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Non-fasting lipid profiles: implications for lipoprotein testing and
reportingConsensus guideline of the European Atherosclerosis Society (EAS) and
European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)
presenter: Michel Langlois MD,PhD
AZ St.-Jan Bruges & University of Ghent, BelgiumChair of EFLM Task & Finish Group – Laboratory Testing for Dyslipidemia
EFLM webinar
moderator: prof. Dr. Jerzy-Roch Noferleader of the scientific Clinical Chemistry division at the University of Münster.
About Presenter• Professor at Ghent University, Department of Cardiovascular
Diseases• Vice-Director at the laboratory of AZ St-Jan hospital, Bruges• President of the Belgian Atherosclerosis Society• Past-president of the Royal Belgian Society of Laboratory Medicine• Chair of the EFLM-EAS Task and Finish Group on Laboratory
Testing for Dyslipidemia• Member of the EFLM WG-Guidelines• Corresponding member for the EFLM WG-Cardiac Markers and
WG-Congresses and Postgraduate Education
Non-fasting Lipid Profiles: EAS-EFLM Consensus Statement
1. Why has fasting been the standard?
2. Which lipoproteins are atherogenic?
3. Influence of food intake on lipid tests?
4. Non-fasting lipid tests: fit for purpose?
5. Implications & guidelines for laboratories
• Postprandial variation of Triglycerides (TG)
• Calculation of LDL-cholesterol (LDLC)Friedewald equation:LDLC = TC – HDLC – TG/2.2(mmol/l)
TG/5 (mg/dl)
Fasting Lipid Profiles: Why?
Invalid when TG >4.5 mmol/l (400 mg/dl)
• Practical§ Patients§ Healthcare practitioners§ Laboratories
• MedicalDaily average lipid status is nonfasting
Fasting Lipid Profiles: disadvantages
QUESTION 1:
Fasting LDL-C sufficiently estimates dyslipidemia-related risk in all patients?• YES• NO
Non-fasting Lipid Profiles: EAS-EFLM Consensus Statement
1. Why has fasting been the standard?
2. Which lipoproteins are atherogenic?
3. Influence of food intake on lipid tests?
4. Non-fasting lipid tests: fit for purpose?
5. Implications & guidelines for laboratories
Atherogenic lipoproteins
• Remnant particles
• LDL-particles
• Lipoprotein(a)
B
B. NordestgaardA. VarboThe Lancet 2014; 384:626-635
A.Varbo et al. Copenhagen General Population Study, Copenhagen City Heart Study, & Copenhagen Ischemic Heart Disease Study. J Am Coll Cardiol 2013;61:427-36.
Remnant cholesterol is a direct, causal CVD risk factor
LDL-particles
Low LDL-C; underestimated risk
Misleading LDL-C
Atherogenic Dyslipidemia in Diabetes and the Metabolic Syndrome
Lp(a)
LDL particle + apo(a)
2 to >40 KIV2repeats
HDL
VLDL
IDL
Chylo-microns
Lp(a)
LDL
LDLCHDLC
ChylomicronRemnants
Den
sity
(g/m
l)
TC
Size
HDL
VLDL
IDL
Chylo-microns
Lp(a)
LDL
LDLCHDLC ‘Remnant-C’
Non-HDLC
ChylomicronRemnants
ApoB ApoA-I
Den
sity
(g/m
l)
TC
Size
Non-fasting Lipid Profiles: EAS-EFLM Consensus Statement
1. Why has fasting been the standard?
2. Which lipoproteins are atherogenic?
3. Influence of food intake on lipid tests?
4. Non-fasting lipid tests: fit for purpose?
5. Implications & guidelines for laboratories
QUESTION 2:
Food intake significantly influences lipid tests ?
• YES
• NO
A. Langsted et al. Circulation 2008;118:2047-2056.
Non-fasting Lipid Profiles: EAS-EFLM Consensus Statement
1. Why has fasting been the standard?
2. Which lipoproteins are atherogenic?
3. Influence of food intake on lipid tests?
4. Non-fasting lipid tests: fit for purpose?
5. Implications & guidelines for laboratories
Nordestgaard et al. EAS EFLM joint Consensus Panel. Eur Heart J 2016
Population-based studies N >300 000 non-fasting individuals
Statin trials N= 43 000 non-fasting individuals
Tromsø Heart Study Heart Protection Study
Norwegian National Health Service Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
British Population Studies Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
European Prospective Investigation of Cancer–Norfolk
Northwick Park Heart StudyApolipoprotein-related Mortality RiskCopenhagen City Heart StudyWomen's Health StudyNurses' Health StudyPhysicians' Health Study
National Health and Nutrition Examination Survey III
Circulatory Risk in Communities StudyCopenhagen General Population Study
INTERHEART study
Nordestgaard et al. EAS EFLM joint Consensus Panel. Eur Heart J 2016
• Potential for risk misclassification in hypertriglyceridemic samples!
Abbott Beckman Olympus Roche Siemens Ortho
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
Langlois M et al. The EAS-EFLM Collaborative Project. Atherosclerosis 2014; 233:83-90
1.08CDC Reference Laboratory,Rotterdam
EQA survey (n=197 labs) of hypertriglyceridemic serum (~7 mmol/l)
Risk cutpoint
In red: SCORE>5 % and LDL-C ³ 2.50 mmol/L: start statin therapy immediately In green: SCORE>5 % and LDL-C <2.50 mmol/L: not applicable for statin therapy.
Clinical simulation: effect of direct LDL-C method variation on treatment
= TC - HDLC
A.Varbo et al. Copenhagen General Population Study. J Am Coll Cardiol 2013;61:427-36.
Non-fasting non-HDLC includes ‘remnant-cholesterol’
Abbott Beckman Olympus Roche Siemens Ortho
5.3
5.1
4.9
4.7
4.5
4.3
Langlois M et al. The EAS-EFLM Collaborative Project. Atherosclerosis 2014; 233:83-90
EQA survey (n=197 labs) of hypertriglyceridemic serum
In cases with TG 200-400 mg/dL(2.3-4.5 mmol/L)
De, Denka; Ky, Kyowa; Ro, Roche; Sr, Serotec; Sk, Sekisui, Sy, Sysmex; Um, UMA; Wa, Wako.
van Deventer HE et al. Clin Chem 2011;57:490-501
Misclassification of CVD risk(A) direct LDLC(B) calculated LDLC(C) non–HDLCcompared to Reference Method
TG
CC CTG
C
VLDL VLDL remnant
Small dense LDL
Large LDL
apoB apoB apoB apoB
ApoB : marker of atherogenic particle number
TG: triglycerides C: cholesterol
B B B B
<1%
<10%
~90%
ApoB48
ApoB100
Non-fasting apoB
Apo B 0.6 g/l Apo B 1.2 g/l
LDL cholesterol 100 mg/dl
Triglycerides 120 mg/dl
LDL cholesterol 100 mg/dl
Triglycerides 300 mg/dl
B B B
B B B
B B B B
B
B B B B
B
ApoB vs. LDLC
BB
I. van den Broek et al. Clin Chem 2016;62:188-97.
ApoB assays: traceable to WHO/IFCC reference material
NTG: normotriglyceridemia, HTG: hypertriglyceridemia, ITA: immunoturbidimetric assay
• Non-HDLC§ Calculated as TC – HDLC at no additional cost§ Includes ‘remnant-C’§ Not influenced by TG variability§ HDLC measurement errors!
• ApoB§ Simple, automated assay§ Single, well-defined measurand§ International standard SP3-08 (WHO / IFCC)§ LDL-particle number count
Non-fasting lipoprotein markers beyond LDLC
Comparison of 26 lipid fractions as predictors of first-ever cardiovascular events in apparently healthy women. Data are shown for the top versus bottom quintile of each lipid fraction.
The Lancet 2014;384:607 - 617
Paul M Ridker LDL cholesterol: controversies and future therapeutic directions
Relative Risk Ratios (RRR) for LDLC, non-HDLC, and apoBfrom 12 independent epidemiological studies
Sniderman A et al. Circ Cardiovasc Qual Outcomes 2011;4:337-345
LDL-C 1.25 (1.18-1.33) non-HDL-C 1.34 (1.24-1.44) ApoB 1.43 (1.35-1.51)
Coronary heart disease (CHD) risk among 13 595 women with LDLC < Median (120 mg/dl)
S.Mora et al. Women’s Health Study. Circulation 2014;129:553-61
Copyright © 2014 American Medical Association. All rights reserved.
From: Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins: Meta-analysis of 8 Trials (N=38 153)
Boekholdt SM et al. JAMA. 2012;307:1302-1309.
Hazard ratios (HRs) and 95% CIs for risk of major cardiovascular events for 4 categories of statin-treated patients, based on whether or not they reached the LDL-C target of 100 mg/dL and the non–HDL-C target of 130 mg/dL. HRs were adjusted for sex, age, smoking, diabetes, systolic blood pressure, and trial.
Jepsen AK et al. Clin Chem 2016;62:593-604
Remnant cholesterol explains part of residual risk of mortalityin 5414 patients with ischemic heart disease
“The good,
the bad,
and the ugly”
Non-fasting lipid profile
Non-fasting Lipid Profiles: EAS-EFLM Consensus Statement
1. Why has fasting been the standard?
2. Which lipoproteins are atherogenic?
3. Influence of food intake on lipid tests?
4. Non-fasting lipid tests: fit for purpose?
5. Implications & guidelines for laboratories
QUESTION 3:
Fasting lipid tests are obsolete and should not be used anymore?
• YES
• NO
Key recommendations
Fasting is not routinely required for a lipid profile
At nonfasting TG >4.5mmol/L (>400mg/dL), fasting sampling should be considered
Laboratory reports should flag abnormal concentrations based on desirable cutpoints
Life-threatening or extremely high concentrations should trigger lipid clinic referral
Nordestgaard et al. EAS EFLM joint Consensus Panel. Eur Heart J 2016
EAS-EFLM Consensus GuidelinePublished in Eur Heart J 2016 and Clin Chem 2016
Non-fasting In most patients, including:
· Initial lipid profile testing in any patient
· For CVD risk assessment
· Follow-up of cholesterol-lowering therapy
· In children
· If preferred by the patient
· In diabetic patients (due to hypoglycemic risk)
· In elderly
Fasting Rarely, but fasting can be used if:
· Nonfasting TG >5 mmol/L (>400 mg/dL)
· Diagnosis and follow-up of high TG known in lipid clinic
· Other tests that require fasting, e.g., glycemia
When to use non-fasting and fasting lipid tests?
Nordestgaard et al. EAS EFLM joint Consensus Panel. Eur Heart J 2016
Risk cutpoints Units
mmol/L mg/dL
Triglycerides Fasting
Nonfasting
≥1.7
≥2
≥150
≥175
Total cholesterol ≥5 ≥190
LDL cholesterol ≥3 ≥115
Non-HDL cholesterol Fasting
Nonfasting
≥3.8
≥3.9
≥145
≥150
Lipoprotein(a) ≥50
HDL cholesterol ≤1 ≤40
g/L mg/dL
Apolipoprotein B ≥1 ≥100
Apolipoprotein A1 ≤1.2 ≤120
=LDL-C + TG/5
Risk
SCORE (%)
LDL-C
mg/dl (mmol/l)
Non-HDL-C *
mg/dl (mmol/l)
ApoB *
mg/dl (g/l)
Very high (≥10) < 70 (1.8) < 100 (2.6) < 80 (0.8)
High (5 - <10) < 100 (2.5) < 130 (3.3) < 100 (1.0)
Moderate (1 - <5) < 115 (3.0) < 145 (3.8)
*Secondary targets in patients with combined dyslipidemia, metabolicsyndrome, type 2 diabetes, or chronic kidney disease.
Primary and secondary targets of therapy
Catapano A et al. ESC/EAS Guidelines for Dyslipidemia Management. Atherosclerosis 2011;217:3-46
Definition of hypertriglyceridemia by EAS Consensus
• Mild-to-Moderate§ 175 - 880 mg/dl (2 - 10 mmol/l)§ non-HDLC or apoB secondary target
• Severe§ >880 mg/dl (> 10 mmol/l)§ Prevention of pancreatitis
Hegele RA et al. Lancet Diabetes Endocrinol 2014;2:655-66.
Life-threatening
concentrations
Refer patient to lipid specialist to rule out
TG >10 mmol/L
>880 mg/dL
Chylomicronemia syndrome:
high risk of acute pancreatitis
LDL-C >5 mmol/L
>190 mg/dL
Heterozygous Familial Hypercholesterolemia (FH):
high CVD risk
LDL-C >13 mmol/L
>500 mg/dL
Homozygous Familial Hypercholesterolemia (FH):
very high CVD risk
Lp(a) >150 mg/dL Very high risk of myocardial infarction and
aortic valve stenosis
“Alarm” concentration flagging and reporting
Nordestgaard et al. EAS EFLM joint Consensus Panel. Eur Heart J 2016
® Family cascade screening
Dutch Lipid Clinical Network Criteria Score
Family historyFirst-degree relative with premature coronary and/or vascular disease (men <55 yrs, women <60 yrs) OR with LDL-C >95th percentile 1
First-degree relative with tendinous xanthomata and/or arcus cornealisOR Children <18 yrs with LDL-C >95th percentile 2
Clinical historyPremature coronary artery disease (men <55 yrs, women <60 yrs) 2Premature cerebral or peripheral vascular disease (men <55 yrs, women <60 yrs) 1Physical examinationTendinous xanthomata 6Arcus cornealis before 45 yrs 4Causative mutation in LDL-R, APOB or PCSK9 genes 8LDL-cholesterol ≥8.5 mmol/L (330 mg/dL) 8
6.5–8.4 mmol/L (250–329 mg/dL) 55.0–6.4 mmol/L (190–249 mg/dL) 34.0–4.9 mmol/L (155–189 mg/dL) 1
Diagnosis Total score
Definite FH >8Probable FH 6-8Possible FH 3-5Unlikely FH <3
National Societies for cardiology, endocrinology, atherosclerosis, pediatrics, clinical chemistry, general practice etc.
Key university hospitals and reference centers
National Implementation Strategies
Journalists and key medias disseminate the story that fasting is no longer routinely required for lipid testing
Clinical chemistry laboratories no longer require fasting for lipid testing and use desirable concentration cutpoints for lipid test reporting and flagging
From EFLM: Michel Langlois (Belgium; EFLM co-chair)Hannsjörg Baum (Germany), Christa Cobbaert (The Netherlands), Kari Pulkki (Finland), Grazyna Sypniewska (Poland)From EAS: Børge Nordestgaard (Denmark; EAS co-chair)Jan Borén (Sweden), Olivier Descamps (Belgium), Arnold von Eckardstein (Switzerland), Olov Wiklund (Sweden)Invited expertsEric Bruckert (France), John Chapman (France), Pia Kamstrup (Denmark), Genovefa Kolovou (Greece), Florian Kronenberg (Austria), Anne Langsted (Denmark), Samia Mora (USA), Alan Remaley (USA), Nader Rifai (USA), Emilio Ros (Spain), Gerald Watts ( Australia)
EAS-EFLM Consensus Panelestablished in 2014
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