metabolic syndrome - drug management- chih-hsing wu, md body composition, obesity and osteoporosis...

Metabolic Syndrome- Drug Management-

Chih-Hsing Wu, MD

Body Composition, Obesity and Osteoporosis Research Center, Department of Family Medicine, NCKUH

Definition of Metabolic Syndrome in Taiwan2007-01-18

修正前（臺灣 2004 年版） 修正後（臺灣 2006 年版）

危　險　因　子 異　常　值 危　險　因　子 異　常　值

腹部肥胖 (Central obesity) / 或身體質量指數（ BMI ）

腰圍（ waist ） :男性 ≧ 90 cm 女性 ≧ 80 cm ；或BMI ≧27

腹部肥胖(Central obesity)

腰圍（ waist ） :男性 ≧ 90 cm女性 ≧ 80 cm

血壓 (BP) 上升SBP ≧130 mmHg /DBP ≧85 mmHg

血壓 (BP) 上升SBP ≧130 mmHg /DBP ≧85 mmHg

高密度酯蛋白膽固醇(HDL-C) 過低

男性 <40 mg/dl女性 <50 mg/dl

高密度酯蛋白膽固醇 (HDL-C) 過低

男性 <40 mg/dl ；女性 <50 mg/dl

空腹血糖值(Fasting glucose) 上升

FG ≧110 mg/dl空腹血糖值(Fasting glucose) 上升

FG ≧100 mg/dl

三酸甘油酯(Triglyceride) 上升

TG ≧150 mg/dl三酸甘油酯(Triglyceride)上升

TG ≧150 mg/dl

http://www.bhp.doh.gov.tw

代謝症候群臨床案例• 60 歲陳 xx 先生，有心血管疾病家族史• 不抽煙，偶而應酬喝酒，週末爬山運動• 身高 168 公分，體重 70 公斤，腰圍 92(90) 公分，體脂率

28%• 血壓 136 / 86 (130/85) mmHg ，心跳 72/min• 抽血檢查 空腹血糖 105 mg/dl (100),

膽固醇 204 mg/dl, 三酸甘油脂 156 mg/dl (150), 高密度膽固醇 36 mg/dl (40), 尿酸值 8.1 mg/dl,

肌酸酐 1.1 mg/dl,• 腹部超音波：中度脂肪肝

Metabolic Syndrome = Pre-Disease

MicrovascularMicrovascularComplicationsComplicationsMicrovascularMicrovascularComplicationsComplications

MacrovascularMacrovascularDiseaseDisease

MacrovascularMacrovascularDiseaseDisease

Ris

kR

isk

Rel

ativ

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elat

ive

To

Gen

eral

Pop

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tion

To

Gen

eral

Pop

ula

tion

00

11

22

33

44

-15-15 -10-10 -5-5 55 1010 151500-20-20 2020

55

66

Years of DiabetesYears of Diabetes

Insulin ResistanceInsulin Resistance

DyslipidemiaDyslipidemia

HypertensionHypertension

HyperglycemiaHyperglycemia

©© 2001 International Diabetes Center. All rights reserved. 2001 International Diabetes Center. All rights reserved.Adapted from: Kendall DM. Adapted from: Kendall DM. Am J Manag CarAm J Manag Care 7S327-S343, 2001.e 7S327-S343, 2001.

““Pre-diabetes”Pre-diabetes” Type 2 DiabetesType 2 Diabetes

Metabolic syndromeMetabolic syndrome

新陳代謝症候群個案的主要成份組

人數 佔新陳代謝症候群個案(1023) 之百分比

新陳代謝症候群 1023 100%

肥胖 852 83.3%

肥胖 + 高三酸甘油酯症 696 68.04%

肥胖 + 高三酸甘油酯症 + 高血壓 457 44.67%

肥胖 + 高三酸甘油酯症 + 高血壓+ 低的高密度膽固醇

232 22.68%

CVD Risks and Anthropometric Index in Male Elderly Taiwanese

- Huang KC, et al. Obes Res 2005;13:170-8

CVD Risks and Anthropometric Index in Female Elderly Taiwanese

- Huang KC, et al. Obes Res 2005;13:170-8

Obesity and Metabolic Syndrome:A Cluster of Coronary Heart Disease Risk Factors

Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.

RaisedRaisedBlood PressureBlood Pressure

AutonomicAutonomicDysfunctionDysfunction

ProinflammatoryProinflammatoryStateState

GeneticGeneticSusceptibilitySusceptibility

GeneticGeneticSusceptibilitySusceptibility

InsulinInsulinResistanceResistance

ObesityObesityDiet

Physical InactivityStress

ProthromboticProthromboticStateState

Small Low-DensitySmall Low-DensityLipoprotein ParticlesLipoprotein Particles

High-Density High-Density Lipoprotein CholesterolLipoprotein Cholesterol

TriglyceridesTriglycerides

AtherogenicAtherogenicDyslipidemiaDyslipidemia

O b e s i t y I s S t r o n g ly A s s o c ia te d w i t h O b e s i t y I s S t r o n g ly A s s o c ia te d w i t h M e ta b o l ic S y n d r o m e M e ta b o l ic S y n d r o m e N H A N E S I I IN H A N E S I I I

Ad

jus

ted

Od

ds

Rat

io(±

95%

CI)

< 1 8 . 5 1 8 . 5 - 2 4 . 9 2 5 . 0 - 2 9 . 9 3 0 . 0 - 3 4 . 5 3 5 . 0

B o d y M a s s In d e x ( k g /m 2 )

P a r k Y W , e t a l . A r c h In t e r n M e d . 2 0 0 3 ; 1 6 3 : 4 2 7 - 3 6 .

0 . 1

1

1 0

1 0 0

1 0 0 0

M e n

W o m e n

**

**

**

* P < . 0 0 1 c o m p a r e d t o B M I 1 8 . 5 to 2 4 . 9

肥胖的定義

35 以上 35 以上 40 以上肥胖 ( 第三度 )

30.0~34.9 30.0~34.9 35.0~39.9肥胖 ( 第二度 )

27.0~29.9 25.0~29.9 30.0~34.9肥胖 ( 第一度 )

24.0~26.9 23.0~24.9 25.0~29.9過重18.5~23.918.5~22.918.5~24.9正常小於 18.5小於 18.5小於 18.5過輕

台灣2002

亞太地區(2000)

世界衛生組織1998

定義

身體質量指數 = 體重 ( 公斤 ) 身高 ( 公尺 )2

35 以上 30.0~34.9

27.5~29.9

23.0~23.918.5~22.9

小於 18.5

亞太地區(2005)

24.0~26.9

減重 16 週前後代謝症候群的比例

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

減重前 減重後＊配對 T 檢定

P<0.05*

比例

Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.

亞太肥胖治療建議亞太肥胖治療建議飲食控制 加強運動 藥物治療 極低熱量 手術治療

體重過重(23BMI25 kg/m2) 無慢性病者 腰圍過粗 有慢性病者(糖尿病,高血壓,高血脂,心臟病等)

肥胖 (25BMI30 kg/m2) 無慢性病者 腰圍過粗 有慢性病者(糖尿病,高血壓,高血脂,心臟病等)

過度肥胖 (BMI30 kg/m2) 無慢性病者 腰圍過粗 有慢性病者(糖尿病,高血壓,高血脂,心臟病等)

Drugs Approved by FDA for Treating Obesity

Generic NameTrade Names

DEA Schedule

Approved Use

Year Approved

Orlistat Xenical None Long-term 1999

Sibutramine Meridia IV Long-term 1997

Diethylpropion Tenulate IV Short-term 1973

PhentermineAdipex, lonamin

IV Short-term 1973

PhendimetrazineBontril, Prelu-2

III Short-term 1961

Benzphetamine Didrex III Short-term 1960

--Yanovski SZ, et al. N Engl J Med 2002;346:591-602Yanovski SZ, et al. N Engl J Med 2002;346:591-602

15

羅氏鮮 (Xenical) 減重機轉

30% of triglycerides

pass undigested

and areexcreted.

羅氏鮮可減少食物中 30% 的脂肪攝取量

Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year

Study or Sub-category

WMD (random)95% CI

Hollander 1998*

Sjostrom 1998

Davidson 1999

Finer 2000

Heuptman 2000

Lindgarde 2000

Rossner 2000

Bakris 2002

Broom 2002

Kelley 2002*

Miles 2002*

Total (95% CI)

Padwal et al. Int J Obes 2003;27:1437

*All subjects had type 2 diabetesWMD=weighted mean difference Favours

TreatmentFavoursControl

-10 -5 0 105

•FDA advisory committee approval for a low dose (60 mg) over-the-counter orlistat product (Alli) in 2007.

NANA

5-HT5-HT

Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.

S = sibutramine

= noradrenaline, = serotonin

諾美婷諾美婷 ((Reductil)Reductil) 的作用機轉的作用機轉

RELEASE

RELEASE

S

S

SCa

tabo

lism

Cata

bolis

m

Reuptake

MAO

Reuptake

MAO

S

Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year

Study or Sub-category

WMD (random)95% CI

McMahon 2000

Smith 2001

McMahon 2002 *

Total (95% CI)

Padwal et al. Int J Obes 2003;27:1437

•All subjects had hypertensionWMD=weighted mean difference

-10Favours

TreatmentFavoursControl

-5 0 105

-11.7

-4.4

-13.5

-9.4

-3.6

-14-13.7

-5.1

-16.7

-6.2

-2.5

-8.4

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Sibutramine Orlistat S+O Diet

BW

BMI

WC

Sibutramine, Orlistat or Combination Therapy for 12 week

in Turkey(n=86)-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80

BW change(Kg) BW change(%) BMI(Kg/M2) BF change(%)-17.5

-15.0

-12.5

-10.0

-7.5

-5.0

-2.5

Low caloric diet VLCD Sibutramine Orilstat

the

dif

fere

nc

e o

f m

ea

su

reSimilar Effects

The body weight, BMI and body fat change between baseline and 6-month interval in NCKUH

* *

* *

*

Wu CH, et al. 2008: submitted

Average weight loss of subjects completing a minimum 1-year weight-management intervention; based on review

of 80 studies (N=26,455; 18,199 completers [69%]).

Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.

• 目標• 減輕多餘體重• 維持 BMI• 血壓• 血糖• 血糖控制 (HbA1c)

• 其他危險因素

• 治療成功• 5-6Kg 或初始體重的 10%• < 23 kg/M 2

• 任何程度的下降• 任何程度的下降• 任何程度的改善• 任何程度的減少

合理實際的減重目標2000 年亞太肥胖組織共識

Cardinal Behaviors of Successful Long-term Weight Management

National Weight Control Registry Data

• Self-monitoring:– Diet: record food intake daily, limit certain foods or food

quantity– Weight: check body weight >1 x/wk

• Low-calorie, low-fat diet:– Total energy intake: 1300-1400 kcal/d– Energy intake from fat: 20%-25%

• Eat breakfast daily• Regular physical activity: 2500-3000 kcal/wk

(eg, walk 4 miles/d)Klem et al. Am J Clin Nutr 1997;66:239. McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.

Pathogenesis of Metabolic syndrome

2 major, interacting causes • Obesity and abnormal body fat distribution

disorders of adipose tissue.• Endogenous metabolic susceptibility Insulin resistance• A constellation of independent factors

(e.g. molecules of hepatic, vascular, and immunologic origin) Contributors: aging , proinlfammatory state, hormonal change.

Grundy SM et al: Circulation 2004;109:433-8Grundy SM: Am J Clin Nutr 2006 Aug 1248

- Diabetologia 2003;(suppl 1):M30-M36

Mean Efficacy of Pharmacological Treatment Options in Type II DM

Side Effect of Oral Hypoglycemic Agents- Endocrinol Metab Clin North Am 2001; 30(4): 935-82

-8

-6

-4

-2

0

0 1 2 3 4

Years from Randomization

Wei

ght C

hang

e (k

g)

Placebo

Metformin

Lifestyle

Metformin- Mean Weight Change

The DPP Research Group, NEJM 346:393-403, 2002

Weight Change of DM patients using Acarbose in Taiwan

0

10

20

30

40

50

60

70

80

Patients 65.5 65.5 65.2 65.1

Initial visit First follow-up Second follow-up Third follow-up

kg

Hung YJ, et al. Clin Drug Invest 2006;26:559-65

Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903

0.9 to 1.7% 0/+ +++

HbA1C

reduction

Action on insulin

resistance

Action on insulin

secretion

1% to 2%ConventionalSulfonylureas 0/+ ++++

1% to 2%Biguanides ++ 0

1% to 2%New SU ++ +++

0.5% to 1.3%Glitazones ++++ 0

0.5% to 1%-glucosidase inhibitors

0 0

Glinides

Similar Effect of Hypoglycemic Agents

Postprandial

Primary Goal

Fasting

Fasting

Fasting

Fasting

Postprandial

Characters of individuals in MetS of NHANESIII

- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62

Intra-abdominal adiposity promotes insulin resistance and increased CV risk

Hepatic FFA flux(portal hypothesis)

Secretion ofmetabolically active

substances (adipokines)

suppression of lipolysis by insulin

FFA

Insulin resistance Dyslipidaemia

PAI-1

Adiponectin

IL-6

TNF

Intra-abdominaladiposity

Net result: Insulin resistance Inflammation

Pro-atherogenic

Heilbronn et al 2004; Coppack 2001;Skurk & Hauner 2004

Metabolic Syndrome

• Pathology: Visceral Fat, Atherosclerosis

• Physiology: Insulin Resistance

• Assessment: Abdominal Obesity, CAD risk

• Regimen: Weight reduction, Insulin Sensitizer

Fat Topography in MetS and Diabetic Subjects

High TGHigh FFA

IntramuscularFat

IntrahepaticFat

SubcutaneousFat

IntraabdominalFat

Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..

IntramuscularFat

IntrahepaticFat

IntraabdominalFat

SubcutaneousFat

Effect of Thiazolidinediones on Fat Topography

High TGHigh FFA

TGFFATZD

Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..

Study Intervention RR (%)

ACT NOW Pioglitazone vs placebo 78%

DREAM Rosiglitazone vs placebo 62%

Finnish DPS Intensive lifestyle vs control 58%

Da Qing study Intensive lifestyle vs control 38%

DPP Intensive lifestyle vs placeboMetformin vs placeboTroglitazone vs placebo

58% 31% 75%

IDPP Metformin + lifestyleMetformin

31% 19%

TRIPOD Troglitazone (after gestational diabetes) 50%

Fasting HyperglycemicStudy

Gliclazide or intensive lifestyle No effect

STOP-NIDDM Acarbose vs placebo 25%

XENDOS Orlistat + lifestyle vs placebo 37%

Diabetes prevention trials

Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A, et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002; Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.

ACTosNOW. Diabetologia 2008DREAM Trial Investigators. Lancet 2006; 368:1096–1105.http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.

ADOPT (A Diabetes Outcome Progression Trial)

-Fasting Plasma Glucose Over Time-

Rosiglitazone vs Metformin

9.8 (12.7 to 7.0), P<0.001

Rosiglitazone vs Glyburide17.4 (20.4 to 14.5), P<0.001

mg

/dl

0120

160

140

130

150Glyburide

Metformin

Rosiglitazone

0 1 2 3 4 5Time (years)

Other Adverse Events

335 (23%)

Weight gain, n (%)

Gastrointestinal, n (%)

Hypoglycaemia, n (%)

Oedema, n (%)

557 (38%) 316 (22%)

100 (7%) 18 (1%) 47 (3%)

142 (10%) 168 (12%) 557 (39%)

205 (14%) 104 (7%) 123 (9%)

P<0.05 vs. rosiglitazone

Rosiglitazone(N = 1456)

Metformin(N = 1454)

Glyburide(N = 1441)

NEJM 2007;356;437-40

Role of DPP-4, GLP-1, GIP in glucose homeostasisHerman GA, et al. Clin Pharmacol Ther. 2007;81:761-7

Major Targeted Sites of Oral Drug Classes

Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.

DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.

Glucose Glucose absorptionabsorption

Hepatic glucoseHepatic glucoseoverproductionoverproduction

Impaired insulinImpaired insulinsecretionsecretion

InsulinInsulinresistanceresistance

Pancreas

↓Glucose level

Muscle and fatLiver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

α-Glucosidase inhibitors

Gut

DPP-4 inhibitors

DPP-4 inhibitors

Biguanides (indirect)

DPP-4 inhibitors (indirect)

Developing Avenue of Ideal OADs OADs Glycemic

EffectB-cell

PreserveInsulin

SensitizingNeutral Weight

Low

Hypoglycemia

QD

Dosage

SU +++ +/-

Non-SU ++ +

BG ++ + + ++

A-GI ++ + ++

Glitazone +++ ++ ++ - +

Gliptins ++ ++ +/- + ++ +

-1

0

5

7

2 4 6 8 10

Modified from UKPDS 34. Lancet 1998; 352: 854-65Weight change (kg)

Years from randomisation

Insulin

Metformin, AcarboseDPP-4 inhibitors (?)

Diet alone

ChlorpropamideGlibenclamide

6

4

3

2

1

0

Weight gain with antidiabetic therapyUK Prospective Diabetes Study and Update

Meglitinides (?)

Glitazones (supposed)

Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82

Trends in the prescribing patterns of OADs for outpatients in Taiwan, 1997-2003

Combination = 62.9%Any three OAD = 10.9%

Reilly & Rader 2003;Eckel et al 2005

Plaque rupture/thrombosis

Cardiovascular events

Atherosclerosis

Insulin resistance

TG Metabolic syndrome HDL

BP

Inflammatory markers

Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease

Adipocyte Monocyte/macrophage

Genetic variation Environmental factors

Abdominal obesity

CytokinesAdipokines

Cardiovascular Disease Mortality Increased in the Metabolic Syndrome

Lakka et al. JAMA. 2002;288:2709–16.1515

1010

55

00

00 22 44 66 88 1010 1212

RR (95% Cl), 3.55 (1.98RR (95% Cl), 3.55 (1.98––6.43)6.43)

Metabolic syndromeYesNo

Cu

mu

lati

ve h

azar

d,

%C

um

ula

tive

haz

ard

, %

Follow-up, yFollow-up, y

Disability-adjusted life years (DALYs) attributable to high blood pressure in 2001

Lawes CCM, et al. Lancet 2008; 371: 1513–18

M/L F/L

F/H

Effect of antihypertensive agents in patientswith mild hypertension (TOMHS 4-year data)

-13.9 -14.1 -14.6-13.4

-11.3

-8.6

-20

-15

-10

-5

0

Neaton et al. JAMA 1993;270:713–724.

SBP after 48 months

(mm

Hg

)

DBP after 48 months

*P<0.01 vs placebo

* * * *

* * **

Acebutolol(n=126)

Amlodipine

(n=114)

Chlorthalidone

(n=117)

Doxazosin

(n=121)

Enalapril

(n=119)

Placebo

(n=207)

(mm

Hg

)

Neaton et al. JAMA 1993;270:713–724.

Elliott WJ, Meyer PM. Lancet 2007; 369: 201–207.

New-onset DM with antihypertensives -143,153 subjects, network meta-analysis-

Conditions favouring use of some antihypertensive drugs-ESC 2007 Guideline

Journal of Hypertension 2007, 25:1105–1187

Clinical efficacy and tolerability of alpha-blockerdoxazosin as add-on therapy in patients with

hypertension and impaired glucose metabolismNutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147

16 weeks of combined therapy

ESH-ESC 2007 Guidelines

• a1-blockers… have been shown to adequately lower blood pressure and to also have favorable metabolic effects.

• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT trial) was interrupted before crucial evidence could be obtained, the overall benefits or harm of a1-blockers for antihypertensive therapy remain unproved.

• However, all these agents have been frequently used as added drugs in trials documenting cardiovascular protection and can thus be employed for combination treatment.

• a1-blockers have a specific indication in the presence of benign prostatic hypertrophy.

Journal of Hypertension 2007;25:1105-1187

P. 1141

AASK MAP <92

Target BP (mmHg)

Multiple antihypertensive agents are needed to achieve target BP

Number of antihypertensive agents1

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

Trial 2 3 4

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;Lewis EJ, et al. N Engl J Med 2001;345:851-860;

Cushman WC, et al. J Clin Hypertens 2002;4:393-404DOX-EM-07004

Combination Therapy Emphasized in All Guidelines

JNC 7• Most patients with hypertension will require 2 or more antihypertensive medications to achieve

goal BP• If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy

with 2 agents, 1 of which usually should be a thiazide-type diuretic

WHO/ISH• Less than half of hypertension patients will attain target pressures with monotherapy; as many as

30% will need 3 or more drugs• Diuretic should be a component of combination therapy

ESH-ESC 2007• Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited

number of hypertensive patients• Use of more than one agent is necessary to achieve target BP in the majority of patients.

• In several patients BP control is not achieved by two drugs and a combination of three of more drugs is required.

Chobanian et al. Chobanian et al. JAMAJAMA. 2003;289:2560-2572; WHO Writing Group. . 2003;289:2560-2572; WHO Writing Group. J HypertensJ Hypertens. 2003;21:1983-1992. 2003;21:1983-1992. . ESH-ESC ESH-ESC J. J. HypertensHypertens. . 2007;25:1105-1187

Model for Origins of Atherogenic Dyslipidemia of Obesity and MetS

AdiposityAdiposity High carbohydrate dietHigh carbohydrate diet

Insulin resistanceInsulin resistance Genetic predispositionGenetic predisposition

Pattern APattern APattern APattern A

Pattern BPattern B

Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.

Plasma TGPlasma TGPlasma TGPlasma TG

TGTGpoolpool

HighHigh

SmallLDL

SmallLDL

LowLow

RemnantsRemnantsLargerLargerVLDLVLDL

SmallerSmallerVLDLVLDL

LDL-RLDL-R

LPL/HLLPL/HLLPL/HLLPL/HLLPLLPLLPLLPL

CholCholCholChol

CETPCETPCETPCETPTGTGTGTG

IDLIDLLargeLargeLDLLDL

SmallerLDL

SmallerLDL

HDLHDL SmallerHDL

SmallerHDL

HLHL

<90<90<90<90

>175>175

LPLLPL LPLLPL

CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,

very-low-density lipoprotein.

HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular

EventsN Engl J Med 2007;(Sep 27)357:1301-10.

BNHI Treatment Guideline - Taiwan

• ≧ 2 Risk Factors– TC ≧ 200 mg/dL or LDL ≧ 130

mg/dL

TC < 200mg/dL

LDL < 130mg/dL• TG 200 mg/dL≧

– TC/HDL >5 or

HDL< 40 mg/dL

TG < 200mg/dL

• TC 200mg/dL≧ < 160mg/dL• LDL 130mg/dL≧

100mg/dL

• TG 200 mg/dL≧ - TC/HDL >5 or

HDL< 40 mg/dL

TG < 200mg/dL

With CVD or DM PatientsWithout CVD Patients

Taiwan Association of Diabetes(n=7541)

Source: TADE 2005 data

(%) Total (n = 7541)

A+B+C 4.1 (n=310)

A1C test >1x/year 96.6 (n=7288)

A1C>9.5 14.9 (n=1121)

A1C >9 20.0 (n=1507)

A1C 7-9 11.4 (n=857)

A1C<7 31.3 (n=2363)

BP<140/90 64.9 (n=4893)

BP<130/80 30.6 (n=2305)

LDL-C<130 56.4 (n=4255)

LDL-C<100 or TC<160 33.4 (n=2516)

LDL test frequency 79.8 (n=6018)

Trends of Higher Dosage of StatinsTrends of Higher Dosage of Statins

Statins dosage vs LDL-C reduction rate%

Red

uct

ion

in L

DL

-C

Lovastatin20/80 mg

Fluvastatin20/80 mg

Simvastatin20/80 mg

Pravastatin20/80 mg

Atorvastatin10/80 mg

Response to Minimum/Maximum Statin Dose

31

37*

40

47

55

Adapted from Illingworth. Med Clin North Am. 2000;84:23.*Pravachol® (pravastatin) PI.

*CRESTOR (rosuvastatin) for active control study PI.

Rosuvastatin10/40 mg

55

1927 28

354612

10 12

1218

9

37

0

10

20

30

40

50

60

10 mg 20 mg 40 mg 80 mg0

0,5

1,0

1,5

2,0

2,5

20 mg 40 mg 80 mg

% P

atie

nts

of

AE

s

40 mg 80 mg

4 x

1.7 x 2.3

x

Atorvastatin Lovastatin Simvastatin

“Physicians Desk Reference (PDR)”

10 20 40 80 mg

Statin

LD

L-R

ed

uct

ion

(%

)

-10

-20

-30

+10 mg

- 6%

+20 mg

- 6%

+40 mg

- 6% -40

-50

20 mg

Statins limitation ( rule of 6% )

Lipid Lowering through Dual Inhibition of Both Cholesterol Production and Absorption

HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A

Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;55:710–716.

Production in liver Absorption from intestine

LDL-CVLDL

Biliary cholesterol

Chylomicrons

Points oftherapeuticintervention

Cholesterolsynthesis

(HMG-CoA

reductase)

Bloodstream Dietary cholesterol

Statin Ezetimibe

% of patients achieving target goal of LDL-C

Statin + PL Statin + EZE

N % to goal N % to goal

DM 80 17.5 73 83.6*

Non-DM 149 20.1 128 67.2*

MetS 81 27.2 78 71.8*

Non-MetS 160 15.6 154 65.6*

* p < 0.001 vs. Statin + Placebo•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups

Ezetimibe Plus Statins in Patients with DM and Metabolic Syndrome

Simons L et al Curr Med Res Opin 2004;20:1437-45.

PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.

Athyros VG et al. Athyros VG et al. Curr Med Res Opin.Curr Med Res Opin. 2002;18:220-228. Downs JR et al. 2002;18:220-228. Downs JR et al. JAMAJAMA. 1998;279:1615-1622. Heart Protection . 1998;279:1615-1622. Heart Protection Study Collaborative Group. Study Collaborative Group. LancetLancet. 2002;360:7-22.. 2002;360:7-22. The LIPID Study Group. The LIPID Study Group. N Engl J MedN Engl J Med. 1998;339:1349-1357. 4S . 1998;339:1349-1357. 4S

Study Group. Study Group. Lancet. Lancet. 1995;345:1274-1275. Sacks FM et al. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. N Engl J Med. 1996;335:1996;335:1001-1009. Shepherd J et al. 1001-1009. Shepherd J et al. N Engl J Med. N Engl J Med. 1995;333:1301-1307. 1995;333:1301-1307.

Relation Between CHD Events and LDL-C in Statin Trials

AFCAPS-PIAFCAPS-PI

Mean LDL-C Level at Follow-up (mg/dL)Mean LDL-C Level at Follow-up (mg/dL)

00

55

1010

1515

2020

2525

3030

9090 110110 130130 150150 170170 190190 210210

% With% With

CHD EventCHD Event

CARE-RxCARE-Rx

LIPID-RxLIPID-Rx

4S-Rx4S-Rx

CARE-PICARE-PILIPID-PILIPID-PI

4S-PI4S-PI

SecondarySecondaryPreventionPrevention

PrimaryPrimaryPreventionPrevention

WOSCOPS-PIWOSCOPS-PI

WOSCOPS-RxWOSCOPS-RxAFCAPS-RxAFCAPS-Rx

GREACE-UCGREACE-UC

GREACE-SCGREACE-SC

LIPS-PlLIPS-Pl

LIPS-RXLIPS-RX

Goals for Management of Hyperlipidemia in Patients With Diabetes

LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =

Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III

aOptional/reasonable goals; bOr LDL-C reduction of 30% from baseline

Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;

91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.

Guidelines

LDL-C Goal

Diabetes With CVDa Diabetes Without CVD

ESC/EASD 2007 <70 mg/dL

(<1.8 mmol/L)

<97 mg/dL

(<2.5 mmol/L)

ADA/AHA/ACC 2007 <70 mg/dL

(<1.8 mmol/L)

<100 mg/dL

(<2.6 mmol/L)

JBS2 2005 <77 mg/dLb

(<2.0 mmol/L)

<77 mg/dLb

(<2.0 mmol/L)

NCEP ATP III 2004 <70 mg/dL(<1.8 mmol/L)

<100 mg/dL

(<2.6 mmol/L)

Upcoming 2009

Change Lifestyle is the Key

Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92

AcknowledgementORC, SLRHC, NY, USA• Xavier Pi-Sunyer• Dympna Gallagher• Jack Wang• Stanley Heshka• ZiMian Wang• Richard N. Pierson,Jr• Yiying Zhang • Experts in ORC……Kyoto University, Japan• Kazuwa Nakao• Yoshihiro OgawaInje University, Korea• Jaeheon Kang

NCKU, Taiwan• Chih-Jen Chang• Yi-Ching Yang• Mi-Cha Ma• Wei-Jen Yao • Cho-Jeng Peng• Shu-Hui ChenNTU, Taiwan• Kuo-Chin Huang• Keh-Song Tsai CMCU, Taiwan• Wen-Yuan LinWF Hospital, Taiwan• Liu Tsan-Hung

ChangHwa Christian H, TaiwanShih-Te Tu

VGH Taipei, TaiwanLow-Tone HoChing-Fai Kwok

YangMing University, TaiwanJin-Jong Chen

Beijing Capital H, ChinaXiangyan Ruan

Nat’l KS Normal Univ, TaiwanRay-Tai Chang

TSGH Taipei, TaiwanShih Kwan-JongChu Nan-Fong