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. MODERN INSULIN AN UPDATE Dr. Jobaida Naznin MD Final part Student Department of Endocrinology BSMMU
- 2. Slide No 2June 18, 2013Date What are insulin analogues? • Structure of insulin is modified • Pharmacokinetic properties modified to mimic physiology • Molecular pharmacology of human insulin retained
- 3. Slide No 3June 18, 2013Date Normal physiological profile of serum insulin concentration Kruszynska. Diabetologia 1987;30:16 Mealtime insulin excursions Rapid rise; short duration 0800 1200 1600 2000 2400 0 10 20 30 40 50 0400 Time (h) Seruminsulin(mU/L) 0800 Flat basal insulin profile Breakfast Lunch Dinner
- 4. June 18, 2013 4 Limitations of conventional insulins Profiles are schematic Intermediate-acting insulin Soluble insulin Sum of the added insulins Physiological insulin profile Seruminsulin Time
- 5. Slide No 5June 18, 2013Date Attempts to recreate physiological insulin secretion with basal–bolus therapy Profiles are schematic 60 50 40 30 20 10 0 6 222181410 6 Time of day Rapid-acting insulin Basal insulin Total Predictedplasmainsulin concentrationprofile(mU/L)
- 6. Slide No 6June 18, 2013Date Properties of ideal analogues Properties of an ideal mealtime (bolus) analogue: • Fast onset • Short duration of action • Predictability Properties of an ideal basal analogue: • Long duration of action • Flat profile (no peak) • Predictability
- 7. 7 Factors determining insulin absorption rate • Insulin preparation • Dose, concentration and volume • Physical state (solution or suspension) • 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. Slide No 8June 18, 2013Date Dissociation of insulin after s.c. injection Subcutaneous tissue Molar concentration Diffusion Capillary membrane 10–3 10–4 10–5 10–8 Adapted from Brange. Diabetes Care 1990;13:923
- 9. Slide No 9June 18, 2013Date Currently available insulin analogues Generic name Trade name Manufacturer Rapid-acting analogues Insulin aspart NovoRapid® Novo Nordisk Insulin lispro Humalog® Eli Lilly Insulin glulisine Apidra® sanofi aventis Basal analogues Insulin detemir Levemir® Novo Nordisk Insulin glargine Lantus® sanofi aventis Biphasic premixed analogues Biphasic insulin aspart NovoMix® Novo Nordisk Biphasic insulin lispro Humalog® Mix Eli Lilly
- 10. Slide No 10June 18, 2013Date Rapid-acting insulin analogues
- 11. Slide No 11June 18, 2013Date Insulin lispro Glu Thr Lys Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Leu HisGlnAsnValPheB1 Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Ser CysIleSerThrCys Cys Gln Ile Gly B28B30 Pro Glu Val A21 A1
- 12. Slide No 12June 18, 2013Date Insulin aspart Glu Thr Lys Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Leu HisGlnAsnValPheB1 Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Ser CysIleSerThrCys Cys Gln Glu Val Ile Gly A21 A1 B28B30 Asp Pro Asp
- 13. Slide No 13June 18, 2013Date Insulin glulisine Glu Thr Lys Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Leu HisGlnAsnValPheB1 Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Ser CysIleSerThrCys Cys Gln Glu Val Ile Gly A21 A1 B29B30 Glu Pro Lys B3
- 14. June 18, 2013 14 Action profiles of insulin and rapid-acting insulin analogues Onset (min) Peak (min) Duration (h) Regular human insulin1 30–60 120–180 6–8 Insulin lispro 152 30–702 2−5 Insulin aspart 10–203 40–903 3–5 Insulin glulisine 204 555 3–5 1 Oiknine. Drugs 2005;65:325–40 2 Prescribing information, insulin lispro 3 Prescribing information, insulin aspart 4 Becker. Exp Clin Endocrinol Diabetes 2005;113:292–7 5 Becker. Diabetes 2004;53(Suppl.2):A119
- 15. June 18, 2013 15 Insulin aspart: safety issues Insulin receptor affinity and mitogenicity Mitogenic potency less than human insulin Hypoglycaemia Incidence similar or lower than with human insulin Hypoglycaemic awareness Physiological responses were preserved and equivalent for aspart compared with human insulin Immunogenicity Transient increase in antibodies. No correlation with efficacy or safety Adverse events Similar to soluble human insulin
- 16. Slide No 16June 18, 2013Date Basal insulin analogues
- 17. Slide No 17June 18, 2013Date Strategies for protraction Modification of isoelectric point: precipitation at pH 7.4 • Insulin glargine Acylation with hydrophobic residues (and albumin binding) • Insulin detemir
- 18. Slide No 18June 18, 2013Date Insulin glargine Glu Thr Lys Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Leu HisGlnAsnValPheB1 Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Ser CysIleSerThrCys Cys Gln Glu Val Ile Gly A21 A1 B30 Gly Arg Pro Arg +
- 19. Slide No 19June 18, 2013Date Insulin Insulin detemir Thr Glu Lys ValPhe Asn Glu Leu Gln Tyr Leu SerCysIleSerCys Cys Gln Glu Val Ile Gly Tyr CysAsnLys Pro Thr Tyr Phe Phe ArgGly Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Asn Gln LeuHis C14 fatty acid chain (Myristic acid) Thr
- 20. June 18, 2013 20 Action profiles of insulin and basal analogues Onset (h) Peak (h) Duration (h) NPH insulin1 1–2 5–7 13–18 Insulin glargine 1–21 No peak2 20–301 Insulin detemir3 1–23 No peak3 244 1 Oiknine. Drugs 2005;65:325–40 3 Prescribing information, insulin detemir 2 Prescribing information, insulin glargine 4 Heise. Diabetes Obes Metab 2007;9(8):648–59
- 21. June 18, 2013 21 Insulin detemir: safety issues Insulin receptor affinity and mitogenicity Receptor affinity and mitogenic potency less than human insulin Safety of albumin binding of insulin detemir Insulin detemir has negligible impact on the binding capacity of the serum albumin pool Hypoglycaemia Incidence of hypoglycaemia, especially nocturnal hypoglycaemia, generally lower than with human insulin Immunogenicity No immunogenicity concerns Adverse events Similar to NPH
- 22. June 18, 2013 22 Key benefits:
- 23. June 18, 2013 23 Levemir® gives you More
- 24. Slide No 24June 18, 2013Date Biphasic premixed insulin analogues
- 25. Slide No 25June 18, 2013Date Benefits of dual-release insulin replacement 1. Mimics physiological insulin release • Early release of rapid-acting insulin targets postprandial glucose • Delayed release of intermediate-acting insulin fulfils basal insulin requirement 2. Reduces hypoglycaemic risk 3. Improves HbA1c 4. Simplifies dosing • Option of postprandial dosing
- 26. Slide No 26June 18, 2013Date Biphasic premixed insulin analogues NovoMix®30 Rapid-acting insulin aspart Premixed suspension Intermediate-acting protamine-crystallised insulin aspart
- 27. Slide No 27June 18, 2013Date Biphasic 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. Slide No 28June 18, 2013Date • Mean prandial glucose increment lower in NovoMix® 30 group (p < 0.0001) • Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid) NovoMix® 30 offers better glycaemic control than NPH Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452
- 29. Advancements Animal insulin preparations Recombinant human insulin Rapid-acting insulin analogues Basal insulin analogues New-generation insulin analogues/ combination insulins Isolation of insulin (Banting & Best) Time1922 1977 Biphasic insulin Degludec DegludecPlus 1990s 2000s Advancing insulin therapy Towards a new stage in the evolving story of insulin therapy
- 30. Unique molecular engineering: degludec molecular structure s s s FF 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 PP GG II VV EE QQ CC TT SS II CC SS LL YY QQ LL EE NN YY CC NNCC s s s A chain B chain KK N H O OH O NH O OH O Hexadecandioyl L-γ-Glu desB30 Insulin LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulinGludec de TT
- 31. Hexamer (36 kDa) Dimer Monomer (6 kDa) Blood vessel Cell Engineering insulin analogues Di-Hexamer (72 kDa) Multi-Hexamer (>5000 kDa) Rapid acting Long acting
- 32. Insulin degludec: summary I • The protraction mechanism of insulin degludec involves: • Multi-hexamer formation upon injection • Slow and stable release of monomers • This property is critically dependent on the spacer and side chain used • This design is expected to provide ultra-long and flat PK/PD profiles
- 33. Insulin degludec has a flat and stable insulin action Nosek 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 sampling Insulin-treated Type 2 diabetes (n=49) 0.4, 0.6, 0.8 U/kg once daily for 6 days
- 34. Insulin degludec: summary II • In Steady State: Input = Output • For insulin degludec: Steady state level is reached in 2–3 days • Insulin degludec provides an ultra long duration of action that leads to a flat and smooth pharmacokinetic and pharmacodynamic profile
- 35. HbA1c over time IDeg Flexible/IGlar Non-inferior IDeg Flexible/IDeg Fixed Non-inferior 0 FAS; LOCF Comparisons: Estimates adjusted for multiple covariates IDeg 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. Degludec medical communication platform Novel protraction mechanism Ultra-long action (flat, stable & consistent) Low rate of hypos (also at low FPG) Flexible dosing Excellent efficacy Convenient true OD dosing FlexTouch® Up to 160U Insulinsafety
- 37. Insulin degludec: summary III Excellent improvement in HbA1c Superior FPG reductionDegludecPlus Achieve glycaemic control Efficacy Less hypoglycaemia Reduction of up to 36% in nocturnal hypoglycaemiaDegludecPlus Avoid hypos Safety Dosing flexibility: administration any time on any dayDegludecPlus Flexibility Convenience
- 38. Slide No 38June 18, 2013Date Thank You
Notas del editor
- 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: www.emea.europa.eu/humandocs/PDFs/EPAR/Novorapid/H-088-PI-en.pdf. Accessed 18 February 2008 Prescribing information, Insulin aspart. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/Novorapid/H-258-PI-en.pdf. 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: www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/H-284-PI-en.pdf. Accessed 18 February 2008 Prescribing information, Insulin detemir. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/levemir/H-528-PI-en.pdf. 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.