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INTRODUCTION

Sponsored by PT. Novo Nordisk Indonesia


New INSPIRE by PERKENI and STENO Diabetes Center
A N ti l Di b t M t C A National Diabetes Management Course
Overall Training Objectives g j
To provide participants with a holistic understanding of To provide participants with a holistic understanding of To provide participants with a holistic understanding of
diabetes management from diagnosis to late-stage
complications
To provide participants with a holistic understanding of
diabetes management from diagnosis to late-stage
complications
To provide participants with practical tools, guidelines,
demonstrations and take-home educational materials to
improve and optimize their diabetes treatment
To provide participants with practical tools, guidelines,
demonstrations and take-home educational materials to
improve and optimize their diabetes treatment
To emphasize and demonstrate the importance of early To emphasize and demonstrate the importance of early p p y
treatment of diabetes to avoid long-term complications
p p y
treatment of diabetes to avoid long-term complications
About INSPIRE Training in Indonesia About INSPIRE Training in Indonesia
Curriculum
Sponsorship
Curriculum,
workshops and cases
designed in
The INSPIRE
Training courses,
the development of
collaboration
between PB.
PERKENI and
STENO Diabetes
the curriculum and
all support
programs are
Coordination
and
li
STENO Diabetes
Center
Joint PERKENI
STENO certificates
sponsored by PT.
Novo Nordisk
Indonesia to
support and
Alignment
STENO certificates
will be distributed for
a participation rate of
90%
support and
enhance the quality
of diabetes training
across Indonesia
Why INSPIRE? Why INSPIRE?
BE INSPIRED AS A
DOCTOR
TO INSPIRE YOUR
PATIENTS DOCTOR PATIENTS
A TRULY UNIQUE PLACE A TRULY UNIQUE PLACE
An independent research and patient care institution funded by the
capital Region of Copenhagen and Novo Nordisk
P ti t h d d ti f i l i l 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 the world
Treating 6.200 patients with Type 1 and Type 2 Diabetes through the
team-based method
STENO EDUCATION CENTER
Facts: 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 Rules of the INSPIRE Program
RULES
Certificates can only be
i f i i 80%
RULES
given for minimum 80%
attendance
Li it M bil Ph A ti it Limit Mobile Phone Activity
to the Coffee Breaks
B b k i f Be back on time after
lunch- and coffee breaks
Why do we see a massive increase in people
with Type 2 Diabetes across the World?
Aging population Urbanisation Unhealthy lifestyle
choices
Dietary changes Reduced physical activity
Cockram CS 2000. HKMJ; 6 (1): 43-52
Mohan et al 2007. Indian J Med Res; 125: 217-230
Adapted from IDF Diabetes Atlas 4
th
ed., 2009
High Blood Glucose is now the 3
rd
biggest risk
factor contributor to cardio-vascular deaths factor contributor to cardio vascular deaths
globally
Alcohol use
Childhood underweight
Indoor smoke from solid fuels
Overweight and Obesity
High Cholesterol
Unsafe Sex
Tobacco
High Blood Glucose
Physical Inactivity
0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000
Raised Blood Pressure
Tobacco
Attributable deaths due to selected risk factors (000)
Source: WHO 2011. Global Atlas on CVD prevention and Control 1-164
Diabetes is developing much faster than
ti i t d i I d i 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%
Approximately 10 million people
with diabetes in Indonesia
* Source: RISKESDAS Survey 2007 24.417 subjects , >15 years ol from 33 provinces ** IFT
= Impaired Glucose Tolerance
and our diabetes patients are not in good glycemic control
DiabCare Indonesia 2008 illustrated the need for more intensive DiabCare Indonesia 2008 illustrated the need for more intensive
treatment to decrease FPG and PPG
n: 1.823 patients with diabetes mg/dl
208
160
180
200
220
e
v
e
l
144
100
140
100
120
140
160
c

C
o
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o
l

L
40
60
80
100
G
l
y
c
e
m
i
0
20
PPG (mg/dl) FPG (mg/dl)
PERKENI Guidelines DiabCare 2008
Source: Novo Nordisk Data on File
P T t 20 i t Pre-Test 20 minutes Pre-Test
LECTURE
Early Detection and
Standardized Diabetes
Monitoring
Early Detection and Standardized Diabetes
Lecture:
y
Monitoring
30 minutes
Early Detection and Standardized Diabetes
Monitoring Monitoring
Lecture
Main Learning Points Main Learning Points
Understand the importance of treating diabetes p g
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 blood glucose and HbA1c monitoring
Some Definitions before we start
Common Definitions
Abb i ti D fi iti 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)
IFT
Impaired Fasting Glucose
IFT
(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 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
Difference between Type 1 and Type 2 Diabetes
Comparison of Type 1 and Type 2 Diabetes
Features Type 1 Diabetes Type 2 Diabetes Features Type 1 Diabetes Type 2 Diabetes
Onset Sudden Gradual
Age at Onset Any age (mostly young) Mostly in adults Age at Onset Any age (mostly young) Mostly in adults
Body Habitus Thin or normal Often obese
K t id i C R Ketoacidosis Common Rare
Autoantibodies Usually present Absent
E d L b N l d d Endogenous
Insulin
Low or absent Normal, decreased or
increased
Prevalence Less prevalent More prevalent, typically
90-95% of all people with 90 95% of all people with
diabetes
Type 2 diabetes is a progressive disease
Lebovitz. Diabetes Reviews 1999;7:13953 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:124958)
HOMA: homeostasis model assessment
Diabetes elevated blood glucose due to
insufficient insulin secretion insufficient insulin secretion
Normal glucose and insulin
excursions
Early Type 2 Diabetes Glucose
and insulin excursions
400 120
Glucose Insulin
400 120
Glucose Insulin
200
300
60
80
100
e


m
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200
300
60
80
100
e


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100
20
40
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20
40
G
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06:00 10:00 18:00 14:00 02:00 22:00 06:00
Time of Day
B
r
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a
k
f
a
s
t
L
u
n
c
h
D
i
n
n
e
r
06:00 10:00 18:00 14:00 02:00 22:00 06:00
Time of Day
B
r
e
a
k
f
a
s
t
L
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h
D
i
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t
Classical Diabetes Symptoms
Polyuria Excessive Urination at night
Polyphagia
Excessive Hunger
Polyphagia
Excessive Hunger
Polydipsia
Excessive Thirst
Unexplained
weight loss
Weight Loss even if food
in-take is normal
Other Diabetes Symptoms
Blurred Vision Damaging blood vessels in
the eyes
Numbness and/or
Tingling
the eyes
Numbness and tingling in hands,
legs and feet
Fatigue
legs and feet
Frequent fatigue regardless
of e e cise
Itchy Skin
of exercise
affects legs, feet, and hands
Impotence
g , ,
Physical and Physiological
p
ys ca a d ys o og ca
4 Simple Steps from Screening to Diagnosis
Conduct 1
st
Blood Test
2
Conduct 2
nd
Blood Test
(if required) and
establish Diagnosis
3
Screen patients with
diabetes risk factors
1
Inform Patient and
Initiate treatment
4
Initiate treatment
Step 1: Risk Factors PERKENI screening risk
factor guideline factor guideline
Unmodifiable Risk Modifiable Risk
Diabetes Associated
Risk Risk
Race and Ethnic
Family History of
Overweight (BMI >23)
Hypertension >
Polycystic Ovary
Syndrome (PCOS) or Family History of
Diabetes
History of Gestational
Diabetes
Hypertension >
140/90 mmHg
Dyslipidemia (HDL <
35 mg/dl and/or
Syndrome (PCOS) or
another clinical
condition related to
insulin resistance Diabetes
History of delivery a
baby more than
4 000g
35 mg/dl and/or
triglycerides >250
mg/dl
Unhealthy Diet
insulin resistance
Metabolic Syndrome
(IGT, IFG, History of
Coronary Artery 4.000g
History of low birth
weight <2.500g
Unhealthy Diet
Limited Physical
Activity
Coronary Artery
Disease , stroke
and/or PAD)
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
Step 2: Conduct 1
st
Blood Test
Clinical Test
(+) Classic
Symptoms
(-) Classical
Symptoms
FBG
RBG
>126
>200
<126
<200
FBG
RBG
>126
>200
<100
<140
100-125
140-199
Repeat FBG or RBG
2 Hour Post loading
Plasma Glucose
Diabetes Mellitus IGT IFG Normal
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
Step 3: Conduct 2
nd
Blood Test (if required)
and Establish Diagnosis and Establish Diagnosis
Clinical Test
(+) Classic
Symptoms
(-) Classical
Symptoms
FBG
RBG
>126
>200
<126
<200
FBG
RBG
>126
>200
<100
<140
100-125
140-199
Repeat FBG or RBG
2 Hour Post loading
Plasma Glucose
>126
>200
<126
<200
PPG >200 140-199 <140
Diabetes Mellitus IGT IFG Normal
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
Step 4: Inform Patient and Initiate Treatment
Diabetes Mellitus IGT IFG
E l ti f N t iti l St t Ed ti Evaluation of Nutritional Status
Evaluation of Diabetes
Complications
Education
Food Regulation
Physical Exercise
Evaluation of Required Food
Regulation
Decision on medines
Ideal Body Weight
OADs are unnecessary at
this stage g
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
Cut-points: Diabetes, IGT and IFG
md/dl
F
P
G
)
md/dl
Diabetes
G
l
u
c
o
s
e

(
F
126
IFG (Impaired
Fasting Glucose
n
g

P
l
a
s
m
a

100
NGT (Normal
Glucose
Fasting Glucose
IGT (Impaired
Glucose
Tolerance)
Diabetes
d/dl
F
a
s
t
i
n
140 200
Glucose
Tolerance)
md/dl
2-hour Plasma
Glucose (PPG)
140 200
Diagnosis of Type 2 Diabetes
KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2 KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
1. Symptoms of Diabetes y p
Random plasma glucose concentration > 200 mg/dl
Or
2. Fasting Plasma Glucose:
FBG > 126 mg/dl. No calorie intake for at least 8 hours
N d b d i i i d d d Need to be repeated twice in two independent days
3 2-hour post-OGTT
Or
3. 2-hour post-OGTT
OGTT > 200 mg/dl. 75 g. of glucose dissolved in water
The Importance of treating Type 2 Diabetes
Type 2 diabetes is a progressive disease Type 2 diabetes is a progressive disease
Diagnosis
Postprandial glucose
Diagnosis
Glucose
Fasting glucose
Insulin
Insulin resistance
Inadequate
-cell function
Insulin secretion
Prediabetes
NGT Di b t
Macrovascular changes
Microvascular changes
Insulin secretion
Adapted from Type 2 Diabetes BASICS. International Diabetes Center 2000
Prediabetes
(IFG/IGT)
NGT Diabetes
Treatment therapies for Type 2 diabetes
When and How to start treatment When and How to start treatment
START TREATMENT OAD TREATMENT START INSULIN INSULIN INTENSIFICATION
Lifestyle +
+-other OAD
or GLP-1
Basal
Basal Premix
Basal +
Bolus
Metformin
or GLP 1
agonists
Insulin Insulin
Bolus
Insulin
HbA
1c
7.0%
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
What is good glycemic control?
Overall aim to achieve glucose levels as close to normal as
possible possible
Minimise development and progression of microvascular
and macrovascular complications
FPG
<130 mg/dL
HbA
1c
< 7.0%
PPG
<180 mg/dL
ADA
1
FPG
<110 mg/dl
HbA
1c
< 6.5%
PPG
<145 mg/dL
IDF
2
PERKENI
3
FPG
<100 mg/dl
HbA
1c
< 7%
PPG
<140 mg/dl
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 .
Risk of Complications increases as Hb1Ac
increases and thats why diabetes must be treated increases and that s why diabetes must be treated
80
60
Microvascular disease
0

p
a
t
i
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n
t
-
20
40
Myocardial infarction
e

p
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1
.
0
0
0
y
e
a
r
s
0
5 6 7 8 9 10 11
I
n
c
i
d
e
n
c
e
Mean HbA1c (%)
Adjusted for age, sex, and ethnic group. The relationship between A1C and mg/dl is described
126 97 154 183 212 240 269 Mean mg/dl
Stratton IM et al. BMJ 2000;321:40512
j g , , g p p g/
by the formula 28.7 X A1C 46.7 = mg/dl.
The benefits of good blood glucose control are
l clear
Good control is
Myocardial
infarction
Good control is
7.0% HbA
1c
HbA
1c
measures
infarction
-14%
1c
the average
blood glucose
level over the
Microvascular
complications
HbA
1c
last three
months
-37%
b
1c
-1%
Deaths related
to diabetes
Source: UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM
et al. BMJ. 2000;321(7258):405-412.
-21%
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
ABCD Strategy to guide Diabetes Treatment gy g
ABCD Strategy
Age (older) Increased risk for hypoglycemia & comorbidities
Less stringent therapy
Reduce the use of kidney-excreted drugs if possible
Body Weight BW neutral (gliptins, acarbose, DPPIV inhibitors,
long-acting insulin analogues),
BW gain (human insulin, sulphonylureas, TZDs)
BWloss (metformin GLP1 analogues) BW loss (metformin, GLP1 analogues)
Complications Major macro- & microvascular complication less
stringent
Consider renal or heart failure Consider renal or heart failure
Duration of Disease Strict glycemic control at the early period of the
disease better prevention of macro &
microvascular complications
Source: Diabetes Metab Res Rev 2010; 26: 239244
p
Individualized Treatment based on several criteria
to control blood glucose to control blood glucose
Inzucci SE, et al. Diabetologia. 2012
LECTURE
Diabetes and its
Co-morbidities-Hypertension
and Dyslipidemia
Diabetes and its Co-morbidities
Hypertension and Dyslipidemia
Lecture:
Hypertension and Dyslipidemia
Diabetes
Hypertension Dyslipidemia
30 minutes
Diabetes and its Co-morbidities Hypertension
and Dyslipidemia and Dyslipidemia
Lecture
Main Lea ning Points Main Lea ning Points Main Learning Points Main Learning Points
Understand the relationship between diabetes and
hypertension hypertension
Understand how hypertension should be treated and
how hypertension patients should be treated
Understand the relationship between diabetes and
dyslipidemia
Understand how dyslipidemia should be treated and
how dyslipidemia patients should be treated
Why focus on the triangle of diabetes,
hypertension and dyslipidemia? hypertension and dyslipidemia?
Triangular Focus Treatment Implications g p
40-60% of type 2 diabetes
patients will also have either
Diabetes
patients will also have either
hypertension, dyslipidemia or
both
Hypertension and Dyslipidemia
Hypertensio
n
Dyslipide
mia
yp y p
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 on-set of diabetes
complications complications
Diabetes and its Co-morbidities
Hypertension Hypertension
Categories for Blood Pressure Levels in Adults (JNC VII)*
Blood Pressure Level (mmHg)
Category Systolic Diastolic
Normal < 120 And < 80
Prehypertension 120 -139 Or 80 89
High Blood Pressure g
Stage 1
Hypertension
140 - 159 Or 90 - 99
Stage 2
> 160 Or > 100
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,
* Aged 18 years or older
160/80 mmHg would be stage 2 hypertension (high blood pressure)
Diabetes Is a Major Multiplier of Cardiovascular
Risk in Patients With Hypertension yp
Systolic Blood Pressure and Cardiovascular Mortality
Diabetes
No Diabetes
245
250
r
s
Diabetes
130
153
160
150
200
r
M
o
r
t
a
l
i
t
y
P
e
r
s
o
n
-
Y
e
a
130
85
62
112
73
55
100
r
d
i
o
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a
r
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1
0
,
0
0
0

42
22
18
55
0
50
C
a
r
R
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e

P
Stamler J, et al. Diabetes Care. 1993;16:434444.
120 - 139 <120 >200
Systolic Blood Pressure mm/Hg
160 -179 180 - 199 140 -159
Major Outcomes of the Hypertension Optimal
T t t (HOT) T i l Treatment (HOT) Trial
Diabetes Sub-group shows that lowering blood pressure is
beneficial for diabetes patients with hypertension
30
<85 mmHG (n 501)
<90 mmHG (n=501)
Diastolic Target
24
18
20
25
P
t
-
Y
e
a
r
s
<85 mmHG (n=501)
<80 mmHG (n=499)
11
8
11 11
10
15
v
e
n
t
s
/
1
0
0
0

4
3 3
0
5
E
v
Hansson L, et al. Lancet. 1998;351: 1755-1762.
CV Mortality MI Major CV Events
Effect of Blood Pressure Control in the UKPDS
Tight vs. Less Tight Control Tight vs. Less Tight Control
1,148 Type 2 patients
A BP l d t 144/82 H ( t l 154/87) Average BP lowered to 144/82 mmHg (controls: 154/87);
9-year follow-up
Any diabetes-related endpoint
Diabetes related deaths
Tight Control
24
32
Risk Reduction (%) P value
0.0046
0 019 Diabetes-related deaths
Heart failure
Stroke
32
56
44
0.019
0.0043
0.013
Myocardial infarction
Microvascular disease
21
37
NS
0.0092
UKPDS Group. BMJ. 1998;317:703-713.
UKPDS hypertension sub-study: Tight blood
pressure control reduces complications in diabetes pressure control reduces complications in diabetes
Stroke
20
44% i k d ti
%
)
Diabetes-related deaths
40
32% i k d ti
%
)
15
10
44% risk reduction
P = 0.013
s

w
i
t
h

e
v
e
n
t
s

(
30
20
32% risk reduction
P < 0.02
w
i
t
h

e
v
e
n
t
s

(
%
Years
0
5
3 0 5 7 8 6 4 2 1 9
P
a
t
i
e
n
t
s
Years
0
10
3 0 5 7 8 6 4 2 1 9
P
a
t
i
e
n
t
s

Tight control with captopril or atenolol:
Microvascular disease
n
t
s

(
%
)
20
15
37% risk reduction
P < 0 01
Less tight control: mean BP 154/87 mmHg
Tight control with captopril or atenolol:
mean BP 144/82 mmHg
e
n
t
s

w
i
t
h

e
v
e
n
15
10
5
P < 0.01
UKPDS Group. BMJ. 1998;317:703-713.
Years
P
a
t
i
0
3 0 5 7 8 6 4 2 1 9
Chobanian AV et al. JAMA. 2003;289:2560-72
Most relevant drugs are indicated for hypertension
patients with diabetes patients with diabetes
Chobanian, et al.2004
ADA Recommendations on Hypertension
Systolic Blood Pressure <130 mmHG however depending
GOAL
Systolic Blood Pressure <130 mmHG, however depending
on patient charecteristics and response to therapy, higher
or lower SBP targets may be appropriate
SBP
or DBP
130 139 mmHG
80 89 mmHG
SBP
or DBP
> 140 mmHG
> 90 mmHG
Should receive
Lifestyle therapy alone for
a maximum of 3 months
pharmacological therapy
in addition to lifestyle
therapy
If targets are not
achieved, start treatment
with pharmacological
agents
Diabetes Care 2012; 35 (Suppl. 1): p29
Years
ADA Recommendations on Hypertension Cont.
Lifestyle Treatment Pharmacological Treatment
Weight Control
Increased consumption of
fruit, vegetables and low
Pharmacologic therapy
A regimen that includes either
an ACE I or ARB fruit, vegetables and low
fat diet
Sodium restriction
Increased physical
an ACE I or ARB
If one class is not tolerated, the
other should be substituted
Other classes but RAS are Increased physical
activity
Alcohol moderation
Other classes but RAS are
equally good.
Multiple drugs are generally
required
If ACE I, ARBs, or diuretics are
used:
Monitor: kidney function and
Diabetes Care 2012; 35 (Suppl. 1): p29
s-potassium
Dyslipidemia
Mean Plasma Lipids at Diagnosis of Type 2 Diabetes
UKPDS UKPDS
MEN WOMEN
Number of Pts
Type 2 Control
MEN
2139 52
Type 2 Control
WOMEN
1574 143 Number of Pts
TC (mg/dl)
C ( /dl)
2139
213
39
52
205
32
1574
224
*
143
217
3 LDL-C (mg/dl)
HDL-C (mg/dl)
139
39**
132
43
151*
43*
135
55
TG (mg/dl) 159* 103 159* 95
* P<0.001, ** P<0.02 comparing type 2 vs. control group
UKPDS Group. Diabetes Care 1997;20:1683-1687.
A Guide to Selecting Treatment
BMI (kg/m
2
)
T t t 25 26 9 27 29 9 30 34 9 35 39 9 40 Treatment 25 26.9 27 29.9 30 34.9 35 39.9 40
Diet, exercise, and
behavior therapy
With
comor-
biditi
With
comor-
biditi
+ + +
be a o t e apy
bidities bidities
Pharmacotherapy
With
comor-
biditi
+ + +
bidities
Bariatric surgery
With
comor-
biditi
+
bidities
NIH/NHLBI, NAASO. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. 2000.
Heart Protection Study
Proportions of patients with major vascular events in the Heart p p j
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 39
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 25% reduction in coronary revascularisation
21% reduction in stroke
9% reduction in all-cause mortality 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
Order of Priorities for Treatment of Diabetic
Dyslipidemia in Adults Dyslipidemia in Adults
1
First choice: HMG CoA reductase inhibitor (statin)
LDL Cholesterol Lowering
First choice: HMG CoA reductase inhibitor (statin)
Second choice: Bile acid binding resin or fenofibrate
2 HDL cholesterol raising
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
Triglyceride lowering 3
Glycemic control first priority
Fibric acid derivative (gemfibrozil, fenofibrate)
Statins are moderately effective at high dose in
Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.
Statins are moderately effective at high dose in
hypertriglyceridemic subjects who also have high LDL
cholesterol
Slide 19
Updated ATP III LDL-C Goals and Cutpoints for Therapy
Risk Category
LDL-C (mg/dL)
Goal
Initiation
Level for
Consideration
Level for Drug Goal Level for
TLC
Level for Drug
Therapy
High risk: CHD or
CHD risk equivalents
<100
(optional:
100 100
(<100: consider drug
CHD risk equivalents
(10-yr risk >20%)
<70)
options)
Moderately high
risk: 2+ risk factors
<130
(optional:
130 130
(100129: consider
risk: 2+ risk factors
(10-yr risk 1020%)
( p
<100)
drug options)
Moderate risk:
2+ risk factors
<130 130 160
2+ risk factors
(10-yr risk <10%)
Lower risk:
01 risk factor
<160 160 190
(160189: LDL-C
Grundy SM et al. Circulation 2004;110: 227-239
(
lowering drug
optional)
Conclusions on Statins
Statin therapy should be considered for all individuals
with type 2 diabetes
independent of baseline lipid levels if previously CVD p p p y
Statin therapy should be considered for all patients
above 40 y with more than 1 risk factor
Especially if Especially if
Prior CVD
Albuminuria
Smokers Smokers
Hypertension
Severe family history
Lack of data for age < 40y Lack of data for age < 40y
Should be considered in type 1 diabetes at high risk of CVD or
with signs of diabetic complications
ADA 2012
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 monotherapy
However, the combination of fenofibrate and
simvastatin does not reduce the rate of fatal simvastatin does not reduce the rate of fatal
cardiovascular events, nonfatal MI, or nonfatal stroke,
as compared with simvastatin alone
Nicotonic Aid
Significant reduction in triglycerides and increases
HDL compared to fibrates and statins 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
HbA increase uric acid HbA
1c
, increase uric acid
No data on Nicotinic acid on CVD endpoints
Efficacy of Multiple Risk Factor Intervention in High-Risk
Subjects (Type 2 Diabetes with Microalbuminuria) j ( yp )
The STENO 2 Study
,

(
%
)
72
58
71
63
60
70
80
n
g
M
e
a
n

7
.
8

y
,
51 51
30
40
50
e
n
t
s

R
e
a
c
h
i
n
e
n
t

G
o
a
l
s

a
t

16
20
21
4
10
20
30
P
a
t
i
e
i
v
e
-
T
r
e
a
t
m
e
0
Glycosylated
hemoglobin
<6.5%
Diastolic BP
<80 mm/Hg
I
n
t
e
n
s
i
Treatment Endpoints
Systolic BP
<130 mm/Hg
Triglycerides
>150 mg/dl
Cholesterol
<175 mg/dl
Gde P et al. N Engl J Med 2003;348:383-393
p
Intensive Therapy
Conventional Therapy
Primary Composite Cardiovascular Endpoint
STENO 2 Study STENO 2 Study
85 CVD events in 35 conventional patients (44%)
33 CVD events in 19 intensive patients (24%)
0 5
0,6
Conventional
Probability for primary endpoint
0,3
0,4
0,5
0,1
0,2
0,3
Intensive
0,0
1 2 3 4 5 6 7 8 0
Years of follow up
Hazard ratio 0.47 (0.24 to 0.73); p=0.007
Gde P et al. N Engl J Med 2003;348:383-393.
Years of follow-up
LECTURE
Non-pharmacology
Intervention
Non-Pharmacology Intervention
Lecture:
gy
30 minutes
Non-Pharmacology Intervention
Lecture Lecture
Main Learning Points 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 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 diabetes associated complications
Something went wrong Something went wrong
2.5 million years 50 years
Diet & Exercise in Diabetes 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 Diet and exercise may provide good long term
glycaemic control in some patients
Improved cardiovascular status
Cost-effective
Medical Nutrition Therapy in Diabetes Medical Nutrition Therapy in Diabetes
As integral part of : g p
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
d t f T 2 Di b t and management of Type 2 Diabetes
Individual with Diabetes
Risk-factors or with pre- Individual with diagnosed
diabetes Diabetes
1) To reduce the risk of
diabetes and cardiovascular
1) To achieve and maintain:
Blood Glucose levels in the normal
disease by promoting
healthy food choices and
physical activity leading to
Blood Glucose levels in the normal
range
A lipid profile that reduces the risk
for vascular diseases
moderate weight loss that is
maintained.
Blood Pressure levels in the normal
range
2) To prevent / delay progressivity of
chronic complications p
3) To address individual nutrition needs,
taking into account personal and
cultural preferences and willingness to
change
Diabetes Care, Vol. 31, Suppl. 1, 2008
change
The Fundamentals of food management for
di b t ti t diabetes patients
Similar with healthy people:
B l f d i t k di t l i d t iti d f Balance food intake according to calories and nutrition needs for
each individual
Weight loss, increased physical activity, and weight management
C i t i d t d b h d t i t k t l d 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) Jenis (Type)
Jumlah (Amount)
The relationship between healthy nutrition and
bl d l blood glucose
DSE: Usual Diabetes Care
ILI I t i Lif t l I t ti
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
ILI: Intensive Lifestyle Intervention
Guidelines for a healthy diet
PERKENI 2011 PERKENI 2011
Healthy balanced diet
composed of:
Fat
45-65%
carbohydrate
20-25% fat 20 25% fat
1020% protein
Carbohydrate
i
Carbohydrate
Protein
The Indonesian Food Pyramid
http://www.fagnutrition.com
Carbohydrate
Eat Less of These Eat More of These
Fruit Low fat Milk Beans White sugar Brown sugar Fruit, Low fat Milk, Beans,
Brown rice, Yoghurt, Whole
wheat bread
White sugar, Brown sugar,
White bread, White rice,
Proteins
Eat Less of These Eat More of These
Chicken Fish Tofu Sausages processed meat 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 Coconut Margarine/butter Avocado, Nuts, Olives, Oils rich in
poly and mono unsaturated fats
Coconut, Margarine/butter,
Cheese, Oils/fats rich in
saturated fat
How you cook is important How you cook is important
Less Healthy More Healthy
Understanding portion sizes is important
Recommendation to take smaller portion sizes of the less
f recommended food
Rice boiled 100 g
Calorie 175 kcal
Carbohydrates 40gm
Rice boiled 200 g
Calorie 350 kcal
Carbohydrates 80gm y g y g
Noodles boiled 200 gm
Calorie 175 Kcal
Carbohydrates 40 gm y g
Source: Daftar Bahan Makanan Penukar
The relationship between exercise and
blood glucose g
Both resistance and aerobic exercise were effective in reducing blood glucose
levels and HbA1c levels
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)
Diabetology & Metabolic Syndrome, 2009, 1:27
0.05). A difference between exercise groups is denoted by # (p < 0.008).
Exercise significantly reduces HbA1c
Pooled meta-analysis of 14 exercise trials
%
0 0
0.1
0.2
Exercise
v
e
n
t
i
o
n
n
c
e
)
0.08%
-0.2
-0.1
0.0
Non-exercise control

i
n

H
b
A
1
c
p
o
s
t
-
i
n
t
e
r
v
e
a
n

d
i
f
f
e
r
e
n
-0 5
-0.4
-0.3
C
h
a
n
g
e
b
a
s
e
l
i
n
e

t
o

w
e
i
g
h
t
e
d

m
e
p<0.001
Effect was
-0.66%
-0.7
-0.6
0.5
f
r
o
m

(
w
weight-
independent
Boul NG, et al. JAMA 2001;286:1218-27.
Source: Boule NG et al. Effects of exercise on glycemic control and body mass in T2 Diabetes:
JAMA2001; 286:1218-27
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 Smokers are also lipid intolerant
Smoking cessation increases HDL and reduces LDL levels,
despite weight gain
F hi i F S t l L t (1992) 339 (8802) 1128 1130 Al D l i WK t l A h I t M d 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: 356362. Chaturvedi N, Diabetes Care
1995; 18: 78592.Jacobs DR Jr et al Arch Intern Med 1999;159: 733-40. Axelsen M., et al (1995), Journal of
Internal Medicine, 237: 449455.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
ti t k patients among non-smokers
Non-diabetic woman
Diabetic woman
1,984
2,000
r
s
o
n
-
y
e
a
r
s
)Diabetic woman
1,443
1,219
1,249
1,012
1,000
1,500
1
0
0
.
0
0
0

p
e
r
591
368
323
275
215
500
,
R
a
t
e

(
p
e
r

1
215
0
M
o
r
t
a
l
i
t
y

Past 1-14 cig / day Never 15-34 cig
/ day
35+ cig / day
Source: Wael K. Al-Delaimy et al. Diabetes Care 24: 2043-2048, 2001
cig = cigarette
G Di i Group Discussion
Practical Initiation of Diet Programs for diabetes
patients 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
A B k A G
Ayam Goreng
Ayam Bakar Ayam Goreng
Ayam Goreng
Tepung
Ikan Bakar /
Kukus
Ikan Goreng Udang Goreng
Kukus
Sayur Kukus Kukus Dim Sum
Dim Sum
Goreng
Practical Initiation of Diet Programs for diabetes
patients
Healthy Plate Models
Portion Control Plate was effective in inducing weight loss and decreased use
of hypoglycemic medications in obese patients with type 2 diabetes mellitus
Carbo-
hydrate /
Starch
Protein
Vegetables
Protein
Carbo-
hydrate /
Starch
Vegetables
T-shaped plate
model to loose
Y-shaped plate
model to model to loose
weight
model to
maintain weight
Pedersen DE et al. Arch Intern Med. 2007; 167
Practical Initiation of Exercise Programs for
diabetes patients diabetes patients
CRIPE Pricnciple
CRIPE: Continuous Rhytmic Interval Progressive Endurance CRIPE: Continuous, Rhytmic, Interval, Progressive, Endurance
Continuous
Exercises should be done continuously without
Continuous
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) 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 Endurance cardiorespiratory abilities (e.g. walking,
jogging, swimming, cycling)
LECTURE
Diabetes Acute
Complications-
Hypoglycemia and DKA
Diabetes Acute Complications Hypoglycemia and DKA
Lecture:
Diabetes Acute Complications Hypoglycemia and DKA
30 minutes
Management of Hypoglycemia
Lecture
Main Learning Points Main Learning Points
Understand the hypoglycemia mechanism and how
hypoglycemia should be treated
Understand how to adjust OAD - or insulin dosage after 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
What is hypoglycemia?
neurogenic symptoms due to low plasma glucose
levels
A state of neuroglycopenic and/or neurogenic
symptoms due to low plasma glucose levels
Low plasma glucose levels defined as:
70 mg/dL (ADA)
1
70 mg/dL (ADA)
<60 mg/dl (PERKENI)
2
<72 mg/dL (CDA)
3
g/ ( )
Symptoms respond to the administration of
carbohydrate
3
1 ADA Di b t C 2005 28 1245 9 2 PERKENI K 2011 3 Y l t l C di J
ADA, American Diabetes Association; CDA, Canadian Diabetes Association;
1. ADA. Diabetes Care 2005;28:12459; 2. PERKENI Konsensus 2011. 3. Yale et al. Canadian J
Diabetes 26:2235
Why address hypoglycemia in diabetes training
Reducing HbA
1c
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: 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 t
th
ed., 2009. Roglic and Unwin 2010.
Diabetes Research and Clinical Practice; 87: 15-19
Most common symptoms of Hypoglycemia
Blurred vision
Weakness
Sweating
Slurred speech
Hunger
Palpitations
Weakness
Tremor
Circumoral paraesthesia
Hunger
Vertigo
f
Headache
Cold feeling
Anxiety
Euphoria
Nausea
Patients (%)
Difficulties in concentration
0 20 40 60 80 100
Patients (%)
Pramming 1991
Sequel of hypoglycaemia Sequel of hypoglycaemia
Mild symptomatic hypoglycaemia
N di t i li i l ff t No direct serious clinical effects
May impair subsequent hypoglycaemia awareness
Severe hypoglycaemia associated with
Stroke and transient ischaemic attacks
Memory loss/cognitive impairment Memory loss/cognitive impairment
Myocardial infarction
Injury (direct/indirect)
Death
Turner et al. (UKPDS 33), 1998. The Lancet; 352: 837-853
Risk Factors of Hypoglycemia
General risk factors for hypoglycaemia:
1,2
delayed or missed meal
consuming a smaller meal than planned g p
exercise
use of diabetes medications
drug/alcohol consumption drug/alcohol consumption
increased insulin sensitivity or decreased insulin clearance
Risk factors for major hypoglycaemia:
3,4
/d ti f di b t t t t age/duration of diabetes treatment
intensive glycaemic control
hypoglycaemia unawareness
sleep
antecedent hypoglycaemia
history of major hypoglycaemia
1.Briscoe & Davis. Clin Diabetes 2006;24:11521; 2. ADA Workgroup on Hypoglycemia. Diabetes Care
2005;28:12459. 3. Frier. Diabetes Metab Res Rev 2008;24:8792; 4. Cryer. Diabetes 2008;57:316976
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
e
a
r
s
Conventional Therapy
90
100
DCCT (T1 DM)
e
a
r
s
Intensive Therapy
90
100
DCCT (T1 DM)
0
0

P
a
t
i
e
n
t

Y
e
50
60
70
80 ACCORD (T2 DM)
0
0

P
a
t
i
e
n
t

Y
e
50
60
70
80 ACCORD (T2 DM)
e
n
t
s

p
e
r

1
0
20
30
40
50
e
n
t
s

p
e
r

1
0
20
30
40
50
E
v
e
b (%)
0
10
6.0 6.5 7.0 7.5 8.0 8.5 9.0
E
v
e
b (%)
0
10
6.0 6.5 7.0 7.5 8.0 8.5 9.0
Adapted from DCCT Research Group. Diabetes 1997. Adapted from Bonds D., data presented at
ADA 2009
HbA
1c
(%) HbA
1c
(%)
Prevention of Hypoglycemic Events
Education
Symptoms
Self management
Proper food intake in therapy
R titi d ti i ti t ith d d iti Repetitive education in patients with decreased cognitive
function
Self monitoring blood glucose (SMBG)
Exercise planning
Measuring blood glucose before exercise
Consuming carbohydrate Consuming carbohydrate
Adjust insulin dose based on the blood glucose level
Right type and dose for therapy
Treatment of mild Hypoglycemia
Treating early signs
First: 1020 g fast-acting carbohydrate, e.g.:
36 glucose tablets
90 180 ml fizzy drink or squash (ex: coke drink bottle 90180 ml fizzy drink or squash (ex: coke drink, bottle
tea not diet)
Two teaspoons of sugar added to a cup of cold drink
50 100 l d i k 50100 ml energy drink
Then:
If next meal is due add extra carbohydrate If next meal is due, add extra carbohydrate
If next meal is not due, eat longer-acting carbohydrate,
such as biscuits or a sandwich
RCN 2004
Treatment of moderate-to-major Hypoglycemia Treatment of moderate to major Hypoglycemia
Treating late signs
Patient requires assistance with treatment
If conscious:
Treating late signs
Carer should help the patient to consume
1020 g fast-acting carbohydrate
Dextrose gel may be useful
f If unconscious:
Dont put anything in patients mouth
IM or SC glucagon or IV glucose should be
d i i t d administered
Emergency services should be called
IM: intramuscular SC: subcutaneous IV: intravenous
RCN 2004; Cryer 2010
IM: intramuscular, SC: subcutaneous, IV: intravenous
Adjusting Dosage after a Hypoglycemic Event Adjusting Dosage after a Hypoglycemic Event
If hypoglycemic events are
repeated OAD and / or Insulin
OAD: Depending on drug
repeated, OAD and / or Insulin
dosages should be reduced
Insulin: Initially decrease
with 2 units / day
Di b t K t id i Diabetes Ketoacidosis
What is Diabetes Ketoacidosis What is Diabetes Ketoacidosis
Acute decompensated metabolic state due to
severe insulin deficiency 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%
Watkins et al. In: Diabetes and its Management 2003
Why are patients developing ketoacidosis Why are patients developing ketoacidosis
The most common events that cause a person with
diabetes to develop diabetic ketoacidosis are: 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 newly diagnosed or previously unknown diabetes
(15%)
Various other causes may include a heart attack,
stroke trauma stress alcohol abuse drug abuse stroke, trauma, stress, alcohol abuse, drug abuse,
and surgery.
Approximately 5% to 10% of cases have no
identifiable cause
How to Diagnose Diabetes Ketoacidosis How to Diagnose Diabetes Ketoacidosis
Symptoms Signs
Anorexia
Nausea
Tachycardia
Hypotension
Vomiting
Thirst
Hypotension
Hypothermia
Impaired consciousness
Thirst
Polyuria
Weakness
Impaired consciousness
Warm dry skin
Weakness
Abdominal pain
Weight loss
Kussmaul respiration
Acetone odour on breath
Weight loss
Diabetes Ketoacidosis Definitions Diabetes Ketoacidosis Definitions
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 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)
Diabetes Care, Vol. 29, Number 12, December 2006
Objectives and Management of DKA Treatment
S h & li bl d
Objectives Management
1. Search & treat
precipitating cause
2. Insulin iv (rapid / short-
1. To normalize blood
glucose as soon as
possible with Insulin
( p /
acting)
3. Replacing fluids
2. To replace fluids and
reverse ketoacidosis
3 Monitoring:
4. Replacing electrolytes -
potassium & magnesium- if
required
3. Monitoring:
Vital signs
Fluid and electrolyte
5. For GPs: If you observe a
DKA case, immediately
send the patient to the
Fluid and electrolyte
balance
Glycaemia
send the patient to the
hospital
Initial DKA Treatment in Primary Care
1. Evaluate vital signs and urine volume
2. IV line, start the rehydration
Prepare the patient
3. Check the blood glucose periodically
(per hour if possible)
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 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 Main Learning Points Summary Summary
Understand the
hypoglycemia mechanism
and how hypoglycemia
should be treated
The risk of hypoglycemia is one of the
key limiting factors in reaching
optimal glucose targets
For Insulin hypoglycemia is mainly a
should be treated
Understand how to adjust
OAD - or insulin dosage
after hypoglycemic events
For Insulin, hypoglycemia is mainly a
phenomenon occurring in Type 1
diabetes patients
Prevention of hypoglycemia requires
d f bl d
Understand what causes a
DKA event, how DKA is
treated and what to do if
you experience a patient
patient education, frequent blood
glucose monitoring and exercise
planning
If hypoglycemia occur repeatedly,
you experience a patient
with DKA
yp g y p y,
reduce the dosage of OAD and/or
Insulin
DKA should be regarded as an
emergency situation and prompt emergency situation and prompt
treatment with insulin is vital
LECTURE
Initiating Diabetes
Treatment with OADs
Initiating Diabetes Treatment with OADs
Lecture:
g
30 minutes
Initiating Diabetes Treatment with OADs
Lecture Lecture
Main Learning Points Main Learning Points
Understand the different classes of OADs and when to
use which OADs either as monotherapy or in py
combination with other OADs / Insulin
Factors to Consider when Choosing an Anti-
hyperglycemic agent hyperglycemic agent
Effectiveness in lowering glucose
Extraglycaemic effects that may reduce long-term complications
Safety profile
Tolerability Tolerability
Cost
Effect on body weight
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Treatment therapies for Type 2 diabetes
Wh d H When and How to start treatment
START TREATMENT OAD TREATMENT START INSULIN INSULIN INTENSIFICATION
Lifestyle +
Metformin
+-other OAD
or GLP-1
agonists
Basal
Basal
Insulin
Premix
Insulin
Basal +
Bolus
Insulin agonists
HbA 7 0%
Insulin
HbA
1c
7.0%
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
Updated PERKENI Type 2 Diabetes Treatment
Algorithm Algorithm
Diabetes STEP 1 STEP 2 STEP 3
Healthy life style
Healthy life style
+
Mono therapy
Healthy life style
py
+
2 OAD
Combination
Healthy life style
+
Combination 2
OAD Alternative option, if :
Note:
1. Therapy failed if
target of HbA1c <
7% is not achieved
i hi 2 3 h
+
Basal insulin
p ,
No insulin is available
The patient is objecting insulin
Blood glucose is still not
optimally controlled
within 2-3 months
for each step
2. In case of no HbA1c
test, the use of
blood glucose level
Insulin
Intensification*
Healthy life style
+
3 OAD Combination
optimally controlled
is also permitted.
Average blood
glucose level for a
few BG test in one
day can be
converted to HbA1c
*Intensive Insulin: use of basal insulin together with insulin prandial
converted to HbA1c
(ref: ADA 2010)
Main pathophysiological defects in type 2 DM
pancreatic
insulin
secretion
incretin
effect
Pancreas
Intestines
Brain
pancreatic
glucagon
secretion
gut
?
Kidney
gut
carbohydrate
delivery and
absorption Hyperglycemia
Muscle
Glucose
reabsorpsion
peripheral
glucose
uptake
Liver
Muscle
hepatic
glucose
production
uptake
Adipose
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.
Current available OADs and non-Insulin injectables
in Indonesia in Indonesia
Metformin
Sulfonylureas (SUs) and glinides Sulfonylureas (SUs) and glinides
-glucosidase inhibitors (AGIs)
Glucagon-like peptide-1 (GLP-1) agonists Glucagon like peptide 1 (GLP 1) agonists
Thiazolidinediones (TZDs)
Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)
Primary sites of action of currently available oral
anti-diabetic agents and non-insulin injectables anti diabetic agents and non insulin injectables
Muscle
Blocks
P t
Adipose
Liver
Metformin
TZD
FFA
l
Promotes
Circulatory System
Glucose
release
TZD
Metformin
Pancreas
FFA
Insulin
release
AGI
Glucose
absorption
Intestinal
lipase inhibitor
Fat
Intestines
GLP-1 agonist
Carbohydrates
DPP-4
inhibitor
Cheng A, Fantus G. Can Med Assoc J 2005;172:21326.. Barnett A. Int J Clin Pract 2006;60:145470. Prez Lpez G, et al.
Nefrologia. 2010;30:61825.
AGI: -glucosidase inhibitors; DPP-4: dipeptidyl peptidase-4; FFA: free fatty acid; TZD: thiazolidinedione
Metformin
Mode of Action Mode of Action
The primary effects of metformin are to decrease
hepatic glucose production and increase insulin-
mediated peripheral glucose uptake
Adipose tissue Muscle Liver Intestine
Anaerobic glucose
metabolism
Glucose uptake Glucose uptake
Glucose oxidation
Glucose oxidation
Glycogenesis
Gluconeogenesis
Glycogenolysis
Oxidation of FA
Oxidation of FA
Krentz AJ Bailey CJ Drugs 2005;65:385 411
FA: Fatty Acids
Krentz AJ, Bailey CJ. Drugs 2005;65:385411.
Metformin
Cli i l O i d C t i di ti Clinical Overview and Contraindications
Metformin
S f t
Efficacy
*
Safety,
Tolerability and
Adherence
Contraindications Advantages
HbA1c reduction Associated with Renal Do not cause HbA1c reduction
of 1-2%
FPG reduction
of 40-70 mg/dl
Associated with
diarrhea and
abdominal
discomfort
Renal
insufficiency
Liver failure
Heart failure
Do not cause
hypoglycaemi
a when used
as mono-
therapy
Latic acidosis if
improperly
prescribed
Heart failure
Severe
gastrointestinal
disease
therapy
Do not cause
weight gain;
may
contribute to
weight loss
Krentz AJ, Bailey CJ. Drugs 2005;65:385411.
* Efficacy depends on existing blood glucose levels
Metformin
Titration Titration
Starting dose
850 mg daily or 500 mg daily or bid with
Starting dose
500 1000 d il
MET-XR MET-IR
850 mg daily or 500 mg daily or bid with
breakfast and or dinner
500 mg or 1000 mg once daily
with evening meal
Titration
After 5 to 7 days, advance dose to 850 mg bid
or 1000 mg bid if GI side effects have not
occurred
Titration
Increase dose in 500 mg increments per week
b d FPG d GI t l bilit
If GI side effects occur, decrease to previous
dose and try to advance dose at a later time
based on FPG and GI tolerability
Maximum dose
850 mg bid or 1000 mg bid
Maximum dose
2000 mg qd with evening meal
1. Nathan DM, et. al. Diabetes Care, 2009;32:193203. 2. Jabbour S, Ziring B. Postgraduate Medicine, 2011;123:1523.
Bid: twice daily; FPG: fasting plasma glucose; GI: gastrointestinal; MET-IR: immediate release metformin; MET-XR:
extended release metformin; qd: once daily.
Metformin
Little benefit if any - to go above 2 000 mg Little benefit if any to go above 2.000 mg
Fasting Plasma Glucose HbA1c
Metformin Dose Metformin Dose
0
10
l
)
2500mg 2000mg 1500mg 1000mg 500mg
Metformin Dose
0.0
2500mg 2000mg 1500mg 1000mg 500mg
Metformin Dose
40 9
31.0
18.9
20
30
40
l
a
c
e
b
o

(
m
g
/
d
0.9
0.5
1.0

P
l
a
c
e
b
o

(
%
)
61.9
40.9
50
60
70
C
h
a
n
g
e

v
s
.

P
1.6
1.7
1.2
1.5
C
h
a
n
g
e

v
s
.
77.9
80
Garber AJ, Am J Med 1997;102:491-7.
2.0
1.7
2.0
SUs and Glinides
Mode of Action Mode of Action
Sulfonylureas (SUs) and
glinides increase
endogenous insulin
Pancreatic -cell
Gl
ATP-sensitive
potassiumchannel
g
secretion by binding to
pancreatic -cells and
triggering a cascade of
intracellular events
13
Glucose
uptake
potassium channel
SUs /
glinides
Glycolysis
respiration
Glucokinase
ATP
The mode of action of SUs
and glinides is similar, but
stimulation of insulin
ti i id d secretion is more rapid and
short-acting with glinides
SU receptors are also found
on other cells including the
I li l
on other cells, including the
cardiac myocytes
Insulin release
Voltage-gated
calcium channel
Ca
2+
ATP = orange
Ca
2+
= light green
1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:111. 2. Schuit FC, et al. Diabetes 2001;50:111. 3. Krentz
AJ, Bailey CJ. Drugs 2005;65:385411.
SU: sulfonylurea; GLUT: glucose transporter.
SUs and Glinides
Clinical Overview Clinical Overview
Sulphonylurea
Glinides
Efficacy
*
Safety,
Tolerability and
Adherence
Efficacy
*
Safety,
Tolerability and
Adherence
HbA1c reduction
of 1-2%
FPG reduction
of 40 70 mg/dl
Associated with
hypoglycaemia
and weight gain
HbA1c reduction
of 0.5-1.5%
FPG reduction
of 20-60 mg/dl
Associated with
hypoglycaemia
and weight gain
Frequent
of 40-70 mg/dl
g/
PPG reduction
of 75-100 mg/dl
q
administration
(with every
meal) is
required
.
Krentz AJ, Bailey CJ. Drugs 2005;65:385411. Nathan DM, et al. Diabetologia. 2009;52:1730. Rosenstock J, et al.
Diabetes Care. 2004;27:126570.
* Efficacy depends on existing blood glucose levels
q
;
Alpha glucosidase inhibitors
Mode of Action Mode of Action
Slow digestion of sucrose and starch and
therefore delay absorption therefore delay absorption
Slow post-meal rise in blood glucose
Side effects Side effects
Flatulence, abdominal discomfort , diarrhoea
As mono-therapy will not cause
hypoglycaemia
Hypoglycaemia when used with other
medicine (e.g. a sulphonylurea) medicine (e.g. a sulphonylurea)
1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:111. 2. Schuit FC, et al. Diabetes 2001;50:111. 3. Krentz
AJ, Bailey CJ. Drugs 2005;65:385411.
Alpha glucosidase inhibitors
Clinical Overview Clinical Overview
Alpha glucosidase inhibitors
Efficacy
*
Safety, Tolerability and
Adherence
HbA1c reduction of 0.5-1% Associated with flatulence,
FPG reduction of 10-20
mg/dl
PPG reduction of 40-50
diarrhea and abdominal
discomfort
As mono-therapy will not
cause hypoglycaemia
mg/dl
cause hypoglycaemia
Frequent administration
(with every meal) is
required
.
required
Krentz AJ, Bailey CJ. Drugs 2005;65:385411. Nathan DM, et al. Diabetologia. 2009;52:1730. Rosenstock J, et al.
* Efficacy depends on existing blood glucose levels
, y g ; , g ; ,
Diabetes Care. 2004;27:126570.
Thiazolidinediones (TZDs)
Mode of Action Mode of Action
Thiazolidinediones (TZDs) increase the sensitivity of muscle
and adipose cells to insulin and suppressing hepatic glucose
production
Adipose tissue Muscle Liver
Glucose uptake Glucose uptake Gluconeogenesis
Fatty acid uptake
Lipogenesis
Glycolysis
Glucose oxidation
Glycogenolysis
Lipogenesis
*Inconsistent findings
Pre-adipocyte differentiation Glycogenesis* Glucose uptake*
Krentz AJ, Bailey CJ. Drugs 2005;65:385411.
TZD: Thiazolidinediones
Thiazolidinediones
Clinical Overview Clinical Overview
Thiazolidinediones
Safety Tolerability Contraindicatio
Efficacy
*
Safety, Tolerability
and Adherence
Contraindicatio
ns
Advantages
HbA1c
reduction
Associated with weight
gain and edema
Liver disease,
heart failure or
Reduced levels of
LDL-cholesterol
of 0.5-
1.5%
FPG
reduction
g
Contraindicated in
patients with abnormal
liver function
Warnings regarding risk
history of heart
disease
Pregnancy and
breast feeding
LDL cholesterol
and increased
level of HDL-
cholesterol
of 20-55
mg/dl
Warnings regarding risk
of fractures
May exacerbate or
precipitate congestive
heart failure
g
* Efficacy depends on existing blood glucose levels
heart failure
Krentz AJ, Bailey CJ. Drugs 2005;65:385411. 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;9:2295303.
DPP-4 inhibitors
Mode of Action Mode of Action
Increases and prolongs GLP-1
and GIP effects on -cells
Food intake
-cells
DPP-4
inhibitor
Stomach Pancreas
Glucose-dependent insulin secretion
DPP-4
Net effect:
Increases and prolongs
Stomach
GI tract
a c eas
Incretins
(GLP-1 GIP)
DPP-4
blood glucose
Increases and prolongs
GLP-1 effect on -cells
-cells
Glucose-dependent glucagon secretion
(GLP-1, GIP)
DPP-4: dipetidyl peptidase-4; GI: gastrointestinal; GIP:glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like
peptide
Intestine
* GIP does not inhibit glucagon secretion by -cells
Drucker DJ et al. Nature 2006;368:1696705. Idris I, et al. Diabetes Obes Metab 2007;9:15365. Barnett A. Int J Clin Pract
2006;60:145470. Gallwitz B, et al. Diabetes Obes Metab 2010;12:111.
p p
DPP-4 inhibitors
Clinical Overview Clinical Overview
DPP-4 inhibitors
Safety Tolerability and
Efficacy
*
Safety, Tolerability and
Adherence
HbA1c reduction of 0.5-1%
FPG d ti f 20 /dl
Generally well tolerated
L i k f h l i FPG reduction of 20 mg/dl
PPG reduction of 45-55 mg/dl
Low risk of hypoglycemia
Not associated with weight gain
Upper respiratory tract infection5
has been reported in clinical studies has been reported in clinical studies
Most require only once daily
administration
Ahrn B. Expert Opin Emerg Drugs 2008;13:593607. Gallwitz B, et al. Diabetes Obes Metab 2010;12:111. Amori RE,
* Efficacy depends on existing blood glucose levels
p p g g ; , ; ,
et al. JAMA 2007;298:194206. Saxagliptin, FDAs 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;29:26327.
GLP 1 Agonist
Mode of Action Mode of Action
Glucagon-like peptide-1 (GLP-1) agonist activates the GLP
receptor in the pancreas. This increases insulin release from receptor in the pancreas. This increases insulin release from
the pancreatic -cells, while inhibiting glucagon release by
the pancreatic -cells
Pancreas
Glucose-dependent insulin biosynthesis
and secretion
-cell proliferation
-cells
cell
Pancreas
Glucagon secretion
GLP-1 agonist
Net effect:
blood glucose
GLP-1: glucagon-like peptide
-cell
Glucagon secretion
-cell apoptosis
1. Doyle ME, Egan JM. Pharmacol Ther 2007;113(3):54693.
GLP 1 Agonist
Clinical Overview Clinical Overview
DPP-4 inhibitors
Safety Tolerability and
Efficacy
*
Safety, Tolerability and
Adherence
HbA1c reduction of 1-2%
FPG reduction of 6-12 mg/dl
Associated with moderate and
transient nausea, vomiting and
FPG reduction of 6 12 mg/dl
PPG reduction of 6-18 mg/dl
, g
diarrhea
Low risk of hypoglycemia and no
evidence of increased CV risk
A i t d ith i ht d ti Associated with weight reduction
Associated with reduction in BP
Garber AJ. Diabetes Care 2011;34 (Suppl 2):S27984. Moretto TJ, et al. Clin Ther 2008;30:144860. Drucker DJ.
Cell Metab 2006;3:15365. Amori RE, et al. JAMA 2007;298:194206.
* Efficacy depends on existing blood glucose levels
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
i i iti l di i t i d in initial medicine to maximum dosage
Fewer side effects than mono-therapy at higher
doses doses
Diabetes in elderly people

Always start with the lowest dose

Remember the possibility of


of any blood glucose-lowering
medicine and increase gradually
Using shorter-acting medicines
that reduces the risk of
Forgetfulness
Poor motivation
Depression that reduces the risk of
hypoglycaemia
Hypoglycaemia may increase the
risk of falls and heart attack in
Depression
Cognitive deficits
Poly-pharmacy
older people Reduced manual dexterity
These factors impact on the ability
to maintain self-care and achieve
maximum benefits from blood maximum benefits from blood
glucose-lowering medicines.
OADs a quick summary of the different
mechanism of actions mechanism of actions
Thiazolidinediones
Increase glucose uptake
Thiazolidinediones
Increase glucose uptake
Incretins :GLP-1
analogue(exen- atide)/DPP-4
inhibitors Improves glucose
Incretins :GLP-1
analogue(exen- atide)/DPP-4
inhibitors Improves glucose
Increase glucose uptake
in skeletal muscle and
decrease lipolysis in
adipose tissue
Increase glucose uptake
in skeletal muscle and
decrease lipolysis in
adipose tissue
inhibitors Improves glucose-
dependent insulin secretion
from pancreatic -cells,
suppresses glucagon secretion
from -cells, slows gastric
inhibitors Improves glucose-
dependent insulin secretion
from pancreatic -cells,
suppresses glucagon secretion
from -cells, slows gastric
Meglitinides Meglitinides
from cells, slows gastric
emptying
from cells, slows gastric
emptying
Sulfonylureas Sulfonylureas
Increase insulin secretion
from pancreatic -cells
Increase insulin secretion
from pancreatic -cells
-Glucosidase
inhibitors
-Glucosidase
inhibitors
Sulfonylureas
Increase insulin
secretion from
pancreatic -cells
Sulfonylureas
Increase insulin
secretion from
pancreatic -cells
Delay intestinal
carbohydrate absorption
Delay intestinal
carbohydrate absorption GLP = glucagon-like peptide.
Adapted from Cheng and Fantus. CMAJ. 2005;172:213226.
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
action(s)
Biguanides Metformin Activates
AMP-kinase
Hepatic Glucose
Production
Extensive
Experience
No weight gain
No hypoglycemia
Likely CVD Events
Gastrointestinal side
effects
Lactic acidosis risk
(rare)
Vitamin B12
d fi i 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
h d l schedule
Inzucci SE, et al. Diabetologia. 2012
Properties of available glucose-lowering agents that may
id t t t h i i T 2 Di b t t 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 hypoglycemia
Durability
HDL-C
Triacylglycerols
(pioglitazone)
CVD Events ?
Weight Gain
Oedema / Heart
Failure
Bone Fractures
LDL-C
(rosiglitazone) CVD Events ? (rosiglitazone)
Mn (meta-
analyses,
rosiglitazone)
Bladder Cancer ?
(pioglitazone)
a-Glucosidase Acarbose Inhibits Slows intestinal No hypoglycemia Modest HbA1c a-Glucosidase
Inhibitors
Acarbose
Migitol
Voglibose
Inhibits
intestinal a-
glucosidase
Slows intestinal
carbohydrate
digestions /
absorption
No hypoglycemia
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)
Insulin secretion
(glucose-dependent)
Glucagon secretion
(glucose-dependent)
No hypoglycemia
Well tolerated
Modest HbA1c
efficacy
Urticardia/Angio-
oedema
Pancreatitis ?
(GLP 1, GIP)
concentrations
Inzucci SE, et al. Diabetologia. 2012
Properties of available glucose-lowering agents that
id t t t h i i T 2 Di b t t may guide treatment choice in Type 2 Diabetes cont.
Class Compounds(s) Cellular
mechanism
Primary
Physiological
action(s)
Advantages Disadvantages
action(s)
GLP-1
Receptor
Agents
Exenatide
Liraglutide
Activates GLP-
1 receptors
Insulin secretion
(glucose-dependent)
Glucagon secretion
(glucose-dependent)
Slows gastric
emptying
No hypoglycemia
Weight reduction
Improved beta
cell mass /
function ?
Cardiovascular
Gastrointestinal side
effects (nausea /
vomiting)
Acute pancreatitis ?
C cell hyperplasia /
medullary thyroid emptying
Satiety
Cardiovascular
protective
actions ?
medullary thyroid
tumours
Injectable
Training
Requirements
I li H NPH A i Gl di l U i ll H l i Insulin Human NPH
Human Regular
Lispro
Aspart
Gluisine
Glargine
Determir
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 Determir
Pre-mixed
(several types)
Risk (UKPDS) Stigma for
patients
Inzucci SE, et al. Diabetologia. 2012
OADs and Incretins
Workshop Workshop
Main Learning Points Main Learning Points Summary Summary
Understand the
different classes of
OAD d h t
Different start and
intensification options for
OAD i t d di OADs and when to
use which OADs
either as monotherapy
i bi ti ith
OADs exist depending on
the need for the individual
patient
or in combination with
other OADs / Insulin
Metformin will generally
be the first drug of choice
Group Discussion
LECTURE
Insulin Initiation
and Monitoring
Lecture:
Insulin Initiation and Monitoring
30 minutes
The Usage of Insulin
Lecture Lecture
Main Learning Points 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 the different insulin regiments
Understand the relationship between insulin dosage and blood
glucose measurements
Treatment therapies for Type 2 diabetes
When and How to start treatment When and How to start treatment
START TREATMENT OAD TREATMENT START INSULIN INSULIN INTENSIFICATION
Basal
Lifestyle +
Metformin
+-other OAD
or GLP-1
agonists
Basal
Insulin
Premix
Insulin
Basal +
Bolus
Insulin
HbA
1c
7.0%
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
Insulin remains the most efficacious glucose
l i t lowering agent
Decrease in HbA
1c
: Potency of monotherapy
H
b
A
1
c
%
Nathan et al., Diabetes Care 2009;32:193-203.
What is Insulin What is Insulin
After a meal carbohydrates
are digested and enter the
bl d t hi h t t blood system, which transports
them to the cells
Some cells (those of
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
b d f d ti be used for energy production
The liver needs assistance to
t t th f t f start the process of storage of
glucose in the form of
glycogen
Insulin secretion is delayed and blunted in Type 2
i b Diabetes
The goal of insulin therapy is to restore normal insulin secretion
G h d
Normal
800
Meal Meal Meal
Gap that needs
to be covered
Type 2 diabetes
600
400
Insulin
S ti
400
200
Secretion
(pmol/min)
0
Adapted from: Polonsky KS, et al. N Engl J Med. 1996 Mar 21;334(12):777-783.
Time (24 hours)
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
Promotes uptake and
utilization of glucose
Promotes uptake of
glucose
Suppresses lipolysis
of glycogen and its
storage
Suppresses lipolysis
Objectives of Insulin Treatment
Maintain blood glucose levels between 80-140 mg/dl:
1 By promoting uptake of glucose by target cells
j
1. By promoting uptake of glucose by target cells
subsequent breakdown into energy (glycolysis)
storage as glycogen (glycogenesis) 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)
Most people with type 2 diabetes will, in time,
need insulin therapy because need insulin therapy because
)
60
r
e
q
u
i
r
i
n
g

n
s
u
l
i
n

(
%
)
30
40
50
P
a
t
i
e
n
t
s

r
a
d
d
i
t
i
o
n
a
l

i
10
20
30
Years from start of UKPDS
a
0
10
1 2 3 4 5 6
Wright A et al. Diabetes Care 2002;25:3306
(Patients treated with chlorpropramide)
Years from start of UKPDS
diabetes Patients will eventually fail on OADs
UKPDS
9
Conventional*
Glibenclamide
Metformin
Insulin
8
ADOPT
Metformin
Glibenclamide
Rosiglitazone
A
1
c
(
%
)
8
Insulin
8.5
8
7.5
M
e
d
i
a
n

H
b
A
7
7.5
6 5
Recommended
treatment
target <7 0%

7
6.5
6.2% upper limit of normal range
6
Years from randomisation
2 4 6 8 10 0
6.5
target <7.0%

6
i ( )
0 2 3 4 5 1
Years from randomisation
Time (years)
*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L;
ADA clinical practice recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743
Insulin can be initiated at any time 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 and as soon as
possible
Inadequate
Lifestyle
+ 1 OAD + 2 OAD + 3 OAD
INITIATE INSULIN
but Insulin usage is currently very low in
I d i d t it i hb i t i
Population Total Insulin Used Insulin Usage per Capita
Indonesia compared to its neighbouring countries
Bangladesh 161
Indonesia 248
3,097
694
19
3
Philippines 104 982 9
67
92
Thailand
Vietnam
3,258
417
49
5
29 Malaysia
Million People Mega Units
2,029 70
Insulin Units / Capita
IMS Full year 2011 Data. CIA World Factbook
Million People Mega Units Insulin Units / Capita
Insulin Indications
Absolut Indication
Type 1 Diabetes
Relative Indication 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 History of Pankreotomi
Besides the above, there are a number of condition where insulin is
required, e.g. chronic liver, kidney function interruption and high
dosage steroid therapy
Three Types of Insulin
Schematic Representation Only Schematic Representation Only
BASAL INSULIN
m
i
n
)
BASAL INSULIN
PRE-MIX INSULIN
FAST-ACTING INSULIN
R

(
m
g
/
k
g
/
m
G
I
Time (h)
0 4 8 12 16 20 24
Three Types of Insulin
FAST-ACTING PRE-MIX BASAL
m
i
n
)
m
i
n
)
m
i
n
)
G
I
R

(
m
g
/
k
g
/
m
G
I
R

(
m
g
/
k
g
/
m
G
I
R

(
m
g
/
k
g
/
m
Time (h)
G
0 8 16 20 24 4 12
Time (h)
G
0 8 16 20 24 4 12
Time (h)
G
0 8 16 20 24 4 12
Basal Insulin provides a
steady concentration of
insulin in the bloodstream
Premixed insulins contain
a mixture of rapid-acting
and intermediate-acting
Fast-acting insulins
include single amino acid
replacement that reduce
their ability to self-
over 24 hours. Initially,
basal insulin should be
given at 10 units per day
at night time or in the
morning
1
g
insulin in a fixed
combination to provide
coverage of prandial and
basal insulin
requirements
2
y
associate into diamers and
hexamers. This means
that they are quickly
absorbed into the
bloodstream following
1. Hompesch M. Diabetes Obes Metab 2006; 8:568; 2. Weyer et al. Diabetes Care 1997;10:16121614.; 3. 1. Heinemann et al.
Diabetes Care. 1998;21:19104
morning
1
requirements
2
bloodstream, following
subcutaneous injection.
3
Pharmacokinetics of the different Types of Insulin
available in Indonesia
Profile
Type of Insulin Insulin Name
Onset
(hours)
Peak
(hours)
Fast-acting Analogue Insulin Insulin Aspart (NovoRapid) 0.2 0.5 0.5 - 2
Insulin Lispro (HumaLog) 0.2 0.5 0.5 - 2
Insulin Gluisine (Apidra) 0.2 0.5 0.5 - 2
Fast-acting Human Insulin ActRapid 0.5 1 0.5 - 1
Humulin R 0.5 1 0.5 - 1
Intermediate Human Insulin Insulatard 1.5 4 4 - 10
Humulin N 1.5 4 4 - 10
Long-acting Analogue Insulin Insulin Detemir (Levemir) 1 - 3
Insulin Glargine (Lantus) 1 - 3 Insulin Glargine (Lantus) 1 3
Pre-mix Analogue Insulin Insulin Aspart (NovoMix) 0.2 0.5 1 - 4
Insulin NPL (HumaLog) 0.2 0.5 1 - 4
Pre-mix Human Insulin Mixtard 0 5 1 3 - 12 Pre mix Human Insulin Mixtard 0.5 1 3 12
Humulin Mix 0.5 1 3 - 12
Adapted from Mooradian et al. Ann Intern Med 2006; 145: 125-34
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
Glucose are elevated
OR Start Basal/Bolus Therapy
Source: ADA Guidelines
Insulin Titration schemes
B l d F t A ti I li Basal and Fast-Acting Insulin
Fasting Blood Glucose
Content (mg/dl)
Basal Insulin Titration
Content (mg/dl)
<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
BASAL
INSULIN
>180 mg/dl Increase dosage 4 units per 3 days
Once titrated, continue to monitor HbA1c every 3 months
Fasting Blood Glucose
Content (mg/dl)
Fast-acting Insulin Titration
Start with 4 units / day
Increase by 2 units every 3 days
FAST-
ACTING
Start with 4 units / day
until target is reached
When starting Fast-acting Insulin, secretagogues should be
discontinued
ACTING
INSULIN
Source: KONSENSUS: Insulin Treatment 2011
Insulin Treatment Optimization
H t O ti i T t t ft I iti ti How to Optimize Treatment after Initiation
Basal Insulin Only
Usually with OAD
Start with Basal Insulin
10u / daily with meal
Usually with OAD
10u / daily with meal
or before bedtime.
Same injection time
every day
If glycemic target is not
reached titrate according to
Basal Titration Scheme
If glycemic target is not
reached within 2-3 months,
Basal Insulin Only
Usually with OAD
,
intensify Insulin treatment
Basal with
Prandial
Usually keep OAD
Premix Insulin
Usually keep OAD
Basal Bolus
Usually keep OAD
Usually keep OAD
y p y p
Add Prandial starting
with 4u / day either
once or twice-daily and
Switch to Premix twice-daily.
Start with equal basal dose,
but give 50% per injection
Switch to Basal Bolus
(3 daily prandial) start
with 4u / day and once or twice daily and
titrate accordingly
but give 50% per injection
and titrate accordingly
with 4u / day and
titrate accordingly)
Source: PERKENI Insulin Guidelines 2011
Primarily one type of Insulin device available in Indonesia y yp
Prefilled devices
Disposable disposed of
once empty
Less teaching time
required
Primarily plastic
Easy and Convenient for
Patients
WE WILL COVER HOW TO START A
PATIENT ON INSULIN AND
INJECTION TECHNIQUES IN A INJECTION TECHNIQUES IN A
SEPARATE WORKSHOP
WE WILL COVER HOW TO START A
PATIENT ON INSULIN AND INJECTION
TECHNIQUES IN A SEPARATE GROUP
DISCUSSION
LECTURE
Screening, Treatment
and Evaluation of
Complications
Lecture:
Screening, Treatment and Evaluation
of Complications
Screening, Treatment and Evaluation of
C li ti Complications
Lecture
Main Learning Points Main Learning Points
Understand the treatment options for diabetes associated
l complications:
Nephropathy
Retinopathy Retinopathy
Neuropathy
Erectile Dysfunction Erectile Dysfunction
CVD
CAD
Recap: The goal of diabetes management is to secure
optimal glycemic control to avoid complications optimal glycemic control to avoid complications
Di b ti
Stroke
Microvascular Macrovascular
Diabetic
retinopathy
Leading cause
of blindness
1.2- to 1.8-fold
increase in stroke
3
in working-age
adults
1
Diabetic
75% diabetic
patients Diabetic
nephropathy
Leading
cause of
end-stage
renal
Diabetic
neuropathy
patients
die from CV events
4
renal
disease
2
eu opat y
Leading cause of
non-traumatic lower
extremity
amputations
5
Erectile Dysfunction
The most secretive
amputations
5
1
Fong DS, et al. Diabetes Care 2003;e 26 (Suppl.1):S99S102.
2
Molitch ME, et al. Diabetes Care 2003; 26 (Suppl.1):S94S98.
3
Kannel WB, et al.
Am Heart J 1990; 120:672676.
4
Gray RP & Yudkin JS. Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl.1):S78S79.
Diabetic Foot
Complication of DM
Recap: Risk of Complications increases as
Hb1Ac increases Hb1Ac increases
80
0

40
60
M di l i f ti
Microvascular disease
e

p
e
r

1
.
0
0
0
n
t
-
y
e
a
r
s
20
40
Myocardial infarction
I
n
c
i
d
e
n
c
e
p
a
t
i
e
n
0
5 6 7 8 9 10 11
Updated Mean HbA1c (%)
Stratton IM et al. BMJ 2000;321:40512
Updated Mean HbA1c (%)
Adjusted for age, sex, and ethnic group
Recap: Its the diabetes-related complications not
the diabetes medicine - that carries the biggest cost gg
to the society
Cost increases with a factor of 22.5 if patients develop complications (ASKES Data)
900
700
800
900
US$
400
500
600
700
22.5X
40
100
200
300
400
40
0
With Complications Without Complications
Approximate Annual Cost / Diabetes Patient
ASKES 2010 Unpublished data
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
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)
p=0.01 p=0.001 p=0.007 p=0.04 p=0.052 p=0.0099 p=0.44 p=0.03
Any
diabetes
endpoint
Microvascular
Myocardial
infarction
Death
(any
cause)
Microvascular
disease
RRR: relative risk reduction of intensive therapy over
conventional therapy
UKPDS 80. Holman et al. NEJM 2008; 359:1577-89.
Classification of Micro- and Macrovascular
C li ti Complications
Chronic complications of diabetes
Microvascular complications
Kidney nephropathy kidney failure
Eyes retinopathy blindness Eyes retinopathy blindness
Nerves neuropathy disability
Peripheral Arterial Diseases disability
Erectile Dysfunction y
Macrovascular complications
Heart myocardial infarction
Brain stroke
Atherosclerosis myocardial infarction
Microvascular Complications an overview Microvascular Complications an overview
Retinopathy and blindness p y
Nephropathy Nephropathy
Erectile Dysfunction
Neuropathy
Erectile Dysfunction
International Diabetes Federation. Diabetes Atlas 2006;1112
Diabetes Nephropathy
Ch t i ti Characteristics
Persistent albuminuria
Diabetic retinopathy
H pe tension Hypertension
Decline in kidney function (about 12 ml/min/year)


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 m
2
At least moderate kidney dysfunction (stage 3
5 chronic kidney disease (CKD))
60 90 mL/min per 1,73 m
2
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
Natural history of diabetic nephropathy
Urinary protein excretion GFR
m
g
/
d
)
G
F
R
)

Incipient diabetic
nephropathy
Pre Overt diabetic
nephropathy
End-stage
renal disease
e
x
c
r
e
t
i
o
n

(
m
a
t
i
o
n

r
a
t
e

(
G
/
m
i
n
)
150
100
1000
5000
1 2 3 4 5
a
r
y

p
r
o
t
e
i
n

e
m
e
r
u
l
a
r
f
i
l
t
r
a
(
m
L
/100
50
200
1000
U
r
i
n
a
Years
G
l
o
m
0
5 10 15 20 25
20
Functional
GFR -
(90-95%)
Microalbuminuria,
hypertension
Proteinuria, nephrotic
syndrome, GFR
.
Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000
Treating Albuminuria Treating Albuminuria
Use ACE-I or ARB in nonpregnant patiens with micro-
or macroalbuminuria
Reduce protein intake to 0.8-10 g/kgBW/day in DM &
early CKD; 0.8 g/kgBW/day in later CKD
If ACE-Is /ARBs/diuretics are given, monitor serum If ACE Is /ARBs/diuretics are given, monitor serum
creatinine and potassium
When eGFR <60 ml/min/1.73m
2
, evaluate for CKD
complications complications
Consider referral to experienced physician in kidney
disease care
Diabetes Care. 2012
Diabetes Nephropathy
P ti d T t t Prevention and Treatment
Maintain tight glycaemic
and blood pressure control and blood pressure control
Multifactorial disease
management:
0 4
0.8
0.6
t
y

o
f

m
i
n
u
r
i
a
management:
antihypertensive agents
good blood glucose control
control of dyslipidaemia
0.0
0.4
0.2
P
r
o
b
a
b
i
l
i
m
i
c
r
o
a
l
b
u
m
control of dyslipidaemia
monitoring renal function
lifestyle changes, including
smoking cessation and
Glycated haemoglobin (%)
5 8 12 11 10 9 6 7
smoking cessation and
low-protein diet
DCCT. Diabetes 1996;45:128998
Diabetes Retinopathy
Ri k F t d Cl ifi ti Risk Factors and Classification
Poor glycaemic and
blood pressure control
t
i
o
)35
blood pressure control
increase the risk of
retinopathy
Five categories:
c
e

(
o
d
d
s

r
a
30
25
20
Five categories:
background
preproliferative
lif ti
t
h
y

i
n
c
i
d
e
n
c
10
15
proliferative
advanced diabetic
eye disease
mac lopath
London HbA (%)
R
e
t
i
n
o
p
a
t
4 6 9
0
5
8 7 5 10
maculopathy
London HbA
1c
(%)
DCCT HbA
1c
(%)
5.7 7.7 10.8 9.8 8.8 6.7 11.9
Chaturvedi et al. Diabetes Care 2001;24:2849
Diabetes Retinopathy
Non-
Diabetic
Retina Retina
Diabetic
Maculopathy
Proliferative
Diabetic
Retinopathy
Diabetes Retinopathy
P ti d T t t Prevention and Treatment
Maintain tight glycaemic and blood pressure control Maintain tight glycaemic and blood pressure control
Regular eye examinations
Treat with laser photocoagulation and vitreoretinal
surgery
Klein et al. Ann Intern Med 1996;124:906
Diabetes Neuropathy
Ri k F t d C T Risk Factors and Common Types
Hyperglycaemia
Symmetrical
diffuse
sensorimotor
Femoral
neuropathy
Other acute
mononeuropathies
Pressure palsies
is the leading
cause of diabetic
neuropathy
sensorimotor
neuropathy
(amyotrophy)
mononeuropathies
VI
III
Truncal
Ul
Alcohol makes
neuropathy worse
A number of
Ulnar
Median
Lateral
lit l
clinical
syndromes are
recognisable
Sensory loss 0 +++
Pain + +++
Tendon reflexes N
Sensory loss 0 +
Pain + +++
Tendon reflexes 0
Sensory loss 0 +
Pain + +++
Tendon reflexes N
Sensory loss + +++
Pain + ++
Tendon reflexes N
popliteal
Watkins et al. In: Diabetes and Its Management 2003. Pickup & Williams. In: Slide
Pickup & Williams. In: Slide Atlas of Diabetes 2004

Motor deficit 0 +

Motor deficit + +++ Motor deficit + +++ Motor deficit + +++
Watkins et al. In: Diabetes and Its Management 2003. Pickup & Williams. In: Slide
Atlas of Diabetes 2004
Diabetes Neuropathy
The Most Frequent Diabetes related Complication in The Most Frequent Diabetes related Complication in
Indonesia (and in the World)
A1Chieve Indonesia
(2.240 patients)
IDMPS Indonesia
(715 patients)
80%
90%
100%
( p )
80%
90%
100%
( p )
41.9%
40%
50%
60%
70%
54.0%
40%
50%
60%
70%
6.7%
16.1%
19.1%
21.7%
10%
20%
30%
40%
8.7%
26.5%
33.4%
10%
20%
30%
40%
0%
Neuropathy Eye CV Renal Foot
Ulcer
Frequency of complications
0%
Neuropathy Eye Renal Foot
Ulcer
Frequency of complications
Note: One patient can have more than one complication
Diabetes Neuropathy
P ti d T t t Prevention and Treatment
Maintain tight glycaemic
t l t d th
16
control to reduce the
risk or progression of
neuropathy
Exclude or treat
16
a
f
f
e
c
t
e
d
p<0 001
12
Conventional therapy
Exclude or treat
contributory factors:
alcohol excess
vitamin B
12
8
g
e

o
f

c
a
s
e
s
p<0.001
vitamin B
12
deficiency
uraemia
Offer pain relief based
P
e
r
c
e
n
t
a
g
4
Intensified therapy
O e pa e e based
on the dominant
symptoms
0
0 1
Time (years)
2 3 4 5
DCCT. NEJM 1993;329:97786
Diabetic Foot Complications Diabetic Foot Complications
Erectile Dysfunction
D fi iti Definition
ED is the inability to achieve and maintain an erection
adequate for intercourse to the mutual satisfaction of adequate for intercourse to the mutual satisfaction of
the man and his partner.
Remember both partners in a relationship are affected Remember, both partners in a relationship are affected
Erectile Dysfunction
B k d Background
35%-75% of men with diabetes will experience at least
some degree of ED some degree of ED
Men with diabetes tend to develop erectile dysfunction 10
to 15 years earlier than men without diabetes. o 5 yea s ea e a e ou d a e es
Men with diabetes will have ED
50%-60%in > 50 years old 50% 60% in > 50 years old
95% in >70 years old
Erectile Dysfunction
Ri k F t 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
i Treatment Options
Oral medications: Sildenafil (Viagra), Vardenafil (Levitra),
Tadalafil (Cialis) Tadalafil (Cialis)
Urethral suppositories (MUSE)
Injection therapy: Caverject Trimix Bimix Injection therapy: Caverject, Trimix, Bimix
Vacuum constriction device
Surgery Surgery
Sex therapy
Macrovascular Complications an overview p
Stroke
Cardiovascular/heart
disease
Peripheral vascular disease
Cardiovascular Diseases
P ti t ith T 2 Di b t t i d i k f CVD Patients with Type 2 Diabetes at a increased risk of CVD
Risk of cardiovascular
disease is greater in
Incidence of myocardial
infarction over 7 years
disease is greater in
patients with diabetes
than in those without
Having diabetes results in
y
%
)
Having diabetes results in
a similar risk of heart
attack as a prior heart
attack P
a
t
i
e
n
t
s

(
%
attack
With diabetes n=1059
Without diabetes n=1373
P
Haffner et al. N Engl J Med 1998;339:22934
Poor Control of CV Risk Factors in Diabetes
( ) (NHANES)
Frequency
S Cholesterol < 200 mg/dl (5 2 mmol/l) 52 % S-Cholesterol < 200 mg/dl (5.2 mmol/l) 52 %
BP < 130/80 mmHg 36 %
HbA
1c
< 7.0% 37 %
All three risk factors controlled 7 %
Unchanged CV risk factors from 1991 to 2000
Saydak SH et al. JAMA 2004
g
Cardiovascular Diseases
Risk for Myocardial infaction and stroke increases with Risk for Myocardial infaction and stroke increases with
progression to Type 2 Diabetes
Relative risk for MI and stroke in women
k
R
e
l
a
t
i
v
e

r
i
s
k
R
*Nurses Health Study (NHS) cohort comprised women only
No diabetes
during study
Prior to
diagnosis
After
diagnosis
Diabetic at
baseline
Adapted from Hu et al. Diabetes Care 2002; 25:1129-34
Prevention of Cardiovascular Diseases Prevention of Cardiovascular Diseases
Reduce risk factors for
d l d
e
a
r
s
Non-diabetic
subjects
140
cardiovascular disease:
stop smoking
treat hypertension
0
0
0

p
a
t
i
e
n
t
-
y
Subjects with
type 2 diabetes
100
120
treat hyperlipidaemia
improve glycaemic
control
d i ht i th
a
t
h
s

p
e
r

1
0
,
0
60
80
reduce weight in the
obese
take regular exercise
N
u
m
b
e
r

o
f

d
e
a
20
40
Number of risk factors
N
0 1 2 3
0
Adapted from Stamler et al. Diabetes Care 1993;16:43444
Treatment of Cardiovascular Diseases Risk factors
Hypertension
Dyslipidemia
Treatment of Cardiovascular Diseases Risk factors
Dyslipidemia
Antiplatelet agents
Smoking cessation
CHD screening and treatment CHD screening and treatment
Diabetes Care 2012
Treatment of Cardiovascular Diseases Risk factors
Hypertension SBP 140 or DBP 90 mmHg: Hypertension SBP 140 or DBP 90 mmHg:
Lifestyle modification +pharmacological therapy
Dyslipidemia Lifestyle modification + statins 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) treatment contraindicated)
Diabetes Care 2012
Hypertension 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 mod +
pharmacological therapy pharmacological therapy
Administer one or more anti-HT meds at bedtime
Monitor kidney function and serum potassium in pt
i i ACE I ARB di ti receiving ACE-Is, ARBs, or diuretics
Remember: ACE-Is and ARBs are contraindicated in
pregnancy
Diabetes Care 2012
Meta-analysis of Statin Treatment in Diabetes 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 21% reduction in stroke
9% reduction in all-cause mortality
13% reduction in CVD mortality 13% reduction in CVD mortality
No difference in non-vascular mortality
Independent of baseline LDL or prior CVD
Lancet 371, 117-25. 2008
Independent of baseline LDL or prior CVD
Statin Conclusion
Statin therapy should be considered for all
individuals with type 2 diabetes yp
independent of baseline lipid levels
However lack of data for age < 40y g y
and should be considered for individuals with type
1 diabetes at high risk of CVD or with signs of
di b i li i diabetic complications
The STENO2 Study a multifactorial approach
i b to Type 2 Diabetes
160 patients
Type 2 diabetes and Type 2 diabetes and
microalbuminuria
Mean age 55 yrs, BMI 30
kg/m
2
; HbA
1c
8.4 %
New Engl J Med 2003; 383-93
Randomized to
conventional therapy
assigned to their GPs
i t i t St or intensive care at Steno
Diabetes Center
New Engl J Med 2008; 358: 580-91 New Engl J Med 2008; 358: 580 91
The STENO2 Study Study Design The STENO2 Study Study Design
Conventional treatment
80
Endpoint examinations
Micro-vascular Macro-vascular
80
n=160
Intensive treatment
4 years 8 years
80
Advice to the Intensive Groupp
Food Advice
Cut down on animal fat Cut down on animal fat
Have some kind of seafood every day
5-6 vegetables and fruits every day
Exercise Advice Exercise Advice
Enjoy physical performance
> 150 min/week
Smoking cessation Smoking cessation
Intensification of OHA and insulin
Treatment with ACE/ARB, Statin and / ,
baby aspirin
Patients in the Intensive Group had obtained better
h i i h i l outcomes than patients in the Conventional Group
Intervention
n=55
Standard
n=38 n=55 n=38
Haemoglobin A
1c
(%) 7.7 8.0
F-s-total -cholesterol (mg/dl) 147 155 F s totalcholesterol (mg/dl) 147 155
F-s-LDL-cholesterol (mg/dl) 71 77
F-s-triglycerides (mg/dl) 99 148 g y ( g/ )
Systolic BP (mm Hg) 140 146
Diastolic BP (mm Hg) 74 73
Albumin excretion rate (mg/24h)* 69 75
Values are mean
* median
and Mortality Rate was lower in the Intensive Group y p
90
100
60
70
80
20
30
40
50
0
10
20
30% of patients (n=24) died in the intensive group compared to 30% of patients (n=24) died in the intensive group compared to
50% of patients (n=40) in the conventional group
Absolute risk reduction = 20%
The STENO2 Study
Ri k R d ti i I t i G Risk Reduction in Intensive Group
Relative risk reduction after 8 years
Cardiovascular disease 53%
Diabetic Nephropathy 61%
Diabetic Retinopathy 58% p y
Autonomic Neuropathy 63%
Screening, Treatment and Evaluation of Complications
Lecture Lecture
Main Learning Points Main Learning Points Summary Summary
Complications should be
screened for and treated
according to guidelines
R ti f ll t t t
Understand the treatment
options for diabetes
associated complications:
Routine follow up on treatment
of complications should be
performed
CVD complications are the mail
Nephropathy
Retinopathy
Neuropathy
CVD complications are the mail
cause of death among patients
with diabetes
Risk of end-stage renal disease
f
Neuropathy
Erectile Dysfunction
CVD
and blindness is significantly
reduced by treatment of
hyperglycemia and hypertension
CAD
LECTURE
Simple Diabetes
Foot Care
Simple Diabetes Foot Care
Lecture:
30 minutes
Simple Diabetes Foot Care
Lecture
Main Learning Points Main Learning Points
Understand the risk factors for diabetic Understand the risk factors for diabetic
foot complications
Understand the steps for a simple diabetes
foot examination
Understand the management of foot ulcers
Why foot care is important to diabetes management
Diabetes Patients
Have 15 40
fold higher risk
of leg
amputation
than non
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 % than non
diabetic
diabetes < 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
5 Cornerstones of diabetes foot care management
1. Foot examination
regularly regularly
2. Identification of
risk factors
4. Treatment before
Ulcer occurs
3. Education
(patients, providers
and family)
5. Use appropriate
footwear
and family)
footwear
Risk Factors for diabetic foot ulceration
Intrinsic Factors Extrinsic Factors
Peripheral Neuropathy
Micro- and Macrovascular Diseases
Immunopahty
Minor mechanical trauma
Callus
Thermal Injury u opa y
Structural Deformity
Limited Joint Mobility
Nephropathy
e a ju y
Chemical Burns
Bathroom Surgery
Smoking Nephropathy
Age
Duration of Diabetes
Visual Acuity
Smoking
Poor knowledge of diabetes
Psychological Factors
Visual Acuity
Previous Ulceration
Frykberg, Diabetic Microvascular Complications Today, May/June 2006
Pathway to diabetic foot ulceration
90%
100%
63%
77%
78%
50%
60%
70%
80%
30%
35%
37%
20%
30%
40%
50%
1%
0%
10%
Peripheral
Neuropathy
Peripheral
Ischemia
Edema Deformity Minor
Trauma
Callus Infections
Neuropathy Ischemia Trauma
Components leading to foot ulceration
Reiber GE, Vileikyte, Boyko EJ et al. Causal pathways for incident lowerextremity ulcers in patients with from two settings.
Diabetes Care 1999: 157-162
Peripheral Neuropathy
Intrinsic Factors
Autonomic Sensoric Motoric
Decreased Sweating
Dry Skin
Loss of protective
sensation
Decreased pain
Decreased Elasticity
Fissure / Callus
p
threshold
Lack of temperature
sensation and
Fissure / Callus
Ulcer
proprioception
Th l T Ill fitti Thermal Trauma
in bajaj
Ill fitting
Shoes
Neuropathic Ulcers
Intrinsic Factors
Influenced by:
- Friction
- Pressure
Peripheral Arterial Disease (PAD)
Intrinsic Factors
Risk Factors* PAD
Hyperglycemia
Eleveted systolic blood
pressure
Correlated with atherosclerosis
A1c 1% 26 % PAD
More aggressive pressure
hyperlipidemia
Smoking
Cardiovascular disease
More aggressive
Narrowing vessel lumen
obstructive
Distal tissue necrosis Cardiovascular disease Distal tissue necrosis
* UKPDS
Foot Deformities / Biomechanical
Intrinsic Factors
Causes of Ulcers (Extrinsic Factors)
Kyoto Foot Meeting 2010 Kyoto Foot Meeting 2010
Extrinsic Factors
Pathophysiology of diabetic foot
Di b t M llit Diabetes Mellitus
Neuropathy Trauma Vascular Disease
MOTOR
Weakness
Atrophy
AUTONOMIC SENSORY
Anhidrosis dry
skin
MICROVASCULAR MACROVASCULAR
Structural
capillary BM
Structural
atherosclerosis
High Plantar
Deformity
Abnormal
Stress
Loss of
Protective
Sensation
skin capillary BM
thickening
Functional AV
atherosclerosis
Occlusive
narrowing
High Plantar
Pressure
Callus
Formation
Sympathetic
Tone
Shunting
Ischemia
Structural
Deformity
Cheiroarthropathy
Impaired Response
to Infection
Ischemia
Diabetic Foot Ulcer Amputation Amputation
Diabetic Foot Disorders: A Clinical Practice Guideline (2006 Revision)
From Theory to real-life studies on foot care in RSCM
RSCM 2003 RSCM 2007
32%
16%
14%
26%
50%
26%
36%
Died
Major Amputation and then Improved
Discharge on their own will
Died
Amputation
No Amputation g
Improved without amputation
Clinical Classification of diabetic foot (Edmond)
Grade 1 Grade 1 Grade 2 Grade 2 Grade 3 Grade 3 Grade 4 Grade 4 Grade 5 Grade 5 Grade 6 Grade 6
Normal foot,
no risk factors
of neuropathy
No active
ulcers, have 1
risk factors
Skin
breakdown;
fisurre blitser
Foot develop
infections,
Discharge
Tissue necrosis
with or with
out intake
Unsalvageable
foot, need
major of neuropathy,
ischemia,
deformities
risk factors:
neuropathy,
ischemia,
deformities,
callus and
fisurre, blitser,
ulcer
Usually in
plantar surface
Discharge
purulent,
cellulitis,
neuropathy
and or
out intake
foot,
neuropathy,
ischemia,
neuroischemi
major
amputation,
extensive
necrosis,
destroyed foot callus and
swelling, nail
deformities
and or
ischemia
neuroischemi,
infection
destroyed foot,
severe
infection
6 Steps for a complete Diabetes Foot Examination 6 Steps for a complete Diabetes Foot Examination
DIABETES FOOT EXAMINATION DIABETES FOOT EXAMINATION
Patient
Gross
A
Vascular
Screening
f
Derma-
t l i
Nail Defor-
History
Assess-
ment
Examination
for
neuropathy
tologic
Examination
maties
First 4 steps in the assessment
A t Si ifi t Fi di Assessment Significant Finding
Patient
History
- Previous foot ulceration
- Previous amputation
- Diabetic > 10 years
A1 7 % - A1c > 7 %
- Impaired vision
- Neuropatic symptoms
- Claudicatio
Gross Hammer toes 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 maseration
- Moist
- Uhealing ulceration
N il Y ll thi k d il Nail
Deformaties
- Yellow, thickened nail
- Ingrowing nail edge
- Long or sharp nails
Last 2 steps in the assessment
Assessment Test Significant Finding
Screening for
Neuropathy
- Semmes-Weinstein
monofilamen 10 gram
Lack of perseption at one
or more side
- Tuning fork 128Hz Negative of vibration
perception
- Biothesiometer:
Vibration perseption
Vibration perseption
threshold >25 volt
Vascular - Palpation of dorsalis Decrease or absent
Examination
p
pedis and tibialis
posterior arteri
- Ankle Brachial Index
- Color doppler
pulse
ABI < 0.9 consistent
with PAD
ABI
>1.2
0.9 1.2
0 9
Interpretation
Rigid or calcified vessels or both
Normal (or calcified)
I h i <0.9
<0.6
Ischaemia
Severe ischaemia
Risk Classification based on Foot Assessment
Score Category Risk Profile
Check-up
Frequency
0 Low Risk Pulsation ADP and ATP good Once a year
No deformities (hammer toe, claw
toes, halux valgus, prominent
methatarsal head)
1 Increased Risk Pulsation ADP and ATP good Once every g
And/or deformities (hammer toe,
claw toes, halux valgus, prominent
methatarsal head)
y
6 months
2 High Risk ABI < 0,9 or ADP/ ATP not palpable
Deformities ( hammer toe, claw toes,
halux valgus, , prominent methatarsal
head
Once every
3 months
head
3 Very High Risk History of ulcer or amputation
Ulcer
Once every
1-3 months
Intervention based on Risk Classification
Score Category Intervention
0 Low Risk
Encourage extended knowledge on diabetes and
foot care
0 Low Risk
Encourage self-care
1 Increased Risk
Inspect patients feet
Review need for vascular assessment
1 Increased Risk
Evaluate footwear
Enhance foot care education
Inspect patient's feet
Review need for vascular assessment
2 High Risk
Review need for vascular assessment
Evaluate provision and provide appropriate
Intensified foot care education
Specialist footwear and insoles
Ski d il 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
DONTs
Walk without shoes
Always wear footwear
Check your footwear before
wearing them
U h th t fit
Use shoes that dont fit
Use socks that dont fit to your
foot
L t ki b d Use shoes that fit
Buy shoes in the afternoon
Always use socks of cotton
Let your skin become dry
Use sharp items to remove warts
Smoke
Wash your shoes with soft soap and
dry them
Cut your nails in a flat way
Use ring on finger
Use high heels or shoes with
sharp edges
Check your feet regularly at the
doctor
Use lotion regularly at your skin
p g
Management of Foot Ulcers
Metabolic
Control
2
Control
1 3
Infection
Control
Wound
Control
Vascular
Control
Mechanic
Control
4
5
International Working Group on the Diabetic Foot 2007
Wound Control
1
1 Insision drainage 1. Insision, drainage,
debridemant and
necrotomi
2 Management of 2. Management of
infections in tissue and
bone
3. Exudat Management g
4. Keep control of
proliferation phase and
infections
Metabolic Control
2
1. Hyperglycemia
- Will inhibit process of wound recovery
- Inhibit growth factor, collagen synthesis and
fibroblast activities
2. Hyperalbuminemi
3. Hypertension
4. Decrease of heart and kidney function 4. Decrease of heart and kidney function
5. Dyslipidemia
6. Anemia
7. Other diseases caused by diabetes
Infection Control
3
1 Need aggressive therapy 1. Need aggressive therapy
2. Usually there are no symptoms
or signs of infection
3 E t l I f ti P iti 3. External Infection: Positive
gram bacteria
4. Internal Infection: Negative
gram bacteria gram bacteria
5. Might need surgery
Use of Antibiotics
3
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
- Anarob, aerob, gram positive / gram negative
3. Condition of the patient
- Allergy, heart and kidney function
4 Drug Profile 4. Drug Profile
- Safety, drug interactions, adverse events,
frequency and dosage and price
Vascular Control
4
1. Neuroischemic Foot 1. Neuroischemic Foot
2. Atheroscelrosis can cause total
block in the blood vessels
3. Decrease of blood flow to the
wound
4. Critical Limb ischemia:
Amputation Warning
Mechanic Control
5
1. Princip: p
Reduce stress on the wound
Off loading
Might be bed rest
Non-weight bearing
Use of walker wheel-chair or crutches Use of walker, wheel-chair or crutches
Use special shoes (half-shoes)
Distribute the body weight to all
surfaces of the foot