Materi Workshop Diabetes Melitus untuk Dokter Umum - Practical Management of Diabetes and Its Complication for General Practitioner.
Diselenggarakan oleh Perkeni, Kementerian Kesehatan RI dan STENO Diabetes Center
Materi Workshop Diabetes Melitus untuk Dokter Umum - Practical Management of Diabetes and Its Complication for General Practitioner
1.
2. 2
Sponsored by PT. Novo Nordisk Indonesia
New INSPIRE by PERKENI and STENO Diabetes Center
A National Diabetes Management Course
3. 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. 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. 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. 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
UrbanisationUnhealthy lifestyle choices
7. 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
0
20
40
60
80
100
120
140
160
180
200
220
mg/dl
PPG (mg/dl)FPG (mg/dl)
GlycemicControlLevel
PERKENI GuidelinesDiabCare 2008
Source: Novo Nordisk Data on File
9. 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. 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. 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
13. 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. 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
16. 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)
FastingPlasmaGlucose(FPG)
mg/dL
140 200
100
126
NGT (Normal
Glucose
Tolerance)
Diabetes
IFG (Impaired
Fasting Glucose
IGT (Impaired
Glucose
Tolerance)
Diabetes
17. 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. 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. 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.
Incidenceper1.000patient-
years
12697 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. 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. 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. 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. 23
Diabetes and its Co-morbidities –
Hypertension and Dyslipidemia
Lecture:
30 minutes
Diabetes
HypertensionDyslipidemia
Diabetes and its Co-morbidities – Hypertension and
Dyslipidemia
Lecture
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. 24
Diabetes and its Co-morbidities
Hypertension
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 Pressure
Stage 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. 25
Diabetes Is a Major Multiplier of Cardiovascular Risk in
Patients With Hypertension
Systolic Blood Pressure and Cardiovascular Mortality
Stamler J, et al. Diabetes Care. 1993;16:434–444.
130
85
62
42
2218
245
153
160
112
73
55
0
50
100
150
200
250
CardiovascularMortality
RatePer10,000Person-Years
120 - 139<120 >200
Systolic Blood Pressure mmHg
160 -179 180 - 199140 -159
Diabetes
No Diabetes
Effect of Blood Pressure Control in the UKPDS
Tight vs. Less Tight Control
Any diabetes-related endpoint
Diabetes-related deaths
Heart failure
Stroke
Myocardial infarction
Micro vascular disease
Tight Control
1,148 Type 2 patients
Average BP lowered to 144/82 mmHg (controls: 154/87);
9-year follow-up
24
32
56
44
21
37
Risk Reduction (%) P value
0.0046
0.019
0.0043
0.013
NS
0.0092
UKPDS Group. BMJ. 1998;317:703-713.
26. 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
Patientswithevents(%)
Years
Diabetes-related deaths
0
40
30
20
10
30 5 7 86421 9
32% risk reduction
P < 0.02
Patientswithevents(%)
Less tight control: mean BP 154/87 mmHg
Tight control with captopril or atenolol:
mean BP 144/82 mmHg
Years
Microvascular disease
Patientswithevents(%)
0
20
15
10
5
30 5 7 86421 9
37% risk reduction
P < 0.01
Major Outcomes of the Hypertension Optimal Treatment
(HOT) Trial
Diabetes 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
Events/1000Pt-Years
MIMajor CV Events
<85 mmHG (n=501)
<90 mmHG (n=501)
<80 mmHG (n=499)
Diastolic Target
27. 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
SBP
or DBP
130 – 139 mmHg
80 – 89 mmHg
SBP
or 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 compelling
indications
other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
Without Compelling Indications
Not at Goal
BP
Stage 2 HTN
(SBP 160 or DBP 100 mm Hg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, ARB, BB, or CCB)
Chobanian AV et al. JAMA. 2003;289:2560-72
28. 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
30. 30
Mean Plasma Lipids at Diagnosis of Type 2 Diabetes
UKPDS
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. 31
Heart Protection Study
Proportions 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. 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)
Goal
Initiation
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 National
Institutes of Health Website. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed November 25, 2009.
33. 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 CVD
or with signs of diabetic complications
Risk stratification as per NCEP ATP III guideline
Major risk factors as per ATP III guidelines
Major risk factors to modify treatment of LDL
(excluding LDL cholesterol)
Nonmodifiable Modifiable
Age: 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. 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. 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 Dyslipidemia
in 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. 36
Diabetes and its Co-morbidities – Hypertension and
Dyslipidemia
Lecture
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. 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. 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. 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. 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. 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. 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. 43
Proteins
Eat Less of These Eat More of These
Chicken, Fish, TofuSausages, 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. 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. 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. 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
ChangeinHbA1c
frombaselinetopost-intervention
(weightedmeandifference)
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. 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
MortalityRate(per100.000person-years)
Past 1-14 cig / dayNever 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. 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. 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. 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. 51
Diabetes Acute Complications – Hypoglycemia and DKA
Lecture:
30 minutes
Management of Hypoglycemia
Lecture
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. 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 neurogenic
symptoms due to low plasma glucose levels
53. 53
Most common symptoms of Hypoglycemia
Patients (%)
Circumoral paraesthesia
Difficulties in concentration
Slurred speech
Blurred vision
0 20 40 60 80 100
Hunger
Palpitations
Vertigo
Cold feeling
Anxiety
Euphoria
Weakness
Tremor
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. 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
Eventsper100PatientYears
HbA1c (%)
Conventional Therapy
0
10
20
30
40
50
60
70
80
90
100
6.0 6.5 7.0 7.5 8.0 8.5 9.0
ACCORD (T2 DM)
DCCT (T1 DM)
Eventsper100PatientYears
HbA1c (%)
Intensive Therapy
0
10
20
30
40
50
60
70
80
90
100
6.0 6.5 7.0 7.5 8.0 8.5 9.0
DCCT (T1 DM)
ACCORD (T2 DM)
55. 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. 56
Treatment of moderate-to-major Hypoglycemia
Patient requires assistance with treatment
If 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. 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. 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. 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. 60
Initial DKA Treatment in Primary Care
1. Evaluate vital signs and urine
volume
2. IV line, start the rehydration
3. 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 DKA
Lecture
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. 61
Initiating Diabetes Treatment with OADs
Lecture:
30 minutes
Initiating Diabetes Treatment with OADs
Lecture
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. 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 diabetes
When 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%
Basal
Basal
Insulin
Premix
Insulin
Basal +
Bolus
Insulin
START TREATMENT OAD TREATMENT START INSULIN INSULIN INTENSIFICATION
63. 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 Combination
Healthy life style
+
Combination 2 OAD
+
Basal insulin
Insulin
Intensification*
*Intensive Insulin: use of basal insulin together with insulin prandial
Healthy life style
+
3 OAD Combination
Alternative option, if :
• No insulin is available
• The patient is objecting insulin
• Blood glucose is still not
optimally controlled
Note:
1. Therapy failed if
target of HbA1c <
7% is not achieved
within 2-3 months
for each step
2. In case of no
HbA1c test, the use
of blood glucose
level is also
permitted. Average
blood glucose level
for a few BG test in
one day can be
converted to HbA1c
(ref: ADA 2010)
Updated PERKENI Type 2 Diabetes Treatment Algorithm
64. 64
ADA/EASD Algorithm
Main pathophysiological defects in type 2 DM
hepatic
glucose
production
peripheral
glucose
uptake
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
gut
carbohydrate
delivery and
absorption
incretin
effect
Hyperglycemia
?
Liver
Muscle
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. 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)
Metformin
Mode of Action
The primary effects of metformin are to decrease hepatic
glucose production and increase insulin-mediated peripheral
glucose uptake
Anaerobic glucose
metabolism
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. 66
Metformin
Clinical Overview and Contraindications
Metformin
Efficacy*
Safety,
Tolerability
and
Adherence
Contraindications Advantages
• HbA1c
reduction 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
Metformin
Little 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
Changevs.Placebo(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
Changevs.Placebo(%)
2500mg2000mg1500mg1000mg500mg
Metformin Dose
67. 67
SUs and Glinides
Mode 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 release
Voltage-gated
calcium channel
ATP-sensitive
potassium channel
SUs /
glinides
Glycolysis
respiration
Glucokinase
ATP
Ca2+
ATP = orange
Ca2+ = light green
SUs and Glinides
Clinical Overview
Sulphonylurea
Efficacy*
Safety,
Tolerability and
Adherence
• HbA1c
reduction of
1-2%
• FPG reduction
of 40-70 mg/dl
• Associated with
hypoglycaemia
and 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
• HbA1c
reduction of
0.5-1.5%
• FPG reduction
of 20-60 mg/dl
• PPG reduction
of 75-100
mg/dl
• Associated with
hypoglycaemia
and weight gain
• Frequent
administration
(with every meal)
is required.
68. 68
Alpha glucosidase inhibitors
Mode 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 inhibitors
Clinical 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 not
cause 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. 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
• HbA1c
reduction 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. 70
DPP-4 inhibitors
Mode 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 prolongs
GLP-1 effect on α-cells
Increases and prolongs GLP-1
and GIP effects on β-cells
Food intake
Stomach
GI tract
Intestine
α-cells
Pancreas
Glucose-dependent insulin secretion
β-cells
DPP-4
inhibitor
Glucose-dependent glucagon secretion
Incretins
(GLP-1, GIP)
DPP-4
Net effect:
blood glucose
* GIP does not inhibit glucagon secretion by α-cells
DPP-4 inhibitors
Clinical 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. 71
GLP 1 Agonist
Mode 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 proliferation
β-cells
• Glucagon secretion
• β-cell apoptosis
GLP-1 agonist
Net effect:
blood glucose
GLP 1 Agonist
Clinical 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. 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. 73
OAD’s – a quick summary of the different mechanism
of actions
α-Glucosidase inhibitors
Delay intestinal
carbohydrate absorption
Thiazolidinediones
Increase glucose uptake
in skeletal muscle and
decrease lipolysis in
adipose tissue
Sulfonylureas
Increase insulin
secretion from
pancreatic β-cells
GLP = glucagon-like peptide.
Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.
Meglitinides
Increase insulin secretion
from pancreatic β-cells
Incretins :GLP-1 analogue(exen-
atide)/DPP-4 inhibitors
Improves 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
Experience
No weight gain
No hypoglycaemia
Likely CVD Events ↓
Gastrointestinal side
effects
Lactic acidosis risk
(rare)
Vitamin B12
deficiency
Multiple
contraindications:
CKD, acidosis,
hypoxia,
dehydration etc.
Sulfonylureas Glibenclamide /
glyburide
Glipizide
Gliclazide
Glimepiride
Closes KATP
channels on
beta cell
plasme
membranes
Insulin secretion ↑ Extensive
experience
Microvascular Risk ↓
(UKPDS)
Hypoglycemia
Weight gain
Blunts myocardial
ischaemic
preconditioning ?
Low durability
Meglitinides Repaglinide
Nateglinide
Closes KATP
channels on
beta cell
plasme
membranes
Insulin secretion ↑ Postprandial
glucose excursions ↓
Dosing flexibility
Hypoglycemia
Weight gain
Blunts myocardial
ischaemic
preconditioning ?
Frequent dosing
schedule
Inzucci SE, et al. Diabetologia. 2012
74. 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
Thiazolidinedi
ones
Pioglitazone
Rosiglitazone
Activates the
nuclear
transcription
factor PPAR-y
Insulin Sensitivity ↑ No
hypoglycaemia
Durability
HDL-C ↑
Triacylglycerol ↓
(pioglitazone)
CVD Events ↓?
Weight Gain
Oedema / Heart
Failure
Bone Fractures
LDL-C ↑
(rosiglitazone)
Mn ↑ (meta-
analyses,
rosiglitazone)
Bladder Cancer ↑?
(pioglitazone)
a-Glucosidase
Inhibitors
Acarbose
Migitol
Voglibose
Inhibits
intestinal a-
glucosidase
Slows intestinal
carbohydrate
digestions /
absorption
No
hypoglycaemia
Postprandial
glucose
excursions ↓
CVD Events ↓
Non-systemic
Modest HbA1c
efficacy
Gastrointestinal side
effects (flatulence,
diarrhoea)
Frequent dosing
schedule
DPP-4
Inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
Linagliptin
Alogliptin
Inhibits DPP-4
activity,
increasing
postprandial
active incretin
(GLP-1, GIP)
concentrations
Insulin secretion ↑
(glucose-dependent)
Glucagon secretion ↓
(glucose-dependent)
No
hypoglycaemia
Well tolerated
Modest HbA1c
efficacy
Urticardia/Angio-
oedema
Pancreatitis ?
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-1
Receptor
Agents
Exenatide
Liraglutide
Activates GLP-
1 receptors
Insulin secretion ↑
(glucose-dependent)
Glucagon secretion ↓
(glucose-dependent)
Slows gastric
emptying
Satiety ↑
No
hypoglycaemia
Weight reduction
Improved beta
cell mass /
function ?
Cardiovascular
protective
actions ?
Gastrointestinal side
effects (nausea /
vomiting)
Acute pancreatitis ?
C cell hyperplasia /
medullary thyroid
tumours
Injectable
Training
Requirements
Insulin Human NPH
Human Regular
Lispro
Aspart
Gluisine
Glargine
Determir
Pre-mixed
(several types)
Activates
insulin
receptors
Glucose disposal ↑
Hepatic glucose
production ↓
Universally
effective
Theoretically
unlimited
efficacy
Microvascular
Risk ↓ (UKPDS)
Hypoglycemia
Weight gain
Mitogenic effects ?
Injectable
Training
Requirements
‘Stigma’ for patients
Inzucci SE, et al. Diabetologia. 2012
75. 75
Initiating Diabetes Treatment with OADs
Lecture
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
79. 79
The Usage of Insulin
Lecture
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. 80
Insulin remains the most efficacious glucose
lowering agent
Decrease in HbA1c: Potency of monotherapy
HbA1c%
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. 81
What is Insulin
• After a meal carbohydrates
are digested and enter the
blood system, which
transports them to the cells
INSULIN
is needed
for glucose uptake
and 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 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
0
20
40
60
80
100
120
140
160
180
200
220
mg/dl
PPG (mg/dl)FPG (mg/dl)
GlycemicControlLevel
PERKENI GuidelinesDiabCare 2008
Source: Novo Nordisk Data on File
82. 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.
Normal
Type 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
Tissue
Muscles
• Inhibits glucose
production
• Promotes formation of
glycogen and its
storage
• Promotes uptake and
utilization of glucose
• Promotes uptake of
glucose
• Suppresses lipolysis
83. 83
…diabetes Patients will eventually fail on OAD’s
6.2% – upper limit of normal range
MedianHbA1c(%)
UKPDS
6
7
8
9
Years from randomisation
Conventional*
Glibenclamide
Metformin
Insulin
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
ADOPT
Metformin
Glibenclamide
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
Patientsrequiring
additionalinsulin(%)
0
10
20
30
40
50
60
1 2 3 4 5 6
84. 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. 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. 86
Three Types of Insulin
Schematic Representation OnlyGIR(mg/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 insulins
include 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(mg/kg/min)
0 8 16 20 244 12
Time (h)
GIR(mg/kg/min)
0 8 16 20 244 12
Time (h)
GIR(mg/kg/min)
0 8 16 20 244 12
87. 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. 88
Insulin Titration schemes
Basal 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 Optimization
How to Optimize Treatment after Initiation
Basal Insulin Only
Usually 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 Only
Usually with OAD
Basal with Prandial
Usually keep Metformin
Premix Insulin
Usually keep Metformin
Basal Bolus
Usually 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. 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
92. 92
Screening, Treatment and Evaluation of
Complications
Lecture:
Screening, Treatment and Evaluation of Complications
Lecture
Main Learning Points
• Understand the screening, diagnose and treatment
options / refer for diabetes associated
complications:
• Nephropathy
• Retinopathy
• Neuropathy
• Erectile Dysfunction
• CVD
• CAD
93. 93
Recap: The goal of diabetes management is to secure
optimal glycemic control to avoid complications
Diabetic
retinopathy
Leading cause
of blindness
in working-age
adults1
Diabetic
nephropathy
Leading cause of
end-stage renal disease2
Cardiovascular
disease
Stroke
1.2- to 1.8-fold
increase in stroke3
Diabetic
neuropathy
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 Dysfunction
The most secretive
Complication 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
Incidenceper1.000
patient-years
94. 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
40
0
100
200
300
400
500
600
700
800
900
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
diabetes
endpoint
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 UKPDS
RRR* 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.
96. 96
Diabetes Nephropathy
Characteristics
• Persistent albuminuria
• Diabetic retinopathy
• Hypertension
• Decline in kidney function (about 12 ml/min/year)
Diabetes Nephropathy
Prevention and Treatment
DCCT. Diabetes 1996;45:1289–98
Glycated haemoglobin (%)
5 8 12
0.0
0.4
0.8
0.6
0.2
111096 7
Probabilityof
microalbuminuria
• 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. 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 Macro
In 2 of 3 measurements
Natural history of diabetic nephropathy
.
Functional
GFR -
(90-95%)
Microalbuminuria,
hypertension
Proteinuria, nephrotic
syndrome, GFR ¯
Urinary protein excretionGFR
Urinaryproteinexcretion(mg/d)
Years
Glomerularfiltrationrate(GFR)
(mL/min)
0
150
100
50
5 10 15 20 25
20
200
1000
5000
Incipient diabetic
nephropathy
Pre Overt diabetic
nephropathy
End-stage
renal disease
1 2 3 4 5
Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000
98. 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. 99
Diabetes Retinopathy
Risk 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 (%)
Retinopathyincidence(oddsratio)
4 6 9
0
5
10
875
35
30
25
20
15
10
DCCT HbA1c (%)
5.7 7.7 10.89.88.86.7 11.9
Diabetes Retinopathy
Prevention 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. 100
Diabetes Neuropathy
Risk 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
Median
Lateral
popliteal
Diabetes Neuropathy
The 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. 101
Diabetic Foot Complications
Diabetes Neuropathy
Prevention 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
0
0
Percentageofcasesaffected
p<0.001
12
4
Conventional therapy
Intensified therapy
1
Time (years)
2 3 4 5
102. 102
Erectile Dysfunction
Definition
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 Dysfunction
Background
• 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. 103
Erectile Dysfunction
Risk Factors
Risk Factors
Neuropathy
Peripheral vascular disease
Poor glycemic control
Diabetes duration and complications
Age and high BMI
Smoking doubles the risk
Erectile Dysfunction
Screening
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
105. 105
Macrovascular Complications – an overview
Stroke
Cardiovascular/heart
disease
Peripheral vascular disease
Cardiovascular Diseases
Patients 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
Patients(%)
106. 106
Cardiovascular Diseases
Risk 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
Relativerisk
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
Numberofdeathsper10,000patient-years
Non-diabetic
subjects
Subjects with
type 2 diabetes
0 1 2 3
0
20
40
60
80
100
120
140
107. 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. 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. 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. 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. 111
The STENO2 Study
Risk 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 Complications
Lecture
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. 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. 113
Simple Diabetes Foot Care
Lecture:
30 minutes
Simple Diabetes Foot Care
Lecture
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. 114
From Theory to real-life – studies on foot care in RSCM
32%
26%
16%
26%
RSCM 2003
Died
Major Amputation and then Improved
Discharge on their own will
Improved without amputation
50%
14%
36%
RSCM 2007
Died
Amputation
No 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. 115
5 Cornerstones of diabetes foot care management
Identification of
risk factors
Foot examination
regularly
Education
(patients, providers
and family)
Treatment before
Ulcer 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. 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 Factors
Peripheral 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
119. 119
Pathophysiology of diabetic foot
Diabetes Mellitus
Neuropathy Trauma Vascular Disease
MOTOR
Weakness
Atrophy
High Plantar
Pressure
Deformity
Abnormal
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. 120
First 4 steps in the assessment
Assessment Significant Finding
Patient
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. 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 dorsalis
pedis and tibialis
posterior 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
Interpretation
Rigid or calcified vessels or both
Normal (or calcified)
Ischemia
Severe 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. 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
DO
Check your feet everyday
Always wear footwear
Check your footwear before
wearing them
Use shoes that fit
Buy shoes in the afternoon
Always use socks of cotton
Wash your feet with soft soap
and dry them
Cut your nails in a flat way
Check your feet regularly at the
doctor
Use lotion regularly at your skin
DON’T’s
Walk without shoes
Use shoes that don’t fit
Use socks that don’t fit to your
foot
Let your skin become dry
Use sharp items to remove
warts
Smoke
Use ring on finger
Use high heels or shoes with
sharp edges
Over use of irritative lotion
Use hot water to dip your feet
123. 123
Wound Control1
1. Incision, drainage,
debridement and
necrotomy
2. Management of
infections in tissue and
bone
3. Exudate Management
4. 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
4
5
124. 124
Metabolic Control2
1. Hyperglycemia
- Will inhibit process of wound recovery
- Inhibit growth factor, collagen synthesis
and fibroblast activities
2. Hypoalbuminemi
3. Hypertension
4. Decrease of heart and kidney function
5. Dyslipidemia
6. Anemia
7. Other diseases caused by diabetes
Infection Control3
1. Need aggressive therapy
2. 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. 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 Foot
2. Atherosclerosis can
cause total block in the
blood vessels
3. Decrease of blood flow
to the wound
4. Critical Limb ischemia:
Amputation Warning
126. 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 Care
Lecture
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