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Basal Bolus Regimen in T2DM Prof. Dr. Hala Aly Gamal El Din Professor Of internal medicine Faculty of Medicine - Cairo University.

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Presentation on theme: "Basal Bolus Regimen in T2DM Prof. Dr. Hala Aly Gamal El Din Professor Of internal medicine Faculty of Medicine - Cairo University."— Presentation transcript:


2 Basal Bolus Regimen in T2DM Prof. Dr. Hala Aly Gamal El Din Professor Of internal medicine Faculty of Medicine - Cairo University

3 Targets for glycemic (blood sugar) control Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at Accessed January 6, 2006. AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82. American Diabetes Association. Diabetes Care. 2009;32(suppl 1) ADAAACE A1c (%) <7*6.5 Fasting (preprandial) plasma glucose 70-130 mg/dL <110 mg/dL Postprandial (after meal) plasma glucose <180 mg/dL <140 mg/dL *<6 for certain individuals Goals of Glucose Management

4 4 Relation between PPG control & Achieving A1C Goal Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:881-885.

5 20-25% of Patients Have A1Cs between 8.0% and 7.0% Moving from A1C 8.0% to 7.0% - Reduces Serious Complications UKPDS Study Results –Reduced microvascular complications (kidney, eye, etc.) by 17-33% –Reduced risk of heart attack by 16% –Reduced diabetes-related deaths by 21% Challenge: More difficult to make improvements as A1C gets closer to 7.0% Moving from A1C 8.0% to 7.0% Difficult and Important!!

6 Every 1% drop in HbA 1c can reduce long-term diabetes complications 43% Lower extremity amputation or fatal peripheral vascular disease 37% Microvascular disease 19% Cataract extraction 14% Myocardial infarction 16% Heart failure 12% Stroke UKPDS: Stratton et al. BMJ 2000;32:405–12 Improving control reduces risks of long term complications

7 A1C reduction with glucose – lowering medications Oral agents A1C (%)* Sulfonylureas1.5 Biguanides (metformin)1.5 Glinides1.0–1.5 Thiazolidinediones0.8–1.0 DPP-IV inhibitors0.5–0.9 α-Glucosidase inhibitors0.5–0.8 Parenteral/inhaled agents Insulin2.5 Inhaled insulin1.5 GLP analogues0.6 Amylin analogues0.6 * Monotherapy DPP = dipeptidyl peptidase; GLP = glucagon-like peptide Nathan DM. N Engl J Med. 2007;356:437-40.

8 Insulin is the most effective anti diabetic agent

9 Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation –Acute injury, stress, infection, myocardial ischemia –Severe hyperglycemia with ketonemia and/or ketonuria –Uncontrolled weight loss –Use of diabetogenic medications (eg, corticosteroids) Surgery Pregnancy Insulin therapy in T2DM indications

10 A clinical fact Most Patients with T2DM will eventually need exogenous insulin to maintain recommended targets for glycaemic control Starting insulin treatment in adults with Type 2 diabetes RCN guidance for nurses 2004

11 When to Start Insulin First ADA-EASD Consensus SEVERELY CATABOLIC PATIENT Hemoglobin A1C > 10% FBS > 250 mg/dl (13.9 mmol/l) Random consistently > 300 mg/dl (16.7 mmol/l) Nathan et al. Diabetes Care 2006;29: 1963-1972

12 Insulin 7% 8%9% 10% Combination oral agents Monotherapy Diet and exercise T2DM treatment Old paradigm by A1C level

13 At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea a Lifestyle + Metformin + Intensive insulin Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss Lifestyle + Metformin + Pioglitazone + Sulfonylurea a Tier 1: Well validated core therapies Tier 2: Less well validated therapies STEP 1STEP 2STEP 3 Lifestyle + Metformin + GLP-1 agonist b No hypoglycaemia Weight loss Nausea/vomiting Lifestyle + Metformin + Basal insulin New ADA/EASD treatment algorithm for Type 2 diabetes Reinforce lifestyle interventions at every visit and check HbA 1c every 3 months until HbA 1c is <7 % and then at least every 6 months. The interventions should be changed if HbA 1c is 7 % a Sulfonylureas other than glibenclamide (glyburide) or chlorpropamide b Insufficient clinical use to be confident regarding safety Nathan DM, Buse JB, Davidson MB, et al. Diabetologia. 2009;52:17-30

14 The Ideal Basal Insulin Mimics normal pancreatic basal insulin secretion Long-lasting effect – 24 hours Smooth, peakless profile Reproducible and predictable effects Reduced risk of nocturnal hypoglycemia Once-daily administration

15 Levemir® FlexPen® ?

16 LysB29(N-tetradecanoyl)des(B30)human insulin Detemir Properties: Neutral pH Albumin binding Long extended action More within patient consistency Less hypoglycemia Less weight gain Insulin Detemir (Levemir ® )

17 Hormone BloodTissue Injection site Carrier Protein Carrier Protein Hormone Receptor Mode of Action Use of Serum Carrier Protein (e.g. Albumin) to Extend time of action Carrier Protein

18 Levemir ® FlexPen ® Designed to bind specifically to albumin Albumin binding protracts: –Absorption of insulin detemir from the subcutaneous depot –Residency of insulin detemir in the circulation Albumin binding buffers variability of action of insulin detemir There are no safety concerns with albumin binding of insulin detemir or with changes to its insulin structure

19 Albumin binding of Levemir ® Myristic acid binds at fatty-acid binding sites of albumin 98.8% binding in human plasma Safety of albumin binding At therapeutic doses, insulin detemir occupies a tiny fraction of available albumin binding sites, with more than 60,000-fold excess albumin over insulin

20 Self association (hexameric) Fatty acid side chains bind to albumin in injection depot Albumin binding in circulation Protracted absorption Buffering effect and minor contribution to protraction Mode of prolonging action

21 Why do we say Levemir is predictable? Precipitation Glargine Precipitation Levemir Solution, acid pH, pain Precipitation & de-precipitation is the mechanism of protraction: so factors of precipitation and absorption remain Solution, neutral pH, no pain No precipitation mechanism of protraction depends on increased self -association No absorption factor – albumin binding buffers absorption

22 GIR profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Heise T et al. Diabetes 2004;53: 1614-20 Variability in time-action profile of basal insulin

23 Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 Levemir ® was initiated at 0.1 to 0.2 unit/kg or 10 units once daily at dinner or bedtime Dose titration was based on the PREDICTIVE ® 303 patient-directed self-titration algorithm Patients continued on OAD therapy Levemir ® once daily Self-adjusted target FPG 70-90 mg/dl Levemir ® once daily Self-adjusted target FPG 80-110 mg/dl Prior OAD therapy Screening period (n=122) Main inclusion criteria: Type 2 diabetes, 3 months 7% HbA 1c 9% BMI 45 kg/m 2 Age 18 years Insulin naïve TITRATEStudy

24 Time (study week) FPG 70-90 mg/dl FPG 80-110 mg/dl Baseline 12 20 Mean HbA 1c (%) 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 8.2 7.94 7.04 7.00* 7.99 6.93 6.77* * Change in both groups, p=0.019 at 20 weeks Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 -0.94% reduction in HbA 1C -1.22% reduction in HbA 1C HbA1C Improvement

25 Events per subject/year Hypoglycaemic events p=NS One major hypoglycaemic event was reported by subject in the 70-90 mg/dl target group Low rates of hypoglycaemia with once-daily Levemir ® FPG 80-110 mg/dl FPG 70-90 mg/dl Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31 Hypoglycaemic Events

26 Change in weight Insulin detemir NPH insulin Baseline BMI 25 >25- 30 >30- 35 >35 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Philis-Tsimikas et al. Clin Ther 2006 Dornhorst et al. Int J Clin Pract 2008 0.55 -0.06 -0.56 -0.96 -1.51 -2 0 1 n= 270 395 374 341 640 <2525–<27 27–<2929–<31 31 Baseline BMI

27 303 Titration: Patients who experienced hypoglycaemia reduced their daily dose by 3 units Titration at a once-daily dose 70-90 mg/dL or 80-110 mg/dL FPG Target range Below target Above target Mean 3-day FPG 3 Units 3 no adjustment Maintain dose 3 units Increase dose Decrease dose 3 units 0 3 0 3

28 Insulin analogues compared Insulin receptor affinity IGF-1R affinity Insulin receptor off rate Metabolic potency Mitogenic potency Human insulin =100 Insulin aspart 92 ± 681 ± 981 ± 8101 ± 258 ± 22 Insulin detemir 18 ± 316 ± 1204 ± 92711 Kurtzhals P, et al. Diabetes 2000; 49: 999

29 Insulin analogues compared Insulin receptor affinity IGF-1R affinity Insulin receptor off rate Metabolic potency Mitogenic potency Human insulin =100 Insulin aspart 92 ± 681 ± 981 ± 8101 ± 258 ± 22 Insulin lispro 84 ± 6156 ± 16100 ± 1182 ± 366 ± 10 Insulin glargine 86 ± 3641 ± 51152 ± 1360 ± 3783 ± 13 Insulin detemir 18 ± 316 ± 1204 ± 92711 Kurtzhals P, et al. Diabetes 2000; 49: 999


31 Summary Treatment with basal analogues enables patients to reach HbA 1c target with low rate of hypoglycaemia HbA 1c improves but some patients need more Levemir® + OD is associated with: –reduced hypoglycemia in comparison to NPH, and –reduced weight gain in comparison to any other basal insulin. Initiation of Levemir® + OD with 3-0-3 algorithm is effective, simple and safe.

32 Bolus Insulin

33 Physiologic Insulin Secretion: 24-hour Profile Prandial glucose 150 Time of day Glucose (mg/dL) 100 50 0 789101112123456789 AMPM Basal glucose Prandial insulin Insulin (µU/mL) Basal insulin Breakfast Lunch Dinner 50 25 0

34 Limitations of Human Regular Insulin Slow onset of action –Requires inconvenient administration: 20 to 40 minutes prior to meal –Risk of hypoglycemia if meal is further delayed –Mismatch with postprandial hyperglycemic peak

35 35 Structure of insulin aspart (NovoRapid ® ) NovoRapid ® is designed for low self-association to allow rapid absorption

36 Absorption: human insulin vs. Insulin aspart Insulin aspart Insulin concentration (M) Absorption Monomer Capillary membrane T-type hexamer Dimer R-type hexamer 10 –3 10 –4 10 –6 10 –8 Human insulin This is purely schematic to illustrate absorption of molecules

37 37 NovoRapid ® is designed for rapid, flexible control 1.Rapid absorption Meal time flexibility 2.Rapid time to maximum effect Efficacy 3.Rapid return to baseline insulin level Safety (Less Hypos) BI Yu- fang, ZHAO Lie-bin et al. Compare efficacy and safety of insulin aspart and Novolin R delivered with CSII in 21 Chinese diabetic patients.Chin Med 2007;120(19):1700-1703

38 Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilmans The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A. Estimated Pharmacokinetics of Current Insulin Preparations OnsetPeak Effective Duration Rapid acting analog <15 min0.5-1.5 hr3 hr Human Regular Insulin 0.5-1 hr2-3 hr3-6 hr

39 Bolus Insulin for Pre-prandial Administration Predictable, reproducible time- action profile Rapid onset of action Short duration of action Desirable Kinetic Characteristics Clinical Benefits Precise dosing Optimal glucodynamics Reduced risk of hypoglycemia (day and night)

40 NovoRapid ® FlexPen ®

41 Insulin Aspart vs. Regular Human Insulin: Effect on A1C A1C (%) Time (months) Data represent mean ± SEM * P < 0.05 036 8.5 8.0 7.5 0 * Insulin Aspart Regular Insulin

42 Effect of NovoRapid ® versus Actrapid ® on PP myocardial perfusion in type 2 diabetes Myo- cardial Blood- Flow Scognamiglio R et. al. Diab Care 2006;29:95–100 T2D Patients Healthy group people FastingPosprandial

43 Nippon ultrarapid Insulin and diabetic Complication Evaluation (NICE) Studie Cumulative CV events in 374 Japanese T2 patients after 4.5 years Nishimura M et al. Diabetologia 2008;51(Suppl1):S543 2008;51(Suppl1):S543

44 44 NovoRapid®: approved for every stage of life, from children aged 2 years to the elderly 2 Approved for use in abroad range of patients For patients with Type 1 diabetes 2 For patients with Type 2 diabetes 2 For patients using an insulin pump 2 Even patients requiring special consideration For use in pregnancy- can be used during lactation 2 For use in the elderly 2 For use in children aged 2 years and above 2 For use in special population with renal or hepatic imparement 2,3

45 45 NovoRapid ® : helps T2DM patients attain and maintain their HbA1c goals 4 1.2% reduction in HbA1c from baseline 4 63% of patients achieved ADA target <7% over 3 years4 Reduced mean PPG levels 4 The addition of NovoRapid ® significantly reduced the mean PPG level by 67 mg/dL (3.72 mmol/L) 4 6.9% median HbA1c achieved by patients at 3 years

46 46 NovoRapid ® : Reduced rate of nocturnal hypoglycaemia 24% Lower risk of nocturnal hypoglycaemia was confirmed by a meta-analysis of 3,727 T1DM patients in randomized, controlled trials conducted over 10 years of clinical experience with NovoRapid ®7 Reduced rates of hypoglycaemia, even in pregnant women 8 Initiation of NovoRapid ® preconception may result in lower risk of severe hypoglycaemia in pregnant women with type 1 diabetes 8 Nocturnal events 72% less major nocturnal hypoglycaemia in patients with type 1 diabetes 6

47 47 NovoRapid ® :pre and post meal dosing allows patients to treat according to lifestyle 9 Depending on their lifestyle and eating habits, some patients require more treatment flexibility10-12 NovoRapid ® enabled an overall improved quality of life with increased flexibility compared with regular human insulin T1DM 10 Since children may have unpredictable eating habits, parents preferred NovoRapid ® over regular human insulin 11 Pregnant women with T1DM preferred NovoRapid ® for more flexibility12 in their treatment 9

48 48 FlexPen ® : trusted by millions worldwide 13,14 Next Generation FlexPen® from Novo Nordisk offers

49 New features of FlexPen

50 Approved shelf-life: aspart vs. glulisine The approved shelf-life is greater for NovoRapid ® than for Apidra ® in both the Europe and US Furthermore, once in use NovoRapid ® remain stable for 28 days at 30°C while Apidra ® must be stored at no greater than 25°C Glulisine zinc-free counter - what data do we have? European LabelUS Label Shelf-life (2-8°C) In-useShelf-life (2-8°C) In-use NovoRapid ® /NovoLog ® 30 months28 days <30°C30 months28 days <30°C Insulin glulisine 24 months28 days <25°C24 months28 days <25°C Glulisine US label April 07, European label July 05 NovoRapid Core Data Sheet, version 10, 2007

51 51 After 10 years of study and use 2, no other rapid- acting insulin is part of so many lives 1 Approved for every stage of life, from children aged 2 years to the elderly 2 Helps patients attain and maintain their HbA1c goals 4 NovoRapid ® significantly reduced major nocturnal hypoglycaemia versus regular human insulin by 72% 6,7 Pre- and post-meal dosing allows patients to treat according to lifestyle 10 FlexPen ® : trusted by millions worldwide 14,15

52 Summary

53 Timely addition of prandial insulin reflects a meal plus basal insulin coverage Tight glycaemic control can be achieved and maintained with low rates of hypoglycaemia and minimal weight gain, using insulin Detemir (Levemir®) OD first, then adding short acting analogue insulin (insulin Aspart, NovoRapid®), stepwise or with all meals according to 1-0-1 Initiation and intensification of insulin therapy in type 2 diabetes can be done safely, effectively and conveniently

54 References: 1. IMS Health Inc. IMS MIDAS (MATQ209). 2. NovoRapid [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2009. 3. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60(5):469-476. 4. Holman RR, Farmer AJ, Davies MJ, et al, for the 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747. 5. Holman RR, Thorne KI, Farmer AJ, et al, for the 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357(17):1716-1730. 6. Heller SR, Colagiuri S, Vaaler S, et al. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with type 1 diabetes. Diabet Med. 2004;21(7):769-775. 7. Heller S, Bode BW, Kozlovski P, Svendsen A. Examining the glycaemic and hypoglycaemic benefits with rapid-acting insulin analogues: a meta versus regular human insulin in randomised controlled trials [poster 916]. Diabetologia. 2009;52(suppl 1):S359-S360. 8. Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care. 2010;33(3):473-477. 9. Brunner GA, Hirschberger S, Sendlhofer G, et al. Post-prandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabet Med. 2000;17(5):371-375. 10. Bott U, Ebrahim S, Hirschberger S, Skovlund SE. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with type 1 diabetes. Diabet Med. 2003;20(8):626-634. 11. Danne T, Råstam J, Odendahl R, et al. Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes. Pediatr Diabetes. 2007;8(5):278-285. 12. Mathiesen ER, Kinsley B, Amiel SA, et al, on behalf of the Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30(4):771-776. 13. IMS Health Inc. IMS MIDAS (12 months ending September 2009). 14. Reimer T, Hohberg C, Pfützner AH, Jørgensen C, Jensen KH, Pfützner A. Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling study in patients with type 2 diabetes. Clin Ther. 2008;30(12):2252-2262. 15. Asakura T, Seino H, Kageyama M, Yohkoh N. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother. 2009;10(9):1389-1393. 16. Rissler J, Jørgensen C, Rye Hansen M, Hansen N-A. Evaluation of the injection force dynamics of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2217-2222.17. Sommavilla B, Jørgensen C, Jensen KH. Safety, simplicity and convenience of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2223-2232. 18. Weise A, Pfützner JW, Borig J, et al. Comparison of the dose accuracy of prefilled insulin pens. J Diabetes Sci Technol.2009;3(1):149- 153.


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