1. Challenges Facing Lipid Guidelines
Peter W. F. Wilson, M.D.
Emory University

2. Disclosure Peter W. F. Wilson
Grants
Sanofi-Aventis—Role of adiposity as a risk factor for heart disease in Framingham participants
Liposcience—LDL particle number in US Veterans
ATP III: Clinical Management of Metabolic Syndrome
The management of metabolic syndrome has two goals: to reduce underlying causes and to treat associated lipid and nonlipid risk factors.
Obesity and physical inactivity are underlying risk factors for CHD. If the metabolic syndrome is present after LDL-C has been controlled, then therapeutic lifestyle changes should stress weight reduction and increased physical activity. Weight reduction enhances LDL-C lowering and reduces all of the risk factors of the metabolic syndrome. Regular physical activity reduces VLDL levels and increases HDL-C, and in some people, it lowers LDL-C. Physical activity can also reduce BP and insulin resistance, which are two of the factors associated with the metabolic syndrome, and it can favorably influence cardiovascular function.
After the underlying risk factors have been addressed, therapies should be used to treat the lipid and nonlipid risk factors, including hypertension, elevated TG, and low HDL-C. In addition, aspirin should be given to CHD patients to reduce the prothrombotic state.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:

3. Discussion Items Lipid Measures Recent Evidence Lipids and CVD
Current Guidelines
Specific Groups
Diabetes Mellitus
Familial Hypercholesterolemia
Hypertriglyceridemia
Metabolic Syndrome
Therapy

4. Lipid Research Clinic Program Lipid Measurements
Density
VLDL
1.006
Non-
HDL
LDL
IDL
Total*
Bottom*
fraction
1.063
HDL*
LDLFriedewald = Total - HDL- (Trig/5)
(mg/dl)

5. Serum Lipoprotein Size and Density
VLDL
Chylomicrons
LDL
Density (g/ml)
HDL-1
IDL
Chylomicron
Remnants
HDL-2
HDL-3
Nascent HDL 60
100
140
200
280
400
600
800
1000
Diameter (Angstroms)

6. Cholesterol
Apolipoprotein B-100
Phospholipid
Apolipoprotein (a)

7. Lp(a) Level and Risk for CHD
LRC Men Years with 7-10 Years Follow-up 4
97.5%C.I./2.5% C.I. 3
Relative Risk
Relative Risk for CHD 2 1
0-3.0
Lp (a) Quintile (mg/dL)
Schaefer JAMA 1994: 274: 1002

8. Lifetime Risk of CHD By Total Cholesterol Category Framingham Men and Women63 57 51 42 39 34 36 33 29 43 42 41 21 36 30 26 40 23 24 20 31 34 18 27 19 20 17 15 17 14
Cholesterol
(mg/dL)
Age (y)
Men
Women
After Lloyd-Jones Arch Intern Med 2003; 163:1966

9. Cholesterol Trialists Meta-Analysis
Prevention of Cardiovascular Disease with LDL-C Lowering
Search Investigators: Am Heart J 2007; 157: 815

10. Cholesterol Trialists Meta-Analysis of Statins
Baigent Lancet 2005; 366: 1267

11. Cholesterol Trialists Cause Specific Mortality with Statins (effect of 1 mmol/l [38.6 mg/dl] reduction))
Baigent Lancet 2005; 366: 1267

12. Cholesterol Trialists Major CVD Events with Statins (effect of 1 mmol/l [38.6 mg/dl] reduction)
Baigent Lancet 2005; 366: 1267

13. Cholesterol Trialists Proportional reduction in Major Vascular Events and mean absolute LDLcholesterol reduction at 1 year
Proportional Reduction in Event Rate
Baigent Lancet 2005; 366: 1267

14. Cholesterol Trialists Proportional reduction in Major Vascular Events and Mean absolute LDL-C reduction at 1 year
Baigent Lancet 2005; 366: 1267

15. Framingham Offspring Men
Diabetes and Lipid Extremes
Framingham Offspring
Men 60
p<0.001 50
Non-Diabetic 40
Diabetic
Per cent 30
p<0.001 20
p<0.001 10
HDL-C<35
Total-C 240+
LDL-C 160+
Trig 250+
HDL-C<35
Total-C 240+
Siegel Metabolism 1996; 96: 1267

16. Framingham Offspring Women
Diabetes and Lipid Extremes
Framingham Offspring
Women 50
p<0.001
Non-Diabetic 40
p<0.001
Diabetic
p<0.001 30
Per cent
p<0.001 20 10
HDL-C<35
Total-C 240+
LDL-C 160+
Trig 250+
HDL-C<35
Trig 250+
Siegel Metabolism 1996; 96: 1267

17. CHD Death Risk by non HDL-C, LDL-C, and Diabetes Status ARIC, Framingham, MRFIT Usual Care
Relative Risk
>100
<100
LDL-C
(mg/dL)
Non HDL-C (mg/dL)
Diabetes Present
Diabetes Absent
Liu Diabetes Care 2006; 28: 1916

18. Statins to Prevent CVD in Diabetic Patients Cholesterol Treatment Trialists Meta-Analysis According to Baseline Lipoprotein Measurements
1 mmol/L LDLc effect
Kearney Lancet 2008; 371: 117

19. Statins to Prevent CVD in Diabetic Patients Cholesterol Treatment Trialists Meta-Analysis
1 mmol/L LDLc effect
Kearney Lancet 2008; 371: 117

20. Fibrates and Non-Fatal MI
Abourbih Am J Med 2009; 122: 962 20

21. Fibrates and Mortality
Abourbih Am J Med 2009; 122: 962 21

22. Updated ATP III Cholesterol Guidelines
CHD Risk Category
Recommended Goals
Optional Goals
LDL-C
(mg/dl)
non-HDL-C
High risk
(CHD or CHD Risk Equivalent)
< 100
< 130
< 70
Moderate High risk
(++ risk factors, CHD risk 10-20%)
< 160
(++ risk factors, CHD risk <10%)
Low risk
(0-1 risk factors)
< 190
Grundy Circulation 2004;110:227

23. 2008 ADA-ACC Consensus Conference Suggested Treatment Goals in Patients with Cardiometabolic Risk and Lipoprotein Abnormalities
Risk Category
Goals (all in mg/dL)
LDL-C
Non-HDL-C
ApoB
Highest-risk
including those with 1)known CVD or 2) diabetes plus one or more additional major CVD risk factors*
< 70
< 100
< 80
High-risk patients
including those with a) no diabetes or known clinical CVD but two or more additional major CVD risk factors* or 2) diabetes but not other major CVD risk factors
< 130
< 90
Updated ATP III LDL-C Goals and Cutpoints for Therapy
The National Cholesterol Education Program Adult Treatment Panel III (ATP III) defines high-risk patients as those who have CHD or atherosclerotic disease of the blood vessels to the brain or extremities, or diabetes, or multiple (2 or more) risk factors (e.g., smoking, hypertension) that give them a >20% chance of having a heart attack within 10 years. Very high risk patients are those who have cardiovascular disease together with (1) multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (e.g., continued smoking), (2) metabolic syndrome (a constellation of risk factors associated with obesity including high triglycerides and low high-density lipoprotein cholesterol [HDL-C]) and/or (3) acute coronary syndromes such as heart attack. For high-risk patients, the overall goal is to achieve a low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL. But for patients at very high risk, a group that is considered a "subset" of the high-risk category, a therapeutic option is to decrease LDL-C levels to <70 mg/dL. For very high risk patients whose LDL-C levels are already <100 mg/dL, there is also an option to use drug therapy to reach the <70-mg/dL treatment goal. For moderately high risk patients, the goal is to achieve an LDL-C level <130 mg/dL, but it is a therapeutic option to set a lower LDL-C goal of <100 mg/dL and to use drug therapy for LDL-C levels of 100–129 mg/dL to achieve this lower goal. For high-risk or moderately high risk patients, the report advises that LDL-C–lowering drug therapy be sufficient to achieve at least a 30–40% reduction in LDL-C levels. This can be accomplished by taking statins or by combining lower doses of statins with other drugs (bile acid resins, nicotinic acid, or ezetimibe) or with food products containing plant stanols/sterols. For moderately high risk patients with LDL-C levels of 100–129 mg/dL at baseline or on lifestyle therapy, LDL-C–lowering therapy to reach a goal of <100 mg/dL is recommended, and lipid-altering drug therapy to achieve this goal is a therapeutic option. By definition, almost all people with 0–1 risk factor have a 10-year risk <10%. Drug therapy for primary prevention in this patient population is recommended only for those with higher LDL-C levels.
Major CHD risk factors include cigarette smoking, blood pressure 140/90 mm Hg or on antihypertensive medication, HDL-C <40 mg/dL (1.0 mmol/L), family history of premature CHD (CHD in male first-degree relative aged <55 years; CHD in female first-degree relative aged <65 years), and age (men 45 years; women 55 years). HDL-C  60 mg/dL (1.6 mmol/L) counts as a "negative" risk factor; its presence removes 1 risk factor from the total count. Framingham risk score may also be used to determine 10-year CHD risk.
References:
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:
Grundy SM, Cleeman JI, Bairey Merz CN, et al., for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:
Bays H, Shepherd J.  Diabetes, metabolic syndrome and dyslipidemia. In: Management Strategies in Diabetes.  Hackensack, NJ: Cambridge Medical Publications, 2004:1-28.
*Other major risk factors (beyond lipids) include smoking, hypertension, and family history of premature CAD
Brunzell JACC 2008; 51: 1512

24. Criteria Used for Evaluation of Evidence
Recommendation Grade
Class I
Evidence and/or general agreement that a given diagnostic procedure/
treatment is beneficial, useful and effective
 Class II
Conflicting evidence and /or a divergence of opinion about the usefulness /
efficacy of the treatment
Class II a Weight of evidence in favour
Class II b Usefulness/efficacy less well established
Class III
Evidence that the treatment is not useful and in some cases may be harmful
Level of Evidence
 Level A
Data derived from multiple randomized clinical trials (RCT) or meta-analysis
Level B
Data derived from a single RCT or large non-randomized studies
Level C
Consensus of opinion by experts and/or small studies, retrospective studies, registries I
IIb
III
IIa A C 24

25. Canada 2009 Dyslipidemia Guidelines Moderate Risk Level
Pharmacological therapy indicated if:
LDL-C > 3.5 mmol/L[135 mg/dl] (apoB > 1.00 g/L)
TC/HDL-C ratio > 5.0
hsCRP > 2mg/L in men over 50, women over 60
hsCRP should be performed selectively
Consider cost/benefit of preventive therapy A C B
Genest Can J Cardiol 2009: 25: 567

26. Canada 2009 Targets for LDL-C (or apoB):
In high- and moderate-risk subjects
Nearly all clinical trials measure LDL-C as index of therapy. Recommendations:
Primary target is LDL-C decrease to < 80 mg/dl/L or 50% relative reduction
We recommend apoB < 80 mg/dl as primary alternate target A A
Genest Can J Cardiol 2009: 25: 567

27. Canada 2009 Dyslipidemia Target Levels
Risk Level Initiate treatment if:
Primary Primary
LDL-C Alternate
High Consider treatment in all patients
CAD,PVD
Atherosclerosis
Most Pts with Diabetes
Fram Risk Score ≥ 20%
Reynolds Risk Score ≥ 20%
<2 mmol/L (80 mg/dl)
Or ↓50% LDL-C ApoB<80 mg/dl
Moderate (strive towards )
FRS 10-19% LDLc>135 mg/dl
TC/HDL >5.0
hsCRP >2
(men >50, women>60)
Family history and
hsCRP modulate risk
LDLc<80 mg/dl
Or ↓50% LDL-C ApoB<80 mg/dl ApoB<80 mg/dl
Low
FRS<10% LDL-C>5.0mmol/L
↓50% LDL-C A A A A A
Genest Can J Cardiol 2009: 25: 567 27

28. Canada 2009 Dyslipidemia Recommendations Residual Risk (When LDL-C at target) OPTIONAL Secondary Targets
Test
Cut-point
Intervention
TC/HDL-C
>4.0
Niacin
Fibrate
Non HDL-C
>135 mg/dl
[>3.5 mmol/L]
Apo B/AI
>0.8
Ezetimibe
Triglycerides
>150 mg/dl
[1.7 mmol/L]
hsCRP
>2.0 mg/L
Statin
Genest Can J Cardiol 2009: 25: 567 28 28

29. Targets other than LDL-C (or apoB)
After reaching primary targets (LDL-C or apoB)
High HDL-C predicts atherosclerosis regression
Low HDL-C predicts mortality even when LDL-C < 150 mg/dl (1.8 mmol/L)
No specific target HDL-C or triglyceride levels
Secondary optional targets unproven to reduce risk
Consider secondary optional targets for high-risk patients
Genest Can J Cardiol 2009: 25: 567

30. Canada 2009 Dyslipidemia Risk Assessment and Treatment Targets
Initiate/consider treatment
if any of the following:
Primary Target
LDL-C
Primary Alternate
ApoB
HIGH
FRS ≥ 20%
RRS≥ 20%
CAD
PVD
Atherosclerosis
Most Diabetic Patients
(consider treatment in all patients)
< 2 mmol/L or
↓ LDL-C 50%
ApoB < 0.80
Moderate
FRS 10-19%
LDL-C > 3.5 mmol/L
TC/HDL-C > 5.0
hsCRP > 2 mg/L *
Family history
(strive towards )
LOW
FRS < 10%
LDL-C > 5.0mmol/L A A A
* Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia
Genest Can J Cardiol 2009: 25: 567 30 30

31. Summary Evidence Safety Proven Clinical Efficacy
Case control
Observational Cohorts
Clinical Trials
Safety
Proven Clinical Efficacy
Consideration of long term risk