Dulaglutide

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Dulaglutide
Autoinjector with Trulicity by Lilly (Dulaglutid)-3129.jpg
Clinical data
Trade names Trulicity, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a614047
License data
Pregnancy
category
Routes of
administration 		Subcutaneous
Drug class Incretin mimetics
ATC code
Legal status
Legal status
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C2646H4044N704O836S18
Molar mass 59670.63 g·mol−1

Dulaglutide, sold under the brand name Trulicity among others, [5] is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. [6] [7] 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. [8] It is a once-weekly injection.

Contents

The most common side effects are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite. [5]

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. [5] [9] It was approved for use in the European Union in November 2014. [10] In 2021, it was the 70th most commonly prescribed medication in the United States, with more than 9 million prescriptions. [11] [12]

Medical uses

The compound is indicated for adults with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes 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 cells 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. [13]

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. [9]

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. [14]

Side effects

The most common side effects include gastrointestinal disorders, such as dyspepsia, decreased appetite, nausea, vomiting, abdominal pain, diarrhea. [15] 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. [16] [17] There is also a potential risk of medullary thyroid carcinoma associated with the use of the drug. [18]

Contraindications

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

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. [19] [5]

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. [20]

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). [5]

The U.S. Food and Drug Administration (FDA) approved dulaglutide with a Risk Evaluation and Mitigation Strategy (REMS), [5] and granted the approval of Trulicity to Eli Lilly and Company. [5] 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. [18]

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. [21]

Related Research Articles

Drugs used in diabetes treat diabetes mellitus by decreasing the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Sitagliptin</span> Diabetes medication

Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also available in the fixed-dose combination medication sitagliptin/metformin.

<span class="mw-page-title-main">Saxagliptin</span> Chemical compound

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

<span class="mw-page-title-main">Empagliflozin/linagliptin</span> Pharmaceutical drug

Empagliflozin/linagliptin, sold under the brand name Glyxambi, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes. It is a combination of empagliflozin and linagliptin. It is taken by mouth.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

Insulin glargine/lixisenatide, sold under the brand name Soliqua 100/33 among others, is a fixed-dose combination medication that combines insulin glargine and lixisenatide and is used to treat diabetes.

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic medication

Tirzepatide, sold under the brand names Mounjaro and Zepbound, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

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. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  4. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  5. 1 2 3 4 5 6 7 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. ↑ 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 Review of Endocrinology & Metabolism. 8 (3): 247–259. doi:10.1586/eem.13.20. PMID   30780817. S2CID   73313508.
  7. ↑ "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.
  8. ↑ "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.
  9. 1 2 "Drug Approval Package: Trulicity (dulaglutide) NDA #125469". U.S. Food and Drug Administration (FDA). 27 October 2014. Retrieved 4 February 2020.
  10. ↑ "Trulicity EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 23 February 2020.
  11. ↑ "The Top 300 of 2021". ClinCalc. Retrieved 14 January 2024.
  12. ↑ "Dulaglutide – Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  13. ↑ Terauchi Y, Satoi Y, Takeuchi M, Imaoka T (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". Endocrine Journal. 61 (10): 949–959. doi: 10.1507/endocrj.ej14-0147 . PMID   25029955.
  14. ↑ Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, et al. (June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ. 357: j2499. doi:10.1136/bmj.j2499. PMC   5463186 . PMID   28596247.
  15. ↑ Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z (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): 2149–2158. doi:10.2337/dc13-2761. PMC   4113177 . PMID   24742660.
  16. ↑ Amblee A (April 2014). "Dulaglutide for the treatment of type 2 diabetes". Drugs of Today. 50 (4): 277–289. doi:10.1358/dot.2014.50.4.2132740. PMID   24918645.
  17. ↑ Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E (February 2014). "Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials". Diabetes Research and Clinical Practice. 103 (2): 269–275. doi:10.1016/j.diabres.2014.01.010. PMID   24485345. S2CID   33922845.
  18. 1 2 "Risk Evaluation and Mitigation Strategy (REMS)". United States Food and Drug Administration. September 2014. Retrieved 24 March 2020.
  19. ↑ Samson SL, Garber A (April 2013). "GLP-1R agonist therapy for diabetes: benefits and potential risks". Current Opinion in Endocrinology, Diabetes, and Obesity. 20 (2): 87–97. doi:10.1097/MED.0b013e32835edb32. PMID   23403741. S2CID   6933973.
  20. ↑ Nadkarni P, Chepurny OG, Holz GG (2014). "Regulation of glucose homeostasis by GLP-1". Progress in Molecular Biology and Translational Science. 121: 23–65. doi:10.1016/B978-0-12-800101-1.00002-8. ISBN   978-0-12-800101-1. PMC   4159612 . PMID   24373234.
  21. ↑ Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, et al. (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. PMC   7896253 . PMID   33397768.

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