Diabetes Review[1]

7/27/2019 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


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 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

37


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Documents

Diabetes Review[1]