Insulin glargine

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Insulin glargine
Systematic (IUPAC) name
Recombinant human insulin
Clinical data
Trade names Lantus
AHFS/Drugs.com monograph
MedlinePlus a600027
Pregnancy cat. C (US)
Legal status POM (UK) -only (US)
Routes Subcutaneous
Identifiers
CAS number 160337-95-1 YesY
ATC code A10AE04
DrugBank DB00047
UNII 2ZM8CX04RZ N
KEGG D03250 YesY
Chemical data
Formula C267H404N72O78S6 
Mol. mass 6063 g/mol
 N (what is this?)  (verify)

Insulin glargine, marketed by Sanofi under the name Lantus, 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[edit]

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[edit]

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 in clinical trials.[4]

Adverse effects[edit]

Cancer[edit]

On June 26, 2009, Diabetologia published the results of four large-scale registry studies from Sweden, Germany, Scotland and the rest of the UK. The German study, of around 127,000 insulin-treated patients from an insurance database, suggested a possible link between insulin glargine and increased risk of developing cancer.[5] The risk of cancer was dose-dependent, with those taking higher doses of insulin glargine apparently at increased risk.[6] Whilst the authors stressed the limitations of the study and recommended that patients prescribed Lantus continue to take the drug, the results led to the EASD making "an urgent call for more research into a possible link between use of insulin glargine and increased risk of cancer."[7]

The European Medicines Agency (EMEA) responded, stating that the results of the four studies were inconsistent, and that a relationship between insulin glargine and cancer could neither be confirmed nor excluded.[8] They announced that they would undertake further detailed assessment of the studies’ results and any other relevant information, including several potential confounding factors that had not been fully taken into account by the studies. Patients being treated with insulin glargine were advised to continue their treatment as normal. [8] The following month, the EMEA reported back, concluding that "the available data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary.”[9]

The American Diabetes Association (ADA) also responded to the Diabetologia report, describing the published registry studies as “conflicting and confusing” and “inconclusive”. They advised patients against discontinuing insulin glargine and warned against "over-reaction".[10]

Type 2 diabetics who used insulin glargine had a 2.9-fold greater chance of cancer, while those who took the generic drug metformin had an 8 percent lower risk, according to a study presented on 9 December 2011 at the San Antonio Breast Cancer Symposium. Researchers examined medical records of 23,266 patients in southern Sweden.

The researchers were unable to identify which types of cancer were most common among insulin glargine users, said Hakan Olsson, lead researcher and professor of oncology at Lund University. They plan to follow the patients, and investigate different forms of treatment for Type 1 diabetes, including Novo Nordisk A/S’s long- acting insulin Levemir, to tease out any differences, he said.

“Women should be aware that diabetes and breast cancer may be related,” Olsson said in a telephone interview. “The diabetes itself could play a role in the development of cancer and now data is emerging that drug therapy may also be important in relation to cancer.”[11]

Three studies completed in 2012 with large numbers of experimental subjects found no link between use of insulin glargine and cancer.[12]

Pharmacological specifications[edit]

Mechanism of action (pharmacodynamics)[edit]

Insulin glargine have substitution of glycine for asparagine at N21 (Asn21) and two arginines added to the carboxy terminal of B chain. 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, allowing for the subcutaneous injection of a clear solution. The asparagine substitution prevents deamidization of the acid-sensitive glycine 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.[13] It can achieve a peakless level for at least 24 hours.

Acceptance and repartition in the body (pharmacokinetic)[edit]

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.

Development[edit]

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.[14]

References[edit]

  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 2638025. PMID 19221352. 
  3. ^ American Diabetes Association (2003). "Position statement: Insulin administration". Diabetes Care 26 (Suppl. 1): 121–124. 
  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. ^ Hemkens LG et al (26 June 2009). "Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study". Diabetologia 52 (9): 1732–44. doi:10.1007/s00125-009-1418-4. PMC 2723679. PMID 19565214. 
  6. ^ http://webcast.easd.org/press/glargine/transcript.htm
  7. ^ http://www.diabetologia-journal.org/cancer.html
  8. ^ a b [1] European Medicines Agency update on safety of insulin glargine, June 29, 2009
  9. ^ [2] European Medicines Agency update on safety of insulin glargine, July 23, 2009
  10. ^ [3] Statement from the American Diabetes Association Related to Studies Published in 'Diabetologia', June 26, 2009
  11. ^ Article at www.businessweek.com, 'Sanofi’s Lantus Doubled Risk of Cancer in Study of Diabetics', by Michelle Fay Cortez, December 09, 2011.
  12. ^ Reinberg, Steven (12 June 2012). "No Cancer Risk From Long-Acting Insulin: Studies". philly.com. Retrieved 12 June 2012. 
  13. ^ 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. 
  14. ^ EPAR Lantus, German summary of admission report of EMEA (PDF)

External links[edit]