Hubbry Logo
Insulin lisproInsulin lisproMain
Open search
Insulin lispro
Community hub
Insulin lispro
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Insulin lispro
Insulin lispro
Insulin lispro
View on Wikipedia
from Wikipedia

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
Pharmacokinetic data
Onset of action30 minutes
Duration of action5 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC257H383N65O77S6
Molar mass5807.63 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
 ☒NcheckY (what is this?)  (verify)

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.[5] It is delivered subcutaneously either by injection or from an insulin pump.[5][6] Onset of effects typically occurs within 30 minutes and lasts about 5 hours.[5] Often a longer-acting insulin like insulin NPH is also needed.[5]

Common side effects include low blood sugar.[5] Other serious side effects may include low blood potassium.[5] Use in pregnancy and breastfeeding is generally safe.[7] 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.[5]

Insulin lispro was first approved for use in the United States in 1996.[5][8][9] It is a manufactured analogue of human insulin where two amino acids have swapped positions.[10] In 2023, it was the 84th most commonly prescribed medication in the United States, with more than 8 million prescriptions.[11][12] It is on the World Health Organization's List of Essential Medicines.[13]

Medical uses

[edit]

Insulin lispro is used to treat people with type 1 diabetes or type 2 diabetes.[5] 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.[5]

Side effects

[edit]

Common side effects include skin irritation at the site of injection, hypoglycemia, hypokalemia, and lipodystrophy.[8] Other serious side effects include anaphylaxis, and hypersensitivity reactions.[8]

Mechanism of action

[edit]

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.[14]

Chemistry

[edit]

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.[10] 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.[15]

History

[edit]

Insulin lispro (brand name Humalog) was granted marketing authorization in the European Union in April 1996,[3] and it was approved for use in the United States in June 1996.[9][16]

Insulin lispro (brand name Liprolog) was granted marketing authorization in the European Union in May 1997,[4] and again in August 2001.[17]

Combination drugs combining insulin lispro and other forms of insulin were approved for use in the United States in December 1999.[18][19][20]

Insulin lispro Sanofi was granted marketing authorization as a biosimilar in the European Union in July 2017.[21]

Insulin lispro injection (brand name Admelog) was approved for use in the United States in December 2017.[22][23][24]

In January 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended granting of a marketing authorization for insulin lispro acid (brand name Lyumjev) for the treatment of diabetes in adults.[25][26] Insulin lispro (Lyumjev) was approved for use in the European Union in March 2020, and in the United States in June 2020.[27]

Society and culture

[edit]

Economics

[edit]

In the United States, the price of for a vial of Humalog increased from US$35 in 2001 to $234 in 2015,[28] or $10.06 and $29.36 per 100 units.[29] In April 2019, Eli Lilly and Company announced they would produce a version selling for $137.35 per vial.[28] 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."[28] In March 2023, Lilly announced a program capping their insulin prices at $35 per month.[30]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Insulin lispro

View on Grokipedia
from Grokipedia
Insulin lispro is a rapid-acting human insulin analogue produced via recombinant DNA technology in Escherichia coli, employed for glycemic control in individuals with type 1 and type 2 diabetes mellitus. Chemically, it consists of the same empirical formula (C257H383N65O77S6) and molecular weight (5808 daltons) as endogenous human insulin but features an inversion of the proline-lysine residues at B-chain positions 28 and 29, which diminishes hexamer formation and promotes swift dissociation into monomers upon injection. This structural modification yields an onset of action within 10 to 15 minutes, a peak effect at 30 to 90 minutes, and a duration of 3 to 5 hours, enabling administration immediately before or within 15 minutes after meals for effective postprandial glucose management. Developed by Eli Lilly and Company, insulin lispro received initial U.S. Food and Drug Administration approval in 1996 as Humalog, marking the advent of rapid-acting insulin analogues that more closely mimic physiological prandial insulin secretion than conventional regular insulin. Clinical evaluations have demonstrated its capacity to achieve superior postprandial glycemic excursions relative to human regular insulin, with comparable overall hypoglycemia incidence, thereby enhancing flexibility in diabetes therapy regimens. Subsequent formulations, including biosimilars and ultra-rapid variants like Lyumjev (insulin lispro-aabc), have expanded options, though the original remains a cornerstone for basal-bolus insulin strategies due to its established pharmacokinetic profile and subcutaneous or intravenous administration versatility.

Medical Uses

Indications

Insulin lispro is indicated to improve glycemic control in adults and children with type 1 diabetes mellitus, where it serves as a rapid-acting bolus insulin administered at mealtimes to mitigate postprandial hyperglycemia when used in combination with intermediate- or long-acting insulins. In patients with type 2 diabetes mellitus, it is similarly employed as adjunctive therapy alongside long-acting insulins, oral antidiabetic agents, or both, to address meal-related glucose excursions rather than providing basal coverage independently. Randomized clinical trials have established its efficacy in superior postprandial glucose reduction relative to regular human insulin, with one multicenter study in type 1 diabetes patients showing significantly lower 2-hour postprandial blood glucose levels (mean difference of 2.6 mmol/L, p<0.0001) without elevating hypoglycemia risk. A systematic review of short-acting insulin analogs, including lispro, confirmed reduced postprandial glucose levels across multiple trials in both type 1 and type 2 diabetes populations, supporting its targeted role in bolus regimens for empirical glycemic management per endocrine guidelines.

Administration and Dosage

Insulin lispro is administered subcutaneously, typically within 15 minutes before or immediately after a meal to mimic postprandial insulin secretion and control glycemic excursions. The rapid onset of action occurs within 10-15 minutes following subcutaneous injection, with peak plasma levels and glucose-lowering effect at approximately 30-90 minutes, and a duration of 3-5 hours. Dosage must be individualized based on the patient's metabolic requirements, blood glucose monitoring results, and glycemic control goals, with frequent adjustments to avoid hypoglycemia. Initial total daily insulin requirements for patients with diabetes often range from 0.5 to 1 unit per kg of body weight, divided between basal and prandial components, where insulin lispro serves as the rapid-acting prandial insulin. For mealtime dosing, a starting bolus of approximately 4 units, 0.1 units per kg body weight, or 10% of the basal insulin dose may be used, titrated upward or downward by 10-20% based on pre- and post-meal blood glucose levels. In insulin pump therapy, insulin lispro is delivered as continuous subcutaneous infusion, with basal rates and bolus doses programmed according to individual needs and monitored closely for infusion set occlusion or site reactions. Available formulations include 10 mL vials for syringe use or pump reservoirs, 3 mL prefilled KwikPens for single-patient disposable injection, and 3 mL cartridges compatible with reusable pens or certain insulin pumps; U-100 and U-200 concentrations exist for varying dose volumes. Vials and pens should be stored appropriately, with opened containers discarded after 28 days regardless of remaining volume, and insulin lispro may be mixed with NPH insulin if needed, drawing the lispro first into the syringe. Intravenous administration is reserved for medical supervision in acute settings, diluted in normal saline and infused with potassium and glucose monitoring.

Pharmacology

Mechanism of Action

Insulin lispro is a recombinant analog of human insulin featuring an inversion of amino acids at positions B28 and B29 of the B-chain: lysine replaces proline at B28, and proline replaces lysine at B29. This structural modification disrupts the hydrophobic interactions that promote self-association of insulin molecules into stable dimers and hexamers in solution, favoring rapid dissociation into biologically active monomers upon subcutaneous administration. Consequently, insulin lispro exhibits accelerated absorption from the injection site into the systemic circulation compared to regular human insulin, which forms larger aggregates that delay dissolution. Like endogenous insulin, lispro binds with high affinity to the insulin receptor (IR), a heterotetrameric tyrosine kinase composed of two extracellular α-subunits and two transmembrane β-subunits. Receptor activation triggers autophosphorylation of the β-subunits and downstream phosphorylation of insulin receptor substrates (IRS-1 and IRS-2), activating the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. This cascade promotes the translocation of glucose transporter type 4 (GLUT4)-containing vesicles from intracellular stores to the plasma membrane in skeletal muscle and adipose tissue, facilitating glucose uptake independent of insulin concentration gradients. In hepatocytes, insulin lispro signaling inhibits gluconeogenesis and glycogenolysis by suppressing transcription of gluconeogenic enzymes (e.g., phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) via forkhead box O1 (FOXO1) inactivation and promotes glycogen synthesis through glycogen synthase activation. These effects lower hepatic glucose output, contributing to overall glycemic control. The receptor-binding affinity and intrinsic metabolic potency of lispro are equivalent to human insulin, with the primary distinction arising from its monomeric kinetics rather than altered signaling efficacy. In vitro binding assays and crystallographic studies confirm that the B28-B29 swap minimally impacts receptor interaction while markedly reducing lag phase in absorption profiles; pharmacokinetic analyses report onset within 15 minutes versus 30-60 minutes for insulin, corroborated by reduced hexamer formation in subcutaneous depots.

Pharmacokinetics and Pharmacodynamics

Insulin lispro is rapidly absorbed after subcutaneous injection, achieving onset of action in 10-15 minutes and peak plasma concentrations (Tmax) in 30-90 minutes, owing to its favoring monomeric dissociation at physiological . Absolute bioavailability following subcutaneous administration ranges from 55% to 77%, equivalent to that of regular insulin. Absorption rates are dose-dependent, with higher doses showing slightly delayed Tmax but proportionally increased exposure. Distribution mirrors that of endogenous insulin, primarily to insulin-sensitive tissues including liver, skeletal muscle, and adipose tissue via receptor-mediated binding. Specific volume of distribution data for insulin lispro is limited, but systemic distribution post-absorption parallels human insulin patterns, with minimal plasma protein binding beyond receptor interactions. Metabolism of insulin lispro occurs via enzymatic degradation similar to native insulin, predominantly by insulin-degrading enzyme (IDE) in the liver, kidneys, and muscles, yielding inactive peptides and free amino acids. Clearance totals approximately 600-800 mL/min in healthy adults, involving both hepatic proteolysis and renal filtration of degradation products. The elimination half-life is about 1 hour after subcutaneous dosing, shorter than the 1.5 hours for human regular insulin due to accelerated absorption kinetics. Pharmacodynamically, insulin lispro elicits dose-proportional glucose disposal in euglycemic clamp studies, with peak hypoglycemic effects 1-2 hours post-injection, achieving 20-30% faster time to maximum glucose-lowering action relative to . This profile supports prandial glucose control, as evidenced by reduced postprandial excursions in patients, though duration of action extends 3-5 hours. Individual variability in onset and peak may arise from injection site, dose, and patient factors like .

Chemistry

Molecular Structure

Insulin lispro is a recombinant DNA-derived analog of human insulin, comprising 51 amino acids divided into an A-chain of 21 residues and a B-chain of 30 residues. The defining structural modification involves the inversion of residues at positions B28 and B29 on the B-chain, substituting the native proline-lysine sequence with lysine-proline. This alteration maintains the primary amino acid composition while altering local conformation at the C-terminus of the B-chain. The two chains are covalently linked by two interchain disulfide bridges (A7–B7 and A20–B19) and stabilized by an intrachain bond in the A-chain (A6–A11), preserving the characteristic tertiary of insulin, including alpha-helices and beta-turns critical for receptor binding affinity. Insulin lispro has a molecular of C₂₅₇H₃₈₃N₆₅O₇₇S₆ and a molecular of approximately 5808 Da, identical to insulin due to the isobaric of the swapped residues. Crystallographic studies, such as those using X-ray diffraction on lispro hexamers and dodecamers, confirm the retention of key structural features, including zinc coordination sites, which influence solubility and stability under formulation conditions.

Synthesis and Manufacturing

Insulin lispro is manufactured using recombinant DNA technology in microbial expression systems, predominantly Escherichia coli, where the modified A and B chains (with proline and lysine residues inverted at positions B28 and B29, respectively) are produced separately as inclusion bodies to facilitate high-yield expression. These chains are solubilized under denaturing conditions, purified individually via precipitation and chromatography, and then combined through in vitro refolding processes that promote formation of the three correct disulfide bridges, often aided by enzymatic or oxidative methods to mimic native linkage. Subsequent processing includes enzymatic removal of any pro-peptide extensions if present, followed by multi-step purification using anion-exchange, reversed-phase, and size-exclusion chromatography to eliminate impurities such as host cell proteins, misfolded aggregates, and truncated variants, achieving final purity greater than 99%. The entire production occurs under current Good Manufacturing Practice (cGMP) guidelines, with in-process controls monitoring critical quality attributes like chain stoichiometry and disulfide integrity at each stage. Batch consistency is ensured through analytical validation, including high-performance liquid chromatography (HPLC) for purity and isoform profiling, mass spectrometry for sequence confirmation, and in vitro bioassays measuring receptor binding and glucose uptake potency relative to human insulin standards. Innovations in expression vectors and refolding buffers have optimized yields from early recombinant methods, reducing variability while maintaining bioequivalence to the reference product.

Clinical Evidence

Efficacy Data

In randomized controlled trials from the 1990s establishing insulin lispro's efficacy, the analog achieved glycemic control comparable to regular insulin in terms of HbA1c while providing superior postprandial glucose in patients with . A pivotal multicenter involving 1,003 participants demonstrated that after 6 months, HbA1c changed by -0.07% with insulin lispro versus +0.05% with (no significant difference), but 2-hour postprandial blood glucose was reduced by 1.9 mmol/L (approximately 34 mg/dL) with lispro (p < 0.001). Similar results emerged in other early RCTs, where insulin lispro lowered 2-hour postprandial glucose excursions by 20-50 mg/dL versus , reflecting its faster onset and peak action that better counters meal-related glucose . Meta-analyses of short-acting insulin analogs, including lispro, versus regular human insulin corroborate these findings, showing weighted mean HbA1c differences of -0.1% to -0.4% favoring analogs (p < 0.05 in type 2 diabetes subsets), alongside consistent reductions in postprandial glucose by 1-2 mmol/L. Insulin lispro also reduced nocturnal hypoglycemia rates by 25-50% in pediatric and adult trials, enabling tighter control of hyperglycemia without proportional increases in severe lows, as evidenced by incidence rates of 8% versus 21% in one child-focused RCT. These outcomes stem from lispro's monomeric formulation, which accelerates absorption and aligns insulin peaks (within 1 hour) more closely with postprandial glucose kinetics than regular insulin's dimeric delay. With the advent of continuous glucose monitoring, real-world and controlled studies affirm insulin lispro's role in enhancing time in range (TIR, 70-180 mg/dL), particularly TIR, through optimized postprandial coverage; for example, regimens incorporating lispro have shown TIR increases of 5-10% over baselines by minimizing glucose variability after meals. This efficacy holds across type 1 and when dosed preprandially, supporting HbA1c below 7% in approximately 40-50% of adherent patients in long-term follow-ups.

Safety Profile and Adverse Effects

The most common adverse reaction associated with insulin lispro is hypoglycemia, which is dose-related and occurs with an incidence of symptomatic episodes ranging from 20% to 30% in clinical trials, depending on patient population and glycemic targets, while severe hypoglycemia affects approximately 3% of patients over treatment periods of several months. Weight gain, attributed to insulin's anabolic effects and improved glycemic control reducing glycosuria, typically amounts to 1-2 kg per year in long-term use. Injection site reactions, including erythema, pruritus, edema, or pain, occur in a minority of patients, resolving spontaneously in most cases without discontinuation. Insulin lispro exhibits low immunogenicity, with anti-insulin antibody formation in less than 1% of patients leading to clinically significant effects on efficacy or safety; de novo exposure primarily elevates cross-reactive antibodies without increasing lispro-specific or insulin-specific titers that impair glycemic control. Meta-analyses of insulin analog use, including lispro, have not confirmed causal links to accelerated cancer incidence or diabetic retinopathy progression beyond background risks in diabetic populations, though hyperinsulinemia from any insulin therapy may theoretically contribute to mitogenic signaling in susceptible tissues. Insulin lispro is contraindicated in patients with known hypersensitivity to the active substance or excipients, as severe allergic reactions including anaphylaxis have been reported. In renal impairment, reduced insulin clearance heightens hypoglycemia risk, necessitating frequent monitoring and dose adjustments; hepatic impairment similarly prolongs exposure, requiring cautious titration to avoid excessive effects. Post-marketing surveillance has identified rare events such as lipodystrophy, rash, or generalized hypersensitivity, but these occur at rates comparable to other rapid-acting insulins.

Comparative Effectiveness

Insulin lispro demonstrates superior postprandial glycemic control compared to human regular insulin in head-to-head randomized controlled trials. In a meta-analysis of multiple studies involving patients with type 1 and type 2 diabetes, lispro significantly reduced 2-hour postprandial blood glucose excursions by approximately 1.5-2.8 mmol/L (27-50 mg/dL) relative to regular insulin, without increasing hypoglycemia risk or altering fasting glucose or HbA1c levels substantially. This advantage stems from lispro's faster onset (10-15 minutes versus 30-60 minutes for regular insulin) and earlier peak action, enabling more physiologic meal-time dosing. Against other rapid-acting analogs such as insulin aspart and glulisine, lispro exhibits comparable overall efficacy in glycemic control. Real-world and trial data from over 10,000 patients showed no significant differences in HbA1c reduction, postprandial glucose profiles, or hypoglycemia incidence between lispro, aspart, and glulisine when used in basal-bolus regimens or continuous subcutaneous insulin infusion (CSII). However, formulation-specific variations exist; aspart may offer marginally better chemical stability in insulin pumps, with lower occlusion rates than lispro under prolonged infusion conditions, though both analogs outperform regular insulin in pump compatibility due to reduced precipitation risks. Lispro remains widely utilized in CSII, with equivalent safety profiles across analogs in pediatric and adult populations. Long-term comparative data indicate no differential impact on microvascular complications between lispro and human regular insulin. Observational studies tracking outcomes over 5-10 years in type 2 diabetes patients found equivalent rates of retinopathy, nephropathy, and neuropathy progression, countering initial theoretical concerns about analog immunogenicity or mitogenic potential that lacked empirical support in clinical endpoints. These findings align with class-wide evidence from large cohorts, emphasizing that while lispro provides acute postprandial benefits, chronic complication prevention depends more on overall HbA1c management than analog choice.

History

Discovery and Development

Insulin lispro was developed by scientists at Eli Lilly and Company in the late 1980s to address the pharmacokinetic limitations of regular human insulin, which forms stable hexameric complexes upon subcutaneous injection, delaying dissociation into active monomers and resulting in a slower onset of action mismatched to postprandial glucose excursions. Researchers engineered the analog through site-directed mutagenesis, inverting the proline at position B28 and lysine at position B29 of the human insulin B-chain to lysine B28 and proline B29; this subtle reversal disrupts key hydrophobic interactions at the dimer interface, favoring the monomeric form predominant in physiological secretion while preserving receptor binding affinity and biological potency. Preclinical studies in animal models demonstrated the innovation's efficacy in accelerating absorption. In rats and dogs, insulin lispro exhibited markedly faster subcutaneous uptake compared to regular insulin, with pharmacokinetic profiles showing earlier peak plasma concentrations and reduced time to onset due to diminished hexamer stability, as confirmed through tissue distribution, elimination, and pharmacodynamic assays. These findings highlighted lispro's potential to better replicate the rapid monomeric insulin release from pancreatic beta cells, overcoming the 30-90 minute lag of conventional insulins in controlling prandial hyperglycemia. Eli Lilly filed patents for the lispro analog in the early , protecting the approach driven by the clinical imperative for a true physiologic mealtime insulin that minimizes in glucose disposal. This development marked a pioneering application of to modify insulin's for tailored kinetics, setting for rapid-acting analogs without altering core therapeutic .

Regulatory Approvals and Milestones

Insulin lispro, marketed as Humalog by Eli Lilly and Company, received initial approval from the U.S. Food and Drug Administration (FDA) in June 1996 for subcutaneous administration to improve glycemic control in adults and children with diabetes mellitus. The European Medicines Agency (EMA) granted marketing authorization for Humalog on April 30, 1996, for similar indications in the European Union. These approvals marked the introduction of the first rapid-acting insulin analog, distinguished by its reversed proline-lysine sequence at positions 28 and 29 of the B-chain compared to human insulin. Labeling expansions followed, including FDA approval for use in continuous subcutaneous insulin infusion via external pumps, as reflected in product labeling permitting compatibility with specific pump models by the late 1990s. In June 2011, the FDA updated Humalog labeling to include recommendations for pediatric use in pump systems. Further formulation advancements included FDA approval of Humalog U-200 KwikPen, a higher-concentration pen device, on May 27, 2015. The FDA approved Admelog, Sanofi's follow-on insulin lispro injection, on December 11, 2017, for glycemic control in adults and pediatric patients with diabetes. In June 2020, the FDA approved Lyumjev (insulin lispro-aabc injection), Eli Lilly's ultra-rapid-acting formulation with modified excipients for faster absorption, for adults with type 1 or type 2 diabetes. This approval was expanded in August 2021 to include use in insulin pumps for adults. The EMA authorized Insulin lispro Sanofi, a biosimilar version, in July 2017, and Lyumjev (initially Liumjev) in March 2020.

Society and Culture

Brand Names and Formulations

Insulin lispro is primarily marketed under the brand name Humalog by Eli Lilly and Company in various countries, including the United States and Europe. A follow-on version, Admelog, produced by Sanofi, was approved by the U.S. Food and Drug Administration in December 2017 and is available as an alternative in select markets. Unbranded generic versions of insulin lispro have entered some markets, such as authorized generics of Humalog in the U.S. since 2023. Standard formulations include U-100 (100 units per milliliter) for subcutaneous injection, available in vials, prefilled KwikPen devices (for Humalog), and SoloStar pens (for Admelog). Humalog also offers a U-200 (200 units per milliliter) concentration exclusively in KwikPen format, approved by the FDA in 2015, which contains twice the insulin per milliliter compared to U-100 but requires specific dosing adjustments. Combination products, such as Humalog Mix 25 (25% insulin lispro, 75% insulin lispro protamine suspension) and Humalog Mix 50 (50% each), provide biphasic action and are formulated at U-100 strength in vials and pens. These products are widely distributed in high-income countries through pharmacies and insulin pumps compatible with U-100 formulations, but availability in low- and middle-income countries remains limited, often restricted to urban areas or supplemented by human insulin analogs due to supply chain and regulatory barriers. The World Health Organization has proposed including rapid-acting insulin analogs like lispro on its essential medicines list to improve access, though as of 2024, implementation varies by region.

Economics, Pricing, and Access

In the United States, the list price for a 10 mL vial of Humalog (insulin lispro) was approximately $274 prior to manufacturer reductions announced in March 2023, reflecting the high costs associated with biologic manufacturing, regulatory compliance, and recovery of research and development investments estimated at hundreds of millions for insulin analogs like lispro. These prices contrast sharply with international markets, where a comparable vial of Humalog costs around $70 in Canada due to government-negotiated pricing and public health system controls that limit manufacturer leverage. Such disparities arise from differences in market structures, with U.S. pricing supporting innovation recoupment amid limited generic entry for complex biologics, while single-payer negotiations abroad compress margins. Patent protections for insulin lispro, including compound and formulation claims, have historically provided manufacturers like Eli Lilly with exclusivity periods averaging 16 years, enabling profitability to fund reinvestment in pipeline advancements such as improved analog formulations. This framework has incentivized development of rapid-acting insulins, which empirical pharmacoeconomic analyses indicate are cost-effective relative to human insulins by reducing hypoglycemia events and associated healthcare expenditures, with retrospective studies estimating net savings from fewer emergency interventions. Long-term glycemic improvements from analogs have also correlated with lower overall diabetes complication costs, as modeled in database analyses showing offsets against initial acquisition premiums through averted hospitalizations and chronic care. The Inflation Reduction Act of 2022 introduced a $35 monthly out-of-pocket cap for insulin in Medicare Part D plans effective January 2023, leading to increased prescription fills and improved adherence among enrollees without altering list prices directly. Pharmacy benefit manager rebates and manufacturer responses, including Eli Lilly's reduction of non-branded lispro vial list prices to $25 by May 2023, have further modulated net costs, though access barriers persist for uninsured patients reliant on full list pricing absent competitive pressures from biosimilars. These interventions highlight tensions between price controls enhancing short-term affordability and market-driven incentives that have historically accelerated innovations in insulin delivery and efficacy.

Biosimilars and Market Competition

Admelog (insulin lispro injection), manufactured by Sanofi, was approved by the U.S. Food and Drug Administration (FDA) on December 11, 2017, as the first follow-on biologic to the reference product Humalog (insulin lispro) by Eli Lilly, demonstrating bioequivalence through pharmacokinetic (PK) and pharmacodynamic (PD) studies in healthy volunteers and patients with diabetes. These studies confirmed comparable onset, peak, and duration of action, with no clinically meaningful differences in glucose-lowering effects or immunogenicity. Unlike full biosimilars under the Biologics Price Competition and Innovation Act (BPCIA) pathway established in 2010, Admelog was approved as a follow-on product under pre-existing provisions for insulin demonstration of sameness in manufacturing and clinical performance, without designation as interchangeable, meaning pharmacists cannot substitute it without prescriber approval. Despite approval, Admelog's market uptake for insulin lispro biosimilars has remained low, achieving approximately 8% share among products with at least three years on the market as of 2024, limited by factors including complex manufacturing requirements for recombinant insulin analogs, prescriber reluctance due to perceived differences in delivery devices, and originator dominance through rebates and formulary preferences. Biosimilar entry has nonetheless exerted competitive pressure, with Admelog priced 21-67% lower than Humalog in certain channels by 2021, contributing to broader insulin analog cost reductions through originator responses like authorized generics, though overall biosimilar penetration trails that of other classes due to these barriers. The presence of biosimilars like Admelog supports ongoing market competition by offering clinically equivalent alternatives, potentially expanding access without eroding incentives for originator innovation, as evidenced by continued R&D in ultra-rapid formulations such as Eli Lilly's Lyumjev (insulin lispro-aabc), approved in 2019 under the full BPCIA pathway. This dynamic balances supply diversification—reducing risks from single-source dependency—with sustained investment, as biosimilar development still requires substantial clinical bridging studies amid insulin's high manufacturing complexity involving precise glycosylation and purity controls. Emerging pipelines, including additional lispro biosimilars in late-stage development, signal potential for further competition, projected to grow biosimilar share at a compound annual rate exceeding 11% through 2030.

Controversies in Pricing and Regulation

Insulin lispro, marketed as Humalog by Eli Lilly, has been at the center of debates over escalating U.S. list prices, which rose from approximately $21 per vial in 1996 to $274 by 2016, and from $93 in 2009 to over $275 by 2017, amid claims of excessive profiteering by manufacturers. Critics, including patient advocacy groups, argue these increases—totaling over 1,200% since launch for Humalog—exacerbate affordability crises, particularly for uninsured individuals facing out-of-pocket costs averaging $97 per lispro unit at pharmacies in 2023, contributing to rationing and adverse health outcomes. However, analyses reveal that pharmacy benefit managers (PBMs) and intermediaries capture significant portions of list price hikes; for instance, Eli Lilly's net revenue per Humalog pen remained stable at about $25 from 2013 to 2018, even as list prices doubled from $57 to $106, underscoring that gross prices do not equate to manufacturer profits. Marginal production costs for analog insulins like lispro are estimated at $2–$4 per vial or $3–$6 broadly, reflecting low variable expenses post-R&D, yet defenders emphasize that recouping multibillion-dollar fixed development costs for innovations—such as lispro's rapid onset enabling better glycemic control—necessitates extended patent protections, including reformulations critiqued as "evergreening" but essential for incentivizing biotech advancements in a high-risk field. U.S. prices for insulin products, including lispro, average 5–10 times higher than in other nations, fueling arguments for international reference (IRP) to align costs, but empirical evidence indicates such mechanisms distort global markets by shifting R&D burdens disproportionately to the U.S., which funds 40–50% of worldwide pharmaceutical despite comprising 4% of the . IRP in reference countries suppresses prices through , potentially delaying or deterring launches of complex biologics like insulin analogs abroad, as manufacturers offset losses via U.S. premiums that subsidize global access; studies link aggressive to reduced in subsequent therapies, with historical precedents showing fewer new drugs post-implementation in referencing nations. This dynamic justifies lispro's , as its analog —despite low per-dose —stemmed from costly to mimic physiological insulin kinetics, yielding outcomes improvements that warrant recovery periods exceeding human insulin's simpler profile. Regulatory interventions, such as the 2022 Inflation Reduction Act's Medicare price negotiations and state-level , have prompted manufacturer responses like Eli Lilly's 2019 launch of an unbranded lispro at half the Humalog price ($137 per ) and a $35 monthly for certain insured/uninsured patients from 2023, reducing some access barriers. Yet, proposals like the INSULIN Act for broader federal risk stifling future by compressing revenues needed for pipeline drugs, as evidenced by modeling showing could elevate overall insulin costs through shortages or delayed entry, while failing to address uninsured gaps comprehensively. Balanced reforms targeting PBM rebates and transparency may mitigate distortions without undermining the incentives that drove lispro's development, though mainstream critiques often overlook causal links between U.S.-funded R&D and global insulin advancements.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Insulin-Lispro
  2. https://www.ncbi.nlm.nih.gov/books/NBK507840/
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20563s10-11-12-13lbl.pdf
  4. https://go.drugbank.com/drugs/DB00046
  5. https://www.aafp.org/pubs/afp/issues/1998/0115/p279.html
  6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020563s115lbl.pdf
  7. https://pubmed.ncbi.nlm.nih.gov/32208559/
  8. https://pubmed.ncbi.nlm.nih.gov/9339963/
  9. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761109Orig1s000SumR.pdf
  10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020563s172%2C205747s008lbl.pdf
  11. https://pubmed.ncbi.nlm.nih.gov/9377611/
  12. https://dmsjournal.biomedcentral.com/articles/10.1186/s13098-018-0397-3
  13. https://pi.lilly.com/insulin-lispro-uspi.pdf
  14. https://www.merckmanuals.com/professional/multimedia/table/onset-peak-and-duration-of-action-of-human-insulin-preparations
  15. https://pi.lilly.com/us/humalog-pen-pi.pdf
  16. https://reference.medscape.com/drug/admelog-humalog-insulin-lispro-999005
  17. https://www.droracle.ai/articles/372646/how-many-units-to-start-with-lispro-injection
  18. https://pi.lilly.com/us/insulin-lispro-uspi.pdf
  19. https://pubmed.ncbi.nlm.nih.gov/8314011/
  20. https://www.drugs.com/monograph/insulin-lispro.html
  21. https://pubmed.ncbi.nlm.nih.gov/12403642/
  22. https://www.rcsb.org/structure/1LPH
  23. https://pdb101.rcsb.org/global-health/diabetes-mellitus/drugs/insulin/drug/insulin-lispro/insulin-lispro
  24. https://iubmb.onlinelibrary.wiley.com/doi/10.1002/bab.2664
  25. https://bioresourcesbioprocessing.springeropen.com/articles/10.1186/s40643-021-00419-w
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC4203937/
  27. https://pubmed.ncbi.nlm.nih.gov/40544397/
  28. https://patents.google.com/patent/US10155799B2/en
  29. https://www.pharmaceutical-technology.com/uncategorized/eli_lilly/
  30. https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/insulin-lispro-ira-guid-2e960c29-2785-4a44-a9b6-8a280272ee36.pdf
  31. https://www.tandfonline.com/doi/full/10.4155/fmc-2019-0134
  32. https://pubmed.ncbi.nlm.nih.gov/9000704/
  33. https://pubmed.ncbi.nlm.nih.gov/9183237/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC7048883/
  35. https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1463-1326.2008.00934.x
  36. https://onlinelibrary.wiley.com/doi/10.1111/pedi.12401
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC10081815/
  38. https://link.springer.com/article/10.1007/s13300-022-01290-4
  39. https://pubmed.ncbi.nlm.nih.gov/9773738/
  40. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020563s196s198s199%2C205747s022s025s026lbl.pdf
  41. https://www.drugs.com/sfx/insulin-lispro-side-effects.html
  42. https://pubmed.ncbi.nlm.nih.gov/12502663/
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC10358051/
  44. https://pubmed.ncbi.nlm.nih.gov/11084559/
  45. https://www.researchgate.net/publication/23141956_Short-acting_insulin_analogues_vs_regular_human_insulin_in_type_2_diabetes_A_meta-analysis
  46. https://www.jmcp.org/doi/full/10.18553/jmcp.2017.23.3.291
  47. https://www.tandfonline.com/doi/full/10.1080/14712598.2024.2371046
  48. https://www.sciencedirect.com/science/article/abs/pii/S1530891X20422682
  49. https://journals.sagepub.com/doi/10.1177/193229681300700620
  50. https://diabetesjournals.org/care/article/31/2/210/25210/A-Randomized-Trial-Comparing-Continuous
  51. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0033-1363684
  52. https://diabetesjournals.org/care/article/37/6/1771/30072/Insulin-Analogs-Is-There-a-Compelling-Case-to-Use
  53. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/486628
  54. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/insulin-lispro
  55. https://www.sciencedirect.com/topics/medicine-and-dentistry/insulin-lispro
  56. https://www.ema.europa.eu/en/documents/scientific-discussion/humalog-epar-scientific-discussion_en.pdf
  57. https://pubmed.ncbi.nlm.nih.gov/8821525/
  58. https://pmc.ncbi.nlm.nih.gov/articles/PMC7366348/
  59. https://www.ema.europa.eu/en/medicines/human/EPAR/humalog
  60. https://investor.lilly.com/news-releases/news-release-details/fda-approves-updates-lillys-humalogr-insulin-lispro-injection
  61. https://www.endocrinologyadvisor.com/news/fda-approves-humalog-u-200-kwikpen/
  62. https://www.drugs.com/history/admelog.html
  63. https://www.prnewswire.com/news-releases/fda-approves-lyumjev-insulin-lispro-aabc-injection-100-unitsml-for-use-in-insulin-pumps-301355407.html
  64. https://www.ema.europa.eu/en/medicines/human/EPAR/insulin-lispro-sanofi
  65. https://www.ema.europa.eu/en/medicines/human/EPAR/lyumjev
  66. https://insulins.lilly.com/humalog
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC8597930/
  68. https://cdn.who.int/media/docs/default-source/2025-eml-expert-committee/addition-of-new-medicines/a.18_insulin-analogue-rapid-acting.pdf?sfvrsn=bb183144_7
  69. https://firstwordpharma.com/story/5711184
  70. https://www.buycanadianinsulin.com/product/humalog-vial/
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC10653475/
  72. https://www.ajmc.com/view/nov08-3731p766-775
  73. https://ajmc.s3.amazonaws.com/_media/_pdf/AJMC_08Nov_Brixner_766to775.pdf
  74. https://aspe.hhs.gov/reports/insulin-affordability-ira-data-point
  75. https://mann.usc.edu/news/study-inflation-reduction-acts-cap-on-insulin-out-of-pocket-costs-boosts-prescription-fills/
  76. https://pricinginfo.lilly.com/insulin-lispro
  77. https://www.iqvia.com/locations/united-states/blogs/2023/05/impact-of-reduction-in-insulin-prices-by-major-drug-manufacturers
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC9262161/
  79. https://diatribe.org/diabetes-medications/admelog-first-biosimilar-rapid-acting-insulin
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC6313268/
  81. https://www.goodrx.com/admelog/humalog-generic
  82. https://www.ajmc.com/view/biosimilar-uptake-lags-in-us-despite-potential-cost-savings
  83. https://www.centerforbiosimilars.com/view/biosimilars-account-for-23-market-share-with-wide-uptake-disparities-across-molecules
  84. https://healthcostinstitute.org/hcci-originals-dropdown/all-hcci-reports/https-healthcostinstitute-org-hcci-research-insulin-prices-in-esi-nearly-doubled-from-2012-2021-with-effects-of-emerging-biosimilars-evident-in-recent-years
  85. https://www.bigmoleculewatch.com/2020/06/17/fda-approves-lyumjev-insulin-lispro-aabc-injection/
  86. https://www.mordorintelligence.com/industry-reports/insulin-lispro-market
  87. https://dataintelo.com/report/biosimilar-insulin-lispro-market
  88. https://www.businessinsider.com/insulin-price-increased-last-decade-chart-2019-9
  89. https://www.visualcapitalist.com/cp/rising-cost-of-insulin-us/
  90. https://www.warren.senate.gov/oversight/reports/new-report-from-warren-warnock-blumenthal-uninsured-patients-face-significant-problems-getting-affordable-insulin
  91. https://kffhealthnews.org/news/article/insulin-costs-pharmacy-benefit-managers-drug-manufacturers/
  92. https://www.cnn.com/2023/03/09/health/insulin-cost-khn-partner
  93. https://www.nbcnews.com/health/health-news/novo-nordisk-lower-list-price-insulin-rcna74836
  94. https://worldpopulationreview.com/country-rankings/cost-of-insulin-by-country
  95. https://www.csis.org/blogs/perspectives-innovation/effect-reference-pricing-pharmaceutical-innovation
  96. https://www.healthaffairs.org/do/10.1377/forefront.20211004.561448/
  97. https://pmc.ncbi.nlm.nih.gov/articles/PMC6157569/
  98. https://www.fiercepharma.com/pharma/lilly-offers-generic-humalog-at-half-price-amid-bipartisan-pressure-rising-insulin-costs
  99. https://www.pharmacy.umn.edu/affordability-breakthroughs-updates-insulin-access-and-pricing
  100. https://paragoninstitute.org/medicare/policy-brief-the-insulin-act-higher-insulin-prices-and-less-innovation/
  101. https://medicine.iu.edu/blogs/bioethics/insulin-price-control-gaps
  102. https://pmc.ncbi.nlm.nih.gov/articles/PMC8249113/
Add your contribution
Related Hubs
User Avatar
No comments yet.