Transcript 1. dia - NEPHROLOGIA

A hagyományos kardiovaszkuláris
rizikófaktorok és a diabetes
microvascularis szövődményeinek
összefüggése
Prof. Dr. Kempler Péter
egyetemi tanár
Semmelweis Egyetem I. sz. Belgyógyászati Klinika, Budapest
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 < 60 ml/min

Age (> 55 years for men, > 65 years for women)

Family history of premature cardiovascular disease
(men < 55 years, women < 65 years)
Risk of CHD Death
According to SBP and DBP in MRFIT
4
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
Relative risk of
CHD mortality
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
1
2
(lowest 10%)
<112
112<71
71-
3
11876-
4
12179-
5
12581-
6
12984-
7
13286-
8
13789-
9
10
(highest 10%)
142>151
92>98
CHD=coronary heart disease
He J, et at. Am Heart J. 1999;138:211-219.
Cholesterol and triglyceride as risk factors of
coronary heart disease
250
200
Triglyceride
mmol \ lit.
150
< 2,0
2,0 <
100
50
0
3,4
PROCAM ( 6 years )
3,4-4,1
4,1-4,9
4,9<
Cholesterol
mmol \ lit.
Atherosclerosis risk factors and the CVD
mortality
among men with and without diabetes
(Diabetes Care, 1993, 16, 434-444)
CVD death/men/year
140
120
100
DMDM
+
80
60
40
20
0
0
1
2
3
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).
Kockázatbecslő táblázat
Fatális szív- és érrendszeri események előfordulási gyakorisága 10 éven belül
Nem dohányzó
4
>15%
5
6
7
8
Férfi
Dohányzó
4
5
6
7
8
10-14%
180
5-9%
160
3-4%
140
2%
<1%
120
Szisztolés vérnyomás (Hgmm)
1%
180
160
140
120
180
160
140
120
180
160
140
120
180
160
140
120
65
éves
60
éves
55
éves
50
éves
40
éves
180
160
140
120
180
160
140
120
180
160
140
120
180
160
140
120
180
160
140
120
Type 2 diabetes is NOT a mild disease
Stroke
Diabetic
retinopathy
1.2- to 1.8-fold increase
in stroke3
Leading cause
of blindness
in working-age
adults1
Cardiovascular
disease
75% diabetic patients
die from CV events4
Diabetic
nephropathy
Leading cause of
end-stage renal disease2
1Fong
Diabetic
neuropathy
Leading cause of nontraumatic lower extremity
amputations5
DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98.
3Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
Type 2 diabetes – the microvascular burden is
already present at diagnosis
Retinopathy1
21%
Nephropathy2
18%
Erectile dysfunction1
20%
Neuropathy1
12%
1. UKPDS Group. Diabetes Res 1990; 13: 1–11.
2. The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317.
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.
Mykkänen L. et al. Microalbuminuria
precedes the development of NIDDM.
Diabetes 1994; 43: 552-557.
Yudkin JS, Forest RO, Jackson CA.
Microalbuminuria as a predictor of
vascular disease in non-diabetic
subjects.
Lancet 1988; II:530-533.
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
Normal HRV
Normoalbuminuria
borderline normal HRV
abnormal HRV
EURODIAB IDDM Complications Study
Risk Factors for Progression to
Microalbuminuria (Univariate Analysis)
• HbA , AER
• Fasting Triglyceride, HDL-C, LDL-C
• BMI, WHR
• Presence of Retinopathy/Neuropathy
• NOT Systolic BP, Diastolic BP, Smoking
1c
Chaturvedi et al, Kidney International 2001;60: 219 - 227
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
1.8
1.0
0.02
Relative Risk of Progression
- Any Retinopathy
Chaturvedi et al, Kidney International 2001;60: 219 - 227
EURODIAB IDDM Complications Study
Standardised Estimates of Relative Risk (SERR)
for Incidence of Complications
NEPHROPATHY
RETINOPATHY
NEUROPATHY
-
1.32 (1.07 - 1.61)*
1.39 (1.13 - 1.61)
HbA1c
1.57 (1.26 - 1.97)
1.93 (1.52 - 2.44)
1.20 (1.00 - 1.44)
AER
1.45 (1.13 - 1.87)
TRIGLYCERIDE
1.31 (1.05 - 1.65)
1.42 (1.01 - 1.54)
1.33 (1.11 - 1.60)
WHR
1.27 (1.02 - 1.58)
1.32 (1.07 - 1.63)
-
BMI
-
-
1.39 (1.16 - 1.65)
AGE/DURATION*
-
Insulin Resistance?
-
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
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
Type 2 diabetes – the microvascular
burden is already present at diagnosis
Retinopathy1
21%
Nephropathy2
18%
Erectile dysfunction1
20%
Neuropathy1
12%
1. UKPDS Group. Diabetes Res 1990; 13: 1–11.
2. The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317.
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 szűrése
• Diabetesesekben a cataracta 1,6x
a glaucoma 1,4x gyakoribb, mint
cukorbetegségben nem szenvedőkben
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; 24:284-289
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
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; 24:284-289
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
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; 24:284-289
Risk factors for the incidence of retinopathy – univariate
analysis:
Fibrinogen
p = 0,05
von Willebrand factor
p = 0,04
γGT
p = 0,02
Waist – hip ratio
p = 0,0001
Insulin dose/weight
p = 0,003
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; 24:284-289
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
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; 24:284-289
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
0,01
1,32 (1,07-1,63)
* Analysis performed on log-transformed variables
Az autonom neuropathia
prognózisa diabetes mellitusban
Halálozás (%)
Követési idő: 5,8 év
100 (metaanalízis)
80
Autonom neuropathia
–
+
60
40
20
29%
6%
0
Ziegler D. Diabetes Metab Rev 1994; 10: 339-383.
Silent myocardialis infarctus
 Balkamra-elégtelenség, tüdőoedema
 Ketoacidozis
 Hányás
 Collapsus
hátterében cukorbetegekben mindig gondolni
kell infarctus lehetőségére is.
A cardialis autonom neuropathia (CAN) és a
néma („silent”) myocardialis infarctus közötti
összefüggés
1,96 (1,53-2,51) összesített adatok, n=1468 p<0,001
DIAD n=1123 CAN = az ISzB erős előrejelzője
0
1
10
100
Logaritmikus prevalencia arány
1000
Vinik et al., Diabetes Care 26: 1553-79, 2003
Wackers et al Diabetes Care 27; 1954-1961, 2005
Hónapok óta fennálló
tünetmentes talpi fekély
Zick R., Brockhaus KE. Diabetes mellitus.
Fußfibel, Kirchheim, Mainz 2000.
Etiology of foot ulcers
Neuropathic
or
neuroischae
mic
85%
15%
Purely
ischaemic
Boulton AJM. Lowering the risk of neuropathy, foot ulcers and
amputation. Diabetic Med 1998; 15 (Suppl 4): 57-59.
Sensoros neuropathia
hypaesthesia
trauma,
microtrauma
Trophicus ulcus
gyakoribb infekciók
rosszabb sebgyógyulás
Gangraena
microangiopathia
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.
Lábsérülések 20km futást követően súlyos
sensoros neuropathia fennállása esetén
Zick R., Brockhaus KE. Diabetes mellitus. Fußfibel, Kirchheim, Mainz 2000.
DIABET ES MELLIT US
HYPERLIPIDAEMIA
DOHÁNYZÁS
NEUROPAT HIA
AUTONOM
"AUTOSYM PATHECTOM IA"
SOMATICUS
orthopaediai
problémák
f ájdalomérzés és
proprioceptio
izületi
mozgások
T ALPI NYOMÁS
EMELKEDÉSE
kisizm ok
sorvadása
izzadás 
száraz bőr
f issurák
PERIFÉRIÁS
keringésszabályozás ÉRSZÜKÜLET
változása
tágult vénák:
meleg láb
ISCHAEMIA
CALLUS
FEKÉLY
Boulton AJM. Diabetic Med 1996; 13 (Suppl 1): 12-1
A diabeteses láb klinikai stádiumai
0
1
2
3
Hámsérülés
nem látható
Felületes
fekély
Mély
fekély
Abscessus,
osteomyelitis
4
5
Gangraena Gangraena
a láb elülső a láb hátsó
részén
részén
Meggitt BF. Diabetes. In: Helal B et al. (eds). The Foot. 1988. pp 710-738
Alsó végtagi amputációk aránya cukorbetegekben a nem-diabetesesekhez
viszonyítva
30,0 x
(Most és mtsai. Diabetes Care 1983;6: 87-91)
37,5 x
(Dánia,1988)
11,7 x
(ADA, 1992)
17,0 x
(Humphrey és mtsai. Arch Intern Med
1994;154: 885-892)
45,0 x
(Standl és mtsai. Diab Stoffw 1996;5: 29-32)
Lábamputációk cukorbetegekben - 2005
• Cukorbetegek kórházi felvételére a fejlett országokban
a leggyakrabban lábszövődmények miatt kerül sor
• A legtöbb amputációt talpi fekély előzi meg
• Napjainkban a diabetesesekben történt alsó végtagi
amputációk 85%-át tartják megelőzhetőnek.
IDF, 2005
Nem traumás eredetű alsó végtagi
amputációk felét cukorbetegekben végzik
Magyarországon évente 3-4000 cukorbeteg lábát
amputálják.
Neuropathiás eredetű amputációnak nem szabadna
előfordulnia.
Charcot osteoarthropathia
Zick R., Brockhaus KE. Diabetes mellitus. Fußfibel, Kirchheim, Mainz 2000.
Type 2 diabetes – the microvascular
burden is already present at diagnosis
Retinopathy1
21%
Nephropathy2
18%
Erectile dysfunction1
20%
Neuropathy1
12%
1. UKPDS Group. Diabetes Res 1990; 13: 1–11.
2. The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317.
Tesfaye et al. Prevalence of diabetic
peripheral neuropathy and its relation to
glycaemic control and potential risk factors:
the EURODIAB IDDM Complications
Study. Diabetologia 1996;1377-1384
Significant correlations were observed between
the presence of diabetic peripheral neuropathy
with
– age
– duration of diabetes (p<0,05)
– quality of metabolic control (p<0,001)
confirming previous associations.
Tesfaye et al. Prevalence of diabetic
peripheral neuropahy and its relation to
glycaemic control and potential risk factors:
the EURODIAB IDDM Complications
Study. Diabetologia 1996;1377-1384
Significant correlations were observed between the
presence of diabetic peripheral neuropathy with
– height (p<0,01)
– the presence of backround of proliferative retinopathy
(p<0,01)
– cigarette smoking (p<0,001)
– HDL-cholesterol (p<0,001)
– presence of cardiovascular disease (p<0,05)
confirming previous associations.
Tesfaye et al. Prevalence of diabetic
peripheral neuropahy and its relation to
glycaemic control and potential risk factors:
the EURODIAB IDDM Complications
Study. Diabetologia 1996;1377-1384
Significant correlations were observed between
the presence of diabetic peripheral neuropathy
with
–
–
–
–
diastolic blood pressure (p<0,05)
presence of severe ketoacidosis (p<0,01)
fasting triglyceride (p<0,001)
presence of microalbuminuria (p<0,01)
identifying new associations.
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*
relative risk of abnormal R-R ratio
(p-value, testing for trend)
Smoking
- ex
- current
p < 0,01**
p < 0,0001**
p < 0,05**
p < 0,0001**
Blood pressure
- systolic
- diastolic
p < 0,05
p < 0,05
N.S.
N.S.
Total cholesterol
HDL-cholesterol
LDL-cholesterol
Total cholesterol/HDL cholesterol ratio
p < 0,001
p < 0,01
p < 0,001
p < 0,001
N.S.
p < 0,01
N.S.
p < 0,001
Fasting triglyceride
p < 0,0001
p < 0,0001
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
Adjusted*relative risk of
abnormal R-R ratio
(p-value, testing for trend)
Peripheral neuropathy
Albumin excretion
p < 0,0001
p < 0,0001
Retinopathy
Severe hypoglycaemia
Severe ketoacidosis
Cardiovascular disease
p < 0,0001
p = 0,03
p < 0,0001
p < 0,0001
Stella et al. Cardiac autonomic neuropathy
(expiration and inspiration ratio) in type 1
diabetes. Incidence and predictors. J Diab
Compl 2000;14:1-6
Significant independent predictors of CAN:
• age (RR: 2.15, p=0,0001)
• HbA1c (RR: 1.50, p=0,0002)
• nephropathy (albumin excretion>200ug/min) (RR: 2.46,
p=0,0001)
Hypertension was predictive if nephropathy was not included
in the model.
Risk factors for incidence of
neuropathy
Development of Neuropathy at FU
No
Yes
p value
n=743
n=243
Age (years)
33
30
0.0001
Duration (years)
14
12
0.0001
HbA 1c (%)
6.2
6.8
0.0001
Systolic pressure (mmHg)
118
121
0.03
Diastolic pressure (mmHg)
74
75
0.5
Current Smokers (%)
27
30
0.35
Tesfaye et al. Vascular risk factors and diabetic neuropathy.
N Engl J Med 2005; 352: 341-350.
Risk factors for incidence of neuropathy
Development of Neuropathy at FU
No
Yes
p value
n=743
n=243
Height (cm)
169
168
0.28
Weight (kg)
66
69
0.004
BMI (kg/m2)
23.1
24.2
0.0001
Waist hip ratio
0.83
0.84
0.6
Tesfaye et al. Vascular risk factors and diabetic neuropathy.
N Engl J Med 2005; 352: 341-350.
Risk factors for incidence of neuropathy
Development of Neuropathy at FU
No
Yes
n=743
n=243
11.8
16.8
0.0004
Any retinopathy (%)
33
51
0.0001
Cardiovascular disease (%)
4
13
0.0002
AER (ug/min)
p value
Tesfaye et al. Vascular risk factors and diabetic neuropathy.
N Engl J Med 2005; 352: 341-350.
Risk factors for for incidence of neuropathy
after adjusting for age and HbA1c
Development of Neuropathy at FU
No
Yes
p value
Cholesterol (mmol/l)
5.12
5.29
0.03
Fasting triglyceride (mmol/L)
0.87
1.02
0.0001
BMI (kg/m2)
23.2
24.0
0.0001
AER (µg/min)
12.6
23.1
0.0001
CVD odds ratio
1.0
3.11
0.0001
Any retinopathy (OR)
1.0
1.80
0.0008
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
macrovascular disease
Vascular factors
microvascular complications
Tesfaye et al. Vascular risk factors and diabetic neuropathy.
N Engl J Med 2005; 352: 341-350.
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
Albuminuria
Hypertension
Smoking
BMI
Triglycerides
Total Cholesterol
LDL-C
2.74
1.48
1.92
1.55
1.40
1.35
1.26
1.22
<0.0001
0.02
<0.001
<0.001
<0.001
<0.001
0.001
0.001
Tesfaye et al NEJM 352: 341-350,2005
A diabeteses neuropathia oki kezelése

Optimális anyagcserehelyzet biztosítása

Rizikófaktorok befolyásolása

Benfotiamin

Alpha-liponsav
A multifaktoriális intervenció hatékonysága –
Steno-2
Mikrovaszkuláris szövődmények
Makrovaszkuláris szövődmények
RR 0,47 (95% CI 0,22-0,74, P=0,01)
n = 160, DM2T, Gaede P et al. N Engl J Med 348:383-393, 2003
”Take home message”
A hagyományos cardiovascularis rizikófaktorok
szerepe nemcsak a macrovascularis, hanem a
microvascularis szövődmények kialakulása
szempontjából is meghatározó fontosságú.
A tudomány csalhatatlan, de a
tudósok mindig tévednek
Anatole France
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.
The epidemiologist can confuse
the non-epidemiologist
Conclusion:
You can eat as you want
English speaking will kill you
A. Adler, EDEG, Oxford, 2002.