Rapid Acting Insulin Analog - PowerPoint Presentation

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2. Rapid Acting Insulin AnalogMajid Valizadeh, M.D.Obesity Prevention and Treatment Research CenterResearch Institute for Endocrine SciencesShahid Behesti University of Medical SciencesRIES 16 Nov 2017 Tehran, Iran

3. AGENDAIntroductionWhy To Use Prandial Insulins? The Importance of Controlling Post Prandial Glucose Prandial InsulinsDifferent Types of Prandial InsulinsMechanism of Action of Insulin GlulisineComparison between different types of SAI (short acting insulin) efficacy / side effects / patient preference Summary & Conclusion

4. Introduction Better glycemic control leads to reduction in development and progression of long term diabetes complications.T1DMT2DM

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6. DCCT/EDIC study in T1DMMicrovascular complications * p=0.006 ** p=0.002 *** p<0.001DCCT/EDIC Group. JAMA 2002;287:2563ConventionalIntensive3-step progressionfrom no retinopathySevere nonproliferative retinopathy or worseProliferative retinopathyMacular oedemaLaser therapyMicroalbuminuriaAlbuminuria*66%***76%***74%***77%**77%**53%***86%024681012141618% of patients who progressed

7. Intensive treatment reduced CV risk by 42% (p=0.02)10% decrease in HbA1c= 20% reduction in CV events (p=0.01)Nathan. N Engl J Med 2005;353:2643–53.0.060.120.100.080.040.020.00Cumulative incidence02468101214161820Years since entryNumber at riskConventional treatment70571468368862961811392ConventionalIntensive(any predefined CV outcome)Intensive treatmentDCCT/EDIC study in T1DMMacrovascular complications

8. 01234567>2-step sustainedretinopathyUAE >30 mg/24 hUAE >300 mg/24 hEvent rate100%Primary prevention cohortShichiri. Diabetes Care 2000;23 (Suppl. 2):B21–9ConventionalIntensive74%68%Kumamoto study in T2DMMicrovascular complications

9. Stratton. BMJ 2000;321:405–412Decrease in risk per1% reduction in HbA1cAny end-point related to diabetesFatal and non-fatal MIFatal and non-fatal strokeAmputation or death from PVDHeart failurep<0.0001p<0.0001p=0.035p<0.0001p=0.021p-value reflects contribution of glycaemia to multivariate model21%14%12%43%16%05101520253035404550UKPDS in T2DMMacrovascular complications

10. Hb A1c as indicator of Glycemic controlEstimation of mean blood glucose during recent 6-12 weeksPreprandialpost prandial

11. 0204060<7.37.3–8.48.5–9.29.3–10.2>10.2PostprandialFastingRelative contribution of FBG vs PPBG (%)HbA1c (%)Monnier L, et al. Diabetes Care 2003;26:881–5. Relative contribution of FBG & PPBG to HbA1c The relative contribution of PPBG is predominant in subjects with moderate diabetes, whereas the contribution of FBG increases as diabetes worsens.

12. Why Prandial (SA) Insulin?

13. Objectives of insulin therapyThe primary objective of insulin therapy is to mimick normal insulin profileCombinations of ‘basal’ and ‘prandial’ insulins in a ‘basal–bolus’ insulin regimen are normally administered to individuals with T1DM or advanced T2DM. Multiple Daily Injection

14. Ideal Insulin Replacement Therapy in DiabetesCombinations of ‘basal’ and ‘prandial’ insulin in a ‘basal–bolus’ insulin regimen are essential to maintain glycemic controlInsulin (mU/l)06.0012.0024.0018.00015304506.00 BreakfastLunchDinnerEndogenous insulin secretionIdeal basal insulinIdeal prandial insulinKruszynska YT, et al. Diabetologia 1987;30:16–21.Time (hours)

15. Which Prandial Insulin?

16. Human Regular Insulin (HRI)Rapid acting analoguesInsulin Lispro (LIS)Insulin Aspart (ASP)Insulin Glulisine (GLU)Different Types of Prandial Insulins

17. Human Regular (unmodified) InsulinOnset of action: 0.5-1 hrPeak activity: 2-4 hrsDuration of activity: 6-8 hrs Med Clin North Am 1998Pharmacokinetic Properties of HRI

18. Human Regular Insulin (HRI)Med Clin North Am 1998After SQ injection HRI tends to dissociate from its normal hexameric form, first into dimers and then monomers.Only dimeric & monomeric forms can pass through the endothelium.The resulting delay in the onset and duration of action, limits its effectiveness in controlling postprandial glucose.Dose dependent pharmacokinetics, with prolonged onset, peak, duration of action with higher doses.

19. Limitations of HRI Slow onset of actionRequires administration 30–45 min before a meal Dose dependent pharmacokineticsMismatch between injection and postprandial peakRisk of interprandial hypoglycaemiaWittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy: 2002:73–85.

20. Short acting insulin analog

21. Insulin aspart is a biosynthetically modified analogue of human insulinA single proline amino acid at position 28 of the insulin B-chain has been replaced with an aspartic acid residueIn all other respects, insulin aspart and human insulin are structurally identicalStructure of insulin aspart moleculeAspAsp

22. Zinc-free formulationBecker RH. Diabetes Technol Ther 2007;9:109–21.A chainHuman 3BLys-29BGlu-insulinB chainGly1515101520SS201510GlyGlnIleGlnCysPheHisHisLeuSSSSPhe2530ProLysThrAlaGluLys= substitutionAsnMolecular structure of insulin GLU (Apidra®)x-----------stabilising agentPolysorbate 20---xxxcomplexing agentZinc FunctionComponentsGLUASPQualitative compositionx---------buffering agentTrometamolLISRHI

23. RA-insulins uptake from subcutaneous tissueCapillaryStructuresHexamersR-formatT-formatDimerMonomerRA-insulin analogue:GLUNo added zincPolysorbate 20 (Tween 20)Phenolic residues ( ) Zn2+ atoms ( )RA-insulin analogues:LISASPTTTTTTPhenolZn2+TTTTTTTTTTTTTTTTTTBrange J, et al. Diabetes Care 1990:13;923–54.Becker RH. Diabetes Technol Ther 2007;9:109–21.

24. Dissociation of insulin after subcutaneous injectionSubcutaneous tissueMolar concentration (Mol/l)DiffusionCapillary membraneAdapted from Brange et al. Diabetes Care 1990;13:923-54

25. InsulinOnsetPeak DurationRapid-acting insulin analogues Insulin aspart Insulin glulisine Insulin lispro5 - 15 min5 - 15 min5 - 15 min1 - 2 h1 - 2 h1 - 2 h3 - 4 h3 - 4 h3 - 4 hShort-acting insulin Insulin regular30 - 60 min2 - 4 h6 - 8 hRapid Analogues vs. Regular Insulin

26. Pharmacodynamic profile of insulin aspart in healthy subjectsNosek et al. Diabetes Obes Metab 2013;15:77–83At all doses the early pharmacodynamic activity of insulin aspart was higher than with regular human insulinInsulin aspart was associated with significantly less late pharmacodynamic activity (represented by AUCGIR 6-12h and AUCGIR 4-12h) and a shorter tail than regular human insulin Insulin aspart provides comparable overall pharmacodynamic activity to regular human insulin161514131211109876543210024681012Time from dosing (hours)GIR (mg/kg/min)Regular human insulin 6 IURegular human insulin 12 IURegular human insulin 24 IUInsulin aspart 6 UInsulin aspart 12 UInsulin aspart 24 U

27. InsulinglulisineRHI0.3 U/kg0.15 U/kg0.075 U/kgINS-AUC 2h; p<0.05 vs. HRIN=18 T1DM subjectsINS-AUC= insulin infusion rate - area under the curveTime (hours)0246810Insulin (µU/ml)020406080100120140160GLU vs. HRI in T1DMMore Rapid AbsorptionBecker RH, et al. Diabetes Care, published online August 3, 2007.

28. GLU vs. HRI in T2DMlonger pre- and post-meal dosing windowInsulin GLU with a full 35 minutes dosing window offers flexibility tailored to fit a patient’s lifestyle.

29. Clinical study

30. Asparte vs. HRI

31. Similar glucose excursions for post-meal insulin aspart and pre-meal human insulin in T1DMTest mealPlasma glucose (mmol/L)Brunner et al. Diabet Med 2000;17:371–5HI(–15 min)HI(0 min)Insulin aspart (0 min)Insulin aspart (+15 min)n=20306090120150180210240270–30006789101112131415Randomised, double-blind, double-dummy, four-period crossover study, 20 patients with type 1 diabetes

32. Glulisine vs. HRIPharmacodynamic & Efficacy

33. Garg SK, et al. Endocr Pract 2005;11:11–7.7.27.37.47.57.67.77.8BaselineWeek 8Week 12**Pre-meal insulin glulisinePost-meal insulin glulisinePre-meal RHIMean HbA1c (%)*p<0.01 vs RHI and post-meal insulin glulisine*p=0.0001 vs RHIp<0.05 vs post-meal insulin glulisinePre-breakfast2-h post-breakfastPre-lunch2-h post-lunchPre-dinner2-h post-dinnerBedtime**126144162180Blood glucose (mg/dL)Pre-meal insulin glulisinePost-meal insulin glulisinePre-meal RHISeven-point SMBG profile at study endpointN=860 with T1DM; insulin glargine=basal insulinGLU vs. HRI in T1DMSignificantly greater improvement in PPBG & HbA1c

34. GLU vs. HRI in T2DMSignificantly greater improvement in HbA1c HbA1c (%)*p<0.05 6.97.07.17.27.37.47.57.6Baseline12 weeks26 weeks**Insulin glulisineRHISimilar incidence of symptomatic hypoglycaemia N=876 withT2DMNPH=basal insulin BMI=34.5 kg/m2Dailey G, et al. Diabetes Care 2004;27:2363–8.

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36. Methods:Patients previously on >6 months’ continuous insulin treatment aged 18 years in a randomized, multinational, controlled, open-label, parallel group, 26-week study received twice-daily NPH insulin and either glulisine (0–15 min before breakfast and dinner; n = 448) or RHI (30–45 min before breakfast and dinner; n = 442) at least twice daily.

37. Postprandially, glulisine lowered plasma glucose significantlymore versus RHI at 2 h (14.14 mmol/L versus 15.28 mmol/L; p = 0.0025) and excursions at 1 h (3.99 versus 4.59; p = 0.0151) and 2 h (4.87 versus 6.03; p = 0.0002). No between-group differences occurred in the frequencies and monthly rates of all symptomatic hypoglycaemia; Nocturnal hypoglycaemia from Month 4 to treatment end was less frequent with glulisine versus RHI (9.1% versus14.5%; p = 0.029).

38. Insulin GLU helps physicians reassure their patients around hypoglycemia.Rayman G, et al. Diabetes Res Clin Pract 2007; 76(2): 304-312.GLU vs. HRI in T2DMSignificantly less nocturnal hypoglycemia

39. Methods: Electronic searches (Cochrane Library,MEDLINE, and EMBASE) and additional searching (pharmaceutical companies, experts, approval agencies, abstracts of diabetology meetings) were performed. Two reviewers independently screened randomized controlledtrials to determine inclusionARCH INTERN MED/VOL 165, JUNE 27, 2005

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43. Differences in hemoglobin A1c (HbA1c) values

44. Differences in overall hypoglycemic event rate.

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47. Conclusion:Our analysis suggests only a minor benefitto hemoglobin A1c values in adult patients with type 1 diabetes mellitus but no benefit in the remaining population with type 2 or gestational diabetes from SAI analogue treatment.

48. Method: All randomized controlled trials (RCTs) with a duration >4 weeks comparing short-acting insulin analogues(lispro, aspart or glulisine) with HRI in type 2 diabetic patients were retrieved; data on HbA1c and postprandial glucoseet end-point and incidence of severe hypoglycaemia were extracted and meta-analysed.Diabetes, Obesity and Metabolism, 11, 2009, 53–59

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54. Hypoglycemia:The number of patients experiencing at least one episodeof severe hypoglycaemia (13 and 21 for short-actinganalogues and regular human insulin, respectively) wasreported in five trials only [1,3,4,11,15].Combining those studies, the MH-OR for this event withshort-acting analogues, in comparison with humaninsulin, was 0.61 (0.25–1.45).

55. Method:Data on severe hypoglycaemia (number of patients with at least one event) were extracted, while mild hypoglycaemic episodes were not considered because of theheterogeneity of diagnostic definitions across trials.

56. Conclusion:In type 2 diabetic patients, short-acting insulin analogues provide a better control of HbA1c and postprandialglucose than regular human insulin, without any significant reduction of the risk of severe hypoglycaemia.

57. Take Home MessageIn comparisons between different type of short insulin especially human and analog:Glycemic control:Minor benefit/ No clinically important differenceHypoglycemic episodesNo differenceQuality of life and treatment satisfactionIn favor of analouges (due to flexibility

58. Human Regular Insulin (HRI)Rapid acting analoguesInsulin Lispro (LIS)Insulin Aspart (ASP)Insulin Glulisine (GLU)Different Types of Prandial Insulins

59. Take Home Message Insulin treatment has always beenas much an art as a science.The proper use of insulin analogues allows people with diabetes greater flexibility in the timing of meals, snacks, and exercise, which in turn enhances their ability to lead normal lives.When choosing between insulin analogues and HRI, not only should their differences in glycemic control and treatment flexibility be considered, but also their cost of treatment, type of diet and patients’ preferences.

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61. Thanks for your attention

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63. Pharmacokinetics (serum insulin levels) after subcutaneous (sc) injection of analog insulins

64. Meal-time glucose excursions for insulin lispro, insulin aspart and insulin glulisine when compared separately in people with type 1 diabeteswith unmodified human insulin

65. Insulin aspart: rapid dissociation into monomersB21’ GluB22’ ArgB23’ GlyB30 ThrB29 LysB28 Pro/AspB27 Thr3.7 ÅReproduced with permission from Brange J, Vølund A. Adv Drug Delivery Rev 1999;35:307–35.Hexamer MonomerDimer

66. Glulisine in Special Population

67. Journal of Renal Nutrition, 2014

68. GLU vs. HRI in T2DM and Severe Renal Insufficiency Journal of Renal Nutrition, 2014

69. Journal of Renal Nutrition, 2014GLU vs. HRI in T2DM and Severe Renal Insufficiency

70. Journal of Renal Nutrition, 2014GLU vs. HRI in T2DM and Severe Renal Insufficiency

71. Glulisine vs. Aspart

72. Insulin GLU vs. insulin ASPEarlier effect on postprandial glucose levelsApidra® reduces blood glucose levels more rapidly vs. insulin Aspart.Boli GB, et al. Diabetes Obes Metab 2011; 13: 251-257.

73. Apidra® offers flexibility tailored to fit a patient’s lifestyle.Insulin GLU vs. insulin ASPLonger dosing window

74. Urakami T, et al. J Diabetes Investig. 2015; 6(1): 87–90.

75. Switching from other RA-insulin analogs to GlU in T1DMUrakami T, et al. J Diabetes Investig. 2015 Jan; 6(1): 87–90.Study population:N=26 T1DM Japanese children aged 12.5 ± 5.5 yrsBasal–bolus insulin therapy:18 MDI, 8 CSIIASP or LIS as bolus insulinGlargine as basal insulin for MDINone were obesenone had vascular complications or metabolic-syndrome factors.ProtocolASP or LIS was switched to GLUGlargine was continued as beforeMeasurements:∆ mean SMBG just before, and 1–1.5 h after breakfast and supperfor the 1-month period at baseline, and at 6 months after using GLU.∆ HbA1c, frequency of hypoglycemia , % overweight & daily insulin requirement for the same time periods.

76. Switching from LIS or ASP to GlU in T1DMEFFICACYUrakami T, et al. J Diabetes Investig. 2015; 6(1): 87–90.

77. Switching from LIS or ASP to GlU in T1DMSAFETYUrakami T, et al. J Diabetes Investig. 2015; 6(1): 87–90.

78. How to use Glulisine?

79. Basal plusBasal +1 prandialRaccah et al. Diabetes Metab Res Rev 2007; 23:257.Basal insulinonce daily(treat-to-target)Basal plusBasal +2 prandialBasal bolus Basal +3 prandialLifestyle±Metformin± 2nd/3rd DrugHbA1c > target HbA1c > targetFPG on targetPPG > targetHbA1c > targetFBG > targetProgressive deterioration of -cell functionThe most precise and flexible prandial coverage is possible with “basal-plus/bolus” therapy

80. 80Dosing and Titration

81. 81 Apidra® is rapidly absorbed and has a faster onset of action than RHI. Apidra® has a longer defined dosing window vs. RHI- a full 35 minutes. Apidra® is associated with less nocturnal hypoglycemia in people with T2DM compared with RHI.Summary: GLU vs. RHIApidra® is associated with reduced incidence of cardiovascular complications in people with T2DM vs. RHI in clinical practice.

82. 82 Apidra® has an earlier effect on postprandial glucose levels than insulin Aspart. Apidra® provides equal efficacy and safety, whether it is administered pre- or post-meal.Summary: GLU vs. ASP

83. Apidra® is an ideal partner for Lantus ®