ΣΑΚΧΑΡΩΔΗΣ ΔΙΑΒΗΤΗΣ & ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ

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

ΣΔ & ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΝΟΣΟΣ Meta-analysis of 102 studies (N=530.083) 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: 15-40-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;375:2215-22.

CV Disease Prevention in DM: The Medical Titanic

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.

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 62 7.8 [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) 11.140, aged 66 7.5 [6.5] vs. 7.5 [7.3] Mostly on gliclazide + metformin vs. Standard RECORD (5.5 y) 4447, aged 59 7.9 [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) 12.537, aged 63 6.4 [6.5] vs. 6.4 [6.2] Early basal glargine vs. Standard No difference in CV events, Delay new DM More weight, hypoglycemia

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

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

1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: Τ2ΣΔ CALIBER registry (Ν=1921260) Shah et al. Lancet Diabetes Endocrinol 2015; 3: 105

1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1 vs. Τ2 Juutilainen et al. Diabetes Care 31:714 719, 2008.

1. ΤΥΠΟΣ ΔΙΑΒΗΤΗ: T1 vs. Τ2 Juutilainen et al. Diabetes Care 31:714 719, 2008.

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 31:714 719, 2008.

2. ΦΥΛΟ Observational prospective study (225 T1, 308 T2, 52.2% men, 30 years follow-up) All-cause mortality Patient/ years* 0 2 4 6 8 10 SMR (95% CI) Women 2625 4.7 (3.9-5.8)** Men 3183 3.0 (2.5-3.5) All 5807 3.5 (3.1-4.0) Cardiovascular mortality Women 2591 7.2 (5.3-9.8)** Men 3139 4.4 (3.4-5.6) All 5730 5.2 (4.3-6.3) Non-cardiovascular mortality Women 2591 3.1 (2.3-4.2) Men 3139 2.1 (1.6-2.7) All 5730 2.4 (2.0-3.0) Increased risk of mortality *Follow-up from 1974-2005 for all-cause mortality and 1974-2004 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):576-83.

2. ΦΥΛΟ Meta-analysis: 37 studies, 447064 patients Huxley et al. BMJ. 2006 Jan 14; 332(7533): 73

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

Διαβήτης, υπογλυκαιμία 4. ΓΛΥΚΑΙΜΙΚΟΣ & έμφραγμα: μια «ταραγμένη ΕΛΕΓΧΟΣ εκεχειρία» ΜΕΤΑ - ΑΝΑΛΥΣΗ 5 ΜΕΓΑΛΩΝ ΜΕΛΕΤΩΝ ΜΕ 33.040 ΑΣΘΕΝΕΙΣ: ΕΠΙΔΡΑΣΗ ΤΟΥ ΕΝΤΑΤΙΚΟΥ ΓΛΥΚΑΙΜΙΚΟΥ ΕΛΕΓΧΟΥ ΣΤΑ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΕΠΕΙΣΟΔΙΑ ΕΝΤΑΤΙΚΗ / ΣΥΜΒΑΤΙΚΗ ΘΕΡΑΠΕΙΑ ΛΟΓΟΣ ΠΙΘΑΝΟΤΗΤΩΝ (95% CI) ΛΟΓΟΣ ΠΙΘΑΝΟΤΗΤΩΝ (95% CI) ΑΣΘΕΝΕΙΣ ΕΠΕΙΣΟΔΙΑ UKPDS 3,071/1549 426/259 0.75 (0.54 1.04) PROACTIVE 2,605/2633 164/202 0.81 (0.65 1.00) ADVANCE 5,571/5,569 310/337 0.92 (0.78 1.07) VADT 892/899 77/90 0.85 (0.62 1.17) ACCORD 5,128/5123 205/248 0.82 (0.68 0.99) ΣΥΝΟΛΟ 17,267/15,773 1,182/1,136 0.85 (0.77 0.93) 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 ΥΠΕΡ ΕΝΤΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ ΥΠΕΡ ΣΥΜΒΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ Ray et al. Lancet 2009; 373:1765

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

5. ΥΠΕΡΤΑΣΗ Japan Intervention Trial Shimamoto et al. Hypertens Res 2007; 30: 119 123)

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

7. ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ Aerobics Center Longitudinal Study N = 2138, follow up 6.5 years Church et al. Diabetes Care 32:1289 1294, 2009

8. ΚΑΠΝΙΣΜΑ Nurses Health Study Fagard R. Diabetes Care. 2009 Nov; 32(Suppl 2): S429

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 0.5 1 2 5 10 20 50 100 Dinneen et al. Arch Intern Med 1997;156:1413

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

11. ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΟΠΑΘΕΙΑ Meta-analysis: 20 studies, 19234 patients Kramer C. et al. Diabetes Care 2011;34:1238

Cardiovascular Risk in Diabetes

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

13. ΚΑΡΔΙΑΚΗ ΝΕΥΡΟΠΑΘΕΙΑ ΑΥΤΟΝΟΜΟΥ Meta-analysis: 15 studies, 1966-2001 Maser et al. Diabetes Care 26:1895 1901, 2003

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 1.10 1.07-1.13 <.001 1.16 1.10-1.21 <.001 1.11 1.09-1.14 <.001 Diabetes, % 3.35 1.96-5.73 <.001 4.89 2.83-8.45 <.001 4.03 2.76-5.88 <.001 Smoking 1.48 0.98-2.24.06 2.04 1.00-4.18.05 1.62 1.13-2.34.01 Cholesterol, mmol/l 1.19 1.02-1.38.02 0.94 0.78-1.12.5 1.08 0.96-1.21.2 Systolic BP, mm Hg 1.02 1.02-1.03 <.001 1.01 1.01-1.02.01 1.02 1.01-1.03 <.001 BMI, kg/m 2 0.98 0.93-1.04.5 0.99 0.94-1.04.7 0.99 0.95-1.03.6 Antihypertensive drug 1.11 0.60-2.05.7 1.40 0.81-2.43.2 1.27 0.85-1.90.3 Sex 0.53 0.36-0.75 <.001 Tuomilehto et al. Stroke. 1996; 27: 210

14. ΑΓΓΕΙΑΚΑ ΕΓΚΕΦΑΛΙΚΑ ΕΠΕΙΣΟΔΙΑ Women s Pooling Project (N = 27 269) ΣΔ: ισοδύναμο καρδιαγγειακού κινδύνου με ιστορικό ΑΕΕ Ηο et al. Stroke. 2003;34:2812

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 <0.001 45.0 No history of MI History of MI 40 p <0.001 30 20 20.2 18.8 10 0 n = 890 3.5 n = 169 n = 1304 n = 69 Type 2 diabetes Non-diabetic Haffner SM, et al. N Engl J Med. 1998;339:229-34.

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 28:2901 2907, 2005.

15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Danish Civil Registry: Population Study of 3.3 Million People (1997-2002) Schramm T et al. Circulation. 2008;117:1945-1954.

15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Meta-analysis (13 studies, 45108 patients, follow-up 5 25 years) Bulugahapitiya U et al. Diabet. Med. 26, 142 148 (2009).

15. ΙΣΟΔΥΝΑΜΟ ΣΤΕΦΑΝΙΑΙΑΣ ΝΟΣΟΥ: ΚΑΤΑ Southern Europe Registries REGICOR & GEDAPS (N = 6670) Cano J et al. Diabetes Care 33:2004 2009, 2010

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 4 10 0.700.70* 0.76 Bootstrapping Presentation of risk model Original model and scoring chart 185/1240 Logistic CVD 5 7 0.80 0.74 NA Original model NIDDM from New Zealand 6479/36 127 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 5 109 CVD: 0.68, 0.67 CHD: 0.71, 0.71 Good NA Original model 1482/11 646 Cox CVD 5 6 0.70* 0.08* Split sample Original model 351/7067 Cox CHD 5 7 0.70* Good, p>0.05* Split sample Original model 274/7067 Cox Heart failure 5 6 0.85* Good, p>0.10* Split sample Original model 332/7209 Cox Stroke 5 4 0.75* Good, p>0.05* Split sample Original model 243/4569 Weibull CHD 5 9 0.71 0.54 Split sample Original model 128/1273 Cox CHD 10 817 0.76 (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

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

ΜΟΝΤΕΛΑ ΥΠΟΛΟΓΙΣΜΟΥ ΚΙΝΔΥΝΟΥ Χαρακτηριστικά Area under receiver operating characteristic curve (AUC) is 0.68-0.85. 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

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

Reluctance, Ignorance & Suspension Kill

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.