Therapy Insulin Practical guide to Health Care Providers Quick Reference F Diabetes Mellitus in Type 2

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1 Ministry of Health, Malaysia 2010 First published March 2011 Perkhidmatan Diabetes dan Endokrinologi Kementerian Kesihatan Malaysia Practical guide to Insulin Therapy in Type 2 Diabetes Mellitus Quick Reference For Health Care Providers

2 KEY MESSAGES 1. Pancreatic beta cell dysfunction begins many years prior to diagnosis of Type 2 diabetes 2. Following diagnosis, progressive insulin deficiency combined with insulin resistance results in worsening glycaemic control and failure of oral anti-diabetic therapy. 3. Insulin therapy should be initiated early when HbA1c is persistently above 8% despite optimal doses of oral anti-diabetic therapy. 4. The insulin regimen and insulin doses initiated should be indiviised, based on the patients blood glucose profile, lifestyle factors and patients preferences. 5. Metformin, an insulin sensitizer, should be continued at optimal doses following initiation of insulin therapy unless contraindications or intolerance exist. 6. Self monitoring of blood glucose along with simple patient-directed dose adjustments enable gra, safe and prompt insulin dose optimization. 7. Glycaemic targets need to be indiviised based on patients risk of hypoglycaemia, presence of complications and co-morbidities. 8. Insulin regimens may need to be changed or intensified with time if glycaemic targets are unmet despite dose optimization. 9. Minimizing both hypoglycemia and weight gain are important additional treatment targets for patients with Type 2 diabetes requiring insulin therapy. 10. Continuous patient education and support is a key element for optimal treatment adherence, patient empowerment and successful insulin therapy. SOURCES OF FUNDING The development of this quick reference guide was supported by an educational grant from sanofi-aventis TARGETS AND MONITORING Recommended timing of SMBG in different Insulin Regimens Breakfast Lunch Dinner Bedtime SMBG in basal/basal-bolus regimen Post Post Post Basal only Basal bolus (short-acting) Basal bolus (rapid-acting) SMBG in mixed Regimen -mixed Human BD -mixed Analogues BD -mixed Analogues TDS SMBG and Insulin Titratuion To Control Breakfast BG 2-hours Post-breakfast BG -lunch BG 2 hours Post-lunch BG -dinner BG Post-dinner/-bed BG Adjust -bed intermediate/long-acting insulin or pre-dinner premixed -breakfast rapid-acting or premixed insulin analogue. -breakfast short-acting or premixed insulin. -lunch rapid-acting or pre-breakfast premixed insulin. -lunch short-acting or pre-breakfast premixed insulin. -dinner rapid-acting or pre-dinner premixed insulin.

3 Intensification from mixed Regimen to Basal Bolus Regimen PREMIED INSULIN BD or TDS (Insulin analogue) FPG / premeals > 6 mmol/l HbA1c > 6.5 7% Switch to BOLUS REGIMEN Starting dose 0.5units/kg/day or total dose transfer Split dose 50:50 for basal and prandial insulin Divide prandial doses into 3 main meals Fix FPG < 6mmol/L using basal insulin Titrate bolus dose once / twice a week to achieve FPG and preprandial goal < 6mmol/L Stop SU, continue metformin Intensification from Prandial Regimen to Basal Bolus Regimen PRANDIAL TDS (Optimised prandial doses) FPG > 6 mmol/l HbA1c > 6.5 8% Addition of INSULIN BOLUS REGIMEN 10 units or 0.2U / kg at pre-dinner Monitor FPG, target 4-6 mmol/l Adjust basal insulin doses after 3 consecutive BG values obtained (every 3 7 days) - < 4 mmol/l ( > 1 value ) reduce dose by 2 units mmol/l ( all values ) maintain current dose - > 6 mmol/l ( >1 value, no hypos ) increase by 2 units Insulin preparations available in Malaysia and their pharmacokinetic profiles a) Short-acting, regular - Actrapid * - Humulin R * b) Rapid-acting analogue - Novorapid (Aspart)* - Humalog (Lispro)* - Apidra (Glulisine) c) Intermediate-acting, NPH - Insulatard * - Humulin N * d) Long-acting analogue - Glargine * - Detemir * e) mixed human (30% regular insulin+70% NPH) - Mixtard 30* - Humulin 30/70* f) mixed analogue - NovoMix 30 - Humalog Mix 25 Brand (Generic) Name Onset Peak (Hr) Duration (Hr) Timing of insulin * Available at Ministry of Health, Malaysia min 0-15 min 5-15 min 1.5 Hr 1 Hr 2-4 Hr 1 Hr min 0-15 min peakless peakless s before meal 5-15 mins before or immediately after meals -breakfast / -bed Same time everyday at anytime of the day mins before meals 5-15 mins before meals

4 Insulin regimens and frequency of injections per day No. of injections per day Insulin regimen PREMIED OD PREMIED BD -PLUS (1) -PLUS (2) PRANDIAL PREMIED TDS PREMIED-PLUS PREMIED-PLUS -BOLUS -BOLUS Type of insulin and timing Intermediate acting (NPH) insulin pre-bed Long-acting analogue once daily mixed/ premixed analogue pre-dinner Intermediate acting (NPH) pre-breakfast and pre-dinner mixed insulin pre-breakfast and pre-dinner Basal insulin once daily + 1 prandial insulin Basal insulin once daily + 2 prandial insulin Prandial insulin pre-breakfast, pre-lunch and pre-dinner mixed analogue pre-breakfast, pre-lunch and pre-dinner mixed insulin pre-breakfast, pre-dinner + 1 prandial insulin pre-lunch Prandial insulin pre-breakfast and pre-lunch + premixed insulin pre-dinner Basal insulin once daily + prandial insulin pre-breakfast, pre-lunch and pre-dinner Intermediate acting (NPH) insulin pre-breakfast and pre-dinner + prandial insulin pre-breakfast, pre-lunch and pre-dinner Insulin therapy 3 stage process INITIATION Starting insulin Strat requires selection of appropriate insulin regimen, insulin type and starting dose. OPTIMISATION Dose titration to ensure maximum benefit from prescribed treatment Dose should be adjusted every 3-7 days INTENSIFICATION Modification of an insulin regimen to acieve glycemic control Requires switching to more intensive regimens for better glycemic control Intensification of mixed Regimen to mix Plus PREMIED OD (pre-dinner) or BD PREMIED ONCE DAILY (pre-dinner) FPG 4-6 mmol/l, pre-lunch and pre-dinner > 6mmol/L Add PRANDIAL INSULIN (at morning and midday meal) PREMIED TWICE DAILY (pre-breakfast, pre-dinner) -dinner > 6 mmol/l Add PRANDIAL INSULIN (at midday meal) Add prandial insulin 6 units or 0.1unit/kg Titrate to next prandial BG target daily If subsequent pre-meal BG is - < 4 mmol/l ( > 1 value ) reduce dose by 2 units mmol/l ( all values ) maintain current dose - > 6 mmol/l ( >1 value, no hypos ) increase by 2 units

5 Intensification from mixed Regimen PREMIED OD PREMIED BD PREMIED BD PLUS PRELUNCH PRANDIAL PREMIED TDS (FOR ANALOGUES) BOLUS Intensification of mixed Regimen PREMIED OD (pre-dinner) or BD FPG and / or pre-dinner 4-6 mmol/l HbA1c > 6.5 8% FPG and / or pre-dinner > 6 mmol/l Titrate mix OD or BD to achieve FPG and / or predinner < 6mmol/L SWITCH TO PREMIED BD OR TDS (analogues only) DAILY (OD) TWICE DAILY (BD) Starting dose 0.3units/kg/day or total dose transfer Split the dose 50:50 pre-breakfast and pre-dinner Titrate insulin dose to achieve FPG and pre-dinner<6mmol/l TWICE DAILY (BD) THREE TIMES DAILY (TDS) Add 6 units or 10% total daily dose at lunch Titrate dose once or twice a week to next pre prandial goal < 6mmol/L Down titrate morning dose ( 2 4 units ) may be needed after adding lunch dose Continue metformin Consider premixed analogues if hypos Summary of treatment algorithm Newly diagnosed DM & Type 2 DM Symptomatic (osmotic symptoms) regardless HbA1c or FBS HbA1c > 10% or FPG > 13 mmol/l Type 2 DM on maximal OADs (single/double/triple) HbA1c > 8% Glycemic abnormality? FPG, SMBG Normal Fasting / prebreakfast BG High daytime BG High Fasting / prebreakfast BG Normal daytime BG High Fasting / prebreakfast BG High daytime BG INITIATE & OPTIMISE Start PRANDIAL only (usually TDS premeals) Start only (bedtime) Start PREMIED OD (predinner) Start PREMIED BD (prebreakfast & predinner) Start BOLUS (premeals, bedtime) INTENSIFY Add basal insulin Sequential addition of prandial insulin PLUS (premeal and bedtime) Add 3 prandial insulin PREMIED TDS* (premeals) Note: 1. Metformin should be continued while on insulin therapy unless contraindicated or intolerant 2. Sulphonylureas / Meglitinides should be withdrawn once prandial insulin is used regularly with meals 3. Insulin dose should be optimized prior to switching / intensifying regimens PREMIED BD PLUS PRANDIAL (prelunch) BOLUS (prandial insulin at premeals, basal insulin at bedtime) * refers to insulin analogues only

6 Insulin Regimen Starting Dose Dose Optimisation Optimal Dose Basal Insulin Initiation and Optimisation 10 units or 0.2U/kg at bedtime (0.1 units / kg if higher risk for hypos) Adjust insulin doses after 3 consecutive BG values obtained (every 3 7 days) Refer to (*) units/kg in lean patients units/kg in most patients Up to 0.7 units/kg in obese patients mixed Once daily: 10 units or 0.2U/kg at pre-dinner Twice daily: 10 units or 0.2U/ kg at pre-breakfast and predinner (0.1units/kg if higher risk for hypos) Adjust insulin doses after 3 consecutive BG values obtained (every 3 7 days) Refer to (*) -breakfast BG determine pre-dinner premixed dose adjustment -dinner BG determine pre-breakfast premixed dose adjustment Total daily dose of units/kg in most patients (Maybe more than 1.0 units/kg/day in obese, insulin resistant patients) Prandial 6 units or 0.1units/kg for each meal with short-acting or rapid-acting analogue. Adjust insulin doses after 3 consecutive BG values obtained (every 3 7 days) Refer to (*) Adjust the dose of prandial insulin of the preceding meal (eg: if pre lunch BG is high, adjust pre-breakfast prandial insulin) Prandial dose for each meal will vary according to carbohydrate content and amount. Dose should ideally not exceed 0.5U/kg/dose. Basal Bolus Prandial Insulin: 6 units or 0.1U/kg before each meal Basal insulin: 10 units or 0.2U/kg at bedtime Refer to Prandial Section Refer to Basal Section Aim for normal pre-breakfast BG first by adjusting the dose of bed-time basal insulin before adjusting the prandial (bolus) insulin dose. (*) - < 4 mmol/l (> 1 value) reduce dose by 2 units mmol/l (all values) maintain current dose - > 6 mmol/l (>1 value, no hypos) increase by 2 units Generally basal insulin would contribute 50% of total daily insulin dose and prandial insulin would contribute remaining 50% (distributed over three main meals). Refer to Prandial Section & Basal Section Insulin Intensification Intensification from Basal Regimen PREMIED BD BOLUS PLUS (1 / 2 / 3 PRANDIAL) Note: Optimise Basal Before Intensification Fix Fasting Blood Glucose (FBG) first using basal insulin (dose optimisation) Goal FBG 4 6 mmol/l Consider adding bolus / meal insulin when: Hb A1c > 7% and FBG at goal or basal insulin dose > 0.5U/kg Intensification from Basal to mixed Regime Intensification from Basal to Basal Bolus regimen Intensification from Basal to Basal Plus regimen Switch to PREMIED TWICE DAILY Total dose transfer Split dose 50:50 pre-breakfast : pre-dinner Titrate dose once / twice a week to next preprandial goal Stop SU, continue metformin Consider premixed analogue Add prandial insulin 6 units or 0.1unit/kg at each meal Monitor BG up to 4 times per day Titrate to next pre-meal / bedtime BG target daily If subsequent pre-meals BG are Refer to (*) Stop SU and continue metformin If HbA1c > 6.5-7% after 3 months despite titrating prandial doses or prandial doses > 30 units per meal, consider: Resume optimisation of basal insulin up to 0.7 U/kg Perform 7- point BG profile Add initial dose of prandial 6 units or 0.1unit/kg at largest meal Titrate to next pre-meal / bedtime BG target daily If subsequent premeals BG are Refer to (*) Discontinue SU on addition of prandial insulin Continue metformin Patients may need to perform SMBG up to 4 times per day If HbA1c > 6.5-7% after 3 months despite titrating doses, or prandial doses > 30U per meal, consider: Add 2 nd dose of prandial insulin at 6 units or 0.1unit/kg at 2 nd largest meal and titrate as before Subsequently may add 3 rd dose of prandial insulin if required (*) - < 4 mmol/l (> 1 value) reduce dose by 2 units mmol/l (all values) maintain current dose - > 6 mmol/l (>1 value, no hypos) increase by 2 units