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REVIEW TOPIC OF THE WEEK

A Test in Context: Lipid Profile,Fasting Versus Nonfasting

Børge G. Nordestgaard, MD, DMSC

ABSTRACT

Fro

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dis

Ma

Fasting for >8 h, as previously required for lipid profiles, normally only occurs a few hours before breakfast. By contrast,

the nonfasting state predominates most of a 24-h cycle and better captures atherogenic lipoprotein levels. Plasma

contains atherogenic lipoproteins of hepatic origin in the fasting state and additionally those of intestinal origin in the

nonfasting state. Maximal mean changes for random, nonfasting versus fasting levels are þ26 mg/dl for

triglycerides, �8 mg/dl for total cholesterol, �8 mg/dl for low-density lipoprotein cholesterol, þ8 mg/dl for remnant

cholesterol, and �8 mg/dl for non–high-density lipoprotein cholesterol; lipoprotein(a), apolipoprotein B, and

high-density lipoprotein cholesterol are largely unaffected. For patients, laboratories, and clinicians alike, nonfasting lipid

profiles represent a simplification without negative implications for prognostic, diagnostic, and therapeutic options for

cardiovascular disease prevention. Several societies’ guidelines and statements in Denmark, the United Kingdom,

Europe, Canada, Brazil, and the United States endorse nonfasting lipid profiles. (J Am Coll Cardiol 2017;70:1637–46)

© 2017 by the American College of Cardiology Foundation.

F asting for more than 8 h normally only occurs afew hours before breakfast (Figure 1). Bycontrast, the nonfasting state predominates

for most of a 24-h cycle. Therefore, because plasmacontains atherogenic lipoproteins of hepatic originin the fasting state and additionally those of intesti-nal origin in the nonfasting state, the nonfasting statemay better capture the total amount of atherogenic li-poproteins in plasma during the majority of a 24-hperiod.

Despite that, lipid profiles have previously beenmeasured in blood drawn in the fasting state, that is,after 8 to 12 h without food intake, whereas water andother nonfatty fluid intake have typically beenallowed (1,2). However, the tradition of using fastinglipid profiles is currently changing many places in theworld, with random, nonfasting lipid profiles beingendorsed by several societies, guidelines and

m the Department of Clinical Biochemistry and The Copenhagen Gener

penhagen University Hospital, Copenhagen, Denmark; and the Faculty o

gen, Copenhagen, Denmark. Dr. Nordestgaard has reported that he has no

close.

nuscript received June 23, 2017; revised manuscript received August 3, 2

statements in Denmark (3), the United Kingdom (4),Europe (5,6), Canada (7,8), Brazil (9), and the UnitedStates (10–12).

This review first delineates the lipid, lipoprotein,and apolipoprotein components of minimal, stan-dard, and expanded lipid profiles, followed by adescription of the difference in these measurementsbetween the fasting and the random, nonfastingstates. Thereafter, and with focus on the patient, themain goal of this review is to provide a critical eval-uation of the pros and cons of fasting versus non-fasting lipid profiles, and the implications forprognostic, diagnostic, and therapeutic options forpreventing cardiovascular disease. Finally, the re-view mention implications for conducting clinicaltrials and provides a short historical overview for theincreasing use of nonfasting, rather than fasting, lipidprofiles worldwide.

al Population Study, Herlev and Gentofte Hospital,

f Health and Medical Sciences, University of Copen-

relationships relevant to the contents of this paper to

017, accepted August 4, 2017.

FIGURE 1 Nonfasting and Fas

Typical Meals

Non-fasting

Less than 8 hrssince last meal

More than 8 hrssince last meal

Fasting

Fasting for more than 8 h for m

morning.

ABBR EV I A T I ON S

AND ACRONYMS

apoB = apolipoprotein B

CI = confidence interval

HDL = high-density lipoprotein

IDL = intermediate-density

lipoprotein

LDL = low-density lipoprotein

Lp(a) = lipoprotein(a)

VLDL = very low-density

lipoprotein

Nordestgaard J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7

Lipid Profile, Fasting Versus Nonfasting S E P T E M B E R 2 6 , 2 0 1 7 : 1 6 3 7 – 4 6

1638

LIPIDS, LIPOPROTEINS, AND

APOLIPOPROTEINS MEASURED IN

LIPID PROFILES

Lipids such as cholesterol and triglycerides,measured as total plasma values in lipidprofiles, are important for most cells.Cholesterol is an essential component of cellmembranes, and also acts as precursor forbile acids and steroid hormones. Tri-glycerides are important as energy sourcesand, after storage, act as an energy reserve as

well as for insulation against cold weather. Unliketriglycerides, carbohydrates, and proteins, choles-terol cannot be degraded by human cells. Cholesterolthat is newly synthesized or taken up via the intestinewill therefore remain in the body unless it is con-verted to steroid hormones, lost through skin celldetachment, or secreted via bile.

Because lipids will not mix with water, plasma hasa lipid transport system consisting of water-solublelipoproteins. The cores of lipoproteins consist ofapolar lipid triglycerides and cholesterol esters(Table 1) (13). Cholesterol esters are free cholesterolmolecules esterified with a fatty acid coming fromphospholipids; when cholesterol is measured inplasma or lipoproteins, it is a measurement of freeand esterified cholesterol combined. To keep tri-glycerides and cholesterol esters in a water solution,the surface of lipoproteins consists of molecules that

ting Periods During a 24-h Cycle With Intake of

Noon

Midnight

6 pm6 am

ost individuals only represents a few hours in the early

are apolar toward the lipoprotein core, but are polartoward the water phase. These molecules are phos-pholipids, free cholesterol, and apolipoproteins(Table 1). Apolipoproteins act as cofactors for en-zymes in lipid metabolism and as ligands when lipo-proteins are recognized at cell surfaces. Mostimportant are apolipopteins B (apoB) and E, whichfacilitate removal of low-density lipoprotein (LDL)and chylomicron remnant/intermediate-densitylipoprotein (IDL) from plasma, respectively.

Lipoproteins increase in size and decrease in den-sity from high-density lipoprotein (HDL) to LDL tolipoprotein(a) (Lp[a]) to IDL to very low-density li-poprotein (VLDL) to chylomicrons (Table 1). Chylo-micron remnants have size and density like IDL andVLDL.

Cholesterol and triglycerides in the diet areabsorbed in the small intestine and incorporated intochylomicrons (Figure 2). Chylomicrons are transferredto the bloodstream via lymph, where it comes incontact with the triglyceride-degrading enzyme lipo-protein lipase, mainly in fat and muscle tissue. Theresulting chylomicron remnants are taken up rapidlyby liver cells.

Cholesterol in the liver is either secreted via bile asbile acids or cholesterol, or will, together with tri-glycerides, be packed into VLDL particles that aresecreted into the bloodstream (Figure 2). Triglyceridesin VLDL will be degraded in fat and muscle tissue bythe enzyme lipoprotein lipase, and the cholesterol-rich IDL particle is formed. Some IDL particles arecleared by liver cells, whereas others are converted toLDL particles through the action of the triglyceride-degrading enzyme hepatic lipase. LDL particles aretaken up via the LDL receptor in the liver and othertissues.

Lipoprotein(a) particles are LDL particles with anextra apolipoprotein, apo(a) (Table 1); apo(a) has ho-mology with plasminogen, and therefore may inter-fere with fibrinolysis and indirectly promote arterialthrombosis (14). HDL particles were previouslythought to be important in atherosclerosis and car-diovascular disease, but the evidence to support thisis becoming weaker and weaker (15,16).

In hyperlipidemia, there is a surplus of atherogeniclipoproteins circulating in the blood, and a fraction ofthese will penetrate into the arterial intima via simplesize- and concentration-dependent filtration (Figure 3)(17). Chylomicrons and large VLDL with diameterslarger than 75 nm are not able to enter the intima (18),unlike all other lipoproteins (16,17). LDL, lip-oprotein(a) (Lp(a)), IDL, chylomicron remnants, andVLDL all enter the intima and are trapped, as theycannot penetrate the elastic laminas in the media.

TABLE 1 Size, Density, and Core and Surface Components of Lipoproteins

Diameter(nm)

MolecularWeight � 106 (Da)

Density(g/ml)

Components (% of Dry Weight)

MainApolipoproteins

Core Surface

Triglycerides Cholesterol Ester Cholesterol Phospholipid Apolipoproteins

Chylomicrons 75–1,200 50–1,000 0.93 86 3 2 7 2 A, B-48, C, E

VLDL 30–80 10–80 0.93–1.006 55 12 7 18 8 B-100, C, E

IDL 25–35 5–10 1.006–1.019 23 29 9 19 19 B-100, C, E

Lipoprotein(a) 25–30 4–5 1.040–1.090 8 30 8 25 29 B-100, a

LDL 18–25 2.3 1.019–1.063 6 42 8 22 22 B-100

HDL 5–12 0.2–0.4 1.063–1.210 4 15 5 34 42 A, C, E

HDL ¼ high-density lipoprotein; IDL ¼ intermediate-density lipoprotein; LDL ¼ low-density lipoprotein; VLDL ¼ very low-density lipoprotein.

FIGURE 2 Atherogenic Lipoproteins Present in the Blood During Periods of

Fasting and Nonfasting

Chylomicron Chylomicronremnant

VLDL IDL

LDL

Fasting

Nonfasting

Lipoprotein lipaseLipoprotein lipase

Triglycerides Cholesterol

During fasting, only liver-derived lipoproteins are present in plasma, whereas in the

nonfasting state, intestinal-derived lipoproteins are likewise found in plasma.

IDL ¼ intermediate-density lipoprotein; LDL ¼ low-density lipoprotein; VLDL ¼ very

low-density lipoprotein.

J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7 NordestgaardS E P T E M B E R 2 6 , 2 0 1 7 : 1 6 3 7 – 4 6 Lipid Profile, Fasting Versus Nonfasting

1639

All of these apoB-containing lipoproteins can, to somedegree, transfer back from the intima to the lumen ofthe artery against the blood pressure gradient, but thelarger triglyceride-rich lipoproteins IDL, chylomicronremnants and VLDL have particular difficulty leavingthe intima due to their larger sizes (16,19,20).

In isolated hypercholesterolemia, when tri-glycerides are below 176 mg/dl (2 mmol/l), LDLcholesterol is the main atherogenic component inplasma (Figure 4, left). In combined hyperlipidemia,when triglycerides are 176 to 880 mg/dl (2 to10 mmol/l), cholesterol in LDL, IDL, chylomicronremnants, and VLDL combined constitute theatherogenic plasma component (Figure 4, middle).However, when triglycerides are severely elevatedabove 880 mg/dl (10 mmol/l), chylomicrons and largeVLDL are not atherogenic, whereas LDL, IDL, chylo-micron remnants, and small VLDL are atherogenic(Figure 4, right).

MINIMAL, STANDARD, AND EXPANDED

LIPID PROFILES

The decision of which lipid profile to order for a givenpatient depends on the balance between optimaldiagnostic accuracy and cost, while avoiding unnec-essary diagnostic noise from measurement of toomany lipid, lipoprotein, and apolipoprotein compo-nents (Table 2). The minimal lipid profile is valuablein countries and situations where cost is a majorissue, whereas standard and expanded lipidprofiles are most commonly used in modern medi-cine. Single measurements of either total or LDLcholesterol should be avoided, as important elevationof triglycerides and remnant cholesterol can thenbe overlooked. Finally, many laboratories offeradditional measurements, such as lipoproteinsubfractions, other apolipoproteins, and evenmetabolomics phenotyping, all of which, for themajority of patients, are without proven clinical

value and may confuse, rather than enlighten, theclinician.

A minimal lipid profile consists of plasma totalcholesterol and triglycerides (Table 2). A standard lipidprofile also includes measurements of LDL cholesteroland HDL cholesterol. Total cholesterol, HDL choles-terol, and triglycerides are measured directly, whereasLDL cholesterol can either be measured directlyor calculated by the Friedewald equation iftriglycerides are <400 mg/dl (<4.5 mmol/l): totalcholesterol � HDL cholesterol � triglycerides/2.2 (allin mmol/l; or � triglycerides/5 with values in mg/dl)(21), with direct measurement of LDL cholesterol attriglyceride concentrations $400 mg/dl (4.5 mmol/l).Traditionally, the Friedewald equation has been

FIGURE 3 Transfer of Lipoproteins Between Plasma and the Arterial Intima

Plasma Arterial WallIntima

HDL

LDL

Lp(a)

IDL +chylomicronremnants

Chylomicrons+ large VLDL

SmallVLDL

Media Adventitia

This figure depicts the relative speed by which different lipoproteins enter and leave the

arterial intima, and therebywhich lipoproteins that get trappedpreferentially in the intima.

First, the larger the lipoprotein diameter, the fewer that will enter into the intima, where

chylomicrons and large VLDL are simply too large to enter. Second, although HDL is small

enough to penetrate into themedia and leave via the adventitia, other lipoproteins are so

large that they canonly leave the intima via the lumenof the artery. Becauseback transport

is against a blood pressure gradient, the largest lipoproteins, such as IDL, chylomicron

remnants, and small VLDL, get trapped preferentially in the intima. HDL ¼ high-density

lipoprotein; Lp(a) ¼ lipoprotein(a); other abbreviations as in Figure 2.

Nordestgaard J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7

Lipid Profile, Fasting Versus Nonfasting S E P T E M B E R 2 6 , 2 0 1 7 : 1 6 3 7 – 4 6

1640

applied to a fasting lipid profile; however, calculatedLDL cholesterol determined with this equation at tri-glyceride concentrations <400 mg/dl (4.5 mmol/l) issimilar to LDL cholesterol measured directly on bothfasting and nonfasting lipid profiles (22–24). These 4measurements can, without additional cost, be sup-plemented with calculated remnant cholesterol (i.e.,triglyceride-rich lipoprotein cholesterol) and calcu-lated non-HDL cholesterol (i.e., LDL þ remnantcholesterol) levels. Calculated remnant cholesterol isa strong causal risk factor for cardiovascular disease(25–27). The use of non-HDL cholesterol for cardio-vascular disease risk prediction has been emphasizedin several guidelines and consensus papers(6,7,10,28); non-HDL cholesterol is currently not atherapeutic target in U.S. guidelines (29).

An expanded lipid profile should be a standardone, with inclusion of Lp(a) measurement. This ge-netic, causal cardiovascular risk factor (14,30,31)should be measured at least once in all patientsscreened for cardiovascular risk (30); it is noteworthythat Lp(a) concentrations vary little over time (<10%)in any individual. Lp(a) determination should not,however, be included in repeated lipid profile

measurements in the same patient, unless therapeu-tic intervention is aimed at reducing Lp(a) concen-trations. Importantly, the cholesterol content ofLp(a), corresponding to approximately 30% of Lp(a)total mass (32), is included in total, non-HDL, and LDLcholesterol values and its apoB content is included inthe apoB value.

Finally, measurements of apoB can be used as analternative to non-HDL cholesterol (6,7,10,28), butthis measurement adds extra cost. ApoB is a well-standardized measurement that captures all athero-genic lipoproteins.

DIFFERENCES BETWEEN FASTING AND

NONFASTING LIPID PROFILES

Plasma contains remnant lipoproteins of hepaticorigin in the fasting state, whereas remnant lipo-proteins of intestinal origin additionally are presentin the nonfasting state (Figure 2). This means thatfrom 1 to 7 h after a habitual meal, plasma tri-glycerides and remnant cholesterol are slightlyelevated (Figure 5). A habitual meal here meanswhatever the person chose to eat before blood sam-pling, which naturally will differ from person toperson and from country to country. The degree ofplasma triglyceride elevation is related to levels atbaseline; the lower the baseline triglycerides, thesmaller the postprandial effect and vice versa perequivalent fat load.

Themaximalmean changes asmeasured in random,nonfasting versus fasting blood samples areþ26 mg/dl(0.3 mmol/l) for triglycerides, �8 mg/dl (0.2 mmol/l)for total cholesterol, �8 mg/dl (0.2 mmol/l) for LDLcholesterol, þ8 mg/dl (0.2 mmol/l) for remnantcholesterol, and �8 mg/dl (0.2 mmol/l) for non-HDLcholesterol, whereas lipoprotein(a), apoB, HDLcholesterol, and apoA1 are largely unaffected byrandom, nonfasting sampling (Figure 6) (5,33–37).Importantly, in individual subjects, the change in tri-glycerides will depend on baseline triglyceride levels,fat intake, and time since the last meal.

Interestingly, the slight decrease in total, LDL, andnon-HDL cholesterol after a habitual meal intake(Figure 6) occurs 0 to 4 h after meals, at the same timeas a reduction in plasma albumin is observed, but notcoinciding with the observed increase in triglyceridesand remnant cholesterol (35,36). This illustrates thatthe slight reduction in levels of total, LDL, and non-HDL cholesterol is due to fluid intake, and not foodintake, and that this phenomenon therefore will likelyalso occur during standard fasting for lipid profiles, aswater and other nonfatty fluid intake is typicallyallowed (1,2).

FIGURE 4 Cholesterol in Atherogenic Lipoproteins in Different Types of Hyperlipidemia

12463

mg/dL mmol/L

PlasmaCholesterol

309

155

0 0HDL

Isolated Hypercholesterolemia(Triglycerides < 2 mmol/L)

(< 176 mg/dL)

Combined Hypercholesterolemia(Triglycerides 2-10 mmol/L)

(176-880 mg/dL)

Severe Hypertriglyceridemia(Triglycerides > 10 mmol/L)

(> 880 mg/dL)

LDL

VLDL (+IDL) VLDL + IDL+ chylomicron

remnants

LDL

HDL

VLDL + IDL+ chylomicron

remnants

Chylomicrons+ large VLDL

LDL

HDL

Atherogeniccholesterol Atherogenic

cholesterol

Atherogeniccholesterol

4

8

(Top) The visual appearance of the 3 types of hyperlipidemia: isolated hypercholesterolemia; combined hyperlipidemia; and severe hyper-

triglyceridemia. (Bottom) Distribution of atherogenic cholesterol in different lipoproteins, all shown in orange. For severe hypertriglyceridemia,

some cholesterol is found in chylomicrons and largeVLDL that likely arenot atherogenic (shown ingold), as these lipoproteins are too large to enter

into the intima (see Figure 3). Neutral cholesterol in HDL is shown in green. Abbreviations as in Figures 2 and 3.

TABLE 2 Minimal, Standard, and Expanded Lipid Profiles, Nonfasting or Fasting

Measurement

Measurements in Plasma or Serum asPart of Lipid Profiles

Minimal LipidProfile

Standard LipidProfile

Expanded LipidProfile

Not Advised asSingle Measurement

AdditionalMeasurementsLipid Lipoprotein Apolipoprotein

Advantage Inexpensive Low cost Relatively low cost None None

Disadvantage No lipoproteinmeasurements

None None Overlooked elevatedtriglycerides and remnant

cholesterol

Expensive, largelyunnecessary

measurements

Triglycerides O O O O

Total cholesterol O O O O O

LDL cholesterol* O O O O

HDL cholesterol O O O

Remnant cholesterol† O O O

Non-HDL cholesterol‡ O O O

Lipoprotein(a) O O

ApoB O (O) O

ApoA1 O O

Lipoprotein subfractions O O

Other apolipoproteins O O

Metabolomic phenotyping O O O O

*LDL cholesterol can either be measured directly or calculated by the Friedewald equation if triglycerides are <400 mg/dl (4.5 mmol/l): total cholesterol � HDL cholesterol � triglycerides/2.2 (all in mmol/l;or � triglycerides/5 with values in mg/dl) (21), with direct measurement of LDL cholesterol at triglyceride concentrations $400 mg/dl (4.5 mmol/l). †Remnant cholesterol (¼ triglyceride-rich lipoproteincholesterol) is calculated as total cholesterol � LDL cholesterol � HDL cholesterol, using random, nonfasting or fasting lipid profiles; if LDL cholesterol is also calculated, then remnant cholesterol isequivalent to triglycerides/2.2 in mmol/l and to triglycerides/5 in mg/dl. ‡Non-HDL cholesterol is calculated as total cholesterol � HDL cholesterol and is equivalent to LDL and remnant cholesterolcombined.

ApoA1 ¼ apolipoprotein A1; ApoB ¼ apolipoprotein B; other abbreviations as in Table 1.

J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7 NordestgaardS E P T E M B E R 2 6 , 2 0 1 7 : 1 6 3 7 – 4 6 Lipid Profile, Fasting Versus Nonfasting

1641

FIGURE 5 Plasma Triglycerides and Remnant Cholesterol as a Function of Time Since

Last Habitual Meal in Individuals in the General Population

Copenhagen General Population StudyN = 92,285

Time Since Last Meal, Hours

mm

ol/L

Fasting 0-1

2

1-2

Remnant cholesterol

Triglycerides

2-3 3-4 4-5 5-6 7-86-7

1

0

The mean maximal increase in triglycerides of 26 mg/dl (0.3 mmol/l) and in remnant

cholesterol of 8 mg/dl (0.2 mmol/l), compared with fasting levels, occurs 3 to 4 h after

the last meal.

FIGURE 6 Mean Maximal Change in Lipids, Lipoproteins,

and Apolipoproteins in Random, Nonfasting Compared With

Fasting Lipid Profiles in Individuals in the General Population

Copenhagen General Population StudyN = 92,285

Triglycerides

Total cholesterol

LDL cholesterol

Remnant cholesterol

NonHDL cholesterol

Lipoprotein(a)

Apolipoprotein B

HDL cholesterol

Apolipoprotein A1

IncreasedMaximal Change After Normal Food Intake

Decreased

+0.3

–0.2

–0.2

+0.2

–0.2

+26

mmol/L mg/dL

–8

–8

+8

–8

No change

No change

No change

No change

These changes all are clinically insignificant. Adapted with

permission from Nordestgaard et al. (5). Abbreviations as in

Figures 2 and 3.

Nordestgaard J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7

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In patients at Copenhagen University Hospital, re-sults were similar with triglycerides measured both inthe nonfasting and fasting states (Figure 7) (5). Thiswas even true for those with the highest triglyceridelevels or with diabetes.

PROS AND CONS OF NONFASTING VERSUS

FASTING LIPID PROFILES

Because fasting has previously been the standardbefore blood sampling for a lipid profile in mostcountries, the shift toward using nonfasting ratherthan fasting lipid profiles naturally has been debatedover the last few years (5,38–50): many argumentsand novel data for and against have been presentedfrom the perspective of the patient, laboratory, andclinician.

With the current evidence base, it could be arguedthat the use of nonfasting lipid profiles is evidence-driven, whereas continued use of fasting lipid pro-files is largely belief-driven (Central Illustration).Indeed, a main argument for keeping fasting lipidprofiles is that “We have always done it that way!”when today, prospective evidence from more than300,000 individuals is available suggesting thatnonfasting lipid profiles are as good as, if not betterthan, fasting lipid profiles in predicting future car-diovascular events (5,51–54).

For example, in the Emerging Risk Factors Collab-oration, the hazard ratio for predicting coronary heartdisease per 43 mg/dl (1.1 mmol/l) higher non-HDLcholesterol was 1.72 (95% confidence interval [CI]:1.51 to 1.95) in 20 studies combined using nonfastinglipid profiles and including 103,354 subjects, of whom3,829 had an event, whereas the corresponding valuein 48 studies combined using fasting lipid profiles in199,076 subjects, of whom 8,956 had an event, was1.41 (95% CI: 1.30 to 1.53) (51). Similarly, 3 large ran-domized trials of statin therapy used nonfasting lipidprofiles (5).

The pros and the new evidence for using random,nonfasting lipid profiles reflect that many newguidelines and consensus statements endorse non-fasting lipid profiles for most patients (3–9,11,12),whereas a few older guidelines still recommendfasting lipid profiles for most patients (CentralIllustration) (29).

IMPLICATIONS FOR THE PATIENT. From theperspective of the patient, a random, nonfasting lipidprofile is practical compared with a fasting lipid pro-file because it does not interfere with the patient’snormal life and allows going to the laboratory for theblood draw at any time of the day (CentralIllustration). Nonfasting sampling will also be safe,

FIGURE 7 Comparison of Concentrations of Plasma Triglycerides Measured in the

Random, Nonfasting, and Fasting States in the Same Patients

Copenhagen University Hospital 2011-2015

Triglycerides, mmol/L0 1 2 3

< 1.1

All

Diabetes

5538N

Triglycerides, mmol/L1793

1.1-1.5

1.6-2.5

2.6-4.0

> 4.0

No

Yes

4711

418

1582

1454

534

175

4 5 6 7

Nonfasting Fasting

The fluctuation in plasma triglycerides is similar in the fasting and nonfasting states, even

in those with the highest triglycerides or with diabetes. Most patients were outpatients;

however, a minor fraction were likely inpatients, many of whom may experience reduced

appetite and, depending upon diagnosis (and state of recovery), were likely receiving

clear liquids/soft diet with low fat intake at the time of the nonfasting and/or fasting

blood draw. For such patients, the total fat intake likely is lower than in the free-living

state and, therefore, would not be generalizable to a general population. Adapted with

permission from Nordestgaard et al. (5).

FIGURE 8 Historical Development of Endorsement of Random, Nonfasting Lipid

Profiles by Societies, Guidelines, and Statements

Endorsement of nonfasting lipid profiles by societies, guidelines, & statements

Year2017

RegionUS

US

US

Denmark

UK

Europe

CanadaCanadaEurope

Brazil

2014

2011

2009

2014

2016

201620162016

2016

Society/guideline/statementAACE/ACE: American Association of Clinical Endocrinologists& American College of EndocrinologyConsensus of five medical societiesESC/EAS: European Society of Cardiology & EuropeanAtherosclerosis SocietyCCS: Canadian Cardiovascular SocietyCHEP: Canadian Hypertension Education ProgramEAS/EFLM: European Atherosclerosis Society & EuropeanFederation of Clinical Chemistry and Laboratory Medicine

VA/DoD: Veterans Affairs & US Department of DefenseNICE: National Institute for Health and Care Excellence

AHA: American Heart Association

DSKB: Danish Society for Clinical Biochemistry

Before 2009 essentially all societies, guidelines, and statements either requiredfasting before lipid profile measurement or did not mention requirements

Particularly from 2016 and onwards, the use of nonfasting lipid profiles has been

endorsed widely.

J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7 NordestgaardS E P T E M B E R 2 6 , 2 0 1 7 : 1 6 3 7 – 4 6 Lipid Profile, Fasting Versus Nonfasting

1643

whereas fasting for some patients with diabetes onantidiabetic medication may lead to risk of hypogly-cemia (55). Nonfasting lipid profiles will be time-saving and thus cost-saving for patients, becausethe need to return another day for a fasting lipidprofile is eliminated.

IMPLICATIONS FOR PROGNOSTIC AND DIAGNOSTIC

OPTIONS. From the perspective of the laboratory, afasting lipid profile is thought to be superior to anonfasting one because it can be standardized andleads to slightly less variation in the measured ana-lytes (49), most importantly triglycerides. Interest-ingly, however, the median triglyceride values and95% CIs were similar in 5,538 patients who had tri-glycerides measured both in the nonfasting andfasting states (Figure 7). Also, under nonstandardized,random, nonfasting conditions, plasma triglycerideson average only increase by 26 mg/dl (0.3 mmol/l) at4 h after a habitual meal (Figures 5 and 6). Such minorchanges are clinically unimportant, because a clini-cian is only interested in whether plasma tri-glycerides are 176 mg/dl (2 mmol/l) versus say440 mg/dl (5 mmol/l), whereas a difference between176 mg/dl (2 mmol/l) and 202 mg/dl (2.3 mmol/l) isclinically insignificant.

Another argument often presented against elimi-nation of fasting lipid profiles is that, in many coun-tries, other measurements in the blood also requirefasting before blood sampling. In Denmark, however,there is no requirement for fasting for any bloodmeasurements, except for fasting before an oralglucose tolerance test, and random, nonfasting gly-cosylated hemoglobin A1c is used to diagnose andmonitor diabetes, rather than fasting glucose.

Several publications endorsing use of nonfastinglipid profiles for the majority of patients also mentionsituations where a fasting lipid profile, or at least afasting triglyceride measurement, may theoreticallyimprove diagnostic accuracy (3–7,9,11,12). Althougheach of these suggestions for using fasting lipid pro-files in certain situations may sound reasonable, noneare supported by strong scientific evidence, butrather are likely driven by beliefs of some of the au-thors of the various guidelines and statements.Therefore, my recommendation is to use nonfastinglipid profiles widely, whereas any physician, natu-rally, is free to agree with an individual patient to fastfor a given lipid profile.

Taken together, and given the higher and higherdemands for fast, efficient, and inexpensive healthcare services all over the world, it is important thatwe consider what is most convenient for patients,laboratories, and clinicians alike, while, at the same

CENTRAL ILLUSTRATION Comparison of Fasting and Nonfasting Lipid Profiles

Nordestgaard, B.G. J Am Coll Cardiol. 2017;70(13):1637–46.

Direct comparison of arguments for and against use of random, nonfasting, and fasting blood sampling. Nonfasting blood sampling can occur anytime during the 24-h

cycle, irrespective of what and when the individual ate before blood sampling. By contrast, a fasting blood sample can only be drawn after a period without food

intake for 8 or more hours, which often means that a natural small fast of a few hours in the early morning will be extended, possibly until noon, before the blood is

drawn.

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time, being perfectly fine clinically, and maybefocus less on exactly how standardly and preciselywe can measure an analyte (50). In addition, useof nonfasting lipid profiles will improve patient flowin laboratories, as it eliminates large numbers ofpeople all coming for blood draws early in themorning.

IMPLICATIONS FOR THERAPEUTIC OPTIONS. Becausestatin therapy (and other lipid-lowering therapy)is decided on the basis of an individual’s globalcardiovascular risk, including the presence of car-diovascular disease, familial hypercholesterolemia,and diabetes, and not just on plasma lipid values inall major guidelines (4,6,7,11,12,29), minor changes in

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the lipid profile from fasting to nonfasting conditions(Figures 5 to 7) will only affect a few individualsregarding the decision to start a statin or not. Also,many guidelines use total and HDL cholesterol forrisk calculations, and these measurements are mini-mally affected by nonfasting versus fasting states.

Nevertheless, many guidelines use LDL cholesterolto monitor pharmacological treatment and as goalsfor treatment. In individuals with borderline LDLcholesterol, the lower LDL cholesterol observedmainly 0 to 4 h after a habitual meal due to liberalfluid intake and hemodilution (35), particularly inpatients with diabetes (36), needs to be consideredwhen using nonfasting lipid profiles to decidewhether to commence a statin or titrate its dose;however, the same is true for fasting lipid profiles,typically with no restrictions on water intake (1,2).

IMPLICATIONS FOR CLINICAL TRIALS. Nonfasting,compared with fasting lipid profiles will also helprecruit and retain patients in lipid-lowering trials,and likely will reduce trial costs. This is becauseethical committees in many countries do not allowpatients to be asked to fast before the first study visit,which means an extra study visit simply for the lipidprofile. Also, the use of nonfasting lipid profiles dur-ing follow-up visits will be more practical for studyparticipants, and will allow study visits at any time ofthe day, whatever suits the individual study partici-pant. Finally, because nonfasting lipid profile mea-surements are used more and more commonly inclinical practice, it is equally important that futurelipid-lowering trials are conducted under nonfastingconditions to match the clinical reality of the future.

HISTORICAL DEVELOPMENT OF

NONFASTING LIPID PROFILES

The Danish Society for Clinical Chemistry recom-mended nationwide use of nonfasting lipid profiles in2009 (3), followed by similar endorsement in 2011 bythe American Heart Association (10) and, in 2014, bythe U.K. National Institute for Health and CareExcellence guidelines (4) and guidelines from Veter-ans Affairs and U.S. Department of Defense (Figure 8)(11). This was followed by similar recommendationsin 2016 by the European Atherosclerosis Society andEuropean Federation of Clinical Chemistry and Lab-oratory Medicine, in a joint consensus statement withdetailed discussion of the evidence, as well as theclinical implications of using nonfasting, rather thanfasting lipid profiles (5). Later in 2016, this was fol-lowed by a similar endorsement for nonfasting lipidprofiles by the Canadian Hypertension EducationProgram guidelines (8), the Canadian CardiovascularSociety guidelines (7), the European Society of Car-diology and the European Atherosclerosis Societyguidelines for the management of dyslipidemias (6),and by consensus of 5 medical societies in Brazil (9).Finally, in 2017, endorsement of the use of nonfastinglipid profiles came from the American Association ofClinical Endocrinologists and the American College ofEndocrinology (12).

ADDRESS FOR CORRESPONDENCE: Dr. Børge G.Nordestgaard, Clinical Biochemistry, Herlev Hospital,Herlev Ringvej 75, 2730 Herlev, Denmark. E-mail:boerge.nordestgaard@regionh.dk.

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KEY WORDS cardiovascular disease,cholesterol, lipoproteins, low-densitylipoprotein, triglycerides