Insulin lispro

Insulin lispro, sold under the brand name Humalog among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes.[3] It is used by injection under the skin or within an insulin pump.[3][4] Onset of effects typically occurs within 30 minutes and lasts about 5 hours.[3] Often a longer-acting insulin like insulin NPH is also needed.[3]

Insulin lispro
PDB: 6NWV​
Clinical data
Trade namesHumalog, Liprolog, Admelog, others
Other namesURLi, LY900014, LY-275585, insulin lispro-aabc
AHFS/Drugs.comMonograph
MedlinePlusa697021
License data
Pregnancy
category
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
  • CA: ℞-only / Schedule D
  • UK: POM (Prescription only)[2]
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC257H389N65O77S6
Molar mass5813.68 g·mol−1
3D model (JSmol)
  • CCC(C)C(C(=O)NC(C(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CCC(=O)N)C(=O)NC(CS)C(=O)NC(CS)C(=O)NC(C(C)O)C(=O)NC(CO)C(=O)NC(C(C)CC)C(=O)NC(CS)C(=O)NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC1=CC=C(C=C1)O)C(=O)NC(CCC(=O)N)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CC(=O)N)C(=O)NC(CC2=CC=C(C=C2)O)C(=O)NC(CS)C(=O)NC(CC(=O)N)C(=O)O)NC(=O)CN.CC(C)CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CS)C(=O)NCC(=O)NC(CCC(=O)O)C(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)NC(CC2=CC=CC=C2)C(=O)NC(CC3=CC=CC=C3)C(=O)NC(CC4=CC=C(C=C4)O)C(=O)NC(C(C)O)C(=O)NC(CCCCN)C(=O)N5CCCC5C(=O)NC(C(C)O)C(=O)O)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC6=CN=CN6)NC(=O)C(CO)NC(=O)CNC(=O)C(CS)NC(=O)C(CC(C)C)NC(=O)C(CC7=CN=CN7)NC(=O)C(CCC(=O)N)NC(=O)C(CC(=O)N)NC(=O)C(C(C)C)NC(=O)C(CC8=CC=CC=C8)N
  • InChI=1S/C158H234N40O42S2.C99H155N25O35S4/c1-79(2)57-104(181-131(213)86(15)173-136(218)102(50-53-125(211)212)179-152(234)127(84(11)12)194-148(230)107(60-82(7)8)184-145(227)113(67-95-70-166-78-172-95)189-150(232)115(74-199)176-123(208)73-170-134(216)116(75-241)191-140(222)105(58-80(3)4)182-144(226)112(66-94-69-165-77-171-94)188-138(220)101(48-51-119(161)204)178-146(228)114(68-120(162)205)190-153(235)126(83(9)10)193-132(214)98(160)61-89-31-21-18-22-32-89)139(221)185-110(64-92-40-44-96(202)45-41-92)142(224)183-106(59-81(5)6)147(229)195-128(85(13)14)154(236)192-117(76-242)135(217)169-71-121(206)174-100(49-52-124(209)210)137(219)177-99(38-29-55-167-158(163)164)133(215)168-72-122(207)175-108(62-90-33-23-19-24-34-90)141(223)186-109(63-91-35-25-20-26-36-91)143(225)187-111(65-93-42-46-97(203)47-43-93)149(231)196-129(87(16)200)155(237)180-103(37-27-28-54-159)156(238)198-56-30-39-118(198)151(233)197-130(88(17)201)157(239)240;1-12-46(9)77(121-73(134)36-100)97(156)122-76(45(7)8)95(154)108-56(25-29-75(137)138)80(139)105-54(23-27-70(102)131)83(142)117-66(40-161)93(152)119-68(42-163)94(153)124-79(48(11)127)98(157)116-64(38-126)90(149)123-78(47(10)13-2)96(155)120-67(41-162)92(151)115-63(37-125)89(148)110-58(31-44(5)6)85(144)111-59(32-49-14-18-51(128)19-15-49)86(145)106-53(22-26-69(101)130)81(140)109-57(30-43(3)4)84(143)107-55(24-28-74(135)136)82(141)113-61(34-71(103)132)88(147)112-60(33-50-16-20-52(129)21-17-50)87(146)118-65(39-160)91(150)114-62(99(158)159)35-72(104)133/h18-26,31-36,40-47,69-70,77-88,98-118,126-130,199-203,241-242H,27-30,37-39,48-68,71-76,159-160H2,1-17H3,(H2,161,204)(H2,162,205)(H,165,171)(H,166,172)(H,168,215)(H,169,217)(H,170,216)(H,173,218)(H,174,206)(H,175,207)(H,176,208)(H,177,219)(H,178,228)(H,179,234)(H,180,237)(H,181,213)(H,182,226)(H,183,224)(H,184,227)(H,185,221)(H,186,223)(H,187,225)(H,188,220)(H,189,232)(H,190,235)(H,191,222)(H,192,236)(H,193,214)(H,194,230)(H,195,229)(H,196,231)(H,197,233)(H,209,210)(H,211,212)(H,239,240)(H4,163,164,167);14-21,43-48,53-68,76-79,125-129,160-163H,12-13,22-42,100H2,1-11H3,(H2,101,130)(H2,102,131)(H2,103,132)(H2,104,133)(H,105,139)(H,106,145)(H,107,143)(H,108,154)(H,109,140)(H,110,148)(H,111,144)(H,112,147)(H,113,141)(H,114,150)(H,115,151)(H,116,157)(H,117,142)(H,118,146)(H,119,152)(H,120,155)(H,121,134)(H,122,156)(H,123,149)(H,124,153)(H,135,136)(H,137,138)(H,158,159)/t86-,87+,88+,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,126-,127-,128-,129-,130-;46-,47-,48+,53-,54-,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,76-,77-,78-,79-/m00/s1
  • Key:WNRQPCUGRUFHED-DETKDSODSA-N
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Common side effects include low blood sugar.[3] Other serious side effects may include low blood potassium.[3] Use in pregnancy and breastfeeding is generally safe.[5] It works the same as human insulin by increasing the amount of glucose that tissues take in and decreasing the amount of glucose made by the liver.[3]

Insulin lispro was first approved for use in the United States in 1996.[3][6][7] It is a manufactured form of human insulin where an amino acid has been switched.[8] In 2020, it was the 71st most commonly prescribed medication in the United States, with more than 10 million prescriptions.[9][10]

Medical uses

Insulin lispro is used to treat people with type 1 diabetes or type 2 diabetes.[3] People doing well on short-acting insulin should not routinely be changed to insulin lispro, but may benefit from some advantages like flexibility and responsiveness.[3]

Side effects

Common side effects include skin irritation at the site of injection, hypoglycemia, hypokalemia, and lipodystrophy.[6] Other serious side effects include anaphylaxis, and hypersensitivity reactions.[6]

Mechanism of action

Through recombinant DNA technology, the final lysine and proline residues on the C-terminal end of the B-chain are reversed. This modification does not alter receptor binding, but blocks the formation of insulin dimers and hexamers. This allows larger amounts of active monomeric insulin to be immediately available for postprandial injections.[11]

Chemistry

It is a manufactured form of human insulin where the amino acids lysine and proline have been switched at the end of the B chain of the insulin molecule.[8] This switch of amino acids mimics Insulin-like growth factor 1 which also has lysine (K) and proline (P) in that order at positions 28 and 29.[12]

History

Insulin lispro (brand name Humalog) was granted marketing authorization in the European Union in April 1996,[13] and it was approved for use in the United States in June 1996.[7][14]

Insulin lispro (brand name Liprolog) was granted marketing authorization in the European Union in May 1997,[15] and again in August 2001.[16]

Combination drugs combining insulin lispro and other forms of insulin were approved for use in the United States in December 1999.[17][18][19]

Insulin lispro Sanofi was granted marketing authorization as a biosimilar in the European Union in July 2017.[20]

Insulin lispro injection (brand name Admelog) was approved for use in the United States in December 2017.[21][22][23]

In January 2020, the Committee for Medicinal Products for Human Use (CHMP) in the European Union recommended granting of a marketing authorization for insulin lispro acid (brand name Lyumjev) for the treatment of diabetes mellitus in adults.[24][25] Insulin lispro (Lyumjev) was approved for use in the European Union in March 2020, and in the United States on 18 June 2020 as reported by Medscape.[26]

Society and culture

Economics

In the United States, the price of for a vial of Humalog increased from US$35 in 2001 to $234 in 2015,[27] or $10.06 and $29.36 per 100 units.[28] In April 2019, Eli Lilly and Company announced they would produce a version selling for $137.35 per vial.[27] The chief executive said that this was a contribution "to fix the problem of high out-of-pocket costs for Americans living with chronic conditions", but Patients for Affordable Drugs Now said it was just a public relations move, as "other countries pay $20 for a vial of insulin."[27] In March 2023, Lilly announced a program capping their insulin prices at $35 per month.[29]

References
  1. "Insulin lispro Use During Pregnancy". Drugs.com. 7 October 2019. Retrieved 23 February 2020.
  2. "Humalog 100 units/ml, solution for injection in vial - Summary of Product Characteristics (SmPC)". (emc). 30 January 2020. Retrieved 23 February 2020.
  3. "Insulin Lispro Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  4. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 698. ISBN 9780857113382.
  5. "Insulin lispro Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  6. "Humalog- insulin lispro injection, solution Humalog Kwikpen- insulin lispro injection, solution Humalog Junior Kwikpen- insulin lispro injection, solution Humalog Tempo Pen- insulin lispro injection, solution". DailyMed. 25 November 2019. Retrieved 23 February 2020.
  7. "Humalog approval" (PDF). U.S. Food and Drug Administration (FDA). 14 June 1996. Retrieved 23 February 2020.
  8. Koivisto VA (June 1998). "The human insulin analogue insulin lispro". Annals of Medicine. 30 (3): 260–6. doi:10.3109/07853899809005853. PMID 9677011.
  9. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  10. "Insulin Lispro - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  11. Noble SL, Johnston E, Walton B (January 1998). "Insulin lispro: a fast-acting insulin analog". American Family Physician. 57 (2): 279–86, 289–92. PMID 9456992. Archived from the original on 29 September 2007. Retrieved 5 September 2007.
  12. Ratledge, C., & Kristiansen, B. (2007). Basic biotechnology. Cambridge: Cambridge University Press. Page 513 "insulin lispro, where, in analogy to the naturally occur- ring insulin homologue insulin-like growth factor-I (IGF-I), the order of the amino acid residues B28 and B29 was changed;"
  13. "Humalog EPAR". European Medicines Agency (EMA). 11 February 2020. Retrieved 23 February 2020.
  14. "Humalog: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 23 February 2020.
  15. "Liprolog EPAR". European Medicines Agency (EMA). 1 August 2001. Retrieved 23 February 2020.
  16. "Liprolog EPAR". European Medicines Agency (EMA). 11 February 2020. Retrieved 23 February 2020.
  17. "Drug Approval Package: Humalog Mix (75/25 & 50/50) NDA# 21-017 & 21-018". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 23 February 2020.
  18. "Humalog Mix50/50- insulin lispro injection, suspension Humalog Mix50/50 Kwikpen- insulin lispro injection, suspension". DailyMed. 19 November 2019. Retrieved 23 February 2020.
  19. "Humalog Mix75/25- insulin lispro injection, suspension Humalog Mix75/25 Kwikpen- insulin lispro injection, suspension". DailyMed. 3 February 2020. Retrieved 23 February 2020.
  20. "Insulin lispro Sanofi EPAR". European Medicines Agency (EMA). 17 June 2019. Retrieved 23 February 2020.
  21. "Drug Approval Package: Admelog (insulin lispro)". U.S. Food and Drug Administration (FDA). 17 May 2018. Retrieved 23 February 2020.
  22. "FDA Approves Sanofi's Admelog (insulin lispro injection) - Dec 11, 2017". Sanofi (Press release). 11 December 2017. Retrieved 23 February 2020.
  23. "FDA approves Admelog, the first short-acting "follow-on" insulin product to treat diabetes". U.S. Food and Drug Administration (FDA) (Press release). 11 December 2017. Retrieved 12 December 2017.
  24. "Lyumjev: Pending EC decision". European Medicines Agency (EMA). 30 January 2020. Retrieved 23 February 2020.
  25. "CHMP Recommends Approval of Lilly's New Fast-Acting Mealtime Insulin to Improve Glycemic Control in Adults with Diabetes". Eli Lilly and Company (Press release). 31 January 2020. Retrieved 23 February 2020.
  26. "Ljumjev EPAR". European Medicines Agency (EMA). 29 January 2020. Retrieved 16 April 2020.
  27. Sullivan, Peter (3 April 2019). "Drug company announces new version of insulin at half the price". The Hill. Retrieved 15 April 2019.
  28. Langreth R (29 June 2016). "Decoding Big Pharma's Secret Drug Pricing Practices". Bloomberg. Retrieved 15 July 2016.
  29. "Lilly Cuts Insulin Prices by 70% and Caps Patient Insulin Out-of-Pocket Costs at $35 Per Month". Eli Lilly and Company (Press release). 1 March 2023. Retrieved 14 April 2023.
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