PERJALANAN KOMPLIKASI DIABETES MELITUS

LUTHFAN BUDI PURNOMO

PERKENI CABANG YOGYAKARTA
SMF PENYAKIT DALAM RSUP DR SARDJITO
Kejadian Diabetes di dunia
2000 2030
Ranking Negara Jumlah diabetes Negara Jumlah diabetes
(juta)) (juta)

1 India 31.7 India 79.4

2 China 20.8 China 42.3
3 US 17.7 US 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russia 4.6 Bangladesh 11.1
8 Brazil 4.6 Japan 8.9
9 Italy 4.3 Philippines 7.8
10 Bangladesh 3.2 Egypt 6.7

Wild S et al. Diabetes Care 2004;27:1047-53

 Complication at the Time of
Diagnosis

9% neuropathy
20% retinopathy
Diagnosed DM = 1,5% 8% nephropathy
50% heart & blood
Undiagnosed DM = 4,2% vessel
Total DM = 5,7%
IGT = 10,2 %
 DIABETES IS NOT MILD DISEASE
Microvascular complication Macrovascular complication
Stroke
Diabetic 2 to 4 fold increase in
cardiovascular
Retinopathy mortality and stroke3
Leading cause
of blindness
in working age Cardiovascular
adults1
Disease
8/10 diabetic patients
die from CV events4

Diabetic
Nephropathy Diabetic
Leading cause of
Neuropathy
end-stage renal disease2 Leading cause of non-
traumatic lower
extremity amputations5

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

Impaired glucose tolerance Frank diabetes

Insulin resistance
Hepatic glucose
production

Endogenous insulin
Postprandial blood glucose
Asymptomatic stage Fasting blood glucose

Microvascular complications

Macrovascular complications
Years to
Time decades Typical diagnosis of diabetes

Ramlo-Halsted BA and Edelman SV. Primary Care. 1999;26:771-789.

DIABETIC NEPHROPATHY
Chronic Kidney Disease/CKD
Definition of diabetic nephropathy

 Diabetic nephropathy (DN) is defined by either

macroalbuminria (a urinary albumin excretion of
greater than 300 mg/day or urinary albumin:
creatinine ratio/ACR >30 mg/mmol) or by
abnormal renal function and with existing
diabetic retinopathy
 Microalbuminuria (earliest sign of DN or
incipient DN) is defined by a urinary albumin
excretion of 30-300 mg/day or ACR >2.5
mg/mmol in men and >3.5 in women

(DeFronzo, 2005; Augustine and Vidt, 2003)

Natural course of diabetic nephropathy

-3 0 3 Time (years) 15 20 25

120 150 150 GFR (mL/mnt) 120 60 <10

1.0 0.8 0.8 Serum creatinine (mg/dL) 1.0 >2.0 >10
15 10 10 Serum urea nitrogen (mg/dL) 15 >30 >100

Microalbuminuria

-3 0 3 10 15 20 25
Prior to Onset of Onset of Onset Onset ESRD
onset of diabetes diabetic of of
diabetes glomerulosclerosis proteiuria azotemia

(DeFronzo, 2005)
Flowchart for diagnosis of diabetic nephropathy

Annual dipstick
Urinalysis for protein
Positive Negative

Previously positive Test for microalbuminria

on ≥2 occasions over Positive
previous 12 months
YES NO
YES NO
ACR >2,5 mg/mmol
or >3,5 mg/mmol
Retinopathy + Retest over next
12 months
YES NO
YES
Positive
Confirm with
2 samples if
2/3 positive
Retest over next
Clinical nephropathy YES NO 6 months
Microalbuminuria

Jones et. al., 2006

Features that suggest non-diabetic kidney
disease

 Rapid deterioration in renal function

 Sudden development of nephrotic
syndrome
 Heavy hematuria/red cell casts
 Absence of diabetic retinopathy
 Short duration of type 1 diabetes
 Clinical or laboratory evidence of non-
diabetic systemic disease
 Blood pressure higher than expected for
degree of proteinuria Jones et. al., 2004
Risk factors of diabetic nephropathy

 Blood glucose level

 Blood pressure
 Male sex
 Duration of diabetes
 Total cholesterol level
DIABETIC FOOT
Neuropathic ulcer
 TERJADINYA AMPUTASI PADA KAKI DIABETIK

DIABETES MELLITUS

Penyakit pembuluh Neuropati otonom Neuropati perifer

darah tepi
Aliran Indera Gerak
 Keringat darah raba
Sumbatan Aliran
oksigen, nutrisi,
Resorpsi
antibiotik Kehilangan
tulang Atropi
Kult kering, rasa sakit
pecah Kerusakan
sendi Kehilangan
Luka sulit
sembuh Trauma bantalan
Kerusakan lemak
kaki
Tumpuan berat
yang baru
Sindrom jari biru INFEKSI ULKUS
Gangren
Gangren mayor
AMPUTASI
TANDA-TANDA NEUROPATI PERIFER

 Perubahan indera raba

 Berkurangnya indera raba
 Hilangnya rasa sentuhan dan posisi
 Tidak berkeringat
 “Kapalen”
 Ulkus tropik disertai infeksi
 Perubahan bentuk kaki
 Kaki teraba panas
TANDA-TANDA PENYAKIT PEMBULUH
DARAH PERIFER

 Nyeri berulang
 Kaki dingin
 Nyeri malam hari
 Nyeri saat istirahat
 Denyut nadi hilang
 Rambut kaki dan jari tidak tumbuh
 Kuku menebal
 Gangren
FAKTOR RISIKO ULKUS DAN AMPUTASI

 Jenis kelamin laki-laki

 Lamanya sakit diabetes
 Retinopati/nefropati
 Kadar gula darah tinggi
 Kehilangan indera raba pada tungkai
 Sebelumnya pernah ulkus atau amputasi
 Perubahan bentuk kaki
DIABETIC EYE DISEASE
Examination of the eyes in diabetic patients

When to examine:
 On diagnosis
 Annually after 5 years of diabetes or if aged >30 years at
diagnosis, or if background retinopathy alone is present
 Three- to 6-monthly if retinopathy is more severe than
background
 Immediately if any change in vision or visual symptoms occur
Examination should include:
 Visual acuity
 Afferent pupillary defect
 Ophthalmoscopy through dilated pupils unless
contraindicated
DIABETIC NEUROPATHY
A classification of diabetic neuropathy
Rapidly reversible phenomena
 Distal sensory symptoms
 Reduced nerve conduction velocity
 Resistance to ischaemic conduction failure
Established neuropathy
Focal and multifocal neuropathies
 cranial mononeuropathies
 Thoracoabdominal neuropathy
 Focal limb neuropathies
 Asymmetric proximal lower limb motor neuropathy
Symmetrical neuropathies
 Sensory/autonomic polyneuropathy
 Proximal lower limb motor neuropathy
 Cardiovascular autonomic function tests

Blood pressure test

 Blood pressure response to standing up (fall in systolic blood
pressure): 10 mmHg (normal), 11-29 mmHg (borderline), ≥30
mmHg (abnormal)
 Blood pressure response to sustained handgrip (increase in
diastolic blood pressure): ≥16 mmHg (normal), 11-15 mmHg
(borderline), 10 mmHg (abnormal)
Macro-vascular Complications

 Ischemic heart disease

 Cerebrovascular disease
 Peripheral vascular disease

Diabetic patients have a 2 to 6 times higher risk for

development of these complications than the
general population
Macro-vascular Complications

The major cardiovascular risk factors in the

non-diabetic population (smoking,
hypertension and hyperlipidemia) also
operate in diabetes, but the risks are
enhanced in the presence of diabetes.
Overall life expectancy in diabetic patients is 7
to 10 years shorter than non-diabetic people.
 Macro-vascular Disease

Once clinical macro-vascular disease develops in

diabetic patients they have a poorer prognosis
for survival than normoglycemic patients with
macrovascular disease
The protective effect females have for the
development of vascular disease are lost in
diabetic females
 DM-, MI-
1,0
DM+, MI-

0,8 DM-, MI+

Cumulative Survival

0,6
DM +; MI +

0,4

0,2

0,0
0 5 10 15 20
Year
Figure 2. Incidence per 1,000 person-year and Cox model hazard ratio for CHD death (adjusted for age,
area of residence, and sex) during the 18-year follow-up according to the presence of diabetes
and prior evidence of MI in 1,373 nondiabetic and 1,059 diabetic subjects. Adapted from ref. 8.
Diabetes Care, volume 33, number 2, February 2010
 The Progression from CV Risk Factors to
Endothelial Injury and Clinical Events
LDL-C BP Risk factors Diabetes Smoking Heart failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

Endothelium Growth factors Proteolysis

PAI-1 VCAM
matrix
ICAM cytokines

Thrombosis Inflammation Vasoconstriction Vascular lesion and Plaque rupture

remodelling

Clinical endpoints

NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431–1438.
PATHOGENESIS OF DIABETIC ATHEROSCLEROSIS

D1abetes/Insulin Resistance

Hypertension Impaired Obesity

Insulin
Hyperglycemia Action Dyslipidemia

Endothelial dysfunction SMC hyperplasia/

Vascular inflammation hypertrophy
Fibrosis Intimal lipid
accumulation
Hypercoagulation

Atherosclerosis/Thrombosis
(Feenera & Dzau, 2005)
 Myocardial Infarction

Non-diabetes Diabetes
Without prior MI 3.5% 20.2%

With prior MI 18.8% 45%

(Haffner et al., 1998)

Diabetes increases the risk of death by 57% from

unstable angina pectoris and non-Q wave MI
Increase 28-day mortality:
male by 58% (hazard ratio 1.58)
female by 160% (hazard ratio 2.60)

(Beckman et al., 2002)

 Coronary Heart Disease (CHD) Risk in Patients with
Type 2 Diabetes
50
No diabetes (n=1373) 45
Type 2 diabetes (n=1059)
40

30
7-year
MI event Diabetes is regarded as a
rate† 20 CHD20 risk equivalent
19

10
4

0
No prior MI Prior MI

CHD=coronary heart disease; MI=myocardial infarction

†Events/100 person-years

Haffner SM et al. N Engl J Med 1998; 339: 229–234

Prevention of chronic diabetic complications

 Tight control of diabetes

 Control of risk factors
- blood pressure
- dyslipidemia
- overweight
- cessation of smoking
 Specific intervention according the chronic
complication: diabetic foot, diabetic
nephropathy, etc.
 Intensive Therapy for Diabetes:
Reduction in Incidence of Complications
Type 1 Type 2 Type 2
DCCT1 Kumamoto2 UKPDS3
A1c 9  7% 9  7% 8  7%

Retinopathy 63% 69% 17-21%

Nephropathy 54% 70% 24-33%
Neuropathy 60% - -
Cardiovascular 41%* - 16%*4
disease
*Not statistically significant due to small number of events.
 Showed statistical significance in subsequent epidemiological analysis

1. DCCT Research Group. N Engl J Med. 1993;329:977-986. 2. Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.
3. UKPDS 33: Lancet 1998; 352, 837-853. 4. Stratton IM et al. BMJ. 2000;321:405-412.
 Target of Treatment

Risk CVD (-) Risk CVD (+)

BMI (kg/m2) 18.5 – <23 18.5 – <23
Blood Glucose
• FPG (mg/dL) <100 <100
• Post Prandial BG (mg/dL) <140 <140
A1C (%) <7.0 <7.0
Blood Pressure <130/80 <130/80
Lipid
Total Cholesterol (mg/dL) <200 <200
Triglyceride (mg/dL) <150 <150
HDL Cholesterol (mg/dL) >40 / >50 >40 / >50
LDL Cholesterol (mg/dL) <100 <70

PERKENI GUIDELINES 2011