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A hagyományos kardiovaszkuláris rizikófaktorok és a diabetes microvascularis szövődményeinek összefüggése Semmelweis Egyetem I. sz. Belgyógyászati Klinika,

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1 A hagyományos kardiovaszkuláris rizikófaktorok és a diabetes microvascularis szövődményeinek összefüggése Semmelweis Egyetem I. sz. Belgyógyászati Klinika, Budapest Prof. Dr. Kempler Péter egyetemi tanár

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:  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)

3 Relative risk of CHD mortality He J, et at. Am Heart J. 1999;138: <112 <71 Risk of CHD Death According to SBP and DBP in MRFIT Decile >151 >98 (lowest 10%)(highest 10%) SBP (mmHg) DBP (mmHg) Systolic blood pressure (SBP) Diastolic blood pressure (DBP) CHD=coronary heart disease

4 Cholesterol and triglyceride as risk factors of coronary heart disease Cholesterol mmol \ lit. Triglyceride mmol \ lit. CHD cases ( per 1000 ) PROCAM ( 6 years )

5

6 DM- DM + CVD death/men/year Atherosclerosis risk factors and the CVD mortality among men with and without diabetes (Diabetes Care, 1993, 16, )

7 Howard BV. et al. Coronary Heart Disease Risk Equivalence in Diabetes Depends on Concomitant Risk Factors. Diabetes Care 29: , The 10-year cumulative incidence of CHD by numbers of risk factors (men and women combined).

8 Kockázatbecslő táblázat 65 éves 60 éves 55 éves 50 éves 40 éves Nem dohányzóDohányzó Szisztolés vérnyomás (Hgmm) Férfi 10-14% >15% 5-9% 3-4% 2% <1% 1% Fatális szív- és érrendszeri események előfordulási gyakorisága 10 éven belül

9 Diabetic retinopathy Leading cause of blindness in working-age adults 1 Diabetic nephropathy Leading cause of end-stage renal disease 2 Cardiovascular disease Stroke 1.2- to 1.8-fold increase in stroke 3 Diabetic neuropathy Leading cause of non- traumatic lower extremity amputations 5 75% diabetic patients die from CV events 4 Type 2 diabetes is NOT a mild disease 1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672– Gray RP & Yudkin JS. In Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

10 1. UKPDS Group. Diabetes Res 1990; 13: 1– The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317. Type 2 diabetes – the microvascular burden is already present at diagnosis21% Retinopathy 1 Nephropathy 218% 20% Erectile dysfunction 1 12% Neuropathy 1

11 Jarrett RJ. et al. Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabetic Med 1; 17-19, Mogensen CE.: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310; , 1984.

12 Mykkänen L. et al. Microalbuminuria precedes the development of NIDDM. Diabetes 1994; 43:

13 Yudkin JS, Forest RO, Jackson CA. Microalbuminuria as a predictor of vascular disease in non-diabetic subjects. Yudkin JS, Forest RO, Jackson CA. Microalbuminuria as a predictor of vascular disease in non-diabetic subjects. Lancet 1988; II:

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: Normal HRV borderline normal HRV abnormal HRV Cardiovascular morbidity and mortality NephropathyNormoalbuminuria

15 EURODIAB IDDM Complications Study Risk Factors for Progression to Microalbuminuria (Univariate Analysis) HbA 1c, AER Fasting Triglyceride, HDL-C, LDL-C BMI, WHR Presence of Retinopathy/Neuropathy NOT Systolic BP, Diastolic BP, Smoking Chaturvedi et al, Kidney International 2001;60:

16 EURODIAB IDDM Complications Study Risk Factors for Progression to Microalbuminuria Adjusted for Duration, HbA 1c and AER Progressors Non-progressors P Mean Fasting Triglyceride (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) BMI (Kg/m 2 ) WHR Relative Risk of Progression - Any Retinopathy Chaturvedi et al, Kidney International 2001;60:

17 EURODIAB IDDM Complications Study Standardised Estimates of Relative Risk (SERR) for Incidence of Complications NEPHROPATHY AGE/DURATION*- HbA 1c 1.57 ( ) AER 1.45 ( ) TRIGLYCERIDE 1.31 ( ) WHR 1.27 ( ) BMI - RETINOPATHY 1.32 ( )* 1.93 ( ) ( ) 1.32 ( ) - NEUROPATHY 1.39 ( ) 1.20 ( ) ( ) ( ) 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: Factors associated with progression to macroalbuminuria higher AER valueshigher AER values sub-optimal metabolic controlsub-optimal metabolic control excess body fatexcess body fat peripheral neuropathyperipheral 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: Familial insulin resistance segregates with diabetic complicationsFamilial insulin resistance segregates with diabetic complications Lipid disorders and obesity segregate with diabetic nephropathyLipid disorders and obesity segregate with diabetic nephropathy Arterial hypertension and obesity segregate with diabetic retinopathyArterial hypertension and obesity segregate with diabetic retinopathy

20 1. UKPDS Group. Diabetes Res 1990; 13: 1– The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317. Type 2 diabetes – the microvascular burden is already present at diagnosis 21% Retinopathy 1 Nephropathy 2 18% 20% Erectile dysfunction 1 12% Neuropathy 1

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 szűrése Diabetesesekben a cataracta 1,6x a glaucoma 1,4x gyakoribb, mint cukorbetegségben nem szenvedőkben

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; 24: 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; 24: Duration of diabetesp = 0,0002 HbA1cp = 0,0001 AER (μg/min)p = 0,001 Cholesterolp = 0,008 Fasting triglyceridep = 0,0001 Risk factors for the incidence of retinopathy – univariate analysis:

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; 24: Fibrinogenp = 0,05 von Willebrand factorp = 0,04 γGTp = 0,02 Waist – hip ratiop = 0,0001 Insulin dose/weightp = 0,003 Risk factors for the incidence of retinopathy – univariate analysis:

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; 24: 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; 24: Risk factorSRE (95% CI)P Duration1,32 (1,07-1,61)0,008 HbA1c1,93 (1,52-2,44)0,0001 Fasting triglyceride*1,24 (1,01-1,54)0,04 Waist-to-hip ratio1,32 (1,07-1,63)0,01 * Analysis performed on log-transformed variables Standardized regression estimates

27 Autonom neuropathia Ziegler D. Diabetes Metab Rev 1994; 10: – + Az autonom neuropathia prognózisa diabetes mellitusban Követési idő: 5,8 év (metaanalízis)

28 Silent myocardialis infarctus  Balkamra-elégtelenség, tüdőoedema  Ketoacidozis  Hányás  Collapsus hátterében cukorbetegekben mindig gondolni kell infarctus lehetőségére is.

29 Logaritmikus prevalencia arány 1,96 (1,53-2,51) összesített adatok, n=1468 p<0,001 DIAD n=1123 CAN = az ISzB erős előrejelzője Vinik et al., Diabetes Care 26: , 2003 Wackers et al Diabetes Care 27; , 2005 A cardialis autonom neuropathia (CAN) és a néma („silent”) myocardialis infarctus közötti összefüggés

30 Hónapok óta fennálló tünetmentes talpi fekély Zick R., Brockhaus KE. Diabetes mellitus. Fußfibel, Kirchheim, Mainz 2000.

31 Etiology of foot ulcers Neuropathic or neuroischae mic Purely ischaemic Boulton AJM. Lowering the risk of neuropathy, foot ulcers and amputation. Diabetic Med 1998; 15 (Suppl 4):

32 Sensoros neuropathia hypaesthesia Trophicus ulcus Gangraena gyakoribb infekciók rosszabb sebgyógyulás trauma, microtrauma microangio- pathia

33 32 éves diabeteses férfi32 éves diabeteses férfi Diabetes tartam: 20 évDiabetes tartam: 20 év HbA1C: 6,7%HbA1C: 6,7% Súlyos sensoros neuropathia, orvosa tanácsa ellenére 20km-t futottSúlyos sensoros neuropathia, orvosa tanácsa ellenére 20km-t futott Esetismertetés Zick R., Brockhaus KE. Diabetes mellitus. Fußfibel, Kirchheim, Mainz 2000.

34 Lábsérülések 20km futást követően súlyos sensoros neuropathia fennállása esetén

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36 Meggitt BF. Diabetes. In: Helal B et al. (eds). The Foot pp A diabeteses láb klinikai stádiumai

37 Alsó végtagi amputációk aránya cukor- betegekben 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: ) 45,0 x(Standl és mtsai. Diab Stoffw 1996;5: 29-32)

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39 Lábamputációk cukorbetegekben Cukorbetegek kórházi felvételére a fejlett országokban a leggyakrabban lábszövődmények miatt kerül sorCukorbetegek kórházi felvételére a fejlett országokban a leggyakrabban lábszövődmények miatt kerül sor A legtöbb amputációt talpi fekély előzi megA legtöbb amputációt talpi fekély előzi meg Napjainkban a diabetesesekben történt alsó végtagi amputációk 85%-át tartják megelőzhetőnek.Napjainkban a diabetesesekben történt alsó végtagi amputációk 85%-át tartják megelőzhetőnek. IDF, 2005

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41 Nem traumás eredetű alsó végtagi amputációk felét cukorbetegekben végzik Magyarországon évente cukorbeteg lábát amputálják. Neuropathiás eredetű amputációnak nem szabadna előfordulnia.

42 Charcot - osteoarthropathia Zick R., Brockhaus KE. Diabetes mellitus. Fußfibel, Kirchheim, Mainz 2000.

43 1. UKPDS Group. Diabetes Res 1990; 13: 1– The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317. Type 2 diabetes – the microvascular burden is already present at diagnosis21% Retinopathy 1 Nephropathy 218% 20% Erectile dysfunction 1 12% Neuropathy 1

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 1996; 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.

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 1996; 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.

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 1996; 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.

47 * adjusted for age, duration and HbA 1C ** testing difference from non-smoking CrudeAdjusted* 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 N.S.N.S. Total cholesterol p < 0,001 N.S. HDL-cholesterol p < 0,01 LDL-cholesterol p < 0,001 N.S. Total cholesterol/HDL cholesterol ratio p < 0,001 Fasting triglyceride 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:

48 * adjusted for age, duration and HbA 1C Adjusted*relative risk of abnormal R-R ratio (p-value, testing for trend) Peripheral neuropathy p < 0,0001 Albumin excretion p < 0,0001 Retinopathy Severe hypoglycaemia p = 0,03 Severe ketoacidosis p < 0,0001 Cardiovascular disease 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:

49 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.

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:

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:

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:

53 Risk factors for for incidence of neuropathy after adjusting for age and HbA 1c 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, HbA 1c, 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 disease microvascular complications Tesfaye et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:

55 Risk Factors for Neuropathy after Adjustment for HBA1c and Duration of Diabetes Tesfaye et al NEJM 352: ,2005 Eurodiab: 276/1172 patients developed neuropathy in 7.3y VariableOdds RatioP value CVD2.74< Albuminuria Hypertension1.92<0.001 Smoking1.55<0.001 BMI1.40<0.001 Triglycerides1.35<0.001 Total Cholesterol LDL-C

56 A diabeteses neuropathia oki kezelése  Optimális anyagcserehelyzet biztosítása  Rizikófaktorok befolyásolása  Benfotiamin  Alpha-liponsav

57 A multifaktoriális intervenció hatékonysága – Steno-2 n = 160, DM2T, Gaede P et al. N Engl J Med 348: , 2003 Mikrovaszkuláris szövődmények Makrovaszkuláris szövődmények RR 0,47 (95% CI 0,22-0,74, P=0,01)

58 ”Take home message” A hagyományos cardiovascularis rizikófaktorok szerepe nemcsak a macrovascularis, hanem a microvascularis szövődmények 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  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 A. Adler, EDEG, Oxford, Conclusion: You can eat as you want English speaking will kill you Conclusion: You can eat as you want English speaking will kill you

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