Starting Insulin Ronnie Aronson MD, FRCPC, FACE Executive Director, LMC Endocrinology Centres Disclosures Scientific Consultant Abbott, AstraZeneca, GSK, Merck, Sanofi-Aventis, Janssen- Ortho, Servier Speakers Bureau Abbott, AstraZeneca, Eli Lilly, GSK, Merck, Pfizer, Sanofi- Aventis, Servier Clinical Research Abbott, Amgen, AstraZeneca, Eli Lilly, GSK, Merck, Novartis, Janssen-Ortho, Pfizer, Roche, Sanofi-Aventis, Schering Ownership none Starting Insulin Oral Hypoglycemic Agent (OHA) failure objections to insulin patient physician moving on to basal analogue how why moving on to mixed analogues OD/BID/TID 1
Clinical Pearls setting practice targets consistent with the recommended CDA targets understanding the benefits of tight glycemic control gaining insight into the common features of Psychological Insulin Resistance Recognizing physician barriers to reaching targets with insulin Gaining comfort with Basal insulin prescribing the 1 st step Recognizing the opportunities to use a mixed analogue insulin Hans K. 56-year-old male Diabetes since 1994 DEC well-educated, active, very diet-conscious weight 87 kg, BMI 28.4, waist 98 cm metformin 1gm 2, Actos 45mg 1, Diamicron MR 120mg 1 Breakfast Lunch Dinner Bedtime 9.5 7.5 7.1 7.0 A1c 8.2 Recommended Targets for Glycemic Control Target A1C (%) Fasting/ac-meal (mmol/l) 2-hr pc-meal (mmol/l) Target most patients 7.0 4.0 7.0 5.0 10.0 Normal Range for patients in whom it can be achieved safely 6.0 4.0 6.0 5.0 8.0 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S19 2003 2
Lessons from UKPDS: Lower A1c = Fewer Complications Every 1% reduction in HbA 1c Risk reduction* Deaths from diabetes 21% 1% Myocardial infarctions Microvascular complications 14% 37% Peripheral vascular disorders 43% Stratton IM et al. UKPDS 35. BMJ. 2000;321:405 412. Psychological Insulin Resistance 1. Perceived loss of control over one s life 2. Lack of self-efficacy / confidence 3. Sense of personal failure 4. Implications to Disease Severity 5. Perceived lack of benefit adapted from Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. 1. Perceived Loss of Control over One s Life Once I start insulin, I ll never be able to stop. Provide a sense of control regarding insulin Present it as a temporary experiment: Try it for a month and see how you feel. Start with a therapy that minimizes lifestyle restrictions Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. 3
2. Lack of Self-Efficacy/Confidence Taking insulin is too complicated. Show patients how simple insulin is to use Build patient confidence Recognize patient abilities Empower patient Keep it simple Demonstrate: have patient inject in office Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. Novolin Pen4 (Novo Nordisk) HumaPen Luxura (Eli Lilly) 4
Supplies 3. Sense of Personal Failure I did this to myself. I should have kept going to the gym. Stress that the need for insulin is a function of the underlying disease, not an indication of failure at proper diabetes self-care Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. UKPDS Progression of β-cell Loss 100 75 β-cell function (%) 50 25 0-12 -10-6 -2 0 2 6 10 14 Diagnosis Years from diagnosis Lebovitz H. Diabetes Rev 1999;7:139 153. Holman RR. Diabetes Res Clin Pract 1998;40(suppl):S21-S25. 5
Progression of Hyperglycemia (A1c) 9 UKPDS 8.0 ADOPT A1C (%) 8 7 % 7.5 7.0 6.5 6 0 0 2 4 6 8 years Glyburide Chlorpropamide Metformin 6.0 0 0 1 2 3 4 5 years Glyburide Rosiglitazone Metformin 4. Implications to Disease Severity My uncle went on insulin right before he lost his leg. Frame the insulin message properly Emphasize that Type 2 diabetes is a progressive disease and that requiring insulin is a natural part of this progression Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. 5. Perceived Lack of Benefit Insulin won t help me. Pass along the good news Review positive benefits Explain that insulin is the best way to ensure continued good health and diabetes control Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147 50. 6
Physician Barriers to Initiating Insulin relying on lifestyle - giving diet/weight loss a last chance concerns over hypoglycemia potential for weight gain lack of resources to initiate insulin and educate patient unwilling to convince reluctant patient Potential impact on patient s employment 1. Wallace, TM., Q.J. Med. 2000; 93(6): 369-74 2. Polonsky, WH., Clinical Diabetes, 2004; 22(3): 147-50 3. Home, PD., Pract. Diab. Int., 2003; 20(2): 63-71 Type 2 Diabetes Insulin Options Basal NPH OD (or BID) Glargine OD (or BID) Detemir OD (or BID) Premixed (BID or TID) Novolin or Humulin 30/70 NovoMix30 Humalog Mix 25 Others Multiple daily injections (meal-time + basal) Initiating Insulin Consider adding bedtime intermediate-acting insulin, longacting insulin, or extended long-acting insulin analogue to daytime oral antihyperglycemic agents. Better glycemic control achieved with less insulin Less weight gain, especially when metformin continued, compared to insulin alone Decreased risk of hypoglycemia Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2003;27(Suppl 2):S1 152. 7
Normal Pancreatic Function Basal: Beta cells secrete small amounts of insulin throughout the day. Bolus: At mealtime, insulin is rapidly released in response to food. Bolus Insulin Basal Insulin Meal Meal Meal Time-Action profiles of bolus & basal insulins Plasma Insulin levels mu/l 80 60 40 20 aspart/lispro 3-5 hours regular 5-8 hours NPH ~14 hours Diagrammatic representation Action curves are approximations taken from different data sources. Actual patient response will vary detemir/glargine ~24 hours 0 12 24 Hours Achieving Target Levels with Insulin A1C target 7% (or 6%): Fix the Fasting glucose First (FFF) Start with one initial injection (basal) As beta cells fail over time, basal insulin plus oral agent may no longer keep glucose levels optimal Mealtime insulin may be added later - started at all meals, or possibly just at larger meals such as dinner 8
Example of an Insulin Initiation Dosage Schedule Once-daily dose of basal insulin Choices: NPH Detemir Glargine Recommended starting dose 10 IU/day Increase insulin dose by 1 IU/day until FPG target is achieved Gerstein HC. INSIGHT Study. Diabet Med 2006;23:736-42. Self-Titration of Insulin Insulin Dosage Instructions Your target fasting blood sugar level is 6 mmol/l You will inject 10 units of insulin each evening You will continue to increase by 1 unit every day until your blood sugar level is 6.5 mmol/l before breakfast Do not increase your insulin when your fasting blood sugar is 4.5 mmol/l NB - INSIGHT and TREAT to TARGET studies used an FPG target of <5.5 Alternate Algorithm Treat to Target Trial Start dose 10 units - forced weekly insulin titration schedule to target FBG 5.6 mmol/l Mean of Self-Monitored FPG values from preceding 2 days Increase of Insulin Dosage Units/Day 10 mmol/l 7.8-10.0 mmol/l 6.7-7.8 mmol/l 5.6-6.7 mmol/l Exceptions: No increase in dosage if FPG 4 mmol/l at any time in the preceding week Decreases of 2-4 units/day/adjustment if severe hypoglycemia requiring assistance or FPG 3.1 mmol/l documented in the preceding week Adapted from Riddle MC, et al. Diabetes Care 2003;26(11):3080 3086. 8 6 4 2 9
Oral Hypoglycemic Agent Instructions Metformin continue at 500mg BID 1000mg BID ~30% dose-sparing effect consider renal function for dosing Sulfonylureas (glyburide, gliclazide, glimepiride) also ~30% dose-sparing increased risk of hypoglycemia TZD s (rosiglitazone, pioglitazone) discontinue ~30 40% dose-sparing not an indicated usage in Canada increased risk of CHF Insulin titration - scenario 1 Breakfast Lunch Supper Before After Before After Before After Bedtime Dose Sunday 9.7 7.8 7.5 22 Monday 9.4 7.6 6.9 23 Tuesday 9.0 8.9 6.5 7.8 24 Wednesday 9.1 8.5 7.5 25 Thursday 8.8 OHAs Metformin 1000 mg BID Glyburide 10 mg BID 10
Insulin titration - scenario 2 Breakfast Lunch Supper Before After Before After Before After Bedtime Dose Sunday 7.5 6.2 5.0 7.2 22 Monday 7.5 5.9 4.2 23 Tuesday 7.4 4.3 6.7 24 Wednesday 7.2 5.0 4.1 6.5 25 Thursday 7.1 OHAs Metformin 1000 mg BID Glyburide 10 mg BID Insulin Schedule Review 3 Breakfast Lunch Supper Before After Before After Before After Bedtime Dose Sunday 6.5 6.2 5.0 7.2 32 Monday 5.9 5.9 5.7 6.9 33 Tuesday 5.7 5.5 6.0 6.7 33 Wednesday 5.8 5.8 6.2 6.5 33 Thursday 5.5 5.1 OHAs Metformin 1000 mg BID Morning vs Bedtime Insulin - glargine Baseline A1c: 9.1±1.0 0 Morning Glargine Bedtime Glargine Bedtime NPH A1C Change From Baseline (%) -1-2 1.24 0.96 0.84 P=0.008 P<0.001 Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952 11
Morning vs Bedtime Insulin - detemir Baseline A1c: 9.1±1.0 0 Morning Detemir Bedtime Detemir Bedtime NPH A1C Change From Baseline (%) -1-2 1.6 1.7 1.5 Philis-Tsimikas et al. Clinical Therapeutics. 28:10, 2006, 1569-81. Which Basal analogue? Variability and profile - NPH 12
Variability and profile - NPH & glargine Variability and profile NPH, glargine & detemir Response Variability CV (%) (Glucose infusion rate AUC0 24) 80% 70% 60% 50% 40% 30% 20% 10% 0% 68% NPH insulin p < 0.001 48% p < 0.001 Insulin glargine 27% Insulin detemir NPH insulin Insulin glargine Insulin detemir Heise T et al. Diabetes 2004;53:1614-20 13
Nocturnal hypoglycaemia Events per subject per month 1.5 1.0 0.5 0 Insulin detemir NPH insulin Overall p = 0.016 1 2 3 4 5 6 7 8 9 10 11 12 Months I. De Leeuw et al. Diabetes Obes Metab 2005;7:73-82 Nocturnal Hypoglycemia analogue basal comparison Nocturnal Hypoglycemia 7 6 5 4 3 2 1 Risk reduction = 32% 4.3 6.6 detemir glargine p<0.05 0 Pieber T et al. Diabetologia 2005;48(Suppl. 1):A92 Weight gain in type 2 diabetes: UKPDS data 10.0 Conventional group Intensive group Change in weight (kg) 7.5 5.0 2.5 0 0 3 6 9 12 15 Years from randomisation UKPDS Group (33). Lancet 1998;352:837 53. 14
Weight change in Insulin therapy studies - treat-to-target Basal comparisons 86 85 Weight (kg) 84 83 82 81 Insulin detemir NPH insulin 80-2 1 3 5 7 9 11 13 15 17 19 21 23 Weeks K. Hermansen et al. Diabetologia 2004;47(Suppl. 1):A273 Weight change 3 2.5 *p < 0.05, insulin detemir vs NPH insulin Insulin detemir NPH insulin Weight change (kg) 2 1.5 1 0.5 0-0.5-1 * * * * * * * * * * * Standl 2004 Vague 2003 De Leeuw 2005 Pieber 2005 Pieber 2005 # Home 2004 ## Home 2004 Russell- Jones 2004 Hermansen 2004 Studies in type 2 diabetes Rašlová 2004 Haak 2005 * ### Hermansen 2006 Basal Analogue benefits Less likely to go low, especially at night Reduced fear of going low, both for patients and their families Less need for snacking less weight gain 15
Switching existing NPH patients NPH OD Insulin Detemir or Insulin Glargine: Switch unit for unit and give once daily NPH BID Insulin Detemir or Insulin Glargine: use~80% of total NPH dose, given once or twice daily Levemir (insulin detemir [rdna origin] injection) prescribing information. Novo Nordisk, Inc. 2005. Lantus (insulin glargine) [rdna origin] injection) prescribing information. Sanofi-aventis, 2006. Hans K. 53-year-old male Diabetes since 1994 well-educated, active weight 87 kg, BMI 28.4, waist 98 cm metformin 1gm 2, Actos 45mg 1, Diamicron MR 120mg 1 Pre-meal and 2 hr post-meal glucose (mmol/l) Breakfast Lunch Dinner Bedtime 9.5 10.2 10.4 12.6 11.6 13.5 14.0 A1c 9.8, 10.2 BID NPH and Regular Insulin Therapy - Compared to Normal Physiology Basal needs: NPH Bolus needs: Regular Meal Meal Meal Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500 16
Multiple Daily Injections (MDI) Strive to Mimic Normal Physiology MDI insulin therapy addresses: Basal needs: Glargine, Detemir Bolus needs: Lispro, Aspart Meal Meal Meal Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500 Multiple Daily Injections (MDI) Strive to Mimic Normal Physiology but 4 injections MDI insulin daily therapy addresses: Basal needs: Glargine, Detemir Bolus needs: Lispro, Aspart Meal Meal Meal Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500 A Simpler Approach: Pre-Mixed Analogues Breakfast Lunch Dinner Normal insulin secretion Biphasic insulin aspart Insulin action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Nathan DM. N Engl J Med 2002;347:1342 17
Type 2 Diabetes Insulin Options Basal NPH QHS or BID Glargine QHS or at any time of the day Detemir QHS or BID Premixed Premixed BID or TID Others Multiple daily injections (meal-time + basal) Type 2 Diabetes Insulin Options Premixed Premixed BID or TID 30/70 insulin (novolin or humulin) Biphasic Insulin Aspart 30 (BIAsp 30; NovoMix 30 ) insulin lispro protamine (Humalog Mix25 ) BIAsp 30 (NovoMix30 ) Glucose Levels in Type 2 Diabetes * Serum glucose (mg/dl) 300 250 200 150 * Aspart Mix 30/70 30/70 Premix * 0 6:00 PM 10:00 PM 8:00 AM 1:00 PM 6:00 PM Dinner Breakfast Lunch *Glucose excursions 0-4 h, P<0.05. McSorley. Clin Ther. 2002;24(4):530-539. 18
Humalog Mix25 vs 30/70: 2-hr Post-meal BG lower at Breakfast & Dinner Mean ± SEM BG (mmol/l) 11 10 9 8 7 6 * Fasting Breakfast 2h pp Pre- Lunch Mean A1C 8.1 vs. 7.8, p=ns N=89 type 2 DM pts. Lunch 2h pp Pre- Dinner * Dinner 2h pp Lispro Mix25 Human Insulin Mixture 30/70 *p<0.05 Bedtime 3 AM Data derived from Roach P et al. Diabetes Care 1999;22(8):1258-1261. Humalog Mix25 vs 30/70: Hypoglycemia Episodes per Patient 2.0 1.5 1.0 0.5 0.0 0.7 0.17 Lispro Mix25 p=0.037 1.4 0.34 Human Insulin Mixture 30/70 Roach P, et al. Clinical Therapeutics, 1999; 3:523-34. Starting or Switching BID premixed insulin Dose if using insulin - total daily dose (TDD) if new - Calculate 0.5 units/kg Frequency ½ ac-breakfast & ½ ac-supper or 2/3 of total ac-breakfast & 1/3 ac-supper. D/C secretagogues 1. Hirsch IB, et al. Clinical Diabetes 2005; 23(2):78-86 2. Can J Diabetes 2003;27(suppl 2):S135 19
Hans K. 53-year-old male Diabetes since 1994 well-educated, active weight 87 kg, BMI 28.4, waist 98 cm metformin 1gm 2, NovoMix30 30 U qam; 15 U qpm Pre-meal and 2 hr post-meal glucose (mmol/l) Breakfast Lunch Dinner Bedtime 7.1 8.2 7.8 11.6 10.6 7.5 6.8 NovoMix30 1-2-3 Study design Phase 1 100 subjects QD Pre-dinner x 16 wks Start with 12 U at dinner A1c 6.5% End of study If A1c > 6.5%, go to BID, d/c secretagogues Phase 2 68 subjects BID Pre-breakfast & dinner x 16 wks Add 3 U at breakfast if FPG 6.1 Add 6 U at breakfast if FPG > 6.1 A1c 6.5% End of study Phase 3 25 subjects TID TID x 16 wks Add 3 U at lunch If A1c > 6.5%, go to TID End of study Titrate according to schedule every 3 days Garber AJ, et al. Diabetes Obes Metab 2006;8:58 NovoMix30 1-2-3 Study Titration Algorithm Blood glucose (mmol/l) <4.4 4.4 6.1 6.2 7.8 7.8 10 >10 Dose change (U) -3 No change +3 +6 +9 20
NovoMix30 1-2-3 Study Conclusions 1. can be initiated OD and intensified to BID or TID 2. with OD dosing, 41% of patients achieved A1c < 7.0% 3. with progression to BID dosing, 70% of patients achieved A1c < 7.0% 4. with progression to TID dosing, 77% of patients achieved A1c < 7.0% 5. no significant relationship between number of injections & frequency of hypoglycemia Garber AJ, et al. Diabetes Obes Metab 2006;8:58 Starting Insulin OHA failure objections to insulin patient physician moving on to basal analogue how why moving on to mixed analogues OD/BID/TID Clinical Pearls setting practice targets consistent with CDA targets anticipating and being prepared for the common features of Psychological Insulin Resistance Recognizing our own physician barriers to insulin therapy Gaining comfort with Basal insulin prescribing as a 1 st step Recognizing the opportunities to use a mixed analogue insulin OD, BID, TID for ease of use 21
Resource Slides Hypoglycemia Hypoglycemia Causes: Increased physical activity Not eating on time Eating less than normal Taking too much medication/insulin The effects of drinking alcohol 22
Hypoglycemia Treatment Check your blood glucose right away. If you do not have your meter with you, but are experiencing symptoms, you are always safer to treat! If your blood sugar is < 4 mmol/l eat or drink 15 g of a fast acting carbohydrate such as: 3 glucose tablets, 1/2 cup of juice (half a juice box), 3 packets of sugar dissolved in water, 6 Life Savers (chew them) Wait 15 minutes, then check your blood sugar again. If your blood sugar is still < 4mmol/L, treat again. If your next meal is more than one hour a way eat a snack (15g of carbohydrates and a protein source ex: 1 oz of cheese and 7 soda crackers). 1. Pick Your Site The ideal sites for injection provide the best absorption while avoiding overuse of the same patch of skin from the lower rib edge to the upper front hip crest; and from the seam in the shirt on each side Move over by 1 cm in a straight line for each injection; 20 30 shots can be given in one straight line Then move 1 cm lower and start the next line of shots across your abdomen It may be months before having to re-use the same skin site 2. Prime Your Pen Safety test Should be done before each injection and after changing cartridges Set for 2 4 units, hold pen or needle pointing upward and press dosage button until it is engaged Drops of insulin should appear from the top of the needle 23
3. Inject Pinch an inch of skin between thumb and forefinger of one hand Inject at a 90 o angle into the loose tissue under the skin at your chosen site Push plunger down completely Leave needle in to a count of 10 to ensure proper absorption Pull out needle Dispense in sharps container Insulin Storage Refrigerate unused insulin until use Insulin should only be used at room temperature Insulin can be kept for up to 28 days in the pen at room temperature (up to 42 days for insulin detemir) Keep insulin away from direct sunlight and high temperatures (i.e. don t leave in a car in the summer) 24