lipoproteins diabeteschd role of statins atherosclerosis

LIPOPROTEINSLIPOPROTEINSDiabetes CHD

Role Of Statins

Atherosclerosis

L1-2

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

L1-3

Development of Atherosclerotic Plaques

Normal

Fatty streak

Foam cells

Lipid-rich plaque

Lipid coreThrombus

Fibrous cap

L1-4

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

L1-10

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

L1-12

*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

L1-14

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

L1-15

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

L1-23

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

L1-24

*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

L1-27

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

L1-28

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

L1-29

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

L1-30

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


• 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

L1-31

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


• 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

L1-32

Cholesterol and Recurrent Events Trial (CARE)

• Study design – Secondary prevention in 4159 men and

women with average cholesterol levels


• 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

L1-33

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).



• 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.



• 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.)

lipoproteins diabeteschd role of statins atherosclerosis

Documents