Dulaglutide

Dulaglutide, sold under the brand name Trulicity among others,[3] is a medication used for the treatment of type 2 diabetes in combination with diet and exercise.[4][5] It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors.[6] It is a once-weekly injection.

Dulaglutide
Clinical data
Trade namesTrulicity, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa614047
License data
Pregnancy
category
Routes of
administration		Subcutaneous
Drug classIncretin mimetics
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC2646H4044N704O836S18
Molar mass59670.63 g·mol−1

The most common side effects are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.[3]

It is a glucagon-like peptide-1 receptor agonist (GLP-1 agonist) consisting of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4. GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia). The Food and Drug Administration (FDA) approved dulaglutide for use in the United States in September 2014.[3][7] It was approved for use in the European Union in November 2014.[8] In 2020, it was the 96th most commonly prescribed medication in the United States, with more than 7 million prescriptions.[9][10]

Medical uses

The compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis because these problems are the result of the islet cells being unable to produce insulin and one of the actions of dulaglutide is to stimulate functioning islet cell to produce more insulin. Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.[11]

The medication's phase 3 clinical trial program demonstrated reductions in hemoglobin A1c of approximately 1% with the 0.75 mg and 1.5 mg doses of the medication, along with approximately 5 pounds of weight loss on average. The higher 3.0 mg and 4.5 mg doses that were approved in 2020 demonstrated hemoglobin A1c reductions closer to 1.5% and slightly more weight loss.[7]

A 2017 meta-analysis did not support the suggestion that treatment with GLP-1 agonists or DPP-4 inhibitors increased all-cause mortality in type 2 diabetics.[12]

Side effects

The most common side effects include gastrointestinal disorders, such as dyspepsia, decreased appetite, nausea, vomiting, abdominal pain, diarrhea.[13] Some patients may experience serious adverse reactions: acute pancreatitis (symptoms include persistent severe abdominal pain, sometimes radiating to the back and accompanied by vomiting), hypoglycemia, renal impairment (which may sometimes require hemodialysis). The risk of hypoglycemia is increased if the drug is used in combination with sulfonylureas or insulin.[14][15] There is also a potential risk of medullary thyroid carcinoma associated with the use of the drug.[16]

Contraindications

The compound is contraindicated in subjects with hypersensitivity to the active ingredient or any of the product's components.

People with a personal or family history of medullary thyroid cancer (MTC) or affected by multiple endocrine neoplasia type 2 should not take dulaglutide, because it could increase the risk of these cancers.[17][3]

Mechanism of action

Dulaglutide binds to glucagon-like peptide 1 receptors, slowing gastric emptying and increases insulin secretion by pancreatic Beta cells. Simultaneously the compound reduces the elevated glucagon secretion by inhibiting alpha cells of the pancreas, as glucagon is known to be inappropriately elevated in diabetic patients. GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.[18]

History

The safety and effectiveness of dulaglutide were evaluated in six clinical trials in which 3,342 subjects with type 2 diabetes received dulaglutide. Subjects receiving dulaglutide had an improvement in their blood sugar control as observed with reductions in HbA1c level (hemoglobin A1c is a measure of blood sugar control).[3]

The U.S. Food and Drug Administration (FDA) approved dulaglutide with a Risk Evaluation and Mitigation Strategy (REMS),[3] and granted the approval of Trulicity to Eli Lilly and Company.[3] The REMS consists of a number of steps that Eli Lilly will take to make physicians aware of the risk of pancreatitis and the potential risk of medullary thyroid carcinoma associated with the drug.[16]

In 2020, the FDA approved two higher doses of the medication, 3.0 mg and 4.5 mg, based on results of the AWARD-11 trial demonstrating improved glucose lowering and weight benefits.[19]

References
  1. "Dulaglutide international". Drugs.com. 3 January 2020. Retrieved 4 February 2020.
  2. "Dulaglutide (Trulicity) Use During Pregnancy". Drugs.com. 15 July 2019. Retrieved 4 February 2020.
  3. "FDA approves Trulicity to treat type 2 diabetes" (Press release). U.S. Food and Drug Administration (FDA). 18 September 2014. Archived from the original on 20 April 2016. Retrieved 4 February 2020. This article incorporates text from this source, which is in the public domain.
  4. Tibble CA, Cavaiola TS, Henry RR (May 2013). "Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes: A Review of Current Literature". Expert Rev Endocrinol Metab. 8 (3): 247–59. doi:10.1586/eem.13.20. PMID 30780817. S2CID 73313508.
  5. "Lilly's Once-Weekly Dulaglutide Shows Non-Inferiority to Liraglutide in Head-to-Head Phase III Trial for Type 2 Diabetes" (Press release). Eli Lilly. 25 February 2014.
  6. "Trulicity (dulaglutide) is the first and only type 2 diabetes medicine approved to reduce cardiovascular events in adults with and without established cardiovascular disease". Eli Lilly and Company (Press release). 21 February 2020. Retrieved 23 February 2020.
  7. "Drug Approval Package: Trulicity (dulaglutide) NDA #125469". U.S. Food and Drug Administration (FDA). 27 October 2014. Retrieved 4 February 2020.
  8. "Trulicity EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 23 February 2020.
  9. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  10. "Dulaglutide – Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  11. Terauchi Y, Satoi Y, Takeuchi M, et al. (July 2014). "Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study". Endocr. J. 61 (10): 949–59. doi:10.1507/endocrj.ej14-0147. PMID 25029955.
  12. Liu J, Li L, Deng K, et al. (June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ (Clinical Research Ed.). 357: j2499. doi:10.1136/bmj.j2499. PMC 5463186. PMID 28596247.
  13. Nauck M, Weinstock RS, Umpierrez GE, et al. (August 2014). "Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5)". Diabetes Care. 37 (8): 2149–58. doi:10.2337/dc13-2761. PMC 4113177. PMID 24742660. Retrieved 1 March 2015.
  14. Amblee A (April 2014). "Dulaglutide for the treatment of type 2 diabetes". Drugs Today. 50 (4): 277–89. doi:10.1358/dot.2014.50.4.2132740. PMID 24918645.
  15. Monami M, Dicembrini I, Nardini C, et al. (February 2014). "Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials". Diabetes Res. Clin. Pract. 103 (2): 269–75. doi:10.1016/j.diabres.2014.01.010. PMID 24485345. S2CID 33922845.
  16. "Risk Evaluation and Mitigation Strategy (REMS)". United States Food and Drug Administration. September 2014. Retrieved 24 March 2020.
  17. Samson SL, Garber A (April 2013). "GLP-1R agonist therapy for diabetes: benefits and potential risks". Curr Opin Endocrinol Diabetes Obes. 20 (2): 87–97. doi:10.1097/MED.0b013e32835edb32. PMID 23403741. S2CID 6933973.
  18. Nadkarni P, Chepurny OG, Holz GG (2014). "Regulation of glucose homeostasis by GLP-1". Glucose Homeostatis and the Pathogenesis of Diabetes Mellitus. Prog Mol Biol Transl Sci. Progress in Molecular Biology and Translational Science. Vol. 121. pp. 23–65. doi:10.1016/B978-0-12-800101-1.00002-8. ISBN 9780128001011. PMC 4159612. PMID 24373234.
  19. Frias, Juan P.; Bonora, Enzo; Nevarez Ruiz, Luis; Li, Ying G.; Yu, Zhuoxin; Milicevic, Zvonko; Malik, Raleigh; Bethel, M. Angelyn; Cox, David A. (March 2021). "Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)". Diabetes Care. 44 (3): 765–773. doi:10.2337/dc20-1473. ISSN 1935-5548. PMC 7896253. PMID 33397768.

Further reading
  • "Dulaglutide". Drug Information Portal. U.S. National Library of Medicine.
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