Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cutpoints--a joint consensus statement from the European atherosclerosis society and European federation of clinical chemistry and laboratory medicine.
Interestingly, evidence is lacking that fasting is superior to non-fasting when evaluating the lipid profile for cardiovascular risk assessment. However, there are advantages to using non-fasting samples rather than fasting samples for measuring the lipid profile (3-7). Since 2009, non-fasting lipid testing has become the clinical standard in Denmark, based on recommendations from the Danish Society for Clinical Biochemistry that all laboratories in Denmark use random non-fasting lipid profiles as the standard, while offering clinicians the option of re-measuring triglyceride concentrations in the fasting state if non-fasting values are >4 mmol/L (350 mg/dL) (8, 9). Furthermore, the UK NICE (National Institute of Health and Care Excellence) guidelines have endorsed non-fasting lipid testing in the primary prevention setting since 2014 (10).
The most obvious advantage of non-fasting rather than fasting lipid measurements is that it simplifies blood sampling for patients, laboratories, general practitioners, and hospital clinicians and is also likely to improve patient compliance with lipid testing (3-7). Indeed, patients are often inconvenienced by having to return on a separate visit for a fasting lipid profile and may default on essential testing. Also, laboratories are burdened by a large volume of patients attending for tests in the morning. Finally, clinicians are burdened by having to review and make decisions on the findings in the lipid profile at a later date. This situation may also require an additional phone call, e-mail, or even a follow-up clinic visit, placing extra workloads on busy clinical staff.
Perceived limitations to adopting non-fasting lipid measurements include the following; (i) fasting before a lipid profile measurement is believed to provide more standardized measurements; (ii) non-fasting lipid profiles are perceived as providing less accurate measurements and may make calculation of LDL cholesterol via the Friedewald equation invalid; and (iii) as fasting has been the clinical standard, it is unclear what values should be flagged as abnormal when using non-fasting rather than fasting plasma lipid profiles. These perceived limitations will be addressed in this report. The aims of the present joint consensus statement are to critically evaluate the use of non-fasting rather than fasting lipid profiles and the clinical implications of this question with a view to providing appropriate guidance for laboratory and clinicians. Based on evidence from large-scale population studies and registries and on consensus of expert opinions, the European Atherosclerosis Society (EAS)  / European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) joint consensus statement proposes recommendations on (i) situations when fasting is not required for a lipid profile and (ii) how laboratory reports should flag abnormal lipid profiles to improve compliance of patients and clinicians with concentration goals used in guidelines and consensus statements on cardiovascular disease prevention (11-15). This joint consensus statement is aimed at internists, general practitioners, pediatricians, cardiologists, endocrinologists, clinical biochemists, laboratory professionals, public health practitioners, health service planners, other health professionals, healthcare providers, and patients worldwide. Key recommendations are given in Table 1.
Constituents of the Plasma Lipid Profile
A standard lipid profile includes measurements of plasma or serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (Fig. 1).
Total cholesterol, HDL cholesterol, and triglycerides are measured directly, while LDL cholesterol can either be measured directly or calculated by the Friedewald equation if triglycerides are <4.5 mmol/L (400 mg/ dL): total cholesterol minus HDL cholesterol minus triglycerides/2.2 (all in mmol/L; or minus triglycerides/5 with values in mg/dL) (16), with direct measurement of LDL cholesterol at triglyceride concentrations [greater than or equal to] 4.5 mmol/L (400 mg/dL). Traditionally, the Friedewald equation has been applied to a fasting lipid profile; however, calculated LDL cholesterol determined with this equation at triglyceride concentrations <4.5 mmol/L (400 mg/dL) is similar to LDL cholesterol measured directly on both fasting and non-fasting lipid profiles (Fig. 2) (17, 18). These four measurements can, without additional cost, be supplemented with remnant cholesterol and non-HDL cholesterol.
Remnant cholesterol (i.e., triglyceride-rich lipoprotein cholesterol) is calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol, using nonfasting or fasting lipid profiles; if LDL cholesterol is also calculated, then remnant cholesterol is equivalent to triglycerides/2.2 in mmol/L and to triglycerides/5 in mg/dL. Calculated remnant cholesterol is a strong causal risk factor for cardiovascular disease (19-21). Non-HDL cholesterol is calculated as total cholesterol minus HDL cholesterol and is equivalent to LDL cholesterol, remnant cholesterol, and lipoprotein(a) [Lp(a)] cholesterol combined (Fig. 1). The use of non-HDL cholesterol for cardiovascular disease risk prediction has been emphasized in several guidelines and consensus papers (12-15)?
The most important additional measurement for inclusion for cardiovascular disease risk prediction is Lp(a). This genetic, causal cardiovascular risk factor (11, 22) should be measured at least once in all patients screened for cardiovascular risk (11); it is noteworthy that Lp(a) concentrations vary little over time (< 10%) in any individual. The determination of Lp(a) should not, however, be included in repeated lipid profile measurements in the same patient, unless therapeutic intervention is aimed at reducing Lp(a) concentrations or in selected circumstances. Importantly, the cholesterol content of Lp(a), corresponding to 30% of Lp(a) total mass (23), is included in total, non-HDL, and LDL cholesterol values and its apolipoprotein B content in the apolipoprotein B value.
Finally, measurements of apolipoprotein B and apolipoprotein A1 can be used as alternatives to non-HDL and HDL cholesterol measurements, respectively (Fig. 1) (13-15, 24), but these determinations come at extra cost.
Why Has Fasting Been the Standard?
Venipuncture is a universal practice involved in testing the lipid profile with the purpose of predicting cardiovascular risk and/or monitoring responses to lipid-lowering therapy. Some guidelines continue to promulgate the conventional practice of measuring the lipid profile in the fasting state (25), although other organizations endorse non-fasting lipid profiles (8, 10). The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not require fasting for atherosclerotic cardiovascular disease risk estimation; however, they do recommend a fasting lipid panel before statin initiation to calculate LDL cholesterol and for individuals with non-HDL cholesterol [greater than or equal to] 5.7 mmol/L (220 mg/ dL) or triglycerides [greater than or equal to] 5.7 mmol/L (500 mg/dL), since these may be clues to genetic and/or secondary causes of hypertriglyceridemia (25). One reason among others for preferring fasting lipid profiles is the increase in triglyceride concentration seen during a fat tolerance test (26, 27); however, the increase in plasma triglycerides observed after habitual food intake in most individuals is much less than that observed during a fat tolerance test (3, 4, 9, 28-31 ). As a fast-food meal consisting of, for example, a burger, a shake, and fries might be considered a fat tolerance test, in areas where fast-food consumption is especially high, patients may be advised to avoid high-fat, fast-food meals on the day of lipid profile testing. Also, as LDL cholesterol is often calculated by the Friedewald equation, which includes the triglyceride concentration, calculated LDL cholesterol has been thought to be affected substantially by food intake; however, directly measured and calculated LDL cholesterol values are similar using both fasting and non-fasting lipid profiles (Fig. 2) (17, 18). If this Friedewald equation is used, there may be some underestimation of LDL cholesterol when chylomicrons are present, which may even be circumvented if a modification of this equation is used (32). Also, many randomized lipid-lowering trials have used fasting lipid measurements, and, to follow evidence-based practice, fasting blood sampling has often been the standard in everyday risk assessment. However, numerous population-based studies and at least three major statin trials used random, non-fasting blood sampling (Table 2), providing a robust evidence base for a change in the conventional practice of using fasting samples.
Influence of Food Intake on the Plasma Lipid Profile
Several large-scale, population-based studies and registries including children, women, men, and patients with diabetes have now established that plasma lipids and lipoproteins change only modestly in response to habitual food intake (Figs. 3 and 4, Table 3) (3, 4, 9, 29, 30); this applies to the majority of individuals, but rarely some exhibit exaggerated responses. These studies were the Women's Health Study from the US, the Copenhagen General Population Study from Denmark, the National Health and Nutrition Examination Survey from the US (Fig. 3), and the Calgary Laboratory Services from Canada (Fig. 4). Among all studies comparing non-fasting with fasting lipid profiles, minor increases in plasma triglycerides and minor decreases in total and LDL cholesterol concentrations were observed, with no change in HDL cholesterol concentrations.
These minor and transient changes in lipid concentrations appear to be clinically insignificant; however, Langsted et al. observed a transient drop in LDL cholesterol concentration of 0.6 mmol/L (23 mg/dL) at 1-3 h after a meal in diabetic patients, which could be of clinical significance (33), particularly if this is used as an argument to withhold statins in a given patient. Of note, the reduction in total and LDL cholesterol at 1-3 h after the last meal observed in individuals with and without diabetes became statistically insignificant after adjusting for plasma albumin concentration as a marker of fluid intake (3, 9); therefore, such a drop in total and LDL cholesterol is unrelated to food intake, noting that a similar drop may even be observed in a fasting lipid profile, since water intake is allowed ad libitum before a fasting blood test (2). Thus, the only way to prevent this drop in LDL cholesterol concentrations using either fasting or non-fasting lipid profiles is to forbid water intake before lipid profiles testing, while so-called fasting sampling will not remove this phenomenon. Importantly, in patients with diabetes, a fasting lipid profile may further disguise postprandial triglyceride increases that may be particularly important in the diabetic state.
For the purpose of the present joint consensus statement, we updated the analyses of Langsted et al. (3, 34) (Fig. 5), based on the Copenhagen General Population Study, and including 92 285 men and women from the Danish general population. As in previous reports (Table 3) (3, 4, 9, 29, 30, 34), the maximal mean changes at 1-6 h after habitual meals were considered clinically insignificant at +0.3 mmol/L (26 mg/dL) for triglycerides, -0.2 mmol/L (8 mg/dL) for total cholesterol, -0.2 mmol/L (8 mg/dL) for LDL cholesterol, +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol, and -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol, while concentrations for HDL cholesterol, apolipoprotein Al, apolipoprotein B, and Lp(a) remained unchanged (Fig. 5). Naturally, the corresponding changes in concentrations in individual patients will differ from the mean changes seen in Table 3 and in Figs. 3-3, exactly as concentrations will differ from one fasting measurement to another in the same individual.
Influence of Food Intake on the Prediction of Cardiovascular Risk
We exist mostly in the non-fasting state, which therefore reflects our habitual physiological status. However, blood samples typically measured after an 8-12 h fast have been the standard for assessing the plasma lipid profile (1, 2). Postprandial effects do not appear to diminish and may in fact enhance the strength of the associations between plasma lipid, lipoprotein, and apolipoprotein concentrations and risk of cardiovascular disease.
Since the 1970s, numerous reports from well-conducted, large, representative, and mostly prospective studies with medium- to long-term follow-up have consistently found that non-fasting lipids suffice for screening of cardiovascular disease risk (3, 4, 31, 35-39). These studies have examined clinical outcomes ranging from incident cardiovascular disease events (myocardial infarction, stroke, and revascularization) to cardiovascular or all-cause mortality, with consistent associations for non-fasting lipid profiles with cardiovascular disease risk. Furthermore, studies that included fasting and/or nonfasting individuals have found generally similar or sometimes superior cardiovascular disease risk associations for non-fasting compared with fasting lipid profiles, including for triglycerides (3, 4, 31, 38, 39); the challenge of taking small amounts of alcohol during non-fasting hours of the day and its influence on lipid profile values has often not been studied. Prospective studies that have assessed non-fasting lipid profiles are shown in Table 2.
A meta-analysis from the Emerging Risk Factors Collaboration that analyzed the association of lipid profiles and risk of coronary heart disease events from 68 prospective studies and included over 300 000 individuals, equally found no attenuation of the strength of the association between plasma lipid and lipoprotein concentrations and incident cardiovascular events in the 20 studies that used non-fasting blood samples; indeed, non-fasting non-HDL cholesterol and non-fasting calculated LDL cholesterol were superior to fasting measurements for predicting cardiovascular risk (n = 103 354; number of events 3829) (36). Furthermore, at least three large clinical trials of statin therapy (Heart Protection Study, Anglo-Scandinavian Cardiac Outcomes Trial: Lipid-Lowering Arm, and the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) involving nearly 43 000 participants used nonfasting lipid profile measurements (Table 2).
Finally, for the purpose of this joint consensus statement and based on the Copenhagen General Population Study including 92 285 men and women from the Danish general population, we examined the risk of ischemic heart disease and myocardial infarction for the highest vs lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins as part of standard and expanded lipid profiles (Fig. 6); all lipids, lipoproteins, and apolipoproteins were associated strongly with the risk of both end points.
Hence, numerous prospective cohorts have found significant associations for non-fasting lipids, lipoproteins, and apolipoproteins with cardiovascular disease risk, and several landmark clinical trials of statin therapy have used non-fasting lipids for trial entry criteria and for monitoring the efficacy of lipid-lowering therapy. Collectively, these observations suggest that non-fasting blood sampling is highly effective, practical, and advantageous in assessing lipid-mediated cardiovascular disease risk and treatment responses.
Recommendations on the Use of Non-fasting Lipid Profiles
To improve patient compliance with lipid testing, we therefore recommend that non-fasting lipid profiles be used in the majority of patients (Table 4), whereas with non-fasting plasma triglyceride >5 mmol/L (440 mg/ dL), a fasting sampling may be considered. However, because lipid profile measurements often are taken repeatedly in the same patient, a single, spurious, nonfasting very high triglyceride concentration due to a very high fat intake preceding blood sampling will be followed by other measurements with lower concentrations.
Fasting can be a barrier to population screening, is unpopular with children, is often unsuitable for patients with diabetes, and counters the use of point-of-care testing. Fasting requirements can add to the overall costs of lipid testing. Non-fasting tests are also used to assess other metabolic disorders, such as hemoglobin [A.sub.1c] in diabetes. The collective sources of evidence reviewed above have therefore led to the notion that fasting samples are not essential for evaluation of cardiovascular risk.
Arguments against the use of non-fasting samples also merit consideration. There is evidence that the nonfasting condition may marginally lower plasma LDL cholesterol concentrations owing to liberal intake of fluids (Table 3) and therefore lead to a potential minor misclassification of cardiovascular risk, as well as to error in initiating or altering lipid-lowering medication; although not all studies agree, this risk is small and may chiefly apply to diabetic subjects (5, 9, 33). Although a nonfasting sample is sufficient to diagnose an isolated hypercholesterolemia, such as familial hypercholesterolemia, or elevated Lp(a), it can possibly confuse the distinction between familial hypercholesterolemia and genetic forms of high triglycerides. Because non-fasting may therefore impair the accuracy in diagnosing some forms of hyperlipidemia, we recommend that laboratories should also offer measurement of fasting triglycerides according to clinical context and indications, as in the case of very high non-fasting triglyceride concentration. Plasma lipids can be highly variable in children and a precise diagnosis of a lipid disorder that requires drug therapy may necessitate at least a second sample in the fasting state. From an evidence-based perspective, fasting and non-fasting samples have never been tested head-to-head in a clinical trial to assess how the corresponding lipid profiles alter clinical management and the disposition of patients, and what the relative cost-effectiveness of both approaches is.
It is unlikely that such a study will ever be funded, however.
What pragmatic recommendations can be made? First, non-fasting and fasting measurements of the lipid profile must be viewed as complementary and not mutually exclusive (Table 4). Commonsense must prevail and a distinction must be made between non-fasting and fasting measurement use in screening, assessment, and diagnosis. Fasting is less critical for first-stage screening, but may be more important when trying to establish a phenotypic diagnosis of genetically determined dyslipidemias. Further, one circumstance where fasting may be especially valued is getting a baseline lipid determination for individuals about to start medications that cause severe hypertriglyceridemia in genetically predisposed individuals. Noting that fasting triglycerides are elevated can thus be useful before, for example, steroid, estrogen, or retinoid acid therapy. Also, fasting lipids have been used to follow the course of patients recovering from hypertriglyceridemic pancreatitis. Nevertheless, nonfasting blood samples can routinely be used for assessment of plasma lipid profiles in most situations (T able 4).
Potential for Risk Misclassification
It is important to consider whether transferring from fasting to non-fasting lipid profiles could lead to misclassification of cardiovascular risk and error in initiating statin therapy. Importantly, since statin treatment is decided on the basis of an individual's global cardiovascular risk, including the presence of cardiovascular disease, familial hypercholesterolemia, and diabetes, and not just on plasma lipid values in both European and US guidelines (15, 25), minor changes in the lipid profile from fasting to non-fasting conditions (Figs. 3-5, Table 3) will affect only a few individuals regarding the decision to start a statin or not. However, most guidelines use LDL cholesterol to monitor pharmacological treatment and as goals for treatment. In individuals with borderline LDL cholesterol, the lower LDL cholesterol observed 1-6 h after a habitual meal, particularly in diabetic patients (Table 3), needs to be considered when using non-fasting lipid profiles to decide whether to commence a statin or titrate its dose. Of note, because the observed reduction in LDL cholesterol is due to liberal fluid intake and hemodilution rather than to food consumption, a similar LDL reduction is likely to occur when using fasting lipid profiles with no restrictions on water intake (2).
Novel Findings from Experience in Denmark
In 2009, the Danish Society for Clinical Biochemistry recommended that all laboratories in Denmark use random non-fasting lipid profile measurements rather than fasting profiles (8, 9). It was believed that a single spurious, non-fasting very high triglyceride concentration due to high fat intake preceding blood sampling would be followed by other measurements with lower concentrations. However, it was also recommended that laboratories should offer the option of re-measurement of triglyceride concentrations in the fasting state, if non-fasting triglyceride values were at >4 mmol/L (350 mg/dL).
This change in blood sampling was easy to implement in Denmark: after adoption of the non-fasting strategy by major university hospitals in Copenhagen and subsequent corresponding reports in written and electronic media nationwide, patients and clinicians in the entire country pushed for similar changes at their local clinical biochemical laboratory. Only a few laboratories refused initially to follow this new practice, but by 2015 practically all laboratories in Denmark use non-fasting lipid profiles.
To illustrate the consequences of implementing this new blood sampling policy and for the purpose of the present joint consensus statement, we retrieved results for all triglyceride measurements at Herlev Hospital, Copenhagen University Hospital, in the period April 2011 through April 2015: of approximately 60 000 triglyceride measurements, only 10% were measured in the fasting state. Further, among the 5538 patients with both a non-fasting and a fasting triglyceride measurement, concentrations were similar for fasting and non-fasting measures overall as well as when stratified by triglyceride concentrations and the presence or absence of diabetes (Fig. 7, top). In groups stratified for triglyceride concentrations, the interquartile ranges were wider for fasting than for non-fasting triglycerides, which is explained by regression dilution bias, since the initial groups were made based on non-fasting concentrations and then fasting concentrations were compared afterwards. Thus, if groups were made initially based on fasting concentrations, then the confidence intervals for non-fasting triglycerides were wider than for fasting triglycerides (data not shown). In other words, the variation in fasting and non-fasting triglyceride concentrations measured in the same individuals at two different occasions is similar, as is also clear for the value in all 5538 individuals combined (Fig. 7, top). Results were also similar for LDL cholesterol comparing non-fasting and fasting values (Fig. 7, bottom).
Recommendations on Laboratory Reporting of Abnormal Non-fasting and Fasting Lipid Profiles
We recommend that laboratory reports should flag abnormal values based on desirable concentration cutpoints, defined by guidelines and consensus statements (11-15), and for non-fasting samples, flag abnormal concentrations as triglycerides [greater than or equal to] 2 mmol/L (175 mg/dL) (40, 41) (corrected for endogenous glycerol), total cholesterol [greater than or equal to]5 mmol/L (190 mg/dL), LDL cholesterol [greater than or equal to]3 mmol/L (115 mg/dL), calculated remnant cholesterol [greater than or equal to]0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol [greater than or equal to]3.9 mmol/L (155 mg/dL), HDL cholesterol [less than or equal to] 1 mmol/L (40 mg/dL) (sex-specific cutpoints can be used for HDL cholesterol), apolipoprotein A1 [less than or equal to]1.25 g/L (125 mg/dL), apolipoprotein B [greater than or equal to] 1.0 g/L (100 mg/dL), and Lp(a) [greater than or equal to]50 mg/dL (80th percentile) (Table 5); for fasting samples, abnormal concentrations should be triglycerides [greater than or equal to]1.7 mmol/L (150 mg/dL), remnant cholesterol [greater than or equal to]0.8 mmol/L (30 mg/dL), and non-HDL cholesterol [greater than or equal to]3.8 mmol/L (145 mg/dL), while other measurements should use identical cutpoints for non-fasting values.
The majority of these cutpoints correspond to desirable concentrations from guidelines and consensus statements (11-15)? However, a desirable concentration cutpoint for non-fasting triglycerides was documented only recently (40, 41 ); we therefore choose to recommend flagging of abnormal concentrations of non-fasting triglycerides as [greater than or equal to]2 mmol/L (175 mg/dL), according to the Women's Health Study, which found that this cutpoint was optimal for cardiovascular risk prediction. Interestingly, this result is almost identical to the cutpoints previously suggested by the EAS and the Athens Expert Panel (12, 24, 42). A concentration cutpoint for fasting triglycerides at 1.7 mmol/L (150 mg/dL) was taken as 0.3 mmol/L lower than for non-fasting triglycerides, corresponding to the mean maximal increase of triglycerides following habitual food intake (Fig. 5, Table 3). Interestingly, this cutpoint is identical to those proposed previously for fasting triglycerides by the American Heart Association (14) and the EAS (12).
Usually, in laboratory medicine, results of measured parameters are considered to be abnormal if they exceed the age- and sex-specific reference interval (2.5th to 97.5th percentiles). All results below or above these recommended cutpoints are flagged with a character to show at a glance that this value deserves attention. Also, automatic validation and flagging are used in many laboratories.
Depending on the laboratory, this labeling can vary. Theoretically, the reference intervals should be established by each laboratory, but in most cases, they are taken over from the general information provided by the manufacturer in the package insert. Because of the widespread unhealthy lifestyle, in most populations, the upper reference cutpoint (i.e., 97.5th percentile) of total cholesterol (>7.8 mmol/L in Denmark) and LDL cholesterol (>5.5 mmol/L) as well as triglycerides (>4.4 mmol/L) are very high and place individuals at consider ably increased cardiovascular risk. Therefore, flagging abnormal values based on desirable concentration cutpoints rather than reference intervals are recommended to identify abnormal test results. Especially for LDL cholesterol, the desirable values vary with the individual's global risk between <1.8 mmol/L (70 mg/dL) (very high risk), <2.5 mmol/L (100 mg/dL) (high risk), and <3.0 mmol/L (115 mg/dL) (moderate risk) (15, 25) (Tables 6 and 7). These different values are classified according to the presence or absence of comorbidities (atherosclerotic cardiovascular disease, diabetes, chronic kidney disease) and other risk factors (age, sex, hypertension, smoking).
This personalized reporting of desirable values is difficult to implement in laboratory reports because usually the clinical conditions and risk factors of the individual patient are not known to the laboratory professional. We therefore propose a simplified system of flagging abnormal values based on desirable concentration cutpoints for moderate risk only, which may be complemented by more detailed information on risk-stratified cutoffs in footnotes on the laboratory report or by references to web-based information of the same laboratory.
Using flagging emphasizes the importance of harmonization and standardization in laboratory medicine and the responsibility of EAS and European Federation of Clinical Chemistry and Laboratory Medicine to communicate to laboratories when updates of cutpoints are necessary as guidelines for cardiovascular disease prevention are revised.
According to the flagging of abnormal values based on desirable concentration cutpoints proposed in Table 5, the following percentages of adults in the general population of a typical Western or Northern European country will have flagged test results in non-fasting lipid profiles: 27% will have triglycerides [greater than or equal to] 2 mmol/L (175 mg/ dL), 72% will have total cholesterol [greater than or equal to]5 mmol/L (190 mg/dL), 60% will have LDL cholesterol [greater than or equal to]3 mmol/L (115 mg/dL), 27% will have calculated remnant cholesterol [greater than or equal to]0.9 mmol/L (35 mg/dL), 50% will have calculated non-HDL cholesterol [greater than or equal to]3.9 mmol/L (150 mg/dL), 20% will have Lp(a) [greater than or equal to]50 mg/dL (80th percentile), 59% will have apolipoprotein B [greater than or equal to]1.0 g/L (100 mg/dL), 10% will have HDL cholesterol [less than or equal to] 1 mmol/L (40 mg/dL), and 9% will have apolipoprotein A1 [less than or equal to] 1.25 g/L (125 mg/dL) (Fig. 8).
Life-Threatening Plasma Lipid Concentrations: What To Do?
Life-threatening or extremely abnormal test results deserve special attention and reactions from the clinical biochemical laboratory. In this regard, the following extreme hyperlipidemias should be noted: triglycerides >10 mmol/L (880 mg/dL) because of risk of acute pancreatitis (24)', LDL cholesterol >5 mmol/L (190 mg/dL) in adults or >4 mmol/L (155 mg/dL) in children and particularly >13 mmol/L (500 mg/dL) because of suspicious heterozygous and homozygous familial hypercholesterolemia (43-45), respectively; and Lp(a) >150 mg/dL (99th percentile) for very high risk of myocardial infarction and aortic valve stenosis (11, 46, 47) (Table 8). Because such concentrations are always much above a common decision cutpoint, they should be flagged with special symbols to quickly initiate further diagnostic and possibly therapeutic actions, preferably with direct referral to a lipid clinic or to a physician with special interest in lipids. It is also important to refer patients with very low concentrations of LDL cholesterol, apolipoprotein B, HDL cholesterol, or apolipoprotein A1 to a specialist lipid clinic for further evaluation of a major monogenic disorder of lipid metabolism (Table 8).
Implementation of Recommendations
Each country, state, and/or province in individual countries should adopt strategies for implementing routine use of non-fasting rather than fasting lipid profiles as well as flagging of abnormal values based on desirable concentration cutpoints rather than using traditional reference intervals. Ideally, there should be one standard for reporting lipid profiles in each country and accreditation bodies should be aware of the present consensus statement. Fig. 9 suggests implementation strategies; however, the strategy might differ from country to country based on existing local practice in relation to use of non-fasting lipid profiles and flagging of abnormal values based on desirable concentration cutpoints used for assessing cardiovascular risk, making diagnoses, and initiating lipidlowering drug therapy. Finally, within countries with differing ethnic groups, the policy on non-fasting might need to be further refined. Indeed, for example, individuals of South Asian or Fatin American descent are more likely to have severe triglyceride elevations when compared with individuals of non-Hispanic white and black descent. This finding could be another reason to have a caveat about avoiding a high-fat, fast-food meal on the day of lipid profile testing.
The article has been co-published with permission in European Heart Journal and Clinical Chemistry. All rights reserved in respect of European Heart Journal. (c)American Association for Clinical Chemistry.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
EAS/EFLM Joint Consensus Panel members were nominated by EAS, EFLM, and the Co-chairs B.G. Nordestgaard and M. Langlois to represent expertise across clinical and laboratory management and research in lipids from across the world. The Panel met twice, organized and chaired by M. Langlois and B.G. Nordestgaard. The first meeting critically reviewed the literature while the second meeting reviewed additional literature and scrutinized the first draft of the joint consensus statement. All Panel members agreed to conception and design, contributed to interpretation of available data, suggested revisions for this document, and approved the final document before submission.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures are presented here in the style of European Heart Journal. Disclosures and/or potential conflicts of interest:
Employment or Leadership: N. Rifai., Clinical Chemistry, AACC; M.R Langlois, European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).
Consultant or Advisory Role: E. Ros, California Walnut Commission.
Stock Ownership: None declared.
Research Funding: Supported by unrestricted educational grants to EAS and EFLM from Merck, Roche Diagnostics, and Denka Seiken. These companies were not present at the Joint Consensus Panel meetings, had no role in the design or content of the joint consensus statement, and had no right to approve or disapprove of the final document. Funding to pay the Open Access publication charges for this article was provided by the European Atherosclerosis Society and the European Federation of Clinical Chemistry and Laboratory Medicine.
Expert Testimony: None declared.
Patents: None declared.
Other Remuneration: S. Mora, European Atherosclerosis Society.
Conflict of Interest Statement: Consensus Panel members have received lecture honoraria, consultancy fees, and/or research funding from Aegerion (B.G.N., M.J.C., E.B., and E.R.), Amgen (A.v.E., B.G.N., M.J.C., E.R., F.K., E.B., G.K., and O.S.D.), Atherotech Diagnostics (S.M.), Pfizer (M.J.C., J.B., G.F.W., O.S.D., O.W., E.R., and S.M.), Astra Zeneca (B.G.N., M.J.C., J.B., G.F.W., O.S.D., O.W., E.B., and S.M.), Cerenis Therapeutics (S.M.), Danone (M.J.C. and E.B.), Genzyme (M.J.C. and E.B.), Merck/ Schering Plough (A.v.E., B.G.N., M.J.C., J.B., G.F.W., O.S.D., O. W., E.B., and E.R.), Abbott (G.F.W.), Sanofi/Regeneron (A.v.E., B.G.N., M.J.C., P.R.K., J.B., G.F.W., O.S.D., O.W., E.B., E.R., and G.K.), Lilly (B.G.N., S.M., E.B., and G.K.), Kowa (M.J.C.), Unilever (A.v. E. and E.B.), Genfit (E.B.), Roche Diagnostics and Pharmaceuticals (M.L., E.R., A.v.E., M.J.C., M.L., and E.B.), Denka Seiken (B.G.N. and P.R.K.), Dezima (B.G.N. and P. R.K.), Kaneka (B.G.N.), Fresenius (B.G.N. and P.R.K.), B Braun (B.G.N.), IONIS Pharmaceuticals (B.G.N. and E.B.), VIANEX (G.K.), and Alexion (E.R.).
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, and final approval of manuscript.
Acknowledgments: We thank Jane Stock for preparing summaries of meeting discussions. Ciber Fisiopatologia de la Obesidady Nutricion is an initiative of Instituto de Salud Carlos III, Spain.
(1.) Rifai N, Warnick GR. Lipids, lipoproteins, apolipoproteins, and other cardiovascular risk factors. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. Philadelphia: Elsevier Saunders; 2006, p. 903-982.
(2.) Simundic AM, Cornes M, Grankvist K, Lippi G, Nybo M. Standardization of collection requirements for fasting samples: for the Working Group on Preanalytical Phase (WG-PA) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). Clin Chim Acta 2014;432:33-7.
(3.) Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation 2008;118:2047-56.
(4.) Mora S, Rifai N, Buring JE, Ridker PM. Fasting compared with nonfasting lipids and apolipoproteins for predicting incident cardiovascular events. Circulation 2008; 118:993-1001.
(5.) Watts GF, Cohn JS. Whither the lipid profile: feast, famine, or no free lunch? Clin Chem 2011;57:363-5.
(6.) Gaziano JM. Should we fast before we measure our lipids? Arch Intern Med 2012;172:1705-6.
(7.) Khera AV, Mora S. Fasting for lipid testing: is it worth the trouble? Arch Intern Med 2012;172:1710-2.
(8.) Nordestgaard BG, Hilsted L, Stender S. [Plasma lipids in non-fasting patients and signal values of laboratory results.] [in Danish] Ugeskr Laeger 2009;171:1093.
(9.) Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins, and apolipoproteins in individuals with and without diabetes: 58 434 individuals from the Copenhagen General Population Study. Clin Chem 2011; 57: 482-9.
(10.) NICE clinical guideline CG181. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease, https://wwwnice.org.uk/ guidance/cg181/evidence/lipidmodification-updatefull-guideline-243786637 (Accessed October 2015).
(11.) Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31: 2844-53.
(12.) Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32: 1345-61.
(13.) Reiner Z, Catapano AL, De BG, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
(14.) Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
(15.) Perk J, De BG, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635-701.
(16.) Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
(17.) Tanno K, Okamura T, Ohsawa M, Onoda T, Itai K, Sakata K, et al. Comparison of low-density lipoprotein cholesterol concentrations measured by a direct homogeneous assay and by the Friedewald formula in a large community population. Clin Chim Acta 2010;411: 1774-80.
(18.) Mora S, Rifai N, Buring JE, Ridker PM. Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27,331 women. Clin Chem 2009;55:88894.
(19.) Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
(20.) Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298-309.
(21.) Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
(22.) Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301:2331-9.
(23.) Kinpara K, Okada H, Yoneyama A, Okubo M, Murase T. Lipoprotein(a)-cholesterol: a significant component of serum cholesterol. Clin Chim Acta 2011;412:1783-7.
(24.) Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2:655-66.
(25.) Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
(26.) Cohn JS, McNamara JR, Schaefer EJ. Lipoprotein cholesterol concentrations in the plasma of human subjects as measured in the fed and fasted states. Clin Chem 1988;34:2456-9.
(27.) Mihas C, Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, et al. Diagnostic value of postprandial triglyceride testing in healthy subjects: a metaanalysis. Curr Vasc Pharmacol 2011;9:271-80.
(28.) Klop B, Cohn JS, van Oostrom AJ, van Wijk JP, Birnie E, Castro CM. Daytime triglyceride variability in men and women with different levels of triglyceridemia. Clin ChimActa 2011;412:2183-9.
(29.) Sidhu D, Naugler C. Fasting time and lipid levels in a community-based population: a cross-sectional study. Arch Intern Med 2012;172:1707-10.
(30.) Steiner MJf Skinner AC, Perrin EM. Fasting might not be necessary before lipid screening: a nationally representative cross-sectional study. Pediatrics 2011;128:463-70.
(31.) Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299 -308.
(32.) Martin SS, Biaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA2013;310:2061-8.
(33.) Lund SS, Jensen T. Using nonfasting lipids: hemodilution or convenience? Clin Chem 2011;57:1336-8.
(34.) Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 2014; 234:95-101.
(35.) Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease: 10 158 incident cases among 262 525 participants in 29 Western prospective studies. Circulation 2007;115:450-8.
(36.) Di AE, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipo proteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
(37.) Doran B, Guo Y, Xu J, Weintraub H, Mora S, Maron DJ, Bangalore S. Prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol levels on longterm mortality: insight from the National Health and Nutrition Examination Survey III (NHANES-III). Circulation 2014;130:546-53.
(38.) Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008;300: 2142-52.
(39.) Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309-16.
(40.) White KT, Moorthy MV, Akinkuolie AO, Dernier 0, Ridker PM, Cook NR, Mora S. Identifying an optimal cutpoint for the diagnosis of hypertriglyceridemia in the nonfasting state. Clin Chem 2015;61:1156-63.
(41.) Langsted A, Nordestgaard BG. Nonfasting lipid profiles: the way of the future. Clin Chem 2015;61:1123-5.
(42.) Kolovou GD, Mikhail id is DP, Kovar J, La iron D, Nordestgaard BG, Ooi TC, et al. Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. Curr Vase Pharmacol 2011 ;9: 258-270.
(43.) Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hyper cholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90.
(44.) Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical management: a position paper from the Consensus Panel on Familial HypercholesteroIaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
(45.) Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercho lestero I aemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
(46.) Thanassouiis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503-12.
(47.) Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63: 470-7.
(48.) Jessen RH, Dass G, Eckfeldt JH. Do enzymatic analyses of serum triglycerides really need blanking for free glycerol? Clin Chem 1990;36:1372-5.
Borge G. Nordestgaard,  * Anne Langsted,  Samia Mora,  Genovefa Kolovou,  Hannsjorg Baum,  Eric Bruckert,  Gerald F. Watts,  Grazyna Sypniewska,  Olov Wiklund,  Jan Boren,  M. John Chapman,  Christa Cobbaert,  Olivier S. Descamps,  Arnold von Eckardstein,  Pia R. Kamstrup,  Kari Pulkki,  Florian Kronenberg,  Alan T. Remaley,  Nader Rifai,  Emilio Ros, [17,18] and Michel Langlois, [19,20] for the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Joint Consensus Initiative
 Department of Clinical Biochemistry, Herlevand Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev, Denmark;  Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Bos ton, MA;  Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece;  In stitute for Laboratory Medicine, Blutdepot und Krankenhaushygiene, Regionale Klini ken Holding RKH GmbH, Ludwigsburg, Germany;  Pitie-Salpetriere University Hospital, Paris, France;  University of Western Australia, Perth, Australia;  Department of Laboratory Medicine, Collegium Medicum, NC University, Bydgoszcz, Poland;  Sahlgrenska University Hospital, Gothenburg, Sweden;  INSERM U939, Pitie-Salpetriere University Hospital, Paris, France;  Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands;  Hopital de Jolimont, Haine-Saint-Paul, Belgium;  Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland;  Department of Clinical Chemistry, University of Eastern Finland, Kuopio, Finland;  Department of Medical Genetics, Molecular and Clinical Pharmacol ogy, Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria;  Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;  Children's Hospital, Laboratory Medicine, Harvard University, Boston, MA;  Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigadons Biomediques August Pi Sunyer, Hospital Clfnic, Barcelona, Spain;  Ciber Fisiopatologfade la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain;  Department of Laboratory Medicine, AZ St-Jan, Brugge, Belgium; and  University of Ghent, Ghent, Belgium.
 Nonstandard abbreviations: EAS, European Atherosclerosis Society; EFLM, European Federation of Clinical Chemistry and Laboratory Medicine; Lp(a), lipoprotein(a).
* Address correspondence to this author at: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, DK-2730 Herlev, Denmark. Fax +45 38683311; e-mail email@example.com.
Received April 9,2016; accepted April 19,2016.
Previously published online at DOI: 10.1373/clinchem.2016.258897
Caption: Fig. 1. Lipids, lipoproteins, and apolipoproteins as part of standard and expanded lipid profiles.
Standard lipid profiles consist of triglycerides and total, LDL, and HDL cholesterol; however, a standard lipid profile could also report calculated remnant cholesterol and calculated non-HDL cholesterol, since these come at no additional cost. Calculated remnant cholesterol is non-fasting total cholesterol minus LDL cholesterol minus HDL cholesterol. Calculated non-HDL cholesterol is total cholesterol minus HDL cholesterol. Lp(a) should be measured at least once in every individual screened for cardiovascular risk to detect potentially high concentrations of this genetic risk factor. Finally, apolipoprotein B (Apo B) and apolipoprotein A1 (Apo A1) can be used as alternatives to non-HDLand HDL cholesterol, but these measurements come at an extra cost. Figure designed by B.G. Nordestgaard.
Caption: Fig. 2. Comparison of calculated LDL cholesterol using the Friedewald equation with LDL cholesterol measured directly using random non-fasting and fasting lipid profiles.
Only lipid profiles with triglycerides <4.5 mmol/L (400 mg/dL) were included, since LDL is typically measured using a direct LDL cholesterol assay when triglycerides are [greater than or equal to] 4.5 mmol/L. Mes, measured; Cal, calculated using the Friedewald equation (LDL cholesterol = total cholesterol --HDL cholesterol--triglycerides/2.2; all values in mmol/L; if values are in mg/dL then use triglycerides/5). Figure designed by B.G. Nordestgaard and A. Langsted based on unpublished data from individuals participating in the Copenhagen City Heart Study 2001-2003 examination.
Caption: Fig. 3. Mean concentrations of lipids and lipoproteins as a function of the fasting period after the last meal in children from the US general population.
The last meal simply represents what the particular child chose to eat at that particular day before blood sampling, with no information or requirement on amount or type of food eaten. Data are based on 12744 children from the National Health and Nutrition Examination Survey (30).
Caption: Fig. 4. Mean concentrations of lipids and lipoproteins as a function of the period of fasting afterthe last meal in men and women from the Canadian general population.
The last meal simply represents what the particular individual chose to eat at that particular day before blood sampling, with no information or requirement on amount or type of food eaten. Data are based on 209180 men and women from Calgary Laboratory Services (29).
Caption: Fig. 8. Proportion of non-fasting individuals in the general population with flagged abnormal concentrations in laboratory reports using desirable concentration cutpoints as shown in Table 5. Of all participants, 12% were receiving statins.
Figure designed by B.G. Nordestgaard and A. Langsted based on unpublished data on 92 285 non-fasting individuals from the Copenhagen General Population Study recruited from 2003 to 2014.
Table 1. Key recommendations. Fasting is not required routinely for assessing the plasma lipid profile. When non-fasting plasma triglyceride concentration is >5 mmol/L (440 mg/dL), consideration should be given to repeating the lipid profile in the fasting state. Laboratory reports should flag abnormal values based on desirable concentration cutpoints. Life-threatening or extremely high concentrations should trigger an immediate referral to a lipid clinic or to a physician with special interest in lipids. Table 2. Population-based studies and statin trials that have used non-fasting plasma lipid profiles to assess cardiovascular disease risk and trial outcomes, respectively. Population-based studies totaling Statin trials totaling 43 000 non- >300 000 non-fasting individuals fasting individuals Tromso 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 Study Apolipoprotein-related Mortality Risk Copenhagen City Heart Study Women's Health Study Nurses' Health Study Physicians' Health Study National Health and Nutrition Examination Survey III Circulatory Risk in Communities Study Copenhagen General Population Study The global 52-country case-control INTERHEART study Table 3. Maximal mean changes in lipids and lipoproteins at 1-6 h after consumption of habitual meals as part of a standard lipid profile in individuals in large-scale population based studies and registries. Study population Mora et al. (4) 26330 women from the Women's Health Study Langsted et al. (3) 33391 men and women from the Copenhagen General Population Study Steiner et al. (30) 12744 children from the National Health and Nutrition Examination Survey Langsted and 2270 men and women with diabetes Nordestgaard (9) from the Copenhagen General Population Study 56164 men and women without diabetes from the Copenhagen General Population Study Sidhu and Naugler (29) 209180 men and women from Calgary Laboratory Services Random non-fasting compared with fasting concentrations (a) Triglycerides Mora et al. (4) [up arrow] 0.2 mmol/L [up arrow] 18 mg/dL [up arrow] 16% Langsted et al. (3) [up arrow] 0.3 mmol/L [up arrow] 26 mg/dL [up arrow] 21% Steiner et al. (30) [up arrow] 0.1 mmol/L [up arrow] 9 mg/dL [up arrow] 10% Langsted and [up arrow] 0.2 mmol/L Nordestgaard (9) [up arrow] 18 mg/dL [up arrow] 11% [up arrow] 0.2 mmol/L [up arrow] 18 mg/dL [up arrow] 14% Sidhu and Naugler (29) [up arrow] 0.3 mmol/L [up arrow] 26 mg/dL [up arrow] 21% Total cholesterol Mora et al. (4) [down arrow] 0.1 mmol/L [down arrow] 4 mg/dL [down arrow] 1% Langsted et al. (3) [down arrow] 0.2 mmol/L (b) [down arrow] 8 mg/dL [down arrow] 4% Steiner et al. (30) [down arrow] 0.1 mmol/L [down arrow] 4 mg/dL [down arrow] 2% Langsted and [down arrow] 0.4 mmol/L (b) Nordestgaard (9) [down arrow] 15 mg/dL [down arrow] 8% [down arrow] 0.3 mmol/L (b) [down arrow] 12 mg/dL [down arrow] 5% Sidhu and Naugler (29) No change LDL cholesterol Mora et al. (4) [down arrow] 0.2 mmol/L [down arrow] 8 mg/dL [down arrow] 5% Langsted et al. (3) [down arrow] 0.2 mmol/L (b) [down arrow] 8 mg/dL [down arrow] 6% Steiner et al. (30) [down arrow] 0.1 mmol/L [down arrow] 4 mg/dL [down arrow] 4% Langsted and [down arrow] 0.6 mmol/L (b) Nordestgaard (9) [down arrow] 23 mg/dL [down arrow] 25% (c) [down arrow] 0.3 mmol/L (b) [down arrow] 1 2 mg/dL [down arrow] 9% Sidhu and Naugler (29) [down arrow] 0.1 mmol/L [down arrow] 4 mg/dL [down arrow] 4% HDL cholesterol Mora et al. (4) No change Langsted et al. (3) [down arrow] 0.1 mmol/L [down arrow] 4 mg/dL [down arrow] 6% Steiner et al. (30) No change Langsted and No change Nordestgaard (9) No change Sidhu and Naugler (29) No change (a) Values in mmol/L were converted to mg/dL by multiplication with 38.6 for cholesterol and by 88 for triglycerides. (b) No longer statistically significant after adjustment for reduction in plasma albumin concentrations; thus, this drop in total and LDL cholesterol is due to fluid intake, not to food intake. In other words, because water intake is allowed during the up to 8-h fasting before lipid profile testing (2), this reduction in total and LDL cholesterol will also occur for fasting lipid profiles. (c) Langsted et al. (3) observed a drop in LDL cholesterol of 0.6 mmol/L (23 mg/dL) at 1-3 h after a meal in patients with diabetes, which could be of clinical significance, particularly if this precluded initiation of statin therapy. However, such an LDL reduction may also occur for fasting lipid profiles with water intake allowed (2), since the likely explanation for the LDL cholesterol drop is fluid intake and ensuing hemodilution. Table 4. When to use non-fasting and fasting blood sampling to assess the plasma lipid profile. Patients for lipid profile testing Non-fasting In most patients, including: * Initial lipid profile testing in any patient * For cardiovascular risk assessment * Patients admitted with acute coronary syndrome (a) * In children * If preferred by the patient * In diabetic patients (b) (due to hypoglycemic risk) * In the elderly * Patients on stable drug therapy Fasting Can sometimes be required if: * Non-fasting triglycerides >5 mmol/L (440 mg/dL) * Known hypertriglyceridemia followed in lipid clinic * Recovering from hypertriglyceridemic pancreatitis * Starting medications that cause severe hypertriglyceridemia * Additional laboratory tests are requested that require fasting (c) or morning samples (e.g., fasting glucose (c), therapeutic drug monitoring) (a) Will need repeated lipid profile testing later because acute coronary syndrome lowers lipid concentrations. (b) Diabetic hypertriglyceridemia may be masked by fasting. (c) In many countries, fasting blood sampling is restricted to few analytes besides lipid profiles: one example is fasting glucose; however, in many countries, even fasting glucose measurement is being replaced by measurement of hemoglobin [A.sub.1c] without the need to fast. Table 5. Abnormal plasma lipid, lipoprotein, and apolipoprotein concentration values that should be flagged in laboratory reports based on desirable concentration cutpoints. (a) Non-fasting Abnormal concentrations mmol/L Triglycerides (c) [greater than or equal to] 2 Total cholesterol [greater than or equal to] 5 LDL cholesterol [greater than or equal to] 3 Remnant cholesterol (d) [greater than or equal to] 0.9 Non-HDL cholesterol (e) [greater than or equal to] 3.9 Lp(a) f Apolipoprotein B HDL cholesterol (h) [less than or equal to]1 Apolipoprotein A1 Abnormal concentrations mg/dL (b) Triglycerides (c) [greater than or equal to] 175 Total cholesterol [greater than or equal to] 190 LDL cholesterol [greater than or equal to] 115 Remnant cholesterol (d) [greater than or equal to] 35 Non-HDL cholesterol (e) [greater than or equal to] 150 Lp(a) [greater than or equal to] 50s Apolipoprotein B [greater than or equal to] 100 HDL cholesterol (h) [less than or equal to] 40 Apolipoprotein A1 [less than or equal to] 125 Abnormal concentrations g/L Triglycerides (c) [greater than or equal to] 1.75 Total cholesterol [greater than or equal to] 1.90 LDL cholesterol [greater than or equal to] 1.15 Remnant cholesterol (d) [greater than or equal to] 0.35 Non-HDL cholesterol (e) [greater than or equal to] 1.50 Lp(a) [greater than or equal to] 0.50 Apolipoprotein B [greater than or equal to] 1.00 HDL cholesterol (h) [less than or equal to] 0.40 Apolipoprotein A1 [less than or equal to] 1.25 Fasting Abnormal concentrations mmol/L Triglycerides (c) [greater than or equal to] 1.7 Total cholesterol [greater than or equal to] 5 LDL cholesterol [greater than or equal to] 3 Remnant cholesterol (d) [greater than or equal to] 0.8 Non-HDL cholesterol (e) [greater than or equal to] 3.8 Lp(a) f Apolipoprotein B HDL cholesterol (h) [less than or equal to] 1 Apolipoprotein A1 Abnormal concentrations mg/dLb Triglycerides (c) [greater than or equal to] 150 Total cholesterol [greater than or equal to] 190 LDL cholesterol [greater than or equal to] 115 Remnant cholesterol (d) [greater than or equal to] 30 Non-HDL cholesterol (e) [greater than or equal to] 145 Lp(a) [greater than or equal to] 503 Apolipoprotein B [greater than or equal to] 100 HDL cholesterol (h) [less than or equal to] 40 Apolipoprotein A1 [less than or equal to] 125 Abnormal concentrations g/L Triglycerides (c) [greater than or equal to] 1.50 Total cholesterol [greater than or equal to] 1.90 LDL cholesterol [greater than or equal to] 1.15 Remnant cholesterol (d) [greater than or equal to] 0.30 Non-HDL cholesterol (e) [greater than or equal to] 1.45 Lp(a) [greater than or equal to] 0.50 Apolipoprotein B [greater than or equal to] 1.00 HDL cholesterol (h) [less than or equal to] 0.40 Apolipoprotein A1 [less than or equal to] 1.25 (a) These values for flagging in laboratory reports are in some instances higher than corresponding to recommended desirable values in high-risk and very-high-risk patients (Tables 6 and 7). We recommend using SI units (e.g., mmol/L for lipids and g/L for apolipoproteins); however, because these values are not used in all countries, we also provide outpoints for other commonly used units. (b) Values in mmol/L were converted to mg/dL by multiplication with 38.6 for cholesterol and 88 for triglycerides, followed by rounding to the nearest 5 mg/d L; for total cholesterol, we used 5 mmol/L and 190 mg/dL, since these are the two desirable concentration outpoints typically used in guidelines. (c) Triglyceride outpoints based on assays with correction for endogenous glycerol. In most laboratories, however, triglycerides are measured without subtraction of the glycerol blank; thus, triglycerides may wrongly be flagged as abnormal in rare individuals with very high plasma glycerol. That said, not accounting for the glycerol blank in outpatients rarely affected the triglyceride concentration >0.1 mmol/L; in inpatients, the effect was rarely over 0.28 mmol/L (48). High endogenous glycerol is seen, e.g., during intravenous lipid or heparin infusion. (d) Calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol, that is, VLDL, intermediate-density lipoprotein, and chylomicron remnants in the non-fasting state and VLDL and intermediate-density lipoprotein in the fasting state. (e) Calculated as total cholesterol minus HDL cholesterol. (f) There is no consensus on which cut point value in mmol/L should be used for Lp(a). (g) Value for Lp(a)should represent [greater than or equal to] 80th percentile of the specific Lp(a) assay. (h) Sex-specific cutpoints can be used for HDL cholesterol. Table 6. Treatment goals for prevention of cardiovascular disease according to current European Atherosclerosis Society/European Society of Cardiology guidelines (13). Cardiovascular LDL cholesterol Non-HDL cholesterol disease risk Very high <1.8 mmol/L <70 mg/dL <2.6 mmol/L <100 mg/dL High <2.5 mmol/L <100 mg/dL <3.3 mmol/L <125 mg/dL Moderate <3.0 mmol/L <115 mg/dL <3.8 mmol/L <145 mg/dL Cardiovascular Apolipoprotein B disease risk Very high <80 mg/dL <0.8 g/L High <100 mg/dL <1.0 g/L Moderate Table 7. Definition of hypertriglyceridemia by European Atherosclerosis Society consensus statement (24). Severe >10 mmol/L >880 mg/dL hypertriglyceridemia Mild-to-moderate 2-10 mmol/L 180-880 mg/dL hypertriglyceridemia Table 8. Life-threatening and extremely abnormal concentrations with separate reporting and consequent direct referral to a lipid clinic or to a physician with special interest in lipids. Life-threatening concentrations Triglycerides >10 mmol/L >880 mg/dLa LDL cholesterol >1 3 mmol/L (a) >500 mg/dLa LDL cholesterol >5 mmol/L >190 mg/dLa LDL cholesterol in >4 mmol/L children >155 mg/dLa Lp(a) >1 50 mg/dL >99th percentile LDL cholesterol <0.3 mmol/L Apolipoprotein B <10 mg/dL HDL cholesterol <0.2 mmol/L Apolipoprotein A1 <10 mg/dL Refer patient to a lipid clinic or to a physician with special interest in lipids for further assessment of the following conditions Triglycerides Chylomicronemia syndrome with high risk of acute pancreatitis (24) LDL cholesterol Homozygous familial hypercholesterolemia with extremely high cardiovascular risk (44) LDL cholesterol Heterozygous familial hypercholesterolemia with high cardiovascular risk (43) LDL cholesterol in Heterozygous familial children hypercholesterolemia with high cardiovascular risk (45) Lp(a) Very high cardiovascular risk, i.e., for myocardial infarction and aortic valve stenosis (11, 46, 47) LDL cholesterol Genetic abetalipoproteinemia Apolipoprotein B HDL cholesterol Genetic hypoalphalipoproteinemia (e.g., lecithin cholesterol acyltransferase Apolipoprotein A1 deficiency) (a) Values in mmol/L were converted to mg/dL by multiplication with 38.6 for cholesterol and 88 for triglycerides, followed by rounding to nearest 5 mg/dL. Fig. 5. Maximal mean changes at 1-6 h after habitual food intake of lipids, lipoproteins, and apolipoproteins as part of standard and expanded lipid profiles in individuals in the Danish general population. Calculated remnant cholesterol is non-fasting total cholesterol minus LDL cholesterol minus HDL cholesterol. Calculated non-HDL cholesterol is total cholesterol minus HDL cholesterol. Data are adapted and updated from Langsted et al. (3,34) based on 92285 individuals from the Copenhagen General Population Study recruited from 2003 to 2014. Of all participants, 12% were receiving statins. Values in mmol/L were converted to mg/dL by multiplication with 38.6 for cholesterol and by 88 for triglycerides. n = 92285 mmol/L mg/dL Triglycerides +0.3 +26 Total cholesterol -0.2 -8 LDL cholesterol -0.2 -8 Remnant cholesterol +0.2 +8 Non-HDL cholesterol -0.2 -8 Lipoprotein(a) No change Apolipoprotein B No change HDL cholesterol No change Apolipoprotein Al No change Maximal mean change after habitual food intake Fig. 6. Risk of ischemic heart disease and myocardial infarction for highest vs lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins as part of standard and expanded lipid profiles in individuals in the general population. Hazard ratios were adjusted for age, sex, smoking, hypertension, diabetes, and use of statins. Figure designed by B.G. Nordestgaard and A. Langsted based on unpublished data on 92 285 individuals from the Copenhagen General Population Study recruited from 2003 through 2014. Of all participants, 12% were receiving statins. Maximal and median follow-up were 11 and 6 years, respectively. n = 92285 Ischemic heart disease Myocardial infarction Triglycerides 1.38(1.23-1.53) 1.74(1.46-2.09) Total cholesterol 1.33(1.19-1.49) 1.78(1.50-2.11) LDL cholesterol 1.45(1.29-1.62) 2.04 (1.72-2.43) Remnant cholesterol 1.35(1.21-1.51) 1.71 (1.43-2.05) Non-HDL cholesterol 1.57(1.41-1.75) 2.28(1.91 2.72) Lipoprotein(a) 1.18(1.03-1.37) 1.62(1.33-2.01) Apolipoprotein B 1.60(1.43-1.78) 2.29 (1.92-2.74) HDL cholesterol 0.61 (0.55-0.68) 0.49 (0.41-0.59) Apolipoprotein A1 0.72 (0.65-0.80) 0.60 (0.50-0.71) Fig. 7. Comparison of concentrations of plasma triglycerides and LDL cholesterol measured in the non-fasting and fasting states in the same patients. Diabetes was determined as a hemoglobin [A.sub.1c] >7.1% (of all 5538 patients with both fasting and non-fasting triglyceride measurements, 371 did not have a hemoglobin Admeasurement). Values are medians and interguartile ranges; in strata of plasma triglycerides, the interguartile ranges are larger for fasting than for nonfasting values, which is explained by regression dilution bias, since the groups were defined initially based on the non-fasting measurements. Figure designed by B.G. Nordestgaard and A. Langsted based on unpublished dataon patients from Herlevand Gentofte Hospital, Copenhagen University Hospital in the period 2011-2015. n All 5538 Triglycerides (mmol/L] <1.1 1793 1.1-1.5 1582 1.6-2.5 1454 2.6-4.0 534 >4.0 175 Diabetes No 4711 Yes 418 n All 4141 LDL (mmol/L) <1.8 800 1.8-2.4 949 2.5-2.9 761 3.0-4.9 1482 >4.9 149 Diabetes No 3066 Yes 622 Fig. 9. Suggested implementation strategies in individual countries, states, and/or provinces for use of non-fasting lipid profiles and for flagging in laboratory reports of abnormal values based on desirable concentration cutpoints. Implementation strategies in individual countries, states, and provinces for Non-fasting lipid profiles Key university hospitals start using non-fasting lipid profiles National societies for cardiology, endocrinology, atheroslerosis, pediatrics, clinical chemistry, general practice, and others adapt non-fasting lipid profiles Journalists at key medias are invited to bring the story that fasting is no longer routinely required for lipid profile testing Clinical chemistry laboratories no longer require fasting before lipid profile testing Laboratory reporting on abnormal concentrations Key university hospitals start using desirable concentration cutpoints to indicate abnormal concentrations as in Table 5 National societies for clinical chemistry, cardiology, endocrinology, atheroslerosis, pediatrics, general practice, and other adapt desirable concentration cutpoints Clinical chemistry laboratories use desirable concentration cutpoints for lipid profile testing National societies enforce strategy
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Special Report|
|Author:||Nordestgaard, Borge G.; Langsted, Anne; Mora, Samia; Kolovou, Genovefa; Baum, Hannsjorg; Bruckert, E|
|Date:||Jul 1, 2016|
|Next Article:||Recombinase polymerase amplification for diagnostic applications.|