diabetes review[1]
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Insulin(Review )
Tjokorda Gde Dalem Pemayun
Sub-Bagian Endokrinologi, Bagian Ilmu Penyakit Dalam
Fakultas Kedokteran Universitas Diponegoro Semarang2012
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Burden of Disease will continue to increase in the years to come
Slide 2
World 2011 = 366 million
2030 = 552 million
Increase 51%
North AmericaEurope
Middle East and North
Africa
Africa
South and Central
America
Western Pacific
Southeast Asia
38 mil.
51 mil.
36%
25 mil.
40 mil.
59%
53 mil.
64 mil.
22%
33 mil.
60 mil.
83%
15 mil.
28 mil.
90%
71 mil.
121 mil.
69%
132 mil.188 mil.
42%
Source: International Diabetes Federation; World Diabetes Atlas, 5th Edition 2011
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Classification
Slide 3
1. Type 1 diabetes
Absolute insulin deficiencydue to the destruction of pancreatic
beta-cells
2. Type 2 diabetes
Characterized by insulin resistance with relative insulin deficiency toa predominately secretary defect with insulin resistance
3. Other specific types
4. Gestational diabetes
Glucose intolerance first detected in pregnancy that often resolvesafter the birth of the baby
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The Ominous Octet
Source: Ralph .A DeFronzo Banting Lecture Diabetes 2009; 58:773-95
Slide 5
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Slide 6
What is good glycemic control?
1. Overall aim to achieveglucose levels as close to normal as
possible
2. Minimise development and progression ofmicrovascular andmacrovascular complications
FPG
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High Blood Glucose is now the 3rd biggest risk factor
contributor to cardio-vascular deaths globally
Slide 7
0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000
Unsafe Sex
High Cholesterol
Overweight and Obesity
Physical Inactivity
High Blood Glucose
Tobacco
Raised Blood Pressure
Indoor smoke from solid fuels
Childhood underweight
Alcohol use
Attributable deaths due to selected risk factors (000)
Source: WHO 2011. Global Atlas on CVD prevention and Control 1-164
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Slide 8
Treatment therapies for Type 2 diabetes
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
Lifestyle +Metformin
+-otherOAD orGLP-1
agonists
BasalInsulin
(Once-dailytreat-to-target)
BasalInsulin(Basal + 1prandial)
Basal
Insulin(Basal +2prandial)
BasalInsulin
(Basal + 3prandial)
HbA1c7.0% HbA1c7.0%, FBG on target, PPG 160 mg/dl
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Slide 9New position statement of the ADA and EASD on management of
hyperglycemia in type 2 diabetes
Inzucci SE, et al. Diabetologia. 2012
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Slide 10
Treatment options for type 2 diabetes
-Glucosidase inhibitorsDelay intestinal carbohydrate
absorption
ThiazolidinedionesIncrease glucose uptake in
skeletal muscle and decrease
lipolysis in adipose tissue
SulfonylureasIncrease insulin secretion from
pancreatic -cells
GLP = glucagon-like peptide.
Adapted from Cheng and Fantus. CMAJ. 2005;172:213226.
Meglitinides
Increase insulin secretion from
pancreatic -cells
Incretins :GLP-1 analogue(exen-
atide)/DPP-4 inhibitors Improves glucose-
dependent insulin secretion from pancreatic
-cells, supp resses glucagon secret ion
f rom-cells, slows gastric emptying
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Treatment options for type 2 diabetes
Sulfonylureas
1st generation e.g. chlorpropamide,
tolbutamide
2nd generation e.g. glyburide,
gliclazide, glipizide, gliquidone
3rd generation e.g. glimepiride
Modified release
Glinides/meglitinides
Non-sulfonylureic e.g. repaglinide
Amino acid derivatives e.g. nateglinide
Biguanides
e.g. metformin
Thiazolidinediones
e.g. rosiglitazone, pioglitazone
-glucosidase inhibitors e.g. acarbose
Insulin
regular
intermediate/long acting pre-mixed analogs
rapid acting long acting
DPP-4 Inhibitors
GLP-1 Receptor Agents
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INSULIN
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Indikasi terapi Insulin
1. DM tipe 1
2. DM tipe 2 yang tidak terkontrol diet, olah raga, OHO.3. DM gestasional
4. Gangguan faal hati & ginjal yang berat.
5. Dengan infeksi akut (selulitis, gangren),
6. TBC berat, penyakit kritis (stroke/AMI)
7. Dengan KAD/HHS
8. Dengan fraktur atau pembedahan mayor
9. Kurus (BB rendah), terkait malnutrisi /DMTM.
10. Dengan penyakit Graves
11. Dengan tumor ganas12. Dengan pemberian kortikosteroid
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Pharmacokinetics of the different Types of Insulin
Slide 14
Profil
Type of Insulin Insulin Name Onset Peak
Fast-acting Analogue Insulin Insulin Aspart (NovoRapid) 0.2 0.5 0.5 - 2
Insulin Lispro (HumaLog) 0.2 0.5 0.5 - 2
Insulin Gluisine (Apidra) 0.2 0.5 0.5 - 2
Fast-acting Human Insulin ActRapid 0.5 1 0.5 - 1
Humulin R 0.5 1 0.5 - 1
Intermediate Human Insulin Insulatard 1.5 4 4 - 10
Humulin N 1.5 4 4 - 10
Long-acting Analogue Insulin Insulin Detemir (Levemir) 1 - 3
Insulin Glargine (Lantus) 1 - 3
Pre-mix Analogue Insulin Insulin Aspart (NovoMix) 0.2 0.5 1 - 4
Insulin NPL (HumaLog) 0.2 0.5 1 - 4
Pre-mix Human Insulin Mixtard 0.5 1 3 - 12
Humulin Mix 0.5 1 3 - 12
Adapted from Mooradian et al. Ann Intern Med 2006; 145: 125-34
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Slide 15
Time-Action Profiles of Insulin
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Slide 16
New ADA/EASD Position on Sequential Insulin Strategy in Type 2 Diabetes
Non-InsulinRegimes
Basal Insulin OnlyUsually with OAD
Basal Insulin + 1 mealtimerapid-acting injection
Pre-mixed Insulin twice-daily
Basal Insulin + >2mealtime rapid-acting
injection
1
2
+3
Low
Mod.
High
Number ofInjections
RegimenComplexity
FlexibilityLess FlexibleMore Flexible
Convenience*More ConvenientLess Convenient
Inzucci SE, et al. Diabetologia. 2012. * Gumprecht et al. Intensification to to biphasic insulin aspart 30/70. Int J Clin Pract 2009
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Slide 17
Insulin Titration schemesBasal and Fast-Acting Insulin
Fasting Blood GlucoseContent (mg/dl)
Basal Insulin Titration
180 mg/dl Increase dosage 4 units per 3 daysOnce titrated, continue to monitor HbA1c every 3 months
BASALINSULIN
Fasting Blood GlucoseContent (mg/dl) Fast-acting Insulin Titration
Start with 4 units / day Increase by 2 units every 3 daysuntil target is reached
When starting Fast-acting Insulin, secretagogues should bediscontinued
FAST-
ACTINGINSULIN
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Slide 18
Insulin Titration schemesPre-mix Insulin
Blood Glucose BeforeBreakfast or Evening Meal
(mg/dl)Pre-mix Insulin Titration
144 mg/dl Increase dosage with 4 units
During Titration, measure FBG and PPG morning andevening every second day. When target reached monitor
once to twice weekly
PRE-MIXINSULIN
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
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Slide 19
Insulin Treatment Optimization
Basal Insulin OnlyUsually with OAD
Start with Basal Insulin10u / daily with mealor before bedtime.Same injection timeevery day
If glycemic target is not reachedwithin 2-3 months the intensifyInsulin treatment
If glycemic target is not reachedtitrate according to Basal TitrationScheme
Basal Insulin OnlyUsually with OAD
Basal withPrandial
Usually keep OADPremix InsulinUsually keep OAD
Basal BolusUsually keep OAD
Add Prandial startingwith 4u / day either
once or twice-daily andtitrate accordingly
Switch to Premix twice-daily.Start with equal basal dose,but give 50% per injection
and titrate accordingly
Switch to Basal Bolus(3 daily prandial) start
with 4u / day andtitrate accordingly)
Source: PERKENI Insulin Guidelines 2011
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Slide 20
Insulin Treatment OptimizationHow to Optimize Treatment after Pre-mix Initiation
Pre-mix Once-Daily
Usually with OAD
Start with Premix 10u / dayand titrate accordingly ifglycemic target is notreached. Inject at dinnertime
Pre-mix Twice-Daily
Usually with OAD
Source: PERKENI Insulin Guidelines 2011
Pre-mix Thrice-Daily
Usually with OAD
Switch to Pre-mix twice-daily ifglycemic target is not reached.Initially keep the dose but split itin half and inject at morning anddinner time. If high blood glucosebefore evening meal increase
morning mix and if high fastingBlood glucose increase eveningmix.
Switch to Pre-mix thrice-daily ifglycemic target is not reached.Add 2-6 unit or 10% of daily doseto the total dose and inject atmorning, lunch and dinner time.
Reduce morning dose with 2-4units after staring lunch timeinjections
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Slide 21
Primarily one type of Insulin device available in Indonesia
Disposable disposed ofonce empty
Less teaching time required
Primarily plastic
Prefilled devices
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Slide 22
Diabetes Retinopathy
Non-
DiabeticRetina
DiabeticMaculopathy
ProliferativeDiabeticRetinopathy
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Slide 23
Diabetes NeuropathyPrevention and Treatment
Maintain tight glycaemic control toreduce the risk or progression ofneuropathy
Exclude or treat contributoryfactors:
alcohol excess
vitamin B12 deficiency
uraemia
DCCT. NEJM 1993;329:97786
16
8
00
Percentageofcas
esaffected
p
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Update insulin initiation strategy : from the latest study in
indonesia(A1chieve)
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Type 2 diabetes is a progressive disease
Lebovitz. Diabetes Reviews1999;7:13953 (data are from the UKPDS population: UKPDS 16. Diabetes
1995;44:124958)
HOMA: homeostasis model assessment
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The Importance of treating Type 2 DiabetesType 2 diabetes is a progressive disease
Adapted from Type 2 Diabetes BASICS. International Diabetes Center 2000
Diagnosis
Insulin
Glucose
Prediabetes
(IFG/IGT)NGT Diabetes
Macrovascular changes
Microvascular changes
Inadequate
-cell function
Postprandial glucose
Fasting glucose
Insulin resistance
Insulin secretion
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Over time, glycemic control deteriorates inpatients with Type 2 diabetes
6.2% upper limit of normal rangeMedianHbA1c
(%)
UKPDS
6
7
8
9
Years from randomisation
Conventional*
GlibenclamideMetforminInsulin
2 4 6 8 100
7.5
8.5
6.5
Recommended
treatment
target 15 mmol/L; ADA clinical practice recommendations.
UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743
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Most people with type 2 diabetes will, in time,need insulin therapy because
Wright A et al. Diabetes Care 2002;25:3306
(Patients treated with chlorpropramide)
Years from start of UKPDS
Patientsrequirin
g
additionalinsulin
(%)
0
10
20
30
40
50
60
1 2 3 4 5 6
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Updated PERKENI Type 2 Diabetes TreatmentAlgorithm
Diabetes STEP 1 STEP 2 STEP 3
Healthy life styleHealthy life style
+
Mono therapy
Healthy life style+
2 OAD Combination Healthy life style
+
Combination 2 OAD
+
Basal insulin
Insulin Intensification*
*Intensive Insulin: use of basal insulin together with insulin prandial
Healthy life style
+3 OAD Combination
Alternative option, if :
No insulin is available
The patient is objecting insulin
Blood glucose is still not optimally
controlled
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,
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)
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The benefits of good blood glucose control areclear
Good control is
7.0% HbA1c
HbA1c measures the
average
blood glucose level
over the
last three months
Source: UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM et al.BMJ. 2000;321(7258):405-412.
Deaths related
to diabetes
Microvascular
complications
Myocardialinfarction
-14%
-37%
-21%
HbA1c
-1%
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Insulin remains the most efficacious glucoselowering agent
Decrease in HbA1c: Potency of monotherapy
H
bA1c
%
Nathan et al., Diabetes Care 2009;32:193-203.
CHOOSING INSULIN EARLIER
FOR BETTER EFFICACY
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Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerCys
Cys
Gln
Glu
Val
Ile
Gly
Tyr
CysAsn
Lys
ThrTyr
PhePhe
ArgGly
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Asn GlnLeu
HisB1
A21
A1
B29
Thr
Pro
Levemir (Insulin Detemir)
Pro
LysB29(N-tetradecanoyl)des(B30)human insulin
Levemir/Glargine Head-to-Head:
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Levemir/Glargine Head to Head:
Time (h)
Klein O et al. Diab Obes Metab 2007; 9:290-299
Glucoseinfusionrate
(mg/kg/min
)
0 2 4 6 8 10 12 14 16 18 20 22 24
0
0.5
1.0
1.5
2.0
2.5
3.0
0.4 U/kg 0.8 U/kg
Insulin detemir
Insulin glargine
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Levemir Demonstrated More Consistent Insulin Action54 Type 1 Diabetic Subjects Randomly Assigned to receive one type of Insulin, single dose 0.4 u/kg, 4 Different
Times
34
Adapted from Heise T et al. Diabetes. 2004;53:1614-20.
NPH NPHNPH
Glargine GlargineGlargine
Detemir
Detemir
Detemir
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Levemir reduces nocturnal hypoglycaemia by up to 65% compared to NPH
Phillis-Tsimikas. Clin Ther 2006;28(10):156981; Riddle et al 2003. Diabetes Care; 26 (11): 3080-6; Asakura T et
al, 2008. Expert Opin Pharmacother; 10 (9): 1-5; Hanel H et al 2008. J Diabetes Sci Technol; 2 (3): 478-81
Insulin NPH
Insulin Determir
Insulin glargine
RelativeRisk
Riddle et al., 2003 Phillis-Tsimikas et al., 2006
-29% -44% -53% -65%
NPH vs. glargine NPH vs. detemir
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Levemir Dose Titration Guidelines:3-0-3 Algorithm
Dose Adjustment for Each Arm
Patients who experienced hypoglycemia reduced their daily dose by 3 units
FPG target range70-90 mg/dL
FPG 90 mg/dl (5.0 mm/L)
Mean 3-day FPG(mg/dL)
0 maintaindose
3 units
3 unitsincrease dose
decrease dose
FPG target range80-110 mg/dL
FPG 110 mg/dL (6.1 mmol/L)
Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.
Start with Levemir 10 U or 0,1-0,2 U per Kg BB
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