Insulin analogue

File:Insulin_monomer_dimer_hexamer.tif

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. These modifications are designed to either accelerate or prolong subcutaneous absorption while maintaining the biological function of insulin in regulating blood glucose levels. Native human insulin, commonly referred to as regular insulin,{{cite book |title=British national formulary : BNF 69 |date=2015 |publisher=British Medical Association |isbn=9780857111562 |edition=69th |page=464472}} naturally assembles into hexamers, which must gradually dissociate into dimers and then monomers before they can be absorbed into the bloodstream. This process results in a delayed onset of action, making the timing of insulin administration a critical factor in diabetes management.

short-acting insulin analogues are developed to have a shorter duration of action than regular insulin, while long-acting insulin analogues are meant to have a peakless action profile and a prolonged duration of action.{{Cite journal |last1=Mathieu |first1=Chantal |last2=Gillard |first2=Pieter |last3=Benhalima |first3=Katrien |date=July 2017 |title=Insulin analogues in type 1 diabetes mellitus: getting better all the time |url=https://pubmed.ncbi.nlm.nih.gov/28429780/ |journal=Nature Reviews Endocrinology |volume=13 |issue=7 |pages=385–399 |doi=10.1038/nrendo.2017.39 |pmid=28429780}}

File:Insulin glulisine 6GV0 cartoon.png

Short-acting insulin analogues are modified forms of recombinant human insulin designed to enhance subcutaneous absorption and accelerate glycemic control. In standard insulin formulations, regular insulin monomers naturally aggregate into hexamers, a configuration that delays absorption and prolongs the onset of action.{{Cite book |title=Pharmacology and physiology for anesthesia: foundations and clinical application |date=2019 |publisher=Elsevier |isbn=978-0-323-48110-6 |editor-last=Hemmings |editor-first=Hugh C. |edition=2nd |location=Philadelphia, PA |chapter=36 - Endocrine Pharmacology |editor-last2=Egan |editor-first2=Talmage D.}} Before entering the bloodstream, these hexamers must dissociate into dimers and then monomers, which slows their availability for glucose regulation.{{Cite journal |last=Home |first=P. D. |date=September 2012 |title=The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences |url=https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/j.1463-1326.2012.01580.x |journal=Diabetes, Obesity and Metabolism |language=en |volume=14 |issue=9 |pages=780–788 |doi=10.1111/j.1463-1326.2012.01580.x |pmid=22321739 |issn=1462-8902}} 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. Insulin lispro, insulin aspart, and insulin glulisine are the most widely used short-acting insulin analogues. 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.

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.{{cite journal |vauthors=Noble SL, Johnston E, Walton B |date=January 1998 |title=Insulin lispro: a fast-acting insulin analog |url=http://aafp.org/afp/980115ap/noble.html |url-status=dead |journal=American Family Physician |volume=57 |issue=2 |pages=279–86, 289–92 |pmid=9456992 |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}} This modification does not alter receptor binding, but blocks the formation of insulin dimers and hexamers. Clinical studies have demonstrated that the use of insulin lispro instead of regular

File:Insulin_Aspart_Structural_Formula.gif

insulin can reduce hypoglycemia incidence and improve glycemic control. 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. It works by replacing a proline with an aspartic acid at the B28 position.{{cite book |url=https://books.google.com/books?id=Rv10neRV3R8C&pg=PA32 |title=New Drug Development: An Introduction to Clinical Trials: Second Edition |vauthors=Turner JR |date=2010 |publisher=Springer Science & Business Media |isbn=9781441964182 |page=32 |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}} 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.{{cite web |date=25 July 2023 |title=Apidra- insulin glulisine injection, solution; Apidra Solostar- insulin glulisine injection, solution |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7af6a7a-8046-4fb4-9979-4ec4230b23aa |access-date=10 August 2024 |website=DailyMed}} It was approved in 2004 and is sold under the name Apidra.{{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 |access-date=10 August 2024 |website=U.S. Food and Drug Administration (FDA)}}

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. By closely mimicking endogenous insulin secretion, these analogues enhance glycemic stability, reduce post-meal blood sugar spikes, and minimize the risk of hypoglycemic events. Their pharmacokinetic properties make them particularly beneficial for individuals requiring flexible meal timing and those using intensive insulin therapy.

Long-acting insulin analogues are designed to provide continuous basal insulin coverage for up to 24 hours,{{Cite journal |last1=Niloy |first1=Kumar Kulldeep |last2=Lowe |first2=Tao L. |date=December 2023 |title=Injectable systems for long-lasting insulin therapy |url=https://linkinghub.elsevier.com/retrieve/pii/S0169409X23004362 |journal=Advanced Drug Delivery Reviews |language=en |volume=203 |pages=115121 |doi=10.1016/j.addr.2023.115121|pmid=37898336 }} with the exception of ultra-long-acting analogues, which work for up to a week. 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. 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,{{cite journal |vauthors=Baeshen NA, Baeshen MN, Sheikh A, Bora RS, Ahmed MM, Ramadan HA, Saini KS, Redwan EM |date=October 2014 |title=Cell factories for insulin production |journal=Microbial Cell Factories |volume=13 |pages=141 |doi=10.1186/s12934-014-0141-0 |pmc=4203937 |pmid=25270715 |doi-access=free}} reducing glycemic fluctuations and nocturnal hypoglycemia.

Insulin glargine (100 U/mL), first approved by the FDA in 2000 and marketed as Lantus, forms zinc-mediated hexamer aggregates after injection, resulting in a slow insulin release.{{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}}{{Citation |last1=Cunningham |first1=Abigail M. |title=Glargine Insulin |date=2025 |work=StatPearls |url=https://ncbi.nlm.nih.gov/books/NBK557756/#:~:text=Insulin%20glargine%20is%20a%20synthetic,improve%20and%20maintain%20glycemic%20control. |access-date=2025-03-10 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491688 |last2=Freeman |first2=Andrew M.}} 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.{{Cite web |title=Toujeo SoloStar Uses, Dosage & Side Effects |url=https://drugs.com/toujeo.html |access-date=2025-03-10 |website=Drugs.com |language=en}} 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. While effective, insulin detemir often requires twice-daily dosing for optimal glycemic control.

File:Insulin degludec hexamer 4AKJ.png

Insulin degludec, marketed as Tresiba and approved in 2015, is an ultra-long-acting insulin with a duration of up to 42 hours.{{cite journal |vauthors=Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T |date=May 2007 |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 |doi=10.1111/j.1463-1326.2006.00685.x |pmid=17391154 |s2cid=23810204}} It utilizes multi-hexamer formation and albumin binding to provide a steady insulin release with lower intra-individual variability and greater dosing flexibility. 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. These advancements have improved diabetes management by providing more stable blood sugar control, fewer hypoglycemic episodes, and greater convenience for patients.

Insulin icodec is, as of 2025, the newest and longest-acting insulin analogue.{{Cite web |title=Summary Basis of Decision for Awiqli |url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1734642660051 |website=Health Canada}} It has a plasma half-life that is more than eight days, meaning it is a once-weekly insulin.{{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 |date=July 2021 |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 |doi=10.1021/acs.jmedchem.1c00257 |pmid=33944562 |s2cid=233718893 |doi-access=free}} It was approved in 2024 and is marketed as Awuqli by Novo Nordisk. 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.{{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 |date=August 2021 |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 |pages=e002301 |doi=10.1136/bmjdrc-2021-002301 |pmc=8378355 |pmid=34413118}} 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.{{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 |date=August 2021 |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 |pages=e002301 |doi=10.1136/bmjdrc-2021-002301 |pmc=8378355 |pmid=34413118}}

The most common side effect in all insulin analogues is low blood sugar, while in more serious cases, side effects may include low blood potassium.{{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}} Insulin allergies are also a concern, although they are not prevalent, affecting only about 2% of people in some form.{{Cite journal |vauthors=Ghazavi MK, Johnston GA |date=May–Jun 2011 |title=Insulin allergy |journal=Clinics in Dermatology |volume=29 |issue=3 |pages=300–5 |doi=10.1016/j.clindermatol.2010.11.009 |pmid=21496738}} Insulin analogues are generally considered safe during pregnancy,{{Cite journal |vauthors=Subiabre M, Silva L, Toledo F, Paublo M, López MA, Boric MP, Sobrevia L |date=September 2018 |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 |doi=10.1016/j.bbadis.2018.06.005 |pmid=29890222 |s2cid=48362789 |doi-access=free |title-link=doi}} and many are used in the treatment of gestational diabetes.

All insulin analogs undergo carcinogenicity testing due to insulin's interaction with IGF (insulin-like growth factor) pathways,{{Cite journal |last1=Redwan |first1=Elrashdy M. |last2=Linjawi |first2=Moustafa H. |last3=Uversky |first3=Vladimir N. |date=2016-03-17 |title=Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism |journal=Scientific Reports |language=en |volume=6 |issue=1 |pages=23320 |bibcode=2016NatSR...623320R |doi=10.1038/srep23320 |issn=2045-2322 |pmc=4794765 |pmid=26983499}} which can promote abnormal cell growth and tumorigenesis.{{Cite journal |last=Szablewski |first=Leszek |date=October 2014 |title=Diabetes mellitus: influences on cancer risk |url=https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2573 |journal=Diabetes/Metabolism Research and Reviews |language=en |volume=30 |issue=7 |pages=543–553 |doi=10.1002/dmrr.2573 |issn=1520-7552 |pmid=25044584}} Structural modifications to insulin always carry the risk of unintentionally enhancing IGF signaling, potentially increasing mitogenic activity alongside the intended pharmacological effects.{{Cite journal |last1=Seewoodhary |first1=Jason |last2=Bain |first2=Stephen C |date=2011-09-01 |title=Diabetes, diabetes therapies and cancer: what's the link? |url=https://journals.sagepub.com/doi/10.1177/1474651411421024 |journal=The British Journal of Diabetes & Vascular Disease |language=EN |volume=11 |issue=5 |pages=235–238 |doi=10.1177/1474651411421024 |issn=1474-6514}} Concerns have been raised specifically regarding the carcinogenic potential of insulin glargine, prompting several epidemiological studies to investigate its safety.

{{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.{{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}} It has an onset of about 90 minutes and lasts up to 24 hours, making it suitable for once- or twice-daily administration.{{cite book |url=https://books.google.com/books?id=r6OhBQAAQBAJ&pg=PA134 |title=Human Insulin: Clinical Pharmacological Studies in Normal Man |vauthors=Owens DR |date=1986 |publisher=Springer Science & Business Media |isbn=9789400941618 |pages=134–136 |archive-url=https://web.archive.org/web/20170118052228/https://books.google.ca/books?id=r6OhBQAAQBAJ&pg=PA134 |archive-date=2017-01-18 |url-status=live}} NPH insulin is available as a recombinant human insulin and is sometimes premixed with short-acting insulin for combined basal and mealtime glucose control.

During the 1980s, many individuals experienced difficulties when transitioning to intermediate-acting insulins, particularly NPH formulations of porcine and bovine insulins.Owens DR, Bolli GB. 2008 Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther. Oct;10(5):333-49. These issues stemmed from variability in absorption and inconsistent glucose control. In response, basal insulin analogues were developed to provide a more stable and predictable absorption profile,Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. 2012 Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012 Aug;29(8):2104-14.Zinman B. 2013 Newer insulin analogs: advances in basal insulin replacement. Diabetes Obes. Metab. 2013 Mar;15 Suppl 1:6-10 leading to improved clinical efficacy and glycemic management.

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).{{Cite journal |last=Rosenfeld |first=Louis |date=2002-12-01 |title=Insulin: Discovery and Controversy |url=https://academic.oup.com/clinchem/article/48/12/2270/5642437 |journal=Clinical Chemistry |language=en |volume=48 |issue=12 |pages=2270–2288 |doi=10.1093/clinchem/48.12.2270 |pmid=12446492 |issn=0009-9147}} Porcine insulin differs from human insulin by a single amino acid, while bovine insulin has three variations,{{Cite journal |last1=Richter |first1=Bernd |last2=Neises |first2=Gudrun |date=2005-01-24 |editor-last=Cochrane Metabolic and Endocrine Disorders Group |title='Human' insulin versus animal insulin in people with diabetes mellitus |journal=Cochrane Database of Systematic Reviews |language=en |volume=2010 |issue=1 |pages=CD003816 |doi=10.1002/14651858.CD003816.pub2 |pmc=8406912 |pmid=15674916}} yet both exhibit similar activity at the human insulin receptor.{{Cite journal |last=Conlon |first=J.Michael |date=July 2001 |title=Evolution of the insulin molecule: insights into structure-activity and phylogenetic relationships |url=https://linkinghub.elsevier.com/retrieve/pii/S0196978101004235 |journal=Peptides |language=en |volume=22 |issue=7 |pages=1183–1193 |doi=10.1016/S0196-9781(01)00423-5|pmid=11445250 }} 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.{{Cite journal |last=Nagasawa |first=Kakuma |date=1968-03-01 |title=Use of Fish and Whale Insulin as Drugs in Japan |url=https://academic.oup.com/jaoac/article/51/2/326-329/5720924 |journal=Journal of AOAC International |language=en |volume=51 |issue=2 |pages=326–329 |doi=10.1093/jaoac/51.2.326 |issn=0004-5756}}

While non-human insulins were widely used, they sometimes triggered allergic reactions, primarily due to impurities and preservatives in insulin preparations. Although the formation of non-neutralizing antibodies was rare, some patients experienced immune responses that affected insulin efficacy. The development of biosynthetic human insulin significantly reduced these issues, leading to its widespread adoption and largely replacing animal-derived insulin in clinical practice.

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.{{Cite web |last=Agency |first=European Medicines |date=2017-05-05 |title=Biosimilar medicines: Overview {{!}} European Medicines Agency (EMA) |url=https://www.ema.europa.eu/en/human-regulatory-overview/biosimilar-medicines-overview |access-date=2025-03-17 |website=www.ema.europa.eu |language=en}} These medicines are large, complex molecules produced through biotechnology in living systems, such as microorganisms, plant cells, or animal cells.{{Cite web |last=Research |first=Center for Drug Evaluation and |date=2020-04-24 |title=Scientific Considerations in Demonstrating Biosimilarity to a Reference Product |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product |access-date=2025-03-17 |website=www.fda.gov |language=en}} 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.{{Cite journal |last1=Heinemann |first1=Lutz |last2=Davies |first2=Melanie |last3=Home |first3=Philip |last4=Forst |first4=Thomas |last5=Vilsbøll |first5=Tina |last6=Schnell |first6=Oliver |date=2022-07-11 |title=Understanding Biosimilar Insulins - Development, Manufacturing, and Clinical Trials |journal=Journal of Diabetes Science and Technology |language=en |volume=17 |issue=6 |pages=1649–1661 |doi=10.1177/19322968221105864 |pmid=35818669 |pmc=10658691 |issn=1932-2968 }} 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. 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.{{cite journal |author=Nick, C |year=2012 |title=The US Biosimilars Act: Challenges Facing Regulatory Approval |journal=Pharm Med |volume=26 |issue=3 |pages=145–152 |doi=10.1007/bf03262388 |s2cid=14604362}}

The expiration of patents for first-generation insulin analogs has facilitated the development of biosimilar insulins, offering potential to improve global insulin access. Despite the essential role of insulin, approximately half of individuals who require it do not have access due to high costs and limited availability.{{Cite journal |last1=Basu |first1=Sanjay |last2=Yudkin |first2=John S |last3=Kehlenbrink |first3=Sylvia |last4=Davies |first4=Justine I |last5=Wild |first5=Sarah H |last6=Lipska |first6=Kasia J |last7=Sussman |first7=Jeremy B |last8=Beran |first8=David |date=January 2019 |title=Estimation of global insulin use for type 2 diabetes, 2018–30: a microsimulation analysis |url=https://linkinghub.elsevier.com/retrieve/pii/S2213858718303036 |journal=The Lancet Diabetes & Endocrinology |language=en |volume=7 |issue=1 |pages=25–33 |doi=10.1016/S2213-8587(18)30303-6|pmid=30470520 |hdl=20.500.11820/31689153-c908-4a3a-b797-a6b1a73badfe |hdl-access=free }} This issue is particularly pronounced in low-income countries,{{Cite journal |last1=Baumgart |first1=Daniel C. |last2=Misery |first2=Laurent |last3=Naeyaert |first3=Sue |last4=Taylor |first4=Peter C. |date=2019-03-28 |title=Biological Therapies in Immune-Mediated Inflammatory Diseases: Can Biosimilars Reduce Access Inequities? |journal=Frontiers in Pharmacology |volume=10 |doi=10.3389/fphar.2019.00279 |doi-access=free |issn=1663-9812 |pmc=6447826 |pmid=30983996}} where economic factors can restrict the use of biologic treatments such as insulin.{{Cite journal |last1=Ewen |first1=Margaret |last2=Joosse |first2=Huibert-Jan |last3=Beran |first3=David |last4=Laing |first4=Richard |date=June 2019 |title=Insulin prices, availability and affordability in 13 low-income and middle-income countries |journal=BMJ Global Health |language=en |volume=4 |issue=3 |pages=e001410 |doi=10.1136/bmjgh-2019-001410 |issn=2059-7908 |pmc=6570978 |pmid=31263585}} 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.{{Cite journal |last1=Agbogbo |first1=Frank K |last2=Ecker |first2=Dawn M |last3=Farrand |first3=Allison |last4=Han |first4=Kevin |last5=Khoury |first5=Antoine |last6=Martin |first6=Aaron |last7=McCool |first7=Jesse |last8=Rasche |first8=Ulrike |last9=Rau |first9=Tiffany D |last10=Schmidt |first10=David |last11=Sha |first11=Ma |last12=Treuheit |first12=Nicholas |date=2019-10-01 |title=Current perspectives on biosimilars |journal=Journal of Industrial Microbiology and Biotechnology |language=en |volume=46 |issue=9–10 |pages=1297–1311 |doi=10.1007/s10295-019-02216-z |issn=1476-5535 |pmc=6791907 |pmid=31317293}} These products could help improve access to treatment and reduce disparities in insulin availability.

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.[https://www.medicinesforeurope.com/wp-content/uploads/2016/03/IMS-Institute-Biosimilar-Report-March-2016-FINAL.pdf IMS Institute for Healthcare Informatics. Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets Introduction. 2016.] 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. 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.[https://www.iqvia.com/-/media/iqvia/pdfs/library/white-papers/the-impact-of-biosimilar-competition-in-europe-2021.pdf The IQVIA Institute for Human Data Science. The Impact of Biosimilar Competition in Europe. 2021.] 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. 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.

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.{{Cite journal |last1=Kabir |first1=Eva Rahman |last2=Moreino |first2=Shannon Sherwin |last3=Sharif Siam |first3=Mohammad Kawsar |date=2019-08-24 |title=The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy |journal=Biomolecules |language=en |volume=9 |issue=9 |pages=410 |doi=10.3390/biom9090410 |doi-access=free |issn=2218-273X |pmc=6770099 |pmid=31450637}} Regulatory agencies, such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), have established approval pathways to ensure biosimilar insulins meet the same quality, safety, and efficacy standards as reference products.

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 reveived FDA approval in July 2021, but development began before that.{{Cite web |last=Commissioner |first=Office of the |date=2021-07-30 |title=FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes |access-date=2025-03-17 |website=FDA |language=en}} The approval was granted to Mylan, which was merged with another company into Viatris in 2020.{{cite news |last1=Gough |first1=Paul J. |date=16 November 2020 |title=After nearly 60 years, Mylan makes way for Viatris |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}} 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.{{Cite web |date=2022-11-23 |title=Rezvoglar Becomes Second Interchangeable Insulin Biosimilar |url=https://www.centerforbiosimilars.com/view/rezvoglar-becomes-second-interchangeable-insulin-biosimilar |access-date=2025-03-17 |website=Center for Biosimilars |language=en}} 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.{{Cite web |last=Commissioner |first=Office of the |date=2025-02-18 |title=FDA Approves First Rapid-Acting Insulin Biosimilar Product for Treatment of Diabetes |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-rapid-acting-insulin-biosimilar-product-treatment-diabetes |access-date=2025-03-17 |website=FDA |language=en}}

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.{{Cite web |title=FDA approves Lyumjev™ (insulin lispro-aabc injection), Lilly's new rapid-acting insulin {{!}} Eli Lilly and Company |url=https://investor.lilly.com/news-releases/news-release-details/fda-approves-lyumjevtm-insulin-lispro-aabc-injection-lillys-new#:~:text=Lyumjev%20is%20also%20known%20as,available%20only%20with%20a%20prescription. |archive-url=http://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=2025-01-29 |access-date=2025-03-18 |website=Eli Lilly and Company |language=en}}

Before biosynthetic human recombinant analogues became available, porcine insulin was chemically modified to create human insulin.{{Cite journal |last1=Redwan |first1=Elrashdy M. |last2=Linjawi |first2=Moustafa H. |last3=Uversky |first3=Vladimir N. |date=2016-03-17 |title=Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism |journal=Scientific Reports |language=en |volume=6 |issue=1 |pages=23320 |doi=10.1038/srep23320 |pmid=26983499 |pmc=4794765 |bibcode=2016NatSR...623320R |issn=2045-2322}} 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.{{Cite journal |last=Redwan |first=EL-Rashdy M. |date=2009-06-30 |title=Animal-Derived Pharmaceutical Proteins |url=https://tandfonline.com/doi/abs/10.1080/15321810903084400 |journal=Journal of Immunoassay and Immunochemistry |language=en |volume=30 |issue=3 |pages=262–290 |doi=10.1080/15321810903084400 |pmid=19591041 |issn=1532-1819}} Novo Nordisk developed one such method by enzymatically converting porcine insulin into human insulin by replacing the single differing amino acid. Unmodified human and porcine insulins naturally form hexamers with zinc, requiring dissociation into monomers before binding to insulin receptors.{{Cite journal |last1=Horuk |first1=R. |last2=Blundell |first2=T. L. |last3=Lazarus |first3=N. R. |last4=Neville |first4=R. W. J. |last5=Stone |first5=D. |last6=Wollmer |first6=A. |date=August 1980 |title=A monomeric insulin from the porcupine (Hystrix cristata), an Old World hystricomorph |url=https://nature.com/articles/286822a0 |journal=Nature |language=en |volume=286 |issue=5775 |pages=822–824 |doi=10.1038/286822a0 |pmid=6995860 |bibcode=1980Natur.286..822H |issn=0028-0836}} This delays insulin activity when injected subcutaneously, making it less effective for postprandial glucose control.{{Cite journal |last1=Gingras |first1=Véronique |last2=Taleb |first2=Nadine |last3=Roy-Fleming |first3=Amélie |last4=Legault |first4=Laurent |last5=Rabasa-Lhoret |first5=Rémi |date=February 2018 |title=The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes |journal=Diabetes, Obesity and Metabolism |language=en |volume=20 |issue=2 |pages=245–256 |doi=10.1111/dom.13052 |issn=1462-8902 |pmc=5810921 |pmid=28675686}}

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. Some, like insulin detemir, bind to albumin rather than fat, prolonging their action.{{Cite journal |last1=Philips |first1=Jean-Christophe |last2=Scheen |first2=Andre |date=August 2006 |title=Insulin detemir in the treatment of type 1 and type 2 diabetes |journal=Vascular Health and Risk Management |language=en |volume=2 |issue=3 |pages=277–283 |doi=10.2147/vhrm.2006.2.3.277 |doi-access=free |issn=1176-6344 |pmc=1993987 |pmid=17326333}} Non-hexameric (monomeric) insulins were later introduced for faster-acting mealtime coverage, mimicking naturally occurring monomeric insulins found in certain animal species. 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.

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.{{Cite journal |last=Owens |first=David R. |date=June 2011 |title=Insulin Preparations with Prolonged Effect |url=https://liebertpub.com/doi/10.1089/dia.2011.0068 |journal=Diabetes Technology & Therapeutics |language=en |volume=13 |issue=S1 |pages=S–5–S-14 |doi=10.1089/dia.2011.0068 |pmid=21668337 |issn=1520-9156}} The development of monomeric insulins addressed the limitations of hexameric formulations, ensuring faster absorption and better glycemic control. 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.

File:Banting and Best.jpg

The development of insulin therapy has progressed significantly since the early 20th century, starting with animal-derived insulins. In 1922, Frederick Banting and Charles Best successfully used bovine insulin extract to treat humans for the first time.{{Cite web |date=June 2016 |title=Frederick Banting, Charles Best, James Collip, and John Macleod |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}} This breakthrough led to the commercial production of bovine insulin in 1923 by Eli Lilly and Company. That same year, Hans Christian Hagedorn founded the Nordisk Insulinlaboratorium in Denmark, which later became Novo Nordisk.{{cite web |title=The History of Insulin |url=https://karger.com/ProdukteDB/Katalogteile/isbn3_8055/_83/_53/Insulin_02.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160304202218/https://karger.com/ProdukteDB/Katalogteile/isbn3_8055/_83/_53/Insulin_02.pdf |archive-date=March 4, 2016 |access-date=June 10, 2015 |website=Karger.com/ |publisher=Karger Publishers |location=Basel, Switzerland}} In 1926, Nordisk received a Danish charter to produce insulin as a non-profit entity.{{cite web |title=Insulin 100 years |url=https://novonordisk.com/about/insulin-100-years.html}} In 1936, Canadian researchers D.M. Scott and A.M. Fisher developed a zinc insulin mixture,{{Cite journal |last1=Scott |first1=D. A. |last2=Fisher |first2=A. M. |date=1938-11-01 |title=The Insulin and the Zinc Content of Normal and Diabetic Pancreas |url=http://jci.org/articles/view/101000 |journal=Journal of Clinical Investigation |language=en |volume=17 |issue=6 |pages=725–728 |doi=10.1172/JCI101000 |issn=0021-9738 |pmc=434829 |pmid=16694619}} which was licensed to Novo. During this time, Hagedorn discovered that adding protamine to insulin could prolong its action,{{Citation |last1=Saleem |first1=Fatima |title=NPH Insulin |date=2025 |work=StatPearls |url=https://ncbi.nlm.nih.gov/books/NBK549860/#:~:text=NPH%20(Neutral%20Protamine%20Hagedorn)%20insulin%20is%20an%20insoluble%20intermediate-,scientist%20name%20Hans%20Christian%20Hagedorn. |access-date=2025-03-10 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31751050 |last2=Sharma |first2=Ashish}} which led to the development of Neutral Protamine Hagedorn (NPH) insulin in 1946. 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.{{cite journal |last1=Hallas-Møller |first1=K. |last2=Petersen |first2=K. |last3=Schlichtkrull |first3=J. |date=1952 |title=Crystalline and Amorphous Insulin-Zinc Compounds with Prolonged Action |journal=Science |volume=116 |issue=3015 |pages=394–398 |bibcode=1952Sci...116..394H |doi=10.1126/science.116.3015.394 |issn=0036-8075 |jstor=1680777 |pmid=12984132}}

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.{{Cite web |last=Genentech |title=Cloning Insulin |url=https://gene.com/stories/cloning-insulin |access-date=2025-03-10 |website=Genentech: Breakthrough science. One moment, one day, one person at a time. |language=en-us}} This allowed for the production of insulin identical to that produced by the human pancreas. In 1981, Novo Nordisk chemically and enzymatically converted porcine insulin into human insulin.{{Cite web |title=Insulin |url=https://cen.acs.org/articles/83/i25/Insulin.html |access-date=2025-03-10 |website=Chemical & Engineering News |language=en}} Genentech's synthetic human insulin, produced in partnership with Eli Lilly, was approved by the U.S. Food and Drug Administration in 1982.{{Cite journal |last=Commissioner |first=Office of the |date=2024-08-09 |title=100 Years of Insulin |url=https://fda.gov/about-fda/fda-history-exhibits/100-years-insulin#:~:text=signed%20an%20agreement%20with%20Genentech,that%20derived%20from%20this%20technology. |journal=FDA |language=en}} 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.{{Cite journal |last1=Ullrich |first1=A. |last2=Bell |first2=J. R. |last3=Chen |first3=E. Y. |last4=Herrera |first4=R. |last5=Petruzzelli |first5=L. M. |last6=Dull |first6=T. J. |last7=Gray |first7=A. |last8=Coussens |first8=L. |last9=Liao |first9=Y.-C. |last10=Tsubokawa |first10=M. |last11=Mason |first11=A. |last12=Seeburg |first12=P. H. |last13=Grunfeld |first13=C. |last14=Rosen |first14=O. M. |last15=Ramachandran |first15=J. |date=February 1985 |title=Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes |url=https://nature.com/articles/313756a0 |journal=Nature |language=en |volume=313 |issue=6005 |pages=756–761 |doi=10.1038/313756a0 |pmid=2983222 |bibcode=1985Natur.313..756U |issn=0028-0836}} By 1988, Novo Nordisk produced synthetic recombinant human insulin, which further improved insulin availability and consistency.

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. Humalog was designed to be absorbed more quickly than regular insulin, offering improved flexibility in meal timing and postprandial glucose control. In 2000, Lantus (insulin glargine) was approved by the FDA and the European Medicines Agency (EMA).{{Cite web |title=Drug Approval Package |url=https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm |archive-url=http://web.archive.org/web/20250208160300/https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm |archive-date=2025-02-08 |access-date=2025-03-11 |website=accessdata.fda.gov}} 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. In 2004, Apidra (insulin glulisine), another short-acting insulin analog, was approved by Sanofi-Aventis to improve postprandial glucose control.

In 2005, Levemir (insulin detemir), developed by Novo Nordisk, was approved for clinical use.{{Cite web |title=Drug Approval Package |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021-536_LevemirTOC.cfm#:~:text=Approval%20Date:%206/16/2005 |archive-url=http://web.archive.org/web/20250228201310/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021-536_LevemirTOC.cfm |archive-date=2025-02-28 |access-date=2025-03-18 |website=www.accessdata.fda.gov}} Levemir is a long-acting insulin analogue similar to Lantus but with a slightly shorter duration of action. It provides stable basal insulin coverage with a reduced risk of hypoglycemia compared to older insulins.

File:L'insulina icodec one weekly.jpg

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.{{Cite journal |last1=Jarosinski |first1=Mark A |last2=Chen |first2=Yen-Shan |last3=Varas |first3=Nicolás |last4=Dhayalan |first4=Balamurugan |last5=Chatterjee |first5=Deepak |last6=Weiss |first6=Michael A |date=2021-11-24 |title=New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals |journal=The Journal of Clinical Endocrinology & Metabolism |language=en |volume=107 |issue=4 |pages=909–928 |doi=10.1210/clinem/dgab849 |pmid=34850005 |pmc=8947325 |issn=0021-972X }} Insulin degludec, an ultra-long-acting insulin analog, was developed by Novo Nordisk and approved by the FDA in 2015. Insulin degludec has an extended duration of action, lasting up to 42 hours, offering greater flexibility in dosing schedules.

In March 2024, insulin icodec was approved for medical use in 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.{{cite web |date=21 March 2024 |title=Awiqli EPAR |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}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Following the CHMP's recommendation, insulin icodec was approved for medical use in the European Union in May 2024.{{Cite web |last=Agency |first=European Medicines |date=2024-06-03 |title=Awiqli {{!}} European Medicines Agency (EMA) |url=https://ema.europa.eu/en/medicines/human/EPAR/awiqli |access-date=2025-03-11 |website=ema.europa.eu |language=en}} Insulin icodec has a plasma half-life more than eight days (compared to 25 hours of the previous longest-acting insulin analogue insulin degludec), making it a once-weekly basal insulin.

Insulin tregopil is an experimental ultra-fast-acting{{cite journal |last1=Khedkar |first1=Anand |last2=Lebovitz |first2=Harold |last3=Fleming |first3=Alexander |last4=Cherrington |first4=Alan |last5=Jose |first5=Vinu |last6=Athalye |first6=Sandeep N. |last7=Vishweswaramurthy |first7=Ashwini |date=January 2020 |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 |doi=10.1002/cpdd.730 |pmc=7004075 |pmid=31392840 |doi-access=free}} insulin that is being developed by Biocon.{{cite journal |last1=Khedkar |first1=Anand |last2=Lebovitz |first2=Harold |last3=Fleming |first3=Alexander |last4=Cherrington |first4=Alan |last5=Jose |first5=Vinu |last6=Athalye |first6=Sandeep N. |last7=Vishweswaramurthy |first7=Ashwini |date=May 2019 |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 |doi=10.1111/cts.12609 |pmc=6510383 |pmid=30592549 |doi-access=free}} 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.{{cite journal |last1=Joshi |first1=Shashank |last2=Jayanth |first2=Vathsala |last3=Loganathan |first3=Subramanian |last4=Sambandamurthy |first4=Vasan K. |last5=Athalye |first5=Sandeep N. |date=September 2023 |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 |doi=10.1007/s40265-023-01925-1 |pmid=37578592 |s2cid=260885799}} This modification, along with the use of sodium caprate as a permeation enhancer, allows insulin tregopil to be absorbed through the gastrointestinal tract. Another oral analogue called ORMD-0801 is, as of 2025, in development by Oramed Pharmaceuticals.{{cite journal |last1=Eldor |first1=Roy |last2=Arbit |first2=Ehud |last3=Corcos |first3=Asher |last4=Kidron |first4=Miriam |date=9 April 2013 |title=Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study |journal=PLOS ONE |language=en |volume=8 |issue=4 |pages=e59524 |bibcode=2013PLoSO...859524E |doi=10.1371/journal.pone.0059524 |issn=1932-6203 |pmc=3622027 |pmid=23593142 |doi-access=free}}{{cite journal |last1=Eldor |first1=Roy |last2=Neutel |first2=Joel |last3=Homer |first3=Kenneth |last4=Kidron |first4=Miriam |date=November 2021 |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 and Metabolism |volume=23 |issue=11 |pages=2529–2538 |doi=10.1111/dom.14499 |pmid=34310011 |s2cid=236432013}}{{cite journal |last1=Eldor |first1=Roy |last2=Fleming |first2=G. Alexander |last3=Neutel |first3=Joel |last4=Homer |first4=Kenneth E. |last5=Kidron |first5=Miriam |last6=Rosenstock |first6=Julio |date=1 June 2020 |title=1004-P: Oral Insulin (ORMD-0801) Effects on Glucose Parameters in Uncontrolled T2DM on OADs |journal=Diabetes |volume=69 |issue=Supplement_1 |doi=10.2337/db20-1004-P |s2cid=225845842}}{{cite journal |last1=Eldor |first1=Roy |last2=Francis |first2=Bruce H. |last3=Fleming |first3=Alexander |last4=Neutel |first4=Joel |last5=Homer |first5=Kenneth |last6=Kidron |first6=Miriam |last7=Rosenstock |first7=Julio |date=April 2023 |title=Oral insulin ( ORMD -0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study |journal=Diabetes, Obesity and Metabolism |volume=25 |issue=4 |pages=943–952 |doi=10.1111/dom.14901 |pmid=36281496 |s2cid=253108516}}

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.{{cite journal |last1=Heise |first1=Tim |last2=Chien |first2=Jenny |last3=Beals |first3=John M. |last4=Benson |first4=Charles |last5=Klein |first5=Oliver |last6=Moyers |first6=Julie S. |last7=Haupt |first7=Axel |last8=Pratt |first8=Edward John |date=2023 |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 and Metabolism |volume=25 |issue=4 |pages=1080–1090 |doi=10.1111/dom.14956 |pmid=36541037 |s2cid=255034380}}{{cite journal |last1=Moyers |first1=Julie S. |last2=Hansen |first2=Ryan J. |last3=Day |first3=Jonathan W. |last4=Dickinson |first4=Craig D. |last5=Zhang |first5=Chen |last6=Ruan |first6=Xiaoping |last7=Ding |first7=Liyun |last8=Brown |first8=Robin M. |last9=Baker |first9=Hana E. |last10=Beals |first10=John M. |date=2022 |title=Preclinical Characterization of LY3209590, a Novel Weekly Basal Insulin Fc-Fusion Protein |journal=Journal of Pharmacology and Experimental Therapeutics |volume=382 |issue=3 |pages=346–355 |doi=10.1124/jpet.122.001105 |pmid=35840338 |doi-access=free}}{{cite journal |last1=Kazda |first1=Christof M. |last2=Bue-Valleskey |first2=Juliana M. |last3=Chien |first3=Jenny |last4=Zhang |first4=Qianyi |last5=Chigutsa |first5=Emmanuel |last6=Landschulz |first6=William |last7=Wullenweber |first7=Paula |last8=Haupt |first8=Axel |last9=Dahl |first9=Dominik |date=2023 |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 |url=https://diabetesjournals.org/care/article/46/5/1052/148588/Novel-Once-Weekly-Basal-Insulin-Fc-Achieved |journal=Diabetes Care |volume=46 |issue=5 |pages=1052–1059 |doi=10.2337/dc22-2395 |pmc=10154655 |pmid=36920867}}

NNC2215 is a bioengineered glucose-sensitive insulin analogue developed by Novo Nordisk researchers.{{Cite web |last=PhD |first=Jonathan D. Grinstein |date=2024-10-21 |title=Novo Nordisk Researchers Engineer Glucose-Sensitive Insulin Switch |url=https://insideprecisionmedicine.com/topics/translational-research/novo-nordisk-researchers-engineer-glucose-sensitive-insulin-switch/ |access-date=2025-01-01 |website=Inside Precision Medicine |language=en-US}} 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.{{Cite journal |last=Kwon |first=Diana |date=2024-10-16 |title='Smart' insulin prevents diabetic highs — and deadly lows |url=https://nature.com/articles/d41586-024-03357-7 |journal=Nature |language=en |doi=10.1038/d41586-024-03357-7 |pmid=39414970}} 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 October 16, 2024, describing its potential as a major advancement in diabetes treatment and the role of protein engineering in future medicine.{{Cite journal |last1=Hoeg-Jensen |first1=Thomas |last2=Kruse |first2=Thomas |last3=Brand |first3=Christian L. |last4=Sturis |first4=Jeppe |last5=Fledelius |first5=Christian |last6=Nielsen |first6=Peter K. |last7=Nishimura |first7=Erica |last8=Madsen |first8=Alice R. |last9=Lykke |first9=Lennart |last10=Halskov |first10=Kim S. |last11=Koščová |first11=Simona |last12=Kotek |first12=Vladislav |last13=Davis |first13=Anthony P. |last14=Tromans |first14=Robert A. |last15=Tomsett |first15=Michael |date=16 October 2024 |title=Glucose-sensitive insulin with attenuation of hypoglycaemia |journal=Nature |language=en |volume=634 |issue=8035 |pages=944–951 |bibcode=2024Natur.634..944H |doi=10.1038/s41586-024-08042-3 |issn=1476-4687 |pmc=11499270 |pmid=39415004}} The development of glucose-sensitive insulin has been an area of interest in diabetes research since 1979, aiming to address blood sugar fluctuations.{{Cite journal |last1=Brownlee |first1=Michael |last2=Cerami |first2=Anthony |date=1979-12-07 |title=A Glucose-Controlled Insulin-Delivery System: Semisynthetic Insulin Bound to Lectin |url=https://science.org/doi/10.1126/science.505005 |journal=Science |volume=206 |issue=4423 |pages=1190–1191 |bibcode=1979Sci...206.1190B |doi=10.1126/science.505005 |pmid=505005}} Several previous attempts have been made to create glucose-responsive insulin, with varying degrees of success.{{Cite journal |last1=Jarosinski |first1=Mark A |last2=Chen |first2=Yen-Shan |last3=Varas |first3=Nicolás |last4=Dhayalan |first4=Balamurugan |last5=Chatterjee |first5=Deepak |last6=Weiss |first6=Michael A |date=2022-04-01 |title=New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals |journal=The Journal of Clinical Endocrinology & Metabolism |volume=107 |issue=4 |pages=909–928 |doi=10.1210/clinem/dgab849 |issn=0021-972X |pmc=8947325 |pmid=34850005}}{{Cite journal |last1=Liu |first1=Yun |last2=Wang |first2=Shiqi |last3=Wang |first3=Zejun |last4=Yu |first4=Jicheng |last5=Wang |first5=Jinqiang |last6=Buse |first6=John B. |last7=Gu |first7=Zhen |date=2024-06-10 |title=Recent Progress in Glucose-Responsive Insulin |url=https://diabetesjournals.org/diabetes/article-abstract/73/9/1377/156832/Recent-Progress-in-Glucose-Responsive-Insulin?redirectedFrom=fulltext |journal=Diabetes |volume=73 |issue=9 |pages=1377–1388 |doi=10.2337/dbi23-0028 |issn=0012-1797 |pmid=38857114}}

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. Since 2021, three insulin biosimilars have been approved, two of which are long-acting and one of which is short-acting.

• 1996: Insulin lispro, which was originally manufactured by Eli Lilly and Company, is granted approval.
• 2000: Insulin aspart, which was created by Novo Nordisk, is approved.{{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 |language=en}}
• 2000: Insulin glargine, which was developed by Sanofi-Aventis, is approved.{{Cite web |title=Drug Approval Package |url=https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm |archive-url=http://web.archive.org/web/20250208160300/https://accessdata.fda.gov/drugsatfda_docs/nda/2000/21081_lantus.cfm |archive-date=2025-02-08 |access-date=2025-03-11 |website=accessdata.fda.gov}}
• 2004: Insulin glulisine, also developed by Sanofi-Aventis, is approved.
• 2005: Insulin detemir, which was formulated by Novo Nordisk, gets approval.{{Cite web |title=Levemir (insulin detemir) FDA Approval History |url=https://drugs.com/history/levemir.html |access-date=2025-03-11 |website=Drugs.com |language=en}}
• 2015: Insulin degludec, created by Novo Nordisk, is approved.
• 2020: Insulin lispro-aabc, a faster insulin lispro formulation created by Elly Lilly and Company, is approved.
• 2021: Insulin glargine-yfgn, the first approved insulin biosimilar, which is produced by Viatris, is approved.
• 2021: Insulin glargine-aglr, a biosimilar produced by Eli Lilly and Company, is granted approval.
• 2024: Insulin icodec, the newest commercially available analogue by Novo Nordisk, gets approval.
• 2025: Insulin aspart-szjj, the first short-acting biosimilar, created by Viatris, is approved.

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DateFormat = mm/dd/yyyy

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id:long value:rgb(0,0.4,1) legend:Long-acting

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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

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.{{cite report |url=https://cadth.ca/short-acting-insulin-analogues-diabetes-mellitus-meta-analysis-clinical-outcomes-and-assessment-0 |title=Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness |date=March 2007 |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 |url-status=dead |vauthors=Banerjee S, Tran K, Li H, Cimon K, Daneman D, Simpson S, Campbell K}}

{{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.{{Cite web |date=2008-02-08 |title=IQWiG - Rapid-acting insulin analogues in diabetes mellitus type 1: Superiority not proven |url=http://iqwig.de/index.658.en.html |access-date=2025-03-10 |archive-url=https://web.archive.org/web/20080208123345/http://iqwig.de/index.658.en.html |archive-date=8 February 2008 }} Many of the studies reviewed were criticized for being too small to provide statistically reliable results, and notably, none were blinded.

• List of commercially available insulins

{{Oral hypoglycemics and insulin analogs}}

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