Insulin glargine

Insulin glargine
Clinical data
Trade names Lantus, Toujeo, other
AHFS/Drugs.com Monograph
MedlinePlus a600027
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Subcutaneous
ATC code A10AE04 (WHO)
Legal status
Legal status
Identifiers
CAS Number 160337-95-1 YesY
IUPHAR/BPS 7572
DrugBank DB00047 YesY
ChemSpider none
UNII 2ZM8CX04RZ N
KEGG D03250 YesY
Chemical and physical data
Formula C267H404N72O78S6
Molar mass 6063 g/mol
 NYesY (what is this?)  (verify)

Insulin glargine, marketed under the names Lantus among others, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours, with a "peakless" profile (according to the insulin glargine package insert). Pharmacokinetically, it resembles basal insulin secretion of non-diabetic pancreatic beta cells. Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. In the absence of endogenous insulin—type 1 diabetes, depleted type 2 (in some cases) or latent autoimmune diabetes of adults in late stage—insulin glargine needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose.

Medical uses

The long acting insulins, which includes insulin glargine, do not appear much better than neutral protamine Hagedorn (NPH) insulin but have a significantly greater cost making them, as of 2010, not cost effective.[1] It is unclear if there is a difference in hypoglycemia and not enough data to determine any differences with respect to long term outcomes.[2]

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.[3] However, this restriction has been questioned.[4]

Adverse effects

Cancer

As of 2012 tentative evidence shows no association between insulin glargine and cancer.[5] Previous studies had raised concerns.[6]

Pharmacology

Mechanism of action

Insulin glargine has a substitution of glycine for asparagine at N21 (Asn21) and two arginines added to the carboxy terminal of B chain. The arginine amino acids shifts 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.[7] 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

The development of insulin glargine was conducted at Sanofi-Aventis's biotechnology competence center in Frankfurt-Höchst. Sanofi supplies the product to over 100 countries and more than 3,5 million patients worldwide. This makes Lantus Germany's largest and most important export pharmaceutical product. Sanofi-Aventis increased its turn-over with Lantus around 28% to 2,45 Billion €, therefrom 130 Million € in Germany, where approx. 1.8 million people with diabetes use the product. In 2007 Lantus was the 15th highest selling pharmaceutical product in Germany.

The investment in the production of Lantus and insulin-pen-manufacturing in Frankfurt-Höchst cost 700 Million €. In 2008 a new manufacturing plant was established for further insulin-pen manufacturing with an investment of 150 Million €. At Sanofi-Aventis the production of Lantus created 3000 jobs in Berlin and Frankfurt-Höchst.

On June 9, 2000 the European Commission formally approved the launching of Lantus by Sanofi-Aventis Germany Ltd. in the entire European Union. The admission was prolonged on June 9, 2005.[8]

A three-fold more concentrated formulation, brand name Toujeo, was introduced after FDA approval in 2015.[9]

Patent expiry

Patent protection for insulin glargine expired in most countries in 2015. Biosimilar insulin glargine from competitor Eli Lilly became available in most countries during 2015, under the brand names Basaglar and Abasaglar. Biosimilar insulin glargine has only been released in 100U/mL strength to date, and biosimilar equivalents in the 300U/mL strength of Toujeo are yet to launch.[10]

See also

References

  1. ↑ Waugh, N; Cummins, E; Royle, P; Clar, C; Marien, M; Richter, B; Philip, S (July 2010). "Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation". Health technology assessment (Winchester, England). 14 (36): 1–248. doi:10.3310/hta14360. PMID 20646668.
  2. ↑ 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): 385–97. doi:10.1503/cmaj.081041. PMC 2638025Freely accessible. PMID 19221352.
  3. ↑ American Diabetes Association (2003). "Position statement: Insulin administration". Diabetes Care. 26 (Suppl. 1): 121–124. doi:10.2337/diacare.26.2007.S121.
  4. ↑ Kaplan, W.; et al. (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.
  5. ↑ 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. doi:10.1371/journal.pone.0051814. PMC 3526637Freely accessible. PMID 23284776.
  6. ↑ Rendell, M; Akturk, HK; Tella, SH (March 2013). "Glargine safety, diabetes and cancer.". Expert opinion on drug safety. 12 (2): 247–63. doi:10.1517/14740338.2013.770469. PMID 23394441.
  7. ↑ Bolli, G.; et al. (1999). "Insulin analogues and their potential in the management of diabetes mellitus.". Diabetologia. 42 (10): 1151–1167. doi:10.1007/s001250051286.
  8. ↑ EPAR Lantus, German summary of admission report of EMEA (PDF)
  9. ↑ Sanofi (press release) (2015-02-25). "Sanofi Receives FDA Approval of Once-Daily Basal Insulin Toujeo".
  10. ↑ https://www.lillypro.co.uk/diabetes/hcps/our-products/Abasaglar

External links

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