ΣΑΚΧΑΡΩΔΗΣ ΔΙΑΒΗΤΗΣ & ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ

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1 ΣΑΚΧΑΡΩΔΗΣ ΔΙΑΒΗΤΗΣ & ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ Δρ. Σταμάτης Ευσταθίου MD, MSc, PhD Επιμελητής Α Κέντρο Πρόληψης Καρδιαγγειακών Νόσων «Υγείας Μέλαθρον»

2 ΣΔ & ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΝΟΣΟΣ Meta-analysis of 102 studies (N= ) Overall, people with diabetes are 2-4 times more likely to develop cardiovascular disease than those without diabetes The cardiovascular triad Cerebrovascular disease 2 4 times increased risk of stroke 2-6-times greater risk of TIA Coronary heart disease 2-times increased risk of CHD 2-times increased risk of non-fatal MI 2-3-times increased risk of heart failure Peripheral vascular disease Alongside microvascular disease and neuropathy, contributes to: times higher risk of lowerlimb amputation 3-9-times higher risk of intermittent claudication 75% of diabetics die from CV disease Emerging Risk Factors Collaboration. Lancet. 2010;375:

3 CV Disease Prevention in DM: The Medical Titanic

4 ΣΔ & ΚΑΡΔΙΑΓΓΕΙΑΚOΣ ΚΙΝΔΥΝΟΣ This is the great tragedy of Science: the slaying of a beautiful hypothesis by an ugly fact Thomas Huxley "Biogenesis and abiogenesis" (1870); published in Collected Essays, Vol. 8, p. 229.

5 STUDY (Duration) Population characteristics HbA1C (Initial [Final]) Intervention Outcome UKPDS 33 (10 y) 3867, newly diagnosed, aged 54 7 [7] vs. 7 [7.9] Intensive sulfonylurea/insulin vs. diet Less microvascular events, No difference in CV events UKPDS 34 (10 y) 1704, obese, aged 53 7 [7.4] vs. 7 [8] Metformin vs. diet Less MI, all cause mortality KUMAMOTO (6 y) 110, Japanese, UAE < 300 mg/24hr 9.3 [7.1] vs. 8.9 [9.4] Multiple insulin injection vs. Conventional insulin Less microvascular events PROACTIVE (3 y) ACCORD (3.5 y) 5238, obese, high CV risk 10251, obese with high CV risk, aged [7] vs. 7.8 [7.5] Pioglitazone 45 vs. Placebo No difference in primary CV endpoint, Less secondary CV endpoints, More weight, HF, edema 8.1 [6.4] vs. 8.1 [7.5] Mostly 3 OAD + insulin vs. Standard ADVANCE (5 y) , aged [6.5] vs. 7.5 [7.3] Mostly on gliclazide + metformin vs. Standard RECORD (5.5 y) 4447, aged [7.4] [Metformin or sulfonylurea]+ rosiglitazone vs. Metformin + sulfonylurea STENO-2 (13 y) 160, with MAU 8.4 [7.7] Multifactorial intensive vs. Conventional ADDITION (5.3 y) 3057, newly diagnosed, aged 60 7 Multifactorial intensive vs. Conventional More all-cause mortality, weight, hypoglycemia, HALTED Less microvascular events, More hypoglycemia No difference in CV events, More HF, fractures Less mortality, macro- and microvascular events, No difference in mortality, CV events, Slight improvement in surrogates (HbA1C, LDL, BP) UGDP (10 y) 1027, follow-up 13 y - Intensive vs. Standard More CV mortality with tolbutamide VADT (5.6 y) 1791, aged 60, 40% CAD 9.4 [6.9] vs. 9.4 [8.4] Intensive vs. Standard No difference in CV events, More hypoglycemia ORIGIN (6.2 y) , aged [6.5] vs. 6.4 [6.2] Early basal glargine vs. Standard No difference in CV events, Delay new DM More weight, hypoglycemia

6 ΣΔ & ΚΑΡΔΙΑΓΓΕΙΑΚOΣ ΚΙΝΔΥΝΟΣ δυσλειτουργία του ενδοθηλίου υπερέκφραση αναπτυξιακών παραγόντων/κυτοκινών οξειδωτικό stress Sowers J et al. Hypertension. 2013; 61: 943

7 1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1ΣΔ Ferranti et al. Diabetes Care 2014;37:2843

8 1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: Τ2ΣΔ CALIBER registry (Ν= ) Shah et al. Lancet Diabetes Endocrinol 2015; 3: 105

9 1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1 vs. Τ2 Juutilainen et al. Diabetes Care 31: , 2008.

10 1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1 vs. Τ2 Juutilainen et al. Diabetes Care 31: , 2008.

11 1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1 vs. Τ2 Deaths per 1,000 person-years (y-axis) by GHb (x-axis) plotted by group-specific medians of tertile ranges. Black lines, type 1 diabetic participants; gray lines, type 2 diabetic participants; solid lines, men and women; long dashes, men; short dashes, women. Juutilainen et al. Diabetes Care 31: , 2008.

12 2. ΦΥΛΟ Observational prospective study (225 T1, 308 T2, 52.2% men, 30 years follow-up) All-cause mortality Patient/ years* SMR (95% CI) Women ( )** Men ( ) All ( ) Cardiovascular mortality Women ( )** Men ( ) All ( ) Non-cardiovascular mortality Women ( ) Men ( ) All ( ) Increased risk of mortality *Follow-up from for all-cause mortality and for cardiovascular and non-cardiovascular mortality **p<0.01 for difference between men and women (N=308) Allemann S et al. Swiss Med Wkly. 2009;139(39-40):

13 2. ΦΥΛΟ Meta-analysis: 37 studies, patients Huxley et al. BMJ Jan 14; 332(7533): 73

14 3. ΕΘΝΙΚΟΤΗΤΑ & ΦΥΛΗ Northern Manhattan Cohort Study (N = 3298) Willey et al. J Am Heart Assoc. 2014;3:e001106

15 Διαβήτης, υπογλυκαιμία 4. ΓΛΥΚΑΙΜΙΚΟΣ & έμφραγμα: μια «ταραγμένη ΕΛΕΓΧΟΣ εκεχειρία» ΜΕΤΑ - ΑΝΑΛΥΣΗ 5 ΜΕΓΑΛΩΝ ΜΕΛΕΤΩΝ ΜΕ ΑΣΘΕΝΕΙΣ: ΕΠΙΔΡΑΣΗ ΤΟΥ ΕΝΤΑΤΙΚΟΥ ΓΛΥΚΑΙΜΙΚΟΥ ΕΛΕΓΧΟΥ ΣΤΑ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΕΠΕΙΣΟΔΙΑ ΕΝΤΑΤΙΚΗ / ΣΥΜΒΑΤΙΚΗ ΘΕΡΑΠΕΙΑ ΛΟΓΟΣ ΠΙΘΑΝΟΤΗΤΩΝ (95% CI) ΛΟΓΟΣ ΠΙΘΑΝΟΤΗΤΩΝ (95% CI) ΑΣΘΕΝΕΙΣ ΕΠΕΙΣΟΔΙΑ UKPDS 3,071/ / ( ) PROACTIVE 2,605/ / ( ) ADVANCE 5,571/5, / ( ) VADT 892/899 77/ ( ) ACCORD 5,128/ / ( ) ΣΥΝΟΛΟ 17,267/15,773 1,182/1, ( ) ΥΠΕΡ ΕΝΤΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ ΥΠΕΡ ΣΥΜΒΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ Ray et al. Lancet 2009; 373:1765

16 ΣΔ & ΚΑΡΔΙΑΓΓΕΙΑΚΟΙ ΠΑΡΑΓΟΝΤΕΣ MRFIT Study Stamler et al. Diabetes Care 1993;16:434

17 5. ΥΠΕΡΤΑΣΗ Japan Intervention Trial Shimamoto et al. Hypertens Res 2007; 30: )

18 6. ΔΥΣΛΙΠΙΔAIΜΙΑ Strong Heart Study Howard et al. Arterioscler Thromb Vasc Biol 2000;20:830

19 7. ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ Aerobics Center Longitudinal Study N = 2138, follow up 6.5 years Church et al. Diabetes Care 32: , 2009

20 8. ΚΑΠΝΙΣΜΑ Nurses Health Study Fagard R. Diabetes Care Nov; 32(Suppl 2): S429

21 9. ΜΙΚΡΟΑΛΒΟΥΜΙΝΟΥΡΙΑ 11 studies, N = 2138, follow up 6.5 years Niskanen et al, 1993 Neil et al, 1993 Stehouwer et al, 1990 Stiegler et al, 1992 Patrick et al, 1990 Subtotal Macleod et al, 1993 TOTAL Odds ratios of CV morbidity & mortality in T2DM with microalbuminuria vs. normoalbuminuria Dinneen et al. Arch Intern Med 1997;156:1413

22 10. ΝΕΦΡΟΠΑΘΕΙΑ NID-2 Prospective Cohort Study Sasso F. et al. Nephrol Dial Transplant 2012;27:2269

23 11. ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΟΠΑΘΕΙΑ Meta-analysis: 20 studies, patients Kramer C. et al. Diabetes Care 2011;34:1238

24 Cardiovascular Risk in Diabetes

25 12. KAΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ Strong Heart Study (N=2740) & LIGHT Study (N=1091) ΣΔ: X 4 κίνδυνος ΣΚΑ & Χ 2 θνητότητα στα άτομα με ΣΚΑ Simone et al. J Hypertens. 2010;28:353, Cubbon R et al. Diabetes & Vascular Disease Research 2013;10:330

26 13. ΚΑΡΔΙΑΚΗ ΝΕΥΡΟΠΑΘΕΙΑ ΑΥΤΟΝΟΜΟΥ Meta-analysis: 15 studies, Maser et al. Diabetes Care 26: , 2003

27 14. ΑΓΓΕΙΑΚΑ ΕΓΚΕΦΑΛΙΚΑ ΕΠΕΙΣΟΔΙΑ Easter Finland Survey (N = 16649) ΣΔ: o δυσμενέστερος παράγων κινδύνου μετά από ΑΕΕ Men (No. of Stroke Deaths 95) Women (No. of Stroke Deaths 71) Men and Women (No. of Stroke Deaths 166) RR 95% CI P RR 95% CI P RR 95% CI P Age, y < < <.001 Diabetes, % < < <.001 Smoking Cholesterol, mmol/l Systolic BP, mm Hg < <.001 BMI, kg/m Antihypertensive drug Sex <.001 Tuomilehto et al. Stroke. 1996; 27: 210

28 14. ΑΓΓΕΙΑΚΑ ΕΓΚΕΦΑΛΙΚΑ ΕΠΕΙΣΟΔΙΑ Women s Pooling Project (N = ) ΣΔ: ισοδύναμο καρδιαγγειακού κινδύνου με ιστορικό ΑΕΕ Ηο et al. Stroke. 2003;34:2812

29 Incidence of CV events (%) 15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΥΠΕΡ 7-year incidence of CV events among 1059 patients with T2 DM vs no diabetes stratified by history of MI 50 p < No history of MI History of MI 40 p < n = n = 169 n = 1304 n = 69 Type 2 diabetes Non-diabetic Haffner SM, et al. N Engl J Med. 1998;339:

30 15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΥΠΕΡ CHD mortality among 1059 patients with T2 DM vs no diabetes stratified by history of MI Juutilainen A, et al. Diabetes Care 28: , 2005.

31 15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Danish Civil Registry: Population Study of 3.3 Million People ( ) Schramm T et al. Circulation. 2008;117:

32 15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Meta-analysis (13 studies, patients, follow-up 5 25 years) Bulugahapitiya U et al. Diabet. Med. 26, (2009).

33 15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Southern Europe Registries REGICOR & GEDAPS (N = 6670) Cano J et al. Diabetes Care 33: , 2010

34 Table 1. Cardiovascular prediction models specifically developed for patients with type 2 diabetes Reference Kengne 2011 (ADVANCE) Davis 2010 (Fremantle) Elley 2010 (DCS) Cederholm 2008 Yang 2008 Yang 2008 Yang 2007 Donnan 2006 (DARTS) Folsom 2003 (ARIC) Kothari 2002 (UKPDS risk engine) Stevens 2001 (UKPDS risk engine) Yudkin 1999 Development population NIDDM from 20 countries NIDDM from Australia n events/ n total Type of model Outcome Predicted years Number of predictors Apparent discrimination (AUC) Apparent calibration (p value Hosmer Lemeshow) Method of internal validation 473/7168 Cox CVD * 0.76 Bootstrapping Presentation of risk model Original model and scoring chart 185/1240 Logistic CVD NA Original model NIDDM from New Zealand 6479/ Cox CVD and CHD NIDDM from Sweden NIDDM from China NIDDM from China NIDDM from China NIDDM from Scotland NIDDM from USA Newly diagnosed NIDDM from UK Newly diagnosed NIDDM from UK NIDDM from US CVD: 0.68, 0.67 CHD: 0.71, 0.71 Good NA Original model 1482/ Cox CVD * 0.08* Split sample Original model 351/7067 Cox CHD * Good, p>0.05* Split sample Original model 274/7067 Cox Heart failure * Good, p>0.10* Split sample Original model 332/7209 Cox Stroke * Good, p>0.05* Split sample Original model 243/4569 Weibull CHD Split sample Original model 128/1273 Cox CHD (men), 0.78 (women)0.70 (men), 0.72 (women) NA 188/4549 Gompertz Stroke Variable 7 NR NR NA NR/4540 Gompertz CHD Variable 7 NR NR NA Original model and simplified model Original model, risk software Original model, risk software NR/2138 NR CHD 10 6 NR NR NA Scoring chart

35 ΜΟΝΤΕΛΑ ΥΠΟΛΟΓΙΣΜΟΥ ΚΙΝΔΥΝΟΥ Χαρακτηριστικά Twelve prediction models are specifically designed for T2 DM patients & 33 in the general population accounting for T2DM as a predictor. Six of these prediction models estimate CHD risk, while 4 estimate total CVD risk. The majority of the prediction models predict 5-year risk. They include an average of 8 predictors (most commonly age, sex, duration of diabetes, HbA1c & smoking) Van Dieren S et al. Heart. 2012;98(5):360

36 ΜΟΝΤΕΛΑ ΥΠΟΛΟΓΙΣΜΟΥ ΚΙΝΔΥΝΟΥ Χαρακτηριστικά Area under receiver operating characteristic curve (AUC) is The more contemporary models (DCS, Fremantle, DARTS) seem to have the best external validity, but these were validated in other patient populations only once. Guidelines most commonly recommend use of UKPDS, Framingham, PROCAM and DECODE DM-specific models perform better than those from general population. Van Dieren S et al. Heart. 2012;98(5):360

37 ΣΥΜΠΕΡΑΣΜΑΤΑ Τα διαβητικά άτομα έχουν 2-4 φορές μεγαλύτερη πιθανότητα να εμφανίσουν καρδιαγγειακά νοσήματα και το 75% των διαβητικών πεθαίνουν από καρδιαγγειακά αίτια Η αύξηση της καρδιαγγειακής θνησιμότητας είναι παρόμοια για τους δύο βασικούς τύπους διαβήτη, αλλά η δυσμενής επίδραση της υπεργλυκαιμίας στο καρδιαγγειακό σύστημα είναι μεγαλύτερη στο διαβήτη τύπου 1 Ο σχετικός κίνδυνος στεφανιαίας θνησιμότητας είναι 50% μεγαλύτερος στις γυναίκες σε σύγκριση με τους άνδρες διαβητικούς Η παρουσία νευροπάθειας του αυτόνομου νευρικού συστήματος (και ιδιαίτερα η καρδιακή) είναι δυσμενέστερος παράγων κινδύνου σε σύγκριση με τους παραδοσιακούς παράγοντες Η άποψη ότι ο διαβήτης είναι ισοδύναμο στεφανιαίας νόσου είναι υπό επανεκτίμηση

38 Reluctance, Ignorance & Suspension Kill

39 When assessing risk reduction, remember that the true enemy of truth is not falsity, but certainty David L Sackett, Professor Emeritus, Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada. Evidence-based medicine: How to practice and teach EBM DL Sackett, WS Richardson, W Rosenberg and RB Haynes. 1997, New York: Churchill Livingston.