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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
eR
elat
ive
To
Gen
eral
Pop
ula
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
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