Modern Insulin : An Update


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Symposium on 17th June, 2013. Presented by Dr. Jobaida Naznin (MD Final part student), Endocrinology Department, BSMMU

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  • The physiological insulin profile comprises a basal component with meal-related peaks References Kruszynska. Diabetologia 1987;30:16
  • The pharmacokinetics of injected insulin do not match the physiological secretion profile. Bolus insulins (e.g. soluble human insulin) are absorbed too slowly and their effect lasts too long Basal insulins (e.g. NPH, lente insulin) are absorbed too quickly, their profile is not flat enough, and absorption rates are variable As a result, there is a risk of hypoglycaemia, and it is difficult to refine treatment
  • Basal–bolus therapy attempts to mimic the physiological insulin profile. The theory is that a rapidly-absorbed insulin preparation will have a rapid onset and short duration of action and thereby mimic the prandial insulin response if taken before meals, while a longer-acting preparation with protracted absorption will substitute the basal insulin output In practice, however, available preparations of human insulin are poorly able to reproduce such a profile. Soluble human insulins are absorbed with too protracted an action to accurately recreate the prandial insulin response, while basal products such as NPH insulin poorly recreate the low constant and consistent profile of overnight insulin secretion
  • Among these factors, self-association is one that is related to the properties of the insulin molecule. Insulin analogues were developed on the principle of changing the rate of association/dissociation
  • Human regular insulin tends to associate into dimers and hexamers. However, monomers are the form recognised by the insulin receptor The rapid-acting analogues were developed to dissociate more rapidly after s.c. injection The b asal analogues, on the other hand, were designed to be absorbed at a protracted, steady absorption rate References Figure adapted from Adapted from Brange. Diabetes Care 1990;13:923
  • Three types of insulin analogues are currently available, as shown Some of these analogues have slightly different names in the USA: NovoRapid ® is NovoLog ® , and NovoMix ® is NovoLog ® Mix
  • In lispro, the two amino acids at positions 28 and 29 of the insulin B chain have been transposed. This change disrupts the strength of the bond between monomer units in the insulin dimer
  • In aspart, the proline residue at position B28 has been replaced with an asparagine residue. As with lispro, this change disrupts the strength of the bond between monomer units in the insulin dimer
  • In glulisine, residues at positions B3 and B29 have been replaced as shown
  • Typical action profiles for human insulin and the rapid-acting analogues are shown. These values are from studies in healthy volunteers or patients with type 1 diabetes, as available The values quoted in different references may vary somewhat according to the conditions of the study. Nevertheless, it is clear that the analogues reach a peak concentration faster than human insulin, and that their activity is also of shorter duration References Oiknine . Drugs 2005;65:325 – 40 Prescribing information, Insulin lispro. Available at: Accessed 18 February 2008 Prescribing information, Insulin aspart. Available at: Accessed 18 February 2008 Becker . Exp Clin Endocrinol Diabetes 2005;113:292 – 297 Becker . Diabetes 2004;53(Suppl. 2):A119
  • All the rapid-acting analogues have undergone studies to establish their safety with respect to the aspects shown, but we will focus on aspart Insulin aspart has been shown to be safe in the following special populations: patients with hepatic or renal impairment, obese patients, children and adolescents, pregnant women. These will be covered in more detail in Session 9 References Mitogenic potency Kurtzhals P . Diabetes 2000;49:999 – 1005 Hypoglycaemic awareness Frier. Diabet Metab Res Rev 2000;16:262 – 268 Immunogenicity Lindholm . Diabetes Care 2002;25:876 – 882 Adverse events Prescribing information, Novo Nordisk
  • When insulin is injected into subcutaneous tissue, it forms a depot. It must then pass through capillary walls into the circulation, and from there must pass back through capillary walls to reach the interstitial fluid of the target tissues. Thus, the route to the receptor involves passage through three compartments, giving three potential sites of protraction One strategy has been to modify the isoelectric point such that the insulin is liquid upon injection (when in a suitable medium), but crystallises into a slowly-absorbed precipitate depot in the neutral pH of the subcutaneous environment. This method has been used with some success with insulin glargine, which has a very protracted action, but variability may still be a problem – perhaps as a result of physical differences in the nature of precipitation from one injection to another Another strategy has been to acylate fatty acid residues to the insulin molecule, enabling the resulting analogue to bind to albumin. This approach was used in the development of insulin detemir
  • Amino acid changes in glargine shift its isoelectric point (pH 5.4 → 6.7). It is presented in an acidic solution (pH 4.0) and forms a microprecipitate in neutral subcutis The result is slow dissolution and absorption, but precipitation and the subsequent dissolution are unpredictable processes
  • Insulin detemir has a C14 fatty acid attached to a Lys residue at B29. The fatty-acid side chains enable insulin detemir to bind to albumin. This is possible in all three compartments between injection and receptor interaction – in the s.c. depot, in the circulation and in the interstitium of the target tissue itself. Thus, there are three potential sites where protraction of action could take place The acylation with myristic acid stabilises hexamers, allows dihexamerisation, and allows albumin binding Absorption is slow due to prolonged self-association and albumin binding at the injection site Dynamic, reversible plasma albumin binding ‘buffers’ changes in the absorption rate
  • Glargine and detemir both have a longer duration of action than NPH. References Oiknine . Drugs 2005;65:325 – 40 Prescribing information, Insulin glargine. Available at: Accessed 18 February 2008 Prescribing information, Insulin detemir. Available at: Accessed 18 February 2008 Heise. Diabetes Obes Metab 2007;9(8):648 – 59  
  • Safety issues have been investigated for detemir as shown, and no cause for clinical concern has been noted Special populations: small studies have suggested that neither hepatic nor renal impairment affect the pharmacokinetics of detemir in a clinically significant way. Detemir has been shown to be effective and tolerable in children and adolescents. Detemir has not been studied in pregnant women. These issues will be covered more fully in Session 10
  • Premixed insulin analogues contain just one rapid-acting insulin analogue, together with enough protamine to crystallise a certain proportion For example, NovoMix ® 30 is a modern premixed insulin analogue, but contains just one insulin: insulin aspart. NovoMix ® 30 contains enough protamine to crystallise 70% of the insulin aspart, leaving 30% soluble aspart Similarly, Humalog ® Mix 25 contains insulin lispro in a formulation in which 25% is soluble lispro and 75% is protaminated The soluble rapid-acting insulin analogue and intermediate-acting, protamine-crystallised insulin analogue in premixes allow the targeting of poor postprandial glycaemic control and fasting blood glucose, respectively
  • In NovoMix ® 30, rapid-acting, soluble, insulin aspart is absorbed more quickly than soluble human insulin, thus, unit-for-unit, reaching a higher plasma insulin concentration in a shorter time. This soluble aspart covers prandial insulin needs The 70% protamine-crystallised aspart is absorbed more slowly and has a similar duration of action to NPH . It thus addresses basal insulin needs Premixed analogues can be injected once-, twice- or three-times-daily. They can offer patients the possibility of fewer injections compared with basal-bolus therapy. In some situations this is particularly advantageous (e.g. for young schoolchildren who may require adult help to inject) NovoMix ® 30 will be covered in more detail in Session 11
  • Manuscript submitted BIAsp 1069 NPH monotherapy = once- or twice-daily NPH. The study did not distinguish between patients taking NPH either once a day or twice a day.
  • The insulin degludec molecule retains the human insulin (HI) amino acid sequence except for the deletion of ThrB30 and the addition of a 16-carbon fatty di-acid chain attached to LysB29 via a glutamic acid spacer (linker). The primary structure is designed to allow the formation of soluble multi-hexamer assemblies upon subcutaneous injection, to give an ultra-long peak-less PK profile. The degludec molecule differs from human insulin in that the amino acid residue threonine in position B30 has been omitted and the ε-amino group of lysine in position B29 has been coupled to a C16 fatty di-acid (hexadecanedioic acid) via a spacer of glutamic acid (chemical name: LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin).
  • In this double-blind, two-period, crossover trial, we investigated the dose-response relationship of three doses of IDeg (0.4, 0.6, and 0.8 U/kg) at steady state (SS) in people with type 2 diabetes. Participants (insulin-treated people with type 2 diabetes without concomitant oral anti-diabetic agents, n=49; mean age, 58.7 years; BMI, 29.6 kg/m²; A1C, 7.6%; duration of diabetes, 14.1 years) were given IDeg once daily for 6 days, with a washout period of 13–21 days between treatments. Following dosing on Day 6, subjects underwent a euglycemic glucose clamp (Biostator; clamp blood glucose level: 90 mg/dL). Pharmacokinetic samples were taken up to 120 h after the last injection of IDeg. For all dose levels, mean 24 h glucose infusion rate (GIR) profiles were flat and stable (Figure 1). Total glucose-lowering effect (AUCGIR,total,SS) increased linearly with increasing dose. Over 24 h, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h for all 3 dose levels (AUCGIR,0-12h,SS / AUCGIR,total,SS = 0.5). The blood glucose levels of all participants stayed very close to the clamp level until the end of the experiment (mean blood glucose levels in the last 10min of a 24-h dosing interval were 90–92 mg/dL for all IDeg doses). The terminal half-life estimated across the three dose levels after the last dose was 25.1 h. IDeg was well tolerated and no safety concerns were identified. In conclusion, IDeg has a flat and stable blood glucose-lowering effect, and a duration of action beyond 24 h in people with type 2 diabetes
  • Data are LOCF ± SEM Please note that due to regulatory requirements the statistics shown are model-based (using LS means) to account for possible confounding factors.
  • Modern Insulin : An Update

    1. 1. MODERN INSULINAN UPDATEDr. Jobaida NazninMD Final part StudentDepartment of EndocrinologyBSMMU
    2. 2. Slide No 2June 18, 2013DateWhat are insulin analogues?• Structure of insulin is modified• Pharmacokinetic properties modified to mimicphysiology• Molecular pharmacology of human insulinretained
    3. 3. Slide No 3June 18, 2013DateNormal physiological profile of seruminsulin concentrationKruszynska. Diabetologia 1987;30:16Mealtime insulin excursionsRapid rise; short duration0800 1200 1600 2000 2400010203040500400Time (h)Seruminsulin(mU/L)0800Flat basal insulin profileBreakfast Lunch Dinner
    4. 4. June 18, 2013 4Limitations of conventional insulinsProfiles areschematicIntermediate-acting insulinSoluble insulinSum of the added insulinsPhysiological insulin profileSeruminsulinTime
    5. 5. Slide No 5June 18, 2013DateAttempts to recreate physiological insulinsecretion with basal–bolus therapyProfiles areschematic60504030201006 222181410 6Time of dayRapid-acting insulinBasal insulinTotalPredictedplasmainsulinconcentrationprofile(mU/L)
    6. 6. Slide No 6June 18, 2013DateProperties of ideal analoguesProperties of an ideal mealtime (bolus) analogue:• Fast onset• Short duration of action• PredictabilityProperties of an ideal basal analogue:• Long duration of action• Flat profile (no peak)• Predictability
    7. 7. 7Factors determining insulinabsorption rate• Insulin preparation• Dose, concentration andvolume• Physical state (solution orsuspension)• Injection site factors• Region of injection• Injection device• Depth of injection/injection technique• Lipodystrophy• Insulin state- self-association- precipitation• Bloodflow changes, e.g.- temperature- exercise• Metabolic state, e.g.- hypoglycaemia- ketoacidosis
    8. 8. Slide No 8June 18, 2013DateDissociation of insulin after s.c. injectionSubcutaneoustissueMolarconcentrationDiffusionCapillarymembrane10–310–4 10–5 10–8Adapted from Brange. Diabetes Care 1990;13:923
    9. 9. Slide No 9June 18, 2013DateCurrently available insulin analoguesGeneric name Trade name ManufacturerRapid-actinganaloguesInsulin aspart NovoRapid®Novo NordiskInsulin lispro Humalog®Eli LillyInsulin glulisine Apidra®sanofi aventisBasalanaloguesInsulin detemir Levemir®Novo NordiskInsulin glargine Lantus®sanofi aventisBiphasicpremixedanaloguesBiphasic insulinaspartNovoMix®Novo NordiskBiphasic insulinlisproHumalog®Mix Eli Lilly
    10. 10. Slide No 10June 18, 2013DateRapid-acting insulinanalogues
    11. 11. Slide No 11June 18, 2013DateInsulin lisproGluThrLysThrTyrPhePhe Gly ArgGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysLeuHisGlnAsnValPheB1Asn CysTyrAsnGluLeuGlnTyrLeuSerCysIleSerThrCysCysGlnIleGlyB28B30ProGluValA21A1
    12. 12. Slide No 12June 18, 2013DateInsulin aspartGluThrLysThrTyr PhePhe Gly ArgGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysLeuHisGlnAsnValPheB1Asn CysTyrAsnGluLeuGlnTyrLeuSerCysIleSerThrCysCysGlnGluValIleGlyA21A1B28B30AspProAsp
    13. 13. Slide No 13June 18, 2013DateInsulin glulisineGluThrLysThrTyr PhePhe Gly ArgGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysLeuHisGlnAsnValPheB1Asn CysTyrAsnGluLeuGlnTyrLeuSerCysIleSerThrCysCysGlnGluValIleGlyA21A1B29B30GluProLysB3
    14. 14. June 18, 2013 14Action profiles of insulin andrapid-acting insulin analoguesOnset (min) Peak (min) Duration (h)Regular humaninsulin130–60 120–180 6–8Insulin lispro 15230–7022−5Insulin aspart 10–20340–9033–5Insulin glulisine 2045553–51Oiknine. Drugs 2005;65:325–402Prescribing information, insulin lispro3Prescribing information, insulin aspart4Becker. Exp Clin Endocrinol Diabetes 2005;113:292–75Becker. Diabetes 2004;53(Suppl.2):A119
    15. 15. June 18, 2013 15Insulin aspart: safety issuesInsulin receptor affinity andmitogenicityMitogenic potency less than humaninsulinHypoglycaemia Incidence similar or lower than withhuman insulinHypoglycaemic awareness Physiological responses werepreserved and equivalent for aspartcompared with human insulinImmunogenicity Transient increase in antibodies. Nocorrelation with efficacy or safetyAdverse events Similar to soluble human insulin
    16. 16. Slide No 16June 18, 2013DateBasal insulinanalogues
    17. 17. Slide No 17June 18, 2013DateStrategies for protractionModification of isoelectric point: precipitation at pH 7.4• Insulin glargineAcylation with hydrophobic residues (and albumin binding)• Insulin detemir
    18. 18. Slide No 18June 18, 2013DateInsulin glargineGluThrLysThrTyr PhePhe Gly ArgGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysLeuHisGlnAsnValPheB1Asn CysTyrAsnGluLeuGlnTyrLeuSerCysIleSerThrCysCysGlnGluValIleGlyA21A1B30GlyArgProArg+
    19. 19. Slide No 19June 18, 2013DateInsulinInsulin detemirThrGluLysValPheAsnGluLeuGlnTyrLeuSerCysIleSerCysCysGlnGluValIleGlyTyrCysAsnLysProThrTyrPhePheArgGlyGluGlyCysValLeuTyrLeuAlaValLeuHisSerGlyCysAsn Gln LeuHisC14 fatty acid chain(Myristic acid)Thr
    20. 20. June 18, 2013 20Action profiles of insulin andbasal analoguesOnset (h) Peak (h) Duration (h)NPH insulin11–2 5–7 13–18Insulinglargine1–21No peak220–301Insulindetemir31–23No peak32441Oiknine. Drugs 2005;65:325–40 3Prescribing information, insulin detemir2Prescribing information, insulin glargine 4Heise. Diabetes Obes Metab 2007;9(8):648–59
    21. 21. June 18, 2013 21Insulin detemir: safety issuesInsulin receptor affinity andmitogenicityReceptor affinity and mitogenicpotency less than human insulinSafety of albumin binding ofinsulin detemirInsulin detemir has negligibleimpact on the binding capacity ofthe serum albumin poolHypoglycaemia Incidence of hypoglycaemia,especially nocturnal hypoglycaemia,generally lower than with humaninsulinImmunogenicity No immunogenicity concernsAdverse events Similar to NPH
    22. 22. June 18, 2013 22Key benefits:
    23. 23. June 18, 2013 23Levemir®gives you More
    24. 24. Slide No 24June 18, 2013DateBiphasic premixedinsulin analogues
    25. 25. Slide No 25June 18, 2013DateBenefits of dual-release insulin replacement1. Mimics physiological insulin release• Early release of rapid-acting insulin targetspostprandial glucose• Delayed release of intermediate-acting insulin fulfilsbasal insulin requirement2. Reduces hypoglycaemic risk3. Improves HbA1c4. Simplifies dosing• Option of postprandial dosing
    26. 26. Slide No 26June 18, 2013DateBiphasic premixed insulin analoguesNovoMix®30Rapid-actinginsulin aspartPremixedsuspensionIntermediate-actingprotamine-crystallisedinsulin aspart
    27. 27. Slide No 27June 18, 2013DateBiphasic premixed insulin analogues• 30% soluble aspart → rapid absorption→ covers prandial insulin needs• 70% protamine-crystallised aspart → slower absorption→ addresses basal insulin needs• Fewer injections
    28. 28. Slide No 28June 18, 2013Date• Mean prandial glucose increment lower in NovoMix®30 group(p < 0.0001)• Patients receiving NPH monotherapy benefit from switchingto NovoMix®30 (bid)NovoMix®30 offers better glycaemiccontrol than NPHChristiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452
    29. 29. AdvancementsAnimal insulinpreparationsRecombinanthumaninsulinRapid-actinginsulinanaloguesBasalinsulinanaloguesNew-generationinsulin analogues/combination insulinsIsolationof insulin(Banting & Best)Time19221977BiphasicinsulinDegludecDegludecPlus1990s2000sAdvancing insulin therapyTowards a new stage in the evolving story of insulintherapy
    30. 30. Unique molecular engineering:degludec molecular structuresssFF VV NN QQ HH LL CC GG SS HH LL VV EE AA LL YY LL VV CC GG EE RR GG FF FF YY TT PPGG II VV EE QQ CC TT SS II CC SS LL YY QQ LL EE NN YY CC NNCCss sA chainB chainKKNHOOHO NHOOHOHexadecandioylL-γ-GludesB30 InsulinLysB29Nε-hexadecandioyl-γ-Glu desB30 human insulinGludec deTT
    31. 31. Hexamer(36 kDa)Dimer Monomer(6 kDa) Blood vesselCellEngineering insulin analoguesDi-Hexamer(72 kDa)Multi-Hexamer(>5000 kDa)Rapid actingLong acting
    32. 32. Insulin degludec: summary I• The protraction mechanism of insulin degludecinvolves:• Multi-hexamer formation upon injection• Slow and stable release of monomers• This property is critically dependent on the spacer andside chain used• This design is expected to provide ultra-long and flatPK/PD profiles
    33. 33. Insulin degludec has a flat and stableinsulin actionNosek et al. IDF 2011:P-1452 NN1250-1987; Diabetologia 2011;54(suppl. 1):S429 (1055-P); Diabetes 2011;60(suppl. 1A):LB14.T2DM, N=49, 26h EG clamp on days 6 and 12, 120 min PK samplingInsulin-treated Type 2 diabetes (n=49)0.4, 0.6, 0.8 U/kg once daily for 6 days
    34. 34. Insulin degludec: summary II• In Steady State: Input = Output• For insulin degludec: Steady state level is reachedin 2–3 days• Insulin degludec provides an ultra long duration ofaction that leads to a flat and smooth pharmacokineticand pharmacodynamic profile
    35. 35. HbA1c over timeIDeg Flexible/IGlarNon-inferiorIDeg Flexible/IDeg FixedNon-inferior0FAS; LOCFComparisons: Estimates adjusted for multiple covariatesIDeg Flexible (n=229)IDeg Fixed (n=228)IGlar (n=230)NN1250-3668; IDeg Flexible vs IDeg Fixed and IGlar in T2. Submitted for ADA 2011
    36. 36. Degludec medical communicationplatformNovel protraction mechanismUltra-long action (flat, stable & consistent)Low rateof hypos(also at low FPG)FlexibledosingExcellentefficacyConvenienttrue ODdosingFlexTouch®Up to 160UInsulinsafety
    37. 37. Insulin degludec: summary IIIExcellent improvement in HbA1cSuperior FPG reductionDegludecPlusAchieveglycaemiccontrolEfficacyLess hypoglycaemiaReduction of up to 36% innocturnal hypoglycaemiaDegludecPlusAvoidhypos SafetyDosing flexibility: administrationany time on any dayDegludecPlusFlexibility Convenience
    38. 38. Slide No 38June 18, 2013DateThank You