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ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ. ΥΠΕΡΤΑΣΗ ΚΑΙ ΔΥΣΛΙΠΙΔΑΙΜΙΑ Δημήτριος Ρίχτερ, MD, FESC, FAHA - Διευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών Αντιπρόεδρος ΕΚΟΜΕΝ.

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Presentation on theme: "ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ. ΥΠΕΡΤΑΣΗ ΚΑΙ ΔΥΣΛΙΠΙΔΑΙΜΙΑ Δημήτριος Ρίχτερ, MD, FESC, FAHA - Διευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών Αντιπρόεδρος ΕΚΟΜΕΝ."— Presentation transcript:

1 ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ. ΥΠΕΡΤΑΣΗ ΚΑΙ ΔΥΣΛΙΠΙΔΑΙΜΙΑ Δημήτριος Ρίχτερ, MD, FESC, FAHA - Διευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών Αντιπρόεδρος ΕΚΟΜΕΝ - Γενικός Γραμματέας Ελληνικής Εταιρείας Λιπιδιολογίας. - Μέλος ΔΣ ΕΛΙΚΑΡ

2 NCEP ATP III: The Metabolic Syndrome <40 mg/dL (1.0 mmol/L) <50 mg/dL (1.3 mmol/L) Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women 110 mg/dL (6.0 mmol/L) Fasting glucose 130/85 mmHg Blood pressure HDL-C 150 mg/dL (1.7 mmol/L) TG Abdominal obesity (Waist circumference) Defining Level Risk Factor Recommends a diagnosis when 3 of these risk factors are present Adapted from NCEP, Adult Treatment Panel III, JAMA 2001:285;2486–2497.

3 PREVALENCE OF METS IN GREECE Mets-Greece study (Athyros et al) adults. Prevalence 22.8%. Similar men and women. Increasing with age ( 4,7% 18-29y, 44,2% >60y). 62% 3 components, 28% 4, 10% all 5. 74th EAS Congress, Seville, April 2004 ATTICA study (Panagiotakos et al) adults. Prevalence 19,8%. Men 25,2%, women 14,6%. Prevalence increased with age. Am Heart J 2004; 147:

4 The presence of the Metabolic Syndrome is associated with increased CHD, CVD and total mortality Unadjusted Kaplan-Meier hazard curves for men with and without the Metabolic Syndrome based on factor analysis. Median follow-up was 11.6 ( ) years. Relative risks were determined by age-adjusted Cox proportional hazards regression analysis. Lakka HM et al, J Am Med Assoc 2002;288:

5 ©2004 PPS ® Odds Ratio95% CIP Value Metabolic syndrome < Syndrome components Abdominal obesity High triglycerides Low HDL-C Hypertension Insulin resistance † Ninomiya JK et al. Circulation. 2004;109: *Self-reported. † Fasting plasma glucose 110 mg/dL. Association of MI* With the Metabolic Syndrome and Individual Components

6 ©2004 PPS ® Ninomiya JK et al. Circulation. 2004;109: *Self-reported. † Fasting plasma glucose 110 mg/dL. Association of Stroke* With the Metabolic Syndrome and Individual Components Odds Ratio95% CIP Value Metabolic syndrome Syndrome components Abdominal obesity High triglycerides Low HDL-C Hypertension Insulin resistance †

7 Major causes of death in USA 1990 and 2000 Mokdad AH et al. JAMA 2004

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9 Risk of AMI associated with risk factors in the overall population Risk factor % Cont % Cases OR (99% IC) adj age, sex, smoking OR (99% IC) adj for all ApoB/ApoA-1 (5 v 1) (3.39, 4.42) 3.25 (2.81, 3.76) Smoking (2.72, 3.20) 2.87 (2.58, 3.19) Diabetes (2.77, 3.42) 2.37 (2.07, 2.71) Hypertension (2.30, 2.68) 1.91 (1.74, 2.10) Abd Obesity (3 v 1) (2.03, 2.42) 1.62 (1.45, 1.80) Psychosocial (2.15, 2.93) 2.67 (2.21, 3.22) Veg et fruits DIE (0.64, 0.77) 0.70 (0.62, 0.79) Exercise (0.65, 0.79) 0.86 (0.76, 0.97) Alcohol intake (0.73, 0.86) 0.91 (0.82, 1.02) Yusuf S et al, Lancet 2004

10 Declining HDL-C in the Population >12,000 respondents to a biennial population survey in the Pawtucket Heart Health Program Between 1981 and 1993, 0.08 mmol/L (3.1 mg/dL) decline Adjusted for other risk factor changes Reprinted from Ann Epidemiol, Vol. 8, Derby CA et al., 84-91, copyright 1998, with permission from Elsevier. HDL-C (mmol/L) MenWomen Nonsmokers Smokers Nonsmokers Smokers Alcohol No Alcohol Alcohol BMI <22.9 BMI <24.5 BMI 27.6 BMI 27.9 '83-84'87-89'92-93 '85-86'81-82'89-90 '83-84'87-89'92-93 '85-86'81-82'89-90

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13 Treatment of obesity Modest weight loss can be effective  ~ kcal/day restriction  energy expenditure as tolerated Monitor blood pressure with anorectic drugs Treat CHD, LVH and RVH risk factors aggressively lipids, blood pressure, diabetes, hypertension obstructive sleep apnea and respiratory problems Poirier et al, Circulation 2006

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17 Finnish Diabetes Prevention Study: Treating the IGT* Patient With Lifestyle Changes Study Design –522 middle-aged, overweight † subjects –172 men, 350 women with IGT –BMI 31 kg/m 2 –mean age: 55 years –mean duration: 3.2 years –intervention group: individualized counseling reducing weight, total intake of fat and saturated fat increasing intake of fiber, physical activity Study Design –522 middle-aged, overweight † subjects –172 men, 350 women with IGT –BMI 31 kg/m 2 –mean age: 55 years –mean duration: 3.2 years –intervention group: individualized counseling reducing weight, total intake of fat and saturated fat increasing intake of fiber, physical activity *Plasma glucose concentration of 140 to 200 mg/dL. † BMI  25 kg/m 2. IGT=impaired glucose tolerance; BMI=body mass index. Tuomilehto J et al. N Engl J Med. 2001;344:

18 Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes* Tuomilehto J et al. N Engl J Med. 2001;344: % 23% Intervention Control (n=265) (n=257) *P<0.001; 4-year results Diabetes (%)

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20 Bariatric surgery and mortality Prospective study Prospective study SOS study SOS study N=4047 patients N=4047 patients 10.9 yrs follow-up 10.9 yrs follow-up Information: 99.9% Information: 99.9% Sjostrom L et al, NEJM 2007

21 SOS: Mortality reduction with weight-loss surgery Deaths: Control: 129 (6.3%) Surgery: 101 (5.0%) Unadjusted HR 0.76 ( ), P = 0.04 Adjusted HR 0.71* ( ), P = 0.01 *Adjusted for age, sex, risk factors Sjöström L et al. N Engl J Med. 2007;357: Years Cumulative mortality (%) Control Surgery

22 Surgery (n) Controls (n) Cardiovascular condition4353 Cardiac Myocardial infarction Heart failure Sudden death Stroke 6 6 Other 2 3 Noncardiovascular condition58 76 Cancer/meningioma29/047/1 Infection 12 3 Thromboembolic disease 5 7 Other Total mortality SOS: Causes of death Sjöström L et al. N Engl J Med. 2007;357:

23 2007 Guidelines for the Management of Arterial Hypertension Journal of Hypertension 2007;25: European Society of Hypertension European Society of Cardiology

24 Initiation of antihypertensive treatment Other risk factors, OD or disease Normal SBP or DBP High normal SBP or DBP Grade 1 HT SBP or DBP Grade 2 HT SBP or DBP Grade 3 HT SBP ≥180 or DBP ≥110 No other risk factors No BP intervention Lifestyle changes for several months then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes + immediate drug treatment 1-2 risk factorsLifestyle changes Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes + immediate drug treatment 3 or more risk factors, MS, OD or diabetes Lifestyle changes Lifestyle changes and consider drug treatment Lifestyle changes + drug treatment Lifestyle changes + immediate drug treatment DiabetesLifestyle changes Lifestyle changes + drug treatment Established CV or renal disease Lifestyle changes + immediate drug treatment

25 The Metabolic Syndrome Subjects with the metabolic syndrome also have a higher prevalence of microalbuminuria, left ventricular hypertrophy and arterial stiffness than those without the metabolic syndrome. Their cardiovascular risk is high and the chance of developing diabetes markedly increased In patients with a metabolic syndrome diagnostic procedures should include a more in-depth assessment of subclinical organ damage. Measuring ambulatory and home BP is also desirable

26 The Metabolic Syndrome In all individuals with metabolic syndrome individuals intense lifestyle measures should be adopted. When there is hypertension drug treatment should start with a drug unlikely to facilitate onset to diabetes. Therefore, a blocker of the renin-angiotensin system should be used followed, if needed, by the addition of a calcium antagonist or a low-dose thiazide diuretic. It appears desirable to bring BP to the normal range Lack of evidence from specific clinical trials prevents firm recommendations on use of antihypertensive drugs in all metabolic syndrome subjects with a high normal BP. There is some evidence that blocking the renin-angiotensin system may also delay incident hypertension

27 Hypertension Guidelines: ESH/ESC 2013

28 Definitions and classification of office blood pressure levels (mmHg) CategorySystolicDiastolic Optimal< 120And< 80 Normal And/or80-84 High normal And/or85-89 Grade 1 hypertension And/or90-99 Grade 2 hypertension And/or Grade 3 hypertension > = 180And/or> = 110 Isolated systolic hypertension >= 140and< 90

29 BP Goals all be treated to <140/90 mm Hg Except : diabetes (<85 mm Hg diastolic) In patients near 80 years age, the systolic blood- pressure target should be 140 to 150 mm Hg, but physicians can go lower than 140 mm Hg if the patient is fit and healthy-mentally & physically

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31 Life style changes Salt A reduction to 5 g per day can decrease systolic blood pressure about 1 to 2 mm Hg in normotensive individuals and 4 to 5 mm Hg in hypertensive patients, he said. Wt loss Losing about 5 kg can reduce systolic blood pressure by as much as 4 mm Hg, aerobic endurance training can reduce systolic blood pressure 7 mm Hg

32 When to start drug Rx Consider BP level and correlate with overall risk: cardiovascular risk factors overt cardiovascular disease asymptomatic organ damage diabetes chronic kidney disease.

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34 Asymptomatic Target Organ Damage (TOD) √ √ Pulse pressure ( in the elderly) >= 60 mmHg Electrocardiograhic LVH( Sokolow-Lyon index > 3.5 mV; RaVL > 1.` mV; Cornell voltage duration product> 244 mV* ms), or Echocardiographic LVH [ LVM index: men > 115 g/m2; women > 95 g/m2 (BSA)]a Carotid wall thickening (IMT > 0.9 mm) or plaque Carotid- femoral PWV > 10 m/s Ankle- brachial index < 0.9 CKD with Egfr ml/min/1.73 m2 (BSA) Microalbuminuria ( mg/24 h), or albumin- creatinine ratio( mg/g; mg/mmol) (preferentially on morning spot urine)

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36 Combination Rx For patients at high risk for cardiovascular events or those with a markedly high baseline blood pressure In those at low or moderate risk for cardiovascular events or with mildly elevated blood pressure, a single starting agent is preferred. For a high-risk individual, you can't play around with one drug after another, trying to control blood pressure

37 Drugs to be preferred in specific conditions

38 Compelling and possible contra-indications to the use of antihypertensive drugs

39 Effects of lipid-lowering therapy on CHD events in statin trials Patients with CHD event (%) S=statin treated P=placebo treated *Extrapolated to 5 years 4S-P CARE-P LIPID-P 4S-S WOSCOPS-S -P AFCAPS-P -S LIPID-S CARE-S Primary Prevention Simvastatin Pravastatin Lovastatin Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21. HPS-S -P Atorvastatin ASCOT-S * -P * Secondary Prevention LDL-C (mg/dL)

40 Metabolic syndrome was based on the updated NCEP ATP III definition, 1 and was defined as  3 of the following prior to open-label run-in: Waist circumference: Men  40 inches (102 cm); Women  35 inches (88 cm)* Waist circumference: Men  40 inches (102 cm); Women  35 inches (88 cm)* Triglycerides  150 mg/dL (  1.7 mmol/L) Triglycerides  150 mg/dL (  1.7 mmol/L) HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L) HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L) Blood pressure  130/  85 mm Hg Blood pressure  130/  85 mm Hg Fasting glucose  100 mg/dL (  5.6 mmol/L) Fasting glucose  100 mg/dL (  5.6 mmol/L) TNT Study Design: Post-Hoc Analysis of Patients With Metabolic Syndrome Atorvastatin 10 mg Open-label run-in 8 weeks 1-8 weeks Screening and wash-out Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) Median follow-up = 4.9 years Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) Double-blind period n=5584 n=2764 n=2820 Baseline 1 Grundy SM et al. Circulation. 2005;112: Metabolic Syndrome Subgroup  28 substituted for waist circumference *BMI  28 substituted for waist circumference

41 Time to First Major Cardiovascular Event in Patients with Metabolic Syndrome (MetS) Time (years) Metabolic Syndrome Subgroup Cumulative incidence of major cardiovascular events* *Coronary heart disease death, nonfatal non–procedure- related myocardial infarction, resuscitated cardiac arrest, fatal or nonfatal stroke Deedwania P et al. Lancet. 2006;368: Metabolic syndrome, no diabetes Atorvastatin 10 mg (n=2191) Atorvastatin 80 mg (n=2162) HR = 0.70 (95% CI: 0.57, 0.84) P=.0002 All metabolic syndrome Atorvastatin 10 mg (n=2820) Atorvastatin 80 mg (n=2764) HR = 0.71 (95% CI: 0.61, 0.84) P<.0001

42 First Major Cardiovascular Event in Patients With Metabolic Syndrome: Summary End pointNo. of patients (%) Atorvastatin 10 mg (n=2820) Atorvastatin 80 mg (n=2764) Major cardiovascular event*367 (13.0)262 (9.5) CHD death66 (2.3)46 (1.7) Nonfatal non–PR MI201 (7.1)139 (5.0) Resuscitated cardiac arrest6 (0.2)10 (0.4) Fatal/Nonfatal stroke94 (3.3)67 (2.4) *HR = 0.71 (95% CI: 0.61, 0.84) P<.0001 *HR = 0.71 (95% CI: 0.61, 0.84) P<.0001 Metabolic Syndrome Subgroup Data on file, Pfizer Inc, New York, NY.

43 Secondary Event Rates in Patients With Metabolic Syndrome (MetS) and Overall Major coronary9.9%7.3% Cerebrovascular6.0%4.5% PAD6.5%6.3% CHF with hosp.4.2%3.1% All-cause mortality6.3%6.2% Any coronary29.8%23.3% Any CV event37.6%30.9% Event rate (MetS)10 mg80 mg 26.5%21.6% 26.5% 21.6% 5.0%3.9% 5.0% 3.9% 3.3%2.4% 5.6%5.5% 5.6% 5.5% 5.6%5.7% 5.6% 5.7% 8.3%6.7% 8.3% 6.7% 33.5%28.1% 33.5% 28.1% Event rate (overall)10 mg80 mg Atorvastatin 80 mg betterAtorvastatin 10 mg better Metabolic Syndrome Subgroup Deedwania P et al. Lancet. 2006;368:

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51 Slide Source LipidsOnline Couillard C et al. Arterioscler Thromb Vasc Biol 2001;21: | Kraus WE et al. N Engl J Med 2002;347: Copyright 2002 Massachusetts Medical Society. All rights reserved. Treating HDL: Nonpharmacologic Methods Exercise overrated  HDL only when TG high  HDL only with intense, frequent exercise Alcohol Raises TG Affects CETP activity Modest HDL changes Smoking cessation Weight loss Changes in HDL-C Concentration (mg/dL) P=0.015 Intense Control Moderate Infrequentexercise Frequent, intense exercise

52 HDL-C Response to Exercise

53 Lipids and Exercise Duration of exercise effect on lipids  TG increase delays for several hours after exercise and this effect can persist for hours or several days when exercise is prolonged and intense.  Usually HDL begins to rise after >10 weeks of exercise  Single exercise sessions reduce postprandial hyperlipidemia but have no other effect on lipids.  After exercise cessation lipids return on original values  The longer the exercise program lasted the longer the favorable lipid profile remains after exercise cessation.

54 Smoking Cessation Increases HDL-C Level In study by Moffatt, smokers had HDL-C levels 15–20% lower than nonsmokers (P < 0.05). 1 –PROCAM showed less of an effect of smoking on HDL-C (7% lower than nonsmokers). 2 HDL-C levels returned to normal within 30–60 days after smoking cessation. 1 In eight women who smoked > 1 packs per day for 5 years, HDL-C levels increased from 51 to 64 mg/dL after quitting for 60 days Moffatt RJ. Atherosclerosis 1988;74:85–89 2. Cullen P et al. Eur Heart J 1998;19:1632–1641

55 Weight and HDL-C Inverse correlation between body weight and HDL-C is consistently observed in both men and women. For every 3 kg of weight loss, HDL-C levels increase 1 mg/dL. Dattilo AM, Kris-Etherton PM. Am J Clin Nutr 1992;56:320–328

56 Caloric Restriction Acutely Lowers HDL-C Level Trials of very-low-calorie diets show that HDL-C levels decrease by 2–12 mg/dL during acute caloric restriction. After 12 wks, HDL-C returned to pretreatment range, and this trend was still apparent after 1 year. Therefore, benefits of weight-loss programs should not be assessed during acute caloric restriction. Rössner S et al. Atherosclerosis 1987;64:125–130

57 Alcohol Increases HDL-C Level Alcohol increases HDL-C level in a dose-dependent manner. Half bottle of wine per day (39 g alcohol) for 6 weeks significantly increased mean HDL-C level by 7 mg/dL in 12 healthy subjects. 1 –Wine intake did not significantly affect Total-C, Total-TG, or LDL-C. 1 One beer per day (13.5 g alcohol) for 6 weeks significantly increased mean HDL-C level by 2 mg/dL in 20 healthy subjects. 2 –Beer intake did not significantly affect LDL-C, VLDL-C, TG, or apolipoproteins. 1. Thornton J et al. Lancet 1983;ii:819– McConnell MV et al. Am J Cardiol 1997;80:1226–1228

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60 HDL-C Response to Pharmacological Intervention

61 ACCORD Study Design Overall ACCORD Glycemia Trial: 10,251 participants Lipid Trial: 5,518 in Lipid Trial 2765 randomized to fenofibrate 2753 randomized to placebo Primary Outcome: First occurrence of a major cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death) 87% power to detect a 20% reduction in event rate, assuming placebo rate of 2.4%/yr and 5.6 yrs follow-up in participants without events.

62 ACCORD Lipid Trial Eligibility Stable Type 2 Diabetes >3 months HbA1c 7.5% to 11% High risk of CVD events = clinical or subclinical disease or 2+ risk factors Age (limited to <80 years after Vanguard) ≥ 40 yrs with history of clinical CVD (secondary prevention) ≥ 55 yrs otherwise Lipids 60 < LDL-C < 180 mg/dl HDL-C < 55 mg/dl for women/Blacks; < 50 mg/dl otherwise Triglycerides < 750 mg/dl if on no therapy; < 400 mg/dl otherwise No contraindication to either fenofibrate or simvastatin

63 CharacteristicMean or %CharacteristicMean or % Age (yrs)62Total Cholesterol (mg/dl)175 Women %31LDL-C (mg/dl)101 Race / EthnicityHDL-C (mg/dl)38 White %68Triglyceride (mg/dl)*162 Black %15Blood pressure (mm Hg)134/74 Hispanic %7Serum creatinine (mg/dl)0.9 Secondary prevent %37Current smoking %15 DM duration (yrs) * 9On a statin %60 A1c (%) * 8.3On another LLA %8 BMI (kg/m 2 )32On Insulin %33 Baseline Characteristics * Median values

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65 Primary Outcome Rate (%/yr) HR (95% CI)P Value Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event ( ) 0.32 FenofibratePlacebo (N=2765)(N=2753) N of Events N of Events

66 Prespecified Secondary Outcomes

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