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Insulin glargine

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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.[7] It is injected just under the skin.[7] Effects generally begin an hour after use.[7]

Insulin glargine
Toujeo branded insulin glargine
Clinical data
Trade namesLantus, Toujeo, Basaglar, others
Biosimilarsinsulin glargine-aglr, insulin glargine-yfgn, Rezvoglar, Abasaglar, Semglee
AHFS/Drugs.comMonograph
MedlinePlusa600027
License data
Pregnancy
category
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Onset of action~1 hour[7]
Duration of action24–36 hours[7]
Identifiers
  • Recombinant human insulin
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.241.126 Edit this at Wikidata
Chemical and physical data
FormulaC267H404N72O78S6
Molar mass6062.96 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain.[7] Other serious side effects include low blood potassium.[7] NPH insulin rather than insulin glargine is generally preferred in pregnancy.[8] After injection, microcrystals slowly release insulin for about 24 hours.[7] This insulin causes body tissues to absorb glucose from the blood and decreases glucose production by the liver.[7]

Insulin glargine was approved for medical use in the United States in 2000.[7] It is on the World Health Organization's List of Essential Medicines.[9] In 2022, it was the 28th most commonly prescribed medication in the United States, with more than 18 million 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.[12]

Medical uses

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The long-acting insulin class, which includes insulin glargine, do not appear much better than neutral protamine Hagedorn (NPH) insulin,[13] but do have a greater cost, making them, as of 2010, not cost effective for the treatment of type 2 diabetes.[14] 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,[15] 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.[13] It is not typically the recommended long acting insulin in the United Kingdom.[8]

Semglee is indicated to improve glycemic control in adults and children with Type 1 diabetes and in adults with Type 2 diabetes.[12] Semglee is both biosimilar to, and interchangeable with (can be substituted for), its reference product Lantus (insulin glargine), a long-acting insulin analog.[12]

Mixing with other insulins

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Unlike some other longer-acting insulins, glargine must not be diluted or mixed with other insulin or solution in the same syringe.[16] However, this restriction has been questioned.[17]

Adverse effects

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Common side effects include low blood sugar, problems at the site of injection, itchiness, and weight gain.[7] Serious side effects include low blood potassium.[7]

As of 2012, tentative evidence shows no association between insulin glargine and cancer.[18] Previous studies had raised concerns.[19]

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.[13]

Pharmacology

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Mechanism of action

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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.[20] It can achieve a peakless level for at least 24 hours.

Acceptance and repartition in the body

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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

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On 9 June 2000, the European Commission formally approved the launching of Lantus by Sanofi-Aventis Germany Ltd. in the entire European Union.[21] The admission was prolonged on 9 June 2005.[22]

A three-fold more concentrated formulation, brand name Toujeo, was introduced after FDA approval in 2015.[23][24]

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Biosimilars

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Abasaglar was approved for medical use in the European Union in September 2014.[25][26]

Lusduna was approved for medical use in the European Union in January 2017.[27]

In March 2018, insulin glargine (Semglee) was approved for medical use in the European Union.[28]

In July 2021, insulin glargine-yfgn (Semglee) was approved for medical use in the United States as the first interchangeable biosimilar of Lantus.[12] The FDA granted approval of Semglee to Mylan Pharmaceuticals Inc.[12]

Patent expiry

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Patent protection for insulin glargine expired in most countries in 2015[citation needed] 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).[citation needed]

References

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  1. ^ "Insulin glargine Use During Pregnancy". Drugs.com. 6 April 2020. Archived from the original on 21 October 2020. Retrieved 4 September 2020.
  2. ^ "Summary Basis of Decision - Semglee". Health Canada. 23 August 2022. Archived from the original on 29 September 2022. Retrieved 29 September 2022.
  3. ^ "Lantus 100 units/ml solution for injection in a cartridge - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 9 January 2021. Retrieved 7 May 2020.
  4. ^ "Lantus- insulin glargine injection, solution Lantus SoloStar- insulin glargine injection, solution". DailyMed. Archived from the original on 29 July 2021. Retrieved 29 July 2021.
  5. ^ "Lantus EPAR". European Medicines Agency (EMA). 8 May 2009. Archived from the original on 4 August 2020. Retrieved 28 July 2021.
  6. ^ "Toujeo EPAR". European Medicines Agency (EMA). 11 May 2009. Archived from the original on 29 July 2021. Retrieved 28 July 2021.
  7. ^ a b c d e f g h i j k l "Insulin Glargine Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 5 December 2020. Retrieved 23 December 2018.
  8. ^ a b British national formulary: BNF 76 (76th ed.). Pharmaceutical Press. 2018. p. 701. ISBN 9780857113382.
  9. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  10. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  11. ^ "Insulin Glargine Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  12. ^ a b c d e "FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes". U.S. Food and Drug Administration (FDA) (Press release). 28 July 2021. Archived from the original on 28 August 2021. Retrieved 28 July 2021.   This article incorporates text from this source, which is in the public domain.
  13. ^ a b c Hemmingsen B, Metzendorf MI, Richter B (March 2021). "(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus". The Cochrane Database of Systematic Reviews. 3 (4): CD013498. doi:10.1002/14651858.cd013498.pub2. PMC 8094220. PMID 33662147.
  14. ^ Waugh N, Cummins E, Royle P, Clar C, Marien M, Richter B, et al. (July 2010). "Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation". Health Technology Assessment. 14 (36): 1–248. doi:10.3310/hta14360. PMID 20646668.
  15. ^ Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H (February 2009). "Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis". CMAJ. 180 (4): 385–397. doi:10.1503/cmaj.081041. PMC 2638025. PMID 19221352.
  16. ^ American Diabetes Association (January 2003). "Insulin administration". Diabetes Care. 26 (Suppl. 1): S121–S124. doi:10.2337/diacare.26.2007.S121. PMID 12502637.
  17. ^ Kaplan W, Rodriguez LM, Smith OE, Haymond MW, Heptulla RA (November 2004). "Effects of mixing glargine and short-acting insulin analogs on glucose control". Diabetes Care. 27 (11): 2739–2740. doi:10.2337/diacare.27.11.2739. PMID 15505016.
  18. ^ Tang X, Yang L, He Z, Liu J (2012). "Insulin glargine and cancer risk in patients with diabetes: a meta-analysis". PLOS ONE. 7 (12): e51814. Bibcode:2012PLoSO...751814T. doi:10.1371/journal.pone.0051814. PMC 3526637. PMID 23284776.
  19. ^ Rendell M, Akturk HK, Tella SH (March 2013). "Glargine safety, diabetes and cancer". Expert Opinion on Drug Safety. 12 (2): 247–263. doi:10.1517/14740338.2013.770469. PMID 23394441. S2CID 9224923.
  20. ^ Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA (October 1999). "Insulin analogues and their potential in the management of diabetes mellitus". Diabetologia. 42 (10): 1151–1167. doi:10.1007/s001250051286. PMID 10525654.
  21. ^ "Lantus EPAR". European Medicines Agency (EMA). 8 May 2009. Archived from the original on 4 August 2020. Retrieved 7 May 2020.
  22. ^ EPAR Lantus Archived 22 November 2006 at the Wayback Machine, German summary of admission report of the European Medicines Agency (PDF)
  23. ^ "Sanofi Receives FDA Approval of Once-Daily Basal Insulin Toujeo" (Press release). Sanofi. 25 February 2015. Archived from the original on 27 February 2015.
  24. ^ "Toujeo: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 14 August 2020. Retrieved 7 May 2020.
  25. ^ "Abasaglar EPAR". European Medicines Agency (EMA). 14 October 2014. Archived from the original on 2 April 2022. Retrieved 28 July 2021.
  26. ^ "Abasaglar Product information". Union Register of medicinal products. 11 September 2014. Retrieved 1 October 2023.
  27. ^ "Lusduna EPAR". European Medicines Agency (EMA). 12 January 2017. Archived from the original on 29 July 2021. Retrieved 28 July 2021.
  28. ^ "Semglee EPAR". European Medicines Agency (EMA). 23 May 2018. Archived from the original on 15 February 2022. Retrieved 28 July 2021.
  29. ^ "Amidated insulin glargine". Archived from the original on 29 September 2022. Retrieved 17 August 2020.
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