1. Insulin Therapy Melissa Meredith, M.D. 2005

2. History of Insulin 1921: Pancreatic extract lowers blood glucose 1922: Insulin extract first used in humans 1925: Crystalline insulin (Regular) developed 1950/51: NPH/lente insulins developed 1982: Human recombinant insulin developed 1997: First insulin analog (lispro) 2001: Introduction of glargine and aspart insulin analogs 2005 (pending FDA approval): Insulin glulisine and insulin detemir

3. Insulin therapy Control of blood glucose is a balance between insulin therapy, diet and activities The goal is to keep glucose as near normal as possible The type of insulin regimen used depends on many factors, e.g. patient age, compliance, patient schedule, etc.

4. Insulin (µU/mL) Glucose (mg/dL) 150 100 50 0 789101112123456789 AMPM Basal Glucose Time of Day 50 25 0 Basal Insulin Breakfast Lunch Dinner 24-hr Profile Physiologic Insulin Secretion Mimicking Nature With Insulin Therapy Skyler JS. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St. Louis: Mosby- Year Book; 1998:108-116; Galloway JA, Chance RE. Horm Metab Res. 1994;26:591

5. The Basal/Bolus Insulin Concept Basal Insulin –Suppresses glucose production between meals and overnight –50% of daily needs Bolus Insulin (Mealtime or Prandial) –Limits hyperglycemia after meals –Immediate rise and sharp peak at 1 hour –10% to 20% of total daily insulin requirement at each meal

6. Comparison of Human Insulins and Analogues Insulin Onset ofDuration of Preparations Action Peak Action Lispro/Aspart5-15 minutes1-2 hours4-6 hours Human Regular30-60 minutes2-4 hours6-10 hours Human NPH/Lente1-2 hours4-8 hours10-20 hours Human Ultralente2-4 hoursUnpredictable16-20 hours Glargine1-2 hoursFlat~24 hours The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

7. Insulin Action Profiles 0 20 40 60 80 100 120 140 0246810121416 Short acting (Regular) Rapid acting (lispro, aspart) Insulin Level (  U/ml) Hours Intermediate (NPH, Lente) Long acting (glargine)

8. A-chain B-chain 2 Insulin Aspart 2 Asp Insulin Lispro1 1 Lys Pro Gly 1 5 1 5 10 15 20 S S 15 10 Gly Gln Ile Gln Cys Phe His Leu S S S S Phe 25 30 Pro Lys Thr Ala Fast-acting analogs Rapid-Acting Insulin Analogs Insulin Lispro and Insulin Aspart Human Insulin Insulin aspart Aspartate at position B28 instead of proline Insulin lispro Positions of proline and lysine reversed at B28 and B29 Humalog ® [package insert]. Indianapolis, IN: Eli Lilly and Company; 2002 NovoLog ® [package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc;2002

10. Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Lispro Regular Human 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Aspart Regular Human Plasma Insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.

12. Comparison of bolus insulins Regular insulin –Requires administration 20 to 40 minutes prior to meal –Mismatch with postprandial hyperglycemic peak –Potential for late postprandial and nocturnal hypoglycemia Rapid-acting (lispro, aspart, glulisine) –Convenient administration at/after meal –Matches postprandial glycemic peak –Reduced late postprandial hypoglycemia –Frequent late postprandial hyperglycemia –Risk for early hyopglycemia

13. Structure Insulin Glargine: 21 A -Gly-30 B a-L-Arg-30 B b-L-Arg-insulin Metabolites: M1-21 A -Gly-insulin M2-21 A -Gly-des-30 B -Thr-insulin pH=4; Clear solution; Do not mix15101520Asn 151015202530 Arg SUBSTITUTION EXTENSION Gly A-CHAIN B-CHAIN

14. Insulin glargine clamp study: activity profile in T1DM 30 (Hourly Mean Values) Time (h) after sc Injection =End of observation period 0 1 2 3 4 5 6 0 Glucose Utilization Rate (mg/kg/min) Insulin Glargine NPH insulin 20 10 Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015

15. Comparison of basal insulins NPH/lente –Pronounced peaks –Less than 24-hour duration of action-requires BID dosing –Increased risk of hypoglycemia if meal delayed –Increased nocturnal hypoglycemia Glargine –Usually once-a-day dosing –Flat peakless profile causes less hypoglycemia, esp. nocturnal –Risk of hypoglycemia when used as the only insulin

16. Insulin regimens Split mixed (N/R BID) –2 injections/day –Inflexible- need to eat meals at consistent times with snacks to avoid hypoglycemia –MORE hypoglycemia with this regimen when control is “tight” –Does not allow for adjustments of insulin through the day

17. 4:0016:0020:0024:004:00 BreakfastLunchDinner Insulin Action 8:00 12:008:00 Time REG NPH/Lente Twice-Daily Split-Mixed Regimen Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

18. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time NPH/Lente Lispro Lispro Lispro Aspart Aspart Aspart or Basal/Bolus Insulin Absorption Pattern With Rapid- Acting Insulin Analogs Insulin Action Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342 NPH/Lente

19. Intensive insulin regimens Combine a basal insulin with injections of rapid-acting insulin before each meal Typically 3-4 injections/day or insulin pump therapy Requires more patient education and motivation

20. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine Basal/Bolus Treatment Program With Rapid- and Long-Acting Analogs Insulin Action Adapted with permission from Leahy JL. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker Inc.; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342 Aspart or Lispro

21. Intensive Therapy of Diabetes More flexible: timing and amount of meals Allows patient to be in control, instead of insulin controlling lifestyle Allows for frequent corrections/adjustments through the day Requires multiple daily self-monitoring of BG to get best results When used correctly will provide the best A1c with less hypoglycemia!

22. Drawbacks of intensive insulin regimens Requires frequent monitoring of glucose Multiple daily injections of insulin Requires intensive patient education/on- going support Newer insulin analogues are more expensive

23. Other insulins and devices Pre-mixed insulins –70/30 (N/R), 50/50 (N/R), 75/25 (N/Lispro) or 70/30 (N/Aspart) –All available in pens (except 50/50) –Best used in type 2 patients NPH, Regular, Aspart, Lispro, and glargine are also available in pens

24. Insulin nomenclature - don’t be confused! Humulin insulin is Lilly brand of human insulin- can be Regular, NPH, 70/30, or 50/50 Humalog is insulin lispro Humalog mix is 75/25 (NPL/lispro) Novolin is Novo-Nordisk brand of human insulin- Regular, NPH, or 70/30 Novolog is insulin aspart NovoMix is 70/30 (NPA/aspart) Lantus is insulin glargine Apidra is insulin glulisine; and soon available will be insulin detemir (Levemir)

25. Insulin pumps Insulin pumps constantly infuse insulin subcutaneously Program amount of insulin to infuse during basal hours and can deliver a bolus of insulin before a meal Typically use aspart or lispro insulin in pumps, which makes the pumps very responsive Considered the “gold standard” of treatment of type 1 diabetes

26. What exactly is an insulin pump? First Insulin Pump (early 1970s)!!!

27. Insulin pumps A small computerized device that delivers insulin continuously throughout the day. AnimasDisetronic Minimed

28. Insulin pumps-benefits The most physiological way to deliver insulin The most flexible way to deliver insulin –Timing of meals –Exercise –Sick-days Can attain excellent glucose control with less hypoglycemia

29. Insulin pumps-basal rate Pumps now allow for up to 48 basal rates per day Up to 3 basal “patterns” Can program to match individual patient needs, e.g. strong dawn phenomenon Have temporary basal rates- e.g. use for exercise

30. Insulin pumps- bolus 3 different types of bolus –Standard: bolus delivered immediately –Dual wave: can give certain percent immediately and rest over time (used for high carb, high fat meals) –Square wave: bolus delivered over a certain time, e.g. 3 hours: used for certain types of meals, gastroparesis

31. Insulin pump features Program in carb ratio and insulin sensitivity factor Enter blood glucose (or beam data from BD Logic meter) and carb amount and pump will automatically calculate bolus dose Pump will calculate correction dose integrating data on glucose and insulin-on-board Medtronic pumps can download to Website for analysis of data and data is available to provider who is linked to site

32. Insulin pumps-disadvantages Cost ($5500 with $1-2000/yr. for supplies) Skin problems –allergies/reactions to tape –infection at infusion site Occasional pump malfunction Lack of depot insulin- can rapidly develop DKA if infusion is disrupted

33. Which regimen to use? Depends on patient characteristics –daily schedule, timing of meals, exercise –patient willingness/ability to monitor, take multiple injections Current pattern of high and low blood glucoses What is goal of therapy?

34. Normal Type 2 Diabetes Glucose mg/dL Insulin 100 200 300 400 0600100018001400020022000600 Time of Day BLD 0600100018001400020022000600 Time of Day 20 40 60 80 100 120 BLD U/mL Insulin and Glucose Patterns: Normal and Type 2 Diabetes Adapted with permission from Polonsky KS et al. N Engl J Med. 1988;318:1231 B=breakfast; L=lunch; D=dinner

35. Correcting Fasting Hyperglycemia… 100 200 300 Normal A1C 5%–6% PG (mg/dL) 0800120018000800 Time of Day Uncontrolled A1C ~9% A1C ~6% Is Usually the First Task!! …then, Tackle Postprandial Hyperglycemia if A1C still >7%! “Controlled” A1C <7% Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1

36. Initiating Basal Insulin Therapy Continue oral agent(s) at same dosage (eventually reduce) Add single bedtime insulin dose (10 U) –Glargine insulin –NPH insulin –(70/30 before evening meal is also an option) Adjust dose by fasting self-monitored BG with goal of 100-120 Titrate insulin dose weekly as needed: –Increase 2 U if FBG 121–140 mg/dL –Increase 4 U if FBG 141–160 mg/dL –Increase 6 U if FBG 161–180 mg/dL –Increase 8 U if FBG >180 mg/dL

37. Advancing Basal/Bolus Insulin Indicated when FBG acceptable but –HbA 1c >7% and/or –SMBG before dinner >180 mg/dL Insulin options –To bedtime NPH, add morning NPH and mealtime Regular or Lispro/aspart –To suppertime 70/30, add morning 70/30 –To Glargine, add mealtime Regular or Lispro/aspart Oral agent options –Usually stop sulfonylurea –Continue metformin for weight control? –Continue glitazone for glycemic stability?

38. Total insulin dose is based on weight (0.5 units/kg in DM 1 patients and 1 unit/kg in DM 2) If adding one shot of insulin to oral meds, use 0.15 units/kg as starting dose Base supplemental insulin dose on the “1700” rule (1700/total daily insulin= effect of 1 unit of insulin to lower blood glucose) Use carbohydrate counting to estimate bolus dose Patient education is essential- PLEASE refer patients to a diabetes educator! Helpful hints to using insulin