Usefulness of the Lipid Panel:

NCEP vs. ACC/AHA

Robert Hardy PhD

What is a Lipid Panel? LDLc – Cholesterol associated with low density

lipoproteins, directly linked to cardiovascular disease

(CVD): calculated or detergent based assay

HDLc – Cholesterol associated with high density

lipoproteins, inversely associated with CVD, detergent

based assay (others)

Total Cholesterol – Esterified and non-esterified

cholesterol, necessary for calculating LDLc, enzymatic

assay (others)

Triglyceride – Circulating triglycerides, enzymatic

assay actually measures glycerol, also atherogenic and

high concentrations (>500 mg/dL) associated with

pancreatitis

Other species are atherogenic besides LDLc

e.g. VLDL remnants

Friedewald calculation:

LDLc = TC - HDLc - VLDLc

(VLDLc = TG*/5)

*TG<400 mg/dL

Non-HDL cholesterol:

TC – HDLc = Non-HDLc

Calculating LDLc

• Recent CAP survey indicated 3,100 labs calculated LDLc (54%) and

2,589 labs (46%) measured it directly.

Why order a Lipid Panel?

• Important risk indicator for CVD

• Currently estimate 10-year and lifetime risks for

atherosclerotic cardiovascular disease (ASCVD),

defined as coronary death or nonfatal myocardial

infarction, or fatal or nonfatal stroke using

ASCVD risk calculator (online)

Why order a Lipid Panel?

What drives the orders for

Lipid Panels? Recommendations by the NHLB/NCEP Adult

treatment panels:

The most current NCEP is the ATP III:

• LDL identified as a major cause of ASCVD and

was the centerpiece of the ATP III

• Used various sources of relevant science to

flush out guidelines (RCT, epidemiological,

genetic, metabolic, in vivo and in vitro studies)

Adult Treatment Panel III

(ATP III) Guidelines (2002)

National Cholesterol Education

Program

For more information see

www.nhlbi.nih.gov

option ATP III Cholesterol guidelines

ATP II ATP III

Non-fasting 9-12 h Fasting

Total cholesterol Total cholesterol

HDL cholesterol HDL cholesterol

LDL cholesterol

Triglycerides

Lipoprotein Screening:

ID High Risk Patients >20% probability of CHD event in the

next 10 years

1.

Very High Risk Patients Factors that favor a decision to reduce LDL-C levels to 70 mg/dL

are those that place patients in the category of very high risk.

Among these factors are the presence of established CVD plus

(1)multiple major risk factors (especially diabetes),

(2) severe and poorly controlled risk factors (especially continued cigarette smoking),

(3) multiple risk factors of the metabolic syndrome (especially high triglycerides 200 mg/dL plus non-HDL-C 130 mg/dL with low HDL-C [40 mg/dL])

(4) on the basis of PROVE IT, patients with acute coronary syndromes.

The optional goal of 70 mg/dL does not apply to individuals who are not high risk.

See NCEP Report Circulation:2004;110:227-239.

Table 3

Determine risk based on factors other than LDLc

2.

3.

2013 ACC/AHA Guideline on the

Treatment of Blood Cholesterol to Reduce

Atherosclerotic Cardiovascular Risk in

Adults

Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women with Heart Disease © American College of Cardiology Foundation and American Heart Association, Inc.

Current Recommendations 1:

NHLBI began updating the ATP III:

• So called ATP IV panel followed the rules of

guideline development by the Institute of

Medicine (IOM) and used evidence based

medicine, RCT (excluding other types of

evidence).

Current Recommendations 2:

NHLBI then decided to discontinue the

development of clinical guidelines and gave their

evidence review to the ACC and AHA who

transformed the evidence reviews into treatment

guidelines (2013):

• The ACC/AHA do not make LDL the centerpiece

of their guidelines

• The IOM paradigm makes LDL irrelevant to

guideline development

• Instead they make statins the linchpin of their

recommendations

Current Recommendations 3:

• The new guidelines abandoned LDL targets of

therapy in favor of simply using a dose of

statin (details to follow for primary and

secondary treatment).

• Less detailed and leaves clinicians to often

make their own clinical judgements

• Criticized for not providing ample guidance to

evaluate and monitor efficacy of therapy

• Still use LDLc level to initiate therapy and in

monitoring

New Perspective on LDL-C & Non–HDL-C

• Lack of RCT evidence to support titration of

drug therapy to specific LDL-C and/or non–HDL-

C goals

• Strong evidence that appropriate intensity of

statin therapy should be used to reduce ASCVD

risk in those most likely to benefit

• Quantitative comparison of statin benefits with

statin risk

• Nonstatin therapies – did not provide ASCVD

risk reduction benefits or safety profiles

comparable to statin therapy

Why Not Continue to Treat to Target?

Major difficulties:

• Current RCT data do not indicate what the target

should be

• Unknown magnitude of additional ASCVD risk

reduction with one target compared to another

• Unknown rate of additional adverse effects from

multidrug therapy used to achieve a specific goal

• Therefore, unknown net benefit from treat-to-

target approach

• Use the newly developed Pooled Cohort Equations

for estimating 10-year ASCVD risk.

• Initiate the appropriate intensity of statin therapy to

reduce ASCVD risk.

• Evidence is inadequate to support treatment to

specific LDL-C or non-HDL-C treatment goals.

• Regularly monitor patients for adherence to lifestyle

and appropriate intensity of statin therapy.

• Nonstatin drug therapy may be considered in

selected individuals.

Key Points

4 Statin Benefit Groups

• Clinical ASCVD*

• LDL-C ≥190 mg/dL, Age ≥21 years

• Primary prevention – Diabetes: Age 40-75 years,

LDL-C 70-189 mg/dL

• Primary prevention - No Diabetes†: ≥7.5%‡ 10-year

ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dL

*Atherosclerotic cardiovascular disease †Requires risk discussion between clinician and patient before statin initiation ‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD

risk calculator

Current Recommendations 4:

• For secondary treatment all patients with

established ASCVD are to be put on high

intensity statin treatment (other drugs not

recommended vs ATP III).

• For primary prevention both the ATP III and

ACC/AHA have calculators for 10 year risk.

ATP III considered drug treatment when risk

≥10%

• ACC/AHA set threshold for statin treatment at

7.5% and set 5% to consider statins as a

therapeutic option.

Current Recommendations 5:

• ACC/AHA set threshold for statin treatment

when LDLc >70 mg/dL while the ATP III allowed

drug treatment at >100mg/dL (Jupiter trial not

available to ATPIII)

• For risk assessment ACC/AHA developed a

new calculator that was criticized for over

estimating risk ~2 fold (Ridker and Europe).

• These differences mean more low risk people

will be put on statins.

Current Recommendations 6: • ATP III acknowledges the metabolic syndrome

as essentially doubling the risk for ASCVD and

is a big target for TLC.

• ACC/AHA discard the metabolic syndrome due

to a lack of clinical trials that target it with drug

therapy.

• Again leaving the clinician to make the call

• ATP III is still useful for guiding the physicians

clinical judgment

Summary of Statin Initiation Recommendations to

Reduce ASCVD Risk (Revised Figure)

Summary of Statin Initiation Recommendations to

Reduce ASCVD Risk (Revised Figure)

Individuals Not in a Statin Benefit Group

• In those for whom a risk decision is uncertain, these

factors may inform clinical decision making:

• Family history of premature ASCVD

• Elevated lifetime risk of ASCVD

• LDL-C ≥160 mg/dL

• hs-CRP ≥2.0 mg/L

• CAC score ≥300 Agaston units

• ABI (ankle-brachial index) <0.9

• Statin use still requires discussion between clinician

and patient

Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.

There might be a biologic basis for a less-than-average response.

†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).

‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is

not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

• Still require LDLc measurements which means for 60%

of the country a lipid profile still needs to be done and

LDLc will continue to be needed for treatment and

monitoring purposes (but likely not as often since not

treating to target levels)

• Need HDLc and Total Cholesterol to do risk

assessment so these tests will also continue to be done

(strange that they discredit non-HDLc as being useful

but it appears to be a part of their risk assessment).

Other Considerations:

Other Considerations: Labs still use LDLc reference ranges:

Mayo also states “therapeutic” targets

Quest

UAB

ARUP

Lab Tests Online (AACC): ”the updated guidelines recommend evaluating therapeutic

response compared to LDL-C baseline values, with reduction thresholds differing based

on the intensity of the lipid-lowering drug therapy. Use of the updated risk calculator

and guidelines remains controversial. Many still use the older guidelines from

the NCEP Adult Treatment Panel III to evaluate lipid levels and CVD risk:”

LDL Cholesterol:

Optimal: Less than 100 mg/dL (2.59 mmol/L); for those with known disease

(ASCVD or diabetes), less than 70 mg/dL (1.81 mmol/L) is optimal

Near/above optimal: 100-129 mg/dL (2.59-3.34 mmol/L)

Borderline high: 130-159 mg/dL (3.37-4.12 mmol/L)

High: 160-189 mg/dL (4.15-4.90 mmol/L)

Very high: Greater than 190 mg/dL (4.90 mmol/L)

Other Considerations: 10 months of comparative HDLc and Lipid profile testing

(thanks to Carolyn Chaffin):

• HDLc tests are 7% higher vs Lipid

Profiles, P<0.0019 (n=3 months)

• HDLc Mean in 2013 is 30% higher

than Lipids profiles in 2016 (n= 10)

• or 23% when corrected for the

7% difference between HDLc and

Lipid Profile

• Not a completely fair comparison

but suggests that Lipid Profile

testing has decreased since the

new Guidelines were released.

Why order a Lipid Panel?

• Important risk indicator for CVD

• Currently estimate 10-year and lifetime risks for

atherosclerotic cardiovascular disease (ASCVD),

defined as coronary death or nonfatal myocardial

infarction, or fatal or nonfatal stroke using

ASCVD risk calculator (online)

• http://tools.acc.org/ASCVD-Risk-Estimator/