Why, when & How to add Prandial insulin after Basal Optimization - PowerPoint Presentation

1. Why, when & How to add Prandial insulin after Basal OptimizationFOCUS OF PROFILE GLULISINE

2. The main targetTo normalize Blood glucoseDelay progressionReduce complicationsDiabetes Managementᵛᵛfastingpostprandial

3. 1.Fasting hyperglycemia ( Provide after 10 hrs fasting ) ◘ Basal insulin levels ◘ Hepatic response to insulin 2.Postprandial hyperglycemia ( A meal contains 6 to 20 times the glucose content of the blood ) ◘ Early insulin release ◘ Hepatic, muscle, and adipocyte responses to insulin ◘ Glucagon suppression Pathophysiology of hyperglycemia

4. Basal Insulin ( will cover fasting blood glucose & between meals ) Analog Insulin - Glargine (Lantus) - Detemir (Levemir) Human Insulin - Humulin N, - Insulatard HMPrandial Insulin (Bolus) ( will cover prandial glucose ) Analog Insulin - Glulisine ( Apidra ) - Lispro (Humalog) - Aspart (Novorapid ) Human Insulin - Humulin R, - ActrapidINSULIN IS STILL THE MOST EFFICACIOUS ANTI HYPERGLYCEMIC AGENT

5. Adding Prandial InsulinWhy

6. 50%55%60%70%50%45%40%30%30%70%<7.37.3–8.48.5–9.29.3–10.2>10.2PPGFPG020406080100HbA1c range (%)% contribution to HbA1cTo normalise HbA1c : both FPG and PPG must be reducedAdapted from Monnier et al. Diabetes Care 2003;26:881–5.Majority patients on DiabCare and A1chieve baseline data

7. Why do we need to intensify from basal insulin?Within 1 year, the majority of basal insulin patients will need another insulin to reach their glycaemic target 1. Holman et al. N Engl J Med 2007;357:1716–30;2 Garber AJ, et al. Diabetes, Obesity and Metabolism, 8, 2006, 58–66.

8. -cell function(% of normal by HOMA)Years020406080100109876543210123456Time of diagnosis?HOMA=homeostasis model assessmentDecline of -Cell Function in the UKPDS Illustrates Progressive Nature of DiabetesPancreatic function= 50% of normalAdapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;UKPDS. Diabetes. 1995;44:1249-1258

9. However, at the time of diagnosis : ● 50% of patients already have complications1 ● < 50% of -cell function has already been lost2 ● 2/3 of patients do not achieve target HbA1c3,4 The majority of patients require polypharmacy to meet glycaemic goals across time51. UKPDS Group. Diabetologia. 1991;34:877–890; 2. Holman RR. Diabetes Res Clin Prac. 1998;40:S21–S25;3. Saydah SH, et al. JAMA. 2004;291:335–342; 4. Liebl A, et al. Diabetologia. 2002;45:S23–S28; 5. Turner RC, et al. JAMA. 1999;281:2005–2012.

10. ßßßßRRRRobesesedentaryinactivitycalori Normoglyc pre-DiabDM ( late)DM (early )Environmental factorsDiabetes progression Compl ↑HyperglycemiaDM ( term )GlucolipotoxicityßßRRComplic ?ComplCompl ↑Compl↑↑ Compl↑↑↑

11. IDF Recommendation on post-meal glucose management increased risk of retinopathy, increased CIMT, decreased myocardial blood volume/blood flow, increased risk of cancer, impaired cognitive function in the elderlyPostprandial hyperglycaemia:harmful, and should be addressedPostprandial hyperglycaemia causes: oxidative stress, inflammation endothelial dysfunction

12. Adding Prandial InsulinWhen

13. Insulin can be initiated at any timeTraditionally, insulin has been reserved as the last line of therapy……However, considering the benefits of normal glycemic status, Insulin can be initiated earlier and as soon as possibleInadequate Lifestyle+ 1 OAD+ 2 OAD+ 3 OADINITIATE INSULIN( F i r s t l y b a sa l I n s u l i n )Inadequate LifestyleInadequate LifestyleInadequate Lifestyle

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15. 1. Lifestyle changes plus metformin (± other agents)2. BasalAdd basal insulin and titrateBasal PlusAdd prandial insulin at main meal4. Basal BolusAdd prandial insulin before each mealBasal Plus: once-daily basal insulin glargine plus once-daily* rapid-acting insulin glulisine Stepwise approach :Matching treatment to disease progression *As the disease progresses, a second daily injection of glulisine may be addedAdapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64Stepwise approachBasal Bolus: once-daily basal insulin glargine plus 3 injections of rapid-acting insulin Glulisine (each injection before a meal)The Gold Standardfor advanced type 2 diabetes 3. Basal PlusAdd prandial insulin at main mealProgressive deterioration of ß cell function

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17. Adding Prandial InsulinHow

18. Slide 18Three Types of Insulin1. Hompesch M. Diabetes Obes Metab 2006; 8:568; 2. Weyer et al. Diabetes Care 1997;10:1612–1614.; 3. 1. Heinemann et al. Diabetes Care. 1998;21:1910–4Basal Insulin provides a steady concentration of insulin in the bloodstream over 24 hours. Initially, basal insulin should be given at 10 units per day at night time or in the morning1Time (h)Premixed insulins contain a mixture of rapid-acting and intermediate-acting insulin in a fixed combination to provide coverage of prandial and basal insulin requirements2Fast-acting insulins include single amino acid replacement that reduce their ability to self-associate into dimers and hexamers. This means that they are quickly absorbed into the bloodstream, following subcutaneous injection.3FAST-ACTINGPRE-MIXBASALGIR (mg/kg/min)08162024412Time (h)GIR (mg/kg/min)08162024412Time (h)GIR (mg/kg/min)08162024412

19. Insulin glulisine : a novel rapid-acting insulin analogue Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21( Human Recombinant Insulin Analogue )Glu + Lys = GlulisineA chainB chainInsulin glulisine:Substitution of asparagine B3with lysine, and of lysine B29with glutamic acid15GlyGlnGlnCysPheHisLeuProLysThrAlaGluLysAsn15SS10Ile10SS1515SS20HisGlyPhe252030The two substitutions favour monomer formation and facilitate rapid absorption from the tissue following subcutaneous injectionUnique Formula insulin GlulisineQualitative compositionComponentsFunctionHuman InsulinLisproAspartGlulisineGlyserol (85%)Tonicity agent√√√─ZincComplexing agent √√√─Polysorbate 20Stabilizing agent───√

20. TitleStudy DesignPrimary End PointResultBolli et al., 2011multinational, randomized, double-blind, two-way crossover trial.To compare PK PD in insulin naïve between Glulisine vs Aspart, obese patients with type 2 diabetesGlulisine was associated with lower glucose levels during the first hourArnold et al., 2010randomized, doubleblind,crossover trial.compared the PK PDof Glulisine with those of insulin aspartGlulisine showed a signifi cantly higherearly metabolic eff ect, earlier onset, faster absorption than AspartHeise et al., 2007randomized, single-centre, double-blind, crossover studycompared the PK PD of insulin glulisine and insulin lispro in lean to obese subjects.absorption of glulisine was significantlyfaster than lispro : lesser time required to achieveearly exposure with glulisine (INS-t10% approximately5–6 min less).Becker et al., 2003single-center, randomized,dose-exposure and dose-response relationshipsof insulin glulisine comparedwith RHI in subjects with type 1 diabetes.insulin glulisine is absorbed +/- twice as fast and takes effect twice as rapidly compared with RHI, while disposing the same quantity of glucose as RHIStudy Faster onset of Apidra

21. Glulisine has flexible dosing windowImmediately after15 mins beforeApidra® Product Information – Agustus 2013

22. Studies Flexibility usage of GlulisineTitleStudy DesignPrimary end PointResultOPAL StudyN=399multicentre, randomized, open-label, parallel-group studyGlargine+Glulisine at Breakfast vs Main MealImproves glycemic control irrespective of whether given with breakfast or the main mealThe timing of glulisine addition to glargine does not affect safety or weight gainRatner et al., 2011N = 716multicenter, randomized, open-label trialeffect of postprandial vs. preprandial glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin.Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically Indicated

23. Glulisine usage in CKDAll available insulin preparations can be used in patients with CKD, and there is no specified advised reduction in dosing for patients on insulin. The insulin type, dose and administration must be tailored to each patient to achieve goal glycemic levels but limit hypoglycemia. Hahr and Molitch Clinical Diabetes and Endocrinology (2015) 1:2

24. Studies usage of Glulisine in CKDTitleStudy DesignPrimary end PointResultFukumoto et al., 2015according to the tenets of the declaration of Helsinki, and its protocol was approved by the local ethics committee (Registration No. 1739). To compare the efficacy and safety of insulin glulisine over regular insulin in patients with type 2 diabetes and severe renal insufficiency (GFR 13.2 mL/min/1.73 m2 (5.8-27.6), corresponds to stage 4-5 CKDInsulin glulisine effectively suppressed postprandial hyperglycemia, whereas regular insulin caused a prolonged hypoglycemic action.Svenson et al., 2017N = 17,620a nation-wide observational cohort study. The treatment groups were comparedusing a weighted Cox proportional hazards model.examine HbA1c and weight, and the occurrence of severehyperglycemia or hypoglycemia, renal failure, cardiovascular events or death in the usage of RAI (glulisine, lispro, aspart) There do not appear to be any major important differences in effects on hypoglycemia, hyperglycemia, weight or long-term safety between the three available RAIs among insulin-naive individuals with T2DM in clinical practice.

25. Insulin Glulisine has a more rapid time-action profile than aspart in pharmacokinetic & Pharmacodynamic result single-centre, randomized, double-blind, two-period crossover euglycaemic glucose clamp trial comparing fractional and total glucose infusion rates (GIR) and insulin AUCs of subcutaneous (s. c.) injections of 0.2 U / kg GLU and ASP. Twelve (6 male,6 female) healthy volunteers were randomized and completed the study (age 42 ± 12 years, BMI 24.6 ± 2.2 kg / m2 , A1C and fasting plasma glucose in the normal range). The trial comprised of a screening visit, two glucose clamp visits separated by a washout period of 5 – 28 days, and a follow-up visit.GIR max-tx%: waktu untuk mencapai x% dari maksimum glucose infusion rate

26. Insulin Glulisine has a more rapid time-action profile than aspart in pharmacokinetic & Pharmacodynamic result n= 30 subjects [9/21 females/males; mean ± SD age: 60.7 ± 7.7 years; body mass index (BMI): 33.5 ± 3.3 kg/m2; duration of diabetes: 6.8 ± 4.6 years; HbA1c: 7.1 ± 0.8%] were included in the analysis. fasted overnight and then received a 0.2 U/kg subcutaneous dose of glulisine or aspart 2 min before starting a standardized test meal, 7 days apart, according to a randomization schedule. Blood samples were taken every 15 min, starting 20 min before the meal and ending 6 h postprandially.

27. Insulin Glulisine has a more rapid time-action profile than Regular Human Insulin (RHI) and insulin lispro in non-diabetic obese subjectsInsulin concentration (mU/l)Time (minutes)Time (minutes)Glucose infusion rate (mg/kg/min)non-diabetic subjects ( n=18 ) mean BMI: 34.7 kg/m2 (30–40) dose: 0.3 IU/kg012024036048060005010015020002460120240360480600Insulin glulisineInsulin lisproRHIBMI=body mass indexBecker RH, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43. Reproduced with permission.

28. Significantly greater improvement in HbA1c with insulin glulisine compared with RHI HbA1c (%)*p<0.05 6.97.07.17.27.37.47.57.6Baseline12 weeks26 weeks**Insulin glulisineRHISimilar incidence of symptomatic hypoglycaemia N=876 withT2DM; BMI=34.6 kg/m2 and 34.51kg/m2 in the insulin glulisine and RHI groups respectively Dailey G, et al. Diabetes Care 2004;27:2363–8. Reproduced with permission.◦◦◦◦

29. How to titrate prandial insulin?Injection TimeBG Check TimeDosage adjustment Before breakfast Before lunch Next breakfast the day after Before lunch Before dinner Next lunch the day after Before dinner Before bed time Next dinner the day afterPre-meal (mg/dL)Prandial Titration Dose (U)< 70- 170-1300> 130+ 1Pfutzner A. Int J Clin Pract. 2009How much ?

30. TARGETS OF THERAPY*( Note : Patients need to have targets individualised ).● A1C : Patients with Type 2 diabetes should be <7% (6.5% in those at particular risk of cardiovascular disease).● Aim for a pre-breakfast or fasting glucose level of <5.5mmol/l ( < 110 mg/dl )● Pre-prandial levels at other times of the day at <6mmol/l ( < 126 mg/dl ).● Post-prandial (i.e. 2 hours after a main meal) <8mmol/l ( < 180 mg /dl ). ( Post-prandial glucose monitoring may not be appropriate for all patients)*Note : Patients need to have targets individualised

31. Strategies for dose intensification from a basal to a basal-bolus regimenA. Pfu¨ tzner, T. ForstInt. J Clin Pract, October 2009, 63 (Suppl. 164), 11–14Fix the FPG first using basal insulin (dose optimisation)Goal: FPG 70-130 mg/dl. Consider adding bolus insulin if :A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2 Fix the FPG first using basal insulin (dose optimisation)Goal: FPG 70-130 mg/dl. Consider adding bolus insulin when: A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2 Add bolus 2U at each mealTitrate to next pre-prandial goals (and bedtime) daily <70 mg/dl -1 U 70-130 mg/dl 0 U >130 mg/dl +1 UDiscontinues SU on addition of bolus insulinPatients need to monitor up to 4x per dayAdd bolus 4U at the largest mealTitrate to next pre-prandial goals (and bedtime) goal daily If subsequent pre-meal sugars are: <70 mg/dl -1 U 70-130 mg/dl 0 U >130 mg/dl +1 UDiscontinues SU on addition of bolus insulinPatients need to monitor up to 4x per dayIf A1C >7% after 3 months despite titrating bolus dose, or bolus doses are more than 30 U per meal:Resume titration of basal insulin and/or considerperforming a 7 point profileIf A1C >7% after 3 months despite titrating bolus dose, or bolus dose is more than 30 U per meal:Add 2nd bolus of 4U at 2nd largets meal and titrate as before. Repeat for 3rd dose at final meal of the dayStraight to three bolus dosesSequential addition of bolus doses

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34. Perkeni 1ADA/EASD 2GDP80-130 mg/dL 80- 130 mg/dLHbA1c (%)< 6,5< 7 Target Glicaemic Control (mg/dL)Individualized1Konsensus PERKENI pengendalian & pencegahan DM tipe 2 di Indonesia 20152American Diabetes Association /European Association Study of Diabetes 2015 Post prandial<180< 180

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37. TitleStudy DesignResultRiddle et al., 2014 N =588 iGla+iGlu vs premixed insulinBasal insulin plus a single prandial injection is as effective in improving glycaemic control as premixed insulin. GINGER StudyN=310iGla+iGlu vs premixed insulinSignificantly superior glycaemic control vs. premix therapyin a population with long-standing insulin-treated T2D, with no increase in the rates of hypoglycaemiaLACE StudyN=197iGla+iGlu vs premixed insulinGreater improvement in glycemic controlthan premixed insulin regimensStudy Basal plus vs Premix

38. OPAL study: glargine + glulisine improves glycemic control irrespective of whether glulisine is given with breakfast or the main mealBaselineEndpointp=NSp<0.0001HbA1c (%) 67897.357.037.296.94BreakfastgroupMain mealgroupp<0.0001The main meal group also included subjects whose main meal was breakfastLankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

39. OPAL study: the timing of glulisine addition to glargine does not affect safety or weight gain p=NSBreakfastgroupMainmeal0.00.20.40.60.81.01.2Mean body weight changefrom baseline (kg)1.00.9012342.723.69Confirmed hypo(event/patient-year)BreakfastgroupMainmealp=NS0.000.010.020.030.040.05BreakfastgroupMainmealSevere hypo(event/patient-year)0.010.04p=NSLankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

40. GINGER STUDY : Basal bolus insulin lebih superior dari pada insulin premix dalam kontrol glukosa darah310 subjects, HbA1c 8-11 %, 52 weeks

41. LACE STUDY : Glargine + Glulisine ( Basal bolus ) lebih superior daripada insulin premix dalam kontrol glukosa darah LACE STUDY : Glargine + Glulisine ( Basal bolus ) lebih superior daripada insulin premix dalam kontrol glukosa darahn =197, HbA1c ≥, 9months

42. Animal Insulin species analogues Nevertheless It is far from perfect and impossible to replicate normal insulin secretion Insulin treatment has always been as much an art as a science.Irl B. Hirsch, M.D.The evolution in insulins more than 80 years of collaboration many experts and patients

43. Conclusion • Blood glucose control, fasting and postprandial, is the main target in DM management for delaying progressivity and complication of disease • Early initiation of insulin addresses the issues of glucotoxicity, lipotoxicity, inflammation, first phase insulin response, insulin resistance and many other factors • Basal insulin will be the best of choice in starting diabetes treatment in which fasting blood glucose is considered as the first step to be controlled • Prandial insulin such as glulisine, should be added as combination treatment with basal insulin in order to get comprehensive blood glucose control, after fasting blood glucose is controlled. •There is evidences from studies that glulisine is superior to other prandial insulin, either human or insulin analogue, in efficacies and adverse events.