
Decreased appetite	1.6	4.9	8.6
Dyspepsia	2.3	4.1	5.8
Fatigue	2.6	4.2	5.6

The 3 mg and 4.5 mg doses were added later and have their own tables in the label's section 6.1.

Boxed warning and other warnings

The class boxed warningboxed warningThe FDA's strongest label warning, printed in a box at the top; for these medicines it concerns thyroid C-cell tumours seen in rodents., in the dulaglutide wording: in male and female rats, a dose-related and duration-dependent increase in thyroid C-cellC-cellThyroid cells that make calcitonin; rodent studies of these medicines showed tumours in them, which is why the boxed warning exists. tumors after lifetime exposure; human relevance unknown; contraindicatedcontraindicationA condition listed on the label under which the medicine should not be used. with a personal or family history of medullary thyroid carcinomamedullary thyroid carcinomaA rare thyroid cancer arising from C cells; a personal or family history is a listed contraindication. or MEN 2MEN 2An inherited condition that raises the risk of medullary thyroid cancer; a listed contraindication for these medicines.. Section 5 covers pancreatitispancreatitisInflammation of the pancreas, felt as severe upper-abdominal pain; the labels say to stop the medicine if it is suspected., hypoglycemiahypoglycemiaBlood sugar falling too low; uncommon with these medicines alone but more likely alongside insulin or a sulfonylurea. with insulin or secretagogues, hypersensitivity, acute kidney injury, severe gastrointestinal reactions, retinopathyretinopathyDamage to the blood vessels of the retina from diabetes; a rapid fall in blood sugar can temporarily worsen it. complications, gallbladder disease, and aspirationaspirationFood or fluid entering the airway; a concern under anaesthesia because these medicines slow stomach emptying. under anaesthesia.

Status and manufacturer

Approved and marketed by Eli Lilly, which also makes tirzepatide and orforglipron.

Where next

The other antibody-and-albumin approach to weekly dosing, albiglutide, was discontinued by its manufacturer; reading the two entries together shows why fusion proteins lost to fatty-acid peptides. The comparison table has a preset for the older GLP-1s.