LIPOPROTEINS Diabetes CHD Role Of Statins Atherosclerosis
LIPOPROTEINSLIPOPROTEINSDiabetes CHD
Role Of Statins
Atherosclerosis
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Lipoproteins & Atherosclerosis An Overview
Clinical Manifestations of Atherosclerosis
• Coronary heart disease– Stable angina, acute myocardial infarction, sudden
death, unstable angina/NSTEMI
• Cerebrovascular disease– Stroke, TIAs
• Peripheral arterial disease– Intermittent claudication, amputation
Normal arterial wall
Tunica adventitia
Tunica media
Tunica intima
Endothelium
Subendothelial connective tissue
Internal elastic membrane
Smooth muscle cells
Elastic/collagen fibers
External elastic membrane
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Development of Atherosclerotic Plaques
Normal
Fatty streak
Foam cells
Lipid-rich plaque
Lipid coreThrombus
Fibrous cap
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Magnitude of the Burden—Causes of Death in the United States
0
100
200
300
400
500
600
700
800
900
1,000
Deat
hs in
199
6 (th
ousa
nds)
CVD Cancer Accidents HIV/AIDS
959.2
544.7
93.832.7
American Heart Association. 1999 Heart and Stroke Statistical Update. 1998. L1-5
Risk Factors for CHD• Modifiable
– Dyslipidemia• Raised LDL• Low HDL• Raised TGs
– Smoking – Hypertension– Diabetes mellitus– Obesity– Dietary factors– Thrombogenic factors– Sedentary lifestyle
• Non-modifiable– Family history of
premature CHD
– Age
– Sex
Smoking
Serum total cholesterol level(>240 mg/dL
OR >6.2 mmol/L)
Hypertension(DBP >90 mm Hg)
x2.5
x7
x11x6x3
x3 x3
Adapted from Kannel WB, et al. Am Heart J. 1986;12:825-836.L1-6
Relationship between Cholesterol and CHD risk: The Framingham Study
0
25
50
75
100
125
150
204 205-234 235-264
265-294 295
Castelli WP. Am J Med. 1984;76:4-12.
CH
D in
cide
nce
per
1000
Serum cholesterol (mg/100 mL)
mg/dL x 0.0259= mmol/LL1-7
Cholesterol—a Modifiable Risk Factor
• 10% reduction in TC = 15% reduction in CHD mortality and 11% reduction in total mortality2
• LDL-C is the primary target to prevent CHD3
• Intensity of intervention depends on total CV risk3
1. AHA. 2000 Heart and Stroke Statistical Update.2. Gould AL, et al. Circulation. 1998;97:946-952.3. NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023. L1-8
LDL cholesterol
• Remains the cornerstone of dyslipidemia therapy• Strongly associated with atherosclerosis and
CHD events• 10% increase results in a 20% increase in
CHD risk1
• Most patients with elevated LDL untreated– Only 5.5 million out of 22 million treated2
1. Wood D, et al. Atherosclerosis. 1998;140:199-270.2. National Centre for Health Statistics. National Health and Nutrition Examination Survey (III) 1994. L1-9
HDL cholesterol • Elevated HDL cholesterol has a protective effect for risk of atherosclerosis and CHD1
• The lower the HDL cholesterol level the higher the risk for atherosclerosis and CHD1
• HDL cholesterol tends to be low when triglycerides are high2
• Risk assessment– Routinely measured in all adult patients– HDL-C <0.9 mmol/L is a major positive risk factor– HDL-C 1.55 mmol/L is a negative risk factor;
subtract 1 risk factor from total
1. NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023. 2. Wood D, et al. Atherosclerosis. 1998;140:199-270.3. Kannel WB. Am J Cardiol 1983;52:9B–12B
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4.0
3.0
2.0
1.0
25 45 65HDL-C (mg/dL)
CH
D r
isk r
ati
o
2.0
1.0
0
4.0
CHD Risk According to HDL-C Levels
Framingham Study3
mg/dL x 0.0259= mmol/L
Triglycerides
• Associated with increased risk of CHD events• Link with increased CHD risk is complex
– May be related to low HDL levels and highly atherogenic forms of LDL cholesterol
• Normal triglyceride levels <2.26 mmol/L• Very high triglycerides (>11.3 mmol/L) increase
pancreatitis risk
NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023. L1-11
• Adult Treatment Panel I (1988) Adult Treatment Panel II (1993) Adult Treatment Panel III (2001)
• Recommendations for Improving Cholesterol Measurement (1990)Recommendations on Lipoprotein Measurement (1995)
• Population Strategies for Blood Cholesterol Reduction (1990)
• Blood Cholesterol Levels in Children and Adolescents (1991)
National Cholesterol Education Program, (NCEP) Reports
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*Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. †Some men develop metabolic risk factors when circumference is only marginally increased.
Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Risk Factor Defining Level
Abdominal obesity (Waist circumference†)
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
TG 150 mg/dL
HDL-C
MenWomen
<40 mg/dL<50 mg/dL
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL
*Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. †Some men develop metabolic risk factors when circumference is only marginally increased.
Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Risk Factor Defining Level
Abdominal obesity (Waist circumference†)
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
TG 150 mg/dL
HDL-C
MenWomen
<40 mg/dL<50 mg/dL
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL
ATP III: The Metabolic SyndromeDiagnosis is established when 3 of these risk
factors are present.
New Features of ATP III
Focus on Multiple Risk Factors
• Diabetes: CHD risk equivalent
• Framingham projections of 10-year CHD risk– Identify certain patients with multiple risk factors for
more intensive treatment
• Multiple metabolic risk factors (metabolic syndrome)– Intensified therapeutic lifestyle changes
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New Features of ATP III
Modification of Lipid and Lipoprotein Classification
• LDL cholesterol <100 mg/dL—optimal• HDL cholesterol <40 mg/dL
– Categorical risk factor– Raised from <35 mg/dL
• Lower triglyceride classification cut points– More attention to moderate elevations
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Hypertriglyceridemia andRisk for CHD
• TG elevation is generally associated with increased risk for CHD on univariate analysis
• Is the relation causal?• Or is the TG elevation simply a marker for
CHD risk through its associations with such conditions as type 2 diabetes mellitus, low HDL-C, and obesity?
• The TG-CHD relation tends to weaken or disappear on multivariate analysis
Hypertriglyceridemia and CHD Risk:Associated Abnormalities
•Accumulation of chylomicron remnants•Accumulation of VLDL remnants•Generation of small, dense LDL-C•Association with low HDL-C•Increased coagulability
– plasminogen activator inhibitor (PAI-1)– factor VIIc–activation of prothrombin to thrombin
A BIntermediatepattern
0
2
4
6
8
10
12
Glucose(mmol/L)
Adapted from Reaven GM et al. J Clin Invest. 1993;92:141-146.
Steady-state plasma glucose
n=19
n=17
n=19
Association of Small, Dense LDLWith Insulin Resistance
Garber AJ. Clin Cornerstone. 2003;5:22-37.Garber AJ. Med Clin North Am. 1998;82:931-948.
National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Atherosclerosis in Diabetes
• Accelerated atherosclerosis is multifactorial and begins years/decades prior to diagnosis of type 2 diabetes
• >50% of patients with newly diagnosed type 2 diabetes have CHD
• Risk for atherosclerotic events is 2- to 4-fold greater in diabetics than in nondiabetics
• Atherosclerosis accounts for 65% of all diabetic mortality
– 40% due to ischemic heart disease– 15% due to other heart disease– 10% due to cerebrovascular disease
Accelerated atherosclerosis
Clinical diabetes
Hyperinsulinemia Impairedglucose
tolerance
HypertriglyceridemiaDecreased HDL-C
Essentialhypertension
Insulin resistance
Insulin Resistance and Atherosclerosis: Posited Relationships
Hypertension Obesity Hyper-insulinemia Diabetes
Hypertri-glyceridemia
Small,dense LDL
Low HDL Hypercoagu-lability
Atherosclerosis
Insulin Resistance
Interrelation Between Atherosclerosisand Insulin Resistance
AGE=advanced glycation end products; CRP=C-reactive protein; HDL=high-density lipoprotein; HTN=hypertension; IL-6=interleukin-6; LDL=low-density lipoprotein; PAI-1=plasminogen activator inhibitor-1; SAA=serum amyloid A protein; TF=tissue factor; TG=triglycerides; tPA=tissue-type plasminogen activator
Subclinical Atherosclerosis
Atherosclerotic Clinical Events
Hyperglycemia
AGE Oxidative
stress
Inflammation
IL-6 CRP SAA
Infection
Defensemechanisms
Pathogen burden
Insulin Resistance
HTN Endothelial dysfunction
Dyslipidemia
LDL TG HDL
Thrombosis
PAI-1 TF tPA
Disease Progression
Biondi-Zoccai GGL et al. J Am Coll Cardiol. 2003;41:1071-1077.
Progression to Atherosclerotic ClinicalEvents in Patients With Diabetes
New Recommendation for Screening/Detection
• Complete lipoprotein profile preferred– Fasting total cholesterol, LDL, HDL, triglycerides
• Secondary option– Non-fasting total cholesterol and HDL
– Proceed to lipoprotein profile if TC 2.26 mmol/L or HDLc <1.04 mmol/L
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4.9 (4.1–4.89: LDL-lowering drug
optional)
4.14<4.140–1 Risk Factor
10-year risk 10–20%: 3.37
10-year risk <10%: 4.14
3.37<3.372+ Risk Factors
(10-year risk 20%)
3.37 (2.59–3.34: drug
optional)2.59<2.59
CHD or CHD Risk Equivalents(10-year risk
>20%)
LDL Level at Which to Consider
Drug Therapy (mmol/L)
LDL Level at Which to Initiate
Therapeutic Lifestyle Changes (TLC)
(mmol/L)
LDL Goal(mmol/L)Risk Category
LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in
Different Risk Categories
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*Referenced to a nondiabetic range of 4.0%–6.0% using a DCCT-based assay.†ATP III guidelines suggest when TG is 200 mg/dL, use non–HDL-C (TC minus HDL-C); goal in patients with diabetes is 130 mg/dL (LDL-C goal + 30 mg/dL). ‡For women, an HDL-C goal 10 mg/dL higher may be appropriate.DCCT = Diabetes Control and Complications Trial
ADA. Diabetes Care. 2003;26(suppl 1):S33-S50.
Glycemic controlHemoglobin A1c
Preprandial plasma glucosePeak postprandial plasma glucose
Goal<7.0%*90-130 mg/dL<180 mg/dL
Blood pressure <130/80 mm Hg
LipidsLDL-CTG†
HDL-C
<100 mg/dL<150 mg/dL>40 mg/dL‡
ADA: Glycemic Control, BP, and Lipid Targets in Type 2 Diabetes
Initiation LDL-C Initiation LDL-CStatus level goal level goal
With CHD, PVD,or CVD 100 <100 100 <100
Without CHD,PVD, and CVD 100 <100 130† <100
*Values represent mg/dL.†Some authorities recommend initiation of drug therapy between 100 and 129 mg/dL.
CHD=coronary heart disease; PVD=peripheral vascular disease; CVD=cardiovascular disease
Medical nutrition tx Drug tx
ADA. Diabetes Care. 2003;26(suppl 1):S83-S86.
ADA: Treatment Decisions by LDL-C Levels* in Adults With Type 2 Diabetes
Meta-analysis of 38 primary and secondary intervention trials Meta-analysis of 38 primary and secondary intervention trials Benefits of cholesterol lowering
Total mortality (Total mortality (pp=0.004)=0.004)
CHD mortality (CHD mortality (pp=0.012)=0.012)
% in cholesterol reduction% in cholesterol reduction
Mor
talit
y lo
g od
ds r
atio
Mor
talit
y lo
g od
ds r
atio
Gould AL, et al. Circulation. 1998;97:94-952.
00 44 88 1212 1616 2020 2424 2828 3232 3636-1.0-1.0
-0.8-0.8
-0.6-0.6
-0.4-0.4
-0.2-0.2
-0.0-0.0
4040 4444 4848 5252
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Lipid Lowering Compounds
Adapted from NCEP ATP III. JAMA. 2001;285:2491; *Cater NB. Prev Cardiol. 2000;3:127.
Agents Lipid Effects Selected Side EffectsSelected
Contraindications/Warnings
HMG-CoAreductaseinhibitors (statins)
LDL
HDL
TG
Myopathy, liverenzymes
Active or chronic liver diseaseConcomitant use of certaindrugs
Bile acidsequestrants
LDL
HDL
TG no change or
Gastrointestinal distress,constipation, absorptionof other drugs
Dysbetalipoproteinemia, TG>400 mg/dLTG >200 mg/dL
Nicotinic acid LDL
HDL
TG
Flushing; hyperglycemia,hyperuricemia (or gout),upper GI distress,hepatotoxicity
Chronic liver disease,severe gout,diabetes, hyperuricemia,peptic ulcer disease
Fibric acids LDL
(may be in patients withhigh TG)HDL
TG
Dyspepsia; gallstones,myopathy, unexplainednon-CHD deaths in WHOstudy
Severe renal, severe hepaticdisease
Plant stanols* LDL Not available Not available
Plant sterols* LDL Not available Not available
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The Pyramid of Recent Trials (Relative Size of the Various Segments of the Population)
Very high cholesterol with CHD or MI
Moderately high cholesterol in high risk CHD or MI
Normal cholesterol with CHD or MI
High cholesterol without CHD or MI
No history of CHD or MI
4S
LIPID
CARE
WOSCOPS
AFCAPS/TexCAPS
Landmark Clinical TrialsLandmark Clinical Trials• Primary prevention
WOSCOPS
AFCAPS/TexCAPS
• Secondary prevention 4S
CARE
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Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.
West of Scotland Coronary Prevention Study (WOSCOPS)
• Study design– Primary prevention of
myocardial infarction in 6595 men
– Mean baseline LDL: 4.97 mmol/L
• Study intervention – Pravastatin 40 mg or placebo
• Primary endpoint– Nonfatal MI and CHD death
YearsYears
00
11
22
44
66
PercentPercentwithwith
eventevent
88
1010
1212
22 3 3 44 55 66
Pravastatin (n=3302)Pravastatin (n=3302)
Placebo (n=3293)Placebo (n=3293)
31% 31% relativerelativerisk risk reductionreductionpp < 0.001 < 0.001
Nonfatal MI & CHD death
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Downs JR, et al. JAMA. 1998;279:1615-1622.
AFCAPS/TexCAPS• Study design
– Primary prevention of myocardial infarction in 6605 men and women with LDL cholesterol levels 2.98 mmol/L and TG <5.65 mmol/L
– Mean baseline LDL: 3.89 mmol/L
• Study intervention
– Lovastatin 20-40 mg (to target LDL of 2.85 mmol/L) or placebo
• Primary endpoint
– Composite of fatal or nonfatal MI, sudden cardiac death, unstable angina
0.03
0.06
0.04
0.01
Cum
ulat
ive
inci
denc
e
Years of follow-up
0.0 >5
0.07
54321
0.05
0.02
37% riskreductionp<0.001
LovastatinLovastatinPlaceboPlacebo
Fatal/nonfatal MI, sudden cardiac death, unstable angina
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Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
Scandinavian Simvastatin Survival Study (4S)
• Study design – Secondary prevention in 4444
patients with a history of angina pectoris or acute MI
– Mean baseline LDL: 4.87 mmol/L
• Study intervention– Simvastatin 20-40 mg or placebo
• Primary endpoint– Total mortality
0.85
0.80
0.00
0.0
1.00
0.95
0.90P
ropo
rtio
n al
ive
Years since randomization
PlaceboPlacebo
SimvastatinSimvastatin
64321 5
Log rank p=0.0003
This improvement in survival is accounted for by the 42% reduction in coronary events.
Total mortality
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Cholesterol and Recurrent Events Trial (CARE)
• Study design – Secondary prevention in 4159 men and
women with average cholesterol levels
– Mean baseline LDL: 3.6 mmol/L
• Study intervention– Pravastatin 40 mg or placebo
• Primary endpoints– Nonfatal MI or CHD death
Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
0
5
10In
cide
nce
%
Years
0.0
15
54321
Change in risk,24% reductionp=0.003
PravastatinPravastatinPlaceboPlacebo
Nonfatal MI or CHD death
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ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ADA 2005:Treatment recommendations & goals for Dyslipidemia & Diabetes
• Patients with type 2 diabetes have an increased prevalence of lipid abnormalities that contributes to higher rates of CVD.
• Lifestyle modification focusing on the reduction of saturated fat and cholesterol intake, weight loss (if indicated),and increased physical activity has been shown to improve the lipid profile in patients with diabetes.
• In individuals with diabetes over the age of 40 years with a total cholesterol >=135 mg/dl, without overt CVD, statin therapy to achieve an LDL reduction of 30-40% regardless of baseline LDL levels is recommended. The primary goal is an LDL<100 mg/dl (2.6 mmol/l).
ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ADA 2005:Treatment recommendations & goals for Dyslipidemia & Diabetes
• For individuals with diabetes aged<40 years without overt CVD, but at increased risk (due to other cardiovascular risk factors or long duration of diabetes), who do not achieve lipid goals with lifestyle modifications alone, the addition of pharmacological therapy is appropriate and the primary goal is an LDL cholesterol <100 mg/dl (2.6 mmol/l).
• People with diabetes and overt CVD are at very high risk for further events and should be treated with a statin.
• A lower LDL cholesterol goal of < 70 mg/dl (1.8 mmol/l), using a high dose of a statin, is an option in these high risk patients with diabetes and overt CVD.
ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ADA 2005:Treatment recommendations & goals for Dyslipidemia & Diabetes
• Lower triglycerides to<150 mg/dl (1.7mmol/l) and raise HDL cholesterol to> 40 mg/dl (1.15 mmol/l). In women,an HDL goal 10 mg/dl higher (>50 mg/dl) should be considered.
• Lowering triglycerides and increasing HDL cholesterol with a fibrate is associated with a reduction in cardiovascular events in patients with clinical CVD,low HDL, and near-normal levels of LDL.
• Statin therapy is contraindicated in pregnancy.
ABCs of CVD Risk Management
CVD=cardiovascular disease; ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; BP=blood pressure; EF=ejection fraction;MI=myocardial infarction.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
Intervention Goals
A
B
• Antiplatelets/anticoagulants
• ACE inhibitors/ARBs
• Antianginals
• BP control
• Treat all high-risk patients with one of these
• Optimize BP especially if CVD, type 2 diabetes, or low EF present
• Relieve anginal symptoms, allow patient to exercise
• Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes
• Post MI or low EF• ß-blockers
ABCs of CVD Risk Management (Cont.)
1. Braunstein JB et al. Cardiol Rev. 2001;9:96-105.2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Intervention Goals
C • Cholesterol Management• LDL-C targets,ATP III
guidelines
-CHD,CHD risk
equivalents:<100 mg/dL
->2 RF<130 mg/dL
-0-1 RF:<160 mg/dL
• HDL-C:>40 mg/dL (men)• >50 mg/dL (women)• TG:<150 mg/dL• Long term smoking cessation
• Cigarette smoking cessation
BMI=body mass index; HbA1c=glycosylated hemoglobin;CAD=coronary artery disease.
Intervention Goals
D • Dietary/weight counseling
• Diabetes management
• Achieve optimal BMI saturated fats; fruits, vegetables,
fiber
• Achieve HbA1c <7%
E • Exercise
• Education of patients and families
• Improve physical fitness (aim for 30 min/d on most days per week)
• Optimize awareness of CAD risk factors
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
ABCs of CVD Risk Management (cont.)