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{{Short description|Long-acting insulin}}
{{Drugbox
{{Use dmy dates|date=September 2022}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Verifiedfields = changed
| verifiedrevid = 458271727
| verifiedrevid = 458271727
| image = Toujeo 300 IU-ml inj.jpg
| IUPAC_name = Recombinant human insulin
| width =
| alt =
| caption = Toujeo branded insulin glargine


<!--Clinical data-->
<!-- Clinical data -->| pronounce =
| tradename = Lantus
| tradename = Lantus, Toujeo, Basaglar, others
| Drugs.com = {{drugs.com|monograph|insulin_glargine}}
| Drugs.com = {{drugs.com|monograph|insulin_glargine}}
| MedlinePlus = a600027
| MedlinePlus = a600027
| DailyMedID = Insulin glargine
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Insulin glargine Use During Pregnancy | website=Drugs.com | date=6 April 2020 | url=https://www.drugs.com/pregnancy/insulin-glargine.html | access-date=4 September 2020 | archive-date=21 October 2020 | archive-url=https://web.archive.org/web/20201021163744/https://www.drugs.com/pregnancy/insulin-glargine.html | url-status=live }}</ref>
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| pregnancy_category =
| routes_of_administration = [[Subcutaneous injection|Subcutaneous]]
| class =
| ATC_prefix = A10
| ATC_suffix = AE04
| ATC_supplemental =
| biosimilars = insulin glargine-aglr, insulin glargine-yfgn, Rezvoglar, Abasaglar, Semglee

<!-- Legal status -->| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = /{{nbsp}}Schedule D<ref>{{cite web | title=Summary Basis of Decision - Semglee | website=Health Canada | date=23 August 2022 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00600&lang=en | access-date=29 September 2022 | archive-date=29 September 2022 | archive-url=https://web.archive.org/web/20220929045655/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00600&lang=en | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Lantus 100 units/ml solution for injection in a cartridge - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/2376/smpc | access-date=7 May 2020 | archive-date=9 January 2021 | archive-url=https://web.archive.org/web/20210109065757/https://www.medicines.org.uk/emc/product/2376/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Lantus- insulin glargine injection, solution Lantus SoloStar- insulin glargine injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5e07a0c-7e14-4756-9152-9fea485d654a | access-date=29 July 2021 | archive-date=29 July 2021 | archive-url=https://web.archive.org/web/20210729050000/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5e07a0c-7e14-4756-9152-9fea485d654a | url-status=live }}</ref>
| routes_of_administration = Subcutaneous
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Lantus EPAR | website=[[European Medicines Agency]] (EMA) | date=8 May 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/lantus | access-date=28 July 2021 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804155233/https://www.ema.europa.eu/en/medicines/human/EPAR/lantus | url-status=live }}</ref><ref>{{cite web | title=Toujeo EPAR | website=[[European Medicines Agency]] (EMA) | date=11 May 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/toujeo-previously-optisulin | access-date=28 July 2021 | archive-date=29 July 2021 | archive-url=https://web.archive.org/web/20210729050012/https://www.ema.europa.eu/en/medicines/human/EPAR/toujeo-previously-optisulin | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only


<!-- Pharmacokinetic data -->| bioavailability =
<!--Identifiers-->
| protein_bound =
| metabolism =
| metabolites =
| onset = ~1 hour<ref name=AHFS2018/>
| elimination_half-life =
| duration_of_action = 24–36 hours<ref name=AHFS2018/>
| excretion = <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 160337-95-1
| CAS_number = 160337-95-1
| ATC_prefix = A10
| CAS_supplemental =
| ATC_suffix = AE04
| PubChem =
| IUPHAR_ligand = 7572
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00047
| DrugBank = DB00047
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 2ZM8CX04RZ
| UNII = 2ZM8CX04RZ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03250
| KEGG = D03250
| ChEBI_Ref =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = NA
| ChEBI =
| ChEMBL_Ref =

| ChEMBL =
<!--Chemical data-->
| NIAID_ChemDB =
| C=267 | H=404 | N=72 | O=78 | S=6
| PDB_ligand =
| molecular_weight = 6063 g/mol
| synonyms = <!-- Chemical and physical data -->
| IUPAC_name = Recombinant human insulin
| C = 267
| H = 404
| N = 72
| O = 78
| S = 6
| SMILES =
| Jmol =
| StdInChI =
| StdInChI_comment =
| StdInChIKey =
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
}}

'''Insulin glargine''', marketed by [[Sanofi-Aventis]] 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 [[diabetes mellitus type 2|type 2]] (in some cases) or [[Latent autoimmune diabetes|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.
<!-- Definition and medical uses -->
'''Insulin glargine''' sold under the brand name '''Lantus''' among others is a long-acting [[insulin analogue|modified]] form of [[insulin (medication)|medical insulin]], used in the management of [[type 1 DM|type I]] and [[type II diabetes]].<ref name=AHFS2018/> It is [[subcutaneous injection|injected just under the skin]].<ref name=AHFS2018/> Effects generally begin an hour after use.<ref name=AHFS2018/>

<!-- Side effects and mechanism -->
Common side effects include [[low blood sugar]], problems at the site of injection, itchiness, and weight gain.<ref name=AHFS2018/> Other serious side effects include [[low blood potassium]].<ref name=AHFS2018/> [[NPH insulin]] rather than insulin glargine is generally preferred in [[pregnancy]].<ref name=BNF76>{{cite book |title=British national formulary: BNF 76 |date=2018 |publisher=Pharmaceutical Press |isbn=9780857113382|page=701|edition=76th}}</ref> After injection, [[microcrystal]]s slowly release insulin for about 24 hours.<ref name=AHFS2018/> This insulin causes body tissues to absorb [[glucose]] from the blood and decreases glucose production by the liver.<ref name=AHFS2018/>

<!-- Society and culture -->
Insulin glargine was approved for medical use in the United States in 2000.<ref name=AHFS2018>{{cite web |title=Insulin Glargine Monograph for Professionals |url=https://www.drugs.com/monograph/insulin-glargine.html |website=Drugs.com |publisher=AHFS |access-date=23 December 2018 |archive-date=5 December 2020 |archive-url=https://web.archive.org/web/20201205095655/https://www.drugs.com/monograph/insulin-glargine.html |url-status=live }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2022, it was the 28th most commonly prescribed medication in the United States, with more than 18{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Insulin Glargine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/InsulinGlargine | access-date = 30 August 2024 }}</ref> 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.<ref name="FDA PR 20210728" />


==Medical uses==
==Medical uses==
{{Update|documentation|date=January 2022}}
Previously, some positional statements have articulated that the long acting insulins, which include insulin glargine, do not appear much better than neutral protamine Hagedorn [[NPH insulin|(NPH) insulin]] but have a significantly greater cost making them. As of 2010, their market value is higher.<ref>{{cite journal|last=Waugh|first=N|coauthors=Cummins, E, Royle, P, Clar, C, Marien, M, Richter, B, Philip, S|title=Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation|journal=Health technology assessment (Winchester, England)|date=2010 Jul|volume=14|issue=36|pages=1–248|pmid=20646668|doi=10.3310/hta14360}}</ref> Although it has been stated that it is unclear if there is a difference in [[hypoglycemia]] and that not enough data is available to determine any differences with respect to long term outcomes, <ref name=Singh2009>{{cite journal |author=Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H|title=Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis |journal=CMAJ|volume=180 |issue=4 |pages=385–97 |year=2009 |month=February |pmid=19221352 |pmc=2638025 |doi=10.1503/cmaj.081041|url=http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=19221352}}</ref>, the fact that long acting insulin analogues such as glargine are almost peakless, and that insulin peaks are known appetite stimulants, logically suggests their benefit in treating both type I patients who are sensitive to hypoglycemia, or have schedules where peaking insulin presents a problem (school or otherwise institutionalized situations), and obese insulin-dependent patients who need to control appetite.
The long-acting insulin class, which includes insulin glargine, do not appear much better than [[NPH insulin|neutral protamine Hagedorn (NPH) insulin]],<ref name=":0">{{cite journal | vauthors = Hemmingsen B, Metzendorf MI, Richter B | title = (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 4 | pages = CD013498 | date = March 2021 | pmid = 33662147 | pmc = 8094220 | doi = 10.1002/14651858.cd013498.pub2 }}</ref> but do have a greater cost, making them, as of 2010, not cost effective for the treatment of type 2 diabetes.<ref>{{cite journal | vauthors = Waugh N, Cummins E, Royle P, Clar C, Marien M, Richter B, Philip S | title = Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation | journal = Health Technology Assessment | volume = 14 | issue = 36 | pages = 1–248 | date = July 2010 | pmid = 20646668 | doi = 10.3310/hta14360 | doi-access = free }}</ref> 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,<ref name=Singh2009>{{cite journal | vauthors = Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H | title = Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis | journal = CMAJ | volume = 180 | issue = 4 | pages = 385–397 | date = February 2009 | pmid = 19221352 | pmc = 2638025 | doi = 10.1503/cmaj.081041 }}</ref> however a more recent [[Cochrane (organisation)|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.<ref name=":0" /> It is not typically the recommended long acting insulin in the United Kingdom.<ref name=BNF76/>

Semglee is indicated to improve glycemic control in adults and children with Type 1 diabetes and in adults with Type 2 diabetes.<ref name="FDA PR 20210728" /> Semglee is both biosimilar to, and interchangeable with (can be substituted for), its reference product Lantus (insulin glargine), a long-acting insulin analog.<ref name="FDA PR 20210728" />


===Mixing with other insulins===
===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.<ref>{{cite journal |author=American Diabetes Association |year=2003 |title=Position statement: Insulin administration |journal=Diabetes Care |volume=26 |issue=Suppl. 1 |pages=121–124 }}</ref> However, this restriction has been questioned in clinical trials.<ref>{{cite journal |last=Kaplan |first=W. |last2=''et al.'' |title=Effects of Mixing Glargine and Short-Acting Insulin Analogs on Glucose Control |journal=Diabetes Care |year=2004 |volume=27 |issue=11|pages=2739–2740 |pmid=15505016 |doi=10.2337/diacare.27.11.2739 }}</ref>
Unlike some other longer-acting insulins, glargine must not be diluted or mixed with other insulin or solution in the same syringe.<ref>{{cite journal |author=American Diabetes Association | title = Insulin administration | journal = Diabetes Care | volume = 26 | issue = Suppl. 1 | pages = S121–S124 | date = January 2003 | pmid = 12502637 | doi = 10.2337/diacare.26.2007.S121 | doi-access = free }}</ref> However, this restriction has been questioned.<ref>{{cite journal | vauthors = Kaplan W, Rodriguez LM, Smith OE, Haymond MW, Heptulla RA | title = Effects of mixing glargine and short-acting insulin analogs on glucose control | journal = Diabetes Care | volume = 27 | issue = 11 | pages = 2739–2740 | date = November 2004 | pmid = 15505016 | doi = 10.2337/diacare.27.11.2739 | doi-access = free }}</ref>


==Adverse effects==
==Adverse effects==
Common side effects include [[low blood sugar]], problems at the site of injection, itchiness, and weight gain.<ref name=AHFS2018/> Serious side effects include [[low blood potassium]].<ref name=AHFS2018/>
===Cancer===
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.<ref name="pmid19565214">{{cite journal |author=Hemkens LG et al|title=Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study|journal=Diabetologia |date=26 June 2009|pmid=19565214|doi=10.1007/s00125-009-1418-4 |volume=52 |issue=9 |pages=1732–44 |pmc=2723679}}</ref> The risk of cancer was dose-dependent, with those taking higher doses of insulin glargine apparently at increased risk.<ref>http://webcast.easd.org/press/glargine/transcript.htm</ref> 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''."<ref>http://www.diabetologia-journal.org/cancer.html</ref>

The [[European Medicines Agency|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.<ref name=EMEA1>[http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/40847409en.pdf] European Medicines Agency update on safety of insulin glargine, June 29, 2009</ref> They announced that they would undertake further detailed assessment of the studies’ results and any other relevant information, including several potential[[confounding|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.
<ref name=EMEA1/> 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''.”<ref>[http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/47063209en.pdf] European Medicines Agency update on safety of insulin glargine, July 23, 2009</ref>


As of 2012, tentative evidence shows no association between insulin glargine and [[cancer]].<ref>{{cite journal | vauthors = Tang X, Yang L, He Z, Liu J | title = Insulin glargine and cancer risk in patients with diabetes: a meta-analysis | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51814 | date = 2012 | pmid = 23284776 | pmc = 3526637 | doi = 10.1371/journal.pone.0051814 | doi-access = free | bibcode = 2012PLoSO...751814T }}</ref> Previous studies had raised concerns.<ref>{{cite journal | vauthors = Rendell M, Akturk HK, Tella SH | title = Glargine safety, diabetes and cancer | journal = Expert Opinion on Drug Safety | volume = 12 | issue = 2 | pages = 247–263 | date = March 2013 | pmid = 23394441 | doi = 10.1517/14740338.2013.770469 | s2cid = 9224923 }}</ref>
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".<ref>[http://www.diabetes.org/for-media/pr-glargine-0602609.jsp] Statement from the American Diabetes Association Related to Studies Published in 'Diabetologia', June 26, 2009</ref>


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.<ref name=":0" />
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.


==Pharmacology==
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.


===Mechanism of action===
“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.” <ref>Article at www.businessweek.com, 'Sanofi’s Lantus Doubled Risk of Cancer in Study of Diabetics', by Michelle Fay Cortez, December 09, 2011.</ref>
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.<ref name="Bolli">{{cite journal | vauthors = Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA | title = Insulin analogues and their potential in the management of diabetes mellitus | journal = Diabetologia | volume = 42 | issue = 10 | pages = 1151–1167 | date = October 1999 | pmid = 10525654 | doi = 10.1007/s001250051286 | doi-access = free }}</ref> It can achieve a peakless level for at least 24 hours.


===Acceptance and repartition in the body===
Three studies completed in 2012 with large numbers of experimental subjects found no link between use of insulin glargine and cancer. <ref>{{cite news|accessdate=12th June, 2012|title=|url=http://www.philly.com/philly/health/HealthDay665657_20120611_No_Cancer_Risk_From_Long-Acting_Insulin__Studies.html?cmpid=138896554|date=12th June, 2012|last=Reinberg|first=Steven|title=No Cancer Risk From Long-Acting Insulin: Studies|publisher=philly.com}}</ref>


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.
== Pharmacological specifications==
===Mechanism of action (pharmacodynamics)===
Insulin glargine have substitution of glycine for asparagine at A21 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.<ref name="Bolli">{{cite journal |author=Bolli, G. et al. |year=1999 |title=Insulin analogues and their potential in the management of diabetes mellitus. |journal=Diabetologia |volume=42 |issue=10 |pages=1151–1167 |url=http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=10525654&retmode=ref&cmd=prlinks}}</ref> It can achieve a peakless level for at least 24 hours.


==History==
===Acceptance and repartition in the body (pharmacokinetic)===
On 9 June 2000, the European Commission formally approved the launching of Lantus by Sanofi-Aventis Germany Ltd. in the entire European Union.<ref>{{cite web | title=Lantus EPAR | website=[[European Medicines Agency]] (EMA) | date=8 May 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/lantus | access-date=7 May 2020 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804155233/https://www.ema.europa.eu/en/medicines/human/EPAR/lantus | url-status=live }}</ref> The admission was prolonged on 9 June 2005.<ref>[http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/061500de1.pdf EPAR Lantus] {{webarchive|url=https://web.archive.org/web/20061122101428/http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/061500de1.pdf |date=22 November 2006 }}, German summary of admission report of the [[European Medicines Agency]] (PDF)</ref>


A three-fold more concentrated formulation, brand name Toujeo, was introduced after FDA approval in 2015.<ref>{{cite press release |url=http://www.news.sanofi.us/2015-02-25-Sanofi-Receives-FDA-Approval-of-Once-Daily-Basal-Insulin-Toujeo|title=Sanofi Receives FDA Approval of Once-Daily Basal Insulin Toujeo|publisher=Sanofi|date=25 February 2015|url-status=live|archive-url=https://web.archive.org/web/20150227175634/http://www.news.sanofi.us/2015-02-25-Sanofi-Receives-FDA-Approval-of-Once-Daily-Basal-Insulin-Toujeo|archive-date=27 February 2015}}</ref><ref>{{cite web | title=Toujeo: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206538 | access-date=7 May 2020 | archive-date=14 August 2020 | archive-url=https://web.archive.org/web/20200814020233/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206538 | url-status=live }}</ref>
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==
== Legal status ==
=== Biosimilars ===
Abasaglar was approved for medical use in the European Union in September 2014.<ref>{{cite web | title=Abasaglar EPAR | website=[[European Medicines Agency]] (EMA) | date=14 October 2014 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/abasaglar-previously-abasria#authorisation-details-section | access-date=28 July 2021 | archive-date=2 April 2022 | archive-url=https://web.archive.org/web/20220402171234/https://www.ema.europa.eu/en/medicines/human/EPAR/abasaglar-previously-abasria#authorisation-details-section | url-status=live }}</ref><ref>{{cite web | title=Abasaglar Product information | website=Union Register of medicinal products | date=11 September 2014 | url=https://ec.europa.eu/health/documents/community-register/html/h944.htm | access-date=1 October 2023}}</ref>


Lusduna was approved for medical use in the European Union in January 2017.<ref>{{cite web | title=Lusduna EPAR | website=[[European Medicines Agency]] (EMA) | date=12 January 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/lusduna | access-date=28 July 2021 | archive-date=29 July 2021 | archive-url=https://web.archive.org/web/20210729050001/https://www.ema.europa.eu/en/medicines/human/EPAR/lusduna | url-status=live }}</ref>
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.


In March 2018, insulin glargine (Semglee) was approved for medical use in the European Union.<ref name="Semglee EPAR">{{cite web | title=Semglee EPAR | website=[[European Medicines Agency]] (EMA) | date=23 May 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/semglee | access-date=28 July 2021 | archive-date=15 February 2022 | archive-url=https://web.archive.org/web/20220215172501/https://www.ema.europa.eu/en/medicines/human/EPAR/semglee | url-status=live }}</ref>
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.


In July 2021, insulin glargine-yfgn (Semglee) was approved for medical use in the United States as the first interchangeable biosimilar of Lantus.<ref name="FDA PR 20210728">{{cite press release | title=FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes | website=U.S. [[Food and Drug Administration]] (FDA) | date=28 July 2021 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes | access-date=28 July 2021 | archive-date=28 August 2021 | archive-url=https://web.archive.org/web/20210828201228/https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes | url-status=live }} {{PD-notice}}</ref> The FDA granted approval of Semglee to [[Mylan|Mylan Pharmaceuticals Inc]].<ref name="FDA PR 20210728" />
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.<ref>[http://www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/061500de1.pdf EPAR Lantus], German summary of admission report of [[European Medicines Agency|EMEA]] (PDF)</ref>


==== Patent expiry ====
Insulin glargine is available without a prescription over-the-counter in pen form in Canada, and also in Spain.
Patent protection for insulin glargine expired in most countries in 2015{{citation needed|date=April 2019}} and in the U.S.A. is expected to expire on 2027-07-05.<ref>{{Cite web|url=https://patents.google.com/patent/US8048854B2/en%3C/|title=Amidated insulin glargine|access-date=17 August 2020|archive-date=29 September 2022|archive-url=https://web.archive.org/web/20220929045656/https://patents.google.com/patent/US8048854B2/en%3C/|url-status=live}}</ref> Insulin glargine from competitor [[Eli Lilly and Company|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|date=April 2019}}


==References==
== References ==
{{reflist}}
<references/>


==External links==
*[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a600027.html Insulin glargine] - [[MedlinePlus]]
*[http://www.lantus.com Lantus website] (Sanofi-Aventis)
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Insulin+glargine U.S. National Library of Medicine: Drug Information Portal - Insulin glargine]
* [http://www.postgradmed.com/index.php?article=2116 Comparing Insulins Detemir and Glargine in Type 2 Diabetes: More Similarities than Differences]
{{Oral hypoglycemics and insulin analogs}}
{{Oral hypoglycemics and insulin analogs}}
{{Eli Lilly and Company}}
{{Portal bar | Medicine}}
{{Authority control}}


{{DEFAULTSORT:Insulin Glargine}}
{{DEFAULTSORT:Insulin Glargine}}
[[Category:Insulin therapies]]
[[Category:Insulin receptor agonists]]
[[Category:Human proteins]]
[[Category:Human proteins]]
[[Category:Recombinant proteins]]
[[Category:Recombinant proteins]]
[[Category:Peptide hormones]]
[[Category:Peptide hormones]]
[[Category:Peptide therapeutics]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:Drugs developed by Boehringer Ingelheim]]
[[Category:Sanofi]]
[[Category:World Health Organization essential medicines]]

Latest revision as of 07:49, 5 October 2024

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)

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]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

Mechanism of action

[edit]

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

[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.

History

[edit]

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]

[edit]

Biosimilars

[edit]

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

[edit]

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

[edit]
  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. Public Domain 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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