RTD Stepwise approach in Insulin Intensification. Focus on Efficacy & Safety of Insulin Glargine + Glulisine Semester II 2016.pptx

RTD Insulin

1. Stepwise approach in Insulin Intensification. Focus on Efficacy & Safety of Insulin Glargine + Glulisine

2. Diabetes mellitus is a chronic and progressive disease with steadily worsening glycemia Addition of medication is needed to maintain treatment goals Long term damage, dysfunction and failure of various organ Requires continuing medical care and ongoing patient self-management education and support to prevent acute complications and to reduce the risk of long-term complications BACKGROUND FACTS ABOUT DIABETES

3. Beta Cell Function Deterioration vs Insulin Resistance Years from Diagnosis Lebovitz H. Diabetes Review 1999;7:139-53 (modified) IGT Postprandial Hyperglycemia –10 -2 0 2 6 10 14 100 75 50 25 Insulin resistance HOMA, homeostasis model assessment Adapted from Holman 1 1. Holman RR. Diabetes Res Clin Pract 1998;40( Suppl 1):S21 – 5 2. UKPDS Group. Diabetologia 1991; 34:877–90 DIAGNOSIS Beta -cell function (% of normal by HOMA) Pancreatic function = 50% of normal undiagnosed

4. T2DM is a progressive condition Years 350 300 250 200 150 100 50 Insulin level Insulin resistance  -cell failure 250 200 150 100 50 Relative  -cell function (%) Fasting glucose Post-meal glucose Glucose (mg/dl) DIAGNOSIS Clinical features Obesity IGT T2DM Uncontrolled hyperglycaemia −10 −5 5 10 15 20 30 25 IGT = impaired glucose tolerance Adapted from Bergenstal RM. In: Int. Textbook of Diabetes Mellitus, third edition: John Wiley & Sons; 2004: p995―1015. Risk for diabetes complications

5. Chronic Complications in Newly Diagnose Diabetes Mellitus 50% of patients had ≥ 1 complications Retinopathy: 21% Hypertension: 35% Stroke or TIA: 1% Pedal pulse (-) : 13% Intermittent Claudicasio : 3% Foot skin ischemia : 6% Erectal Dysfuntion : 20% Plasma creatinine >120 mol/l: 3% Abnormal ECG : 18% NEWLY DIABETES UKPDS 6, Diabetes Res . 1990 Jan;13(1):1-11. J Hypertens 1993 Jun;11(6):681. Acta Medica Iranica , 44(6): 415-419; 2006 International Journal of Diabetes Mellitus, 2010 April; 2(1):61-3 .

6. Early diagnosis is important ! Primary prevention Secondary prevention Tertiary prevention E arly intervention is important !

7. 1 2 Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53 The benefits of early tight control: UKPDS 10-year post-trial follow-up 2

8. A meta-regression of data from ACCORD, ADVANCE, PROactive , UKPDS and VADT shows that a longer duration of diabetes at enrolment was associated with a negative effect of intensified glucose control on cardiovascular mortality 0.40 Duration of diabetes (years) 1 2 4 5 3 6 7 8 9 10 0.32 0.24 0.08 0.16 –0.08 –0.24 –0.32 –0.40 –0.16 0.00 MH odds ratio (log transformed) Delayed treatment can increase risk ACCORD, Action to Control Cardiovascular Risk in Diabetes Trial; ADVANCE, Action in Diabetes and Vascular Disease; PROactive , PROspective pioglitAzone Clinical Trial in macroVascular Events; VADT, Veterans Affairs Diabetes Trial; MH, Mantel– Haenszel Mannucci et al . Nutr Metab Cardiovasc Dis 2009;373:1765–72

9. Treatment target HOW LOW SHOULD WE GO ? MANAGEMENT of TYPE 2 DM: Early Intervention

10. Blood pressure Blood glucose Others Body weight Lipid A1C < 7 % FPG 80 – 130 mg/ dL PPG < 180 mg/ dL Konsensus Perkeni 2015

11. Physiologic Insulin Secretion: 24-hour Profile 150 Time of day Insulin (µU/mL) 50 25 Breakfast Lunch Dinner Glucose (mg/dL) 100 50 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM PM Prandial insulin Post Prandial Glucose Basal Glucose Basal Insulin

12. Insulin secretion (Rosenzweigh,1994) Insulin serum U/ml 24 hour Prandial secretion Breakfast Lunch Dinner Basal 40 Snack

13. Basal Insulin will cover fasting blood glucose & between meals Analog Insulin: Insulin Glargine Bolus / Prandial / Mealtime Insulin will cover prandial glucose Insulin Analog Insulin Glulisine

14. ±16 hours 24 hours

15. A stepwise approach for the treatment of patients with type 2 diabetes Once daily (optimized ) One prandial for largest glucose excursion Two prandial for largest glucose excursion Basal + three prandial OHA mono or combination therapy Diet and exercise HbA1c uncontrolled HbA1c uncontrolled, FBG on target PPBG>8.8 mmol/l (>160 mg/dl) Time Basal Insulin Basal Bolus Basal Plus Basal Plus A1C <7.0% Preprandial capillary PG 8 0–130 mg/dl Peak postprandial capillary PG <180 mg/dl ADA-201 5 Raccah D. Diabetes Ob Met 2008; 10: 76-82 Adapted from ADA. Diabetes Care 2015;38(Suppl.1)

16. How to Start?

17. Glukosa Darah sedikitnya 3 bulan terapi GHS + 2 OHO: A1c >7 % dan Glukosa Puasa >100 A1c > 9 % Konsensus Perkeni 2011 GHS: Gaya Hidup Sehat KAPAN MEMULAI TERAPI INSULIN?

18. The simple way to add basal insulin Initiate insulin with a single injection of a basal insulin Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 units/kg Increase dose by 2 units every 3 days until FBG is 3.89–7.22 mmol /L (70–130 mg/ dL ) If FBG is > 10 mmol /L (> 180 mg/ dL ), increase dose by 4 units every 3 days Continue regimen and check HbA 1c every 3 months FBG, fasting blood glucose In the event of hypoglycemia or FBG level < 3.89 mmol /L (< 70 mg/ dL ) Reduce bedtime insulin dose by ≥ 4 units, or by 10% if > 60 units Adapted from Nathan DM, et al . Diabetologia 2006;49:1711–21 INITIATE MONITOR TITRATE Check FBG Daily

19. Basal insulin limitations When we add once-daily basal injection to existing OAD regimen Inadequate postprandial glycaemic control 1 Significant postprandial hyperglycemia 2 (case 2 and 3) To overcome the above shortcomings, bolus therapy (rapid acting insulin injections) added for prandial hyperglycemia More number of injections 2 Increased self monitoring 2 Patient motivation, educational-emotional support and good cognitive function is needed – increased burden on healthcare resources 2 Barnett A et al. Int J Clin Pract 2008; 62:1647-1653 Liebl A. Int J Clin Pract 2009; 63 ( Suppl 164):1-5

20. Lifestyle changes plus metformin ( ± other agents) Basal Add basal insulin and titrate Basal Plus Add prandial insulin at main meal Basal Bolus Add prandial insulin before each meal Progressive deterioration of  -cell function Basal Plus: once-daily basal insulin glargine plus once-daily* rapid-acting insulin glulisine Matching treatment to disease progression using a stepwise approach *As the disease progresses, a second daily injection of glulisine may be added Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64

21. The Basal Plus strategy using once-daily glargine + once-daily glulisine Optimize fasting blood glucose Titrate insulin glargine to control fasting BG to as close to normal levels as possible Add once-daily insulin glulisine at the main meal 1 to control postprandial BG in candidates with: HbA 1c >7% to <9% despite optimal titration of glargine 2 And FBG control close to or at target 3 1 Nathan DM, et al. Diabetes Care 2008;31:1–11; 2 Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452; 3 Sanofi-aventis data on file. Glargine titration optimization: Using algorithms employed by clinical studies for patients with type 2 diabetes, the target FPG should be ≤100 mg/dL (5.5 mmol/l)

22. Strategies for dose intensification from a basal to a basal-bolus regimen A. Pfu¨ tzner, T. Forst Int . J Clin Pract , October 2009, 63 (Suppl. 164), 11–14 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/kg 2 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/kg 2 Add bolus 2U at each meal Titrate to next pre-prandial goals (and bedtime) daily <70 mg/dl -1U 70-130 mg/dl 0 >130 mg/dl +1U Discontinues SU on addition of bolus insulin Patients need to monitor up to 4x per day Add bolus 4U at the largest meal Titrate to next pre-prandial goals (and bedtime) goal daily If subsequent pre-meal sugars are: <70 mg/dl -1U 70-130 mg/dl 0 >130 mg/dl +1U Discontinues SU on addition of bolus insulin Patients need to monitor up to 4x per day If 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 consider performing a 7 point profile If 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 befor. Repeat for 3rd dose at final meal of the day Straight to three bolus doses Sequential addition of bolus doses

23. I nsulin glulisine : A novel rapid-acting insulin analogue Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21 x --- --- --- stabilising agent Polysorbate 20 --- x x x complexing agent Zinc --- x x x tonicity agent Glycerol (85%)       Insulin Function Components Glulisine Aspart Lispro Human Qualitative composition Unique Formula insulin glulisine Human Rekombinan insulin analog Glu + Lys= Gluisine A chain B chain Insulin glulisine: Substitution of asparagine B3 with lysine, and of lysine B29 with glutamic acid =substitution 1 5 Gly Gln Gln Cys Phe His Leu Pro Lys Thr Ala Glu Lys Asn 1 5 S S 10 Ile 10 S S 15 15 S S 20 His Gly Phe 25 20 30 The two substitutions favour monomer formation and facilitate rapid absorption from the tissue following subcutaneous injection

24. Components of rapid-acting insulins From human insulin, insulin lispro, insulin aspart and insulin glulisine summary product characteristics (SmPCs) Component Function Qualitative composition Human insulin Insulin lispro Insulin aspart Insulin glulisine Insulin or insulin analogue Active ingredient 100 U 100 U 100 U 100 U Metacresol Preservative     Phenol Preservative     Trometamol Buffering agent     Sodium dihydrogen phosphate Buffering agent     Sodium chloride Tonicity agent     Glycerol (85%) Tonicity agent     Zinc Complexing agent     Polysorbate 20 Stabilising agent     Sodium hydroxide Alkalising agent     Hydrochloric acid Acidifying agent     Water for injection Solvent    

25. Insulin Glulisine has a more rapid time-action profile than RHI and insulin lispro in non-diabetic obese subjects Insulin concentration (mU/l) Time (minutes) Time (minutes) Glucose infusion rate (mg/kg/min) N=18 non-diabetic subjects; mean BMI: 34.7 kg/m 2 (range: 30–40); d ose: 0.3 IU/kg 120 240 360 480 600 50 100 150 200 2 4 6 120 240 360 480 600 Insulin glulisine Insulin lispro RHI BMI=body mass index Becker RH, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43. Reproduced with permission.

26. GIR max -t 10% GIR max -t 20 % min min INS max -t 10 % INS max -t 20 % min min Arnolds S, et al. Exp Clin Endocrinol Diabetes 2010:118:662-64 Insulin glulisine has a more rapid onset of action than insulin Aspart p=0.0146 p=0.0435 p=0.0005 p=0.0005

27. Insulin glulisine has a more rapid onset of action than insulin lispro in lean to obese non-diabetic subjects Heise T, et al. Diabetes Obes Metab 2007;9:746 − 53. BMI groups (kg/m 2 ) BMI groups (kg/m 2 ) Dose 0.2 U/kg (N=80) <25 25–30 30–35 ≥ 35 GIR AUC (0-1 h) /GIR AUC (0-10 h) (%) 2 4 6 8 10 Dose 0.4 U/kg (N=80) <25 25–30 30–35 ≥35 Insulin lispro Insulin glulisine GIR AUC (0-1 h) /GIR AUC (0-10 h) (%) 2 4 6 8 10 All All * * ** ** ** ** ** * p<0.05; ** p<0.001 vs insulin lispro

28. Significantly greater improvement in HbA 1c with insulin glulisine compared with RHI HbA 1c (%) *p<0.05 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Baseline 12 weeks 26 weeks * * Insulin glulisine RHI Similar incidence of symptomatic hypoglycaemia N=876 withT2DM; BMI=34.6 kg/m 2 and 34.51kg/m 2 in the insulin glulisine and RHI groups respectively; NPH=basal insulin NPH=neutral protein Hagedorn Dailey G, et al. Diabetes Care 2004;27:2363–8. Reproduced with permission.

29. POC study: adding glulisine to glargine further improves glycemic control Control group Glargine + glulisine p=0.0499 10 20 30 40 % achieving HbA 1c <7.0 8.8 22.4 p=0.029* Control group Glargine + glulisine Randomization Endpoint 6 7 8 9 HbA 1c (%) 8.0 7.8 7.8 7.5 *for difference in change in HbA 1c Sanofi-aventis data on file. Basal Plus (POC) study

30. OPAL study: glargine + glulisine improves glycemic control irrespective of whether glulisine is given with breakfast or the main meal Baseline Endpoint Breakfast group Main meal group 20 40 60 % achieving HbA 1c <7.0 36.5 52.2 p=0.028 p=NS p<0.0001 HbA 1c (%) 6 7 8 9 7.35 7.03 7.29 6.94 Breakfast group Main meal group p<0.0001 The main meal group also included subjects whose main meal was breakfast Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

31. POC study: the Basal Plus approach is safe and associated with only minor weight gain Control group Glargine + glulisine p=NS 0.0 0.2 0.4 0.6 Mean body weight change from baseline (kg) 0.5 0.2 Glargine + glulisine Control group 2 4 6 8 7.68 8.19 10 p=NS Symptomatic hypo (event/patient-year) Glargine + glulisine 0.0 Control group 0.0 0.1 0.2 0.3 Severe symptomatic hypo (event/patient-year) 0.2 p=NS Sanofi-aventis data on file. Basal Plus (POC) study

32. OPAL study: the timing of glulisine addition to glargine does not affect safety or weight gain p=NS Breakfast group Main meal 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Mean body weight change from baseline (kg) 1.0 0.9 1 2 3 4 2.72 3.69 Confirmed hypo (event/patient-year) Breakfast group Main meal p=NS 0.00 0.01 0.02 0.03 0.04 0.05 Breakfast group Main meal Severe hypo (event/patient-year) 0.01 0.04 p=NS Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

33. Matching treatment to disease progression using a stepwise approach Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64 Lifestyle changes plus metformin ( ± other agents) Basal Add basal insulin and titrate Basal Plus Add prandial insulin at main meal Basal Bolus Add prandial insulin before each meal Progressive deterioration of  -cell function Basal Bolus: once-daily basal insulin glargine plus 3 injections of rapid-acting insulin glulisine (each injection before a meal) The Gold Standard for advanced type 2 diabetes

34. Endogenous insulin secretion Ideal basal insulin Ideal prandial insulin Adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21 In advanced type 2 diabetes, Basal Bolus therapy reproduces physiological insulin secretion Insulin (mU/L) 06.00 12.00 24.00 18.00 15 30 45 06.00 Breakfast Lunch Dinner Time (hours)

35. Basal Bolus therapy delivers comparable good efficacy whatever the titration algorithm used Bergenstal RM, et al. Diabetes Care 2008;31:1305–10 20 40 60 80 100 73 69 % achieving HbA 1c <7.0 Simple algorithm CHO counting p=NS 2 6 12 18 Baseline Endpoint 8.16 8.16 6.70 6.54 Simple algorithm CHO counting 6.0 6.5 7.0 7.5 8.0 8.5 HbA 1c (%) ADA/EASD target p=NS Weeks

36. The Basal Bolus strategy is safe and associated with acceptable weight gain Bergenstal RM, et al. Diabetes Care 2008;31:1305–10 1 2 3 4 Simple algorithm CHO counting Mean body weight change from baseline (kg) 3.6 2.4 p=NS 2 4 6 8 BG <50 mg/dL with symptoms (event/patient-year) Simple algorithm CHO counting 4.9 8.0 p=0.02 Severe hypo (event/patient-year) 0.0 0.2 0.4 0.6 0.8 1.0 Simple algorithm CHO counting 0.67 0.89 p=NS

37. 3.2 GINGER study Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83 p=0.0004 % achieving HbA 1c <7.0 10 20 30 40 50 Glargine + glulisine Premixed insulin 47 28 GINGER: Basal Bolus provides superior glycemic control vs. intensified premixed insulin therapy Months 7.0 8.0 9.0 6.0 p=0.0001 3 6 9 12 8.5 8.6 7.7 7.3 HbA 1c (%) Premixed insulin Glargine + glulisine

38. GINGER: Basal Bolus has an acceptable safety profile in late stage type 2 diabetes 3.2 GINGER study Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83 1 2 3 4 Glargine + glulisine Premixed insulin Mean body weight change from baseline (kg) 3.6 2.2 p=0.007 Symptomatic hypo (event/patient-year) 5 10 15 Glargine + glulisine Premixed insulin 9.9 13.4 p=NS Severe hypo (event/patient-year) 0.00 0.05 0.10 0.15 0.20 0.25 Glargine + glulisine Premixed insulin 0.1 0.2 p=NS

39. 3.3 LACE study Lee F, et al. Diabetologia 2008;51 Suppl. 1:S406 LACE: glargine + glulisine in Basal Bolus provides superior glycemic control to premixed insulin in real-life conditions 10 20 30 40 50 % achieving HbA 1c <7.0 Glargine + glulisine Premixed insulin 42 30 p=NS Baseline Endpoint p=0.009 6 7 8 9 10 Glargine + glulisine Premixed insulin HbA 1c (%) 9.25 9.25 Baseline Endpoint 7.52 7.52 6.93 6.93

40. Conclusions (1/2) Type 2 diabetes is a progressive disease that requires insulin intensification after several years of evolution Shorten delays in treatment changes to achieve and maintain normal glycemic goals A single daily injection of basal insulin glargine is a simple and effective way to start insulin therapy Maintains targets with a low risk of hypoglycemia The dose of insulin glargine should be titrated for maximum and long-lasting efficacy If, despite adequate titration, the patient is still or no longer at target (HbA 1c <7%), addition of one shot of insulin glulisine at the main meal should be considered The Basal Plus strategy, i.e. glargine once daily with glulisine once daily, demonstrated combined efficacy with an acceptable safety profile

41. Conclusions (2/2) As the disease progresses, a second injection of prandial insulin at the second main meal can be considered as a transition towards a Basal Bolus regimen For patients with advanced type 2 diabetes who are still not at target, a Basal Bolus regimen with insulin glargine and three daily doses of insulin glulisine should be considered Insulin Glulisine has unique molecule structure and zinc-free formula. The unique molecular structure of insulin Glulisine provides faster absorption and onset of action, plus stability without the need for zinc The Basal Bolus strategy reflects normal physiology of insulin secretion The Basal Bolus strategy with once daily glargine and three times daily glulisine has an acceptable safety profile, and has superior efficacy vs. premixed insulin regimens Basal Bolus has superior efficacy compared with premixed insulin and an acceptable safety profile: In the GINGER study, significantly more subjects reached target HbA 1c (47% vs. 28%) In the real-life LACE study, HbA 1c levels were significantly reduced Basal-bolus strategy was associated with a lower incidence of hypoglycemia than premix insulin, although not significant Findings from a ‘real life’ prospective study confirm the results of randomized controlled clinical trials in terms of the superior efficacy of Basal-Bolus vs. premixed insulins The Basal Bolus strategy is an optimized approach for patients with advanced type 2 diabetes

42. Thank you