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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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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