For Patients Failing Oral Therapy

DM2 ADVANCEMENT TO INSULIN: When Patient Fails Oral Rx Patty Glatt, MD 10/09 I. Initiating Single Basal Injection Describe to patient as the "background" amount of insulin needed to run the fuel cells of their body's motor; Mealtime insulin is the extra insulin needed to handle the calories eaten.  Add Basal “Background” insulin to oral regimen when A1C> 7.5-8.0 or FBS> 130 on maximum optimal oral regimen. Early use reduces CV/macrovascular complications. Single basal dose sufficient when FBS elevated but orals control postprandial  Basal therapy offers opportunity for patient efficacy, establish control FBS, transition to prandial and MDI insulin.  Oral DM agents: Continue MTF for weight control and insulin resistance. Caution w/TZD with insulin may ↑CHF. SU: Usually ↓ reduce to ½ max dose or DC.

BLOOD GLUCOSE GOALS ON HOME MONITORING Before meals: 90-130: w/o significant hypoglycemia 120-180: for elderly or patients with hypoglycemic unawareness 80-100: for those desiring tighter physiologic control After meals: under 160; Recommended under 135 Bedtime: under 180; Recommended under 130

Basal Insulin Treat to Target (T2T) Protocol: Achieves quicker A1C control with patient-driven titration. Avoids hypoglycemia GOAL: Titrate to FBS 90-130 mg/dl. (May adjust to tighter goal ≤110 individually per MD outside of protocol) How? 1. Start with minimum 10 units once daily Lantus/Glargine®, or Levemir/Detemir® or use guideline below to guide decision. For 100kg, on average needs 40-50 units ultimately. Some start at 50% calculated for T2T. 2. ↑ by 2 units until FBS <130; Option to ↑ by 4 units for FBS >180. When? ↑ insulin dose every 3-4 days (“twice a week- patient picks”) Warn: Hypoglycemia: ↓ by 4U or 10-15% if pre-breakfast glucose <70 or 2AM < 100 ˂ CALCULATING BASAL INSULIN DOSE (Usually dosed at bedtime) 0.5 U/kg normally 0.3 U/kg if concerned about risk of hypoglycemia (elderly, impaired renal, cardiac or hepatic function) 0.7 U/kg for presumed high insulin resistance (obesity, post-CABG, open wounds)

II. Moving Beyond Single Basal Dosing After Basal T2T goal is reached, if HgbA1C remains >8.0, on add pre-meal "Prandial" insulin PREMIXED INSULIN(Humalog ®75/25 or Novolog ®70/30): Advantage of Premixed Insulins  For patients unable to manage multiple dose injections for whatever reason  Improved control when Basal insufficient Disadvantages of Premixed Insulins  Must eat at regular times and consistent calories; Skipping meals may lead to hypoglycemia  Premixed insulin offers no flexibility in adjustment of rapid portion PREMIXED INSULIN OPTIONS: 1.) Switch to single Premixed before dinner. Titrate Premixed T2T to 2hrpost prandial BS (based on start of meal). Best when mostly elevated FBS and dinner or as initial Pre-mix when dinner is highest meal. 2.) Advance to BID premixed Humalog®75/25 or Novolog ®70/30. Occasional use for Humalog®50/50 for PM dose when more PM prandial insulin needed 3.) AM Premixed Humalog ®75/25 or Novolog ®70/30 or NPH+Lispro(Humalog®) and PM (dinner or HS) NPH When most elevations are daytime only. III. MDI (Multi-Dose Injection) Basal +Bolus Regimen: Add pre-meal (Humalog®)Lispro, (Novolog®)Aspart, or (Apirdra)Glulisine® to single meal; start with largest meal. Gradually add additional largest meals, one at a time, until control. T2T for each prandial rapid insulin to 2hr postprandial. Features:  Test glucose before meal and 2 hours after meal (from first bite) being targeted. Adjust twice a week until readings are within 40mg/dl of each other or goal achieved  Basal insulin Glargine usually given at bedtime. Adjust until FBS at target  Rapid-acting Lispro (Humalog) before each meal. May start with highest meal.  Add supplemental Lispro(Humalog) meal bolus insulin ( see Correction Factors below) if above target before giving prandial insulin

Benefits  Can be used with Type 2 DM and Type 1  Assoc w/ improved glycemic control leading resulting in less microvascular ds  Patient not tied to rigid eating schedule as with fixed-split  Elimination of dietary restrictions for those who do CHO counting

Disadvantages  Intensive management requires high level compliance and literacy to master  Frequent testing required or learning Carb counting

Starting Basal/Bolus Insulin Regimen 1. Calculate Total Daily Dose (TDD)-see box. [Alternative: 0.25-0.3 U/kg/d]

CALCULATE THE TDD: Calculate the TDD based on patient size for premixed insulin Dialysis patient (regardless of BMI): 0.3 U/kg/d Lean (BMI <25): 0.4 U/kg/d Overweight (BMI 25-30): 0.5 U/kg/d Obese (BMI >30): 0.6 U/kg/d

2. Basal =50% of TDD, usually at bedtime; alternatively 30% TDD as NPH pre-breakfast and 20% TDD as NPH pre-dinner 3. Prandial (pre-meal) Bolus = 50% of TDD, as Lispro, Aspart, or Apirdra : 20% pre- breakfast, 10% pre-lunch, and 20% pre-dinner. Alternative: Basal 40%; Premeal = 20% each

Alternative Basal = 0.125units/kg/d Pre-Breakfast Lispro= 0.025 units/kg/d Pre-Lunch Lispro = 0.0125 units/kg/d Pre-Dinner Lispro = 0.023 units/kg/d Patient Self Adjustment Instructions: SELF ADJUSTMENT FOR PREMIX AND MDI LISPRO When? Every 3-4 days. Adjust one dose at a time, usually first targeting dinner control. Target Goal: ↑ 1-2 units until at target goal 90-130 before meals.

WHEN? Uncontrolled Pre-Meal BG Adjust Before Breakfast Glucose Bedtime Basal Before lunch Before Breakfast Lispro or Breakfast premixed 2 hr after Lunch Before Lunch Lispro insulin or Before Lunch Premixed insulin 2 hr after Dinner Before Dinner Lispro or Before Dinner premixed insulin Bedtime Glucose Before Dinner Lispro or Before Dinner premixed

HOW MUCH? If Blood Glucose Adjust Insulin <20 below goal ↓ dose 3 Units or 10-15% At goal No Change over 5-10 ↑ dose 1 unit over 11-19 ↑ dose 2 units >20 above goal ↑ dose 3 Units

TARGET GOALS: FBS, PREMEAL ≤ 130 ≥90 , Recommended ˂100 2 HR POSTPRANDIAL ˂160 -135; recommend goal ˂135 BEDTIME ˂130 HYPOGLYCEMIA ANY ˂70 http://care.diabetesjournals.org/content/32/1/193.full.pdf+html http://clinical.diabetesjournals.org/content/23/2/78.full.pdf+html http://care.diabetesjournals.org/content/31/7/1305.full.pdf+html

MISCELLANEOUS PRACTICE TIPS  Fix lows values first. If only once or twice (not a pattern), ask about skipped meals. Adjust insulin in response to a pattern, not in response to a single abnormal value  Hypoglycemia: Review signs, symptoms, treatment and strategies for preventing  Give patients early opportunity to try a “dry practice insulin injection”  Offer pen devices to patients with low vision, poor hand control, true needle phobia. Medi-Cal TAR approval feasible for all of these. PAR for CCHP.  Don’t underprescribe low dose syringes. Better to use 0.5 for T2T  NEVER THREATEN A PATIENT WITH INSULIN  CCHP limits Lantus to 60 cc/month.  Pens 5/box

IV. Pens and Needles PEN DEVICES Patient Selection: . Poor Dexterity- OA, neuropathy - Approved indication . Mental or Cognitive impairment - Approved indication . Poor eyesight - Approved indication . Poor adherence –Requires explanation for authorization . Needle Phobia –Requires explanation for authorization

Manufacturer Product Timing Cost

Aventis-Sanofi Solostar PrefilledPen Lantus (Glargine) *Once daily/ HS $195 Solostar PrefilledPen Apidra (Glulisine)* 15 mins AC Reusuable Opticlick* Most used in EU *Order B-D Ultra Fine Needles 31g ,3/16"mini, 5/16"short; 29g 1/2" standard

Novo Nordisk Novolog® Mix 70/30 FLEXPENǂ 15 mins AC $195 Reusable Novolog ® (Aspart) FLEXPENǂ 10 mins AC $195 ǂOrder NovoFine 30,32 disposable needles or B-D Ultra Fine Needles 31g,3/16", 5/16";29g 1/2" standard

Lilly Humalog® Mix 75/25 Prefilled Pen 5 mins AC $195 Humalog® (Lispro) Prefilled Pen 15 mins AC $195 Humulin® N (NPH) Pen 30 mins AC $140 Humulin® 70/30 (NPH/R) 30 mins AC $140 *Order B-D Ultra Fine Needles 31g ,3/16", 5/16";[29g 1/2" original]

“Pre-filled” pens are disposable. All supplied 3ml=300 units/ pen or cartridge; 5 pen/per box. Max delivery is 60 units max per injection, except Solostar Lantus and Opticlick with max 80 units per injection [Innolet Device with large dial and numbers for use with Novolin ®(NPH/Reg) - soon to be discontinued] All covered on medical plans but require Prior Authorization/ Treatment Authorization Requests Store all unopened cartridges in refrigerator until use or expiration date; Store open unrefrigerated pen cartridges for 10-14 days. Good cost alternative are Prefilled Syringes for selective patients e.g. learning impaired, family members

NEEDLES Gauge: Thinness. Higher number refers to finer needle. Order highest gauge available for patient comfort 30, 31 (“microfine”) gauge: needles are painless Lengths: Thin patients can use shorter needles. Obese patients need longer needles. 1/2" Standard ( comes in 29, 30, 31 gauge) for more obese patients 5/16” Short ( comes in 28, 29, 20, 31 gauge) for thinner patients 3/16" Mini May be most comfortable for the Volume: Don’t underprescribe. Patient may not exceed their monthly insurance allotment 0.3cc =Low dose - up to 30 units. Best visibility if low dose used. May exceed dose if T2T pt. 0.5cc = Low dose- up to 50 units. Best for starting T2T to avoid running out of syringes 1.0 cc = Standard- up to 100 units. Best if obeseT2T and likely will need high dose V. Talking Points: OVERCOMING BARRIERS TO STARTING INSULIN TX  Using insulin does not mean failure. "You haven't failed' your pancreas has."  Educate early that diabetes is a progressive disease; prepare your patient that most patients will eventually need insulin.  Oral medication only work when the body makes enough insulin.  Starting Insulin early is about reducing complications over 10 years (death, MI, Stroke, amputation). We can all agree on a goal to live a long healthy life.  Insulin allows a person the freedom to eat a relatively “normal” diet again The patient does not have to choose between good control and foods they enjoy  Insulin is the only “natural therapy” we have  Just one shot a day of insulin may be sufficient  Insulin does not require refrigeration  Starting insulin does not cause complications; untreated advanced disease does.  INSULIN ALWAYS WORKS VI. Addendum Bolus Pre-prandial Insulin Correction Dose Calculating the Insulin Sensitivity Factor: Adjust blood glucose before/between meals as needed for deviations from goal. Approximation if patient is not well controlled on current insulin regimen.

APPROXIMATION OF INSULIN SENSITIVITY FACTORS: Patient Characteristic Amount ↓BG/1U Lispro Highly insulin sensitive and/or bad kidneys Lower 60-100 mg/dl Normally insulin sensitive Lower 50 mg/dl Mild insulin resistance BMI> 25 Lower 30 mg/dl Moderate insulin resistance BMI>30 Lower 20 mg/dl Severe insulin resistance BMI>40 Lower <10 mg/dl

"RULE OF 1800" For patients well controlled, use the Rule of 1800 for a more precise patient-specific value. This is the amount of Lispro needed to bring current BG down to target BG.

“ Rule of 1800” Insulin Sensitivity Factor: To estimate expected drop in blood glucose for each unit of Lispro insulin, use the “1800 Rule” [Feasible to calculate only when pt. in reasonable control on known insulin regimen] 1.) To calculate the Correction Factor: Divide 1800 by total current Total Daily Dose insulin (TDD)= glucose mg/dl point drop for every unit of Lispro insulin. 2.) Current BG – Target BG (110)= # points over target. 3.) Divide this by “correction factor” (round # as needed). INSULIN:CARBOHYDRATE CORRECTION FACTOR  To estimate the insulin required to cover the carbohydrate load of an upcoming meal. (CHO counting). Method used for intensive Bolus + 3X Prandial  Package labels and food lists with carbohydrate grams and portions sizes assist with this. I:C ratio is the amount of carbohydrate covered by one unit of rapid-acting insulin analog (Lispro, Aspart). The insulin-to-carbohydrate ratio can be determined using the 500 rule (see below), in which the total daily dose of insulin (TDD) is divided by 500. Typically, insulin-to-carbohydrate ratios are in the range of 1U: 10-15 gram of carbohydrate. This method can be modified for patients who prefer a simpler method of counting carbohydrates or food intake. Patients round their carbohydrate choices to a 15 g portion size and count their carbohydrates in denominations of portions rather than grams. An example would be 1 unit of insulin per 1 portion of carbohydrate.

The Carbohydrate Coverage “500 Rule”: Gives an approximation for how many grams of CHO will be covered by 1U of Lispro insulin. Divide 500 by the TDD of insulin (basal + bolus) to determine how many grams of carbohydrate will be covered by 1U of Lispro. This is this individuals “correction factor”.

EXAMPLES OF CORECTION FACTORS

Calculating Carbohydrate Coverage with “500 rule” Example: Pt uses total 30 units per day (15 units Glargine and 15 units Lispro): 500/30= 17 grams carbohydrate covered by 1 unit of Lispro Therefore, for this patient, there CHO: Lispro insulin ratio is 17:1

Calculating Insulin Sensitivity Factor- Example: Joe typically uses 30 units of glargine at bedtime, 10 units of lispro at breakfast, 5 units at lunch, and 15 units at dinner. TDD= 30glargine = 30lispro = 60 units insulin/day 1800/60 = 30 Therefore every 1 unit of Lispro should drop Joe’s blood glucose 30 mg/dl. Or stated another way, for Joe, his insulin sensitivity correction factor is 30 mg/dl for each unit of Novolog (Lispro).This can be used to estimate what supplemental dose Joe will need for a pre-meal correction dose in addition to his usual dose if his pre-meal glucose value is exceeds target value.

Calculating Bolus- Example: Joe has a tooth infection. His pre-lunch blood sugar has shot up to 240 from his usual 120. He needs a correction factor for 120mg/dl. Therefore, he needs 120mg/dl divided by 30mg/dl per 1 unit = 4 units Novolog for correction. . Therefore Joe’s dose will be his usual 5 + 4 = 9 units Novolog before eating lunch. Example: Calculating Pre-Prandial Correction with CHO counting and Bolus Correction: By way of example, consider a patient who has a target blood sugar before meals of 110, premeal glucose of 170, insulin-to-carbohydrate ratio of 1:15, and an insulin sensitivity factor of 1:30. This person is about to eat a meal estimated to contain 60 g of carbohydrate. He currently takes a dose of Glargine/Lantus every evening and a rapid- acting analog (lispro or aspart) before each meal. With the I:C ratio of 1:15 and 60 g of carbohydrate intake, this patient would require 4 units of rapid-acting insulin to cover the carbohydrates at this meal. With a premeal glucose of 170, target glucose of 110 and a 1:30 insulin sensitivity factor, an additional 2 units would be required as the correction factor. Four units of lispro or aspart will be needed to cover the carbohydrate intake, and an additional 2 units will be needed as a correction factor based on the premeal glucose, for a total dose of 6 units of lispro or aspart.