1. dia

1
A hagyományos kardiovaszkuláris rizikófaktorok és
a diabetes microvascularis szövodményeinek összefü
ggése
Prof. Dr. Kempler Péter
egyetemi tanár
Semmelweis Egyetem I. sz. Belgyógyászati Klinika,
Budapest
2
The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. The JNC7
Report. JAMA 2003 289 2560-2572.

• Hypertension
• Cigarette smoking
• Obesity (BMI 30)
• Physical inactivity
• Dyslipidaemia
• Diabetes mellitus
• Microalbuminuria or estimated GFR lt 60 ml/min
• Age (gt 55 years for men, gt 65 years for women)
• Family history of premature cardiovascular
  disease
• (men lt 55 years, women lt 65 years)

3
Risk of CHD Death According to SBP and DBP in
MRFIT
4
Systolic blood pressure (SBP) Diastolic blood
pressure (DBP)
3
Relative risk of CHD mortality
2
1
0
Decile
(lowest 10)
(highest 10)
lt112lt71
112-71-
118-76-
121-79-
125-81-
129-84-
132-86-
137-89-
142-92-
gt151gt98
SBP (mmHg)
DBP (mmHg)
CHDcoronary heart disease
He J, et at. Am Heart J. 1999138211-219.
4
Cholesterol and triglyceride as risk factors
of coronary heart disease
Triglyceride mmol \ lit.
CHD cases ( per 1000 )
Cholesterol mmol \ lit.
PROCAM ( 6 years )
5
(No Transcript)
6
Atherosclerosis risk factors and the CVD
mortality among men with and without
diabetes (Diabetes Care, 1993, 16, 434-444)
CVD death/men/year
DM- DM
0 1
2 3
7
Howard BV. et al. Coronary Heart Disease Risk
Equivalence in Diabetes Depends on Concomitant
Risk Factors. Diabetes Care 29 391-397, 2006.
The 10-year cumulative incidence of CHD by
numbers of risk factors (men and women combined).
8
Kockázatbecslo táblázat
Fatális szív- és érrendszeri események
elofordulási gyakorisága 10 éven belül
Nem dohányzó
Dohányzó
Férfi
4
5
8
7
6
65 éves
60 éves
55 éves
Szisztolés vérnyomás (Hgmm)
50 éves
40 éves
9
Type 2 diabetes is NOT a mild disease
Stroke
Diabeticretinopathy
1.2- to 1.8-fold increase in stroke3
Leading cause of blindness in working-age adults1
Cardiovasculardisease
75 diabetic patients die from CV events4
Diabetic nephropathy
Diabeticneuropathy
Leading cause of end-stage renal disease2
Leading cause of non-traumatic lower extremity
amputations5
1Fong DS, et al. Diabetes Care 2003 26 (Suppl.
1)S99S102. 2Molitch ME, et al. Diabetes Care
2003 26 (Suppl. 1)S94S98. 3Kannel WB, et al.
Am Heart J 1990 120672676. 4Gray RP Yudkin
JS. In Textbook of Diabetes 1997. 5Mayfield JA,
et al. Diabetes Care 2003 26 (Suppl. 1)S78S79.
10
Type 2 diabetes the microvascular burden is
already present at diagnosis
1. UKPDS Group. Diabetes Res 1990 13 111.2.
The Hypertension in Diabetes Study Group. J
Hypertens 1993 11 309317.
11
Jarrett RJ. et al. Microalbuminuria predicts
mortality in non-insulin-dependent
diabetes. Diabetic Med 1 17-19, 1984. Mogensen
CE. Microalbuminuria predicts clinical
proteinuria and early mortality in maturity-onset
diabetes. N Engl J Med 310 356-360, 1984.
12
Mykkänen L. et al. Microalbuminuria precedes the
development of NIDDM. Diabetes 1994 43 552-557.
13
Yudkin JS, Forest RO, Jackson CA. Microalbuminuria
as a predictor of vascular disease in
non-diabetic subjects.
Lancet 1988 II530-533.
14
Astrup, AS. et al. Cardiac Autonomic Neuropathy
Predicts Cardiovascular Morbidity and Mortality
in Type 1 Diabetic Patients With Diabetic
Nephropathy Diabetes Care 2006 29 334-9.
Cardiovascular morbidity and mortality
Nephropathy
Normoalbuminuria
Normal HRV borderline normal HRV
abnormal HRV
15
EURODIAB IDDM Complications Study Risk Factors
for Progression to Microalbuminuria (Univariate
Analysis)

• HbA1c, AER
• Fasting Triglyceride, HDL-C, LDL-C
• BMI, WHR
• Presence of Retinopathy/Neuropathy
• NOT Systolic BP, Diastolic BP, Smoking

Chaturvedi et al, Kidney International 200160
219 - 227
16
EURODIAB IDDM Complications Study Risk Factors
for Progression to Microalbuminuria Adjusted
for Duration, HbA1c and AER

Progressors
Non-progressors P Mean Fasting
Triglyceride (mmol/L) 0.99 0.88 0.01 HDL-C
(mmol/L) 1.44 1.53 0.02 LDL-C
(mmol/L) 3.5 3.2 0.02 BMI (Kg/m2) 24.0 23.4
0.01 WHR 0.85 0.83 0.009 Relative Risk of
Progression - Any Retinopathy 1.8 1.0
0.02
Chaturvedi et al, Kidney International 200160
219 - 227
17
EURODIAB IDDM Complications Study Standardised
Estimates of Relative Risk (SERR) for Incidence
of Complications

NEPHROPATHY AGE/DUR
ATION - HbA1c 1.57 (1.26 - 1.97) AER 1.45
(1.13 - 1.87) TRIGLYCERIDE 1.31 (1.05
- 1.65) WHR 1.27 (1.02 - 1.58) BMI -

NEUROPATHY 1.39 (1.13 - 1.61) 1.20 (1.00 -
1.44) - 1.33 (1.11 - 1.60)
- 1.39 (1.16 - 1.65)
RETINOPATHY 1.32 (1.07 - 1.61) 1.93 (1.52 -
2.44) - 1.42 (1.01 - 1.54) 1.32 (1.07
- 1.63) -

Insulin Resistance?
18

• Giorgino et al. Factors associated with
  progression to macroalbuminuria in
  microalbuminuric Type 1 diabetic patients The
  EURODIAB Prospective Complications Study.
  Diabetologia 2004 47 1020-1028.
• Factors associated with progression to
  macroalbuminuria
• higher AER values
• sub-optimal metabolic control
• excess body fat
• peripheral neuropathy

19

• Hadjadj et al. Different patterns of insulin
  resistance in relatives of Type 1 diabetic
  patients with retinopathy and nephropathy.
  Diabetes Care 2004 27 2661-2668.
• Familial insulin resistance segregates with
  diabetic complications
• Lipid disorders and obesity segregate with
  diabetic nephropathy
• Arterial hypertension and obesity segregate with
  diabetic retinopathy

20
Type 2 diabetes the microvascular burden is
already present at diagnosis
1. UKPDS Group. Diabetes Res 1990 13 111.2.
The Hypertension in Diabetes Study Group. J
Hypertens 1993 11 309317.
21
Retinopathia diabetica

• A fejlett ipari országokban a munkaképes korúak
  körében a vakság leggyakoribb oka cukorbetegekben
• Vakság 25x gyakrabban alakul ki, mint nem
  diabetesesekben
• A diabetes gondozás leghatékonyabb része a
  retinopathia szurése
• Diabetesesekben a cataracta 1,6x
• a glaucoma 1,4x gyakoribb, mint
  cukorbetegségben nem szenvedokben

22
Chaturvedi N et al. Markers of insulin resistance
are strong risk factors for retinopathy incidence
in Type 1 diabetes. The EURODIAB Prospective
Complications Study.Diabetes Care 2001 24284-289

Retinopathy incidence during 7,3 year follow-up
was 56 Key risk factors - diabetes duration
- glycemic control no evidence of a
threshold effect for HbA1c
23
Chaturvedi N et al. Markers of insulin resistance
are strong risk factors for retinopathy incidence
in Type 1 diabetes. The EURODIAB Prospective
Complications Study. Diabetes Care 2001
24284-289
Risk factors for the incidence of retinopathy
univariate analysis

Duration of diabetes p 0,0002 HbA1c p
0,0001 AER (µg/min) p 0,001 Cholesterol p
0,008 Fasting triglyceride p 0,0001
24
Chaturvedi N et al. Markers of insulin resistance
are strong risk factors for retinopathy incidence
in Type 1 diabetes. The EURODIAB Prospective
Complications Study. Diabetes Care 2001
24284-289
Risk factors for the incidence of retinopathy
univariate analysis
Fibrinogen p 0,05 von Willebrand factor p
0,04 ?GT p 0,02 Waist hip ratio p
0,0001 Insulin dose/weight p 0,003
25
Chaturvedi N et al. Markers of insulin resistance
are strong risk factors for retinopathy incidence
in Type 1 diabetes. The EURODIAB Prospective
Complications Study. Diabetes Care 2001
24284-289

• No associations were observed for cardiovascular
  disease, smoking, or blood pressure
• mean blood pressures were relatively low at
  baseline in the study
• blood presssure was one of the few key risk
  factors measured locally

26
Chaturvedi N et al. Markers of insulin resistance
are strong risk factors for retinopathy incidence
in Type 1 diabetes. The EURODIAB Prospective
Complications Study. Diabetes Care 2001
24284-289
Standardized regression estimates
Risk factor SRE (95 CI) P Duration 1,32
(1,07-1,61) 0,008 HbA1c 1,93
(1,52-2,44) 0,0001 Fasting triglyceride 1,24
(1,01-1,54) 0,04 Waist-to-hip ratio 1,32
(1,07-1,63) 0,01 Analysis performed on
log-transformed variables
27
Az autonom neuropathia prognózisa diabetes
mellitusban
Követési ido 5,8 év (metaanalízis)
Autonom neuropathia


Ziegler D. Diabetes Metab Rev 1994 10 339-383.
28
Silent myocardialis infarctus

• Balkamra-elégtelenség, tüdooedema
• Ketoacidozis
• Hányás
• Collapsus

hátterében cukorbetegekben mindig gondolni kell
infarctus lehetoségére is.
29
A cardialis autonom neuropathia (CAN) és a néma
(silent) myocardialis infarctus közötti
összefüggés
1,96 (1,53-2,51) összesített adatok, n1468
plt0,001 DIAD n1123 CAN az ISzB eros
elorejelzoje
0 1 10
100 1000
Vinik et al., Diabetes Care 26 1553-79,
2003 Wackers et al Diabetes Care 27 1954-1961,
2005
Logaritmikus prevalencia arány
30
Hónapok óta fennálló tünetmentes talpi fekély
Zick R., Brockhaus KE. Diabetes
mellitus.Fußfibel, Kirchheim, Mainz 2000.
31
Etiology of foot ulcers
Purely ischaemic
Neuropathic or neuroischaemic
Boulton AJM. Lowering the risk of neuropathy,
foot ulcers and amputation. Diabetic Med 1998 15
(Suppl 4) 57-59.
32
Sensoros neuropathia
hypaesthesia
trauma, microtrauma
microangio-pathia
Trophicus ulcus
gyakoribb infekciókrosszabb sebgyógyulás
Gangraena
33
Esetismertetés

• 32 éves diabeteses férfi
• Diabetes tartam 20 év
• HbA1C 6,7
• Súlyos sensoros neuropathia, orvosa tanácsa
  ellenére 20km-t futott

Zick R., Brockhaus KE. Diabetes mellitus.
Fußfibel, Kirchheim, Mainz 2000.
34
Lábsérülések 20km futást követoen súlyos sensoros
neuropathia fennállása esetén
Zick R., Brockhaus KE. Diabetes mellitus.
Fußfibel, Kirchheim, Mainz 2000.
35
(No Transcript)
36
A diabeteses láb klinikai stádiumai
Meggitt BF. Diabetes. In Helal B et al. (eds).
The Foot. 1988. pp 710-738
37
Alsó végtagi amputációk aránya cukor-betegekben a
nem-diabetesesekhez viszonyítva
30,0 x (Most és mtsai. Diabetes Care 19836
87-91) 37,5 x (Dánia,1988) 11,7 x (ADA,
1992) 17,0 x (Humphrey és mtsai. Arch Intern Med
1994154 885-892) 45,0 x (Standl és mtsai.
Diab Stoffw 19965 29-32)
38
(No Transcript)
39
Lábamputációk cukorbetegekben - 2005

• Cukorbetegek kórházi felvételére a fejlett
  országokban a leggyakrabban lábszövodmények miatt
  kerül sor
• A legtöbb amputációt talpi fekély elozi meg
• Napjainkban a diabetesesekben történt alsó
  végtagi amputációk 85-át tartják megelozhetonek.

IDF, 2005
40
(No Transcript)
41
Nem traumás eredetu alsó végtagi amputációk felét
cukorbetegekben végzik
Magyarországon évente 3-4000 cukorbeteg lábát
amputálják. Neuropathiás eredetu amputációnak nem
szabadna elofordulnia.
42
Charcot - osteoarthropathia
Zick R., Brockhaus KE. Diabetes mellitus.
Fußfibel, Kirchheim, Mainz 2000.
43
Type 2 diabetes the microvascular burden is
already present at diagnosis
1. UKPDS Group. Diabetes Res 1990 13 111.2.
The Hypertension in Diabetes Study Group. J
Hypertens 1993 11 309317.
44
Tesfaye et al. Prevalence of diabetic peripheral
neuropathy and its relation to glycaemic control
and potential risk factors the EURODIAB IDDM
Complications Study. Diabetologia 19961377-1384

• Significant correlations were observed between
  the presence of diabetic peripheral neuropathy
  with
• age
• duration of diabetes (plt0,05)
• quality of metabolic control (plt0,001)
• confirming previous associations.

45
Tesfaye et al. Prevalence of diabetic peripheral
neuropahy and its relation to glycaemic control
and potential risk factors the EURODIAB IDDM
Complications Study. Diabetologia 19961377-1384

• Significant correlations were observed between
  the presence of diabetic peripheral neuropathy
  with
• height (plt0,01)
• the presence of backround of proliferative
  retinopathy (plt0,01)
• cigarette smoking (plt0,001)
• HDL-cholesterol (plt0,001)
• presence of cardiovascular disease (plt0,05)
• confirming previous associations.

46
Tesfaye et al. Prevalence of diabetic peripheral
neuropahy and its relation to glycaemic control
and potential risk factors the EURODIAB IDDM
Complications Study. Diabetologia 19961377-1384

• Significant correlations were observed between
  the presence of diabetic peripheral neuropathy
  with
• diastolic blood pressure (plt0,05)
• presence of severe ketoacidosis (plt0,01)
• fasting triglyceride (plt0,001)
• presence of microalbuminuria (plt0,01)
• identifying new associations.

47
Kempler P, Tesfaye S, Chaturvedi N. et al.
Autonomic neuropathy is associated with increased
cardiovascular risk factors the EURODIAB IDDM
Complications Study. Diabetic Med 2002 19
900-09.
adjusted for age, duration and HbA1C testing difference from non-smoking Crude Adjusted
adjusted for age, duration and HbA1C testing difference from non-smoking relative risk of abnormal R-R ratio(p-value, testing for trend) relative risk of abnormal R-R ratio(p-value, testing for trend)
Smoking - ex - current p lt 0,01 p lt 0,0001 p lt 0,05 p lt 0,0001
Blood pressure - systolic - diastolic p lt 0,05 p lt 0,05 N.S. N.S.
Total cholesterol p lt 0,001 N.S.
HDL-cholesterol p lt 0,01 p lt 0,01
LDL-cholesterol p lt 0,001 N.S.
Total cholesterol/HDL cholesterol ratio p lt 0,001 p lt 0,001
Fasting triglyceride p lt 0,0001 p lt 0,0001
48
Kempler P, Tesfaye S, Chaturvedi N. et al.
Autonomic neuropathy is associated with increased
cardiovascular risk factors the EURODIAB IDDM
Complications Study. Diabetic Med 2002 19
900-09.
adjusted for age, duration and HbA1C Adjustedrelative risk of abnormal R-R ratio(p-value, testing for trend)
Peripheral neuropathy p lt 0,0001
Albumin excretion p lt 0,0001
Retinopathy p lt 0,0001
Severe hypoglycaemia p 0,03
Severe ketoacidosis p lt 0,0001
Cardiovascular disease p lt 0,0001
49
Stella et al. Cardiac autonomic neuropathy
(expiration and inspiration ratio) in type 1
diabetes. Incidence and predictors. J Diab Compl
2000141-6

• Significant independent predictors of CAN
• age (RR 2.15, p0,0001)
• HbA1c (RR 1.50, p0,0002)
• nephropathy (albumin excretiongt200ug/min) (RR
  2.46, p0,0001)
• Hypertension was predictive if nephropathy was
  not included in the model.

50
Risk factors for incidence of neuropathy
Development of Neuropathy at FU
Tesfaye et al. Vascular risk factors and diabetic
neuropathy. N Engl J Med 2005 352 341-350.
51
Risk factors for incidence of neuropathy
Development of Neuropathy at FU
Tesfaye et al. Vascular risk factors and diabetic
neuropathy. N Engl J Med 2005 352 341-350.
52
Risk factors for incidence of neuropathy
Development of Neuropathy at FU
Tesfaye et al. Vascular risk factors and diabetic
neuropathy. N Engl J Med 2005 352 341-350.
53
Risk factors for for incidence of neuropathy
after adjusting for age and HbA1c
Development of Neuropathy at FU
54
Conclusions

• The incidence of neuropathy over approximately a
  7 year period was 25
• Independent risk factors for incidence were age,
  HbA1c, cholesterol, fasting triglyceride,
  presence of CVD at baseline and presence of
  retinopathy at baseline
• Existence of previous CVD independently increased
  the risk of neuropathy threefold
• Vascular factors

macrovascular diseasemicrovascular complications
Tesfaye et al. Vascular risk factors and diabetic
neuropathy. N Engl J Med 2005 352 341-350.
55
Risk Factors for Neuropathy after Adjustment for
HBA1c and Duration of Diabetes
Eurodiab 276/1172 patients developed neuropathy
in 7.3y
Variable Odds Ratio P value
CVD 2.74 lt0.0001
Albuminuria 1.48 0.02
Hypertension 1.92 lt0.001
Smoking 1.55 lt0.001
BMI 1.40 lt0.001
Triglycerides 1.35 lt0.001
Total Cholesterol 1.26 0.001
LDL-C 1.22 0.001
Tesfaye et al NEJM 352 341-350,2005
56
A diabeteses neuropathia oki kezelése

• Optimális anyagcserehelyzet biztosítása
• Rizikófaktorok befolyásolása
• Benfotiamin
• Alpha-liponsav

57
A multifaktoriális intervenció hatékonysága
Steno-2
Makrovaszkuláris szövodmények
Mikrovaszkuláris szövodmények
RR 0,47 (95 CI 0,22-0,74, P0,01)
n 160, DM2T, Gaede P et al. N Engl J Med
348383-393, 2003
58
Take home message A hagyományos
cardiovascularis rizikófaktorok szerepe nemcsak a
macrovascularis, hanem a microvascularis
szövodmények kialakulása szempontjából is
meghatározó fontosságú.
59
A tudomány csalhatatlan, de a tudósok mindig
tévednek
Anatole France
60
The epidemiologist can confuse the
non-epidemiologist

• Japanese eat very little fat and suffer far less
  from heart attack than British or American
• French eat a lot of fat and suffer far less from
  heart attack than British or American
• Japanese drink very little red vine and suffer
  far less from heart attack than British or
  American
• French and Italian drink lot of red vine and
  suffer far less from heart attack than British or
  American

A. Adler, EDEG, Oxford, 2002.
61
The epidemiologist can confuse the
non-epidemiologist
Conclusion You can eat as you want English
speaking will kill you
A. Adler, EDEG, Oxford, 2002.
62
(No Transcript)