Demystifying Insulin The Science and The Art Davida F. Kruger, MSN,APN-BC,BC-ADM Certified Nurse Practitioner Division of Endocrinology, Diabetes, Bone and Mineral Disorders Henry Ford Health System Detroit, Michigan What I plan to do in this presentation is share our experiences in developing a different model of diabetes care delivery, using diabetes educators as care providers to a population of pts w/ poorly controlled type 2 diabetes. This is not necessarily a new or unique process, as we will discover during the presentation. This model gave diabetes educators the opportunity and responsibility of managing the care of pts under delegated prescribing authority from supervising senior staff physicians in our System.

Diabetes Today: An Epidemic In 2005, 20.8 million Americans (7% of the population) were diagnosed with diabetes1 In 2008, 40% of Americans >age 20 have either pre-DM or DM Complications of diabetes are a major cause of mortality and morbidity1 >224,000 deaths 82,000 lower-limb amputations 44,000 began treatment for end-stage kidney disease 12,000-24,000 new cases of blindness each year Total cost in the United States in 2002: $132 billion1 Diabetes Today: An Epidemic Review as stated. 1. ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed October 11, 2006. 2. ADA. The dangerous toll of diabetes. Available at: http://www.diabetes.org/diabetes-statistics/dangerous-toll.jsp. Accessed October 11, 2006. References ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed October 11, 2006. ADA. The dangerous toll of diabetes. Available at: http://www.diabetes.org/diabetes-statistics/dangerous-toll.jsp. Accessed October 11, 2006.

ADA Glycemic Control Targets A1C < 7% Preprandial plasma glucose 70-130 mg/dl Postprandial plasma glucose (PPG) <180mg/dl A1c goal must be customized for the individual patient, with consideration of numerous factors such as comorbid conditions, duration of diabetes, history of hypoglycemia, hypoglycemia unawareness, patient education, motivation, adherence, age, limited life expectancy, and use of other medications.

Most Patients on Diabetes Therapies not Meeting A1C < 7% These are NHANES data from 1999 that show that pts with diabetes are not reaching goal whether they are receiving oral therapy or insulin. 42% of pts tx’d with oral agents have A1c’s >8% and 51% of pts tx’d with insulin are above 8% as well This is especially troubling when we look at the insulin data, because there is no limit to the A1c lowering effect of insulin, so what’s wrong with this picture?

DCCT Results HbA1c and Relative Risk of Diabetic Complications Title Subtitle 15 13 Average US HbA1c Range 7.8-8.6% 11 Eye disease Relative Risk of Complications 9 Kidney disease AACE recommendation is 6.5% 7 Nerve damage 5 3 The landmark government study, the Diabetes Complications and Control Trial (DCCT) demonstrated that as you reduce your A1c, you can reduce the risk of complications. Participants in the study who followed a regimen of intensive insulin therapy – either multiple daily injections or pump therapy – reduced their risk for serious complications such as retinopathy (eye disease), nephropathy (kidney disease) and neuropathy (nerve damage) by up to 74%. But as this graph shows, each time participants reduced their A1c by a percentage point, they reduce the risk of complications by up to 40%. The mean A1C value in US patients with diabetes has been reported to range between 7.8 and 8.6%, with one third of all patients with diabetes having A1C levels greater than 9.5%. 1 6.5* 6 7 8 9 10 11 12 HbA1c Skyler, J: Endo Met Cl N Am, vol 25, 2, p.243- 254, June 1996 Adapted from DCCT Research Group: NEJM 1993;329:977-986 Minshall M, et al. Clin Ther. 2005;27:940–950. 5

Most patients with T2DM will eventually require insulin therapy 6

What are some of the obstacles? Delayed diagnosis of diabetes Delay in starting insulin in patients failing oral agents Weight gain with intensification of glycemic control Hypoglycemia with intensification of glycemic control Patient and provider resistance to starting insulin as well as clinical inertia Inappropriate managed care practices

Normal Insulin Secretion 70 Serum insulin 50 Insulin (mU/L) 30 10 First and 2d phase release Rapid and complete return to baseline 9:00 AM 12:00 PM 3:00 PM 6:00 PM 9:00 PM 12:00 AM 3:00 AM 6:00 AM Breakfast Lunch Dinner Time of day Polonsky. N Engl J Med. 1996;334:777-783.

Natural History of Type 2 Diabetes Severity of Diabetes Impaired Glucose Tolerance Frank Diabetes Insulin Resistance Hepatic Glucose Production Endogenous Insulin Postprandial Blood Glucose Fasting Blood Glucose Asymptomatic Stage Microvascular Complications Macrovascular Complications Years to Decades Time Typical Diagnosis of Diabetes Ramlo-Halsted and Edelman: Clinics of NA Vol. 26 P771, 1999

Insulin Secretion in Type 2 Diabetes Is Delayed and Blunted: Too Little, Too Late The insulin response in Type 2 diabetes is delayed and blunted, reflecting the progressive dysfunction of the pancreatic beta cells. Key words: Type 2 Beta cell Dysfunction Polonsky KS, Sturis J, Bell GI. NIDDM – a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996;334:777–783.

Type 2 Diabetes Treatment Strategies: Stepwise Management Advance treatment whenever glycemic targets are not met Lifestyle modification MNT, weight loss, physical activity OADs Monotherapy Combination therapy Glp-1 agonist Addition of basal insulin therapy to OADs/exenatide Basal insulin plus prandial insulin ± OADs/pramlintide New Recommendation Metformin Plus: T2DM Treatment Strategies: Stepwise Management  Treatment of T2DM usually begins with lifestyle changes that address environmental factors with potentially adverse effects on disease progress, such as weight, diet, and physical activity.1 A low-calorie diet can lower plasma glucose levels, and even a small decrease in weight of 5 to 10 pounds can help a patient reach normative levels. The American Diabetes Association also recommends medical nutrition therapy (MNT), with input from a registered dietitian, for getting weight and diet under control2  If patients cannot make or maintain appropriate lifestyle modifications, or if these interventions cannot achieve target plasma glucose levels, OADs are often prescribed—although continuing to make healthy lifestyle changes should simultaneously be encouraged. A variety of agents are available, either for monotherapy or combination therapy1  To maintain the glycemic target when OAD therapy is no longer sufficient, insulin therapy can be added. Long-acting basal insulin added to OADs can be a very effective next step. If A1C levels are still not optimum, then prandial insulin can be added around mealtimes3 _________________________________________________________________________________________________________ 1. Nathan DM. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med. 2002;347:1342-1349. 2. American Diabetes Association (ADA). Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36. 3. Riddle MC. Making the transition from oral to insulin therapy. Am J Med. 2005;188(suppl 5A):14S-20S. MNT=medical nutrition therapy; OADs= oral antidiabetic drugs. Adapted from Nathan DM. N Engl J Med. 2002;347:1342-1349.

The Case For Insulin

By the Time of Diagnosis, Beta-Cell Decline Exceeds 50% Data from the UKPDS trial in newly diagnosed diet-treated patients show that the patients’ beta-cell function was between 50% and 60% at the onset of the trial. This function then progressively declined during the trial. In a further analysis, the authors have determined when the patients would have been at 100% function. The results of this extrapolation are shown here; the decline in beta-cell function began ~11–12 years prior to initiation of the study (diagnosis of diabetes). Key words: Type 2 Beta cell Dysfunction Beta-cell function was quantified by measuring insulin levels and blood glucose and then calculating the function based on what the level should be. UKPDS. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249–1258. Treatment should be predicated on the clinical condition of the pt, not because of the point at which diabetes is diagnosed. In other words, let blood glucose levels determine mode of treatment, not when the pt was diagnosed (“we’ll start with diet,” but BG’s are persistently above 300 would be malpractice. 13

Indications for Insulin in T2DM Symptomatic Hyperglycemia BG > 250 mg/dL) Inadequate glycemic control (patient specific (A1c >7%) Oral agents cannot be tolerated/contraindicated Longstanding Type 2 Diabetes/not responding to oral meds Transient poor control Intercurrent illness Glucocorticoid therapy 14

Goals of Insulin Therapy HbA1c < 7% (patient specific) Fasting and pre-prandial: 70 – 130 mg/dL 2 hr after start of meal: < 180 mg/dL Avoid frequent or severe hypoglycemia with physiologic insulin replacement therapies Minimize weight gain A1c goal must be customized for the individual patient, with consideration of numerous factors such as comorbid conditions, duration of diabetes, history of hypoglycemia, hypoglycemia unawareness, patient education, motivation, adherence, age, limited life expectancy, and use of other medications. 15

Mimicking Nature With Insulin Therapy Basal/Bolus Concept Physiologic Insulin Secretion 50 24-hr profile Basal insulin Insulin (uU/mL) 25 Suppresses glucose production between meals and overnight Nearly constant levels 50% of daily needs B L D 150 Mimicking Nature With Insulin Therapy Basal/Bolus Concept When considering glucose control, the focus must be on both postprandial and basal requirements. This slide illustrates the normal diurnal physiologic response, which highlights the need for both basal and meal insulin Meal-insulin release occurs in response to nutrient ingestion Basal insulin is continually secreted over a 24-hour period In the past, insulin formulations did not have adequate pharmacokinetics to duplicate these profiles. However, within the past few years, new insulin analogs have been developed that provide more physiologic profiles 1. Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821 100 Glucose (mg/dL) 50 Basal glucose Insulin ( AM PM Adapted with permission from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821 16

TYPES OF INSULIN AND HOW THEY WORK 17

Pharmacokinetic Profiles of Human Insulin and Insulin Analogs Onset Peak Duration Rapid-acting 10-15 mins 60-90 mins 4-5 hr Regular 30-60 mins 2-4 hours 5-8 hr Plasma Insulin Levels 0200 0400 0600 0800 1000 1200 1400 1600 1800 2000 2200 2400 Rapid-acting NPH 1-3 hr 5-8 hours 12-18 hr Detemir 90 mins Relatively peakless 12-24 hr Regular insulin Glargine 90 mins Peakless 24 hr NPH Detemir Glargine Lepore M et al. Diabetes. 2000;49:21 42-21 48; Howey DC et al. Diabetes. 1994;43:396-402; Plank J et al. Diabetes Care. 2005;28:1107-1112;; Wittlin SD et al. Insulin Therapy. Marcel Dekker, Inc.;2002:73-85.

BASAL INSULIN Intermediate Acting NPH Long-Acting Analogs Glargine (Lantus) Detemir (Levemir) 19

NPH Insulin Human Insulin Isophane Suspension Pharmacokinetics Onset: 2 - 4 hour Peak: 4 - 10 hours Duration: 10 - 16 hours 40% variance!! Can be mixed with Regular and Rapid Acting insulin 20

Insulin Glargine (Lantus) Recombinant human insulin analog Pharmacokinetics Onset: 2 - 4 hour Peak: Peakless Duration: 24 hours Administration: Once Daily at anytime of day When converting from once daily NPH, same dose used. When converting from twice daily NPH, start with 20% less 21

Insulin Detemir (Levemir) Recombinant human insulin analog Pharmacokinetics Onset: 2 - 4 hour Peak: Peakless Duration: 12 hours Administration: Once or Twice Daily Same dose as once daily NPH 20% less than twice daily NPH May actually require more detemir than glargine Shown to be associated with weight loss/less weight gain than other insulin 22

Insulin glargine (Lantus) Insulin detemir (Levemir) Similar rates of absorption from abdominal, thigh and deltoid region Cannot be mixed with any other form of insulin or IV solution Incidence of nocturnal and severe hypoglycemia were less frequent compared to once-daily NPH insulin CLEAR solution Available in Pen Device 23

Basal Insulin Replacement Therapy Normal Insulin Secretion at Meal Time Insulin Glargine/Detemir NPH Insulin Change in Serum insulin . s.c. injection Time (hours) 24

What is Going on in the Real World? Insulin Therapy Trends 2002–2006 Increasingly, patients are only taking a long acting insulin Graph is the results of patient self-reported response Percentage of insulin patients responding that they are taking only a long-acting insulin. The market research study is a syndicated study of people with diabetes, not a study sponsored by Lilly. The total number of patients who answered this question was 212. * Statistically significant difference from prior wave. ** Includes Lantus (75%), Levemir (8%) and Ultralente (5%). Twelve percent (12%) report “don’t know.” Source: 2006 Roper Survey of US Diabetes Patient Market, GfK Market Measures, N-705

PPG Contributes to 50% or More of Overall A1C When A1C Is 8.4 or Below The choice of an initial insulin needs to be based on the pt’s curent state of glucose control. This slides illustarates that when glycemic control is poor, correcting the fasting blood glucose would be the bettr strategy. However, as A1c’s improve, and fall below 8.4%, then PPG becomes more significant PPG Contributes to 50% or More of Overall A1C When A1C Is 8.4 or Below In the past, the belief was that A1C levels were primarily dependent on FPG However, postprandial hyperglycemia also is an important component of generating A1C Postprandial glycemic excursions become more predominant in patients with good control of fasting plasma glucose. Therefore, treatment should focus on both FPG and PPG excursions to reach and maintain A1C targets. Key words: Diagnosis Total glucose control A1C FPG PPG Postprandial glucose Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:881–885. 26

BOLUS INSULIN Short Acting Regular Rapid- Acting Analogs Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) 27

Regular Insulin Human Insulin (soluble) Pharmacokinetics Onset: 0.5 - 1 hour Peak: 2 - 3 hours Duration: 3 - 6 hours (as long as 8 hours) Administration: 30 - 45 minutes BEFORE meals Can be mixed with NPH insulin Only insulin that can be given IV 28

Rapid-Acting Insulin Analogs Equipotent to Regular Insulin Products Lispro (Humalog) Aspart (NovoLog) Glulisine (Apidra) Goal: to mimic physiological prandial response 29

Rapid-Acting Insulin Analogs Pharmacokinetics Onset: < 0.25 – 0.5 hour Peak: 0.5 – 1 hour (lispro 2.5 hour) Duration: 1 - 3 hours (lispro 3 - 4 hours) Administration: Within 15 minutes BEFORE meals Can be mixed with NPH insulin 30

Bolus Insulin Replacement Therapy Normal Insulin Secretion at Meal Time Rapid-acting Analogue Regular insulin Change in Serum insulin . s.c. injection Time (hours) Apidra Humalog Novolog 31

Why is Mealtime Control Important? Patients with poorly controlled type 2 diabetes may spend much of their waking day with postprandial hyperglycemia1 99% of patients with A1Cs ≥7% have 2-hour postprandial glucose (PPG) levels ≥200 mg/dL2 Type 2 diabetes Control 400 Plasma Glucose (mg/dL)2 300 Discussion points Erlinger studied the prevalence of postchallenge hyperglycemia (PCH) in adults with type 2 diabetes who were not taking insulin. PCH was defined as a 2-hour glucose ≥200 mg/dL. Among those with diagnosed diabetes, 74% had PCH. In patients with suboptimal glycemic control (A1C ≥7%), virtually all (99%) presented with PCH. Glucose concentrations measured throughout the day from Polonsky show that in patients with poorly controlled type 2 diabetes (mean A1C ~10%), a postprandial state may be maintained from the first meal of the day (breakfast) through the evening. In many patients with poorly controlled type 2 diabetes, postprandial hyperglycemia is a problem. Erlinger TP, Brancati FL. Postchallenge Hyperglycemia in a National Sample of U.S. Adults With Type 2 Diabetes Diabetes Care 2001;24(10):1734-1738. Polonsky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318(19):1231-1239. 200 100 Breakfast Lunch Dinner 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM Time of Day Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. Erlinger TP, et al. Diabetes Care. 2001;24(10):1734-1738.

Relationship Between 2-Hour Plasma Glucose and All-Cause Mortality Discussion points Data from the DECODE study group showed that: Fasting glucose is not by itself a good predictor of risk of death. High 2-hour glucose is a better predictor of mortality than fasting glucose. For any category of fasting blood glucose, an increase in 2-hour glucose was associated with a significant increase in risk of death. The DECODE Study Group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetic Association diagnostic criteria. Lancet. 1999;354(9179):617-621.

Basal-Bolus Insulin Therapy: Insulin Glargine at HS and Mealtime Lispro or Aspart Insulin Effect Slide 61 Basal-Bolus Insulin Therapy: Insulin Glargine at HS and Mealtime Lispro or Aspart The slide depicts the profile of a “basal-bolus insulin” regimen, with insulin glargine at bedtime (HS) providing the basal component and prandial insulin lispro or insulin aspart providing the bolus component This regimen affords the following advantages: Provides flexibility for varying dietary habits Less risk of nocturnal hypoglycemia due to the 24-hour near-constant effect of insulin glargine, making it an ideal basal insulin Less risk of between-meal hypoglycemic episodes due to the short duration of the rapid-acting insulin analogs, which may also provide insulin coverage for snacks or extra meals with additional injections Avoidance of mixing different insulin preparations in the same syringe as single insulins are administered with each injection. Insulin pens are suggested for maximal convenience and accuracy in dosing 1. Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002:87 B L D HS Insulin lispro or aspart Insulin glargine Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker Inc.; 2002:87

Premixed Insulin HUMAN 70/30 70% NPH 30% REG 50/50 50% NPH 50% REG Dual Peak Administration: Must be injected 30 - 45 minutes before a meal Once or twice daily dosing 35

Premixed Insulin HUMAN Advantages: Convenience Accuracy visually impaired Manual dexterity challenges Disadvantages: Inability to adjust only one component Nocturnal Hypoglycemia MUST eat CONSISTENTLY timed meals 36

Premixed Insulin ANALOG 70/30 MIX (Novolog) 70% Aspart protamine 30% Aspart 75/25 (Humalog) 75% Lispro protamine 25% Lispro One Peak followed by "long Tail” (No NPH) Administration: Must be injected within 15 minutes before a meal Once, twice or three times daily dosing 37

Premixed Insulin ANALOG Advantages: Convenience Accuracy visually impaired Manual dexterity challenges Flexibility with meals Less Nocturnal Hypoglycemia Disadvantages: Inability to adjust only one component 38

Mixed Insulin Replacement Therapy Normal Insulin Secretion at Meal Time Analog Mix PreMix 70/30 (NPH/REG) Change in Serum insulin . s.c. injection Time (hours) 75/25 Humalog Mix 70/30 Novolog Mix 39

Now What ?

…then, Tackle Postprandial if A1C still >7%! FIRST Correct FASTING 300 Time of Day Uncontrolled A1C ~9% “Controlled” A1C <7% 200 PG (mg/dL) A1C ~6% 100 Normal A1C 5%–6% 0800 1200 1800 0800 …then, Tackle Postprandial if A1C still >7%! Adapted with permission from Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1-11. 41

Possible Approaches for Adding Insulin using a basal insulin with continued oral agents using pre-mixed insulin with continued oral agents stopping oral agents and initiating insulin using various regimens: pre-mixed insulin prandial insulin with a basal insulin once (or twice) daily 42

Start a Basal Insulin “Treat to Target” Continue oral agent(s) at same dosage Do NOT stop insulin secreting agent Add single, evening insulin dose (0.1 - 0.2 U/kg) 10 - 20 units Glargine, Detemir or NPH (bedtime) Increase insulin dose every 3-4 days as needed Increase 3 - 5 U if FBG >150 mg/dL Increase 1 - 2 U if FBG = >110,<150 mg/dL Treat to target FBG (usually <120 mg/dL) 6-59

Traditional “Sliding Scale” An arbitrary insulin dosing algorithm based only on pre-meal blood glucose values Pre-Meal BG (mg/dl) Insulin Dose (units) Less than 151 151-200 2 201-250 4 251-300 6 301-350 8 351-400 10

Traditional “Sliding Scale” Breakfast Lunch Dinner Bedtime Day 1 BG (mg/dl) 141 335 89 290 Insulin Dose 8 6 Day 2 381 76 261 121 Day 3 BG >600

Adding a meal time bolus: Only Fasting BGs at target Stop insulin secreting agent Add Bolus insulin before meals (REG or analog) Isocaloric meals Add 10 units and redistribute total dose 50/50 Pt taking 30 units Lantus already Add 10 units to a new total dose of 40 units 50% will be new basal (20 units) 50% in divided doses will be the meal time bolus (i.e. 7/6/7) Carb counting and correction factors BG checks a must! “blind leading the blind” SAFETY

Total Daily Insulin Total daily insulin requirement is calculated by body weight T1: need about 0.6 units/kg (range 0.4 - 0.8) T2: need about 1.2 units/kg (range 1 – 1.4) BGs at goal without hypoglycemia. 40-50% basal (background) 50-60% bolus (meal doses)

Calculating “Basal–Bolus” Insulin Calculate TDD T1: need about 0.6 units/kg (range 0.4-0.8) T2: need about 1.2 units/kg (range 1 – 1.4) Basal dose: 40 – 50% of TDD Bolus dose: 50-60% of TDD: Divide equally for three meals OR Sensitivity Factor = 1700/TDD 1 unit will drop BG by XX points Carbohydrate Ratio = 500/TDD 1 unit for every XX gm carbs (Pt BG – target) / (SF) = CORRECTION Now add carb ratio for meal.

For Example 250 pound T2DM (114 kg) Calculated TDD: 114 x 1.2 = 137 u/day Basal Dose: 68 units a day (50% of TDD) Bolus Dose: (other 50% of TDD) Isocaloric meals: 68/3 = 23 units before each meal Carbohydrate ratio: 500/137 = 3 1 unit for every 3 grams of carbs Insulin Sensitivity: 1700/137 = 12 1 unit will lower BG 12 mg/dL

For Example: Above Target at Lunch Pre meal target: 100 Pt BG before lunch: 160 Will be eating a meal of 65 gm CHO 160 – 100 = 60 points too HIGH before eating Sensitivity Factor = 12 60/12 = 5 (will need 5 units to correct to target) Carb ratio = 1 : 3 65 gm CHO / 3 = 21 (will need 21 units for the meal) 5 units +21 units = 26 units before lunch

For Another Example: Below Target at Lunch Pre meal target: 100 Pt BG before lunch: 80 Will be eating a meal of 65 gm CHO 80 - 100 = - 20 points too LOW before eating Sensitivity Factor = 12 -20/12 = -1.6 >> -2 (will need -2 units to correct to target) Carb ratio = 1 : 3 65 gm CHO / 3 = 21 (will need 21 units for the meal) 21 units – 2 units = 19 units before lunch

Sliding scale: Correction Correction Scales: Helpful for sick days/NPO Still need to calculate the TDD and the insulin sensitivity Example: TDD = 137; SF 1:12 WILL NOT COVER FOR CARBS, ONLY TO CORRECT <100-125, no insulin 126 - 150, 2 units (102-126) 151 - 175, 4 units (103-127) 176 - 200, 6 units (104-128) 201 - 225, 8 units (105-129) 226-250, 10 units, etc (106-130) 52

Sliding scale: Correction + Carbs Incorporates BOTH the correction and the meal requirements Still need to calculate the TDD, sensitivity factor, and carbohydrate ratio Works best for consistent carb intake (may have different scale for each meal) Example: TDD = 137 units SF = 1:12 CR = 1:3 Eats approx 65 gm carbs at each meal <70, no insulin 71 – 125, 21 units 126 - 150, 23 units 151 - 175, 25 units 176 - 200, 27 units 201 - 225, 29 units 226 - 250, 31 units 53

What’s the dose range? Type 2: 0.3 to 1.2 units/kg “Thin type 2’s” are more insulin deficient “Heavy type 2’s” are more insulin resistant Most pts with T2DM need insulin doses of 1 to 1.2 units/kg to achieve an A1c <7% (basal dose of 0.5 to 0.6 units/kg per day)

Lilly Pens: Memoir & Kwikpen NovoNordisk: NovoPen 3 Insulin Pens Lilly Pens: Memoir & Kwikpen Convenient Discreet Protect Insulin from light, heat and agitation Sanofi-Aventis: SoloStar

U-500 Insulin

History: Why U-500? Main reason in early 1950s was for high insulin requirements in type 1 diabetes due to high levels of insulin antibodies developed from other animal insulins Also used for severely insulin resistant type 2’s Only developed as a regular insulin Replaced by pork U-500 regular insulin in 1980 Replaced by human U-500 regular insulin in 1997

What About the Need for More CONCENTRATED Insulins? For more resistant patients, U-100 insulin both impractical and inconvenient When over 100 units (1mL) required at one time, would need more than one injection Large volume of insulin painful Large depot of insulin impedes absorption making it unpredictable (a more concentrated insulin should be more predictable at these doses)

Insulin Resistant Conditions to Consider U-500 Insulin Non-Syndromic Insulin Resistance Obesity with T2DM requiring > 200 u/day Post-op or post-transplant state High-dose steroids or pressors Systemic infection Pregnancy with underlying T2DM

Most Recent PK/PD U-500 Data Duration of action was shown to be prolonged for U-500 vs. U-100; mean late tRmax50 was 3.4 hr longer than at the 100-U dose (p<0.001) The longer duration of effect of U-500 compared to U-100 suggests that multiple daily injections of U-500 without use of a basal insulin may be a plausible treatment option for insulin-resistant patients with type 2 diabetes

So Is U-500 Regular Insulin a Basal or a Prandial Insulin? It is BOTH! Lag times never studied, but it only makes sense that when used as mealtime insulin timing between injection and eating is even more important than with U-100 regular (or analogue) Main secret for success with U-500 insulin FREQUENT SMBG!

Communicating U-500 Dosing Two ways: “units” on a U-100 insulin syringe or volume (mL) on a tuberculin syringe Ideally, would be nice if everyone used both; most patients will discuss this in units My compromise with patients and in charting: always note U-500.

Example Patient is taking 10 units of U-500 insulin at breakfast (the equivalent of 50 units of U-100 regular) and it is decided to increase the dose to 14 units U-500 I tell the patient to increase the dose to 14 units U-500 in his U-100 syringe I chart the dose was increased to 14 units of U-500 (which is 70 units of U-100 regular)

Example This can also be done in tuberculin syringes and only discussed in terms of volume of insulin Problem: in the US tuberculin syringes only available in 27G needles So 10 units of U-500 insulin would be 0.10 mL of insulin An increase to 14 units would be 0.14 mL of insulin My observation: patients and nurses prefer “units”

Implementing U-500 Insulin 150-300 units/day U-500 has been shown effective with or without traditional basal insulin Without basal insulin, U-500 can be split into ac breakfast and dinner shots (60/40) or ac TID (40/30/30 or 40/35/20) Many continue basal insulin, esp. during transition from U-100 Like most insulin management, what we do with U-500 is generally anecdotal. The good news: these patients don’t generally get hypoglycemic!

Injection Problems Lipoatrophy (immune response) Lipohypertrophy Breakdown (pitting) of fat tissue Indentation in the skin Lipohypertrophy Thickening (lumps) of SQ fat Causes: repeated injections same site, needle reuse Delays insulin absorption Bruising at Site:  technique 66

Insulin Delivery Systems Insulin syringes Know Needle Gauges (29-32), Lengths Short Needle: 8mm, Longer: 12.7mm Syringe size- 1/4ml, 3/10ml, 1/2ml,1ml Insulin pens: Nano ® (4mm), mini (5mm), short (8mm), long (12.7mm) needles Continuous insulin infusion pump Uses bolus insulin only 67

Insulin Pen Once Opened Humulin & Novolin R 28 days Humalog®, Novolog® Humulin & Novolin N 14 days Humulin & Novolin 70/30® 10 days Humalog Mix 75/25® Novolog Mix 70/30® Levemir® Lantus®, Apidra® 42 days

Thank You Many individuals freely shared their slides for this presentation: Roger Austin Steve Edleman Irl Hirsch Lucia Novak Jane Seely Geri Spollet Virginia Valentine