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

NCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic Syndrome

<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

³110 mg/dL (6.0 mmol/L)Fasting glucose

³130/³85 mmHgBlood pressure

HDL-C

³150 mg/dL (1.7 mmol/L)TG

Abdominal obesity (Waist circumference)

Defining LevelRisk Factor

Recommends a diagnosis when ³3 of these risk factors are present

Adapted from NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486–2497.

PREVALENCE OF METS IN GREECEPREVALENCE OF METS IN GREECE

• Mets-Greece study (Athyros et al). 4056 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, 17-20 April 2004

ATTICA study (Panagiotakos et al). 2282 adults.

Prevalence 19,8%. Men 25,2%, women 14,6%.

Prevalence increased with age.

Am Heart J 2004; 147: 106-12.

The presence of the Metabolic Syndrome is associated with increased CHD, CVD and

total mortality

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 (9.1-13.7) years. Relative risks were determined by age-adjusted Cox proportional hazards regression analysis.

Lakka HM et al, J Am Med Assoc 2002;288:2709-2716

©2004 PPS®

Odds Ratio 95% CI P Value

Metabolic syndrome 2.01 1.53-2.64 <0.0001

Syndrome components

Abdominal obesity 1.15 0.86-1.54 0.3475

High triglycerides 1.51 1.04-2.20 0.0311

Low HDL-C 1.41 1.03-1.95 0.0353

Hypertension 1.42 0.94-2.15 0.0947

Insulin resistance† 1.25 0.92-1.71 0.1461

Ninomiya JK et al. Circulation. 2004;109:42-46.

*Self-reported.†Fasting plasma glucose ³110 mg/dL.

Association of MI* With the Metabolic Syndrome and Individual Components

©2004 PPS®

Ninomiya JK et al. Circulation. 2004;109:42-46.

*Self-reported.†Fasting plasma glucose ³110 mg/dL.

Association of Stroke* With the Metabolic Syndrome and Individual Components

Odds Ratio 95% CI P Value

Metabolic syndrome 2.16 1.48-3.16 0.0002

Syndrome components

Abdominal obesity 0.97 0.58-1.64 0.9154

High triglycerides 1.87 1.22-2.87 0.0052

Low HDL-C 1.18 0.73-1.90 0.5012

Hypertension 1.56 0.94-2.59 0.0827

Insulin resistance† 1.36 0.93-1.98 0.1119

191418,1 16,6

0

20

40

60

80

100

Smoking Diet and sedentarity

Pe

rce

nta

ge

1990 2000

Major causes of death in USA 1990 and 2000

Mokdad AH et al. JAMA 2004

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) 20.0 33.5 3.87 (3.39, 4.42) 3.25 (2.81, 3.76)

Smoking 26.8 45.2 2.95 (2.72, 3.20) 2.87 (2.58, 3.19)

Diabetes 7.5 18.4 3.08 (2.77, 3.42) 2.37 (2.07, 2.71)

Hypertension 21.9 39.0 2.48 (2.30, 2.68) 1.91 (1.74, 2.10)

Abd Obesity (3 v 1) 33.3 46.3 2.22 (2.03, 2.42) 1.62 (1.45, 1.80)

Psychosocial - - 2.51 (2.15, 2.93) 2.67 (2.21, 3.22)

Veg et fruits DIE 42.4 35.8 0.70 (0.64, 0.77) 0.70 (0.62, 0.79)

Exercise 19.3 14.3 0.72 (0.65, 0.79) 0.86 (0.76, 0.97)

Alcohol intake 24.5 24.0 0.79 (0.73, 0.86) 0.91 (0.82, 1.02)

Yusuf S et al, Lancet 2004

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.

HD

L-C

(m

mol/L)

1.5

1.4

1.3

1.2

1.1

0.0

1.3

1.2

1.1

1.0

0.0

1.3

1.2

1.1

1.0

0.0

1.3

1.2

1.1

1.0

0.0

MenWomen

1.5

1.4

1.3

1.2

1.1

0.0

1.5

1.4

1.3

1.2

1.1

0.0

Nonsmokers

Smokers

Nonsmokers

Smokers

Alcohol

No 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

Treatment of obesity

Modest weight loss can be effective

~250-500 kcal/day restriction energy expenditure as tolerated

Monitor blood pressure with anorectic drugs

Treat CHD, LVH and RVH risk factors aggressivelylipids, blood pressure, diabetes, hypertensionobstructive sleep apnea and respiratory

problems

Poirier et al, Circulation 2006

Finnish Diabetes Prevention Study: Treating the IGT* Patient With Lifestyle Changes

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/m2

– 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/m2.IGT=impaired glucose tolerance; BMI=body mass index.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes*

Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes*

Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

11%

23%

0

5

10

15

20

25

Intervention Control

(n=265)

(n=257)

*P<0.001; 4-year results

Diabetes (%)

Bariatric surgery and mortality

• Prospective study

• SOS study

• N=4047 patients

• 10.9 yrs follow-up

• Information: 99.9%

Sjostrom L et al, NEJM 2007

SOS: Mortality reduction with weight-loss surgery

Deaths:Control: 129 (6.3%)Surgery: 101 (5.0%)

Unadjusted HR 0.76 (0.59-0.99), P = 0.04

Adjusted HR 0.71*(0.54-0.92), P = 0.01

*Adjusted for age, sex, risk factors Sjöström L et al. N Engl J Med. 2007;357:741-52.

Years

14

12

0

0 2

Cumulativemortality

(%)

Control

Surgery

4 1614121086

10

8

6

4

2

Surgery(n)

Controls(n)

Cardiovascular condition 43 53

Cardiac Myocardial infarction Heart failure Sudden death

13 220

25 5 14

Stroke 6 6

Other 2 3

Noncardiovascular condition 58 76

Cancer/meningioma 29/0 47/1

Infection 12 3

Thromboembolic disease 5 7

Other 12 18

Total mortality 101 129

SOS: Causes of death

Sjöström L et al. N Engl J Med. 2007;357:741-52.

2007 Guidelines for the Management of

Arterial Hypertension

Journal of Hypertension 2007;25:1105-1187

European Society of Hypertension European Society of Cardiology

Initiation of antihypertensive treatmentOther risk factors, OD or disease

Normal SBP 120-129 or DBP 80-84

High normal SBP 130-139 or DBP 85-89

Grade 1 HTSBP 140-159 or DBP 90-99

Grade 2 HTSBP 160-179 or DBP 100-109

Grade 3 HT SBP ≥180 or DBP ≥110

No other risk factors

No BP intervention

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 factors Lifestyle changes Lifestyle changes

Lifestyle changes for several weeks then drug treatment if BP uncontrolled

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 changesLifestyle changes and consider drug treatment Lifestyle changes

+ drug treatmentLifestyle changes + drug treatment

Lifestyle changes + immediate drug treatmentDiabetes Lifestyle changes Lifestyle changes

+ drug treatment

Established CV or renal disease

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

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

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

Hypertension Guidelines: ESH/ESC 2013

Definitions and classification of office blood pressure levels (mmHg)

Category Systolic Diastolic

Optimal < 120 And < 80

Normal 120-129 And/or 80-84

High normal 130-139 And/or 85-89

Grade 1 hypertension

140-159 And/or 90-99

Grade 2 hypertension

160-179 And/or 100-109

Grade 3 hypertension

> = 180 And/or > = 110

Isolated systolic hypertension

>= 140 and < 90

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

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

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.

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 30-60 ml/min/1.73 m2 (BSA)

Microalbuminuria (30-300 mg/24 h), or albumin- creatinine ratio(30-300 mg/g; 3.4-34 mg/mmol) (preferentially on morning spot urine)

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

Drugs to be preferred in specific conditions

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

Effects of lipid-lowering therapy on CHD events in statin trials

25

20

15

10

5

0

Pat

ient

s w

ith C

HD

eve

nt (

%)

90 110 130 150 170 190 210

S=statin treated P=placebo treated

*Extrapolated to 5 years

4S-P

CARE-P

LIPID-P4S-S

WOSCOPS-SWOSCOPS-P

AFCAPS-PAFCAPS-S

LIPID-S

CARE-S

Primary Prevention

Simvastatin

Pravastatin

Lovastatin

Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21.

HPS-S

HPS-P

Atorvastatin

ASCOT-S*ASCOT-P*

Secondary Prevention

LDL-C (mg/dL)

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)* 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) Blood pressure 130/85 mm Hg 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 weeks1-8 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 periodn=5584

n=2764

n=2820

Baseline

1Grundy SM et al. Circulation. 2005;112:2735-2752.

Metabolic Syndrome Subgroup

*BMI 28 substituted for waist circumference

0 1 2 3 4 5 60

2

4

6

8

10

12

14

16

18

20

Time to First Major Cardiovascular Event in Patients with Metabolic Syndrome (MetS)

Time (years)

Metabolic Syndrome Subgroup

Cu

mu

lati

ve i

nci

den

ce o

f m

ajo

r ca

rdio

vasc

ula

r ev

ents

*

*Coronary heart disease death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, fatal or nonfatal stroke Deedwania P et al. Lancet. 2006;368:919-928.

Metabolic syndrome, no diabetesAtorvastatin 10 mg (n=2191)Atorvastatin 80 mg (n=2162)

HR = 0.70 (95% CI: 0.57, 0.84) P=.0002

All metabolic syndromeAtorvastatin 10 mg (n=2820)Atorvastatin 80 mg (n=2764)

HR = 0.71 (95% CI: 0.61, 0.84) P<.0001

First Major Cardiovascular Event in Patients With Metabolic Syndrome: Summary

End point No. of patients (%)

Atorvastatin 10 mg (n=2820)

Atorvastatin 80 mg (n=2764)

Major cardiovascular event* 367 (13.0) 262 (9.5)

CHD death 66 (2.3) 46 (1.7)

Nonfatal non–PR MI 201 (7.1) 139 (5.0)

Resuscitated cardiac arrest

6 (0.2) 10 (0.4)

Fatal/Nonfatal stroke 94 (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.

Secondary Event Rates in Patients With Metabolic Syndrome (MetS) and Overall

Major coronary 9.9% 7.3%

Cerebrovascular 6.0% 4.5%

PAD 6.5% 6.3%

CHF with hosp. 4.2% 3.1%

All-cause mortality 6.3% 6.2%

Any coronary 29.8% 23.3%

Any CV event 37.6% 30.9%

Event rate (MetS) 10 mg 80 mg

26.5% 21.6%

5.0% 3.9%

3.3% 2.4%

5.6% 5.5%

5.6% 5.7%

8.3% 6.7%

33.5% 28.1%

Event rate (overall) 10 mg 80 mg

Atorvastatin 80 mg better Atorvastatin 10 mg better

Metabolic Syndrome Subgroup

Deedwania P et al. Lancet. 2006;368:919-928.

0.4 0.6 0.8 1.0 1.2 1.4

All-cause mortality

MetS

PAD

MetS

CHF with hospitalization

MetS

Cerebrovascular event

MetS

Any coronary event

MetS

Major coronary event

MetS

Any CV event

MetS

Hazard ratio (95% CI)

Slide SourceLipidsOnline

www.lipidsonline.org

Couillard C et al. Arterioscler Thromb Vasc Biol 2001;21:1226-1232. | Kraus WE et al. N Engl J Med 2002;347:1483-1492. 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

Ch

an

ges

in H

DL-

CC

on

cen

trati

on

(m

g/d

L)

7

4

1

0

-2

P=0.015

Intense

Control

Moderate

Infrequent exercise

Frequent, intense exercise

HDL-C Response to Exercise

Lipids and Exercise Duration of exercise effect on lipids TG increase delays for several hours after exercise and this effect

can persist for 24-48 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.

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.1

1. Moffatt RJ. Atherosclerosis 1988;74:85–892. Cullen P et al. Eur Heart J 1998;19:1632–1641

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

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

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:819–8222. McConnell MV et al. Am J Cardiol 1997;80:1226–1228

HDL-C Response to Pharmacological Intervention

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.

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

Characteristic Mean or % Characteristic Mean or %

Age (yrs) 62 Total Cholesterol (mg/dl)

175

Women % 31 LDL-C (mg/dl) 101

Race / Ethnicity HDL-C (mg/dl) 38

White % 68 Triglyceride (mg/dl)* 162

Black % 15 Blood pressure (mm Hg)

134/74

Hispanic % 7 Serum creatinine (mg/dl)

0.9

Secondary prevent %

37 Current smoking % 15

DM duration (yrs)* 9 On a statin % 60

A1c (%) * 8.3 On another LLA % 8

BMI (kg/m2) 32 On Insulin % 33

Baseline Characteristics

* Median values

140

150

160

170

180

190

200

0 1 2 3 4 5 6 7

mg

/dl

Years Post-Randomization

Mean Total Cholesterol

Feno

Placebo

N = 5483 5180 4988 4783 5250 3377 1668 491

60

70

80

90

100

110

120

0 1 2 3 4 5 6 7

mg

/dl

Years Post-Randomization

Mean LDL-C

Feno

Placebo

N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491

37

38

39

40

41

42

0 1 2 3 4 5 6 7

mg

/dl

Years Post-Randomization

Mean HDL-C

Feno

Placebo

N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491

110

120

130

140

150

160

170

0 1 2 3 4 5 6 7

mg

/dl

Years Post-Randomization

Median Triglycerides

Feno

Placebo

N = 5432 5180 4988 4783 5250 3377 1668 491

Primary Outcome

Rate Rate(%/yr) (%/yr) HR (95% CI) P Value

Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event

291 2.24 310 2.41 0.92 (0.79 - 1.08)

0.32

Fenofibrate Placebo(N=2765) (N=2753)

N of Events

N of Events

Prespecified Secondary Outcomes

Rate Rate(%/yr) (%/yr) HR (95% CI) P Value

Primary + Revasc + hospitalized CHF

641 5.35 667 5.64 0.94 (0.85-1.05) 0.30

Major Coronary Event 332 2.58 353 2.79 0.92 (0.79-1.07) 0.26

Nonfatal MI 173 1.32 186 1.44 0.91 (0.74 - 1.12) 0.39

Total Stroke 51 0.38 48 0.36 1.05 (0.71 - 1.56) 0.80

Nonfatal Stroke 47 0.35 40 0.30 1.17 (0.76 - 1.78) 0.48

Total Mortality 203 1.47 221 1.61 0.91 (0.75 - 1.10) 0.33

Cardiovascular Death 99 0.72 114 0.83 0.86 (0.66 - 1.12) 0.26

Fatal/Nonfatal CHF 120 0.90 143 1.09 0.82 (0.65 - 1.05) 0.10

Fenofibrate Placebo

Outcome

(N=2765) (N=2753)N of

EventsN of

Events