Insulin Therapy Management. Insulin Therapy

Transcription

1 Insulin Therapy Management Insulin Therapy

2 Contents Insulin and its effect on glycemic control Physiology of insulin secretion Insulin pharmacokinetics and regimens Insulin dose adjustment for pregnancy Barriers to insulin therapy

3 Insulin and its effect on glycemic control

4 Benefits with Insulin Initiation: Progressive loss of beta-cell function Beta-cell function (%) Loss of beta cell function continues with disease progression 20 UKPDS, UK Prospective Diabetes Study Holman. Diabetes Res Clin Pract 1998;40(Suppl.):S Time from diagnosis (years)

5 Plasma-immunoreactive insulin (µu/ml) Benefits with Insulin Initiation: Addressing the secretory defect in T2DM Plasma-immunoreactive insulin (µu/ml) Normal Type 2 diabetes st phase (acute secretion) Insulin secretory defects in T2DM can be mitigated with exogenous Insulin therapy nd phase Time (min) Time (min) Fonseca. Curr Med Res Opin 2003;19:635 41

6 Median HbA 1c (%) Benefits with Insulin Initiation: Disease progression is inevitable Conventional Glibenclamide Metformin Insulin UKPDS Rosiglitazone Metformin Glibenclamide ADOPT Recommended treatment target <7.0% Most therapies fail over time warranting Insulin Initiation 6.2% upper limit of normal range Time from randomisation (years) Diet initially then SUs, insulin and/or metformin if FPG >270 mg/dl; ADA clinical practice recommendations UKPDS 34, n=1704 ADA, American Diabetes Association; FPG, fasting plasma glucose; SU, sulphonylurea UKPDS 34. Lancet 1998;352:854 65; Kahn et al. (ADOPT) N Engl J Med 2006;355: Time (years)

7 Benefits with Insulin Initiation: Type 2 diabetes treatment efficacy DPP-4i a Glinides AGI GLP-1 RA b TZDs SUs Insulin Insulin offers maximal HbA1c reduction of 1.5% to 3.5% Metformin Lifestyle Range of HbA 1c reduction as a monotherapy a adapted to include sitagliptin and saxagliptin b adapted to include exenatide and liraglutide Campbell et al. Journal of family practice September 2010;59:S5-S9

8 Benefits with Insulin Initiation: Early insulin therapy beta-cell function and glycaemic control Patients in remission (%) Early Insulin initiation 40 may have favorable outcomes on beta cell function. 20 p= CSII MDI OHA Time in remission (days) n=382 CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent Weng et al. Lancet 2008;371:

9 DCCT: clinical evidence for benefits of glycemic control (T1DM) Risk reduction (%) for intensive therapy * * * *Statistically significant HbA1c change: 9% to 7% (75 to 53 mmol/mol) 1 DCCT 1993; 2 Leahy 2002

10 Positive legacy effect of earlier glucose control Provides long-term reductions in both microvascular and macrovascular complications RRR* at end of UKPDS RRR* at end F/U (median 8.5 years) 16% p= % p= % p= % p= % p= % p= % p=0.03 9% p=0.04 Myocardial infarction Microvascular disease RRR: relative risk reduction of intensive therapy over conventional therapy Death (any cause) Any diabetes endpoint Holman 2008

11 Contents Insulin Therapy Management Slide no 13 Insulin and its effect on glycemic control Physiology of insulin secretion Insulin pharmacokinetics and regimens Insulin dose adjustment for pregnancy Barriers to insulin therapy

12 Physiology of insulin secretion

13 Insulin (µu/ml) Aim of insulin therapy is to recreate the normal blood insulin profile Polonsky :00 Short-lived, rapidly generated meal-related insulin peaks (prandial) 10:00 14:00 18:00 Breakfast Lunch Dinner Flat basal insulin profile 22:00 2:00 6:00 Time of day

14 24-h physiological insulin secretion 24-h insulin secretion is 0.6 units/kg/d The basal insulin level is a result of stress, illness, activity, and body weight Typically the hourly basal insulin secretion rate is (0.3 x body weight in kilograms) / 24 The meal-related insulin requirement is based on CHO content and timing of the meal. Because breakfast occurs during the peak of the growth hormone and cortisol surges, more insulin is needed at breakfast time. Usually people are less active during the evening, insulin requirements tend to be slightly higher from 6:00 pm to 12:00 am (midnight) Insulin requirements are minimal (maximal insulin sensitivity) between midnight and 4:00 am CHO: carbohydrate ADA 2017

15 Recreating a normal insulin profile Most appropriate for patient s lifestyle and treatment preferences Optimum insulin regimen depends on: Pattern of insulin deficiency (T2DM) Lifestyle and treatment preferences Closest to physiological insulin delivery Optimum regimen will change over time in T2DM as disease progresses DCPNS 2010

16 Options in insulin therapy Type of insulin Human or analogue insulins Rapid-, short-, intermediate- or long-acting insulin Injections Number Insulin pump therapy DCPNS 2010

17 Contents Insulin and its effect on glycemic control Physiology of insulin secretion Insulin pharmacokinetics and regimens Insulin dose adjustment for pregnancy Barriers to insulin therapy

18 Insulin pharmacokinetics

19 Pharmacokinetics of available insulin preparations Insulin Onset Peak Effective duration Rapid-acting analogues 5-15 min min <5 h RHI min 2-3 h 5-8 h NPH 2-4 h 4-10 h h Long-acting analogues 2-8 h No peak Up to 24 h Premixed analogues 5-15 min Dual h AACE 2007

20 Factors affecting absorption rate Insulin type Basal: long-acting insulin analogs < NPH Prandial: regular human insulin < rapid-acting insulin analogs Site Rate of absorption: abdomen > arms > thigh > buttocks Depth of injection Rate of absorption: IV > IM > SQ Regional blood flow, which is affected by: Exercise Skin temperature Hydration status Local heat Leahy 2002

21 Insulin analogue development Altered absorption characteristics Insulin analogues are derivatives of human insulin that have undergone one or more chemical modifications to alter the time-action profile of the insulin Both are produced by recombinant DNA (rdna) technology Insulin analogues were designed to more closely mimic normal physiologic insulin secretion patterns Brange 1999; Leahy 2002

22 Currently available insulins Fast-acting: onset within 30 min, peak effect 2 4 h, duration 6 hours Regular insulin (Actrapid, Humulin R) Rapid-acting: onset within 15 min; peak duration 1-2 h, duration up to 4-5 h insulin aspart (NovoRapid ) insulin lispro (Humalog ) insulin glulisine (Apidra ) Intermediate-acting: onset within 2 h, peak effect 4 8 h, duration h NPH (Insulatard, Humulin N) Long-acting: onset within 2 h, duration h insulin detemir (Levemir ) insuline glargine (Lantus ) Pre-mixed: contain both a fast- or rapid- and an intermediate-acting insulin 30% short-acting/70% NPH (biphasic human insulin - Mixtard 30) 30% insulin aspart/70% protaminated insulin aspart (NovoMix 30)

23 Currently available insulins Rapid-acting insulins Onset within 15 min Peak duration 30 min-2 h Duration up to 4-5 h Mimic meal-stimulated insulin secretin Fast onset improves ability to match insulin dose to CHO intake Ensure that insulin and glucose reach the blood at the same time Should be taken less than 15 min before meal start, can also be given after meal Their short duration of action may lead to hyperlycemia before the next meal unless adequate basal insulin is given Short-acting insulins Onset within 30 min Peak effect 2 4 h Duration up to 6 hours Also intended to allow matching of food and insulin Slow onset results in longer and less predictable lag time Must be taken min before meal starts Can be used in a multiple-injection regimen DCPNS 2010

24 Change in serum insulin Time-action patterns: Prandial (mealtime) insulin Normal insulin secretion at mealtime Regular insulin (human) Rapid-acting Insulin analogue Theoretical representation of profiles associated with different insulins Baseline level SC injection Adapted from Brange 1999 Time

25 Intermediate-acting insulin NPH (Neutral Protamine Hagedorn) or isophane insulin Onset 2-4 h Peak 4-10 h Duration h Can be given at bedtime, or before breakfast and dinner, or before breakfast and at bedtime In regimens with rapid- or short-acting insulin DCPNS 2010

26 Long-acting insulin (basal) Onset: around 1 h Peak: peakless Duration: up to 24 h Flat, smooth action over up to 24 h Given usually once-daily, either in the evening or the morning in some cases, given twice-daily Basl insulin is usually added to oral agents (in T2DM) or with rapidor short-acting insulin (basal-bolus) DCPNS 2010

27 Change in serum insulin Time-action patterns Basal insulin Normal insulin secretion at mealtime NPH insulin (human) Basal analogue Insulin Theoretical representation of profiles associated with different insulins Baseline level SC injection Adapted from Brange 1999 Time

28 Premixed insulins Onset: 5-15 min Peak: varies Duration: 10-18h Most premixed insulins contain either NPH and regular insulin, or protamine suspensions of a rapid-acting analogue and the corresponding rapid-acting analogue Insulin glargine and insulin detemir should not be mixed with other insulins Advantage of premixed insulins: convenience and accuracy They are also very stable DCPNS 2010

29 Insulin regimens

30 Insulin administration Introduction No standards for how to best use insulin therapy No consensus on how to best initiate and maintain insulin therapy Each patient is different Insulin regimen must be individualized DCPNS 2010

31 Most common insulin regimens One injection/day: basal therapy Basal plus: Two injections/day Three injections/day Four injections: basal-bolus, intensive insulin therapy or multiple daily injections NB. Some authors also define multiple daily injections as regimens involving at least 3 injections/day DCPNS 2010

32 One injection per day Theory: oral antidiabetics (OADs) help to control daytime BG levels, while bedtime insulin helps reduce nocturnal hepatic glucose production and fasting BG levels Indications: Type 2 diabetes, in combination with OADs (usually) Not indicated for type 1 diabetes Advantages: This can make the transition and acceptance of insulin therapy easier Bedtime insulin may improve fasting BG contro Examples: Intermediate-acting or long-acting insulin analogue before breakfast, before dinner, or at bedtime Rapid-acting or short-acting insulin with intermediate-acting insulin before breakfast or dinner Premixed insulin regular or premixed analogue before breakfast or dinner ADA 2017

33 Insulin effect Once-daily regimen: basal only Human insulin NPH B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

34 Insulin effect Once-daily regimen: basal only Basal insulin analogue Basal analogue B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

35 Two injections a day Indications: Type 2 diabetes. Commonly used in patients with T2DM who are treated with one or more OADs Advantages: Theory: postprandial glucose levels for breakfast and dinner are covered by short- or rapid-acting insulin. Lunch and overnight glucose levels are covered by NPH before breakfast and dinner Two injections daily Disadvantages: NPH before dinner peaks during the night and often does not last over night until breakfast, causing nocturnal hypoglycemia and/or high fasting BG level Lack of flexibility in dealing with noon (midday) glucose levels ADA 2017

36 Insulin effect Twice-daily regimen Human insulin Regular NPH B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

37 Insulin effect Twice-daily regimen NPH + bolus analogue insulin Rapid acting NPH B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

38 Insulin effect Twice-daily regimen Human insulin premix NPH/Regular Mix B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime Berger 1999; Edelman 1995

39 Insulin effect Twice-daily regimen Premix analogue insulin analogue Premix B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017; Goei 2009

40 Three injections a day Indications: Type 2 diabetes Generally, it is not possible to achieve near-normal glycemic levels in type 1 diabetes with three injections a day Advantages: Theory: same as for 2 injections/day except that giving NPH at bedtime rather than at dinner controls BG better over night Reduction in preprandial and postprandial hyperglycemia Better glucose control overnight Disadvantages: Lack of flexibility dealing with noon glucose DCPNS 2010

41 Insulin effect Three injections a day Premix analogue insulin analogue Premix B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017; Goei 2009

42 Four injections a day (basal-bolus) Theory: 2 doses of NPH or 1 dose of long-acting insulin provides basal coverage during the day and overnight. Rapid- or short-acting insulin covers postprandial glucose increase Indications: All adults with type 1 diabetes Individuals with type 2 diabetes who require intensive insulin supplementation (OAA failure) Advantages: Offers flexibility in meal size and timing Allows meal-to-meal adjustments of insulin based on preprandial BG levels, CHO intake and activity Is usually easily understood by patients If using long-acting insulin analogue, it is often easily titrated to address fasting hyperglycemia with minimal risk of nocturnal hypoglycemia DCPNS 2010

43 Insulin effect Basal-bolus Human insulin Regular NPH B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

44 Insulin effect Basal-bolus Human insulins Regular NPH B L D HS B ADA 2017 B: breakfast, L: lunch, D: dinner, HS: bedtime

45 Insulin effect Basal-bolus NPH+ bolus analogue insulin Rapid acting NPH B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

46 Insulin effect Basal-bolus Basal analogue + bolus regular insulin Regular Basal analogue B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

47 Insulin Effect Basal-bolus Basal + bolus analogue insulin Rapid acting Basal analogue B L D HS B B: breakfast, L: lunch, D: dinner, HS: bedtime ADA 2017

48 Selecting a regimen Set glycemic goals Determine total insulin daily dose HbA1c, FPG, PPG Individualize patient BG goals Age, health status, history of significant hypoglycemia, lifestyle and personal goals Determine basal insulin dose Determine prandial insulin dose Determine correction insulin doses (anticipatory, fix-up) Starting dose and schedule of insulin administration is based on clinical assessment and the individual s meal times, physical activity, work schedule and individual preferences. DCPNS 2010

49 Adjusting insulin: what are the targets? Non-pregnant adults HbA1c Pre-meal 2 hours post-meal Target for most people with diabetes IDF global guideline for T2DM *2 7% (53 mmol/mol) <6.5% (48 mmol/mol) 4-7 mmol/l * mg/dl * mmol/l * <180 mg/dl *1 <6.0 mmol/l <110 mg/dl <8.0 mmol/l <145 mg/dl Treatment targets should be individualized, especially for the very young and the elderly Balance with risk of hypoglycemia * CDA 2008; * 1 ADA 2017; * 2 IDF 2015

50 Contents Insulin and its effect on glycemic control Physiology of insulin secretion Insulin pharmacokinetics and regimens Insulin dose adjustment for pregnancy Barriers to insulin therapy

51 Insulin for pregnancy

52 Definition and prevalence of GDM GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy 1 The prevalence of GDM has been steadily increasing with the rise of obesity and type 2 diabetes mellitus 2 Recent estimates suggest that GDM affects up to 15% of pregnant women worldwide 1 GDM, gestational diabetes mellitus

53 Risk factors for GDM Hypertension or pregnancy-related hypertension Polycystic ovarian syndrome History of GDM in previous pregnancy History of spontaneous abortions and unexplained stillbirths Macrosomia Age >25 years GDM Risk Factors Obesity Ethnicity Strong family history of diabetes Persistent glucosuria GDM, gestational diabetes mellitus Gilmartin et al. Rev Obstet Gynecol 2008;1:129 34

54 Perinatal complications associated with GDM Macrosomia Hypertensive disorders in mother Hyperbilirubinaemia in offspring Risk of stillbirth Preterm delivery Perinatal complications Shoulder dystocia Neonatal hypoglycaemia Caesarean delivery GDM, gestational diabetes mellitus Kim C. International Journal of Women s Health 2010;2:

55 TWO STEPS ONE STEP Diagnostic criteria for GDM ADA 1 ACOG 2 NICE 3 If, during a 75-g OGTT, one of the following PG (mmol/l) values is observed: Fasting: h: h: 8.5 Step 1 If, during a 50-g GLT, 1-h PG (mmol/l) 7.8 proceed to: Step 2 Diagnosis is confirmed if, during a 100-g OGTT, at least two of the following PG values (mmol/l) are observed: Fasting: h: h: h: 7.8 Guidelines do not include one-step diagnostic criteria Step 1 If, during a 50-g GLT, PG (mmol/l) > proceed to: Step 2 Diagnosis is confirmed if, during a 100-g OGTT, at least two of the following PG values (mmol/l) are observed: Fasting: 5.3 or h: 10.0 or h: 8.6 or h: 7.8 or 8.0 If, during a 100-g OGTT, PG (mmol/l) exceeds two of the following: Fasting: h: h: h: 7.8 Guidelines do not include two-step diagnostic criteria ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; GDM, gestational diabetes mell itus; GLT, glucose load test; NICE, National Institute for Health and Care Excellence; OGTT, oral glucose tolerance test; PG, plasma glucose 1. ADA. Diabetes Care 2014;37(Suppl. 1):S14 80; 2. ACOG. Practice Bulletin no ; 3. Guideline Development Group. BMJ 2008;336:714 17

56 Glycaemic targets in GDM ADA 1 ACOG 2 NICE 3 Fasting (mmol/l) h postprandial (mmol/l) <7.8 or 2-h postprandial (mmol/l) Glycaemic control should be assessed every 1 2 weeks at the diabetes clinic ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; GMD, gestational diabetes mellitus; NICE, National Institute for Health and Care Excellence; OGGT, oral glucose tolerance test 1. ADA. Diabetes Care 2014;37(Suppl. 1):S14 80; 2. ACOG. Practice Bulletin no ; 3. Guideline Development Group. BMJ 2008;336:714 17

57 Recommendations for the treatment of GDM Most women can manage GDM with lifestyle intervention alone Pharmacotherapy should be initiated if glycaemic control is inadequate ADA 1 Initiation of insulin treatment to be based on measures of maternal glycaemia with or without assessment of foetal growth characteristics ACOG 1 Insulin therapy based on measures of maternal glycaemia based on fasting, 1 h and 2 h Glyburide and metformin may be considered NICE 2 Initiate hypoglycaemic therapy if glucose targets are not met over 1 2 weeks or if ultrasound suggests incipient foetal macrosomia Inadequate information to recommend OADs a Insulin, metformin or glibenclamide ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; GDM, gestational diabetes mellitus; NICE, National Institute for Health and Care Excellence; OAD, oral antidiabetic drug 1. Simmons et al. Diabetes Care 2010;33:34 7; 2. Guideline Development Group. BMJ 2008;336:714 17

58 Contents Insulin and its effect on glycemic control Physiology of insulin secretion Insulin pharmacokinetics and regimens Insulin dose adjustment for pregnancy Barriers to insulin therapy

59 Barriers to insulin therapy

60 Clinical inertia: Patient and physician barriers Lack of appropriate education Excess weight gain Patient perceptions of insulin treatment and outcomes Hypoglycaemia Impaired quality of life Complex regimens Risks in patients with comorbidities Barriers Lack of patient adherence to treatment Resource issues Many barriers to overcoming Clinical Inertia Beliefs about patient competence Financial restrictions Peyrot et al. Diabetes Care 2005;28:2673 9; Elgrably et al. Diabet Med 1991;8:773 7; Wallace and Matthews. Q J Med 2000;93:369 74; Kunt and Snoek. Int J Clin Pract 2009;63(Suppl. 164):6 10

61 Clinical inertia: Stepwise management of type 2 diabetes Biggest clinical hurdle? Biggest clinical hurdle? Combination oral agent/ incretin therapy Oral agent(s) + insulin + + More complex insulin strategies Oral agent + Insulin Initiation and complex regimens are still considered big clinical hurdles to Diet and exercise management of T2DM Adapted from Williams. Lancet 1994;343:95 100

62 Clinical inertia: Perceived burden of treating diabetes Lowest burden Greatest burden Moderate diet Self-monitoring of blood glucose once a day Insulin once a day Combination bedtime insulin and daytime oral agents 3.1 Perceived burden of T2DM management highest among Insulin inexperienced patients Self-monitoring of blood glucose three-times a day Insulin twice a day Insulin twice a day + self-monitoring of blood glucose three-times a day Insulin 3 4 times a day n=1653 Rating with experience Rating without experience Vijan et al. J Gen Intern Med 2005;20:479 82

63 Clinical inertia: Patients remain on multiple OAD therapy too long Patients (%) % Clinical inertia exists despite: % had HbA 1c 9.0% 22% had HbA 1c 10.0% The benefits of timely glycaemic control Guidelines encouraging earlier use of insulin At insulin initiation in SOLVE: Average HbA 1c was 8.9% Delay in Insulin initiation to intensify treatment may affect treatment outcomes HbA 1c (%) at insulin initiation OAD, oral antidiabetic drug Khunti et al. Diabetes Obes Metab 2012;14:654 61

64 Clinical inertia: Patient and physician barriers to insulin initiation Percentage p= Patients not treated with insulin 80 Physicians 70 p= p= p<0.001 Clinicians fear Hypoglycaemia more than patients do. 0 Insulin makes one fat Fear of hypoglycaemia Pain from injection Pain from blood tests Nakar et al. J Diabetes Complications 2007;21:220 6

65 Insulin Therapy Management Questions?