Insulin Therapy Melissa Meredith, M.D. 2005

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

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.

Mimicking Nature With Insulin Therapy Physiologic Insulin Secretion 24-hr Profile 50 Insulin (µU/mL) 25 Basal Insulin Breakfast Lunch Dinner 150 Glucose (mg/dL) 100 50 Basal Glucose 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM Time of Day PM 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

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 Slide 6-20 MIMICKING NATURE WITH INSULIN THERAPY The Basal/Bolus Insulin Concept Insulin is capable of restoring glycemia to nearly normal in most patients with type 2 diabetes. The basal/bolus insulin concept attempts to mimic, with insulin therapy, the patterns that normally control glucose in persons without diabetes. Basal insulin suppresses glucose production so that the levels remain nearly constant between meals and overnight. Basal insulin meets about half of the patient’s daily need for insulin and may be sufficient when considerable endogenous insulin remains. Bolus insulin (10% to 20% of the total daily insulin requirement given at each meal) limits hyperglycemia after meals. This tends to smooth the peaks of glucose that occur in response to these meals. Frequent glucose monitoring aids in determining the candidates for basal or mealtime regimens. Ideally, each component of insulin replacement therapy should come from a different type of insulin with a specific profile to fit the patient’s needs. Practical methods to accomplish this basal/bolus strategy will be illustrated later in this module. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:308-334; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

Comparison of Human Insulins and Analogues Insulin Onset of Duration of Preparations Action Peak Action Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours Human Regular 30-60 minutes 2-4 hours 6-10 hours Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours Human Ultralente 2-4 hours Unpredictable 16-20 hours Glargine 1-2 hours Flat ~24 hours Slide 6-22 INSULIN TACTICS Comparison of Human Insulins and Analogues Insulin has been used therapeutically for more than 70 years. In general, human insulin, synthesized by genetically altered microorganisms, has a more rapid onset of action and a shorter duration of action than previous preparations derived from animal pancreas. Regular human insulin has an onset of action ranging from about 30 to 60 minutes with peak concentrations achieved at between 2 and 4 hours. The “intermediate-acting” insulins, NPH and lente, have gradual onset and peak effects usually between 4 and 8 hours, and a total duration of 10 to 20 hours. Human ultralente insulin is somewhat longer-acting, but still usually falls short of a 24-hour effect. Short-acting insulin analogues (lispro and aspart) have very desirable action profiles at mealtimes because they have an onset of action ranging from 5 to 15 minutes; the peak of action occurs 1 hour after injection, and the insulin effect practically vanishes 4 hours after administration. Insulin glargine is a long- acting analogue insulin that has essentially no peak. Glargine is absorbed within 1 to 2 hours and has a plasma concentration about 50% lower than that observed with NPH, but twice the duration of action. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151- 1167; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:308-334; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St Louis, Mo: Mosby-Year Book Inc; 1998:108-116; Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13:676-685. 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.

Insulin Action Profiles 140 Rapid acting (lispro, aspart) 120 100 Insulin Level (U/ml) Short acting (Regular) 80 Intermediate (NPH, Lente) 60 Long acting (glargine) 40 20 2 4 6 8 10 12 14 16 Hours

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

Plasma Insulin (pmol/L) Plasma Insulin (pmol/L) Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles 400 500 Aspart Lispro 450 350 400 300 350 250 300 250 Plasma Insulin (pmol/L) 200 Plasma Insulin (pmol/L) Regular 200 150 Human 150 100 Regular 100 Human Slide 6-28 INSULIN TACTICS Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles This figure shows two separate experiments displaying the plasma insulin profiles after injection of insulin lispro and insulin aspart in comparison to that of human regular insulin. The experiment with lispro, shown on the left, included 10 patients with type 1 diabetes, and the experiment with aspart shows findings from 18 healthy subjects. Both of these analogues have very rapid onset of action, which allows them to be taken immediately before meals. Both reach a peak about 1 hour after injection, with a decline in baseline levels in 4 hours, closely matching normal insulin patterns. The delayed and extended profile of human regular insulin is seen in both studies, with significant elevations above baseline persisting well beyond 4 hours after injection. Heinemann L, Heise T, Wahl LC, et al. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro (B29)] human insulin. Diabet Med. 1996;13:625-629; Mudaliar SR, Strange P, Lindberg FA, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin. Diabetes Care. 1999;22:1501-1506. 50 50 30 60 90 120 150 180 210 240 50 100 150 200 250 300 Time (min) Time (min) Meal SC injection Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.

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 Slide 6-26 INSULIN TACTICS Limitations of Human Regular Insulin The preceding slides illustrate some of the limitations of human regular insulin. If it is given immediately prior to a meal, its onset of action is too slow to match the normal insulin peak and the blood glucose response to the meal is much greater than in a person without diabetes. To improve the relationship between the profile of action of regular insulin and the needs accompanying the meal, patients are routinely advised to administer their injection 20 to 40 minutes prior to the meal. This is inconvenient, is infrequently achieved, and poses the risk of premeal hypoglycemia if the meal is inadvertently delayed. Furthermore, the duration of action of regular insulin is much longer than the normal insulin peak following meals, typically at least 6 hours and up to 12 hours when large doses are injected. This persistence of high insulin levels leads to risk of hypoglycemia, which is often countered by between- meal snacks that foster weight gain in type 2 diabetes patients.

Structure Insulin Glargine: 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin A-CHAIN Gly SUBSTITUTION 1 5 10 15 20 Asn 1 5 10 15 20 25 30 B-CHAIN EXTENSION Arg Insulin Glargine Structure Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is an insulin analog produced by recombinant DNA technology. Insulin glargine has the same intrinsic activity as regular human insulin. Changes in amino acid content shift the isoelectric point, reducing the aqueous solubility of insulin glargine at physiological pH; and stabilizing the hexamer, delaying its dissociation into monomers. Consequently, insulin glargine has a delayed and prolonged absorption from the injection site following subcutaneous administration. Insulin Glargine: 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin Metabolites: M1-21A-Gly-insulin M2-21A-Gly-des-30B-Thr-insulin pH=4; Clear solution; Do not mix

Insulin glargine clamp study: activity profile in T1DM 30 (Hourly Mean Values) Time (h) after sc Injection =End of observation period 1 2 3 4 5 6 Glucose Utilization Rate (mg/kg/min) Insulin Glargine NPH insulin 20 10 PK/PD of Insulin Glargine Glycemic Clamp Study in T1DM In contrast to NPH, insulin glargine had a peakless, long-lasting concentration/action profile closely mimicking a “square wave” shape. The investigators concluded that insulin glargine has more reproducible pharmacokinetics than NPH insulin. Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015 Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015

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 Slide 6-30 THE ROLE OF INSULIN IN TYPE 2 DIABETES Limitations of Human NPH, Lente, and Ultralente Clinical use of insulin lispro, a better mealtime insulin than human regular, has directed attention to the properties of extended-release human insulins that have been used to provide basal insulin replacement. Human NPH, lente, and ultralente insulin all have mean durations of action of less than 24 hours, precluding them from providing adequate basal insulin replacement for many patients. All three, but especially NPH and lente, have pronounced peaks of action. Ultralente is thought to have substantial day-to-day variation of action. These limitations cause variations of glucose levels and unpredictable hypoglycemia, which are the leading factors limiting glycemic control at the present time. Recurrent hypoglycemia with insulin therapy of type 2 diabetes may be one factor in weight gain.

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

Twice-Daily Split-Mixed Regimen Breakfast Lunch Dinner Insulin Action REG NPH/ Lente NPH/Lente 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time 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

Basal/Bolus Insulin Absorption Pattern With Rapid-Acting Insulin Analogs Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro Insulin Action NPH/Lente NPH/Lente 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time 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

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

Basal/Bolus Treatment Program With Rapid- and Long-Acting Analogs Breakfast Lunch Dinner Aspart or Lispro Insulin Action Glargine 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time 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

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!

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

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

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)

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

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

Insulin pumps A small computerized device that delivers insulin continuously throughout the day. Animas Disetronic Minimed Show both pumps and various infusion sets.

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

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

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

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

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

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?

Insulin and Glucose Patterns: Normal and Type 2 Diabetes 100 200 300 400 0600 1000 1800 1400 0200 2200 Time of Day B L D 20 40 60 80 120 mU/mL mg/dL B=breakfast; L=lunch; D=dinner Adapted with permission from Polonsky KS et al. N Engl J Med. 1988;318:1231

Correcting Fasting Hyperglycemia… Is Usually the First Task!! 300 Uncontrolled A1C ~9% “Controlled” A1C <7% 200 PG (mg/dL) A1C ~6% 100 Normal A1C 5%–6% 0800 1200 1800 0800 Time of Day …then, Tackle Postprandial Hyperglycemia if A1C still >7%! Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1

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

Advancing Basal/Bolus Insulin Indicated when FBG acceptable but HbA1c >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?

Helpful hints to using insulin 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!