Insulin glargine explained

Verifiedfields:changed
Verifiedrevid:458271727
Tradename:Lantus, Toujeo, Basaglar, others
Dailymedid:Insulin_glargine
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Routes Of Administration:Subcutaneous
Atc Prefix:A10
Atc Suffix:AE04
Biosimilars:insulin glargine-aglr, insulin glargine-yfgn, Rezvoglar, Abasaglar, Semglee
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[2]
Legal Uk:POM
Legal Uk Comment:[3]
Legal Us:Rx-only
Legal Us Comment:[4]
Legal Eu:Rx-only
Legal Eu Comment:[5] [6]
Legal Status:Rx-only
Onset:~1 hours
Duration Of Action:24 to 36 hours
Cas Number:160337-95-1
Iuphar Ligand:7572
Drugbank:DB00047
Chemspiderid:none
Unii:2ZM8CX04RZ
Kegg:D03250
Iupac Name:Recombinant human insulin
C:267
H:404
N:72
O:78
S:6

Insulin glargine sold under the brand name Lantus among others is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is injected just under the skin. Effects generally begin an hour after use.

Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain. Other serious side effects include low blood potassium. NPH insulin rather than insulin glargine is generally preferred in pregnancy.[7] After injection, microcrystals slowly release insulin for about 24 hours. This insulin causes body tissues to absorb glucose from the blood and decreases glucose production by the liver.

Insulin glargine was approved for medical use in the United States in 2000.[8] It is on the World Health Organization's List of Essential Medicines.[9] In 2021, it was the 29th most commonly prescribed medication in the United States with more than 19million prescriptions.[10] [11] In July 2021, the US Food and Drug Administration (FDA) approved an interchangeable biosimilar insulin product called Semglee (insulin glargine-yfgn) for the treatment of diabetes.

Medical uses

The long-acting insulin class, which includes insulin glargine, do not appear much better than neutral protamine Hagedorn (NPH) insulin,[12] but do have a greater cost, making them, as of 2010, not cost effective for the treatment of type 2 diabetes.[13] In a previous review it was unclear if there is a difference in hypoglycemia, as there was not enough data to determine any differences with respect to long term outcomes,[14] however a more recent Cochrane systematic review did not find clinically significant difference when comparing insulin glargine to NPH insulin, insulin detemir or insulin degludec in the management of type I Diabetes in neither adults or children in periods of 6 months or longer. It is not typically the recommended long acting insulin in the United Kingdom.[7]

Semglee is indicated to improve glycemic control in adults and children with Type 1 diabetes and in adults with Type 2 diabetes. Semglee is both biosimilar to, and interchangeable with (can be substituted for), its reference product Lantus (insulin glargine), a long-acting insulin analog.

Mixing with other insulins

Unlike some other longer-acting insulins, glargine must not be diluted or mixed with other insulin or solution in the same syringe.[15] However, this restriction has been questioned.[16]

Adverse effects

Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain.[8] Serious side effects include low blood potassium.[8]

As of 2012, tentative evidence shows no association between insulin glargine and cancer.[17] Previous studies had raised concerns.[18]

When comparing insulin glargine to NPH insulin, insulin detemir or insulin degludec, no significant adverse effects were found in the management of type I Diabetes in neither adults or children in periods of 6 months or longer.

Pharmacology

Mechanism of action

Insulin glargine differs from human insulin by replacing asparagine with glycine in position 21 of the A-chain and by carboxy-terminal extension of B-chain by 2 arginine residues. The arginine amino acids shift the isoelectric point from a pH of 5.4 to 6.7, making the molecule more soluble at an acidic pH and less soluble at physiological pH. The isoelectric shift also allows for the subcutaneous injection of a clear solution. The glycine substitution prevents deamidation of the acid-sensitive asparagine at acidic pH. In the neutral subcutaneous space, higher-order aggregates form, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection.[19] It can achieve a peakless level for at least 24 hours.

Acceptance and repartition in the body

Insulin glargine is formulated at an acidic pH 4, where it is completely water-soluble. After subcutaneous injection of the acidic solute (which can cause discomfort and a stinging sensation), when a physiologic pH (approximately 7.4) is achieved the increase in pH causes the insulin to come out of solution resulting in the formation of higher order aggregates of insulin hexamers. The higher order aggregation slows the dissociation of the hexamers into insulin monomers, the functional and physiologically active unit of insulin. This gradual process ensures that small amounts of insulin glargine are released into the body continuously, giving an almost peakless profile.

History

On 9 June 2000, the European Commission formally approved the launching of Lantus by Sanofi-Aventis Germany Ltd. in the entire European Union.[20] The admission was prolonged on 9 June 2005.[21]

A three-fold more concentrated formulation, brand name Toujeo, was introduced after FDA approval in 2015.[22] [23]

Legal status

Biosimilars

Abasaglar was approved for medical use in the European Union in September 2014.[24] [25]

Lusduna was approved for medical use in the European Union in January 2017.[26]

In March 2018, insulin glargine (Semglee) was approved for medical use in the European Union.[27]

In July 2021, insulin glargine-yfgn (Semglee) was approved for medical use in the United States as the first interchangeable biosimilar of Lantus.[28] The FDA granted approval of Semglee to Mylan Pharmaceuticals Inc.

Patent expiry

Patent protection for insulin glargine expired in most countries in 2015 and in the U.S.A. is expected to expire on 2027-07-05.[29] Insulin glargine from competitor Eli Lilly became available in most countries during 2015, under the brand names Basaglar (as a follow-on in the US) and Abasaglar (as a biosimilar in the EU).

Notes and References

  1. Web site: Insulin glargine Use During Pregnancy . Drugs.com . 6 April 2020 . 4 September 2020 . 21 October 2020 . https://web.archive.org/web/20201021163744/https://www.drugs.com/pregnancy/insulin-glargine.html . live .
  2. Web site: Summary Basis of Decision - Semglee . Health Canada . 23 August 2022 . 29 September 2022 . 29 September 2022 . https://web.archive.org/web/20220929045655/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00600&lang=en . live .
  3. Web site: Lantus 100 units/ml solution for injection in a cartridge - Summary of Product Characteristics (SmPC) . (emc) . 7 May 2020 . 9 January 2021 . https://web.archive.org/web/20210109065757/https://www.medicines.org.uk/emc/product/2376/smpc . live .
  4. Web site: Lantus- insulin glargine injection, solution Lantus SoloStar- insulin glargine injection, solution . DailyMed . 29 July 2021 . 29 July 2021 . https://web.archive.org/web/20210729050000/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5e07a0c-7e14-4756-9152-9fea485d654a . live .
  5. Web site: Lantus EPAR . European Medicines Agency (EMA) . 17 September 2018 . 28 July 2021 . 4 August 2020 . https://web.archive.org/web/20200804155233/https://www.ema.europa.eu/en/medicines/human/EPAR/lantus . live .
  6. Web site: Toujeo EPAR . European Medicines Agency (EMA) . 17 September 2018 . 28 July 2021 . 29 July 2021 . https://web.archive.org/web/20210729050012/https://www.ema.europa.eu/en/medicines/human/EPAR/toujeo-previously-optisulin . live .
  7. Book: British national formulary: BNF 76 . 2018 . Pharmaceutical Press . 9780857113382. 701. 76th.
  8. Web site: Insulin Glargine Monograph for Professionals . Drugs.com . AHFS . 23 December 2018 . 5 December 2020 . https://web.archive.org/web/20201205095655/https://www.drugs.com/monograph/insulin-glargine.html . live .
  9. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  10. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  11. Web site: Insulin Glargine - Drug Usage Statistics . ClinCalc . 14 January 2024 .
  12. Hemmingsen B, Metzendorf MI, Richter B . (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus . The Cochrane Database of Systematic Reviews . 3 . 4 . CD013498 . March 2021 . 33662147 . 8094220 . 10.1002/14651858.cd013498.pub2 .
  13. Waugh N, Cummins E, Royle P, Clar C, Marien M, Richter B, Philip S . Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation . Health Technology Assessment . 14 . 36 . 1–248 . July 2010 . 20646668 . 10.3310/hta14360 . free .
  14. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H . Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis . CMAJ . 180 . 4 . 385–397 . February 2009 . 19221352 . 2638025 . 10.1503/cmaj.081041 .
  15. American Diabetes Association . Insulin administration . Diabetes Care . 26 . Suppl. 1 . S121–S124 . January 2003 . 12502637 . 10.2337/diacare.26.2007.S121 . free .
  16. Kaplan W, Rodriguez LM, Smith OE, Haymond MW, Heptulla RA . Effects of mixing glargine and short-acting insulin analogs on glucose control . Diabetes Care . 27 . 11 . 2739–2740 . November 2004 . 15505016 . 10.2337/diacare.27.11.2739 . free .
  17. Tang X, Yang L, He Z, Liu J . Insulin glargine and cancer risk in patients with diabetes: a meta-analysis . PLOS ONE . 7 . 12 . e51814 . 2012 . 23284776 . 3526637 . 10.1371/journal.pone.0051814 . free . 2012PLoSO...751814T .
  18. Rendell M, Akturk HK, Tella SH . Glargine safety, diabetes and cancer . Expert Opinion on Drug Safety . 12 . 2 . 247–263 . March 2013 . 23394441 . 10.1517/14740338.2013.770469 . 9224923 .
  19. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA . Insulin analogues and their potential in the management of diabetes mellitus . Diabetologia . 42 . 10 . 1151–1167 . October 1999 . 10525654 . 10.1007/s001250051286 . free .
  20. Web site: Lantus EPAR . European Medicines Agency (EMA) . 17 September 2018 . 7 May 2020 . 4 August 2020 . https://web.archive.org/web/20200804155233/https://www.ema.europa.eu/en/medicines/human/EPAR/lantus . live .
  21. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/061500de1.pdf EPAR Lantus
  22. Sanofi Receives FDA Approval of Once-Daily Basal Insulin Toujeo. Sanofi. 25 February 2015. live. https://web.archive.org/web/20150227175634/http://www.news.sanofi.us/2015-02-25-Sanofi-Receives-FDA-Approval-of-Once-Daily-Basal-Insulin-Toujeo. 27 February 2015.
  23. Web site: Toujeo: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 7 May 2020 . 14 August 2020 . https://web.archive.org/web/20200814020233/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206538 . live .
  24. Web site: Abasaglar EPAR . European Medicines Agency (EMA) . 17 September 2018 . 28 July 2021 . 2 April 2022 . https://web.archive.org/web/20220402171234/https://www.ema.europa.eu/en/medicines/human/EPAR/abasaglar-previously-abasria#authorisation-details-section . live .
  25. Web site: Abasaglar Product information . Union Register of medicinal products . 11 September 2014 . 1 October 2023.
  26. Web site: Lusduna EPAR . European Medicines Agency (EMA) . 17 September 2018 . 28 July 2021 . 29 July 2021 . https://web.archive.org/web/20210729050001/https://www.ema.europa.eu/en/medicines/human/EPAR/lusduna . live .
  27. Web site: Semglee EPAR . European Medicines Agency (EMA) . 17 September 2018 . 28 July 2021 . 15 February 2022 . https://web.archive.org/web/20220215172501/https://www.ema.europa.eu/en/medicines/human/EPAR/semglee . live .
  28. FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes . U.S. Food and Drug Administration (FDA) . 28 July 2021 . 28 July 2021 . 28 August 2021 . https://web.archive.org/web/20210828201228/https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes . live .
  29. Web site: Amidated insulin glargine. 17 August 2020. 29 September 2022. https://web.archive.org/web/20220929045656/https://patents.google.com/patent/US8048854B2/en%3C/. live.

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