2

Sponsored by PT. Novo Nordisk Indonesia

New INSPIRE by PERKENI and STENO Diabetes Center A National Diabetes Management Course

3

Overall Training Objectives

ü  To provide participants with a holistic understanding of diabetes management – from diagnosis to late-stage complications

ü  To provide participants with practical tools, guidelines, demonstrations and take-home educational materials to improve and optimize their diabetes treatment

ü  To emphasize and demonstrate the importance of early treatment of diabetes to avoid long-term complications

About INSPIRE Training in Indonesia

¥  Curriculum, workshops and cases designed in collaboration between PB. PERKENI and STENO Diabetes Center

¥  Joint PERKENI – STENO certificates will be distributed for a participation rate of 80%

Curriculum Sponsorship

¥  The INSPIRE Training courses, the development of the curriculum and all support programs are sponsored by PT. Novo Nordisk Indonesia to support and enhance the quality of diabetes training across Indonesia

Coordination Coordination and Alignment

4

Why INSPIRE?

BE INSPIRED AS A DOCTOR…

…TO INSPIRE YOUR PATIENTS

A TRULY UNIQUE PLACE ¥  An independent research and patient care institution funded by

the capital Region of Copenhagen and Novo Nordisk ¥  Patient care, research and education – focusing exclusively on

diabetes care and prevention ¥  One of the leading diabetes research and health promotion

centers in the world ¥  Treating 6.200 patients with Type 1 and Type 2 Diabetes

through the ‘team-based’ method

5

STENO EDUCATION CENTER Facts:

¥  Collaborating with Novo Nordisk and the Capital Region on education of HCPs ¥  Frontiers Steno Symposium ¥  STAR courses in India/Middle East/China ¥  Educational tools ¥  Partnerships with endocrine society's in selected countries (China / Indonesia)

Rules of the INSPIRE Program

¥ Certificates can only be given for minimum 80% attendance

¥  Limit Mobile Phone Activity to the Coffee Breaks

¥ Be back on time after lunch- and coffee breaks

RULES

6

Why do we see a massive increase in people with Type 2 Diabetes across the World?

Cockram CS 2000. HKMJ; 6 (1): 43-52 Mohan et al 2007. Indian J Med Res; 125: 217-230

Adapted from IDF Diabetes Atlas 4th ed., 2009

Aging population

Dietary changes Reduced physical activity

Urbanisation Unhealthy lifestyle choices

7

Diabetes is developing much faster than anticipated in Indonesia…

RISKESDAS Survey 2007

Diagnosed people with Diabetes

Undiagnosed people with Diabetes

Total people with diabetes

Total people with IGT**

1.5% 4.2% 5.7% 10.2%

* Source: RISKESDAS Survey 2007 – 24.417 subjects , >15 years ol from 33 provinces ** IFT = Impaired Glucose Tolerance

Approximately 10 million people with diabetes in Indonesia

…and our diabetes patients are not in good glycemic control DiabCare Indonesia 2008 illustrated the need for more intensive treatment to decrease FPG and PPG

n: 1.823 patients with diabetes

208

144

100

140

020406080100120140160180200220

mg/dl

PPG (mg/dl) FPG (mg/dl)

Gly

cem

ic C

ontr

ol L

evel

PERKENI Guidelines DiabCare 2008

Source: Novo Nordisk Data on File

8

Pre-Test & Questionnaire

X X Time: 30 minutes

Please fill out the Evaluation Scheme after Day 1 and Day 2 In your participant folder

9

Early Detection and Standardized Diabetes Management

Lecture:

30 minutes

Early Detection and Standardized Diabetes Management Lecture

Main Learning Points

¥  Understand the process from screening to diagnosis and the associated national guidelines

¥  Understand the importance of treating diabetes and intensify treatment on diabetes via blood glucose- and HbA1c monitoring

¥  Understand the reason and need for routine follow-up and reaching individual targets to avoid complications

10

Some Definitions before we start…

Common Definitions

Abbreviation Definition

NGT Normal Glucose Tolerance (Gula Darah Normal)

FPG Fasting Plasma Glucose (Gula Darah Puasa)

PPG Post-Prandial Plasma Glucose (Gula Darah Post Prandial)

IGT Impaired Glucose Tolerance (Toleransi Glukosa Terganggu)

IFG Impaired Fasting Glucose (Gula Darah Puasa Terganggu)

HbA1c Average amount of glucose in the bloodstreams over a 3-month period

Classification of Diabetes

¥  Type 1 diabetes ¥  Absolute insulin deficiency due to the destruction

of pancreatic beta-cells

¥  Type 2 diabetes ¥  Type 2 is characterized by insulin resistance with

relative insulin deficiency to a predominately secretary defect with insulin resistance

¥  Other specific types

¥  Gestational diabetes ¥  Glucose intolerance first detected in pregnancy

that often resolves after the birth of the baby

Diabetes Care 1997; 20: 1183-1197

11

Difference between Type 1 and Type 2 Diabetes

Comparison of Type 1 and Type 2 Diabetes

Features Type 1 Diabetes Type 2 Diabetes

Onset Sudden Gradual

Age at Onset Any age (mostly young) Mostly in adults

Body Habitus Thin or normal Often obese

Ketoacidosis Common Rare

Autoantibodies Usually present Absent

Endogenous Insulin Low or absent Normal, decreased or increased

Prevalence Less prevalent More prevalent, typically 90-95% of all people with diabetes

Type 2 diabetes is a progressive disease

Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)

HOMA: homeostasis model assessment

12

13

Classical Diabetes Symptoms

Polyuria

Unexplained weight loss

Polydipsia

Polyphagia

¥  Excessive Urination at night

¥  Excessive Hunger

¥  Excessive Thirst

¥  Weight Loss even if food in-take is normal

Other Diabetes Symptoms

Blurred Vision

Numbness and/or Tingling

Fatigue

Itchy Skin

Impotence

¥  Damaging blood vessels in the eyes

¥  Numbness and tingling in hands, legs and feet

¥  Frequent fatigue regardless of exercise

¥  Affects legs, feet, and hands

¥  Physical and Physiological

14

4 Simple Steps from Screening to Diagnosis

Conduct 1st Blood Test 2

Conduct 2nd Blood Test (if required) and establish Diagnosis

3 Screen patients with diabetes risk factors

1

Inform Patient and Initiate treatment

4

Step 1: Risk Factors – PERKENI screening risk factor guideline

Unmodifiable Risk Modifiable Risk Diabetes Associated Risk

¥  Race and Ethnic

¥  Family History of

Diabetes

¥  History of Gestational

Diabetes

¥  History of delivery a

baby more than

4.000g

¥  History of low birth

weight <2.500g

¥  Overweight (BMI >23)

¥  Hypertension >

140/90 mmHg

¥  Dyslipidemia (HDL <

35 mg/dl and/or

triglycerides >250

mg/dl

¥  Unhealthy Diet

¥  Limited Physical

Activity

¥  Polycystic Ovary

Syndrome (PCOS) or

another clinical

condition related to

insulin resistance

¥  Metabolic Syndrome

(IGT, IFG, History of

Coronary Artery

Disease , stroke

and/or PAD)

Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2

15

16

Step 4: Inform Patient and Initiate Treatment

Diabetes Mellitus IGT IFG

¥  Evaluation of Nutritional Status

¥  Evaluation of Diabetes

Complications

¥  Evaluation of Required Food

Regulation

¥  Decision on medicines

¥  Education

¥  Food Regulation

¥  Physical Exercise

¥  Ideal Body Weight

¥  OADs are unnecessary at

this stage

Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2

Cut-points: Diabetes, IGT and IFG

mg/dL

2-hour Plasma Glucose (PPG)

Fast

ing

Pla

sma

Glu

cose

(FP

G)

mg/dL

140 200

100

126

NGT (Normal Glucose

Tolerance)

Diabetes

IFG (Impaired Fasting Glucose

IGT (Impaired Glucose

Tolerance) Diabetes

17

Diagnosis of Type 2 Diabetes KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2

1.  Classical symptoms of Diabetes (+) & Random plasma glucose concentration ≥ 200 mg/dl

2.  Classical symptoms of Diabetes (+) & Fasting Plasma Glucose ≥ 126 mg/dl.

3.  2-hour post-OGTT ≥ 200 mg/dl.

Note:

¥  Classical symptom of diabetes (+), only need 1 abnormal BG

¥  No classical symptom of diabetes, need 2 x abnormal BG level in a different days

Or

Or

18

What is good glycemic control?

¥  Overall aim to achieve glucose levels as close to normal as possible

¥  Minimise development and progression of microvascular and macrovascular complications

FPG <130 mg/dL

HbA1c < 7.0%

PPG <180 mg/dL

FPG <110 mg/dl

HbA1c < 6.5%

PPG <145 mg/dL

IDF2

ADA1

PERKENI3

1. American Diabetes Association Diabetes Care 2009;32 (Suppl 1):S1-S97 2. IDF Clinical Guidelines Task Force. International Diabetes Federation 2005. 3. PERKENI 2011 Konsensus .

FPG <100 mg/dl

HbA1c < 7%

PPG <140 mg/dl

HbA1c correlation with blood glucose level

David M. Nathan, Judith Kuenen, Rikke Borg, Hui Zheng, David Schoenfeld, and Robert J. Heine, for the A1c-Derived Average Glucose (ADAG) Study Group. Diabetes Care 2008

The relationship between A1C and eAG is described by the formula 28.7 X A1C – 46.7 = eAG

19

Risk of Complications increases as Hb1Ac increases and that’s why diabetes must be treated

Stratton IM et al. BMJ 2000;321:405–12

0

20

40

60

80

5 6 7 8 9 10 11

Myocardial infarction

Microvascular disease

Adjusted for age, sex, and ethnic group. The relationship between A1C and mg/dl is described by the formula 28.7 X A1C – 46.7 = mg/dl.

Inci

denc

e pe

r 1.

000

patie

nt-

year

s

126 97 154 183 212 240 269

Mean HbA1c (%)

Mean mg/dl

The benefits of good blood glucose control are clear

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

Myocardial infarction

-14%

-37%

-21%

HbA1c

-1%

20

Practical Monitoring Scheme

Source: Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia. PERKENI. 2011. Diabetes Care 2012. Penatalaksanaan Diabetes Melitus Terpadu. 2009

Practical Monitoring Scheme Cont…

Source: Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia. PERKENI. 2011. Diabetes Care 2012. Penatalaksanaan Diabetes Melitus Terpadu. 2009

21

Individualized Treatment based on several criteria to control blood glucose

Early Detection and Standardized Diabetes Management Lecture

Main Learning Points

¥ Understand the importance of treating diabetes and reaching individual targets to avoid complications

¥ Understand the process from screening to diagnosis and the associated national guidelines

¥ Understand the reason and need for routine follow-up and intensify treatment on diabetes via blood glucose- and HbA1c monitoring

Summary

¥ Diabetes is a progressive disease that must be treated in order to avoid long-term complications

¥ Good glycemic control according to PERKENI is:

¥  HbA1c <7% ¥  FPG: <100 mg/dl ¥  PPG: <140 mg/dl

¥  Patient treatment need to be individualized according to the characteristics of each particular patients

22

Handout: Overview of Diabetes National Clinical Practice Guidelines

Ref: Rudianto et al. The Indonesian Society of Endocrinology’s Summary Article of Diabetes Mellitus National Clinical Practice Guidelines. JAFES Vol. 26 (1), May 2011

23

Diabetes and its Co-morbidities –Hypertension and Dyslipidemia

Lecture:

30 minutes

Diabetes

HypertensionDyslipidemia

Diabetes and its Co-morbidities – Hypertension and DyslipidemiaLecture

Main Learning Points

• Understand the relationship between diabetes and hypertension• Understand how hypertension should be treated and how

diabetic patients with hypertension should be treated• Understand the relationship between diabetes and

dyslipidemia• Understand how dyslipidemia should be treated and how

diabetic patients with dyslipidemia should be treated

24

Diabetes and its Co-morbiditiesHypertension

Categories for Blood Pressure Levels in Adults (JNC VII)*

* Aged 18 years or older

Blood Pressure Level (mmHg)Category Systolic Diastolic

Normal < 120 And < 80

Prehypertension 120 -139 Or 80 – 89

High Blood PressureStage 1 Hypertension 140 - 159 Or 90 - 99

Stage 2 Hypertension > 160 Or > 100

When systolic and diastolic blood pressures fall into different categories, the higher category should be used to classify blood pressure level. For example, 160/80 mmHg would be stage 2 hypertension (high blood pressure)

Why focus on the triangle of diabetes, hypertension and dyslipidemia?

Diabetes

HypertensionDyslipidemia

“Triangular Focus’ Treatment Implications

• 40-60% of type 2 diabetes patients will also have either hypertension, dyslipidemia or both

• Hypertension and Dyslipidemia are both well established risk factors for diabetes-related complications like CVD and nephropathy

• Early and correct treatment of hypertension and dyslipidemia can delay the onset of diabetes complications

25

Diabetes Is a Major Multiplier of Cardiovascular Risk in Patients With HypertensionSystolic Blood Pressure and Cardiovascular Mortality

Stamler J, et al. Diabetes Care. 1993;16:434–444.

130

85

62

422218

245

153160

112

7355

0

50

100

150

200

250

Car

dio

vasc

ula

rM

ort

alit

yR

ate

Per

10

,00

0 P

erso

n-Y

ears

120 - 139<120 >200Systolic Blood Pressure mmHg

160 -179 180 - 199140 -159

DiabetesNo Diabetes

Effect of Blood Pressure Control in the UKPDSTight vs. Less Tight Control

Any diabetes-related endpointDiabetes-related deathsHeart failureStrokeMyocardial infarctionMicro vascular disease

Tight Control

1,148 Type 2 patients Average BP lowered to 144/82 mmHg (controls: 154/87);

9-year follow-up

243256442137

Risk Reduction (%) P value

0.00460.019

0.00430.013

NS0.0092

UKPDS Group. BMJ. 1998;317:703-713.

26

UKPDS hypertension sub-study: Tight blood pressure control reduces complications in diabetes

UKPDS Group. BMJ. 1998;317:703-713.

Stroke

Years

0

20

15

10

5

44% risk reduction P = 0.013

30 5 7 86421 9

Patie

nts

with

eve

nts

(%)

Years

Diabetes-related deaths

0

40

30

20

10

30 5 7 86421 9

32% risk reduction P < 0.02

Patie

nts

with

eve

nts

(%)

Less tight control: mean BP 154/87 mmHg

Tight control with captopril or atenolol: mean BP 144/82 mmHg

Years

Microvascular disease

Patie

nts

with

eve

nts

(%)

0

20

15

10

5

30 5 7 86421 9

37% risk reduction P < 0.01

Major Outcomes of the Hypertension Optimal Treatment (HOT) TrialDiabetes Sub-group shows that lowering blood pressure is beneficial for diabetes patients with hypertension

Hansson L, et al. Lancet. 1998;351: 1755-1762.

11

8

24

11

4

18

33

11

0

5

10

15

20

25

30

CV Mortality

Even

ts/

10

00

Pt-

Yea

rs

MIMajor CV Events

<85 mmHG (n=501)<90 mmHG (n=501)

<80 mmHG (n=499)

Diastolic Target

27

ADA Recommendations on Hypertension

Diabetes Care 2012; 35 (Suppl. 1): p29Years

Systolic Blood Pressure <130 mmHg, however depending on patient characteristics and response to therapy, higher

or lower SBP targets may be appropriate

GOAL

SBPor DBP

130 – 139 mmHg80 – 89 mmHg

SBPor DBP

> 140 mmHg> 90 mmHg

• Lifestyle therapy alone for a maximum of 3 months

• If targets are not achieved, start treatment with pharmacological agents

• Should receive pharmacological therapy in addition to lifestyle therapy

JNC 7 Algorithm for Treatment of Hypertension

Lifestyle Modifications

Initial Drug Choices

Not at Goal BP (<140/90 mm Hg)(<130/80 mm Hg for those with diabetes or chronic kidney disease)

Without Compelling Indications

Stage 1 HTN(SBP 140-159 or DBP 90-99 mm Hg)Thiazide-type diuretics for most.May consider ACEI, ARB, BB, CCB,

or combination.

Optimize dosages or add additional drugs until goal BP is achieved.Consider consultation with hypertension specialist.

Drug(s) for the compellingindications

other antihypertensive drugs(diuretics, ACEI, ARB, BB, CCB)

as needed.

Without Compelling Indications

Not at GoalBP

Stage 2 HTN(SBP 160 or DBP 100 mm Hg)

2-drug combination for most (usuallythiazide-type diuretic and

ACEI, ARB, BB, or CCB)

Chobanian AV et al. JAMA. 2003;289:2560-72

28

ADA Recommendations on Hypertension Cont.

Diabetes Care 2012; 35 (Suppl. 1): p29

Lifestyle Treatment Pharmacological Treatment

• Weight Control

• Increased consumption of fruit,

vegetables and low fat diet

• Sodium restriction

• Increased physical activity

• Alcohol moderation

• Pharmacologic therapy

• A regimen that includes either an

ACE I or ARB

• If one class is not tolerated, the

other should be substituted

• Other classes but RAS are equally

good.

• Multiple drugs are generally required

• If ACE I, ARBs, or diuretics are used:

• Monitor: kidney function and s-

potassium

Most relevant drugs are indicated for hypertension patients with diabetes

Chobanian, et al.2004

29

Dyslipidemia

Dyslipidemia in Diabetes

• Total cholesterol

• LDL cholesterol

• HDL cholesterol

• Triglyceride

30

Mean Plasma Lipids at Diagnosis of Type 2 DiabetesUKPDS

Number of Pts

TC (mg/dl)

LDL-C (mg/dl)

HDL-C (mg/dl)

TG (mg/dl)

Type 2 Control

MEN

* P<0.001, ** P<0.02 comparing type 2 vs. control group

2139

213

139

39**

159*

52

205

132

43

103

Type 2 Control

WOMEN

1574

224

151*

43*

159*

143

217

135

55

95

UKPDS Group. Diabetes Care 1997;20:1683-1687.

Diabetes & Dyslipidemia

• NHANES 1999–2000 prevalence of control of LDL-C, HDL-C, and triglycerides (TG) among those with vs. those without diabetes

M.J. Jacobs et al. /Diabetes Research and Clinical Practice 70 (2005) 263–269

Control of LDL-C indicated as <2.6 mmol/l (<100 mg/dl), HDL-C >1.0 mmol/l (40 mg/dl) for men and >1.3 mmol/l (50 mg/dl) for women, and TG <1.7 mmol/l (150 mg/dl).

31

Heart Protection StudyProportions of patients with major vascular events in the Heart Protection Study (HPS) by year of follow-up evaluation and numbers of events prevented with simvastatin treatment per 1,000 individuals

The American Journal of Cardiology, Volume 92, Issue 4, Supplement 2, 21 August 2003, Pages 3–9

Meta-analysis of statin treatment in diabetes

Risk reduction of clinical outcomes per 40 mg/dL (1.0 mmol/L) reduction in LDL cholesterol• 21% reduction major vascular events• 25% reduction in coronary revascularisation• 21% reduction in stroke

• 9% reduction in all-cause mortality • 13% reduction in CVD mortality• No difference in non-vascular mortality

Independent of baseline LDL or prior CVD

Lancet, 371, 117-25, 2008

32

Updated ATP III LDL-C Goals and Cutpoints for Therapy

Grundy SM et al. Circulation 2004;110: 227-239

Risk Category

LDL-C (mg/dL)

GoalInitiation Level for

TLC

Consideration Level for Drug

Therapy

High risk: CHD or CHD risk equivalents (10-yr risk >20%)

<100 (optional:

<70)

≥100 ≥100(<100: consider drug

options)

Moderately high risk: 2+ risk factors (10-yr risk 10–20%)

<130 (optional:

<100)

≥130 ≥130(100–129: consider

drug options)

Moderate risk:2+ risk factors(10-yr risk <10%)

<130 ≥130 ≥160

Lower risk:0–1 risk factor

<160 ≥160 ≥190(160–189: LDL-C–

lowering drug optional)

Statin therapy algorithm

Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report. National Heart, Lung, and Blood Institute and NationalInstitutes of Health Website. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed November 25, 2009.

33

Conclusions on Statins

ADA 2012

• Statin therapy should be considered for all individuals with type 2 diabetes• independent of baseline lipid levels if previously CVD

• Statin therapy should be considered for all patients above 40 y with more than 1 risk factor

• Especially if • Prior CVD• Albuminuria• Smokers• Hypertension• Severe family history

• Lack of data for age < 40y

• Should be considered in type 1 diabetes at high risk of CVDor with signs of diabetic complications

Risk stratification as per NCEP ATP III guidelineMajor risk factors as per ATP III guidelines

Major risk factors to modify treatment of LDL(excluding LDL cholesterol)

Nonmodifiable ModifiableAge: male ≥45 years and female ≥55 years

Hypertension: BP ≥140/90 mm Hg or on antihypertensive agents

Family history of premature CHD: CHD in male first-degree relative <55 years and in female first-degree relative <65 years

Low HDL cholesterol levels: <40 mg/dL

(HDL ≥60 mg/dL is protective)Cigarette smoking

34

Fibrates algorithm

Fibrates

• Greater reductions in triglycerides

• Increase HDL cholesterol more effective than statins

• Combined treatment (fibrates + statins) decrease

triglycerides and LDL cholesterol and increase HDL

cholesterol more than statins or fibrates as

monotherapy

• However, the combination of fenofibrate and

simvastatin does not reduce the rate of fatal

cardiovascular events, nonfatal MI, or nonfatal stroke,

as compared with simvastatin alone

35

Nicotinic Acid

• Significant reduction in triglycerides and increases

HDL compared to fibrates and statins

• Significant effects in combination with statins on

Intima Media Thickness (proxy marker of

atherosclerosis) compared to statins alone

• Adverse effects: vasodilatation (flushing), increases

HbA1c, increase uric acid

• No data on Nicotinic acid on CVD endpoints

Order of Priorities for Treatment of Diabetic Dyslipidemiain Adults

Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

LDL Cholesterol Lowering1

• First choice: HMG CoA reductase inhibitor (statin)• Second choice: Bile acid binding resin or fenofibrate

HDL cholesterol raising2• Behavior interventions such as weight loss, increased

physical activity and smoking cessation• Glycemic control• Difficult except with nicotinic acid, which is relatively

contraindicated, or fibrates. Evidence for treating HDL with drugs is limited and priority should be on lowering LDL

Triglyceride lowering3

• Glycemic control first priority• Fibric acid derivative (gemfibrozil, fenofibrate)• Statins are moderately effective at high dose in

hypertriglyceridemic subjects who also have high LDL cholesterol

36

Diabetes and its Co-morbidities – Hypertension and DyslipidemiaLecture

Main Learning Points

• Understand the relationship between diabetes and hypertension

• Understand how hypertension should be treated and how diabetic patients with hypertension should be treated

• Understand the relationship between diabetes and dyslipidemia

• Understand how dyslipidemia should be treated and how diabetic patients with dyslipidemia should be treated

Summary

• Measure blood pressure at all visits because hypertension should be treated to prevent complications of diabetes

• Target 130/80 mmHg or 125/75 mmHg if proteinuria> 1 gram/24 hrs.

• Control lipid profile to prevent cardiovascular event in diabetes

• Target of LDL-cholesterol in diabetes:

• No CVD :<100 mg/dL

• Prior CVD or high risk : <70 mg/dL

37

Non-Pharmacology Intervention

Lecture:

30 minutes

Non-Pharmacology Intervention Lecture

Main Learning Points

¥ The relationship between nutrition and blood glucose control

¥ Understand the eating pattern in the local region that could play a role on the fat or carbohydrate intake

¥ Determine healthy and unhealthy eating and initiating and assessing dietary intervention in a clinical setting

¥ Understand the importance of exercise and the relationship between exercise and blood glucose control

¥ Understand the relationship between smoking and diabetes associated complications

38

Diet & Exercise in Diabetes

¥  Important in type 1 and type 2 diabetes ¥  In type 2 diabetes:

¥  Obesity and physical inactivity are major risk factors

¥  Diet and exercise may provide good long-term glycaemic control in some patients

¥  Improved cardiovascular status ¥  Cost-effective

Something went wrong…

2.5 million years 50 years

39

Medical Nutrition Therapy in Diabetes

As integral part of : ¥  Prevention and management of diabetes ¥  Component of diabetes education ¥  Prevention of diabetes complication

Source: Diabetes Care, Vol. 31, Suppl. 1, 2008

Targets of Medical Nutrition Therapy in prevention and management of Type 2 Diabetes

Diabetes Care, Vol. 31, Suppl. 1, 2008

Individual with Diabetes Risk-factors or with pre-diabetes Individual with diagnosed Diabetes

1) To reduce the risk of diabetes and cardiovascular disease by promoting healthy food choices and physical activity leading to moderate weight loss that is maintained.

1)  To achieve and maintain:

¥  Blood Glucose levels in the normal range

¥  A lipid profile that reduces the risk for vascular diseases

¥  Blood Pressure levels in the normal range

2)  To prevent / delay progressivity of chronic complications

3)  To address individual nutrition needs, taking into account personal and cultural preferences and willingness to change

40

The relationship between healthy nutrition and blood glucose

Source: Long-term Effects of a Lifestyle Intervention on Weight and Cardiovascular Risk Factors in Individuals with Type 2 Diabetes; Four Yesr Results of the Look AHEAD Trial. The Look AHEAD Reseach Group

DSE: Diabetes Support and Education

ILI: Intensive Lifestyle Intervention

The Fundamentals of food management for diabetes patients

Similar with healthy people: ¥  Balance food intake according to calories and nutrition

needs for each individual ¥  Weight loss, increased physical activity, and weight

management ¥  Consistency in day-to-day carbohydrate intake at

meals and snacks ¥  Nutritional content ¥  Timing of meals and snacks ¥  Carbohydrates are the principal determinant for blood

glucose Emphasis (‘triple Js)’: ¥  Jadwal (Schedule) ¥  Jenis (Type) ¥  Jumlah (Amount)

41

Calorie Requirement Formula

¥  Harris–Benedict formula

¥  Men = 66 + (13.7 x weight in kg) + (5 x height in cm) - (6.8 x age in years)

¥  Women = 65.5 + (9.6 x weight in kg) + (1.7 x height in cm) - (4.7 x age in years)

Frankenfield DC, et al. The Harris-Benedict studies of human basal metabolism: history and limitations. J Am Diet Assoc. 1998;98:439-445

Guidelines for a healthy diet PERKENI 2011

¥  Healthy balanced diet composed of: ¥  45-65% carbohydrate ¥  20-25% fat ¥  10–20% protein

Fat

Carbohydrate Protein

42

Carbohydrate

Eat Less of These Eat More of These

Fruit, Low fat Milk, Beans, Brown rice, Yoghurt, Whole wheat bread

White sugar, Brown sugar, White bread, White rice,

DASH Pyramid

43

Proteins

Eat Less of These Eat More of These

Chicken, Fish, Tofu Sausages, processed meat, Shrimps and shell fish, Red Meat

Fat

Eat Less of These Eat More of These

Avocado, Nuts, Olives, Oils rich in poly and mono unsaturated fats

Coconut, Margarine/butter, Cheese, Oils/fats rich in saturated fat

44

Understanding portion sizes is important Recommendation to take smaller portion sizes of the less recommended food

Rice boiled – 100 g Calorie – 175 kcal

Carbohydrates – 40gm

Rice boiled – 200 g Calorie – 350 kcal

Carbohydrates – 80gm

Noodles boiled – 200 gm Calorie – 175 Kcal Carbohydrates – 40 gm

Source: Daftar Bahan Makanan Penukar

How you cook is important

Less Healthy More Healthy

45

The relationship between exercise and blood glucose

Diabetology & Metabolic Syndrome, 2009, 1:27

HbA1c values collected 12 weeks prior to the initiation of the exercise program (Baseline), at the start of the exercise program (Pre-Intervention) and at the completion of the 10 weeks program (Post-Intervention). Ten week changes are denoted by * (p < 0.05). A difference between exercise groups is denoted by # (p < 0.008).

Both resistance and aerobic exercise were effective in reducing blood glucose levels and HbA1c levels

46

Boulé NG, et al. JAMA 2001;286:1218-27.

-0.66% -0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

Exercise

Non-exercise control

Cha

nge

in H

bA1c

fr

om b

asel

ine

to p

ost-

inte

rven

tion

(wei

ghte

d m

ean

differ

ence

)

p<0.001

Effect was weight-

independent

0.08%

Pooled meta-analysis of 14 exercise trials

%

Exercise significantly reduces HbA1c

Source: Boule NG et al. Effects of exercise on glycemic control and body mass in T2 Diabetes: JAMA2001; 286:1218-27

47

Diabetes and Smoking Background

Before diabetes ¥  Smoking is associated with insulin resistance ¥  dose-response relationship between smoking and the risk

of type 2 diabetes ¥  Stopping to smoke decreases the risk of type 2 diabetes

Additional to diabetes ¥  Smoking increases the risk of developing diabetic

complications - nephropathy, neuropathy and retinopathy ¥  Independent risk factor for CVD and all-cause mortality ¥  Smokers are also lipid intolerant ¥  Smoking cessation increases HDL and reduces LDL levels,

despite weight gain

Facchini. F. S et al Lancet, (1992) 339 (8802) , pp. 1128-1130 . Al-Delaimy WK, et al. Arch Intern Med. 2002;162(3):273-279. Patja, K., et al Journal of Internal Medicine, 258: 356–362. Chaturvedi N, Diabetes Care 1995; 18: 785–92.Jacobs DR Jr et al Arch Intern Med 1999;159: 733-40. Axelsen M., et al (1995), Journal of Internal Medicine, 237: 449–455.D.P. Mikhailidis, et al (1998) The Journal of the Royal Society for the Promotion of Health 118: 91

Significant reduction in mortality of diabetes patients among non-smokers*

591

368323275215

1,984

1,443

1,2191,249

1,012

0

500

1,000

1,500

2,000

Mor

talit

y Ra

te (

per

100.

000

pers

on-y

ears

)

Past 1-14 cig / day Never 15-34 cig / day

35+ cig / day

Non-diabetic woman Diabetic woman

Source: Wael K. Al-Delaimy et al. Diabetes Care 24: 2043-2048, 2001

cig = cigarette

RR of mortality 1.31 1.43 1.64 2.19

* Adjusting BP, high cholesterol & other CV risk factors

48

Practical Initiation of Diet Programs for diabetes patients Food Mapping Systems

Food Mapping System can be used for patient education to increase patient compliance with diet scheme

Beras Merah Kukus Nasi Putih Nasi Goreng

Ayam Bakar Ayam Goreng Ayam Goreng Tepung

Ikan Bakar / Kukus Ikan Goreng Udang Goreng

Sayur Kukus Kukus Dim Sum Dim Sum Goreng

Group Discussion

49

Practical Initiation of Diet Programs for diabetes patients Healthy Plate Models

T-shaped plate model to loose

weight

Y-shaped plate model to

maintain weight

Portion Control Plate was effective in inducing weight loss and decreased use of hypoglycemic medications in obese patients with type 2 diabetes mellitus

Vegetables

Carbo-hydrate /

Starch

Protein

Carbo-hydrate /

Starch Vegetables

Protein

Pedersen DE et al. Arch Intern Med. 2007; 167

Practical Initiation of Exercise Programs for diabetes patients CRIPE Pricnciple

CRIPE: Continuous, Rhytmic, Interval, Progressive, Endurance

Continuous ¥  Exercises should be done continuously without rest (e.g. 30 minutes of jogging without rest)

Rhythmic ¥  Choose more rhythmical sports where regular

contraction and relaxation are possible (e.g. walking, jogging, running and swimming)

Interval ¥  Exercises with both quick and slower actions (e.g. running followed by jogging)

Progressive ¥  Increase intensity according to abilities (heart rate target: 75-85% from maximum heart rate)

Endurance ¥  Exercise for endurance to improve

cardiorespiratory abilities (e.g. walking, jogging, swimming, cycling)

50

Non-Pharmacology Intervention Lecture

Main Learning Points

¥  The relationship between nutrition and blood glucose control

¥ Understand the eating pattern in the local region that could play a role on the fat or carbohydrate intake

¥ Determine healthy and unhealthy eating and initiating and assessing dietary intervention in a clinical setting

¥ Understand the importance of exercise and the relationship between exercise and blood glucose control

¥ Understand the relationship between smoking and diabetes associated complications

Summary

¥  It’s importance to educate the patients about diet, exercise and non-smoking recommendations as sufficient evidence is available about the improvement in HbA1c levels through lifestyle intervention

¥  Simple patient supporting tools like food mapping system or the CRIPE exercise principle are readily available

¥  It is important to negotiate with the patients on which food choices are the healthiest based upon the patient eating patterns

51

Diabetes Acute Complications – Hypoglycemia and DKA

Lecture:

30 minutes

Management of HypoglycemiaLecture

Main Learning Points

• Understand the hypoglycemia mechanism, diagnosis and how hypoglycemia should be treated

• Understand how to adjust OAD - or insulin dosage after hypoglycemic events

• Understand what causes a DKA event, how DKA is treated and what to do if you experience a patient with DKA

52

Why address hypoglycemia in diabetes training

• Reducing HbA1c levels associated with prevention or delay in complications and death

• Hypoglycaemia is a limiting factor in achieving glycaemic targets• Hypoglycaemia is associated with morbidity and rarely

even be fatal• Optimising glycaemic control is of obvious importance:

• $465 billion USD spent to treat diabetes and its complications in 2011; hypoglycaemia is cost-intensive

• 6.8% of global all-cause mortality attributed to diabetes in 2010 (4 million deaths)

Cryer et al 2003. Diabetes Care; 26,6: 1902-1912. IDF Diabetes Atlas tth ed., 2009. Roglic and Unwin 2010. Diabetes Research and Clinical Practice; 87: 15-19

What is hypoglycemia?

neurogenic symptoms due to low plasma glucose levels

• Low plasma glucose levels defined as:• ≤70 mg/dL (ADA)1

• <60 mg/dl (PERKENI)2

• <72 mg/dL (CDA)3

• Symptoms respond to the administration of carbohydrate3

1. ADA. Diabetes Care 2005;28:1245–9; 2. PERKENI Konsensus 2011. 3. Yale et al. Canadian J Diabetes 26:22–35

ADA, American Diabetes Association; CDA, Canadian Diabetes Association;

A state of neuroglycopenic and/or neurogenicsymptoms due to low plasma glucose levels

53

Most common symptoms of Hypoglycemia

Patients (%)

Circumoral paraesthesia

Difficulties in concentration

Slurred speech

Blurred vision

0 20 40 60 80 100

HungerPalpitations

Vertigo

Cold feelingAnxiety

Euphoria

WeaknessTremor

Sweating

Headache

Nausea

Pramming 1991

Sequel of hypoglycaemia

• Mild symptomatic hypoglycaemia • No direct serious clinical effects • May impair subsequent hypoglycaemia awareness

• Severe hypoglycaemia associated with• Stroke and transient ischaemic attacks• Memory loss/cognitive impairment• Myocardial infarction• Injury (direct/indirect)• Death

Turner et al. (UKPDS 33), 1998. The Lancet; 352: 837-853

54

Risk Factors of Hypoglycemia

• General risk factors for hypoglycaemia:1,2

• delayed or missed meal• consuming a smaller meal than planned• exercise• use of diabetes medications• drug/alcohol consumption• increased insulin sensitivity or decreased insulin clearance

• Risk factors for major hypoglycaemia:3,4

• age/duration of diabetes treatment• intensive glycaemic control• hypoglycaemia unawareness

• sleep• antecedent hypoglycaemia• history of major hypoglycaemia

1.Briscoe & Davis. Clin Diabetes 2006;24:115–21; 2. ADA Workgroup on Hypoglycemia. Diabetes Care 2005;28:1245–9. 3. Frier. Diabetes Metab Res Rev 2008;24:87–92; 4. Cryer. Diabetes 2008;57:3169–76

Hypoglycaemic events occur more often in Type 1 diabetes patients and are less frequent and less severe in Type 2 diabetes patients both on conventional and intensive therapy

Adapted from DCCT Research Group. Diabetes 1997. Adapted from Bonds D., data presented at ADA 2009

Even

ts p

er 1

00 P

atie

nt Y

ears

HbA1c (%)

Conventional Therapy

0102030405060708090

100

6.0 6.5 7.0 7.5 8.0 8.5 9.0

ACCORD (T2 DM)DCCT (T1 DM)

Even

ts p

er 1

00 P

atie

nt Y

ears

HbA1c (%)

Intensive Therapy

0102030405060708090

100

6.0 6.5 7.0 7.5 8.0 8.5 9.0

DCCT (T1 DM)ACCORD (T2 DM)

55

Treatment of mild Hypoglycemia

First: 10–20 g fast-acting carbohydrate, e.g.:• 3–6 glucose tablets*

• 90–180 ml fizzy drink or squash (not diet)**

• Two teaspoons of sugar added to a cup of cold drink

• 50–100 ml energy drink (e.g. Lucozade®)*

Then: • If next meal is due, add extra carbohydrate

• If next meal is not due, eat longer-acting carbohydrate, such as biscuits or a sandwich

Treating early signs

RCN 2004

*not widely available in Indonesia** Indonesia processed drinks (tea, etc)

Prevention of Hypoglycemic Events

• Education• Symptoms• Self management• Proper food intake in therapy• For elderly patients, caregiver should also be educated

• Repetitive education in patients with decreased cognitive function

• Self monitoring blood glucose (SMBG)• Exercise planning

• Measuring blood glucose before exercise• Consuming carbohydrate • Adjust insulin dose based on the blood glucose level

• Right type and dose for therapy

56

Treatment of moderate-to-major Hypoglycemia

Patient requires assistance with treatmentIf conscious:

• Carer should help the patient to consume 10–20 g fast-acting carbohydrate

• Dextrose gel* may be useful

If unconscious: • Don’t put anything in patient’s mouth• IM or SC glucagon* or IV glucose should be

administered• Emergency services should be called

Treating late signs

RCN 2004; Cryer 2010

IM: intramuscular, SC: subcutaneous, IV: intravenous

Adjusting Dosage after a Hypoglycemic Event

If hypoglycemic events are

repeated, OAD and / or Insulin

dosages should be reduced

OAD: Depending on drug

Insulin: Initially decrease

with 2 units / day

57

Diabetes Ketoacidosis

What is Diabetes Ketoacidosis

Watkins et al. In: Diabetes and its Management 2003

Acute decompensated metabolic state due to severe insulin deficiency over-activity of glucagon & other counter-regulatory

hormone

Common in Type 1; Rare in Type 2

Potentially life-threatening

High mortality

Incidence : 5-8 /1000 diabetic persons/yr

Mortality rates 9-14 % - Has improved with insulin use 2%

58

How to Diagnose Diabetes Ketoacidosis

Anorexia

Nausea

Vomiting

Thirst

Polyuria

Weakness

Abdominal pain

Weight loss

Tachycardia

Hypotension

Hypothermia

Impaired consciousness

Warm dry skin

Kussmaul respiration

Acetone odour on breath

Symptoms Signs

Why are patients developing ketoacidosis

The most common events that cause a person with diabetes to develop diabetic ketoacidosis are:

infection such as diarrhea, vomiting, and/or high fever (40%)

missed or inadequate insulin (25%)

newly diagnosed or previously unknown diabetes (15%)

Various other causes may include a heart attack,stroke, trauma, stress, alcohol abuse, drug abuse, and surgery.

Approximately 5% to 10% of cases have no identifiable cause

59

Diabetes Ketoacidosis Definitions

Diabetes Care, Vol. 29, Number 12, December 2006

DKA is defined as:

Increase serum concentration of ketones greater than 5 mEq/L (beta hydroxybutirate acid > 0,6)

Blood glucose level greater than 250 mg/dL (although it is usually much higher),

Blood pH less than 7.3

Ketonemia and ketonuria are characteristic, as is a serum bicarbonate level of 18 mEq/L or less (< 5 mEq/L is indicative of severe DKA)

Objectives and Management of DKA Treatment

1. Search & treat precipitating cause

2. Replacing fluids

3. Insulin iv (rapid / short-acting)

4. Replacing electrolytes -potassium & magnesium-if required

5. For GPs: If you observe a DKA case, immediately send the patient to the hospital

1. To normalize blood glucose as soon as possible with Insulin

2. To replace fluids and reverse ketoacidosis

3. Monitoring:

• Vital signs

• Fluid and electrolyte balance

• Glycaemia

Objectives Management

60

Initial DKA Treatment in Primary Care

1. Evaluate vital signs and urine volume

2. IV line, start the rehydration3. Check the blood glucose

periodically (per hour if possible)

Prepare the patient for Hospital

12:00 12:30 1:00 2:00

30 min. 30 min. 60 min.

• Start insulin with bolus IV 180 mU/kgBW, and continue with insulin drip 90 mU/hour/kgBW

• Check blood glucose per hour with glucometer on the way to hospital

Diabetes Acute Complication – Hypoglycemia and DKALecture

Main Learning Points

• Understand the hypoglycemia mechanism and how hypoglycemia should be treated

• Understand how to adjust OAD - or insulin dosage after hypoglycemic events

• Understand what causes a DKA event, how DKA is treated and what to do if you experience a patient with DKA

Summary

• The risk of hypoglycemia is one of the key limiting factors in reaching optimal glucose targets

• For Insulin, hypoglycemia is mainly a phenomenon occurring in Type 1 diabetes patients

• Prevention of hypoglycemia requires patient education, frequent blood glucose monitoring and exercise planning

• If hypoglycemia occur repeatedly, reduce the dosage of OAD and/or Insulin

• DKA should be regarded as an emergency situation and prompt treatment with insulin is vital

61

Initiating Diabetes Treatment with OADs

Lecture:

30 minutes

Initiating Diabetes Treatment with OADsLecture

Main Learning Points

• Understand the different classes of OADs and when to use which OADs – either as mono therapy or in combination with other OAD’s / Insulin

62

Factors to Consider when Choosing an Anti-hyperglycemic agent

Effectiveness in lowering glucose

Extraglycaemic effects that may reduce long-term complications

Safety profile

Tolerability

Cost

Effect on body weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Treatment therapies for Type 2 diabetesWhen and How to start treatment

Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.

Lifestyle + Metformin

+-other OAD or GLP-1 agonists

HbA1c ≥7.0%

BasalBasal

InsulinPremix Insulin

Basal + Bolus

Insulin

START TREATMENT OAD TREATMENT START INSULIN INSULIN INTENSIFICATION

63

Updated PERKENI Type 2 Diabetes Treatment Algorithm

Diabetes STEP 1 STEP 2 STEP 3

Healthy life style Healthy life style

+

Mono therapy Healthy life style

+

2 OAD CombinationHealthy 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)

Updated PERKENI Type 2 Diabetes Treatment Algorithm

64

ADA/EASD Algorithm

Main pathophysiological defects in type 2 DM

hepatic glucose production

peripheralglucose uptake

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery andabsorption

incretineffect

Hyperglycemia

?

LiverMuscle

PancreasIntestines

Adipose

Brain

Kidney

Glucose reabsorpsion

Adapted from:Inzucchi SE, Sherwin RS. Diabetes Mellitus. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 23rd Edn. Philadelphia, Pa: Saunders Elsevier; 2007.

65

Current available OADs and non-Insulin injectables in Indonesia

• Metformin• Sulfonylureas (SUs) and glinides• α-glucosidase inhibitors (AGIs)• Glucagon-like peptide-1 (GLP-1) agonists• Thiazolidinediones (TZDs)• Dipeptidyl peptidase-4 inhibitors (DPP-4

inhibitors)

MetforminMode of Action

The primary effects of metformin are to decrease hepatic glucose production and increase insulin-mediated peripheral

glucose uptake

Anaerobic glucosemetabolism

Glucose uptake

Adipose tissueMuscle Liver

Glucose uptake

Glucose oxidation Glucose oxidation

Glycogenesis

Intestine

Oxidation of FA

Gluconeogenesis

Glycogenolysis

Oxidation of FA

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

FA: Fatty Acids

66

MetforminClinical Overview and Contraindications

Metformin

Efficacy*

Safety, Tolerability and Adherence

Contraindications Advantages

• HbA1creduction of 1-2%

• FPG reduction of 40-70 mg/dl

• Associated with diarrhea and abdominal discomfort

• Lactic acidosis if improperly prescribed

• Renal insufficiency• Liver failure• Heart failure • Severe

gastrointestinal disease

• Do not cause hypoglycaemia when used as mono-therapy

• Do not cause weight gain; may contribute to weight loss

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

* Efficacy depends on existing blood glucose levels

MetforminLittle benefit – if any - to go above 2.000 mg

Fasting Plasma Glucose HbA1c

61.9

77.9

40.9

31.0

18.9

0

10

20

30

40

50

60

70

80

Ch

ang

e vs

. P

lace

bo

(mg

/dl)

2500mg2000mg1500mg1000mg500mg

Garber AJ, Am J Med 1997;102:491-7.

Metformin Dose

1.6

2.0

1.7

1.2

0.9

0.0

0.5

1.0

1.5

2.0

Ch

ang

e vs

. P

lace

bo

(%)

2500mg2000mg1500mg1000mg500mg

Metformin Dose

67

SUs and GlinidesMode of Action

• Sulfonylureas (SUs) and glinides increase endogenous insulin secretion by binding to pancreatic β-cells and triggering a cascade of intracellular events1–3

• The mode of action of SUs and glinides is similar, but stimulation of insulin secretion is more rapid and short-acting with glinides

• SU receptors are also found on other cells, including the cardiac myocytes

1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

SU: sulfonylurea; GLUT: glucose transporter.

Pancreatic β-cell

Glucose uptake

Insulin releaseVoltage-gated

calcium channel

ATP-sensitivepotassium channel

SUs / glinides

Glycolysisrespiration

Glucokinase

ATP

Ca2+

ATP = orange Ca2+ = light green

SUs and GlinidesClinical Overview

Sulphonylurea

Efficacy*Safety, Tolerability and Adherence

• HbA1creduction of 1-2%

• FPG reduction of 40-70 mg/dl

• Associated with hypoglycaemiaand weight gain

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Nathan DM, et al. Diabetologia. 2009;52:17–30. Rosenstock J, et al. Diabetes Care. 2004;27:1265–70.

* Efficacy depends on existing blood glucose levels

Glinides

Efficacy*Safety, Tolerability and Adherence

• HbA1creduction of 0.5-1.5%

• FPG reduction of 20-60 mg/dl

• PPG reduction of 75-100 mg/dl

• Associated with hypoglycaemiaand weight gain

• Frequent administration (with every meal) is required.

68

Alpha glucosidase inhibitorsMode of Action

• Slow digestion of sucrose and starch and therefore delay absorption

• Slow post-meal rise in blood glucose• Side effects• Flatulence, abdominal discomfort , diarrhoea• As mono-therapy will not cause hypoglycaemia• Hypoglycaemia when used with other medicine

(e.g. a sulphonylurea)

1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

Alpha glucosidase inhibitorsClinical Overview

Alpha glucosidase inhibitors

Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction of 0.5-1%• FPG reduction of 10-20 mg/dl• PPG reduction of 40-50 mg/dl

• Associated with flatulence, diarrhea and abdominal discomfort

• As mono-therapy will notcause hypoglycaemia

• Frequent administration (with every meal) is required.

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Nathan DM, et al. Diabetologia. 2009;52:17–30. Rosenstock J, et al. Diabetes Care. 2004;27:1265–70.

* Efficacy depends on existing blood glucose levels

69

Thiazolidinediones (TZDs)Mode of Action

Thiazolidinediones (TZDs) increase the sensitivity of muscle and adipose cells to insulin and suppressing hepatic glucose

production

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

TZD: Thiazolidinediones

Glucose uptake Glucose uptake Gluconeogenesis

*Inconsistent findings

Adipose tissue Muscle Liver

Fatty acid uptake

Lipogenesis

Pre-adipocyte differentiation

Glycolysis

Glucose oxidation

Glycogenesis*

Glycogenolysis

Lipogenesis

Glucose uptake*

Thiazolidinediones Clinical Overview

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Drug Class Review: Thiazolidinediones. Available at:http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/TZD_ClassReview.pdf . Rizzo M, et al. Expert Opin Pharmacother. 2008;9:2295–303.

* Efficacy depends on existing blood glucose levels

Thiazolidinediones

Efficacy*Safety, Tolerability and Adherence

Contraindications Advantages

• HbA1creduction of 0.5-1.5%

• FPG reduction of 20-55 mg/dl

• Associated with weight gain and edema

• Contraindicated in patients with abnormal liver function

• Warnings regarding risk of fractures

• May exacerbate or precipitate congestive heart failure

• Liver disease, heart failure or history of heart disease

• Pregnancy and breast feeding

• Reduced levels of LDL-cholesterol and increased level of HDL-cholesterol

70

DPP-4 inhibitorsMode of Action

Drucker DJ et al. Nature 2006;368:1696–705. Idris I, et al. Diabetes Obes Metab 2007;9:153–65. Barnett A. Int J Clin Pract 2006;60:1454–70. Gallwitz B, et al. Diabetes Obes Metab 2010;12:1–11.

DPP-4: dipetidyl peptidase-4; GI: gastrointestinal; GIP:glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide

Increases and prolongsGLP-1 effect on α-cells

Increases and prolongs GLP-1and GIP effects on β-cells

Food intake

Stomach

GI tract

Intestine

α-cells

Pancreas

Glucose-dependent insulin secretion

β-cellsDPP-4

inhibitor

Glucose-dependent glucagon secretion

Incretins (GLP-1, GIP)

DPP-4Net effect:

blood glucose

* GIP does not inhibit glucagon secretion by α-cells

DPP-4 inhibitorsClinical Overview

DPP-4 inhibitors

Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction of 0.5-1%• FPG reduction of 20 mg/dl• PPG reduction of 45-55 mg/dl

• Generally well tolerated• Low risk of hypoglycemia• Not associated with weight gain• Upper respiratory tract

infection5 has been reported in clinical studies

• Most require only once daily administration

Ahrèn B. Expert Opin Emerg Drugs 2008;13:593–607. Gallwitz B, et al. Diabetes Obes Metab 2010;12:1–11. Amori RE, et al. JAMA 2007;298:194–206. Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. (accessed Nov 2010). Aschner P, et al. Diabetes Care 2006;29:2632–7.

* Efficacy depends on existing blood glucose levels

71

GLP 1 AgonistMode of Action

1. Doyle ME, Egan JM. Pharmacol Ther 2007;113(3):546–93.GLP-1: glucagon-like peptide

Glucagon-like peptide-1 (GLP-1) agonist activates the GLP receptor in the pancreas. This increases insulin release from the pancreatic β-cells, while inhibiting glucagon

release by the pancreatic α-cells

α-cell

Pancreas

• Glucose-dependent insulin biosynthesis and secretion

• β-cell proliferationβ-cells

• Glucagon secretion• β-cell apoptosis

GLP-1 agonist Net effect: blood glucose

GLP 1 AgonistClinical Overview

GLP-1 Agonist

Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction of 1-2%• FPG reduction of 6-12 mg/dl• PPG reduction of 6-18 mg/dl

• Associated with moderate and transient nausea, vomiting and diarrhoea

• Low risk of hypoglycemia and no evidence of increased CV risk

• Associated with weight reduction• Associated with reduction in BP

Garber AJ. Diabetes Care 2011;34 (Suppl 2):S279–84. Moretto TJ, et al. Clin Ther 2008;30:1448–60. Drucker DJ. Cell Metab 2006;3:153–65. Amori RE, et al. JAMA 2007;298:194–206.

* Efficacy depends on existing blood glucose levels

72

The Principles of OAD Combination Theory

• Two (or more) oral blood glucose-lowering medicines that have different mechanisms of action

• Two medications is better rather than increase in initial medicine to maximum dosage

• Fewer side effects than mono-therapy at higher doses

Diabetes in elderly people

• Always start with the lowest dose of any blood glucose-lowering medicine and increase gradually

• Using shorter-acting medicines that reduces the risk of hypoglycaemia

• Hypoglycaemia may increase the risk of falls and heart attack in older people

Remember the possibility of

• Forgetfulness

• Poor motivation

• Depression

• Cognitive deficits

• Poly-pharmacy

• Reduced manual dexterity

• These factors impact on the ability to maintain self-care and achieve maximum benefits from blood glucose-lowering medicines.

73

OAD’s – a quick summary of the different mechanism of actions

α-Glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesIncrease glucose uptake in skeletal muscle and decrease lipolysis in adipose tissue

SulfonylureasIncrease insulin secretion from pancreatic β-cells

GLP = glucagon-like peptide.Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.

MeglitinidesIncrease insulin secretion from pancreatic β-cells

Incretins :GLP-1 analogue(exen-atide)/DPP-4 inhibitorsImproves glucose-dependent insulin secretion from pancreatic β-cells, suppresses glucagon secretion from α-cells, slows gastric emptying

Properties of available glucose-lowering agents that may guide treatment choice in Type 2 Diabetes

Class Compounds(s) Cellular mechanism

Primary Physiological action(s)

Advantages Disadvantages

Biguanides Metformin Activates AMP-kinase

Hepatic Glucose Production ↓

Extensive ExperienceNo weight gainNo hypoglycaemiaLikely CVD Events ↓

Gastrointestinal side effectsLactic acidosis risk (rare)Vitamin B12 deficiencyMultiple contraindications: CKD, acidosis, hypoxia, dehydration etc.

Sulfonylureas Glibenclamide / glyburideGlipizideGliclazideGlimepiride

Closes KATP channels on beta cell plasme membranes

Insulin secretion ↑ Extensive experienceMicrovascular Risk ↓(UKPDS)

HypoglycemiaWeight gainBlunts myocardial ischaemic preconditioning ?Low durability

Meglitinides RepaglinideNateglinide

Closes KATP channels on beta cell plasme membranes

Insulin secretion ↑ Postprandial glucose excursions ↓Dosing flexibility

HypoglycemiaWeight gainBlunts myocardial ischaemic preconditioning ?Frequent dosing schedule

Inzucci SE, et al. Diabetologia. 2012

74

Properties of available glucose-lowering agents that may guide treatment choice in Type 2 Diabetes cont.

Class Compounds(s) Cellular mechanism

Primary Physiological action(s)

Advantages Disadvantages

Thiazolidinediones

PioglitazoneRosiglitazone

Activates the nuclear transcription factor PPAR-y

Insulin Sensitivity ↑ No hypoglycaemiaDurabilityHDL-C ↑Triacylglycerol ↓(pioglitazone)CVD Events ↓?

Weight GainOedema / Heart FailureBone FracturesLDL-C ↑(rosiglitazone)Mn ↑ (meta-analyses, rosiglitazone)Bladder Cancer ↑? (pioglitazone)

a-Glucosidase Inhibitors

AcarboseMigitolVoglibose

Inhibits intestinal a-glucosidase

Slows intestinal carbohydrate digestions / absorption

No hypoglycaemiaPostprandial glucose excursions ↓CVD Events ↓Non-systemic

Modest HbA1c efficacyGastrointestinal side effects (flatulence, diarrhoea)Frequent dosing schedule

DPP-4Inhibitors

SitagliptinVildagliptinSaxagliptinLinagliptinAlogliptin

Inhibits DPP-4activity, increasing postprandial active incretin (GLP-1, GIP) concentrations

Insulin secretion ↑(glucose-dependent)Glucagon secretion ↓(glucose-dependent)

No hypoglycaemiaWell tolerated

Modest HbA1c efficacyUrticardia/Angio-oedemaPancreatitis ?

Inzucci SE, et al. Diabetologia. 2012

Properties of available glucose-lowering agents that may guide treatment choice in Type 2 Diabetes cont.

Class Compounds(s) Cellular mechanism

Primary Physiological action(s)

Advantages Disadvantages

GLP-1Receptor Agents

ExenatideLiraglutide

Activates GLP-1 receptors

Insulin secretion ↑(glucose-dependent)Glucagon secretion ↓(glucose-dependent)Slows gastric emptyingSatiety ↑

No hypoglycaemiaWeight reductionImproved beta cell mass / function ?Cardiovascular protective actions ?

Gastrointestinal side effects (nausea / vomiting)Acute pancreatitis ?C cell hyperplasia / medullary thyroid tumoursInjectableTraining Requirements

Insulin Human NPHHuman RegularLisproAspartGluisineGlargineDetermirPre-mixed (several types)

Activates insulin receptors

Glucose disposal ↑Hepatic glucose production ↓

Universally effectiveTheoretically unlimited efficacyMicrovascularRisk ↓ (UKPDS)

HypoglycemiaWeight gainMitogenic effects ?InjectableTraining Requirements‘Stigma’ for patients

Inzucci SE, et al. Diabetologia. 2012

75

Initiating Diabetes Treatment with OADsLecture

Main Learning Points

• Understand the different classes of OADs and when to use which OADs – either as mono therapy or in combination with other OAD’s / Insulin

Summary

• Different start and intensification options for OADs exist depending on the need for the individual patient

• Metformin will generally be the first drug of choice

76Pro

per

ties

of

avai

lab

le g

luco

se-l

ow

erin

g a

gen

ts t

hat

may

g

uid

e tr

eatm

ent

cho

ice

in T

ype

2 D

iab

etes

Cla

ssC

om

po

un

ds(

s)C

ellu

lar

mec

han

ism

Pri

mar

y P

hys

iolo

gic

al

acti

on

(s)

Ad

van

tag

esD

isad

van

tag

es

Big

uan

ides

Met

form

inA

ctiv

ates

A

MP

-kin

ase

Hep

atic

Glu

cose

P

rod

uct

ion

↓Ex

ten

sive

Ex

per

ien

ceN

o w

eig

ht

gai

nN

o h

ypog

lyca

emia

Like

ly C

VD

Eve

nts

↓

Gas

troi

nte

stin

al s

ide

effe

cts

Lact

ic a

cid

osis

ris

k (r

are)

Vit

amin

B1

2

def

icie

ncy

Mu

ltip

le

con

trai

nd

icat

ion

s:

CK

D,

acid

osis

, h

ypox

ia,

deh

ydra

tion

etc

.

Su

lfon

ylu

reas

Glib

encl

amid

e /

gly

bu

rid

eG

lipiz

ide

Glic

lazi

de

Glim

epir

ide

Clo

ses

KA

TP

chan

nel

s on

b

eta

cell

pla

sme

mem

bra

nes

Insu

lin s

ecre

tion

↑Ex

ten

sive

ex

per

ien

ceM

icro

vasc

ula

r R

isk ↓

(UK

PD

S)

Hyp

ogly

cem

iaW

eig

ht

gai

nB

lun

ts m

yoca

rdia

l is

chae

mic

p

reco

nd

itio

nin

g ?

Low

du

rab

ility

Meg

litin

ides

Rep

aglin

ide

Nat

eglin

ide

Clo

ses

KA

TP

chan

nel

s on

b

eta

cell

pla

sme

mem

bra

nes

Insu

lin s

ecre

tion

↑P

ostp

ran

dia

l g

luco

se e

xcu

rsio

ns ↓

Dos

ing

fle

xib

ility

Hyp

ogly

cem

iaW

eig

ht

gai

nB

lun

ts m

yoca

rdia

l is

chae

mic

p

reco

nd

itio

nin

g ?

Freq

uen

t d

osin

g

sch

edu

le

Inzu

cci S

E, e

t al

. D

iabe

tolo

gia.

201

2

77Pro

per

ties

of

avai

lab

le g

luco

se-l

ow

erin

g a

gen

ts t

hat

may

g

uid

e tr

eatm

ent

cho

ice

in T

ype

2 D

iab

etes

co

nt.

Cla

ssC

om

po

un

ds(

s)C

ellu

lar

mec

han

ism

Pri

mar

y P

hys

iolo

gic

al

acti

on

(s)

Ad

van

tag

esD

isad

van

tag

es

Thia

zolid

ined

ion

esP

iog

litaz

one

Ros

iglit

azon

eA

ctiv

ates

th

e n

ucl

ear

tran

scri

pti

on

fact

or P

PA

R-y

Insu

lin S

ensi

tivi

ty ↑

No

hyp

ogly

caem

iaD

ura

bili

tyH

DL-

C↑

Tria

cylg

lyce

rol ↓

(pio

glit

azon

e)C

VD

Eve

nts

↓?

Wei

gh

t G

ain

Oed

ema

/ H

eart

Fa

ilure

Bon

e Fr

actu

res

LDL-

C↑

(ros

iglit

azon

e)M

n ↑

(met

a-an

alys

es,

rosi

glit

azon

e)B

lad

der

Can

cer ↑?

(pio

glit

azon

e)

a-G

luco

sid

ase

Inh

ibit

ors

Aca

rbos

eM

igit

olV

oglib

ose

Inh

ibit

s in

test

inal

a-

glu

cosi

das

e

Slo

ws

inte

stin

al

carb

ohyd

rate

d

iges

tion

s /

abso

rpti

on

No

hyp

ogly

caem

iaP

ostp

ran

dia

l g

luco

se

excu

rsio

ns ↓

CV

D E

ven

ts ↓

Non

-sys

tem

ic

Mod

est

Hb

A1

c ef

fica

cyG

astr

oin

test

inal

sid

e ef

fect

s (f

latu

len

ce,

dia

rrh

oea)

Freq

uen

t d

osin

g

sch

edu

le

DP

P-4

Inh

ibit

ors

Sit

aglip

tin

Vild

aglip

tin

Sax

aglip

tin

Lin

aglip

tin

Alo

glip

tin

Inh

ibit

s D

PP

-4ac

tivi

ty,

incr

easi

ng

p

ostp

ran

dia

l ac

tive

incr

etin

(G

LP-1

, G

IP)

con

cen

trat

ion

s

Insu

lin s

ecre

tion

↑(g

luco

se-d

epen

den

t)G

luca

gon

sec

reti

on ↓

(glu

cose

-dep

end

ent)

No

hyp

ogly

caem

iaW

ell t

oler

ated

Mod

est

Hb

A1

c ef

fica

cyU

rtic

ard

ia/A

ng

io-

oed

ema

Pan

crea

titi

s ?

Inzu

cci S

E, e

t al

. D

iabe

tolo

gia.

201

2

78Pro

per

ties

of

avai

lab

le g

luco

se-l

ow

erin

g a

gen

ts t

hat

may

g

uid

e tr

eatm

ent

cho

ice

in T

ype

2 D

iab

etes

co

nt.

Cla

ssC

om

po

un

ds(

s)C

ellu

lar

mec

han

ism

Pri

mar

y P

hys

iolo

gic

al

acti

on

(s)

Ad

van

tag

esD

isad

van

tag

es

GLP

-1R

ecep

tor

Ag

ents

Exen

atid

eLi

rag

luti

de

Act

ivat

es G

LP-

1 r

ecep

tors

Insu

lin s

ecre

tion

↑(g

luco

se-d

epen

den

t)G

luca

gon

sec

reti

on ↓

(glu

cose

-dep

end

ent)

Slo

ws

gas

tric

em

pty

ing

Sat

iety

↑

No

hyp

ogly

caem

iaW

eig

ht

red

uct

ion

Imp

rove

d b

eta

cell

mas

s /

fun

ctio

n ?

Car

dio

vasc

ula

r p

rote

ctiv

e ac

tion

s ?

Gas

troi

nte

stin

al s

ide

effe

cts

(nau

sea

/ vo

mit

ing

)A

cute

pan

crea

titi

s ?

C c

ell h

yper

pla

sia

/ m

edu

llary

th

yroi

d

tum

ours

Inje

ctab

leTr

ain

ing

R

equ

irem

ents

Insu

linH

um

an N

PH

Hu

man

Reg

ula

rLi

spro

Asp

art

Glu

isin

eG

larg

ine

Det

erm

irP

re-m

ixed

(s

ever

al t

ypes

)

Act

ivat

es

insu

lin

rece

pto

rs

Glu

cose

dis

pos

al ↑

Hep

atic

glu

cose

p

rod

uct

ion

↓

Un

iver

sally

ef

fect

ive

Theo

reti

cally

u

nlim

ited

ef

fica

cyM

icro

vasc

ula

r R

isk ↓

(UK

PD

S)

Hyp

ogly

cem

iaW

eig

ht

gai

nM

itog

enic

effe

cts

?In

ject

able

Trai

nin

g

Req

uir

emen

ts‘S

tig

ma’

for

pat

ien

ts

Inzu

cci S

E, e

t al

. D

iabe

tolo

gia.

201

2

79

The Usage of InsulinLecture

Main Learning Points

• Understand the insulin mechanism of action and its relationship to blood glucose

• Understand the current usage of Insulin in Indonesia• Understand the different types of insulin, when to

use insulin and the different insulin regiments• Understand the relationship between insulin dosage

and blood glucose measurements

Insulin Initiation and Monitoring

Lecture:

30 minutes

80

Insulin remains the most efficacious glucose lowering agent

Decrease in HbA1c: Potency of monotherapy

HbA

1c%

Nathan et al., Diabetes Care 2009;32:193-203.

IMS Full year 2011 Data. CIA World Factbook

29

67

92

Malaysia

Thailand

Vietnam

Philippines 104

Bangladesh 161

Indonesia 248

Population

Million People Mega Units

Total Insulin Used

2,029

3,258

417

982

3,097

694

70

49

5

9

19

3

Insulin Usage per Capita

Insulin Units / Capita

…but Insulin usage is currently very low in Indonesia compared to its neighbouring countries

81

What is Insulin

•After a meal carbohydrates are digested and enter the blood system, which transports them to the cells

INSULINis needed

for glucose uptakeand storage

•Some cells (those of muscles and fat tissue) need assistance to have blood sugar enter into them and to be used for energy production

•The liver needs assistance to start the process of storage of glucose in the form of glycogen

…and our diabetes patients are not in good glycemic controlDiabCare Indonesia 2008 illustrated the need for more intensive treatment to decrease FPG and PPG

n: 1.823 patients with diabetes

208

144

100

140

020406080

100120140160180200220

mg/dl

PPG (mg/dl)FPG (mg/dl)

Gly

cem

ic C

ontr

ol L

evel

PERKENI GuidelinesDiabCare 2008

Source: Novo Nordisk Data on File

82

Insulin secretion is delayed and blunted in Type 2 Diabetes

Adapted from: Polonsky KS, et al. N Engl J Med. 1996 Mar 21;334(12):777-783.

NormalType 2 diabetes

Time (24 hours)

800

600

400

200

0

Insulin Secretion

(pmol/min)

Meal Meal Meal

The goal of insulin therapy is to restore normal insulin secretion

‘Gap’ that needs to be covered

How Insulin acts in the body

Insulin

Insulin binds to the insulin receptors on the cell membranes of the target cells in the liver, muscles and adipose tissue

Liver Adipose TissueMuscles

• Inhibits glucose production

• Promotes formation of glycogen and its storage

• Promotes uptake and utilization of glucose

• Promotes uptake of glucose

• Suppresses lipolysis

83

…diabetes Patients will eventually fail on OAD’s

6.2% – upper limit of normal range

Med

ian

HbA

1c(%

)

UKPDS

6

7

8

9

Years from randomisation

Conventional*GlibenclamideMetforminInsulin

2 4 6 8 100

7.5

8.5

6.5

Recommended treatment

target <7.0%†

8

6

7.5

7

6.5

Time (years)0 2 3 4 51

ADOPTMetforminGlibenclamide

Rosiglitazone

*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L; †ADA clinical practice recommendations. UKPDS 34, n=1704

UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43

Most people with type 2 diabetes will, in time, need insulin therapy

Wright A et al. Diabetes Care 2002;25:330–6

(Patients treated with chlorpropramide) Years from start of UKPDS

Pat

ient

s re

quiri

ng

addi

tiona

l ins

ulin

(%)

0

10

20

30

40

50

60

1 2 3 4 5 6

84

Maintain blood glucose levels between 80-140 mg/dl:

1. By promoting uptake of glucose by target cells

• subsequent breakdown into energy (glycolysis)

• storage as glycogen (glycogenesis)

2. By inhibiting new glucose formation from non carbohydrate

source (gluconeogenesis) or production of glucose by liver

3. By suppressing lipolysis (breakdown of fat)

Objectives of Insulin Treatment

Absolut Indication

Type 1 Diabetes

Relative Indication

Patients who fail to reach target with OAD optimal

dosage (3-6 months)

Type 2 DM Outpatient with:

Pregnancy not controlled with diet

Infected Diabetes Feet

High Blood Glucose Fluctuations

Repeated History of Ketoacidosis

History of Pankreotomi

Besides the above, there are a number of conditions

where insulin is required, e.g. chronic liver, kidney

function interruption and high dosage steroid therapy

Insulin Indications

85

Insulin can be initiated at any time…

• Traditionally, insulin has been reserved as the last line of therapy…

• …However, considering the benefits of normal glycemic status, Insulin can be initiated earlier.

Inadequate Lifestyle + 1 OAD + 2 OAD + 3 OAD

INITIATE INSULIN

Adapted from Nathan DM, et al. Diabetes Care 2009; 31:193-203

ADA/EASD Guideline

86

Three Types of InsulinSchematic Representation Only

GIR

(m

g/kg

/min

)

Time (h)0 4 8 12 16 20 24

BASAL INSULIN

PRE-MIX INSULIN

FAST-ACTING INSULIN

Three Types of Insulin

1. Hompesch M. Diabetes Obes Metab 2006; 8:568; 2. Weyer et al. Diabetes Care 1997;10:1612–1614.; 3. 1. Heinemann et al. Diabetes Care. 1998;21:1910–4

Basal Insulin provides a steady concentration of

insulin in the bloodstream over 24 hours. Initially, basal insulin should be

given at 10 units per day at night time or in the

morning1

Time (h)

Premixed insulins contain a mixture of rapid-acting and intermediate-acting

insulin in a fixed combination to provide

coverage of prandial and basal insulin

requirements2

Fast-acting insulinsinclude single amino acid replacement that reduce

their ability to self-associate into dimers and

hexamers. This means that they are quickly

absorbed into the bloodstream, following

subcutaneous injection.3

FAST-ACTINGPRE-MIXBASAL

GIR

(m

g/kg

/min

)

0 8 16 20 244 12Time (h)

GIR

(m

g/kg

/min

)

0 8 16 20 244 12Time (h)

GIR

(m

g/kg

/min

)

0 8 16 20 244 12

87

Basic Insulin Start Recommendation

If Fasting Blood Glucose is elevated • Start with Basal Insulin

If both Fasting and Prandial Blood Glucose are elevated

• Start with Premix Insulin• OR add Basal Insulin to OAD• OR Start Basal/Bolus Therapy

Source: ADA Guidelines

Pharmacokinetics of the different Types of Insulin available in Indonesia

Profile

Type of Insulin Insulin Name Onset (hours) Peak (hours)

Duration (hours)

Fast-acting Analogue Insulin Insulin Aspart (NovoRapid) 0.2 – 0.5 0.5 - 2 3 - 5

Insulin Lispro (HumaLog) 0.2 – 0.5 0.5 - 2 2 - 4

Insulin Gluisine (Apidra) 0.2 – 0.5 0.5 - 2 1 – 2.5

Fast-acting Human Insulin ActRapid 0.5 – 1 0.5 - 1 3 – 6

Humulin R 0.5 – 1 0.5 - 1 3 - 6

Intermediate Human Insulin Insulatard 1.5 – 4 4 - 10 10 – 16

Humulin N 1.5 – 4 4 - 10 10 - 16

Long-acting Analogue Insulin Insulin Detemir (Levemir) 1 - 3 Up to 24

Insulin Glargine (Lantus) 1 - 3 Up to 24

Pre-mix Analogue Insulin Insulin Aspart (NovoMix) 0.2 – 0.5 1 - 4 10 -16

Insulin NPL (HumaLog) 0.2 – 0.5 1 - 4 10 -16

Pre-mix Human Insulin Mixtard 0.5 – 1 3 - 12 10 - 16

Humulin Mix 0.5 – 1 3 - 12 10 – 16

Adapted from Mooradian et al. Ann Intern Med 2006; 145: 125-34

88

Insulin Titration schemesBasal and Fast-Acting Insulin

Fasting Blood Glucose Content (mg/dl) Basal Insulin Titration

<70 mg/dl Reduce dosage with 2 units

70-130 mg/dl Maintain dosage

130-180 mg/dl Increase dosage 2 units per 3 days

>180 mg/dl Increase dosage 4 units per 3 days

Once titrated, continue to monitor HbA1c every 3 months

BASAL INSULIN

Subsequent pre-meal Glucose (mg/dl) Fast-acting Insulin Titration

Start with 4 units / day Increase by 2 units every 3 days until target is reached

When starting Fast-acting Insulin, secretagogues should be discontinued

FAST-ACTING INSULIN

Source: KONSENSUS: Insulin Treatment 2011

Insulin Treatment OptimizationHow to Optimize Treatment after Initiation

Basal Insulin OnlyUsually with OAD

Start with Basal Insulin 10u / daily with meal or before bedtime. Same injection time every day

If glycemic target is not reached within 2-3 months, intensify Insulin treatment

If glycemic target is not reached titrate according to Basal Titration Scheme

Basal Insulin OnlyUsually with OAD

Basal with PrandialUsually keep Metformin

Premix InsulinUsually keep Metformin

Basal BolusUsually keep Metformin

Add Prandial starting with 4u / day either

once or twice-daily and titrate 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 and titrate accordingly)

Source: PERKENI Insulin Guidelines 2011

89

Primarily one type of Insulin device available in Indonesia

• Disposable – disposed of once empty

• Less teaching time required

• Primarily plastic

• Easy and Convenient for Patients

Prefilled devices

90

Slid

e 1

Ske

ma

titr

asi i

nsu

lin

Insu

lin B

asal

dan

Fas

t-A

ctin

g

Glu

kosa

Dar

ah P

uas

a (m

g/

dl)

Ti

tras

i In

sulin

Bas

al

<70

mg/

dl

Kura

ngi d

osis

seb

esar

2 u

nit

70-1

30 m

g/dl

Pe

rtah

anka

n do

sis

130-

180

mg/

dl

Ting

katk

an d

osis

2 u

nit

per

3 ha

ri

>18

0 m

g/dl

Ti

ngka

tkan

dos

is 4

uni

t pe

r 3

hari

Set

elah

dit

itra

si,

lan

jutk

an m

onit

or H

bA

1c

seti

ap 3

bu

lan

INS

ULI

N

BA

SA

L

Glu

kosa

Dar

ah P

uas

a (m

g/

dl)

Ti

tras

i In

sulin

Fas

t-ac

tin

g

Mul

ai d

enga

n 4

unit

/ ha

ri

Ting

katk

an d

osis

2 u

nit

setia

p 3

hari s

ampa

i tar

get

terc

apai

Ketik

a m

ulai

men

ggun

akan

Fas

t-ac

ting

Insu

lin,

pem

ebrian

se

cret

agog

ues

haru

s di

hent

ikan

INS

ULI

N

FAS

T-A

CTI

NG

91

Slid

e 2

Ske

ma

titr

asi in

sulin

In

sulin

Pre

-mix

Kad

ar G

luko

sa D

arah

se

bel

um

mak

an p

agi at

au

mak

an m

alam

(m

g/

dl)

Tit

rasi

In

sulin

Pre

-mix

<72

mg/

dl

Kura

ngi d

osis

4 u

nit

72-1

26 m

g/dl

Pe

rtah

anka

n do

sis

126-

144

mg/

dl

Ting

katk

an d

osis

2 u

nit

>14

4 m

g/dl

Ti

ngka

tkan

dos

is

4 un

it

Sel

ama

titr

asi,

uku

r ka

dar

glu

kosa

dar

ah p

uas

a d

an g

luko

sa

po

st-p

ran

dia

l p

agi d

an m

alam

har

i se

tiap

2 h

ari.

Ket

ika

targ

et t

erca

pai

mo

nit

or

1-2

x se

tiap

min

gg

u

INS

ULI

N

PR

E-M

IX

¥ D

osi

s in

sulin

mal

am h

ari d

itit

rasi

ber

das

arka

n k

adar

glu

kosa

dar

ah p

uas

a ¥ 

Do

sis

insu

lin

pag

i h

ari d

itit

rasi

ber

das

arka

n d

osi

s se

bel

um

mak

an m

alam

¥ 

Dis

aran

kan

pas

ien

un

tuk

men

titr

asi d

osi

s in

sulin

mal

am t

erle

bih

dah

ulu

diiku

ti

den

gan

do

sis

pag

i ¥ 

Pen

yesu

aian

do

sis

pal

ing

cep

at s

etia

p 3

har

i

92

Screening, Treatment and Evaluation of Complications

Lecture:

Screening, Treatment and Evaluation of ComplicationsLecture

Main Learning Points

• Understand the screening, diagnose and treatment options / refer for diabetes associated complications:

• Nephropathy

• Retinopathy

• Neuropathy

• Erectile Dysfunction

• CVD

• CAD

93

Recap: The goal of diabetes management is to secure optimal glycemic control to avoid complications

DiabeticretinopathyLeading causeof blindnessin working-ageadults1

Diabeticnephropathy

Leading cause of end-stage renal disease2

Cardiovasculardisease

Stroke

1.2- to 1.8-fold increase in stroke3

Diabeticneuropathy

Leading cause of non-traumatic lower extremity amputations5

75% diabetic patients die from CV events4

1Fong DS, et al. Diabetes Care 2003;e 26 (Suppl.1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl.1):S94–S98. 3Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl.1):S78–S79.

Microvascular Macrovascular

Diabetic Foot

Erectile DysfunctionThe most secretiveComplication of DM

Recap: Risk of Complications increases as Hb1Ac increases

Stratton IM et al. BMJ 2000;321:405–12

0

20

40

60

80

5 6 7 8 9 10 11

Myocardial infarction

Microvascular disease

Updated Mean HbA1c (%)

Adjusted for age, sex, and ethnic group

Inci

denc

e pe

r 1.

000

patie

nt-y

ears

94

Recap: It’s the diabetes-related complications – not the diabetes medicine - that carries the biggest cost to the society

Cost increases with a factor of 22.5 if patients develop complications (ASKES Data)

900

400

100200300400500600700800900

US$

With ComplicationsWithout Complications

Approximate Annual Cost / Diabetes Patient

ASKES 2010 Unpublished data

22.5X

Positive legacy effect of earlier glucose control

Provides long-term reductions in both microvascular and macrovascular complications

15%p=0.01

24%p=0.001

13%p=0.007

9%p=0.04

Any diabetesendpoint

Microvascular disease

Myocardial infarction

Death (any

cause)

16%p=0.052

25%p=0.0099

6%p=0.44

12%p=0.03

RRR* at end of UKPDSRRR* at end F/U (median 8.5 years)

RRR: relative risk reduction of intensive therapy over conventional therapy

UKPDS 80. Holman et al. NEJM 2008; 359:1577-89.

95

Classification of Micro- and Macrovascular Complications

Chronic complications of diabetes

• Microvascular complications• Kidney – nephropathy » kidney failure• Eyes – retinopathy » blindness• Nerves – neuropathy » disability• Peripheral Arterial Diseases » disability• Erectile Dysfunction

• Macrovascular complications• Heart – myocardial infarction• Brain – stroke• Atherosclerosis – myocardial infarction

Microvascular Complications – an overview

Retinopathy and blindness

Nephropathy

Neuropathy

International Diabetes Federation. Diabetes Atlas 2006;111–2

Erectile Dysfunction

96

Diabetes NephropathyCharacteristics

• Persistent albuminuria

• Diabetic retinopathy

• Hypertension

• Decline in kidney function (about 12 ml/min/year)

Diabetes NephropathyPrevention and Treatment

DCCT. Diabetes 1996;45:1289–98

Glycated haemoglobin (%)

5 8 120.0

0.4

0.8

0.6

0.2

111096 7

Prob

abili

ty o

f m

icro

albu

min

uria

• Maintain tight glycaemic and blood pressure control

• Multifactorial disease management:• antihypertensive agents• good blood glucose control• control of dyslipidaemia• monitoring renal function• lifestyle changes, including

smoking cessation and low-protein diet

97

Micro / Macro-albuminuria

24h: 30 - 299 mg/24h >300 mg/24h

Random spot: 30 - 299 mcg/mg >300 mcg/mg

Morning spot: 30 – 299 mcg/mg >300 mcg/mg

Dipstick/overnight albumin: low sensitivity and specificity

Micro MacroIn 2 of 3 measurements

Natural history of diabetic nephropathy

.

FunctionalGFR -

(90-95%)Microalbuminuria,

hypertensionProteinuria, nephrotic

syndrome, GFR ¯

Urinary protein excretionGFR

Urina

ry p

rote

in e

xcre

tion

(mg/

d)

Years

Glo

mer

ular

filt

ratio

n ra

te (

GFR

) (m

L/m

in)

0

150

100

50

5 10 15 20 25

20

200

1000

5000

Incipient diabeticnephropathy

Pre Overt diabeticnephropathy

End-stagerenal disease

1 2 3 4 5

Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000

98

Diabetes Retinopathy

Non-Diabetic Retina

Diabetic Maculopathy

Proliferative Diabetic Retinopathy

Treating Albuminuria

• Use ACE-I or ARB in nonpregnant patiens with micro- or macroalbuminuria

• Reduce protein intake to 0.8-1.0 g/kgBW/day in DM & early CKD; 0.8 g/kgBW/day in later CKD

• If ACE-Is /ARBs/diuretics are given, monitor serum creatinine and potassium

• When eGFR <60 ml/min/1.73m2, evaluate for CKD complications

• Consider referral to experienced physician in kidney disease care

Diabetes Care. 2012

99

Diabetes RetinopathyRisk Factors and Classification

• Poor glycaemic and blood pressure control increase the risk of retinopathy

• Five categories:• Mild Nonproliferative • Moderate

Nonproliferative• Severe

Nonproliferative• proliferative• advanced diabetic

eye disease• maculopathy

Chaturvedi et al. Diabetes Care 2001;24:284–9

London HbA1c (%)

Retin

opat

hy in

cide

nce

(odd

s ra

tio)

4 6 90

5

10

875

35

30

25

20

15

10

DCCT HbA1c (%)5.7 7.7 10.89.88.86.7 11.9

Diabetes RetinopathyPrevention and Treatment

• Maintain tight glycaemic and blood pressure control

• Regular eye examinations• Treat with laser photocoagulation and

vitreoretinal surgery

Klein et al. Ann Intern Med 1996;124:90–6

100

Diabetes NeuropathyRisk Factors and Common Types

• Hyperglycaemia is the leading cause of diabetic neuropathy

• Alcohol makes neuropathy worse

• A number of clinical syndromes are recognisable

Watkins et al. In: Diabetes and Its Management 2003. Pickup & Williams. In: Slide Atlas of Diabetes 2004

Pickup & Williams. In: Slide Atlas of Diabetes 2004

Symmetrical diffuse

sensorimotor neuropathy

Femoral neuropathy

(amyotrophy)

Other acute mononeuropathies Pressure palsies

Sensory loss 0 → +++

Pain + → +++

Tendon reflexes N → ↓

Motor deficit 0 → +

Sensory loss 0 → +

Pain + → +++

Tendon reflexes ↓ → 0

Motor deficit + → +++

Sensory loss 0 → +

Pain + → +++

Tendon reflexes N

Motor deficit + → +++

Sensory loss + → +++

Pain + → ++

Tendon reflexes N

Motor deficit + → +++

VIIII

Truncal

Ulnar

MedianLateralpopliteal

Diabetes NeuropathyThe Most Frequent Diabetes related Complication in Indonesia (and in the World…)

Note: One patient can have more than one complication

6.7%16.1%19.1%21.7%

41.9%

0%10%20%30%40%50%60%70%80%90%

100%

Neuropathy EyeCV Renal Foot Ulcer

Frequency of complications

A1Chieve Indonesia (2.240 patients)

8.7%

26.5%33.4%

54.0%

0%10%20%30%40%50%60%70%80%90%

100%

Neuropathy Eye Renal Foot Ulcer

Frequency of complications

IDMPS Indonesia (715 patients)

101

Diabetic Foot Complications

Diabetes NeuropathyPrevention and Treatment

• Maintain tight glycaemic control to reduce the risk or progression of neuropathy

• Exclude or treat contributory factors:• alcohol excess• vitamin B12

deficiency• uraemia

• Offer pain relief based on the dominant symptoms

DCCT. NEJM 1993;329:977–86

16

8

00

Perc

enta

ge o

f ca

ses

affe

cted

p<0.00112

4

Conventional therapy

Intensified therapy

1Time (years)2 3 4 5

102

Erectile DysfunctionDefinition

ED is the inability to achieve and maintain an erection adequate for intercourse to the mutual satisfaction of the man and his partner.

Remember, both partners in a relationship are affected

Erectile DysfunctionBackground

• 35%-75% of men with diabetes will experience at least some degree of ED

• Men with diabetes tend to develop erectile dysfunction 10 to 15 years earlier than men without diabetes.

• Men with diabetes will have ED• 50%-60% in > 50 years old• 95% in >70 years old

103

Erectile DysfunctionRisk Factors

Risk Factors

Neuropathy

Peripheral vascular disease

Poor glycemic control

Diabetes duration and complications

Age and high BMI

Smoking doubles the risk

Erectile DysfunctionScreening

Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999 Dec;11(6):319-26

104

MACRO VASCULAR COMPLICATION

Erectile DysfunctionTreatment Options

• Oral medications: Sildenafil (Viagra), Vardenafil

(Levitra), Tadalafil (Cialis)

• Urethral suppositories (MUSE)

• Injection therapy: Caverject, Trimix, Bimix

• Vacuum constriction device

• Surgery

• Sex therapy

105

Macrovascular Complications – an overview

Stroke

Cardiovascular/heart disease

Peripheral vascular disease

Cardiovascular DiseasesPatients with Type 2 Diabetes at a increased risk of CVD

• Risk of cardiovascular disease is greater in patients with diabetes than in those without

• Having diabetes results in a similar risk of heart attack as a prior heart attack

Incidence of myocardial infarction over 7 years

Haffner et al. N Engl J Med 1998;339:229–34

With diabetes n=1059

Without diabetes n=1373

Patie

nts

(%)

106

Cardiovascular DiseasesRisk for Myocardial infaction and stroke increases with progression to Type 2 Diabetes

Adapted from Hu et al. Diabetes Care 2002; 25:1129-34

Relative risk for MI and stroke in women

*Nurses’ Health Study (NHS) cohort comprised women only

Rela

tive

risk

No diabetes during study

Prior to diagnosis

After diagnosis

Diabetic at baseline

Prevention of Cardiovascular Diseases

Adapted from Stamler et al. Diabetes Care 1993;16:434–44

• Reduce risk factors for cardiovascular disease:• stop smoking• treat hypertension• treat hyperlipidaemia• improve glycaemic

control• reduce weight in the

obese• take regular exercise

Number of risk factors

Num

ber

of d

eath

s pe

r 10

,000

pat

ient

-yea

rs

Non-diabetic subjects

Subjects with type 2 diabetes

0 1 2 30

20

40

60

80

100

120

140

107

Treatment of Cardiovascular Diseases Risk factors

Hypertension SBP 130-139 or DPB 80-89 mmHg: lifestyle modification (DASH) for 3 months, if fails pharmacological agents

SBP ≥140 or DBP ≥90 mmHg:Lifestyle modification +pharmacological therapy

Dyslipidemia Lifestyle modification + statins

Antiplatelet agents* Aspirin and/or clopidogrel

Smoking cessation Stop smoking, counseling

CHD screening and treatment ACE-I and aspirin and statin (if not contraindicated)

Diabetes Care 2012

*Depends on risk factors (???)

Poor Control of CV Risk Factors in Diabetes (NHANES)

Saydak SH et al. JAMA 2004

CV risk factors target Frequency

• S-Cholesterol < 200 mg/dl (5.2 mmol/l) 52 %

• BP < 130/80 mmHg 36 %

• HbA1c < 7.0% 37 %

• All three risk factors controlled 7 %

• Unchanged CV risk factors from 1991 to 2000

108

STENO-2 STUDY

The STENO2 Study – “a multifactorial approach to Type 2 Diabetes”

New Engl J Med 2003; 383-93

New Engl J Med 2008; 358: 580-91

• 160 patients• Type 2 diabetes and

microalbuminuria• Mean age 55 yrs, BMI 30 kg/m2;

HbA1c 8.4 %

• Randomized to• conventional therapy assigned

to their GPs• or intensive care at Steno

Diabetes Center

109

The STENO2 Study – Study Design

Conventional treatment

Intensive treatment

Endpoint examinations

Micro-vascular Macro-vascular

4 years 8 years

80

80

n=160

Advice to the Intensive Group

• Food Advice• Cut down on animal fat• Have some kind of seafood every day• 5-6 vegetables and fruits every day

• Exercise Advice• Enjoy physical performance

> 150 min/week

• Smoking cessation • Intensification of OHA and insulin• Treatment with ACE/ARB, Statin

and baby aspirin

110

Patients in the Intensive Group had obtained better outcomes than patients in the Conventional Group…

Intervention n=55

Standard n=38

Haemoglobin A1c (%) 7.7 8.0

F-s-total-cholesterol (mg/dl) 147 155

F-s-LDL-cholesterol (mg/dl) 71 77

F-s-triglycerides (mg/dl) 99 148

Systolic BP (mm Hg) 140 146

Diastolic BP (mm Hg) 74 73

Albumin excretion rate (mg/24h)* 69 75

Values are mean

* median

111

The STENO2 StudyRisk Reduction in Intensive Group

Relative risk reduction after 8 years

• Cardiovascular disease 53%

• Diabetic Nephropathy 61%

• Diabetic Retinopathy 58%

• Autonomic Neuropathy 63%

Screening, Treatment and Evaluation of ComplicationsLecture

Main Learning PointsSummary

• Complications should be screened for and treated according to guidelines

• Routine follow up on treatment of complications should be performed

• CVD complications are the mail cause of death among patients with diabetes

• Risk of end-stage renal disease and blindness is significantly reduced by treatment of hyperglycemia and hypertension

• Understand the treatment options for diabetes associated complications:

• Nephropathy

• Retinopathy

• Neuropathy

• Erectile Dysfunction

• CVD

• CAD

112

Assessment of Kidney function in Diabetes Mellitus type 2

GUIDELINES

A.Annual Screening for albuminuria by :

Albumin Excretion Rate (AER) – timed urine collection

AER

mg/ hour ug/min *in timed collection

Microalbuminuria 30 - 300 20 - 200

Macroalbuminuria >300 >200

OR

Albumin : Creatinine Ratio (ACR) – spot urine sample

ACR

Males (mg/mmol) Females (mg/mmol)

Microalbuminuria 2,5 - 25 3,5 - 35

Macroalbuminuria >25 >35

If AER or ACR screening is positive for microalbuminuria : Perform additional ACR or AER measurements one to two times within 3

months. Microalbuminuria is confirmed if at least two or three tests (including the screening test) are positive.

If AER or ACR screening is positive for macroalbuminuria : Perform a 24 h urine collection for quantitation of protein excretion.

AND

B. Annual estimation of the Glomerular Filtration Rate (eGFR)

eGFR Indicates

<60 mL/min per 1,73 m2 At least moderate kidney dysfunction (stage 3 – 5 chronic kidney disease (CKD))

60 – 90 mL/min per 1,73 m2

Mild kidney dysfunction (stage 2 CKD if albuminuria also present)

Continue annual screening for albuminuria and eGFR in the event of negative screening tests.

Reference : Chadban, et al. Nephrology 2010; 15, S146-S161

113

Simple Diabetes Foot Care

Lecture:

30 minutes

Simple Diabetes Foot CareLecture

Main Learning Points

• Understand the risk factors for diabetic foot complications• Understand the steps for a simple diabetes foot

examination• Understand the management of foot ulcers

114

From Theory to real-life – studies on foot care in RSCM

32%

26%

16%

26%

RSCM 2003

DiedMajor Amputation and then ImprovedDischarge on their own willImproved without amputation

50%

14%

36%

RSCM 2007

DiedAmputationNo Amputation

Why foot care is important to diabetes management

Have 15 – 40 fold higher risk of leg amputation than non diabetic

Have a 15 % life time risk of developing foot ulcer

Every 30 seconds a lower limb lost caused by diabetes

5-year suvival rate after major amputation < 50 %

• 85% of diabetes-related amputations are happening in patients with foot ulcers

• Early detection can prevent 40-85 % lower limb amputation

Frykberg et al. J Foot Ankle Surg, 2000. IDF, International Working Group on Diabetic Foot 2007

Diabetes Patients

115

5 Cornerstones of diabetes foot care management

Identification of risk factors

Foot examinationregularly

Education (patients, providers

and family)

Treatment beforeUlcer occurs

Use appropriate footwear

Risk Factors for diabetic foot ulceration

Frykberg, Diabetic Microvascular Complications Today, May/June 2006

Intrinsic Factors Extrinsic Factors

• Peripheral Neuropathy

• Micro- and Macrovascular

Diseases

• Immunopahty

• Structural Deformity

• Limited Joint Mobility

• Nephropathy

• Age

• Duration of Diabetes

• Visual Acuity

• Previous Ulceration

• Minor mechanical

trauma

• Callus

• Thermal Injury

• Chemical Burns

• Improper use of nail

cutter

• Smoking

• Poor knowledge of

diabetes

• Psychological Factors

• Alternative medication

116

Pathway to diabetic foot ulceration

Reiber GE, Vileikyte, Boyko EJ et al. Causal pathways for incident lower–extremity ulcers in patients with from two settings. Diabetes Care 1999: 157-162

1%

30%35%37%

63%

77%78%

0%10%20%30%40%50%60%70%80%90%

100%

Peripheral Neuropathy

Peripheral Ischemia

EdemaDeformityMinor Trauma

Callus Infections

Components leading to foot ulceration

Intrinsic FactorsPeripheral Neuropathy

Autonomic SensoricMotoric

Decreased Sweating

Dry Skin

Decreased Elasticity

Fissure / Callus

Ulcer

• Loss of protective

sensation

• Decreased pain

threshold

• Lack of temperature

sensation and

proprioception

Thermal Trauma in ‘bajaj’

Ill fitting Shoes

117

Intrinsic FactorsPeripheral Arterial Disease (PAD)

Risk Factors*

• Hyperglycemia

• Eleveted systolic blood

pressure

• hyperlipidemia

• Smoking

• Cardiovascular disease

* UKPDS

PAD

• Correlated with atherosclerosis

• A1c 1% 26 % PAD

• More aggressive

• Narrowing vessel lumen …

obstructive

• Distal tissue necrosis

Intrinsic FactorsNeuropathic Ulcers

Influenced by:

- Friction

- Pressure

118

Intrinsic FactorsFoot Deformities / Biomechanical

Causes of Ulcers (Extrinsic Factors)Kyoto Foot Meeting 2010

119

Pathophysiology of diabetic foot

Diabetes Mellitus

Neuropathy Trauma Vascular Disease

MOTOR

Weakness Atrophy

High Plantar Pressure

DeformityAbnormal Stress

Callus Formation

Structural Deformity

Cheiroarthropathy

Impaired Response to Infection

Diabetic Foot Ulcer AmputationAmputation

AUTONOMIC

Ischemia

Diabetic Foot Disorders: A Clinical Practice Guideline (2006 Revision)

SENSORY

Loss of Protective Sensation

Anhidrosis dry skin

Sympathetic Tone

MICROVASCULAR MACROVASCULAR

Structural capillary BM thickening

Functional AV Shunting

Structural atherosclerosis

Occlusive narrowing

Ischemia

Clinical Classification of diabetic foot (Edmond)

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 6

Normal foot, no risk factors of neuropathy,

ischemia, deformities

No active ulcers, have ≥1

risk factors: neuropathy,

ischemia, deformities, callus and

swelling, nail deformities

Skin breakdown;

fisurre, blitser, ulcer

Usually in plantar surface

Foot develop infections,Discharge purulent, cellulitis,

neuropathy and or

ischemia

Tissue necrosis with or with out intake

foot, neuropathy,

ischemia, neuroischemi,

infection

Unsalvageable foot, need

major amputation,

extensive necrosis,

destroyed foot,severe

infection

120

First 4 steps in the assessment

Assessment Significant FindingPatient History

- Previous foot ulceration- Previous amputation - Diabetic > 10 years- A1c > 7 %- Impaired vision- Neuropathic symptoms- Claudicatio

Gross Inspection

- Hammer toes- Claw toes- Halux valgus - Corn, callus, callus with ulcer, bunion- Prominent metatarsal head

Dermatologic Examination

- Dry skin- Absence of hair- Yellow or erythematous scale- Ulcer or healed ulcer - Interspace maceration- Moist - Unhealing ulceration

Nail Deformities

- Yellow, thickened nail- Ingrowing nail edge- Long or sharp nails

6 Steps for a complete Diabetes Foot Examination

DIABETES FOOT EXAMINATION

Patient History

Gross Assess-

ment

Vascular Examination

Screening for

neuropathy

Derma-tologic

Examination

Nail Defor-maties

121

Last 2 steps in the assessment

Assessment Test Significant Finding

Screening for Neuropathy

- Semmes-Weinstein monofilamen 10 gram

Lack of perception at one or more side

- Tuning fork 128Hz Negative of vibration perception

- Biothesiometer: Vibration perception

Vibration perception threshold >25 volt

Vascular Examination

- Palpation of dorsalispedis and tibialisposterior artery

- Ankle Brachial Index- Color doppler

• Decrease or absent pulse

• ABI < 0.9 consistent with PAD

ABI>1.2

0.9 – 1.2<0.9<0.6

InterpretationRigid or calcified vessels or bothNormal (or calcified)IschemiaSevere ischemia

Risk Classification based on Foot Assessment

Score Category Risk Profile Check-up Frequency

0 Low Risk

• Pulsation ADP and ATP good• No deformities (hammer toe, claw

toes, halux valgus, prominent metatarsal head)

Once a year

1 Increased Risk

• Pulsation ADP and ATP good• And/or deformities (hammer toe,

claw toes, halux valgus, prominent metatarsal head)

Once every 6 months

2 High Risk

• ABI < 0,9 or ADP/ ATP not palpable

• Deformities ( hammer toe, claw toes, halux valgus, , prominent metatarsal head

Once every 3 months

3 Very High Risk• History of ulcer or amputation• Ulcer Once every

1-3 months

122

Intervention based on Risk Classification

Score Category Intervention

0 Low Risk• Encourage extended knowledge on diabetes and foot

care• Encourage self-care

1 Increased Risk

• Inspect patient’s feet• Review need for vascular assessment• Evaluate footwear• Enhance foot care education

2 High Risk

• Inspect patient's feet• Review need for vascular assessment• Evaluate provision and provide appropriate• Intensified foot care education• Specialist footwear and insoles• Skin and nail

3 Very High Risk

• Multidisciplinary foot care team : • They should have unhindered access to suites for

managing major wounds,• Urgent inpatient facilities• Antibiotic administration

Prevention of Diabetes Foot

DOCheck your feet everyday

Always wear footwear

Check your footwear before wearing themUse shoes that fit

Buy shoes in the afternoon

Always use socks of cotton

Wash your feet with soft soap and dry themCut your nails in a flat way

Check your feet regularly at thedoctorUse lotion regularly at your skin

DON’T’sWalk without shoes

Use shoes that don’t fit

Use socks that don’t fit to your footLet your skin become dry

Use sharp items to remove wartsSmoke

Use ring on finger

Use high heels or shoes with sharp edgesOver use of irritative lotion

Use hot water to dip your feet

123

Wound Control1

1. Incision, drainage, debridement and necrotomy

2. Management of infections in tissue and bone

3. Exudate Management4. Keep control of

proliferation phase and infections

Metabolic Control

Infection Control

Vascular Control

Mechanic Control

Wound Control

Management of Foot Ulcers

International Working Group on the Diabetic Foot 2007

1

2

3

45

124

Metabolic Control2

1. Hyperglycemia- Will inhibit process of wound recovery- Inhibit growth factor, collagen synthesis

and fibroblast activities2. Hypoalbuminemi3. Hypertension4. Decrease of heart and kidney function5. Dyslipidemia6. Anemia7. Other diseases caused by diabetes

Infection Control3

1. Need aggressive therapy2. Usually there are no

symptoms or signs of infection

3. External Infection: Positive gram bacteria

4. Internal Infection: Negative gram bacteria

5. Might need surgery

125

Use of Antibiotics3

Choice of antibiotics should be determined by:

1. Condition of the Infection:- Stage of infection and history of antibiotics- Bone infection, condition of blood vessels

2. Type of bacteria (sensitivity test)- Anarob, aerob, gram positive / gram negative

3. Condition of the patient- Allergy, heart and kidney function

4. Drug Profile- Safety, drug interactions, adverse events,

frequency and dosage and price

Vascular Control4

1. Neuroischemic Foot2. Atherosclerosis can

cause total block in the blood vessels

3. Decrease of blood flow to the wound

4. Critical Limb ischemia: Amputation Warning

126

Mechanic Control5

Principle:Reduce stress on the wound

• Off loading• Might be bed rest

• Non-weight bearing• Use of walker, wheel-chair

or crutches• Use special shoes (‘half-

shoes’)• Distribute the body weight

to all surfaces of the foot

Simple Diabetes Foot CareLecture

Main Learning PointsSummary

• There are two risk factors for diabetic foot; intrinsic and extrinsic.

• Check feet regularly to prevent ulcers.

• Diabetes foot care management (Identification of risk factors, Foot examination regularly, treatment before ulcer occurs, use appropriate foot wear, education).

• Management of foot ulcers (wound control, metabolic control, infection control, vascular control, mechanic control).

• Understand the risk factors for diabetic foot complications

• Understand the steps for a simple diabetes foot examination

• Understand the management of foot ulcers

127

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