{{Short description|Modified forms of synthetic insulin}} {{Use dmy dates|date=September 2025|cs1-dates=dmy}} {{cs1 config|name-list-style=vanc|display-authors=6}} thumb|300x300px|The relative effectiveness of each insulin analogue over time<ref name="Brateanu_2015">{{Cite journal | vauthors = Brateanu A, Russo-Alvarez G, Nielsen C | title = Starting insulin in patients with type 2 diabetes: An individualized approach | journal = Cleveland Clinic Journal of Medicine | volume = 82 | issue = 8 | pages = 513–519 | date = 2015 | pmid = 26270430 | doi = 10.3949/ccjm.82a.14069 | url = https://www.researchgate.net/publication/280997306 | access-date = 24 February 2025 }}</ref>|alt=Graphs showing relative effectiveness of each insulin analog over timeAn '''insulin analogue''' (also called an '''insulin analog''') is a type of medical insulin that has been modified to alter its pharmacokinetic properties while maintaining the same biological function as human insulin.<ref name="McDermott_2009">{{Cite book | vauthors = McDermott MT | title = Endocrine secrets | location = Philadelphia, PA | date = 2009 | publisher = Mosby/Elsevier | isbn = 978-0-323-05885-8 | edition = 5th | series = Secrets series }}</ref> These modifications are achieved through genetic engineering,<ref>{{Cite journal | vauthors = Mayer JP, Zhang F, DiMarchi RD | title = Insulin structure and function | journal = Biopolymers | volume = 88 | issue = 5 | pages = 687–713 | date = January 2007 | pmid = 17410596 | doi = 10.1002/bip.20734 | url = https://onlinelibrary.wiley.com/doi/10.1002/bip.20734 | issn = 0006-3525 | url-access = subscription }}</ref> which allows for changes in the amino acid sequence of insulin to optimize its absorption, distribution, metabolism, and excretion (ADME) characteristics.<ref name="Hirsch_2005">{{Cite journal | vauthors = Hirsch IB | title = Insulin Analogues | journal = The New England Journal of Medicine | volume = 352 | issue = 2 | pages = 174–183 | date = 13 January 2005 | pmid = 15647580 | doi = 10.1056/NEJMra040832 | url = http://nejm.org/doi/abs/10.1056/NEJMra040832 | issn = 0028-4793 | url-access = subscription }}</ref>
All insulin analogues work by enhancing glucose uptake in tissues and reducing glucose production by the liver.<ref name="Mathieu_2017" /> They are prescribed for conditions such as type 1 diabetes, type 2 diabetes,<ref name="UCSF">{{Cite web | title = Insulin Analogs | url = https://diabetesteachingcenter.ucsf.edu/about-diabetes/type-2-diabetes/types-insulin-use-type-2-diabetes/insulin-analogs | access-date = 10 March 2025 | work = Diabetes Teaching Center | publisher = University of California San Francisco }}</ref> gestational diabetes, and diabetes-related complications such as diabetic ketoacidosis.<ref name="UCSF" /> Additionally, insulin is sometimes administered alongside glucose to treat elevated blood potassium levels (hyperkalemia).<ref>{{cite journal | vauthors = Mahoney BA, Smith WA, Lo D, Tsoi K, Tonelli M, Clase C | title = Emergency interventions for hyperkalaemia | journal = The Cochrane Database of Systematic Reviews | volume = 2005 | issue = 2 | article-number = CD003235 | date = 20 April 2005 | pmid = 15846652 | pmc = 6457842 | doi = 10.1002/14651858.cd003235.pub2 | publisher = Wiley | issn = 1465-1858 | doi-access = free }}</ref>
Insulin analogues are classified based on their duration of action. Short-acting (bolus) insulin analogues, such as insulin lispro, insulin aspart, and insulin glulisine,<ref name="Hartman_2008">{{Cite journal | vauthors = Hartman I | title = Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence | journal = Clinical Medicine & Research | volume = 6 | issue = 2 | pages = 54–67 | date = 7 July 2008 | pmid = 18801953 | pmc = 2572551 | doi = 10.3121/cmr.2008.793 | issn = 1539-4182 }}</ref> have been designed to be absorbed quickly, mimicking the natural insulin response after meals. Long-acting (basal) insulin analogues, including insulin glargine, insulin detemir,<ref name="Hartman_2008" /> and insulin degludec, provide a sustained release of insulin to maintain basal blood glucose levels over an extended period. These modifications enhance the predictability of insulin therapy and reduce the risk of hypoglycemia compared to regular human insulin.<ref name="Burge_1998">{{Cite journal | vauthors = Burge MR, Rassam AG, Schade DS | title = Lispro Insulin: Benefits and Limitations | journal = Trends in Endocrinology and Metabolism | volume = 9 | issue = 8 | pages = 337–341 | date = 1 October 1998 | pmid = 18406299 | doi = 10.1016/S1043-2760(98)00083-6 | url = https://sciencedirect.com/science/article/abs/pii/S1043276098000836 | url-access = subscription }}</ref>
Lispro, the first insulin analogue, was approved in 1996.<ref name="Quianzon_2012">{{Cite journal | vauthors = Quianzon CC, Cheikh I | title = History of insulin | journal = Journal of Community Hospital Internal Medicine Perspectives | volume = 2 | issue = 2 | article-number = 18701 | date = January 2012 | pmid = 23882369 | pmc = 3714061 | doi = 10.3402/jchimp.v2i2.18701 | issn = 2000-9666 }}</ref> This was followed by an influx of new analogues with differing pharmacokinetic properties. The first long-acting analogue, insulin glargine, was approved in 2000. Insulin aspart, insulin glulisine, and insulin detemir were all approved by 2005.<ref name="Quianzon_2012" /> The second wave of insulin analogues, which include insulin degludec<ref>{{cite journal | vauthors = Haahr H, Heise T | title = A review of the pharmacological properties of insulin degludec and their clinical relevance | journal = Clinical Pharmacokinetics | volume = 53 | issue = 9 | pages = 787–800 | date = September 2014 | pmid = 25179915 | pmc = 4156782 | doi = 10.1007/s40262-014-0165-y }}</ref> and insulin icodec,<ref name="Kjeldsen_2021">{{cite journal | vauthors = Kjeldsen TB, Hubálek F, Hjørringgaard CU, Tagmose TM, Nishimura E, Stidsen CE, Porsgaard T, Fledelius C, Refsgaard HH, Gram-Nielsen S, Naver H, Pridal L, Hoeg-Jensen T, Jeppesen CB, Manfè V, Ludvigsen S, Lautrup-Larsen I, Madsen P | title = Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 13 | pages = 8942–8950 | date = July 2021 | pmid = 33944562 | doi = 10.1021/acs.jmedchem.1c00257 | s2cid = 233718893 | doi-access = free }}</ref> started in the 2010s.<ref>{{Cite web | title = Tresiba (insulin degludec) FDA Approval History | url = https://drugs.com/history/tresiba.html | access-date = 10 March 2025 | website = Drugs.com }}</ref> Insulin analogues are on the World Health Organization's List of Essential Medicines.<ref name="WHO24th">{{cite book | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | year = 2025 | hdl = 10665/382243 | publisher = World Health Organization | location = Geneva | hdl-access=free }}</ref>
== Mechanisms of action == thumb|500x500px|Different forms of insulin structure. Insulin monomer (a), dimer (b) and hexamer (c)|alt=3 models of a chemical made of lines arrows, and coils on a black field Insulin analogues are recombinant proteins that are structurally based on human insulin but have been modified through amino acid substitutions or additions to alter their pharmacokinetic properties.<ref name="McDermott_2009" /> These modifications are designed to either accelerate or prolong subcutaneous absorption while maintaining the biological function of insulin in regulating blood glucose levels.<ref name="McDermott_2009" /> Native human insulin, commonly referred to as regular insulin,<ref name="BNF69">{{cite book | title = British national formulary: BNF 69 | page = 464472 | date = 2015 | publisher = British Medical Association | isbn = 978-0-85711-156-2 | edition = 69th }}</ref> naturally assembles into hexamers, which must gradually dissociate into dimers and then monomers before they can be absorbed into the bloodstream.<ref name="McDermott_2009" /> This process results in a delayed onset of action, making the timing of insulin administration a critical factor in diabetes management.<ref name="McDermott_2009" /><ref name="Hartman_2008" />
Short-acting insulin analogues are developed to have a shorter duration of action than regular insulin,<ref name="McDermott_2009" /> while long-acting insulin analogues are meant to have a peakless action profile and a prolonged duration of action.<ref name="McDermott_2009" /><ref name="Mathieu_2017">{{Cite journal | vauthors = Mathieu C, Gillard P, Benhalima K | title = Insulin analogues in type 1 diabetes mellitus: getting better all the time | journal = Nature Reviews. Endocrinology | volume = 13 | issue = 7 | pages = 385–399 | date = July 2017 | pmid = 28429780 | doi = 10.1038/nrendo.2017.39 }}</ref>
=== Short-acting === alt=Cartoon diagram of an insulin glulisine dodecamer. The histidine residues coordinating the central zinc atom are shown as sticks, and the zinc atom itself as a pale blue sphere.|thumb|185x185px|Diagram of an insulin glulisine dodecamer. The histidine residues coordinating the central zinc atom are shown as sticks, and the zinc atom itself as a pale blue sphere. Short-acting insulin analogues are modified forms of recombinant human insulin designed to enhance subcutaneous absorption and accelerate glycemic control.<ref name="Mathieu_2017" /> In standard insulin formulations, regular insulin monomers naturally aggregate into hexamers, a configuration that delays absorption and prolongs the onset of action.<ref name="Hemmings_2019">{{Cite book | veditors = Hemmings HC, Egan TD | chapter = 36 - Endocrine Pharmacology | title = Pharmacology and physiology for anesthesia: foundations and clinical application | location = Philadelphia, PA | date = 2019 | publisher = Elsevier | isbn = 978-0-323-48110-6 | edition = 2nd }}</ref> Before entering the bloodstream, these hexamers must dissociate into dimers and then monomers, which slows their availability for glucose regulation.<ref name="Home_2012">{{Cite journal | vauthors = Home PD | title = The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences | journal = Diabetes, Obesity & Metabolism | volume = 14 | issue = 9 | pages = 780–788 | date = September 2012 | pmid = 22321739 | doi = 10.1111/j.1463-1326.2012.01580.x | url = https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/j.1463-1326.2012.01580.x | issn = 1462-8902 | url-access = subscription }}</ref> To address this limitation, insulin analogues have been engineered to maintain a monomeric or dimeric configuration, allowing for faster absorption and reducing the time to onset to approximately 5 to 15 minutes.<ref name="Hemmings_2019" /> Insulin lispro, insulin aspart, and insulin glulisine are the most widely used short-acting insulin analogues.<ref name="Hirsch_2005" /> These formulations are structurally identical to human insulin, except for amino acid substitutions at one or two positions, which modify their stability and absorption characteristics.<ref name="Hemmings_2019" />
Insulin lispro, which was first approved in 1996 and marketed as Humalog among others, works by reversing the final lysine and proline residues on the C-terminal end of the B-chain.<ref name="Noble_1998">{{cite journal | vauthors = Noble SL, Johnston E, Walton B | title = Insulin lispro: a fast-acting insulin analog | journal = American Family Physician | volume = 57 | issue = 2 | pages = 279–86, 289–92 | date = January 1998 | pmid = 9456992 | url = http://aafp.org/afp/980115ap/noble.html | archive-url = https://web.archive.org/web/20070929095848/http://aafp.org/afp/980115ap/noble.html | archive-date = 29 September 2007 | access-date = 5 September 2007 }}</ref> This modification does not alter receptor binding, but blocks the formation of insulin dimers and hexamers.<ref name="Noble_1998" /> Clinical studies have demonstrated that the use of insulin lispro instead of regular insulin can reduce hypoglycemia incidence and improve glycemic control.<ref name="Home_2012" /> alt=A diagram illustrating the structural formula of insulin aspart. The image consists of a sequence of amino acids represented as orange ovals, labeled with their respective three-letter abbreviations. The structure follows the A and B chains of insulin, with disulfide bonds indicated by connecting lines. Specific modifications, such as the substitution of proline (Pro) at position B28 with aspartic acid (Asp), are highlighted|thumb|Structural formula of insulin aspart Insulin aspart, which was approved in 2000 and is marketed under the name Novolog among others, has effects comparable to those of insulin lispro, but has a lesser risk of nocturnal hypoglycemia.<ref name="Hemmings_2019" /> It works by replacing a proline with an aspartic acid at the B28 position.<ref>{{cite book | vauthors = Turner JR | title = New Drug Development: An Introduction to Clinical Trials: Second Edition | page = 32 | date = 2010 | url = https://books.google.com/books?id=Rv10neRV3R8C&pg=PA32 | publisher = Springer Science & Business Media | isbn = 978-1-4419-6418-2 | access-date = 11 September 2020 | archive-url = https://web.archive.org/web/20210420140538/https://books.google.com/books?id=Rv10neRV3R8C&pg=PA32 | archive-date = 20 April 2021 | url-status = live }}</ref> Insulin glulisine has nearly identical properties to the other two short-acting analogues, but differs in the fact that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid.<ref name="Apidra FDA label">{{cite web | title = Apidra- insulin glulisine injection, solution; Apidra Solostar- insulin glulisine injection, solution | date = 25 July 2023 | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7af6a7a-8046-4fb4-9979-4ec4230b23aa | access-date = 10 August 2024 | website = DailyMed }}</ref><ref name="Home_2012" /> It was approved in 2004 and is sold under the name Apidra.<ref name="Approval_package">{{cite web | title = Drug Approval Package: Apidra (Insulin Glulisine [rDNA Origin]) NDA #021629 | url = https://accessdata.fda.gov/drugsatfda_docs/nda/2004/21-629_Apidra.cfm | archive-url = https://web.archive.org/web/20150405010739/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-629_Apidra.cfm | archive-date = 5 April 2015 | access-date = 10 August 2024 | website = U.S. Food and Drug Administration (FDA) }}</ref>
These short-acting insulin analogues play a crucial role in modern diabetes management, as their fast onset and shorter duration of action allow for more precise postprandial glucose control.<ref name="Hemmings_2019" /> By closely mimicking endogenous insulin secretion, these analogues enhance glycemic stability, reduce post-meal blood sugar spikes, and minimize the risk of hypoglycemic events.<ref name="Home_2012" /> Their pharmacokinetic properties make them particularly beneficial for individuals requiring flexible meal timing and those using intensive insulin therapy.<ref name="Hemmings_2019" />
=== Long-acting === Long-acting insulin analogues are designed to provide continuous basal insulin coverage for up to 24 hours,<ref name="Niloy_2023">{{Cite journal | vauthors = Niloy KK, Lowe TL | title = Injectable systems for long-lasting insulin therapy | journal = Advanced Drug Delivery Reviews | volume = 203 | article-number = 115121 | date = December 2023 | pmid = 37898336 | doi = 10.1016/j.addr.2023.115121 | doi-access = free }}</ref> with the exception of ultra-long-acting analogues, which work for up to a week.<ref name="Kjeldsen_2021" /> These include insulin glargine, insulin detemir, insulin degludec, and insulin icodec, which have been modified through amino acid substitutions and fatty acid conjugation to alter their subcutaneous absorption and extend their duration of action.<ref name="Niloy_2023" /> A key feature of long-acting insulin analogues is reversible albumin binding and di-hexamer formation, which slow insulin dissociation and provide a more stable pharmacokinetic and pharmacodynamic profile,<ref name="Baeshen_2014">{{cite journal | vauthors = Baeshen NA, Baeshen MN, Sheikh A, Bora RS, Ahmed MM, Ramadan HA, Saini KS, Redwan EM | title = Cell factories for insulin production | journal = Microbial Cell Factories | volume = 13 | page = 141 | date = October 2014 | pmid = 25270715 | pmc = 4203937 | doi = 10.1186/s12934-014-0141-0 | article-number = 141 | doi-access = free }}</ref> reducing glycemic fluctuations and nocturnal hypoglycemia.<ref name="Niloy_2023" />
Insulin glargine (100 U/mL), first approved by the US Food and Drug Administration (FDA) in 2000 and marketed as Lantus, forms zinc-mediated hexamer aggregates after injection, resulting in a slow insulin release.<ref name="AHFS2018">{{cite web | title = Insulin Glargine Monograph for Professionals | url = https://drugs.com/monograph/insulin-glargine.html | url-status = live | archive-url = https://web.archive.org/web/20201205095655/https://drugs.com/monograph/insulin-glargine.html | archive-date = 5 December 2020 | access-date = 23 December 2018 | website = Drugs.com | publisher = AHFS }}</ref><ref name="Cunningham_2025">{{Citation |last1=Cunningham |first1=Abigail M. |title=Glargine Insulin |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK557756/ |access-date=10 March 2025 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491688 |last2=Freeman |first2=Andrew M.}}</ref> In 2015, a higher-concentration formulation (300 U/mL), marketed as Toujeo, was introduced, offering up to 36-hour coverage and a lower risk of nocturnal hypoglycemia.<ref>{{Cite web | title = Toujeo SoloStar Uses, Dosage & Side Effects | url = https://drugs.com/toujeo.html | access-date = 10 March 2025 | website = Drugs.com }}</ref> Insulin detemir, approved in 2005 as Levemir, features a C14 fatty acid modification at lysine B29, promoting di-hexamer formation and albumin binding for an extended duration.<ref name="Niloy_2023" /> While effective, insulin detemir often requires twice-daily dosing for optimal glycemic control.<ref name="Niloy_2023" /><ref name="Baeshen_2014" /> alt=Space-filling model of an insulin degludec hexamer with lime green representing the A chain, tan representing the B chain, and teal representing the central zinc atom|thumb|185x185px|An insulin degludec hexamer. A chains are chartreuse, B chains are tan, and the central zinc atom is teal. Insulin degludec, marketed as Tresiba and approved in 2015, is an ultra-long-acting insulin with a duration of up to 42 hours.<ref name="Klein_2007">{{cite journal | vauthors = Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T | title = Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes | journal = Diabetes, Obesity & Metabolism | volume = 9 | issue = 3 | pages = 290–299 | date = May 2007 | pmid = 17391154 | doi = 10.1111/j.1463-1326.2006.00685.x | s2cid = 23810204 }}</ref> It utilizes multi-hexamer formation and albumin binding to provide a steady insulin release with lower intra-individual variability and greater dosing flexibility.<ref name="Klein_2007" /> Compared to insulin glargine and detemir, degludec offers a reduced risk of nocturnal hypoglycemia and allows dosing intervals of 8 to 40 hours without compromising glycemic control.<ref name="Niloy_2023" /> These advancements have improved diabetes management by providing more stable blood sugar control, fewer hypoglycemic episodes, and greater convenience for patients.<ref name="Niloy_2023" />
Insulin icodec is, as of 2025, the newest and longest-acting insulin analogue.<ref name="Health_Canada">{{Cite web | title = Summary Basis of Decision for Awiqli | url = https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1734642660051 | website = Health Canada }}</ref><ref name="Kjeldsen_2021" /> It has a plasma half-life that is more than eight days, meaning it is a once-weekly insulin.<ref name="Kjeldsen_2021" /> It was approved in 2024 and is marketed as Awiqli by Novo Nordisk.<ref name="Health_Canada" /> Insulin icodec consists of two peptide chains linked by a disulfide bridge. It contains a C20 fatty diacid-containing side chain, which facilitates strong, reversible binding to albumin.<ref name="Molecular and pharmacological chara">{{cite journal | vauthors = Nishimura E, Pridal L, Glendorf T, Hansen BF, Hubálek F, Kjeldsen T, Kristensen NR, Lützen A, Lyby K, Madsen P, Pedersen TÅ, Ribel-Madsen R, Stidsen CE, Haahr H | title = Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing | journal = BMJ Open Diabetes Research & Care | volume = 9 | issue = 1 | article-number = e002301 | date = August 2021 | pmid = 34413118 | pmc = 8378355 | doi = 10.1136/bmjdrc-2021-002301 }}</ref> Additionally, three amino acid substitutions are introduced to enhance molecular stability, reduce insulin receptor binding, and slow clearance. These modifications collectively contribute to the prolonged half-life.<ref name="Molecular and pharmacological chara"/>
== Side effects == The most common side effect in all insulin analogues is low blood sugar,<ref name="AHFS2019" /> while in more serious cases, side effects may include low blood potassium.<ref name="AHFS20192">{{cite web | title = Insulin Lispro Monograph for Professionals | url = https://drugs.com/monograph/insulin-lispro.html | url-status = live | archive-url = https://web.archive.org/web/20190306234749/https://drugs.com/monograph/insulin-lispro.html | archive-date = 6 March 2019 | access-date = 3 March 2019 | website = Drugs.com | publisher = American Society of Health-System Pharmacists }}</ref> Insulin allergies are also a concern, although they are not prevalent, affecting only about 2% of people in some form.<ref name="Ghazavi_2011">{{Cite journal | vauthors = Ghazavi MK, Johnston GA | title = Insulin allergy | journal = Clinics in Dermatology | volume = 29 | issue = 3 | pages = 300–305 | date = May–Jun 2011 | pmid = 21496738 | doi = 10.1016/j.clindermatol.2010.11.009 }}</ref> Insulin analogues are generally considered safe during pregnancy,<ref>{{Cite journal | vauthors = Subiabre M, Silva L, Toledo F, Paublo M, López MA, Boric MP, Sobrevia L | title = Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1864 | issue = 9 Pt B | pages = 2949–2956 | date = September 2018 | pmid = 29890222 | doi = 10.1016/j.bbadis.2018.06.005 | s2cid = 48362789 | doi-access = free | title-link = doi | hdl = 10533/232608 | hdl-access = free }}</ref> and many are used in the treatment of gestational diabetes.<ref name="AHFS2019" />
=== Carcinogenicity === All insulin analogs undergo carcinogenicity testing due to insulin's interaction with IGF (insulin-like growth factor) pathways,<ref name="Redwan_2016a">{{Cite journal | vauthors = Redwan EM, Linjawi MH, Uversky VN | title = Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism | journal = Scientific Reports | volume = 6 | issue = 1 | article-number = 23320 | date = 17 March 2016 | pmid = 26983499 | pmc = 4794765 | doi = 10.1038/srep23320 | bibcode = 2016NatSR...623320R | issn = 2045-2322 }}</ref> which can promote abnormal cell growth and tumorigenesis.<ref>{{Cite journal | vauthors = Szablewski L | title = Diabetes mellitus: influences on cancer risk | journal = Diabetes/Metabolism Research and Reviews | volume = 30 | issue = 7 | pages = 543–553 | date = October 2014 | pmid = 25044584 | doi = 10.1002/dmrr.2573 | url = https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2573 | issn = 1520-7552 | url-access = subscription }}</ref> Structural modifications to insulin always carry the risk of unintentionally enhancing IGF signaling, potentially increasing mitogenic activity alongside the intended pharmacological effects.<ref>{{Cite journal | vauthors = Seewoodhary J, Bain SC | title = Diabetes, diabetes therapies and cancer: what's the link? | journal = The British Journal of Diabetes & Vascular Disease | volume = 11 | issue = 5 | pages = 235–238 | date = 1 September 2011 | doi = 10.1177/1474651411421024 | url = https://journals.sagepub.com/doi/10.1177/1474651411421024 | issn = 1474-6514 | url-access = subscription }}</ref> Concerns have been raised specifically regarding the carcinogenic potential of insulin glargine, prompting several epidemiological studies to investigate its safety.<ref name="Redwan_2016a"/>
== Comparison with other insulins ==
=== NPH === {{Main|NPH insulin}}
Neutral Protamine Hagedorn (NPH) insulin, or isophane insulin, is an intermediate-acting insulin developed in 1946 to extend insulin activity through the addition of protamine, which slows absorption.<ref name="AHFS2017">{{cite web | title = Insulin Human | url = https://drugs.com/monograph/insulin-human.html | url-status = live | archive-url = https://web.archive.org/web/20161022221822/https://drugs.com/monograph/insulin-human.html | archive-date = 22 October 2016 | access-date = 8 January 2017 | publisher = The American Society of Health-System Pharmacists }}</ref> It has an onset of about 90 minutes and lasts up to 24 hours, making it suitable for once- or twice-daily administration.<ref name="Owens_1986">{{cite book | vauthors = Owens DR | title = Human Insulin: Clinical Pharmacological Studies in Normal Man | pages = 134–136 | date = 1986 | url = https://books.google.com/books?id=r6OhBQAAQBAJ&pg=PA134 | publisher = Springer Science & Business Media | isbn = 978-94-009-4161-8 | archive-url = https://web.archive.org/web/20170118052228/https://books.google.ca/books?id=r6OhBQAAQBAJ&pg=PA134 | archive-date = 18 January 2017 | url-status = live }}</ref> NPH insulin is available as a recombinant human insulin and is sometimes premixed with short-acting insulin for combined basal and mealtime glucose control.<ref name="BNF69" />
During the 1980s, many individuals experienced difficulties when transitioning to intermediate-acting insulins, particularly NPH formulations of porcine and bovine insulins.<ref name="Owens_2008">{{cite journal | vauthors = Owens DR, Bolli GB | title = Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application | journal = Diabetes Technology & Therapeutics | volume = 10 | issue = 5 | pages = 333–49 | date = October 2008 | pmid = 18715209 | doi = 10.1089/dia.2008.0023 }}</ref> These issues stemmed from variability in absorption and inconsistent glucose control.<ref name="Owens_2008" /> In response, basal insulin analogues were developed to provide a more stable and predictable absorption profile,<ref name="Jonassen_2012">{{cite journal | vauthors = Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U | title = Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin | journal = Pharmaceutical Research | volume = 29 | issue = 8 | pages = 2104–14 | date = August 2012 | pmid = 22485010 | pmc = 3399081 | doi = 10.1007/s11095-012-0739-z | url = }}</ref><ref name="Zinman_2013">{{cite journal | vauthors = Zinman B | title = Newer insulin analogs: advances in basal insulin replacement | journal = Diabetes, Obesity & Metabolism | volume = 15 | issue = Suppl 1 | pages = 6–10 | date = March 2013 | pmid = 23448197 | doi = 10.1111/dom.12068 | url = }}</ref> leading to improved clinical efficacy and glycemic management.<ref name="Owens_2008" /><ref name="Jonassen_2012" />
=== Animal-derived insulins === Animal insulins, including porcine and bovine insulin, were the first clinically used insulins, extracted from the pancreas of animals before the availability of biosynthetic human insulin (insulin human rDNA).<ref name="Quianzon_2012" /><ref>{{Cite journal | vauthors = Rosenfeld L | title = Insulin: Discovery and Controversy | journal = Clinical Chemistry | volume = 48 | issue = 12 | pages = 2270–2288 | date = 1 December 2002 | pmid = 12446492 | doi = 10.1093/clinchem/48.12.2270 | issn = 0009-9147 }}</ref> Porcine insulin differs from human insulin by a single amino acid, while bovine insulin has three variations,<ref name="Richter_2005">{{Cite journal | vauthors = Richter B, Neises G | title = 'Human' insulin versus animal insulin in people with diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2005 | issue = 1 | article-number = CD003816 | date = 24 January 2005 | pmid = 15674916 | pmc = 8406912 | doi = 10.1002/14651858.CD003816.pub2 | editor-last = Cochrane Metabolic and Endocrine Disorders Group }}</ref> yet both exhibit similar activity at the human insulin receptor.<ref name="Richter_2005" /><ref>{{Cite journal | vauthors = Conlon J | title = Evolution of the insulin molecule: insights into structure-activity and phylogenetic relationships | journal = Peptides | volume = 22 | issue = 7 | pages = 1183–1193 | date = July 2001 | pmid = 11445250 | doi = 10.1016/S0196-9781(01)00423-5 | url = https://linkinghub.elsevier.com/retrieve/pii/S0196978101004235 | url-access = subscription }}</ref> Prior to the introduction of biosynthetic insulin, shark-derived insulin was commonly used in Japan, and certain fish insulins were also found to be effective in humans.<ref>{{Cite journal | vauthors = Nagasawa K | title = Use of Fish and Whale Insulin as Drugs in Japan | journal = Journal of AOAC International | volume = 51 | issue = 2 | pages = 326–329 | date = 1 March 1968 | doi = 10.1093/jaoac/51.2.326 | url = https://academic.oup.com/jaoac/article/51/2/326-329/5720924 | issn = 0004-5756 | url-access = subscription }}</ref>
While non-human insulins were widely used, they sometimes triggered allergic reactions, primarily due to impurities and preservatives in insulin preparations.<ref name="Richter_2005" /> Although the formation of non-neutralizing antibodies was rare, some patients experienced immune responses that affected insulin efficacy.<ref name="Richter_2005" /> The development of biosynthetic human insulin significantly reduced these issues, leading to its widespread adoption and largely replacing animal-derived insulin in clinical practice.<ref name="Quianzon_2012" />
== Biosimilar insulin == A biosimilar is a biological medicine that is highly similar to an already approved reference biologic in terms of structure, biological activity, efficacy, and safety.<ref name="Agency_2017">{{Cite web | vauthors = Agency EM | title = Biosimilar medicines: Overview |date=5 May 2017|url=https://www.ema.europa.eu/en/human-regulatory-overview/biosimilar-medicines-overview|access-date=17 March 2025|website=European Medicines Agency (EMA) }}</ref> These medicines are large, complex molecules produced through biotechnology in living systems, such as microorganisms, plant cells, or animal cells.<ref name="Research_2020">{{Cite web | vauthors = Research CF | title = Scientific Considerations in Demonstrating Biosimilarity to a Reference Product | date = 24 April 2020 | url = https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product | archive-url = https://web.archive.org/web/20190619202018/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product | archive-date = 19 June 2019 | access-date = 17 March 2025 | website = U.S. Food and Drug Administration (FDA) }}</ref> Due to differences in the manufacturing process, biosimilars cannot be exact copies of reference biologics but must demonstrate high similarity through extensive structural and functional analysis.<ref name="Heinemann_2022">{{Cite journal | vauthors = Heinemann L, Davies M, Home P, Forst T, Vilsbøll T, Schnell O | title = Understanding Biosimilar Insulins - Development, Manufacturing, and Clinical Trials | journal = Journal of Diabetes Science and Technology | volume = 17 | issue = 6 | pages = 1649–1661 | date = 11 July 2022 | pmid = 35818669 | pmc = 10658691 | doi = 10.1177/19322968221105864 | issn = 1932-2968 }}</ref> Manufacturers are required to show that a biosimilar has no clinically meaningful differences from its reference product regarding safety, purity, and potency, which is assessed through pharmacokinetic (PK) and pharmacodynamic (PD) studies, immunogenicity evaluations, and, if necessary, additional clinical studies.<ref name="Heinemann_2022" /> Biosimilars can only be developed and marketed once the patent on the original reference biologic has expired, allowing for competition and increased availability of biologic therapies.<ref name="Nick_2012">{{cite journal | vauthors = Nick C | title = The US Biosimilars Act: Challenges Facing Regulatory Approval | journal = Pharm Med | volume = 26 | issue = 3 | pages = 145–152 | year = 2012 | doi = 10.1007/bf03262388 | s2cid = 14604362 }}</ref>
The expiration of patents for first-generation insulin analogs has facilitated the development of biosimilar insulins, offering potential to improve global insulin access.<ref name="Heinemann_2022" /> Despite the essential role of insulin, approximately half of individuals who require it do not have access due to high costs and limited availability.<ref>{{Cite journal | vauthors = Basu S, Yudkin JS, Kehlenbrink S, Davies JI, Wild SH, Lipska KJ, Sussman JB, Beran D | title = Estimation of global insulin use for type 2 diabetes, 2018–30: a microsimulation analysis | journal = The Lancet. Diabetes & Endocrinology | volume = 7 | issue = 1 | pages = 25–33 | date = January 2019 | pmid = 30470520 | doi = 10.1016/S2213-8587(18)30303-6 | url = https://linkinghub.elsevier.com/retrieve/pii/S2213858718303036 | hdl = 20.500.11820/31689153-c908-4a3a-b797-a6b1a73badfe | hdl-access = free }}</ref> This issue is particularly pronounced in low-income countries,<ref>{{Cite journal | vauthors = Baumgart DC, Misery L, Naeyaert S, Taylor PC | title = Biological Therapies in Immune-Mediated Inflammatory Diseases: Can Biosimilars Reduce Access Inequities? | journal = Frontiers in Pharmacology | volume = 10 | article-number = 279 | date = 28 March 2019 | pmid = 30983996 | pmc = 6447826 | doi = 10.3389/fphar.2019.00279 | doi-access = free | issn = 1663-9812 }}</ref> where economic factors can restrict the use of biologic treatments such as insulin.<ref>{{Cite journal | vauthors = Ewen M, Joosse HJ, Beran D, Laing R | title = Insulin prices, availability and affordability in 13 low-income and middle-income countries | journal = BMJ Global Health | volume = 4 | issue = 3 | article-number = e001410 | date = June 2019 | pmid = 31263585 | pmc = 6570978 | doi = 10.1136/bmjgh-2019-001410 | issn = 2059-7908 }}</ref> Biosimilar insulins, which have a shorter development timeline of about eight years compared to 12 years for novel biologic drugs, provide a more affordable alternative, with development costs ranging from 10% to 20% of those for new biologics.<ref>{{Cite journal | vauthors = Agbogbo FK, Ecker DM, Farrand A, Han K, Khoury A, Martin A, McCool J, Rasche U, Rau TD, Schmidt D, Sha M, Treuheit N | title = Current perspectives on biosimilars | journal = Journal of Industrial Microbiology & Biotechnology | volume = 46 | issue = 9–10 | pages = 1297–1311 | date = 1 October 2019 | pmid = 31317293 | pmc = 6791907 | doi = 10.1007/s10295-019-02216-z | issn = 1476-5535 }}</ref> These products could help improve access to treatment and reduce disparities in insulin availability.<ref name="Heinemann_2022" />
The global market for biologic medicines, including insulin, grew from $46 billion in 2002 to $390 billion in 2020, accounting for 28% of the global pharmaceutical market.<ref>{{cite report | url = https://www.medicinesforeurope.com/wp-content/uploads/2016/03/IMS-Institute-Biosimilar-Report-March-2016-FINAL.pdf | work = IMS Institute for Healthcare Informatics. | title = Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets Introduction. | date = 2016 }}</ref> In the United States, biologics represented 43% of drug expenditures, totaling $211 billion in 2019, with biosimilar spending expected to rise from $5.2 billion in 2019 to nearly $27 billion by 2024.<ref name="Heinemann_2022" /> In Europe, biologics accounted for 34% of medicine spending, reaching US$78.6 billion in 2021, with the biosimilar market valued at $8.8 billion.<ref>{{cite report | url = https://www.iqvia.com/-/media/iqvia/pdfs/library/white-papers/the-impact-of-biosimilar-competition-in-europe-2021.pdf | work = The IQVIA Institute for Human Data Science. | title = The Impact of Biosimilar Competition in Europe. | date = 2021 }}</ref> The global human insulin market was valued at $22.9 billion in 2020, while the biosimilar insulin market stood at $2.3 billion, projected to grow to $5.6 billion by 2027.<ref name="Heinemann_2022" /> The introduction of biosimilar insulins has increased market competition, offering a cost-effective alternative that could lower treatment costs and reduce strain on healthcare systems.<ref name="Heinemann_2022" />
Since the approval of the first biosimilar insulin, interest in the products has increased. However, uncertainty regarding their safety and efficacy has slowed their adoption among healthcare professionals.<ref>{{Cite journal | vauthors = Kabir ER, Moreino SS, Sharif Siam MK | title = The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy | journal = Biomolecules | volume = 9 | issue = 9 | page = 410 | date = 24 August 2019 | pmid = 31450637 | pmc = 6770099 | doi = 10.3390/biom9090410 | doi-access = free | issn = 2218-273X }}</ref> Regulatory agencies, such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), have established approval pathways to ensure biosimilar insulins meet the same quality, safety, and efficacy standards as reference products.<ref name="Agency_2017" /><ref name="Research_2020" /><ref name="Heinemann_2022" />
=== Available biosimilars === As of 2025, there are three commercially available biosimilar insulins. They are insulin glargine-yfgn, insulin glargine-aglr, and insulin aspart-szjj. Insulin glargine-yfgn is marketed under the name Semglee, and received FDA approval in July 2021, but development began before that.<ref name="Commissioner_2021">{{Cite web | title = FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes | date = 30 July 2021 | url = https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes | archive-url = https://web.archive.org/web/20210728212935/http://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes | archive-date = 28 July 2021 | access-date = 17 March 2025 | website = U.S. Food and Drug Administration (FDA) }}</ref> The approval was granted to Mylan,<ref name="Commissioner_2021" /> which was merged with another company into Viatris in 2020.<ref>{{cite news | vauthors = Gough PJ | title = After nearly 60 years, Mylan makes way for Viatris | date = 16 November 2020 | url = https://www.bizjournals.com/pittsburgh/news/2020/11/16/after-nearly-60-years-mylan-makes-way-for-viatris.html | access-date = 10 December 2020 | publisher = Pittsburgh Business Times }}</ref> The second approved biosimilar insulin, insulin glargine-aglr, was approved by the FDA in December 2021 to be produced by Lilly under the name Rezvoglar.<ref name="Biosimilars_Center">{{Cite web | title = Rezvoglar Becomes Second Interchangeable Insulin Biosimilar | date = 23 November 2022 | url = https://www.centerforbiosimilars.com/view/rezvoglar-becomes-second-interchangeable-insulin-biosimilar | access-date = 17 March 2025 | website = Center for Biosimilars }}</ref> In February 2025, the FDA approved the very first short-acting biosimilar insulin, insulin aspart szjj. It is manufactured by Viatris and sold under the name Merilog.<ref name="Commissioner_2025">{{Cite web | vauthors = Commissioner OO | title = FDA Approves First Rapid-Acting Insulin Biosimilar Product for Treatment of Diabetes | date = 18 February 2025 | url = https://www.fda.gov/news-events/press-announcements/fda-approves-first-rapid-acting-insulin-biosimilar-product-treatment-diabetes | access-date = 17 March 2025 | website = U.S. Food and Drug Administration (FDA) }}</ref>
It is of note that although the name of insulin lispro-aabc, which is marketed as Lyumjev by Lilly, is similar to the names of biosimilars, it is not a biosimilar insulin. Insulin lispro-aabc is simply a faster formulation of insulin lispro.<ref name="Lilly">{{Cite web | title = FDA approves Lyumjev™ (insulin lispro-aabc injection), Lilly's new rapid-acting insulin |url=https://investor.lilly.com/news-releases/news-release-details/fda-approves-lyumjevtm-insulin-lispro-aabc-injection-lillys-new |archive-url=https://web.archive.org/web/20250129002107/https://investor.lilly.com/news-releases/news-release-details/fda-approves-lyumjevtm-insulin-lispro-aabc-injection-lillys-new |archive-date=29 January 2025|access-date=18 March 2025|website=Eli Lilly and Company|url-status=live}}</ref>
== Modifications == Before biosynthetic human recombinant analogues became available, porcine insulin was chemically modified to create human insulin.<ref name="Redwan_2016a"/> These semisynthetic insulins were produced by altering amino acid side chains at the N-terminus and C-terminus to modify absorption, distribution, metabolism, and excretion (ADME) characteristics.<ref name="Redwan_2009">{{Cite journal | vauthors = Redwan ER | title = Animal-Derived Pharmaceutical Proteins | journal = Journal of Immunoassay & Immunochemistry | volume = 30 | issue = 3 | pages = 262–290 | date = 30 June 2009 | pmid = 19591041 | doi = 10.1080/15321810903084400 | url = https://tandfonline.com/doi/abs/10.1080/15321810903084400 | issn = 1532-1819 | url-access = subscription }}</ref> Novo Nordisk developed one such method by enzymatically converting porcine insulin into human insulin by replacing the single differing amino acid.<ref name="Richter_2005" /><ref name="Redwan_2009" /> Unmodified human and porcine insulins naturally form hexamers with zinc, requiring dissociation into monomers before binding to insulin receptors.<ref name="Horuk_1980">{{Cite journal | vauthors = Horuk R, Blundell TL, Lazarus NR, Neville RW, Stone D, Wollmer A | title = A monomeric insulin from the porcupine (Hystrix cristata), an Old World hystricomorph | journal = Nature | volume = 286 | issue = 5775 | pages = 822–824 | date = August 1980 | pmid = 6995860 | doi = 10.1038/286822a0 | url = https://nature.com/articles/286822a0 | bibcode = 1980Natur.286..822H | issn = 0028-0836 | url-access = subscription }}</ref> This delays insulin activity when injected subcutaneously, making it less effective for postprandial glucose control.<ref>{{Cite journal | vauthors = Gingras V, Taleb N, Roy-Fleming A, Legault L, Rabasa-Lhoret R | title = The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes | journal = Diabetes, Obesity & Metabolism | volume = 20 | issue = 2 | pages = 245–256 | date = February 2018 | pmid = 28675686 | pmc = 5810921 | doi = 10.1111/dom.13052 | issn = 1462-8902 }}</ref>
Basal insulin analogues were developed with altered isoelectric points, allowing them to precipitate at physiological pH and dissolve slowly, providing insulin coverage for up to 24 hours.<ref name="Redwan_2016a" /> Some, like insulin detemir, bind to albumin rather than fat, prolonging their action.<ref>{{Cite journal | vauthors = Philips JC, Scheen A | title = Insulin detemir in the treatment of type 1 and type 2 diabetes | journal = Vascular Health and Risk Management | volume = 2 | issue = 3 | pages = 277–283 | date = August 2006 | pmid = 17326333 | pmc = 1993987 | doi = 10.2147/vhrm.2006.2.3.277 | doi-access = free | issn = 1176-6344 }}</ref> Non-hexameric (monomeric) insulins were later introduced for faster-acting mealtime coverage, mimicking naturally occurring monomeric insulins found in certain animal species.<ref name="Horuk_1980" /> These advancements in insulin formulation allowed for greater flexibility in diabetes management, with basal insulin analogues providing steady background insulin levels and short-acting analogues offering improved postprandial glucose control.<ref name="Redwan_2016a" />
Zinc-complexed insulins continued to be used for slow-release basal support, covering approximately 50% of daily insulin needs, while mealtime insulin made up the remaining half.<ref>{{Cite journal | vauthors = Owens DR | title = Insulin Preparations with Prolonged Effect | journal = Diabetes Technology & Therapeutics | volume = 13 Suppl 1 | issue = S1 | pages = S5–14 | date = June 2011 | pmid = 21668337 | doi = 10.1089/dia.2011.0068 | url = https://liebertpub.com/doi/10.1089/dia.2011.0068 | issn = 1520-9156 | url-access = subscription }}</ref> The development of monomeric insulins addressed the limitations of hexameric formulations, ensuring faster absorption and better glycemic control.<ref name="Redwan_2016a" /> As research progressed, insulin analogues with enhanced receptor binding, extended duration, and improved stability became standard in modern diabetes treatment, reducing variability in glucose levels and lowering the risk of hypoglycemia.<ref name="Quianzon_2012" />
== History ==
=== Early insulins (1922–1995) === thumb|268x268px|Frederick Banting and Charles Best, the two men who discovered insulin in 1922|alt=Two men standing behind a dog, black and white photo circa 1922 The development of insulin therapy has progressed significantly since the early 20th century, starting with animal-derived insulins.<ref name="Quianzon_2012" /> In 1922, Frederick Banting and Charles Best successfully used bovine insulin extract to treat humans for the first time.<ref name="Discovery2">{{Cite web | title = Frederick Banting, Charles Best, James Collip, and John Macleod | date = June 2016 | url = https://sciencehistory.org/historical-profile/frederick-banting-charles-best-james-collip-and-john-macleod | url-status = live | archive-url = https://web.archive.org/web/20181201105332/https://sciencehistory.org/historical-profile/frederick-banting-charles-best-james-collip-and-john-macleod | archive-date = 1 December 2018 | access-date = 22 August 2018 | website = Science History Institute }}</ref> This breakthrough led to the commercial production of bovine insulin in 1923 by Eli Lilly and Company.<ref name="Quianzon_2012" /> That same year, Hans Christian Hagedorn founded the Nordisk Insulinlaboratorium in Denmark, which later became Novo Nordisk.<ref>{{cite web | title = The History of Insulin | location = Basel, Switzerland | url = https://karger.com/ProdukteDB/Katalogteile/isbn3_8055/_83/_53/Insulin_02.pdf | archive-url = https://web.archive.org/web/20160304202218/https://karger.com/ProdukteDB/Katalogteile/isbn3_8055/_83/_53/Insulin_02.pdf | archive-date = 4 March 2016 | access-date = 10 June 2015 | website = Karger.com/ | publisher = Karger Publishers }}</ref> In 1926, Nordisk received a Danish charter to produce insulin as a non-profit entity.<ref>{{cite web | title = Insulin 100 years | url = https://novonordisk.com/about/insulin-100-years.html }}</ref> In 1936, Canadian researchers D.M. Scott and A.M. Fisher developed a zinc insulin mixture,<ref>{{Cite journal | vauthors = Scott DA, Fisher AM | title = The Insulin and the Zinc Content of Normal and Diabetic Pancreas | journal = The Journal of Clinical Investigation | volume = 17 | issue = 6 | pages = 725–728 | date = 1 November 1938 | pmid = 16694619 | pmc = 434829 | doi = 10.1172/JCI101000 | url = http://jci.org/articles/view/101000 | issn = 0021-9738 }}</ref> which was licensed to Novo. During this time, Hagedorn discovered that adding protamine to insulin could prolong its action,<ref name="Quianzon_2012" /><ref name="Saleem_2025">{{Citation |last1=Saleem |first1=Fatima |title=NPH Insulin |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK549860/ |access-date=10 March 2025 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31751050 |last2=Sharma |first2=Ashish}}</ref> which led to the development of Neutral Protamine Hagedorn (NPH) insulin in 1946.<ref name="Saleem_2025" /> NPH insulin was marketed by Nordisk in 1950. By 1953, Novo also developed Lente insulin by adding zinc to porcine and bovine insulins, resulting in a longer-acting form.<ref>{{cite journal | vauthors = Hallas-Møller K, Petersen K, Schlichtkrull J | title = Crystalline and Amorphous Insulin-Zinc Compounds with Prolonged Action | url = https://archive.org/details/sim_science_1952-10-10_116_3015/page/394 | journal = Science | location = New York, N.Y. | volume = 116 | issue = 3015 | pages = 394–398 | date = 1952 | pmid = 12984132 | doi = 10.1126/science.116.3015.394 | bibcode = 1952Sci...116..394H | issn = 0036-8075 | jstor = 1680777 }}</ref>
A significant advancement in insulin production occurred in 1978 when Genentech developed the biosynthesis of recombinant human insulin using Escherichia coli bacteria and recombinant DNA technology.<ref name="Genentech_cloning">{{Cite web | title = Cloning Insulin | last = Genentech | url = https://gene.com/stories/cloning-insulin | access-date = 10 March 2025 | website = Genentech: Breakthrough science. One moment, one day, one person at a time. }}</ref> This allowed for the production of insulin identical to that produced by the human pancreas.<ref name="Genentech_cloning" /> In 1981, Novo Nordisk chemically and enzymatically converted porcine insulin into human insulin.<ref>{{Cite web | title = Insulin | url = https://cen.acs.org/articles/83/i25/Insulin.html | access-date = 10 March 2025 | website = Chemical & Engineering News | date = 21 January 2025 }}</ref> Genentech's synthetic human insulin, produced in partnership with Eli Lilly, was approved by the U.S. Food and Drug Administration in 1982.<ref>{{Cite web | title = 100 Years of Insulin | website = U.S. Food and Drug Administration (FDA) | date = 9 August 2024 | url = https://fda.gov/about-fda/fda-history-exhibits/100-years-insulin | archive-url = https://web.archive.org/web/20220705152640/https://www.fda.gov/about-fda/fda-history-exhibits/100-years-insulin | archive-date = 5 July 2022 }}</ref> Lilly's biosynthetic recombinant insulin, branded as Humulin, was introduced in 1983. In 1985, Axel Ullrich sequenced the human insulin receptor, further enhancing the understanding of insulin's biological mechanisms.<ref>{{Cite journal | vauthors = Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J | title = Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes | journal = Nature | volume = 313 | issue = 6005 | pages = 756–761 | date = February 1985 | pmid = 2983222 | doi = 10.1038/313756a0 | bibcode = 1985Natur.313..756U | issn = 0028-0836 }}</ref> By 1988, Novo Nordisk produced synthetic recombinant human insulin, which further improved insulin availability and consistency.<ref name="Quianzon_2012" />
=== Initial analogue development (1996–2014) === The development of insulin analogues began with Humalog (insulin lispro), a short-acting insulin analogue developed by Eli Lilly, which was approved by the FDA in 1996.<ref name="Quianzon_2012" /> Humalog was designed to be absorbed more quickly than regular insulin, offering improved flexibility in meal timing and postprandial glucose control.<ref name="Noble_1998" /> In 2000, Lantus (insulin glargine) was approved by the FDA and the European Medicines Agency (EMA).<ref name="Drug Approval Package">{{Cite web | title = Drug Approval Package | url = https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm | archive-url = https://web.archive.org/web/20250208160300/https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm | archive-date = 8 February 2025 | access-date = 11 March 2025 | website = U.S. Food and Drug Administration (FDA) | url-status = live }}</ref> Lantus is a long-acting insulin analogue designed to provide a steady basal level of insulin throughout the day, typically lasting up to 24 hours, thereby reducing the need for multiple daily injections.<ref name="AHFS2018" /><ref name="Cunningham_2025" /> In 2004, Apidra (insulin glulisine), another short-acting insulin analog, was approved by Sanofi-Aventis to improve postprandial glucose control.<ref name="Approval_package" />
In 2005, Levemir (insulin detemir), developed by Novo Nordisk, was approved for clinical use.<ref name="Niloy_2023" /><ref name="Drug_Approval_Package_2">{{Cite web | title = Drug Approval Package | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021-536_LevemirTOC.cfm | archive-url = https://web.archive.org/web/20250228201310/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021-536_LevemirTOC.cfm | archive-date = 28 February 2025 | access-date = 18 March 2025 | website = U.S. Food and Drug Administration (FDA) | url-status = live }}</ref> Levemir is a long-acting insulin analogue similar to Lantus but with a slightly shorter duration of action.<ref name="Mathieu_2017" /> It provides stable basal insulin coverage with a reduced risk of hypoglycemia compared to older insulins.<ref name="Niloy_2023" />
=== Modern analogues (2015–present) === alt=graph showing release lengths of insulin analogues|thumb|300x300px|Pharmacokinetic comparison between daily insulins and once weekly icodec insulin As of 2025, many companies are researching and manufacturing new insulin analogues. These insulins are usually designed to be either ultra-short-acting or ultra-long-acting.<ref name="Jarosinski_2021">{{Cite journal | vauthors = Jarosinski MA, Chen YS, Varas N, Dhayalan B, Chatterjee D, Weiss MA | title = New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 107 | issue = 4 | pages = 909–928 | date = 24 November 2021 | pmid = 34850005 | pmc = 8947325 | doi = 10.1210/clinem/dgab849 | issn = 0021-972X }}</ref> Insulin degludec, an ultra-long-acting insulin analog, was developed by Novo Nordisk and approved by the FDA in 2015.<ref name="Niloy_2023" /> Insulin degludec has an extended duration of action, lasting up to 42 hours, offering greater flexibility in dosing schedules.<ref name="Niloy_2023" />
In March 2024, insulin icodec was approved for medical use in Canada.<ref name="Health_Canada" /> The same month, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion, recommending the granting of marketing authorization for Awiqli, under which insulin icodec is marketed.<ref name="Awiqli EPAR">{{cite web | title = Awiqli EPAR | date = 21 March 2024 | url = https://ema.europa.eu/en/medicines/human/EPAR/awiqli | url-status = live | archive-url = https://web.archive.org/web/20240323162038/https://ema.europa.eu/en/medicines/human/EPAR/awiqli | archive-date = 23 March 2024 | access-date = 23 March 2024 | website = European Medicines Agency (EMA) }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Following the CHMP's recommendation, insulin icodec was approved for medical use in the European Union in May 2024.<ref>{{Cite web | vauthors = Agency EM | title = Awiqli |date=3 June 2024|url=https://ema.europa.eu/en/medicines/human/EPAR/awiqli|access-date=11 March 2025|website=European Medicines Agency (EMA)}}</ref> Insulin icodec has a plasma half-life more than eight days<ref name="Kjeldsen_2021" /> (compared to 25 hours of the previous longest-acting insulin analogue insulin degludec), making it a once-weekly basal insulin.<ref name="Kjeldsen_2021" />
==== Experimental analogues ==== Insulin tregopil is an experimental ultra-fast-acting<ref name="Khedkar_2020">{{cite journal | vauthors = Khedkar A, Lebovitz H, Fleming A, Cherrington A, Jose V, Athalye SN, Vishweswaramurthy A | title = Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus | journal = Clinical Pharmacology in Drug Development | volume = 9 | issue = 1 | pages = 74–86 | date = January 2020 | pmid = 31392840 | pmc = 7004075 | doi = 10.1002/cpdd.730 | doi-access = free }}</ref> insulin that is being developed by Biocon.<ref name="Khedkar_2019">{{cite journal | vauthors = Khedkar A, Lebovitz H, Fleming A, Cherrington A, Jose V, Athalye SN, Vishweswaramurthy A | title = Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study | journal = Clinical and Translational Science | volume = 12 | issue = 3 | pages = 276–282 | date = May 2019 | pmid = 30592549 | pmc = 6510383 | doi = 10.1111/cts.12609 | doi-access = free }}</ref> Unlike other insulin analogues, it is designed to be taken orally. It has been modified with the covalent attachment of a methoxy-triethylene-glycol-propionyl moiety at Lys-β29-amino group of the B-chain.<ref name="Joshi_2023">{{cite journal | vauthors = Joshi S, Jayanth V, Loganathan S, Sambandamurthy VK, Athalye SN | title = Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus | journal = Drugs | volume = 83 | issue = 13 | pages = 1161–1178 | date = September 2023 | pmid = 37578592 | doi = 10.1007/s40265-023-01925-1 | s2cid = 260885799 }}</ref> This modification, along with the use of sodium caprate as a permeation enhancer, allows insulin tregopil to be absorbed through the gastrointestinal tract.<ref name="Joshi_2023" /> Another oral analogue called ORMD-0801 is, as of 2025, in development by Oramed Pharmaceuticals.<ref name="Eldor_2013">{{cite journal | vauthors = Eldor R, Arbit E, Corcos A, Kidron M | title = Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study | journal = PLOS ONE | volume = 8 | issue = 4 | article-number = e59524 | date = 9 April 2013 | pmid = 23593142 | pmc = 3622027 | doi = 10.1371/journal.pone.0059524 | bibcode = 2013PLoSO...859524E | issn = 1932-6203 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Eldor R, Neutel J, Homer K, Kidron M | title = Efficacy and safety of 28-day treatment with oral insulin ( ORMD -0801) in patients with type 2 diabetes: A randomized, placebo-controlled trial | journal = Diabetes, Obesity & Metabolism | volume = 23 | issue = 11 | pages = 2529–2538 | date = November 2021 | pmid = 34310011 | doi = 10.1111/dom.14499 | s2cid = 236432013 }}</ref><ref>{{cite journal | vauthors = Eldor R, Fleming GA, Neutel J, Homer KE, Kidron M, Rosenstock J | title = 1004-P: Oral Insulin (ORMD-0801) Effects on Glucose Parameters in Uncontrolled T2DM on OADs | journal = Diabetes | volume = 69 | issue = Supplement_1 | date = 1 June 2020 | article-number = 1004-P | doi = 10.2337/db20-1004-P | s2cid = 225845842 }}</ref><ref>{{cite journal | vauthors = Eldor R, Francis BH, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J | title = Oral insulin ( ORMD -0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study | journal = Diabetes, Obesity & Metabolism | volume = 25 | issue = 4 | pages = 943–952 | date = April 2023 | pmid = 36281496 | doi = 10.1111/dom.14901 | s2cid = 253108516 }}</ref>
Insulin efsitora alfa is an experimental insulin analogue developed by Eli Lilly for the treatment of diabetes. Its glycemic control and safety were found to be similar to insulin degludec in a phase II clinical trial.<ref name="Heise_2023">{{cite journal | vauthors = Heise T, Chien J, Beals JM, Benson C, Klein O, Moyers JS, Haupt A, Pratt EJ | title = Pharmacokinetic and pharmacodynamic properties of the novel basal insulin Fc (insulin efsitora alfa), an insulin fusion protein in development for once-weekly dosing for the treatment of patients with diabetes | journal = Diabetes, Obesity & Metabolism | volume = 25 | issue = 4 | pages = 1080–1090 | date = 2023 | pmid = 36541037 | doi = 10.1111/dom.14956 | s2cid = 255034380 }}</ref><ref>{{cite journal | vauthors = Moyers JS, Hansen RJ, Day JW, Dickinson CD, Zhang C, Ruan X, Ding L, Brown RM, Baker HE, Beals JM | title = Preclinical Characterization of LY3209590, a Novel Weekly Basal Insulin Fc-Fusion Protein | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 382 | issue = 3 | pages = 346–355 | date = 2022 | pmid = 35840338 | doi = 10.1124/jpet.122.001105 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kazda CM, Bue-Valleskey JM, Chien J, Zhang Q, Chigutsa E, Landschulz W, Wullenweber P, Haupt A, Dahl D | title = Novel Once-Weekly Basal Insulin Fc Achieved Similar Glycemic Control With a Safety Profile Comparable to Insulin Degludec in Patients With Type 1 Diabetes | journal = Diabetes Care | volume = 46 | issue = 5 | pages = 1052–1059 | date = 2023 | pmid = 36920867 | pmc = 10154655 | doi = 10.2337/dc22-2395 | url = https://diabetesjournals.org/care/article/46/5/1052/148588/Novel-Once-Weekly-Basal-Insulin-Fc-Achieved }}</ref>
NNC2215 is a bioengineered glucose-sensitive insulin analogue developed by Novo Nordisk researchers.<ref name="PhD_2024">{{Cite web | vauthors = Grinstein JD | title = Novo Nordisk Researchers Engineer Glucose-Sensitive Insulin Switch | date = 21 October 2024 | url = https://insideprecisionmedicine.com/topics/translational-research/novo-nordisk-researchers-engineer-glucose-sensitive-insulin-switch/ | access-date = 1 January 2025 | website = Inside Precision Medicine }}</ref> The drug is designed to adjust its activity based on blood glucose levels, reducing insulin sensitivity when glucose concentrations are low, thereby lowering the risk of hypoglycemia.<ref>{{Cite journal | vauthors = Kwon D | title = 'Smart' insulin prevents diabetic highs — and deadly lows | journal = Nature | date = 16 October 2024 | pmid = 39414970 | doi = 10.1038/d41586-024-03357-7 | url = https://nature.com/articles/d41586-024-03357-7 | url-access = subscription }}</ref> It also provides more stable blood sugar control by responding dynamically to fluctuations in glucose levels. A study on NNC2215 was published in the journal ''Nature'' on 16 October 2024, describing its potential as a major advancement in diabetes treatment and the role of protein engineering in future medicine.<ref>{{Cite journal | vauthors = Hoeg-Jensen T, Kruse T, Brand CL, Sturis J, Fledelius C, Nielsen PK, Nishimura E, Madsen AR, Lykke L, Halskov KS, Koščová S, Kotek V, Davis AP, Tromans RA, Tomsett M | title = Glucose-sensitive insulin with attenuation of hypoglycaemia | journal = Nature | volume = 634 | issue = 8035 | pages = 944–951 | date = 16 October 2024 | pmid = 39415004 | pmc = 11499270 | doi = 10.1038/s41586-024-08042-3 | bibcode = 2024Natur.634..944H | issn = 1476-4687 }}</ref> The development of glucose-sensitive insulin has been an area of interest in diabetes research since 1979, aiming to address blood sugar fluctuations.<ref>{{Cite journal | vauthors = Brownlee M, Cerami A | title = A Glucose-Controlled Insulin-Delivery System: Semisynthetic Insulin Bound to Lectin | journal = Science | location = New York, N.Y. | volume = 206 | issue = 4423 | pages = 1190–1191 | date = 7 December 1979 | pmid = 505005 | doi = 10.1126/science.505005 | url = https://science.org/doi/10.1126/science.505005 | bibcode = 1979Sci...206.1190B | url-access = subscription }}</ref> Several previous attempts have been made to create glucose-responsive insulin, with varying degrees of success.<ref name="Jarosinski_2021" /><ref>{{Cite journal | vauthors = Liu Y, Wang S, Wang Z, Yu J, Wang J, Buse JB, Gu Z | title = Recent Progress in Glucose-Responsive Insulin | journal = Diabetes | volume = 73 | issue = 9 | pages = 1377–1388 | date = 10 June 2024 | pmid = 38857114 | doi = 10.2337/dbi23-0028 | url = https://diabetesjournals.org/diabetes/article-abstract/73/9/1377/156832/Recent-Progress-in-Glucose-Responsive-Insulin?redirectedFrom=fulltext | issn = 0012-1797 | url-access = subscription }}</ref>
In the 2010s, Eli Lilly and Company developed an experimental basal insulin analogue called peglispro (BIL), which showed a prolonged and flat activity profile with hepato-preferential action. Although BIL demonstrated improved glycemic control, reduced nocturnal hypoglycemia, and less weight gain compared to insulin glargine, it was associated with increased liver fat, triglycerides, and liver enzyme levels.<ref>{{Cite journal | vauthors = Jacober SJ, Prince MJ, Beals JM, Hartman ML, Qu Y, Linnebjerg H, Garhyan P, Haupt A | title = Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action | journal = Diabetes, Obesity & Metabolism | volume = 18 Suppl 2 | pages = 3–16 | date = October 2016 | pmid = 27723228 | doi = 10.1111/dom.12744 | issn = 1463-1326 }}</ref> Due to these concerns and the uncertain regulatory pathway, Lilly discontinued the development of BIL in 2015.<ref>{{Cite web | title = Lilly Ends Basal Insulin Peglispro Development Program | date = 4 December 2015 | url = https://investor.lilly.com/news-releases/news-release-details/lilly-ends-basal-insulin-peglispro-development-program | website = Lilly Investors }}</ref>
Other experimental analogues that are in development include LAPS Insulin115,<ref name="Wronkowitz_2017">{{Cite journal | vauthors = Wronkowitz N, Hartmann T, Görgens SW, Dietze-Schroeder D, Indrakusuma I, Choi IY, Park SH, Lee YM, Kwon SC, Kang Y, Hompesch M, Eckel J | title = LAPS Insulin115: A novel ultra-long-acting basal insulin with a unique action profile | journal = Diabetes, Obesity & Metabolism | volume = 19 | issue = 12 | pages = 1722–1731 | date = December 2017 | pmid = 28497570 | doi = 10.1111/dom.13006 | issn = 1463-1326 }}</ref> an ultralong analogue being researched by Hanmi Pharm, and two basal oral analogues in development by Novo Nordisk, OI338 and OI320.<ref name="Kjeldsen_2021a">{{Cite journal | vauthors = Kjeldsen TB, Hubálek F, Tagmose TM, Pridal L, Refsgaard HH, Porsgaard T, Gram-Nielsen S, Hovgaard L, Valore H, Münzel M, Hjørringgaard CU, Jeppesen CB, Manfè V, Hoeg-Jensen T, Ludvigsen S | title = Engineering of Orally Available, Ultralong-Acting Insulin Analogues: Discovery of OI338 and OI320 | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 1 | pages = 616–628 | date = 14 January 2021 | pmid = 33356257 | doi = 10.1021/acs.jmedchem.0c01576 | issn = 1520-4804 }}</ref><ref name="Jarosinski_2021" />
=== Approval overview === Since 1996, seven novel insulin analogues have been approved. Three short-acting and four long-acting analogues have been made, while one short-acting lispro modification has been produced.<ref name="Lilly" /> Since 2021, three insulin biosimilars have been approved, two of which are long-acting<ref name="Biosimilars_Center" /> and one of which is short-acting.<ref name="Commissioner_2025" /> * 1996: ''Insulin lispro'', which was originally manufactured by Eli Lilly and Company, is granted approval.<ref name="Quianzon_2012" /> * 2000: ''Insulin aspart'', which was created by Novo Nordisk, is approved.<ref name="AHFS2019">{{cite web | title = Insulin Aspart Monograph for Professionals | url = https://drugs.com/monograph/insulin-aspart.html | url-status = live | archive-url = https://web.archive.org/web/20190306234812/https://drugs.com/monograph/insulin-aspart.html | archive-date = 6 March 2019 | access-date = 3 March 2019 | website = Drugs.com | publisher = American Society of Health-System Pharmacists }}</ref> * 2000: ''Insulin glargine'', which was developed by Sanofi-Aventis, is approved.<ref name="Drug Approval Package"/> * 2004: ''Insulin glulisine'', also developed by Sanofi-Aventis, is approved.<ref name="Approval_package" /> * 2005: ''Insulin detemir'', which was formulated by Novo Nordisk, gets approval.<ref>{{Cite web | title = Levemir (insulin detemir) FDA Approval History | url = https://drugs.com/history/levemir.html | access-date = 11 March 2025 | website = Drugs.com }}</ref><ref name="Drug_Approval_Package_2" /> * 2015: ''Insulin degludec,'' created by Novo Nordisk, is approved.<ref name="Niloy_2023" /> * 2020: ''Insulin lispro-aabc'', a faster insulin lispro formulation created by Eli Lilly and Company, is approved.<ref name="Lilly" /> * 2021: ''Insulin glargine-yfgn'', the first approved insulin biosimilar, which is produced by Viatris, is approved.<ref name="Commissioner_2021" /> * 2021: ''Insulin glargine-aglr'', a biosimilar produced by Eli Lilly and Company, is granted approval.<ref name="Biosimilars_Center" /> * 2024: ''Insulin icodec'', the newest commercially available analogue by Novo Nordisk, gets approval.<ref name="Awiqli EPAR" /> * 2025: ''Insulin aspart-szjj'', the first short-acting biosimilar, created by Viatris, is approved.<ref name="Commissioner_2025" /> <timeline> ImageSize = width:800 height:auto barincrement:22 PlotArea = left:170 bottom:65 top:30 right:20 Alignbars = justify DateFormat = mm/dd/yyyy Period = from:01/01/1995 till:12/01/2025 TimeAxis = orientation:horizontal format:yyyy Colors = id:short value:rgb(1,0.0,0) legend:Short-acting id:long value:rgb(0,0.4,1) legend:Long-acting id:shortb value:rgb(1,0.6,0.8) legend:Short-acting_biosimilar id:longb value:rgb(0,0.8,1) legend:Long-acting_biosimilar id:bars value:gray(1) id:grid1 value:rgb(0.5,0.5,0.5) id:grid2 value:gray(0.92) Legend = orientation:vertical position:bottom BackgroundColors = bars:bars ScaleMajor = increment:5 start:1995 gridcolor:grid1 ScaleMinor = increment:1 start:1995 gridcolor:grid2 TextData= pos:(300,272) fontsize:M text:Insulin analogue and biosimilar approvals, 1995-2025 BarData = bar:Lispro text:Insulin_lispro bar:Glargine text:Insulin_glargine bar:Aspart text:Insulin_aspart bar:Glulisine text:Insulin_glulisine bar:Detemir text:Insulin_detemir bar:Degludec text:Insulin_degludec bar:Glargine-yfgn text:Insulin_glargine-yfgn bar:Glargine-aglr text:Insulin_glargine-aglr bar:Icodec text:Insulin_icodec bar:Aspart-szjj text:Insulin_aspart-szjj PlotData= width:10 textcolor:black align:left anchor:from shift:(10,-4) bar:Lispro width:15 from:06/14/1996 till:12/01/2025 color:short bar:Glargine width:15 from:04/20/2000 till:12/01/2025 color:long bar:Aspart width:15 from:06/07/2000 till:12/01/2025 color:short bar:Glulisine width:15 from:04/16/2004 till:12/01/2025 color:short bar:Detemir width:15 from:06/16/2005 till:12/01/2025 color:long bar:Degludec width:15 from:09/25/2015 till:12/01/2025 color:long bar:Glargine-yfgn width:15 from:07/28/2021 till:12/01/2025 color:longb bar:Glargine-aglr width:15 from:12/01/2021 till:12/01/2025 color:longb bar:Icodec width:15 from:03/20/2024 till:12/01/2025 color:long bar:Aspart-szjj width:15 from:02/14/2025 till:12/01/2025 color:shortb </timeline>
=== Unapproved analogues overview === Many experimental insulin analogues are being developed to improve diabetes treatment. These include new injectable types and oral forms. Oral insulin is being studied as a way to avoid injections and better match natural insulin delivery.
* ''Insulin tregopil'', in development by Biocon<ref name="Khedkar_2019" /> * ''Insulin efsitora alfa'', made by Lilly''<ref name="Heise_2023" />'' * ''ORMD-0801'', an oral analogue produced by Oramed<ref name="Eldor_2013" /> * ''NNC2215'', a glucose-sensitive insulin being researched by Novo Nordisk''<ref name="PhD_2024" />'' * ''OI338'' and ''OI320'', two basal oral analogues also by Novo Nordisk''<ref name="Kjeldsen_2021a" />'' * ''LAPS Insulin115'', an ultralong analogue being researched by Hanmi Pharm<ref name="Wronkowitz_2017" />
== Research == The Canadian Agency for Drugs and Technologies in Health (CADTH) conducted a 2008 comparison of insulin analogues and biosynthetic human insulin, concluding that insulin analogues did not demonstrate any clinically significant differences in terms of glycemic control or adverse reaction profiles.<ref>{{cite report | vauthors = Banerjee S, Tran K, Li H, Cimon K, Daneman D, Simpson S, Campbell K | title = Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness | date = March 2007 | url = https://cadth.ca/short-acting-insulin-analogues-diabetes-mellitus-meta-analysis-clinical-outcomes-and-assessment-0 | publisher = Canadian Agency for Drugs and Technologies in Health (CADTH) | id = Technology Report no 87 | access-date = 10 September 2020 | archive-url = https://web.archive.org/web/20191104140933/https://cadth.ca/short-acting-insulin-analogues-diabetes-mellitus-meta-analysis-clinical-outcomes-and-assessment-0 | archive-date = 4 November 2019 }}</ref>
=== Comparative effectiveness === {{Further|Comparative effectiveness research}} A meta-analysis conducted in 2007 and updated in 2020 by the international Cochrane Collaboration, which reviewed numerous randomized controlled trials, found that treatment with glargine and detemir insulins resulted in fewer cases of hypoglycemia compared to NPH insulin. Additionally, treatment with detemir was associated with a reduction in the frequency of severe hypoglycemia. However, the review acknowledged limitations, such as the use of low glucose and Hemoglobin A1c targets, which could affect the generalizability of these findings to routine clinical practice.
In 2007, a report from Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector (IQWiG) concluded that there was insufficient evidence to support the superiority of short-acting insulin analogues over synthetic human insulin for the treatment of adult patients with type 1 diabetes.<ref name="IQWiG_2008">{{Cite web | title = Rapid-acting insulin analogues in diabetes mellitus type 1: Superiority not proven | work = Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) | date = 8 February 2008 | url = http://iqwig.de/index.658.en.html | access-date = 10 March 2025 | archive-url = https://web.archive.org/web/20080208123345/http://iqwig.de/index.658.en.html | archive-date = 8 February 2008 }}</ref> Many of the studies reviewed were criticized for being too small to provide statistically reliable results, and notably, none were blinded.<ref name="IQWiG_2008" />
== See also == * List of commercially available insulins
== References == {{reflist}}
{{Oral hypoglycemics and insulin analogs}} {{Portal bar | Medicine}} {{Authority control}}
{{DEFAULTSORT:Insulin Analogue}} Category:Human proteins Category:Recombinant proteins Category:Peptide hormones Category:Peptide therapeutics Category:Insulin analogues Category:World Health Organization essential medicines