National and international lipid modification guidelines: A critical appraisal

An update on lipidology and cardiovascular risk management

Lipids, Metabolism & Vascular Risk Section - Royal Society of Medicine

Claudia STEFANUTTI (Rome, Italy, EU)

London, UK, September 9, 2016

The guidelines nowadays represent an evidence-based consensus

The guidelines have been developed to support healthcare professionalscommunicating with individuals about their cardiovascular (CV) risk and thebenefits of a healthy lifestyle and early modification of their CV risk

In addition, the guidelines provide tools for healthcare professionals to promotepopulation-based strategies and integrate these into international, national orregional prevention frameworks and to translate these in locally deliveredhealthcare services

This is in line with the recommendations of the World Health Organization(WHO) global status report on non-communicable diseases 2010.

Guidelines: why?

Health impact pyramid.

Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272

© 2016 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please email: journals.permissions@oup.com.

Problems with Guidelines

• Institutional conflicts

• Inter-relationship between related diseases

• Commercial funding

• Personal conflicts

• Personal stakes

• Academic stakes

• Government conflicts

• Cost containment

• Priorities in healthcare

Courtesy of Dr. Handrean Soran

The US guidelines for the treatment of dyslipidemia

Backframe

Similarities between the ACC/AHA Guidelines and the NLA Recommendations

• Lipid screening for primary prevention is recommended at 5-year intervals

• Lifestyle therapy is supported as first step in all treatment algorithms

• ASCVD (*) risk reduction is the goal of therapy

• Moderate- or high-intensity statin therapy is the central focus of pharmacotherapy

• Patient- MD (provider) discussion of risk/benefit ratio precedes alldecisions on drug treatment

• Regular lipid and lipoprotein FU is necessary to assess adherence to therapy

(*): Atherosclerotic Cardio- Vascular Disease

Evidence base

ACC/AHA

• RCT(s) with ASCVD outcomes

• Meta-analyses of RCT

NLA

• RCT(s) with ASCVD outcomes

• Meta-analyses of RCT

• Selected post-hoc analyses of RCT

• Observational epidemiologic studies

• Genetic studies

• Metabolic studies

• Mechanistic studies

Genetic Studies

Genetic epidemiology reduces the likelihood ofconfounding by focusing on single variables: geneticmutations

Identification of specific mutations may serve togenerate hypotheses for other types of trials

Often limited in patient selection and costly

Data Demonstrating Genetic Variants affecting ASCVD Risk

Loss of function mutations in thegene encoding for PCSK9 areassociated in Black subjects with28% LDL-C reduction and 88% CHDrelative risk reduction

Loss of function mutations in thegene encoding for NPC1L1 areassociated with 12 mg/dLreduction in LDL-C and a 55%CHD relative risk reduction

Cohen JC, et al: Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. NEngl J Med. 2006 Mar 23;354(12):1264-72.

Myocardial Infarction Genetics Consortium Investigators: Inactivating mutations in NPC1L1 andprotection from coronary heart disease. N Engl J Med. 2014 Nov 27;371(22):2072-82.

Risk Calculator

• ACC/AHA supports use of pooled Cohort risk calculator as initial step

in non-Hispanic white and African-American non-diabetics, age 40-

79, with no ASCVD and with LDL-C 70-189 mg/dL to assess statin

benefit;

• consider using long-term risk assessment in 20-59 year-old

individuals not in high-risk groups

• NLA recommends risk factors counting and assessment of other

ASCVD risk indicators first, with optional use of any of 3 risk

calculators in patients with 2 major risk factors to aid in clinical

decision-making

2013 ACC/AHA GuidelineAdditional Markers of Increased ASCVD Risk

Consider for additional measurement of ASCVD risk in patientswho do not fall into one of the statin benefit groups (5-7.4% 10–year risk)

• LDL-C ≥ 160mg/dL

• Family history of premature ASCVD

• CAC score ≥ 300 Agatston units or 75%th-ile

• Hs-CRP≥ 2 mg/L

• Ankle-brachial index < 0.9

• High lifetime risk @age 20-59

www.escardio.org/guidelines European Heart Journal (2011) 32, 1769–1818

SCORE chart: 10 year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk

15% and over

10%-14%5%-9%3%-4%2%1%< 1%

SCORE

10-year risk of

fatal CVD in

populations at

Low CVD risk

Non-smoker Smoker

180

160

140

120 3

4

6

9

3

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180

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120 0

0

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1

4 5 6 7 8 4 5 6 7 8

Women

Sys

tolic

blo

od

pre

ssu

re (

mm

Hg

)

Cholesterol (mmol/L)

Age

65

60

55

50

40

Non-smoker Smoker

Men

5

7

10

15

5

8

12

17

6

9

14

20

8

11

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9

13

19

26

2

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4 5 6 7 8 4 5 6 7 8

150 200250 300mg/dl

Note: the SCORE chart is for use in people without overt CVD,

diabetes, chronic kidney disease, or very high levels of individual

risk factors because such people are ALREADY at HIGH RISK and

need INTENSIVE RISK FACTOR ADVICE

ACC/AHA Statin Benefit Groups

H: High intensity statin – M: Moderate intensity statin

• Clinically ASCVD (H preferred; M if age > 75 or if not candidate for

H

• Primary elevations of LDL-C ≥ 190 mg/dL (H preferred; M if not

candidate for H)

• Age 40-75 years with diabetes, and LDL-C 70-189 mg/dL, no clinical

ASCVD (M if 10-year risk < 7.5%; H if ≥ 7.5%)

• Age 40-75 years, no clinical ASCVD or diabetes, LDL-C 70-189

mg/dL, and estimated 10-year ASCVD risk ≥ 7.5% using Pooled

Cohort Equations (M or H)

High- and Moderate-IntensityDaily Statin Therapy

·High intensity (Lowers ·Moderate Intensity (Lowers LDL-C ≥50%) LDL-C 30-50%)

− Atorvastatin 40-80 mg − Atorvastatin 10 (20) mg

− Rosuvastatin 20-40 mg − Fluvastatin XL 80 mg

− Fluvastatin 40 mg 2x/day

− Lovastatin 40 mg

− Pitavastatin 2-4 mg

− Pravastatin 40 (80) mg

− Rosuvastatin (5) 10 mg

− Simvastatin 20-40 mg

− Simvastatin 80 mg**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

Bold= Tested in RCT andreviewed by Expert PanelYellow= Not tested in RCT’sreviewed by Expert Panel

Statin intensity trial showedclear benefit of high-intensityvs moderate intensity statins

Because fixed doses, nodosage titrations, wereemployed, one should notassume that a dosage titrationstrategy is correct or thataddition of non-statins toachieve low LDL-C is indicated

ACC/AHA Perspective on Statin Therapy

ACC/AHA Perspective on Non-statin Lipid Drug Therapy

‘ Non-statin therapies, as compared to statin therapy, do not provide acceptable

ASCVD risk reduction benefits relative to their potential for adverse effects in the

routine prevention of ASCVD ’ Niacin in AIM-HIGH and HPS-2 THRIVE

Fibrates in ACCORD-Lipids and FIELD

Overview of the NLA Recommendations

1. All preventive therapy begins with risk assessment and a provider

(Specialist MD is supposed!)-patient discussion of the pros and cons of

therapy

2. Life-style therapy is the first step in all ASCVD preventive

recommendations, regardless of baseline risk

3. Judicious use of evidence-based drug therapy, particularly M- and H-dose

statins, is associated with optimal ASCVD risk reduction

4. When excessive circulating atherogenic cholesterol (non-HDL-C [primary

target] and LDL-C) persists after appropriate lifestyle and statin therapy, the

use of non-statin therapy should be considered

5. Long-term follow-up fostered by ‘provider’-patient communication is

essential for optimal ASCVD prevention

What is the advantage of Non-HDL-C

over LDL-C in Assessing ASCVD RISK?

• Non-HDL-C is more predictive of ASCVD risk than LDL-C in observational studies. Thesame is true for on-treatment levels in clinical trials of statin therapy

• When Non-HDL-C and LDL-C are discordant, risk follows Non-HDL-C

• Non-HDL-C testing is universally available, requires no additional cost, and accuratevalues may be obtained in the non-fasting state

Boekholdt SM, et al: Lipid-related markers and cardiovascular disease prediction.JAMA. 2012 Jun 20;307(23):2499-506.

Jacobson TA, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary.

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88.

Robinson JG, Wang S, Smith BJ, Jacobson TA.Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and

coronary heart disease risk. J Am Coll Cardiol. 2009 Jan 27;53(4):316-22.

NLA Recommendations: Stepwise Approach to Risk Assessment

1. Identify the highest ASCVD risk category that applies to the patient

2. If very high risk, begin with moderate- or high-intensity statin with non-

HDL-C and LDL-C goals < 100 and < 70 mg/dL, respectively

3. In remaining patients count number of major risk factors and treat to

goals for non-HDL-C < 130 and LDL-C < 100 mg/dL, respectively

Further Risk Assessment in Patients with Two Major Risk Factors

Key Clinical Criteria: multipack/day cigarette smoking; strong family history ofpremature CHD; non-HDL-C > 190 mg/dL or LDL-C > 160 mg/dL

High Risk Quantitative Scoring: 10-year FRS ≥ 10%; ACC/AHA 10-year risk ≥ 15%;lifetime risk ≥ 45%

High Risk Biomarkers: CAC score ≥ 300 Agatston units or ≥ 75th%-ile; hsCRP≥ 2.0 mg/L;Lp(a) ≥ 50 mg/dL (protein; isoform insensitive assay); or urine albumine/creatinineratio≥ 30 mg/g

Joint British Societies-3

• non-HDL-C (TC minus HDL-c=non-HDL-c) to replace LDL-C

• ▸ professional lifestyle support to improve lipid profiles.

• ▸ Cholesterol lowering drug therapy is recommended in:

• Patients with established CVD

• Individuals at high risk of CVD:

• diabetes age >40 years,

• patients with CKD stages 3–5,

• or FH

• Individuals with high 10-year CVD risk (defined by NICE

guidance)

• Individuals with high lifetime CVD risk estimated from heart

age and other JBS3 calculator metrics, in whom lifestyle

changes alone are considered insufficient

JBS-3 board; Heart 2014; 100 ii : 1-167 Courtesy of Dr. Handrean Soran

www.escardio.org/guidelines European Heart Journal (2011) 32, 1769–1818

Recommendations for treatment targetsfor LDL-C

Recommendations Class Level

In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type 1 diabetes with target organ damage, moderate to severe CKD or a SCORE level ≥ 10%) the LDL-C goal is < 1.8 mmol/L (less than ~ 70 mg/dL) and/or ≥ 50% LDL-C reduction when target level cannot be reached.

I A

In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level ≥ 5 to < 10%) an LDL-C goal < 2.5 mmol/L (less than ~ 100 mg/dL) should be considered.

IIa A

In subjects at MODERATE risk (SCORE level > 1 to ≤ 5%) an LDL-C goal < 3.0 mmol/L (less than ~ 115 mg/dL) should be considered.

IIa C

www.escardio.org/guidelines European Heart Journal (2011) 32, 1769–1818

Intervention strategies as a function of total CV risk and LDL-C level

Total CV risk

(SCORE)

%

LDL-C levels

< 70 mg/dL< 1.8 mmol/L

70 to < 100 mg/dL1.8 to < 2.5 mmol/L

100 to < 155 mg/dL2.5 to < 4.0 mmol/L

155 to < 190 mg/dL4.0 to < 4.9 mmol/L

> 190 mg/dL> 4.9 mmol/L

< 1 No lipid intervention No lipid intervention Lifestyle intervention Lifestyle intervention

Lifestyle intervention,

consider drug if

uncontrolled

Class/Level I/C I/C I/C I/C IIa/A

≥ 1 to < 5 Lifestyle intervention Lifestyle intervention

Lifestyle intervention,

consider drug if

uncontrolled

Lifestyle intervention,

consider drug if

uncontrolled

Lifestyle intervention,

consider drug if

uncontrolled

Class/Level I/C I/C IIa/A IIa/A I/A

> 5 to < 10, or

high riskLifestyle intervention

consider drug*

Lifestyle intervention

consider drug*

Lifestyle intervention

and immediate drug

intervention

Lifestyle intervention

and immediate drug

intervention

Lifestyle intervention

and immediate drug

intervention

Class/Level IIa/A IIa/A IIa/A I/A I/A

≥ 10 or very

high riskLifestyle intervention

consider drug*

Lifestyle intervention

and immediate drug

intervention

Lifestyle intervention

and immediate drug

intervention

Lifestyle intervention

and immediate drug

intervention

Lifestyle intervention

and immediate drug

intervention

Class/Level IIa/A IIa/A I/A I/A I/A

NLA Perspective on Statin Therapy

Statin therapy is the most potentand evidence-based approach tolowering non-HDL-C and LDL-C andreduces ASCVD events

Statin intensity trial showed clearbenefit for high-intensity vsmoderate-intensity statins

Broad-based evidence supports«lower is better» concept.Clinicians should address residualrisk by appropriately-dosed statintherapy

Efficacy of Intensive Lowering LDL-C in Subjects with Low Baseline LDL-C

Meta-analysis of RCT of > 1000 participants and ≥ 2 years treatment duration or

more vs less intense statin trials involving 169,138 subjects

The major vascular event (MVE) reduction, among in those with baseline LDL-C <

77 mg/dL per further 39 mg/dL reduction was 29%; in those with baseline LDL-C <

70 mg/dL, similar reduction in LDL-C continued to demonstrate MVE reduction

Cholesterol Treatment Trialists’ (CTT) Collaboration: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81.

Joint British Societies-3

• Statins are recommended

• They are highly effective at reducing CVD events

• Benefit to LDL-c levels <2 mmol/L so intensive non-HDL-

C lowering required.

• Statins are safe

• There is a small increase in risk of developing diabetes

• The benefits of cholesterol lowering greatly exceed any

risk associated with diabetes.

• If statin intolerance develops use a stepwise strategy

• switch agents and re-challenge dosing.

• Low HDL-C values contributes to CVD risk,

• Drug therapy to raise HDL-c no effect on CVD risk

• Drug therapy for HDL-C is not currently indicated.

JBS-3 board; Heart 2014; 100 ii : 1-167 Courtesy of Dr. Handrean Soran

NLA Perspective on Non-Statin Lipid Drug Therapy

If non-HDL-C and LDL-C goals are not achieved with statin therapy, the

addition of evidence-based non-statin therapy should be considered to lower

atherogenic cholesterol level and to achieve goals

• Ezetimibe is a safe, evidence-based non-statin therapy that may be

considered in post MI patients and selected other patients with elevated

non-HDL-C and/or LDL-C

• Resins or Niacin can be considered in selected patients

• Meta-analyses of Fibrate therapy in subgroups with atherogenic

dyslipidemia suggest ASCVD risk reduction

Central Focus of Guidelines: Summary

define statin benefit groups; risk-benefit discussion; use

moderate- or high-intensity statin therapy with life-style change

as background therapy; generally avoid non-statin drug therapy;

no lipid goals

identify ASCVD risk level; risk-benefit discussion; emphasize

healthy life-style; use moderate- or high-intensity statin therapy,

and under appropriate circumstances, adjunctive non-statin

therapy, to lower atherogenic cholesterol; maintain lipid goals

(non-HDL-C is favored lipoprotein lipid target)

ACC/AHA

NLA

The differences

Evidence base

Central focus

Lipid and lipoprotein goals

Non-statin therapies

Risk estimation (calculator)

ACC/AHA

NLA

Major advances have been made in the clinical management of LDL-C. ManyRCTs in the past decades have shown that LDL-C lowering therapy reduces therisk for ASCVD

Despite advances made on different international guidelines and clinicalrecommendations, the real world management remains far from what isrecommended in these guidelines, in terms of best practice for both lifestyleand drug intervention

In addition, significant ASCVD risk persists despite the use of current lipidlowering standard of care, like the available therapies and treatment targetsfor patients at high ASCVD risk, HeFH, HoFH, statin intolerant patients, as wellas HyperLp(a)lipoproteinaemic subjects (Isolated and Combined forms)

Use careful clinical judgement when treat dyslipidaemia and/or any metabolicdisorder predictive of ASCVD risk

TAKE HOME MESSAGE