management of dyslipidemia in the metabolic …presentation outlines •metabolic syndrome (ms)...

Management of Dyslipidemia in

the Metabolic Syndrome: Data

from the MENA Region

KHALID AL RASADI, MD

Head of Lipid and LDL-Apheresis Division

Sultan Qaboos University Hospital, Oman

Advisory Board, Speaker’s Bureau

AstraZeneca

MSD

Aegerion

Disclosure

Presentation Outlines

• Metabolic Syndrome (MS) Definition

• Relation between MS and Cardiovascular

disease(CVD)

• Management of MS

• MS in the MENA region

• Conclusion

Després JP. Ann Med. 2006;38:52-63.

Conceptual Definition of the Most Prevalent Form of the Metabolic Syndrome: Abdominal Obesity

NCEP ATP III

• Waist girth

• HDL cholesterol

• Triglycerides

• Blood pressure

• Glucose

AACE • Glucose

• BMI

• HDL cholesterol

• Triglycerides

• Blood pressure

• Other features

of insulin

resistance

EGIR • Insulin

• Waist girth

• Glucose

• HDL cholesterol

• Triglycerides

• Blood pressure

IDF • Waist girth

• HDL cholesterol

• Triglycerides

• Blood pressure

• Glucose

Hyper TG

Waist

• Waist girth

• Triglycerides

Others

?

WHO • Insulin

• Glucose

• WHR, BMI

• HDL cholesterol

• Triglycerides

• Blood pressure

• Microalbuminuria

Clinical Tools to Find Patients with the Metabolic Syndrome

• Atherogenic dyslipidemia

• Insulin resistance/ Glucose intolerance

• Proinflammatory profile

• Prothrombotic profile

• Raised blood pressure (in about 50% of patients)

may evolve to

type 2 diabetes

Measure (any 3 of 5 constitute

diagnosis of metabolic syndrome)

Categorical cutpoints

Elevated waist circumference ≥102 cm in men

≥88 cm in women

Elevated triglycerides ≥150 mg/dl (1.7 mmol/l) or

on drug treatment for elevated triglycerides

Reduced HDL-cholesterol <40 mg/dl (0.9 mmol/l) in men

<50 mg/dl (1.1 mmol/l) in women

Or on drug treatment for reduced HDL-C

Elevated blood pressure ≥130 mmHg systolic blood pressure or

≥85 mmHg diastolic blood pressure

or on antihypertensive drug treatment in a

patient with a history of hypertension

Elevated fasting glucose ≥100 mg/dl or

on drug treatment for elevated glucose

2005 Revised ATP III Clinical Screening Criteria

to Identify Metabolic Syndrome (AHA and NHLBI)

Current Recommended Waist

Circumference Thresholds for Abdominal

Obesity by Organization

(Circulation. 2009;120:1640-1645.)

Defining Global Cardiometabolic Risk

From global CVD risk to…..

Global Cardiometabolic Risk

+

Traditional Risk Factors Metabolic Syndrome

Diabetes Hypertension

Smoking

LDL

Cholesterol

HDL

Insulin resistance Insulin

Emerging markers

Visceral Obesity

HDL = high-density lipoprotein; LDL = low-density lipoprotein

Cardiometabolic Risk

Global Diabetes/ CVD Risk

Factors Contributing to Cardiometabolic Risk

Diabetes.org/CMR

Overweight/Obesity

Insulin Resistance

Lipids BP Glucose

Insulin Resistance Syndrome

?

Age Genetics

Smoking, Physical Inactivity

Hypertension

Age, Race, Gender, Family History

Inflammation, Hypercoagulation

LDL ApoB HDL Triglycerides

Abnormal Lipid Metabolism

Characteristics of lipid disorders in

Metabolic Syndrome

Atherogenic Dyslipidaemia

TG

Apo B VLDL

LDL

(CETP) TG CE

Insulin

Resistant

Abdominal

Adipocytes

Liver

FFA CE

TG

( HL)

small, Dense

LDL

HD2

(HL)

Kidney

Apo A-1

HDL3

Insulin Resistance of Abdominal Adipose Tissue

and Atherogenic Dyslipidaemia

(CETP)

LDL

St Pierre, et al. Circulation. 2001:104:2295.

Small, Dense, LDL Particles were an Independent

Risk Factor for CAD in Quebec Cardiovascular Study

0

10

20

30

40

50

60

70

80

Downs JR et al. JAMA 1998;279:1615-1622.

Air Force/Texas Coronary Atherosclerosis Prevention

Study (AFCAPS/TexCAPS): Risk Reduction by

HDL-C Tertile at Baseline

HDL-C Levels

Placebo

Lovastatin

<34 mg/dl 35–39 mg/dl >40 mg/dl

71

40

68

41 44 35

44% RR

40% RR

20% RR

0

2

4

6

8

10

12

14

16

Barter PJ et al. J Am Coll Cardiol 2006;47:492499. | Waters DD et al. J Am Coll Cardiol 2006;48:17931799.

Major Cardiovascular Events According to On-treatment HDL-C: Treating to New Targets (TNT) Trial

%

Atorvastatin 10 mg Atorvastatin 80 mg Mean LDL-C

73 mg/dL

Mean LDL-C

99 mg/dL

On-treatment HDL-C (mg/dL)

<40 <40 >40-50 >40-50 >50-60 >60 >60 >50-60

Importance of Identifying Metabolic Syndrome?

• Presence of the metabolic syndrome carries increased

risk for cardiovascular disease (2 folds) and type 2

diabetes (5 folds)

• Others are at less risk in the short term, but are

exposed to a high long-term risk

• Some affected people are at high or moderately high

risk for major cardiovascular events in the short term

(<10 years)

Risk Assessment

CV risk assessment remains imperfect

• Framingham Risk Score (CVD) [FRS may

underestimate risk in some patients]

• Reynolds Risk Score (CVD) [RRS web-based,

includes family history and hsCRP]

0

2

4

6

8

10

Number of Components of the Metabolic Syndrome

CRP (

mg/L

)

Distribution of C-Reactive Protein (CRP) Levels by Number of Components of the Metabolic Syndrome: Women’s Health Study

Reprinted from Ridker PM, et al. Circulation. 2003;107: 391–397, with permission from Wolters Kluwer Health.

0 1 2 3 4 5

Box plots denote median and 25th and 75th percentile CRP values

p-trend < .0001

n=4086

0.68 1.09

1.93

3.01 n=3884

3.88

5.75

n=3152

n=2292

n=1135

n=170

Sattar N, et al. WOSCOPS. Circulation. 2003;108:414-9.

High CRP Adds More Predictive Power for CHD in

Patients with the Metabolic Syndrome In West of Scotland Coronary

Prevention Study (WOSCOPS)

Tzou WS, et al. J Am Coll Cardiol. 2005;46:457-463.

Composite carotid intimal medial thickness (CIMT)

with metabolic syndrome in young adults

The Number of Metabolic Syndrome Components

Correlate with Carotid Intimal Medial Thickness

A Greater Number of Metabolic Syndrome Components Leads to Greater Risk for CV Events: Framingham Offspring Study 8-Year Follow-Up

Wilson PWF et al. Circulation 2005;112:3066-3072. Used with permission of Lippincott Williams & Wilkins.

Event

No. of Metabolic Syndrome Risk

Factors

Age-Adjusted Relative Risk (95% CI)

Men Women

CVD 0 Referent Referent

1–2 1.48 (0.69–3.16) 3.39 (1.31–8.81)

≥3 3.99 (1.89–8.41) 5.95 (2.20–16.11)

Hard CHD 0 Referent Referent

1–2 0.98 (0.36–2.67) 3.77 (0.45–31.28)

≥3 2.55 (0.96–6.79) 7.21 (0.81–64.37)

Total CHD 0 Referent Referent

1–2 1.24 (0.54–2.83) 3.29 (0.95–11.34)

≥3 3.01 (1.33–6.83) 3.96 (1.02–15.38)

T2DM 0 Referent Referent

1–2 4.16 (0.98–17.64) 6.10 (1.85–20.10)

≥3 23.83 (5.80–98.01) 29.69 (9.10–96.85)

With the WHO definition the metabolic syndrome has a stronger

predictive value for the risk of CV event than any of its components

Isomaa B, et al ( Botnia study). Diabetes Care 2005; 683-689.

CHD

(n = 2 401)

MI

(n = 2 404)

Stroke

(n = 2 395)

Independent variables RR P RR P RR P

The metabolic syndrome

Obesity

Dyslipidaemia

Hypertension

Microalbuminuria

Insulin resistance

2.96

1.44

1.73

1.57

0.94

1.53

<0.001

0.07

<0.001

0.002

0.77

0.01

2.63

1.31

1.71

1.31

0.76

2.02

<0.001

0.43

0.01

0.22

0.37

0.009

2.27

1.26

1.30

1.34

0.85

1.39

<0.001

0.59

0.40

0.34

0.73

0.36

Metabolic Syndrome Predictive of CV Events

Association of MI* with the Metabolic Syndrome and Individual Components

Odds Ratio 95% CI p

Metabolic syndrome 2.01 1.53–2.64 <.0001

Syndrome components

Abdominal obesity 1.15 0.86–1.54 .3475

High triglycerides 1.51 1.04–2.20 .0311

Low HDL-C 1.41 1.03–1.95 .0353

Hypertension 1.42 0.94–2.15 .0947

Fasting glucose ≥ 110 1.25 0.92–1.71 .1461

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

* Self-reported

Metabolic Syndrome:

Meta-analysis of Cardiovascular Risk

Motillo S, Eisenberg M. 2009 Unpublished

0

5

10

15

20

25

0 1 2 3 4

Cu

mu

lati

ve

Ra

te o

f D

iab

ete

s (

%)

Presence of Metabolic Syndrome

Absence of Metabolic Syndrome

Events of Incident Diabetes by Presence or Absence of Metabolic Syndrome at Baseline

Time (Years)

Sattar, N. et al., Lancet 2008;1-9.

*In participants without baseline

vascular disease in PROSPER

Incident Diabetes after Stratification by Age or BMI, IGT, and the Metabolic Syndrome

p<0.0001

p<0.0001

P=0.018

NCEP

definition

%

Yes

No No Yes

IGT

0

10

20

30

40

50

60

Copyright © 2003 American Diabetes Association. From Diabetes, Vol. 26, 2003;3153-3159. Reprinted with permission from The American Diabetes Association.

Reduce BMI and waist circumference

Calories, glycemia Daily activity/exercise Behavior therapy Medication-Current, CB1 Antagonists, others in

development, combinations

Adipose Tissue

Diet

Meds

DASH

Na

ETOH

Hypertension

ACEI ARB

Fiber

Glycemic diet

IGT

Metformin Exenatide

Omega-3s MUFA Sat fat Trans fat Glycemia + ETOH

ATP III guidelines: TLC diet

Dyslipidemia

Statins Fibrate

Slide courtesy of Dr. Caroline M. Apovian.

New Treatment Approach

Development of the Metabolic Syndrome by Intervention Group in the Diabetes Prevention Program - Cumulative Incidence

0.00

0.15

0.30

0.45

0.60

0.75

Cum

ula

tive I

ncid

ence o

f th

e

Meta

bolic S

yndro

me

Time Since Randomization,

Orchard TJ et al. Ann Intern Med 2005;142:611-619

0 1 2 3 4

61%

50%

38%

Placebo group (n = 490)

Metformin group (n = 503)

Lifestyle group (n = 530)

41% decrease in the cumulative incidence of MS

Goals for Therapy: 2004 Addendum

Primary prevention ( LDL-C goal therapy < 2.6

mmol/L

Secondary prevention <70 is option for very

high risk patients (CAD + metabolic syndrome)

Goals

LDL-C Non–HDL-C Apo B

Highest-Risk Patients <70 mg/dL <100 mg/dL <80 mg/dL

• Known cardiovascular disease (CVD)

• Diabetes plus ≥1 additional major CVD risk factor

High-Risk Patients <100 mg/dL <130 mg/dL <90 mg/dL

• No diabetes or known CVD but ≥2 major CVD risk factors

• Diabetes but no other major CVD risk factors

“In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C, especially if Apo B levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid…”

Reprinted from Brunzell JD, et al. J Am Coll Cardiol. 2008;51:1512–1524, with permission from Elsevier.

ADA/ACC 2008 Consensus Statement: Treatment Goals for Patients With Cardiometabolic Risk and Lipoprotein Abnormalities

ADA=American Diabetes Association; ACC=American College of Cardiology

Isolated LDL-C RR=0.86 (0.59–1.26)

221

“Metabolic Syndrome” in Scandinavian Simvastatin

Survival Study (4S) Event

Rate

, %

Ballantyne CM et al. Circulation 2001;104:3046-3051. Used with permission of Lippincott Williams & Wilkins.

Simvastatin

Placebo

237 261 284

18.0 20.3 19.0

Lipid Triad RR=0.48 (0.33–0.69)

0

10

20

30

40

36.9

Lancet 2006; 368: 919–28

Reduction of low-density lipoprotein cholesterol in patients with coronary

heart disease and metabolic syndrome: analysis of the Treating to New

Targets study

30%

RRR

Normalization of metabolic

syndrome using fenofibrate,

metformin or their

combination

Nieuwdorp, M. et al., Diabetes Obes Metab 2007;9:869-78.

Normalization of metabolic syndrome using

fenofibrate, metformin or their combination

Methods

• 'Normalized' was defined as not having MetS

biochemical abnormalities at the 3-month

treatment period

• A total of 681 patients were analyzed (mean

age 56 years, 59% men, mean body mass

index 31.6 and 33.3 in male and female

patients respectively)


Normalization of metabolic syndrome using

fenofibrate, metformin or their combination

Results

• Accordingly, F 80mg + M 850mg twice daily

was most effective for normalizing

triglycerides (55.0%), high-density

lipoprotein cholesterol (35.0%) and fasting

glucose (39.4%)

• All the treatments were well tolerated, with

comparable adverse-event rates between

groups


Percentage of patients (plus 95% CI) in whom MetS was reversed

during the treatment period (i.e. patients with ≥3 of the ATP III MetS

criteria at baseline and <3 criteria at treatment end

F160-

M1700

(n=109)

F160-

M1000

(n=104)

F80-

M1700

(n=106)

F80-

M1000

(n=104)

F160

(n=103)

M1700

(n=100)

Placebo

(n=55)


Pa

tie

nts

wit

ho

ut

Me

tS a

t s

tud

y e

nd

(%

)

66.0 59.6

62.9 63.2

53.1

44.0

36.5

*p<0.05 vs. F160-M1700

*

*

Framingham 10-year risk score (mean + s.e.) (Wilson et al. [12]) in

each group at baseline and treatment end


F160-

M1700

(n=102)

F160-

M1000

(n=94)

F80-

M1700

(n=98)

F80-

M1000

(n=94)

F160

(n=92)

M1700

(n=91)

Placebo

(n=53)

Trial

(Drug)

Primary Endpoint:

Entire Cohort

(P-value)

Lipid Subgroup

Criterion

Primary

Endpoint:

Subgroup

HHS (Gemfibrozil)

-34% (0.02)

TG > 200 mg/dl

LDL-C/HDL-C

> 5.0

-71%

BIP (Bezafibrate)

-7.3% (0.24)

TG > 200 mg/dl

-39.5%

FIELD (Fenofibrate)

-11% (0.16)

TG > 204 mg/dl

HDL-C < 42

mg/dl

-27%

ACCORD (Fenofibrate)

-8% (0.32)

TG > 204 mg/dl

HDL-C < 34

mg/dl

-31%

Prevalence of MeS in different Countries

Prevalence

(%)

Sample Year Country

23 542 2003 Arab Americans

21 1419 2001 Oman

36 1121 2002 Jordan

20.8 2250 2004 Saudi Arabia

17* 1998 Palestine

27.6 817 2007 Qatar

33.4* 1637 2004 Turkey

33.7 10368 ? Iran

* Crude rates Mussallam et al. Int J Food Safety and PH 2008

Prevalence of the Metabolic Syndrome in Patients With

Acute Coronary Syndrome in Six Middle Eastern

Countries (n = 8716)

THE JOURNAL OF CLINICAL HYPERTENSION, VOL. 12 NO. 11 NOVEMBER 2010

Overall 46%

In-Hospital Outcomes of Metabolic Syndrome

in Patients With Acute Coronary Syndrome in

Six Middle Eastern Countries (n = 8716)

THE JOURNAL OF CLINICAL HYPERTENSION, VOL. 12 NO. 11 NOVEMBER 2010

Prevalence of the Different Types of Metabolic

Syndrome in Patients With Acute Coronary

Syndrome in Oman (n =1392)

ANGIOLOGY 2011 62: 381

Centralized pan-Middle East Survey on the undertreatment of

hypercholesterolemia: Results from the CEPHEUS Study in

Arabian Gulf States (n = 5276)

Total patients with non-missing data N

Survey Cohort n

Values

Male 5261 3060 58.2%

Race (GCC) 5276 3916 74.2%

Age (mean+SD) years 5276 55.6 (11.3) SBP (mean+SD) mmHg 5268 132.0 (18.2) DBP (mean+SD) mmHg 5268 78.7 (10.3) Body weight (mean+SD) kg 5271 82.1 (17.4) Waist circumference (mean+SD) cm 5133 103.3 (13.9) BMI (mean+SD) 5260 31.4 (6.9) History of CHD 5272 1616 30.7%

History of PAD 5272 149 2.8%

History of Cerebrovascular Disease 5272 192 3.6%

Current Smoker 5276 627 11.9%

Diabetes 5276 3350 63.5%

Metabolic syndrome 5244 1945 37.1%

Arterial hypertension 5276 2607 66.6%

Family history of premature CVD 5276 1086 20.6%

Single LLD

Statins 5272 4926 93.4%

Fibrates 5272 46 0.9%

Other 5272 27 0.5%

Combination LLD 5272 273 5.2%

Unpublished data

Attainment of low-density lipoprotein

cholesterol (LDL-C) goals in the CEPHEUS

Study in Arabian Gulf States (n = 5276)

Unpublished data

(CEPHEUS) LDL Control Across Risk Factor

Secondary Objective: Sub Groups

LDL control according to NCEP

ALL 52.04%

Risk Factor Yes No

Count % Count %

Metabolic Syndrome 891 45.81% 1838 55.71%

Current Smoker 288 45.93% 2457 52.85%

Diabetes 1589 47.43% 1156 60.02%

Arterial Hypertension 1751 50.11% 994 55.78%

CVD Family History 526 48.43% 2219 52.96%

20

04

up

date

d N

CEP

ATP

III

Unpublished data

CONCLUSION

Cardiometabolic risk is defined as the global CVD risk,

resulting from the presence of traditional risk factors, and

the features of the metabolic syndrome.

Presence of the metabolic syndrome carries increased

risk for cardiovascular disease and type 2 diabetes

New studies are needed to clarify better ways of

understanding the implications of the metabolic syndrome

and therefore improve its management.

The prevalence of MS is increasing in the MENA region

and a more aggressive strategies need to be implicated

for its management.

management of dyslipidemia in the metabolic …presentation outlines •metabolic syndrome (ms)...

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