Dulaglutide

Structure

Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. It is a fusion protein produced using mammalian cell culture and consisting of two identical disulphide linked chains, each with an N-terminal GLP-1 analog sequence that is covalently linked by a peptide linker to the Fc component of a modified human immunoglobulin G4 heavy chain (IgG4 Fc). Fusion to this large carrier moiety slows its clearance from the body[2].

Description

Dulaglutide, a GLP-1 receptor agonist that is administered subcutaneously once weekly, has been approved since 2014 for the treatment of adults with type 2 diabetes. 

Indications

Dulaglutide is used together with diet and exercise to help control your blood sugar. This medicine also lowers the risk of death, heart attack, or stroke in patients with diabetes and heart or blood vessel problems.

brand name

Dulaglutide is marketed by Eli Lilly as Trulicity.

Mechanism of action

The dulaglutide mechanism of action involves activation of the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in b cells. Thus, it increases intracellular cyclic AMP in these cells, leading to a glucose-dependent release of insulin. Dulaglutide also reduces secretion of glucagon and slows gastric emptying.

Side effects

The most common side effects of Dulaglutide are gastrointestinal issues such as indigestion, decreased appetite, nausea, vomiting, abdominal pain, and diarrhea. Some patients may also experience more serious adverse reactions including acute pancreatitis (characterized by severe and persistent abdominal pain that may spread to the back and accompanied by vomiting), low blood sugar levels (hypoglycemia), and kidney problems that may require hemodialysis. The risk of hypoglycemia is higher when the drug is used in combination with sulfonylureas or insulin. Additionally, there is a potential risk of developing medullary thyroid carcinoma associated with the use of this medication.

Mode of action

The mechanism of action of dulaglutide is as a Glucagon-like Peptide-1 (GLP-1) Agonist. Structurally, dulaglutide is made by replacing Ala with Gly at position 8, Glu with Gly at position 22, and Arg with Gly at position 36 on the GLP-1 (7-37) chain, with an average biological half-life of up to 90h.

Clinical claims and research

Dulaglutide is a once-weekly GLP-1R agonist approved for the treatment of T2DM in 2014. This drug is an incretin-related drugs. It is a recombinant DNA-produced polypeptide analog of GLP-1(7-37) that is covalently linked to each Fc arm of human immunoglobulin G4 (IgG4). The structure of dulaglutide confers improved solubility, reduced immunogenicity, and reduced rate of renal clearance. The peptide can be used either as a stand-alone therapy or in combination with other medicines for T2DM, in particular metformin and insulin. Dulaglutide has been studied in comparison with other anti-diabetic drugs in multiple trials. In the AWARD-6 trial, once-weekly 1.5 mg dulaglutide showed a comparable efficacy to daily 1.8 mg liraglutide in reducing HbA1c levels, but was less efficacious than liraglutide with respect to weight loss[1].

References

[1] Lear S, et al. Chemical and Synthetic Biology Approaches To Understand Cellular Functions. Methods in Enzymology, 2019; 622: 183-200.
[2] Sanford, Mark. “Dulaglutide: first global approval.” Drugs 74 17 (2014): 2097–103.
[3] Espen Jimenez-Solem. “Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes.” Current Opinion in Molecular Therapeutics 12 6 (2010): 790–7.