Current Concepts of

Chronic Diabetic
Complications
Sarwono Waspadji
Jakarta Diabetes & Lipid Center
Division of Endocrinology & Metabolism,
Department of Medicine, School of Medicine
University of Indonesia, Jakarta

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik
Patogenesis berbagai faktor risiko utama
Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas
Tatalaksana komplikasi kronik DM
Penutup

Vascular Complications

Microangiopathy

Macroangiopathy

Retinopathy

Brain

Blindness

Stroke

Cardiomyopathy

Nephropathy

Heart

Coronary Diseases

Kidney

failiure

Perpheral
Artery Disease
Neuropathy

Pathogenesis of
Microvascular Lesion

Normal

Microvascular

Atherosclerotic Plaque,
Formation, and Rupture
Increased
lipid levels
Endothelial
dysfunction

Plaque
rupture and
thrombosis
Monocyte
migration

Plaque
formation

LDL oxidation
Macrophage
differentiation and
inflammation
Foam cell
formation

Biochemical Pathways of Hyperglycemic Damage

Nonenzymatic
glycation
Pentose
shunt
HK/GK

Glucose

R-5P

GlcN-6P

Hexosamine
pathway

GFAT

G-6P

F-6P

GAPDH

GA-3P

AR

Sorbitol
SD

DHAP

Polyol
pathway

DAG

Fructose

Oxidative
stress

PKC

Glycolysis

Pyruvate
DAG de novo
synthesis

Diabetic Cost : ASKES Data

25

23

20
14

15
9

10
5

126.104 pts

258.208 pts

384.312 pts

Million US$
Without Complications
Total

With Complications

ASKES Data
Annual cost for each diabetes patient
Without Complications + 40 US$
With Complications + 900 US$

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi

vaskular kronik
Patogenesis berbagai faktor risiko utama
Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas
Penutup

The Progression from CV Risk Factors to

Endothelial Injury and Clinical Events
LDL-C

Smoking
Diabetes
Heart failure

Risk Factors

BP

Oxidative stress
Endothelial
Dysfunction
NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM, cytokines
Thrombosis

Inflammation Vasoconstriction

Growth
factors matrix
Vascular Lesion
and Remodelling

Proteolysis

Plaque Rupture

Vascular Complications
NO = nitric oxide

Adapted
Adapted from
from Gibbons
Gibbons GH,
GH, Dzau
Dzau VJ.
VJ. N
N Engl
Engl JJ Med
Med .. 1994;330;14318.
1994;330;14318.

Genetic Susceptability

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik

Patogenesis berbagai faktor risiko utama

Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas
Tatalaksana komplikasi kronik DM
Penutup

cardio-vascular deaths globally -

Metabolic factors
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
12/22/16
0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

Attributable deaths due to selected risk

factors (000)

Slide 17
Source: WHO 2011. Global Atlas
on CVD prevention and Control 1-164

8,000

Obesity
Visceral
Visceral obesity,
obesity, hypertension,
hypertension, dyslipidemia,
dyslipidemia, insulin
insulin
resistance
resistance

TNF-a, Leptin, PAI-1

Endothelial dysfunction

Atherothrombosis and microangiopathy

Dyslipidemia
Increased
Increased postprandial
postprandial TGRL
TGRL (Chylomicron
(Chylomicron and
and VLDL)
VLDL)

Small dense LDL

HDL Cholesterol

Enhance oxidative stress

Impair endothelial function

Hypertension
Decreased availability of NO

Vasoconstriction
Decreased glomerular filtration
Impaired tubuloglomerular feed-back
Decreased medullary blood flow
Impaired pressure natriuresis
Progressive proteinuria

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik
Patogenesis berbagai faktor risiko utama

Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas
Tatalaksana komplikasi kronik DM
Penutup

Natural History of Disease

Progression

Aggressive treatment of established cardiovascular risk factors

Macrovascular
complications
Microvascular
complications

Aggressive glycemic control

-cell function

Insulin
resistance
Blood
glucose

10

Prevention
IGT/IF
G of IGT
Prevention

0
Diagnosis

Treatment

10

Years

Type 2
diabetes

Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In
Endocrinology. 4th ed. 2001.

Strategies for Reduction of Diabetic

Complications
Prevention of impaired glucose tolerance
Prevention of progression of IGT to type 2
diabetes
Aggressive glycemic control
Aggressive treatment of established
cardiovascular risk factors

The Cornerstones of
DM Management Medical Nutrition
Therapy

1. Education

Medications

2. Medical Nutrition
Therapy
3. Physical Activity
4. Pharmacological Intervention

Lifestyle
Modification

Early and Intensive Glycemic Control

Delays Diabetes Complication

CHD with intensive glucose-lowering vs.

standard treatment
Intensive treatment/
standard treatment

Weight of
study size

Odds ratio
(95% CI)

Odds ratio
(95% CI)

Participants

Events

UKPDS

3071/1549

426/259

8.6%

0.75 (0.541.04)

PROactive*

2605/2633

164/202

20.2%

0.81 (0.651.00)

ADVANCE

5571/5569

310/337

36.5%

0.92 (0.781.07)

892/899

77/90

9.0%

0.85 (0.621.17)

5128/5123

205/248

25.7%

0.82 (0.680.99)

17267/15773

1182/1136

100%

VADT
ACCORD
Overall

0.85 (0.770.93)

0.6 0.81.01.21.41.6
Intensive
Standard
treatment
* Included non-fatal myocardial infarction
and death fromtreatment
all-cardiac
mortality
better
better
Ray KK et al. Lancet. 2009;373:176572

Individualized Treatment based on several criteria to control

blood glucose

Slide 27

Inzucci SE, et al. Diabetologia. 2012

Diabetes Care. 2012;35(6):1364-79

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):331

Algoritma Pengelolaan DM tipe 2 tanpa disertai Dekompensasi Metabolik

PB PERKENI. Konsensus Penegelolaan DM tipe 2, 2010

HbA1c Level
7-8%

Lifestyle
Modification

Lifestyle
Modification

PERKENI Guideline 2011

<7%

+
Monotherapy
Met, SU, AGI,
Glinid, TZD,
DPP-IV

8-9%

>9%

9-10%

>10%

Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV

Notes :
Fail : not achieving A1c target <7% after 23 months of treatment.
(A1c = average blood glucose conversion,
ADA 2010)

Lifestyle
Modification
+
3 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV

Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD
+

Lifestyle
Modification

Basal Insulin

+
Intensive
Insulin

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik
Patogenesis berbagai faktor risiko utama
Sepintas tatalaksana DM

Sepintas tatalaksana dislipidemia,

hipertensi pada DM dan obesitas
Tatalaksana komplikasi kronik DM
Penutup

Cardio Vascular Disease in patients

with T2DM
Primary composite
endpoint* (%)

Conclusion
The intensified intervention
aimed at multiple risk
factors reduces the risk of
cardiovascular and
microvascular events by
about 50 %

60
50
40
30

Conventional
treatment
P = 0.007
Intensive treatment

20
10
0

12

24

36

48

60

72

84

96

44
61

41
59

13
19

Follow-up (months)
Number at
risk

80
80

72
78

70
74

63
71

59
66

50
63

Conventional
Intensive
* Composite endpoint = CV death and amputation
(with either therapy), and relative risk for organ damage
Gaede P et al. N Engl J Med. 2003; 348: 3839
(with intensive therapy)

A Model of Steps in
Therapeutic Lifestyle Changes (TLC)
Visit I

Visit 2
6 wks

Begin Lifestyle
Therapies
Emphasize
reduction in

saturated fat &

cholesterol
Encourage

moderate physical
activity

Consider referral

to dietitian

6 wks

Evaluate LDL
response
If LDL goal not
achieved,
intensify
LDL-Lowering
Tx
Reinforce
reduction
in saturated fat and
cholesterol
Consider adding
plant stanols/sterols
Increase fiber intake
Consider referral to
a dietitian

Visit 3
Q 4-6 mo
Evaluate LDL
response
If LDL goal not
achieved,
consider
adding Drug Tx
Initiate Tx for
Metabolic
Syndrome
Intensify weight
management &
physical activity
Consider referral
to a dietitian

Visit N
Monitor
Adherence
to TLC

Diabetic Dyslipidemia
In the Management of Diabetic dyslipidemia,
DM = CHD risk equivalent
TLC is the basis of lipid management in DM
Always intensively treat non-lipid risk factors
Target LDL-C < 100 mg/dL
In general start with LDL lowering (statin)
Consider fibrate or low dose nicotinic acid if
Non HDL-C > 130 mg/dL

Factors that Favor a Decision to Reduce

LDL-C levels to 70 mg/dL (Very High Risk)
The Presence of Established CHD PLUS
1. Multiple major risk factors (especially DM)
2. Severe and poorly controlled risk factors
(especially cigarrete smoking)
3. Multiple risk factors of Metabolic Syndrome
especially High TG> 200 mg/dL
plus non-HDL-C > 130 mg/dL
with Low HDL-C (40 mg/dL)
4. Pts with Acute Coronary Syndrome

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

Algorithm for Treatment of

Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney
disease)
Initial Drug Choices

Without
Compelling
Indications

With Compelling
Indications

Stage 1 Hypertension

Stage 2 Hypertension

(SBP 140159 or DBP 9099

mmHg)
Thiazide-type diuretics for most.

(SBP >160 or DBP >100 mmHg)

2-drug combination for most
(usually thiazide-type diuretic
and
ACEI, or ARB, or BB, or CCB)

May consider ACEI, ARB, BB,

CCB,
or combination.

Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension
specialist.

Drug(s) for the compelling

indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.

orithm for Treatment of Hypertension in Diabe

Syst. 130 - 139
Diast. 80 - 89

Syst. > 140

Diast. > 90

Lifestyle
Modification
months, inadequate response
Lifestyle +ACE Inhibitor Beta Blocker Diuretic
modification

Alpha Blocker

AIIRA

1-2 months, target not achieved

Increase Dose
other antihypert.

Change to other antihypert.

Add

Add other antihypertensive

(second, third, etc., (one of them should be
diuretic) or macroalb./clinical nephropathy present, use
If microalbuminuria,
ACE inhib, or AIIRA or Non Dihydropyridine Ca. Antag.

Algorithm for Management of Obesity

Assesment of Obesity and Its Risks
Initiate: Behaviour modification
Diet therapy
Physical activity
3 - 6 months

No Weight Loss
(< 6 Kg), BMI >27

Continued weight loss

( > 6 Kg )

Initiate drug therapy

Continue diet and exercise

3 - 6 months

Reassess if no weight loss and BMI >27

consider more intensive drug therapy, VLCD
Bariatric Surgery

Potential Benefits of
Moderate
(5-10%)
Weight
Subcutaneous
AdiposeLoss
Tissue
5-10%
weight loss
~30% Visceral
adipose tissue loss
(diet, physical
activity,
pharmacotherapy)

Visceral
Adipose Tissue

Blood Pressure

Deteriorated

Lipid

Improved

Insulinprofile
sensitivity Improved
Impaired

Insulinaemia, Glycaemia
Susceptibility to thrombosis

Inflammation markers

Abdominally
Reduced Obesity
Obese (high waist HighRisk of Coronary Heart DiseaseLow (low waist measurement)
measurement)

Desprs JP, BMJ. 2001;322:716-20

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik
Patogenesis berbagai faktor risiko utama
Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas

Tatalaksana komplikasi kronik DM

Penutup

Diabetic Complications
60

Microangiopathy >>
Macroangiopathy

54

50

Re nopathy
Neuropathy
Proteinuria

40
30

Dialysis

33.4

Foot Ulcer
26.5

Amputa on
Angina
MCI

20
10.9

8.7
10
0.5
0

7.4
1.3

5.3

2.7

5.3

Heart Failure
Stroke
PAD
IDMPS Indonesia

Comorbidities and
Complications Type 2 DM
Variable
Hypertension
Yes with treatment
Yes but no treatment
No hypertension

Dislipidemia
Yes with treatment
Yes but no treatment
No dislipidemia

Late complication
At least one
No complication

Lifestyle

OGLD

Insulin +

Total

8 (38.1)
0
13 (61.9)

230 (44.2)
17 (3.3)
273 (52.5)

59 (45.4)
5 (3.8)
66 (50.8)

297 (44.3)
22 (3.3)
352 (52.5)

8 (40.0)
4 (20.0)
8 (40.0)

179 (42.6)
36 (8.6)
205 (48.8)

53 (50.0)
12 (11.3)
41 (38.7)

240 (44.0)
52 (9.5)
254 (46.5)

9 (69.2)
4 (30.8)

290 (70.6)
121 (29.4)

97 (85.8)
16 (14.2)

396 (73.7)
141 (26.3)

Most diabetic patients have at least one late diabetic complication

Pemeriksaan dan Pemantauan yang

Diperlukan untuk Komplikasi DM
Mata : Pemeriksaan mata/fundus secara berkala setiap 6-12
bulan
Ginjal : Pemeriksaan berkala urin untuk mendeteksi adanya
protein dalam urin - mikroalbuminuria
Paru : Pemeriksaan berkala foto dada setiap 1-2 tahun atau
kalau ada keluhan batuk kronik
Jantung : Pemeriksaan berkala EKG/ Uji Latih Jantung secara
berkala setiap tahun atau kalau ada keluhan nyeri
dada/cepat capai
Kaki : Pemeriksaan kaki secara berkala dan penuyuluhan
mengenai cara perawatan kaki untuk mencegah
kemungkinan timbulnya kaki diabetik dan
kecacatan di
kemudian hari

Penatalaksanaan Komplikasi Kronik

PJK : Pengelolaan gagal jantung dan infark
Pengelolaan penyempitan koroner
Konservatif medikamentosa
Operatif : bedah pintas koroner, angioplasti

PVD:

Pengelolaan rutin konservatif dengan

medikamentosa, debridemen dan atasi infeksi
Gagal ginjal: Pengelolaan konservatif dgn diet dan obat
Pengelolaan dengan tindakan:
Dialisis : hemodialisis
dialisis peritoneal
Transplantasi ginjal

Retina : Fotokoagulasi, vitrektomi, terapi endolaser

Neuropati : simtomatik

**Pengelolaan DM-nya mengikuti pengelolaan

Organ Terkait

Komplikasi kronik DM dan patogenesisnya

Berbagai macam faktor risiko komplikasi vaskular kronik
Patogenesis berbagai faktor risiko utama
Sepintas tatalaksana DM
Sepintas tatalaksana dislipidemia, hipertensi pada DM
dan obesitas
Tatalaksana komplikasi kronik DM

Penutup

Pada Pengelolaan Komplikasi Kronik DM

Strategi pencegahan primer sangat penting
Perubahan gaya hidup ke arah pola hidup sehat sangat penting
Pola hidup sehat juga penting untuk strategi pencegahan:
Diabetes Melitus
Dislipidemia
Hipertensi
Kegemukan
Komponen lain Resistensi Insulin

Tindakan aktif sudah harus dikerjakan, tidak hanya

dalam tingkat wacana saja
Pengelolaan berbagai faktor risiko harus dikerjakan sekali gus
Depkes dapat mengkoordinasi pelaksanaan program
pencegahan dalam tingkat nasional Tingkat Primer
Kerja sama antar institusi dan profesi terkait penting, untuk
menanggulangi DM beserta komplikasi kroniknya

Personal Healthcare Service Flow

*Diambil dari alur pelayanan kesehatan PT. Askes

Health Care Services

Flow
Members

Capitation

Primary Care
Provider
Emergency

Claim Ina
CBG

Referral

BPJS Center

Drug Prescription

Hospital

Apotek

BPJS
Branch Office

Primary Care Provider as a Gate Keeper

Hatur Nuhuu