Insulin

(Review )

Tjokorda Gde Dalem Pemayun
Sub-Bagian Endokrinologi, Bagian Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Diponegoro Semarang 2012

Burden of Disease will continue to increase in the years to come
Europe North America

38 mil. 51 mil. 36%

53 mil. 64 mil. 22%

Middle East and North Africa

Africa

33 mil. 60 mil. 83%

Western Pacific Southeast Asia

South and Central America

15 mil. 28 mil. 90%

71 mil. 121 mil. 69%

132 mil. 188 mil. 42%

25 mil. 40 mil. 59%

World

2011 = 366 million 2030 = 552 million Increase 51%
Slide 2

Source: International Diabetes Federation; World Diabetes Atlas, 5th Edition 2011

Classification
1. Type 1 diabetes
Absolute insulin deficiency due to the destruction of pancreatic beta-cells

2. Type 2 diabetes
Characterized by insulin resistance with relative insulin deficiency to a predominately secretary defect with insulin resistance

3. Other specific types 4. Gestational diabetes
Glucose intolerance first detected in pregnancy that often resolves after the birth of the baby

Slide 3

typically 9095% of all people with diabetes .Slide 4 Difference between Type 1 and Type 2 Diabetes Comparison of Type 1 and Type 2 Diabetes Features Onset Age at Onset Body Habitus Ketoacidosis Autoantibodies Endogenous Insulin Prevalence Sudden Any age (mostly young) Thin or normal Common Usually present Low or absent Less prevalent Type 1 Diabetes Type 2 Diabetes Gradual Mostly in adults Often obese Rare Absent Normal. decreased or increased More prevalent.

Slide 5 The Ominous Octet Source: Ralph . 58:773-95 .A DeFronzo Banting Lecture Diabetes 2009.

Minimise development and progression of microvascular and macrovascular complications ADA1 FPG <130 mg/dL HbA1c < 7. PERKENI 2011 Konsensus .0% PPG <180 mg/dL IDF2 FPG <110 mg/dl HbA1c < 6. 3. International Diabetes Federation 2005.Slide 6 What is good glycemic control? 1.32 (Suppl 1):S1-S97 2. IDF Clinical Guidelines Task Force. . American Diabetes Association Diabetes Care 2009.5% PPG <145 mg/dL PERKENI3 FPG <100 mg/dl HbA1c < 7% PPG <140 mg/dl 1. Overall aim to achieve glucose levels as close to normal as possible 2.

000 4.000 2.000 Attributable deaths due to selected risk factors (000’) Source: WHO 2011.000 3.High Blood Glucose is now the 3rd biggest risk factor contributor to cardio-vascular deaths globally Indoor smoke from solid fuels Childhood underweight Alcohol use Unsafe Sex High Cholesterol Overweight and Obesity Physical Inactivity High Blood Glucose Tobacco Raised Blood Pressure 0 1.000 8.000 7.000 6.000 5. Global Atlas on CVD prevention and Control 1-164 Slide 7 .

23:257. .0% HbA1c ≥7.Slide 8 Treatment therapies for Type 2 diabetes Lifestyle + Metformin +-other OAD or GLP-1 agonists (Once-daily treat-totarget) Basal Insulin (Basal + 1 prandial) Basal Insulin (Basal +2 prandial) Basal Insulin (Basal + 3 prandial) Basal Insulin HbA1c ≥7. PPG ≥160 mg/dl Adapted from Raccah et al. Diabetes Metab Res Rev 2007. FBG on target.0%.

2012 .New position statement of the ADA and EASD on management of hyperglycemia in type 2 diabetes Slide 9 Inzucci SE. Diabetologia. et al.

slows gastric emptying Thiazolidinediones Increase glucose uptake in skeletal muscle and decrease lipolysis in adipose tissue Meglitinides Increase insulin secretion from pancreatic -cells Sulfonylureas Increase insulin secretion from pancreatic -cells -Glucosidase inhibitors Delay intestinal carbohydrate absorption GLP = glucagon-like peptide.Treatment options for type 2 diabetes Incretins :GLP-1 analogue(exenatide)/DPP-4 inhibitors Improves glucosedependent insulin secretion from pancreatic β-cells. suppresses glucagon secretion from -cells. Adapted from Cheng and Fantus. 2005.172:213–226. Slide 10 . CMAJ.

glyburide. metformin • Thiazolidinediones – e.g.g. glimepiride – Modified release • -glucosidase inhibitors – e. acarbose • Insulin – – – – regular intermediate/long acting pre-mixed analogs  rapid acting  long acting • Glinides/meglitinides – Non-sulfonylureic e.g. rosiglitazone. glipizide. chlorpropamide.g. gliquidone – 3rd generation e. gliclazide. nateglinide • DPP-4 Inhibitors • GLP-1 Receptor Agents • Biguanides – e. pioglitazone .g. repaglinide – Amino acid derivatives e. tolbutamide – 2nd generation e.g.g.g.Treatment options for type 2 diabetes • Sulfonylureas – 1st generation e.

INSULIN .

terkait malnutrisi /DMTM. 9. 7. 10. OHO. penyakit kritis (stroke/AMI) Dengan KAD/HHS Dengan fraktur atau pembedahan mayor Kurus (BB rendah). 4. olah raga. Dengan infeksi akut (selulitis. 2. 3. 8. Dengan penyakit Grave’s Dengan tumor ganas Dengan pemberian kortikosteroid . 11. TBC berat. gangren).Indikasi terapi Insulin 1. 5. DM tipe 1 DM tipe 2 yang tidak terkontrol diet. 6. 12. DM gestasional Gangguan faal hati & ginjal yang berat.

5 0. Ann Intern Med 2006.5 Peak 0.12 Adapted from Mooradian et al.2 0.2 – 0.5 – 1 0.5 – 4 1.5 .2 – 0.1 0.5 0.2 – 0.1 4 .5 0.5 0.2 Insulin Gluisine (Apidra) Fast-acting Human Insulin ActRapid Humulin R Intermediate Human Insulin Insulatard Humulin N Long-acting Analogue Insulin Insulin Detemir (Levemir) Insulin Glargine (Lantus) Pre-mix Analogue Insulin Insulin Aspart (NovoMix) Insulin NPL (HumaLog) Pre-mix Human Insulin Mixtard Humulin Mix 0.5 – 1 1.5 .5 – 1 0.10 1-4 1-4 3 .5 .Slide 14 Pharmacokinetics of the different Types of Insulin Profil Type of Insulin Fast-acting Analogue Insulin Insulin Name Insulin Aspart (NovoRapid) Insulin Lispro (HumaLog) Onset 0.12 3 .5 . 145: 125-34 .10 4 .2 – 0.5 .5 – 4 1-3 1-3 0.2 – 0.2 0.5 – 1 0.

Slide 15 Time-Action Profiles of Insulin .

Basal Insulin + >2 mealtime rapid-acting injection +3 High More Flexible Less Flexible Flexibility Less Convenient More Convenient Convenience* Slide 16 Inzucci SE. 2012. et al. Int J Clin Pract 2009 .New ADA/EASD Position on Sequential Insulin Strategy in Type 2 Diabetes Non-Insulin Regimes Number of Injections Regimen Complexity Basal Insulin Only Usually with OAD 1 Low Basal Insulin + 1 mealtime rapid-acting injection Pre-mixed Insulin twicedaily 2 Mod. * Gumprecht et al. Diabetologia. Intensification to to biphasic insulin aspart 30/70.

continue to monitor HbA1c every 3 months FASTACTING INSULIN Fasting Blood Glucose Content (mg/dl) Start with 4 units / day Fast-acting Insulin Titration Increase by 2 units every 3 days until target is reached When starting Fast-acting Insulin. secretagogues should be discontinued Slide 17 .Insulin Titration schemes Basal and Fast-Acting Insulin Fasting Blood Glucose Content (mg/dl) <70 mg/dl Basal Insulin Titration Reduce dosage with 2 units Maintain dosage Increase dosage 2 units per 3 days Increase dosage 4 units per 3 days BASAL INSULIN 70-130 mg/dl 130-180 mg/dl >180 mg/dl Once titrated.

When target reached monitor once to twice weekly • • • • Evening insulin dose is titrated based upon fasting BG Morning insulin dose is titrated based upon evening pre-meal dose Advised that patients first titrate evening insulin dose and then morning dose Dose adjustments earliest every third day Slide 18 .Insulin Titration schemes Pre-mix Insulin Blood Glucose Before Breakfast or Evening Meal (mg/dl) Pre-mix Insulin Titration <72 mg/dl Reduce dosage with 4 units Maintain dosage Increase dosage with 2 units Increase dosage with 4 units PRE-MIX INSULIN 72-126 mg/dl 126-144 mg/dl >144 mg/dl During Titration. measure FBG and PPG morning and evening every second day.

with 4u / day either but give 50% per injection once or twice-daily and and titrate accordingly titrate accordingly Switch to Basal Bolus (3 daily prandial) start with 4u / day and titrate accordingly) Source: PERKENI Insulin Guidelines 2011 .Insulin Treatment Optimization Slide 19 Start with Basal Insulin 10u / daily with meal or before bedtime. Add Prandial starting Start with equal basal dose. Same injection time every day Basal Insulin Only Usually with OAD If glycemic target is not reached titrate according to Basal Titration Scheme Basal Insulin Only Usually with OAD If glycemic target is not reached within 2-3 months the intensify Insulin treatment Premix Insulin Usually keep OAD Basal with Prandial Usually keep OAD Basal Bolus Usually keep OAD Switch to Premix twice-daily.

Inject at dinner time Switch to Pre-mix twice-daily if glycemic target is not reached. Add 2-6 unit or 10% of daily dose to the total dose and inject at morning. Switch to Pre-mix thrice-daily if glycemic target is not reached. lunch and dinner time. Reduce morning dose with 2-4 units after staring lunch time injections Source: PERKENI Insulin Guidelines 2011 . Initially keep the dose but split it in half and inject at morning and dinner time.Slide 20 How to Optimize Treatment after Pre-mix Initiation Insulin Treatment Optimization Pre-mix OnceDaily Usually with OAD Pre-mix TwiceDaily Usually with OAD Pre-mix ThriceDaily Usually with OAD Start with Premix 10u / day and titrate accordingly if glycemic target is not reached. If high blood glucose before evening meal increase morning mix and if high fasting Blood glucose increase evening mix.

Slide 21 Primarily one type of Insulin device available in Indonesia Prefilled devices • Disposable – disposed of once empty • Less teaching time required • Primarily plastic .

Slide 22 Diabetes Retinopathy NonDiabetic Retina Diabetic Maculopathy Proliferative Diabetic Retinopathy .

329:977–86 . NEJM 1993.001 8 4 Intensified therapy • Maintain tight glycaemic control to reduce the risk or progression of neuropathy • Exclude or treat contributory factors: • alcohol excess • vitamin B12 deficiency • uraemia 0 0 1 2 3 4 5 Time (years) DCCT.Slide 23 Diabetes Neuropathy Prevention and Treatment 16 Percentage of cases affected Conventional therapy 12 p<0.

Update insulin initiation strategy : from the latest study in indonesia(A1chieve) .

Diabetes 1995.44:1249–58) .Type 2 diabetes is a progressive disease HOMA: homeostasis model assessment Lebovitz. Diabetes Reviews 1999.7:139–53 (data are from the UKPDS population: UKPDS 16.

International Diabetes Center 2000 .The Importance of treating Type 2 Diabetes Type 2 diabetes is a progressive disease Postprandial glucose Diagnosis Glucose Fasting glucose Insulin Insulin resistance Inadequate β-cell function Microvascular changes Macrovascular changes NGT Prediabetes (IFG/IGT) Diabetes Insulin secretion Adapted from Type 2 Diabetes BASICS.

5 6.5 7 Recommended treatment target <7. NEJM 2006. n=1704 UKPDS 34.5 6 6. †ADA clinical practice recommendations.Over time.5 8 7.355(23):2427–43 . Lancet 1998:352:854–65. UKPDS 34. insulin and/or metformin if FBG>15 mmol/L. Kahn et al (ADOPT).5 Median HbA1c (%) 7 Conventional* Glibenclamide Metformin Insulin ADOPT 8 Rosiglitazone Metformin Glibenclamide 7. glycemic control deteriorates in patients with Type 2 diabetes UKPDS 9 8.2% – upper limit of normal range 0 2 4 6 Years from randomisation 8 10 6 0 1 2 3 Time (years) 4 5 *Diet initially then sulphonylureas.0%† 6.

Diabetes Care 2002.Most people with type 2 diabetes will.25:330–6 . in time. need insulin therapy because… 60 Patients requiring additional insulin (%) 50 40 30 20 10 0 1 2 3 4 5 6 Years from start of UKPDS (Patients treated with chlorpropramide) Wright A et al.

Updated PERKENI Type 2 Diabetes Treatment Algorithm Diabetes Healthy life style STEP 1 STEP 2 STEP 3 Healthy life style + Mono therapy Healthy life style + 2 OAD Combination Note: 1. Therapy failed if target of HbA1c < 7% is not achieved within 2-3 months for each step 2. In case of no HbA1c test. if : • No insulin is available • The patient is objecting insulin • Blood glucose is still not optimally controlled Healthy life style + Combination 2 OAD + Basal insulin Healthy life style + 3 OAD Combination Insulin Intensification* *Intensive Insulin: use of basal insulin together with insulin prandial . the use of blood glucose level is also permitted. Average blood glucose level for a few BG test in one day can be converted to HbA1c (ref: ADA 2010) Alternative option.

. 2000.0% HbA1c HbA1c measures the average blood glucose level over the HbA1c last three months Myocardial infarction -14% Microvascular complications -1% -37% Deaths related to diabetes -21% Source: UKPDS = United Kingdom Prospective Diabetes Study.321(7258):405-412. BMJ.The benefits of good blood glucose control are clear Good control is ≤ 7. Stratton IM et al.

Insulin remains the most efficacious glucose lowering agent Decrease in HbA1c: Potency of monotherapy HbA1c % CHOOSING INSULIN EARLIER FOR BETTER EFFICACY Nathan et al.. . Diabetes Care 2009.32:193-203.

Levemir® (Insulin Detemir) LysB29(N-tetradecanoyl)des(B30)human insulin Tyr Pro Pro Thr A1 Lys Lys B29 Gly Ile Val Glu A21 Thr Phe Phe Gly Arg Glu Gly Cys Val Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Tyr Leu Ala Glu Val Leu His Ser Gly Cys Gln Cys Cys Thr Ser Leu Ser Ile Cys B1 Phe Val Asn Gln His Leu .

8 U/kg 2.5 Insulin glargine Glucose infusion rate 0.0 0.0 (mg/kg/min) 1.Levemir®/Glargine Head-to-Head: 3.5 1.5 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) Klein O et al.0 Insulin detemir 2.4 U/kg 0. 9:290-299 . Diab Obes Metab 2007.

2004.53:1614-20. Diabetes. single dose 0. 4 Different Times Levemir® Demonstrated More Consistent Insulin Action NPH NPH NPH Glargine Glargine Glargine Detemir Detemir Detemir 34 Adapted from Heise T et al.54 Type 1 Diabetic Subjects Randomly Assigned to receive one type of Insulin.4 u/kg. .

28(10):1569–81. Diabetes Care. Asakura T et al. Hanel H et al 2008. 10 (9): 1-5.. 2008. 2 (3): 478-81 . 26 (11): 3080-6.Levemir reduces nocturnal hypoglycaemia by up to 65% compared to NPH NPH vs. Riddle et al 2003. Expert Opin Pharmacother. J Diabetes Sci Technol. 2003 Phillis-Tsimikas et al. Clin Ther 2006. glargine -29% -44% NPH vs. detemir -53% -65% Insulin Determir Insulin NPH Relative Risk Insulin glargine Riddle et al. 2006 Phillis-Tsimikas..

0 mm/L) FPG target range 70-90 mg/dL 3 units FPG>110 mg/dL (6. 2009. Diabetes Obes Metab.1 mmol/L) FPG target range 80-110 mg/dL FPG <80 mg/dL (4.8 mmol/L) decrease dose Patients who experienced hypoglycemia reduced their daily dose by 3 units Blonde L et al. .1-0.Levemir® Dose Titration Guidelines: 3-0-3 Algorithm Start with Levemir 10 U or 0.4 mmol/L) 0 maintain dose 3 units FPG <70 mg/dL (3. 11(6):623-631.2 U per Kg BB Dose Adjustment for Each Arm Mean 3-day FPG (mg/dL) increase dose FPG>90 mg/dl (5.

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