Why we need new analog insulin


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  • Relative contributions of postprandial and fasting hyperglycemia to the overall diurnal hyperglycemia accordingto quintiles of glycosylated hemoglobin (A1C). *Significant difference was observed between postprandialplasma glucose (PPG) and fasting plasma glucose (FPG) (paired t test); †significantly different from all other quintiles(analysis of variance); ‡significantly different from quintile 5 (analysis of variance). From Diabetes Care, Vol. 26, 2003:881–885.16 Reprinted with permission fromThe American Diabetes Association
  • Previous calculations indicated that upto 50% of beta cells may be lost at the time of diagnosis of diabetes. When improved methods of beta cell function estimation are used it appears that upto 80% of beta cell function may be lost at diagnosis necessitating early aggressive therapy to prevent its progression.
  • According to the UKPDS studies it is shown that more than 50% of the patients on OAD require insulin by year 6. this requirement of insulin increases with time. If patients receive insulin early, their beta cells can be preserved to some extent.
  • Ultimately, more intensive insulin regimens may be required (see Figure 3.)Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc).
  • Ultimately, more intensive insulin regimens may be required (see Figure 3.)Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc).
  • So what are the insulin preparation available and what regimen are followed …
  • C. Basal bolus regimenIn this regimen regular and intermediate acting insulin is used. Basal requirement is met by intermediate acting insulin given twice a day before breakfast and dinner. The regular insulin is given before each meal thrice a day. Out of the total daily requirement 50% is given as basal (intermediate) and 50% as regular insulin. The share of regular insulin (50%) is given as 20% BBF, 10% BL and 20% BD. It gives similar results as compared to twice a day but the only disadvantage is that the before lunch (BL) dose is to be taken at school or office.D. Continuous subcutaneous insulin infusion Only short acting insulin is used and is given by insulin pump which the patient has to wear throughout the day. It is neither practical, nor are the results better than twice daily or bolus regimen.All this regimen are available to guide te treatment but still lot of practical aspects need to be consideredSo what are the aspect where we need to stress and improve in future
  • Our current health care system approach to diabetes is not working. Infrequent medical visits, lack of recorded data, and the lack of helpful advice about insulin doses as diet and lifestyle decisions that affect control are made each day, all contribute to the poor A1c results.
  • Why we need new analog insulin

    1. 1. WHY WE NEED NEW INSULIN ANALOG Glaritus 2012 1
    2. 2. Diabetes: Global Scenario Glaritus 2012 2
    3. 3. Diabetes – Growing Threat in Myanmar Diabetes has been noted to be increasingly common in Myanmar!
    4. 4. Patients achieving targets (%) Uncontrolled Hyperglycemia is a Global Problem In Clinical Practice HbA1c <7% 56 HbA1c <7% 51 USA (NHANES) CANADA (DICE) HbA1c <6.5% 31 EUROPE (CODE-2) HbA1c <6.5% 36 Emerging countries (IDPMS)
    5. 5. Progressive nature of Type 2 diabetes Normal Impaired glucose tolerance Late type 2 diabetes complications Type 2 diabetes Insulin sensitive Hyperglycaemia Normal insulin secretion Insulin resistance Normoglycaemia β-cell exhaustion Insulin resistance Fasting plasma glucose Insulin sensitivity Insulin secretion Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876. Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7. Glaritus 2012 6
    6. 6. ADA/ACE Targets for Glycemic control1 FPG PPG HBA1c 90-130 mg/dL <180 mg/dL <7.0% <110 mg/dL <140 mg/dL <6.5% For certain patients, a more stringent goal of <6.0% can be considered. 2 1. 2. ADA, Standards of Medical Care in Diabetes, Diabetes Care 2003;26(Suppl 1): S33S50/AACE, Endocrine Practice 2002;8(Suppl 1):5-11 ADA, Standards of Medical Care in Diabetes, Diabetes Care 2004;27(Suppl 1): S15-S35 Glaritus 2012 7
    7. 7. Contributions of FPG and PPG On Glycosylated Haemoglobin Increasing Contribution of FPG as A1C Increases 100% 30% % Contribution 80% 60% 70% 60% 55% 50% FPG PPG 40% 20% 70% 30% 40% 45% 50% 0% < 10.2 10.2 to 9.3 9.2 to 8.5 8.4 to 7.3 A1C Range (%) 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. < 7.3
    8. 8. Evidence of good glycemic control • Several landmark trials viz; – United Kingdom Prospective Diabetes Study (UKPDS) – Diabetes Control and Complications trial (DCCT) – Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) – ADVANCE study – All reinstate the importance of good glycemic control in reducing the risk of microvascular & macrovascular complications of diabetes – Decrease of 1% in HBA1c levels is associated with a 21% reduction in risk for any diabetes related end points Glaritus 2012 9
    9. 9. ß-Cell Function (% ß) The United Kingdom Prospective Diabetes Study demonstrated that a great majority of patients with Type 2 diabetes will eventually require Insulin and have provided level IA evidence that intensive glycemic control improves patient outcomes* Early Type 2 Late Type 2/ Type 1 Glaritus 2012 10
    10. 10. INSULIN The Most Powerful Agent We Have To Control Glucose Glaritus 2012 11
    11. 11. Indications of Insulin • Absolute – Type 1 diabetic patients – GDM (Gestational Diabetes Mellitus) – Ketoacidosis • Relative – – – – – – – – – Type 2 diabetic patient with primary or secondary failure to OHA Surgery under general anesthesia Type 2 diabetes with symptoms of glucose toxicity Acute illness Acute infections, e.g., Pneumonia, septicemia, etc. Active pulmonary tuberculosis Acute MI, CVA Diabetic nephropathy Chronic liver disease, etc. Glaritus 2012 12
    12. 12. • Traditionally insulin is introduced to patients with only after combination of two or three OHA failed to provide adequate glycemic control • General trend of insulin usage is last resort for Type 2 Diabetes • Superior efficacy of insulin over oral agents in reducing HbA1C levels is augmented by beneficial profile of new insulin analogs versus human insulin • Difference of current treatment guideline is they all recommend to initiate insulin therapy earlier than usual in patients not achieving HbA1C targets Glaritus 2012 13
    13. 13. Algorithm to initiate Insulin Therapy Glaritus 2012 14
    14. 14. Traditionally, insulin is used only when OADs fail to control glucose Lifestyle changes E.g. diet and exercise Adequate in only ~15% of people Oral antidiabetic agents E.g. metformin, sulphonylurea (or glitazone) Poor glycaemic control Oral combination therapy E.g. metformin plus sulphonylurea, metformin plus glitazone Poor glycaemic control INSULIN With/without oral agent* *Glitazones are contraindicated in combination with insulin Bergenstal RM et al. In: Degroot et al. (eds) Endocrinology 2001: pp. 821–35
    15. 15. Diabetologia 2009; 52:17-30 Diabetes Care 2009;32:193-203 Glaritus 2012 16
    16. 16. Beta cell function loss is earlier and greater than expected By the time that the diagnosis of diabetes is made, the patient has lost over 80% of his/her β-cell function DeFronzo RA. Diabetes. 2009 58:773–95.
    17. 17. Need of insulin increases over time Patients requiring additional insulin (%) 60 40 20 0 1 2 3 4 5 6 Years from randomization Chlorpropamide Glipizide ~53% of patients required additional insulin therapy by year 6 Wright A , Burden A.C, Paisey R.B, Cull C. Holman R.R. Ukpds. Sulfonylurea Inadequacy Diabetes Care. 2002;25:330-6.
    18. 18. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
    19. 19. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
    20. 20. Time to insulin initiation and incidence of complications are increasing Median duration until insulin initiation (years) Patients with at least 1 macrovascular event before initiation (%) Kotav K, et al, Diabetologia 2011; 54 Suppl.1)374
    21. 21. “Ideal” & “Real Course” of “Treated” Type-2-Diabetes 9,5 9,0 HbA1c (%) (First) cardiovascular event e.g. Myocardial Infarction  New therapy attempt There is golden window period in diabetes; in first 3 - years Real course Build-up of metabolic memory Ideal course 8,5 Increasing the risk of diabetic late complications 8,0 7,5 7,0 6,5 6,0 1 2 3 4 5 6 7 8 9 10 Time (years after diagnosis) 11 12 13 22 14 15 16 Del Prato, Diabetologia (2009) 52(7),1219- 1226
    22. 22. Need for Insulin EARLY INSULIN SAVES HEALTH; SAVES MONEY Glaritus 2012 23
    23. 23. Insulin Usage Number of diabetics using medication: 25-30 million Oral products 66% Oral/insulin Insulin 7% 27% Patients treated with Insulin were 1.68 times more likely to acheive 2 consecutive HbA1c levels of 6.5% or less, sooner than those on OADs* * Gerstein et al, Diabet Met. 2006;23:736-742 Glaritus 2012 24
    24. 24. Types of Insulin *Leahy JL, Intensive Insulin Therapy in Type 1 diabetes mellitus, in Lehay JL: Insulin Therapy. New York, NY, Marcel Dekker, Inc.2002, p 87-112 Glaritus 2012 25
    25. 25. Normal Insulin Secretion: The Basal-Bolus Insulin Concept Endogenous Insulin Bolus Insulin Insulin Effect Basal Insulin B L D HS Time of Administration B, breakfast; L, lunch; D, dinner; HS, bedtime. Adapted from: 1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. 2. Bolli GB et al. Diabetologia. 1999;42:1151-1167. Glaritus 2012 26
    26. 26. Insulin regimen: Once-daily regimen • Long- or intermediate-acting insulin is given at bedtime. • It is suitable only for patients with type 2 diabetes and may be used in combination with oral hypoglycaemic agents. • This regimen may be used when starting insulin in type 2 diabetes NICE Clinical Guideline (July 2004), NICE Clinical Guideline (May 2009) Glaritus 2012 27
    27. 27. Insulin regimen… Twice-daily regimen • A biphasic insulin is injected twice a day (pre-breakfast and preevening meal). • The peak action varies directly with the proportion of soluble insulin in the combination. • The peak and trough of the evening dose of longer-acting insulin can lead to the combination of nocturnal hypoglycaemia and then fasting hyperglycaemia in the morning. Glaritus 2012 28
    28. 28. Insulin regimen… Three times per day • In uncontrolled FPG • 2/3 in BF, of which 2/3 NPH, 1/3 Regular • 1/6 before EM, Regular • 1/6 HS, NPH Four times per day • Either NPH & Regular (¼ X 3 R and ¼ HS NPH) • Ultrashort and Long analogues (1/6 X 3 Aspart / Lispro and ½ HS Glargine) Glaritus 2012 29
    29. 29. Insulin regimen…. Basal bolus regimen • Regular and Intermediate/long acting insulin is used. • Basal requirement is met by intermediate acting insulin given twice a day before breakfast and dinner. • The regular insulin is given before each meal thrice a day. Out of the total daily requirement 50% is given as basal (intermediate/long) and 50% as regular insulin. Continuous subcutaneous insulin infusion • Only short acting insulin by insulin pump. • It is neither practical, nor are the results better than twice daily or bolus regimen. Glaritus 2012 30 30
    30. 30. When to start the regimens? A. Once daily regimen • In type 2 diabetes patients with secondary failure to OHA: used in combination with OHA. B. Twice daily regimen • In type l, 2, and GDM patients. • When HbA1c is >9% C. Basal Bolus regimen • When adequate control is not achieved by premixed insulin alone D. Continuous subcutaneous insulin infusion • When the patient is very much compliant Glaritus 2012 31
    31. 31. Current Diabetes Therapy Falls Short Inadequate control of Fasting Blood Glucose Glaritus 2012 32
    32. 32. Key of insulin therapy • Control of both FPG and PPBS is essential to improve microvascular and macrovascular outcomes • Ideal goal of insulin therapy is to mimic the pattern of physiologic insulin secretion to control FPG & PPBG • In order to achieve the normal physiological profile, Long acting basal insulin suppress endogenous hepatic glucose output therefore reducing FBG and short acting insulin to address PPG • Newer insulin analogs mimic the profile of endogenous insulin more closely than recombinant human insulin Glaritus 2012 33
    33. 33. Shortfalls of Current Regimen • Unpredictable in insulin absorption • Mismatch between glycemic excursions and insulin levels • Lack of a truly basal insulin • Poor FBG / PPBG control • Events of Hypoglycemia Glaritus 2012 34
    34. 34. Fasting Plasma Glucose • Predicts the degree of post-meal hyperglycemia and the magnitude of the post-meal excursion from baseline* • FPG is a determinant of PPG excursion *Diab Care 25: 1247-1248,2002 Glaritus 2012 35
    35. 35. FPG & Complications… • FPG shows a positive association with the incidence of diabetes related morbidity and mortality • A study showed* FPG Risk of mortality <110 mg/dl No increased risk 110 – 125 mg/dl 40% increased risk 125 – 140 mg/dl Double the risk *Diab Care 2005;28(11):2626-32 Glaritus 2012 36
    36. 36. Insulin Regimen: Balancing Act Can somebody help me ?????? Hyperglycemia Hypoglycemia Glaritus 2012 37
    37. 37. Basal Insulin Supplements NPH has….. • Erratic absorption • Unfavorable plasma insulin profiles with unwanted peaks • Nocturnal hypoglycemia NPH Insulin Glargine Insulin Detemir Glaritus 2012 38
    38. 38. Physiology of basal Insulin • Suppresses lipolysis • Restrains hepatic glucose output • Prevents hypo-neuroglycopenia (in concert with glucagon) • Not relevant to glucose utilization by muscle An adipose-hepato-centric hormone Large metabolic effects for small changes in plasma concentration
    39. 39. Basal Insulin Supplements Basal Insulin Preparations Onset (hours) Peak (hours) Duration (hours) Remarks NPH 2–4 6 – 10 10 – 16 • • • • • • • Glargine 1–2 Peakless 24 • No Unpredictable peaks • No Unpredictable glucose fluctuations • Decreased hypoglycemia Detemir 3–4 Peakless Upto 14 hrs • Injection site reactions and allergic reactions • Higher insulin dosage required Glaritus 2012 Does not mimic basal insulin release profile Component of Premixed Does not provide enough flexibility Unexpected time–action profiles Unpredictable peaks Unpredictable glucose fluctuations Increased hypoglycemia 40
    40. 40. Ideal basal insulin • The ideal basal insulin should have… – Mimic the physiological Insulin secretion pattern – Square-wave action profile, i.e., no peak, long-lasting – Reproducible effects – Pharmacodynamic effects similar to pump insulin This need is fulfilled by: INSULIN GLARGINE Glaritus 2012 41
    41. 41. Insulin Glargine: Structure Phe Gly Arg Tyr Phe Glu Thr Gly Pro Arg Arg Extension Lys A21 Gly Cys Thr A1 Gly lle Asp Glu Gln Cys B30 Asp Gly Substitution Tyr Gln Glu Leu Gln Tyr Cys Thr Ser lle Cys Ser Leu Cys B1 Phe Val Asn Gln His Leu Insulin Glargine: 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin pH = 4; Clear solution; Do not mix Cys Val Leu Tyr Leu Ala Glu Val Leu His Ser Gly
    42. 42. WHAT HAPPENS AFTER GLARGINE INJECTION ? Glargine Clear Solution pH 4.0 pH 7.4 Precipitation Dissolution Hexamers 10-3 M Dimers 10-5M Monomers 10-8 M S.c. Injection of an acidic solution (pH 4.0) Precipitation of glargine in subcutaneous tissue (pH 7.4) Slow dissolution of free glargine hexamers from precipitated Glargine Capillary Membrane Insulin in Blood Protracted action
    43. 43. Are all insulin analogs equally effective? -Pharmacokinetics and pharmacodynamics of insulin glargine and insulin detemir in patients with type 35 IU insulin; PG-Clamp 1 mg/dL X 24h 100 diabetes. Duration of action : (PG < 150 mg/dL) Insulin glargine: >24h Insulin detemir: 17.5 h Porcellati et al, DIABETES CARE , 30,OCTOBER 2007
    44. 44. Factors affecting PK / PD profile of insulin analog • Insulin dose : • area under the curve (AUC) and DOA for long & rapid acting analog increases with dose elevation • Injecting site • Deeper subcutaneous injections cause more rapid insulin diffusion and absorption • High Sc fat slow absorption, altering or delaying the time action profile • Glargine has no clinically significant differences in DOA whether injected in abdomen, thigh or deltoid where as in Determer , bioavailabilty differs, 64%in abdomen, 59%in thigh and 65% in deltoid Glaritus 2012 45
    45. 45. Changes of PK /PD in special patient population Elderly patients Obesity – high subcutaneous fat slow the absorption Renal dysfunction – 30 to 80% of insulin is removed by renal excretion Hepatic dysfunction – liver mainly controls hepatic glucose output and uptake Pregnancy – PK not altered but insulin resistance increased so needing higher dose of insulin Exercise –conditions causing greater blood flow ( exercise, massage, hot bath ) is associated with rapid insulin absorption Glaritus 2012 46
    46. 46. How has insulin Glargine changed the treatment paradigm of diabetes? • Once daily administration • Easy titration algorithm • Sustained glycemic control • Less hypoglycemia • Easy to use for specialist, GP, and patient
    47. 47. Mean HbA1c (%) Insulin glargine: rapid and sustained glycemic control. A 32 month extension of a 9 month, open label, uncontrolled, multicenter, observational study (n=12216) ----------- Months of treatment Insulin glargine + OADs provides sustained glycemic control Schreiber SA et al, Diabetes Techno Ther 2008; 10 121-7
    48. 48. Effect of insulin glargine on β-cell function Insulin Secretion (mU/kg per min) Insulin Secretion (mU/kg per min) First phase (t=0 to 10 min minus basal levels) and second phase insulin secretion (t=-10 to 120 min minus basal levels) in response to IV glucose administration in T2DM(n=14) before and after 8 weeks of insulin glargine treatment Pennartz C, et al, Diabetes Care 2011; 34-204
    49. 49. Insulin glargine has demonstrated effective HbA1c reductions across a wide range of RCTs in T1DM Raskin (2000) n=619, 16 weeks Bolli (2009) n=175, 2 4 weeks Fulcher (2005) n=125, 3 0 weeks Ashwell (2006) n=56, 3 2 weeks Chatterje e (2007) n=53, 3 6 weeks Porcellati (2004) n=121, 5 2 weeks HbA1c reduction with insulin glargine in RCTs of varying duration and size
    50. 50. Lower risk of hypoglycemia for insulin glargine vs NPH at any level of HbA1c in T1DM Rate of hypoglycemia (events per patients-year) Meta-analysis of 5 randomized trails comparing insulin glargine and NPH in HbA1c in T1DM P=0004 HbA1c (%; LOCF) Mullins P, et al, Clin ther 2007; 29; 1607-19
    51. 51. APOLLO: Insulin glargine vs prandial insulin lispro 44 week open label study on 412 T2DM patients treated with OHAs and Glargine (OD) or Lispro (TID) Change in HbA1c 30 Glargine Lispro -1.65 -1.7 -1.71 -1.75 -1.8 -1.85 Difference=.157 95% Cl -.008 to 0.332 -1.87 Hypoglycemic events Change in HbA1c (%) -1.6 24 25 Glargine Lispro 20 13.6 15 10 5.2 5 4.2 0.520.34 0.030.08 0 -1.9 Overall Symptomatic Nocturnal Severe Significant better treatment satisfaction with glargine compare to lispro Bratzel RG et al Lancet 2008; 371:1073-8
    52. 52. THE LANCET • The first clinically available long acting analog *addition of insulin glargine to therapies with oral hypoglycemic agents can be regarded as a first-line insulin initiation approach in type 2 diabetes mellitus* • 42 million patient-years of experience • 80,000 individuals in clinical development programs worldwide • Available in over 100 countries
    53. 53. Setting standards for basal insulin therapy : The contribution of insulin glargine Peak less, 24 hours insulin coverage Effective, sustained glycemic control with the low incidence of hypoglycemia in clinical trail and in real life clinical practice. Favorable impact on quality of life Benefits proven across a wide range of patients populations in T1DM & T2DM. Easy to use, flexible titration algorithms 12 years of clinical experience. Wealth of evidence to support a basal insulin treatment regimen with insulin glargine.