Research

JAMA Internal Medicine | Original Investigation

Association of Nonfasting vs Fasting Lipid Levels With

Risk of Major Coronary Events in the Anglo-Scandinavian
Cardiac Outcomes Trial–Lipid Lowering Arm
Samia Mora, MD, MHS; C. Lan Chang, PhD; M. Vinayaga Moorthy, PhD; Peter S. Sever, PhD, FRCP

Supplemental content
IMPORTANCE Recent guidelines have recommended nonfasting for routine testing of lipid
levels based on comparisons of nonfasting and fasting populations. However, no previous
study has examined the association of cardiovascular outcomes with fasting vs nonfasting
lipid levels measured in the same individuals.

OBJECTIVE To compare the association of nonfasting and fasting lipid levels with
prospectively ascertained coronary and vascular outcomes and to evaluate whether a
strategy of using nonfasting instead of fasting lipid level measurement would result in
misclassification of risk for individuals undergoing evaluation for initiation of statin therapy.

DESIGN, SETTING, AND PARTICIPANTS This post hoc prospective follow-up of a randomized
clinical trial included 8270 of 10 305 participants from the Anglo-Scandinavian Cardiac
Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) with nonfasting and fasting lipid levels
measured 4 weeks apart (including 6855 participants with no prior vascular disease) (median
follow-up, 3.3 years; interquartile range, 2.8-3.6 years). Data were collected from February 1,
1998, to December 31, 2002, and analyzed from February 1, 2016, to November 30, 2018.
Multivariable Cox models, adjusted for cardiovascular risk factors, were calculated for
40-mg/dL (1-mmol/L) higher values of nonfasting and fasting lipids.

MAIN OUTCOMES AND MEASURES The trial’s primary end point consisted of major coronary
events (nonfatal myocardial infarction [MI] and fatal coronary heart disease [212 events]).
Secondary analyses examined atherosclerotic cardiovascular disease (ASCVD) events
(including MI, stroke, and ASCVD death [351 events]).

RESULTS Among the 8270 participants (82.1% male; mean [SD] age, 63.4 [8.5] years),
nonfasting samples had modestly higher triglyceride levels and similar cholesterol levels
compared to fasting samples. Associations of nonfasting lipid levels with coronary events
were similar to those for fasting lipid levels. For example, adjusted hazard ratios (HRs) per
40-mg/dL of low-density lipoprotein cholesterol were 1.32 (95% CI, 1.08-1.61; P = .007) for
nonfasting levels and 1.28 (95% CI, 1.07-1.55; P = .008) for fasting levels. For the primary
prevention group, adjusted HRs were 1.42 (95% CI, 1.13-1.78; P = .003) for nonfasting levels
and 1.37 (95% CI, 1.11-1.69; P = .003) for fasting levels. Results were consistent by randomized Author Affiliations: Center for Lipid
treatment arm (atorvastatin calcium, 10 mg/d, or placebo) and similar for ASCVD events. Metabolomics, Division of Preventive
Medicine, Brigham and Women’s
Concordance of fasting and nonfasting lipid levels for classifying participants into appropriate
Hospital, Harvard Medical School,
ASCVD risk categories was high (94.8%). Boston, Massachusetts (Mora,
Moorthy); Division of Cardiovascular
CONCLUSIONS AND RELEVANCE Measurement of nonfasting and fasting lipid levels yields Medicine, Brigham and Women’s
Hospital, Harvard Medical School,
similar results in the same individuals for association with incident coronary and ASCVD Boston, Massachusetts (Mora);
events. These results suggest that routine measurement of nonfasting lipid levels may help National Heart and Lung Institute,
facilitate ASCVD risk screening and treatment, including consideration of when to initiate Imperial College, London, United
Kingdom (Chang, Sever).
statin therapy.
Corresponding Author: Samia Mora,
MD, MHS, Center for Lipid
Metabolomics, Division of Preventive
Medicine, Brigham and Women’s
Hospital, Harvard Medical School,
900 Commonwealth Ave E,
JAMA Intern Med. doi:10.1001/jamainternmed.2019.0392 Boston, MA 02215 (smora@
Published online May 28, 2019. bwh.harvard.edu).

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 Research Original Investigation Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA
W
e live most of our lives in the nonfasting state, which
is the most representative of our physiology. None-
theless, fasting samples have been the standard for
measurement of lipid profiles, which are typically measured
after an 8- to 12-hour fast.1,2 Recent studies suggest that post-
prandial effects do not weaken, and even may strengthen, the
risk associations of lipids with atherosclerotic cardiovascular
disease (ASCVD).3,4 Multiple reports from well-conducted
prospective studies have found similar risk associations for
nonfasting and fasting lipid levels.5-9
None of these previous studies, to our knowledge, exam-
ined the association of cardiovascular events with lipid levels
measured in the fasting and nonfasting states in the same in-
dividuals; instead, previous prospective studies3-9 relied on com-
parisons across populations of fasting and nonfasting individu-
als for evaluating associations with ASCVD events. Other studies
compared fasting and nonfasting lipid levels cross-sectionally
in the same individuals but without prospective follow-up for
comparison of risk for clinical events. This difference is impor-
tant because individual-level variability in lipid levels when mea-
sured in the fasting or the nonfasting state from the same indi-
vidual may not be captured when looking at population-level
risk associations. This unmeasured variability has been raised
as a limitation of the evidence base against adopting wide-
spread nonfasting lipid level testing.2,10 In addition to estimat-
ing cardiovascular risk and screening for dyslipidemia, an-
other major use for lipid level testing in clinical practice is to
determine eligibility for statin therapy and to tailor therapies
for modifying lipid levels. Therefore, it is important to deter-
mine whether substituting nonfasting for fasting lipid level test-
ing in the cardiovascular risk assessment currently recom-
mended before initiating statin therapy and as part of high blood
pressure management could lead to misclassification of risk.
To address this gap in the evidence, we prospectively tested
individual-level differences in fasting and nonfasting lipid
levels in participants from the large-scale randomized clinical
Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
(ASCOT-LLA). In ASCOT-LLA, fasting and nonfasting lipid levels
were measured in the same individuals before randomization as
part of the trial protocol.11,12 Herein, we compared the association
of nonfasting vs fasting lipid levels with prospectively ascertained
ASCVD outcomes. Furthermore, we evaluated whether a strat-
egy of using nonfasting instead of fasting lipid levels would re-
sult in substantial misclassification of risk for individuals deemed
eligible for statin therapy based on US or European guidelines.
Methods
Patients and Procedures
ASCOT-LLA is a randomized, double-blinded, placebo-
controlled clinical trial that tested whether atorvastatin cal-
cium 10 mg/d or placebo in patients at high risk for ASCVD would
reduce the rates of incident coronary events. The fully de-
tailed ASCOT protocol was published previously11,12 (see eFig-
ure 1 in the Supplement). Briefly, the study included adults aged
40 to 79 years with hypertension and total cholesterol concen-
trations of 250 mg/dL or lower (to convert to millimoles per
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Key Points
Question How do nonfasting lipid levels compare with fasting
lipid levels measured in the same individuals for assessing
cardiovascular risk, and what is their association with incident
cardiovascular events?
Findings In this secondary analysis of 8270 participants in the
Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm,
nonfasting lipid levels were similar to fasting lipid levels measured
4 weeks apart in the same participants in association with incident
cardiovascular events overall and by randomized statin therapy.
Concordance of fasting and nonfasting lipid levels for classifying
participants into appropriate risk categories was high.
Meaning The present study provides robust evidence supportive
of broader adoption of nonfasting lipid level measurement in
clinical practice.
liter, multiply by 0.0259) who were not taking a statin or a
fibrate and who had at least 3 additional ASCVD risk factors, in-
cluding left-ventricular hypertrophy, other specified abnor-
malities on electrocardiography, type 2 diabetes, peripheral
arterial disease, previous stroke or transient ischemic attack,
male sex, age of 55 years or older, microalbuminuria or protein-
uria, smoking, ratio of total to high-density lipoprotein (HDL)
cholesterol of 6.0 or higher, or family history of premature coro-
nary disease.11,12 The protocol and subsequent amendments to
the protocol were reviewed and ratified by central and re-
gional ethics review boards in the UK and by national ethics
and statutory bodies in Ireland and the Nordic countries. All
patients provided written informed consent.
Data for this study were collected from February 1, 1998, to
December 31, 2002. For this post hoc secondary analysis, we in-
cluded a total of 8270 of the 10 305 participants randomized into
ASCOT-LLA who had nonfasting and fasting lipid levels available
for analysis. These measurements were taken using the trial pro-
tocol approximately 4 weeks apart before randomization, with
no intervention or advice given between the 2 visits.11,12 At the
screening visit that occurred approximately 4 weeks before ran-
domization, relevant characteristics of the patients were assessed,
their eligibility for the trial was determined, written informed con-
sent was obtained, and nonfasting blood samples were collected.
The randomization visit approximately 4 weeks later included the
collection of fasting blood samples, with fasting defined as no food
or drink except plain water for at least 8 hours before the blood
draw. Two central laboratories, one located in Ireland (for the
United Kingdom and Ireland) and the other located in Sweden (for
the Nordic countries), analyzed blood samples for levels of total
cholesterol, HDL cholesterol, and triglycerides. Low-density
lipoprotein (LDL) cholesterol was calculated using the Friedewald
equation11,12 and the novel Martin-Hopkins equation.13,14
Outcomes
The trial primary end point of major coronary events was a
composite consisting of nonfatal myocardial infarction (MI) and
fatal coronary heart disease. In secondary analyses, we also ex-
amined the expanded composite end point of ASCVD events
defined as fatal or nonfatal MI, fatal or nonfatal stroke, or
ASCVD death.
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 Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA
Statistical Analysis
Data were analyzed from February 1, 2016, to November 30,
2018. We compared participants with and without coronary
events during follow-up using unpaired two-tailed t tests or
Kruskal-Wallis tests for continuous variables and χ2 tests for
categorical baseline lipid and nonlipid variables. We calcu-
lated Spearman correlation coefficients and 95% CIs between
fasting and nonfasting lipid levels.
We performed unadjusted and multivariable Cox propor-
tional hazards regression with models that adjusted for car-
diovascular risk factors, including age, sex, race (white vs
other), smoking status, diabetes, randomized blood pressure
treatment (atenolol or amlodipine besylate), randomized statin
treatment or placebo, and body mass index.
We investigated associations between each lipid variable
(fasting or nonfasting) per 40-mg/dL (1-mmol/L) higher value with
incident major coronary and ASCVD events using separate mod-
els. We repeated selected analyses per SD increment for compari-
son with prior studies that reported results per SD increment.
Because ASCOT-LLA included a small proportion of participants
with prior vascular disease, we repeated the analyses after exclud-
ing these participants to examine risk associations in an exclu-
sively primary prevention population. We also performed sen-
sitivity analyses after excluding participants with triglyceride
levels greater than 400 mg/dL (n = 370) (to convert to millimoles
per liter, multiply by 0.0113). We tested for statistical interaction
betweenrandomizedstatinassignmentorsexandeachofthelipid
variables in association with outcomes using likelihood ratio tests.
Subsequently, we used 10-fold cross-validated differences in
Harrell C indices15 comparing fasting and nonfasting lipid levels
in multivariable risk factor–adjusted models using bootstrapping
methods to evaluate for statistically significant differences
between fasting and nonfasting models.
To examine the extent of agreement between the associations
of fasting and nonfasting lipid levels with outcomes, we calcu-
lated ASCVD risks using the 2013 American College of Cardiology/
American Heart Association (ACC/AHA) pooled cohorts1 and the
QRISK2 equations (QRESEARCH, University of Nottingham
[https://www.qresearch.org/]). Participants were classified into
low-, moderate-, and high-risk categories using the recommended
clinical categories of less than 5.0%, 5.0% to less than 7.5%, and
at least 7.5% for the ACC/AHA risk scores and less than 10.0%,
10.0% to less than 20.0%, and at least 20.0% for the QRISK2 risk
score. The degree of misclassification of individuals into coronary
and ASCVD risk categories, respectively, was assessed. Finally, we
also examined associations with incident coronary events for par-
ticipants with discordant or concordant concentrations based on
within-individual differences between their nonfasting and fast-
ing lipid levels. Two-tailed P < .05 was considered significant.
Statistical analyses were performed with SAS, version 9.4 (SAS
Institute, Inc).
Results
The ASCOT-LLA trial was terminated prematurely after a me-
dian follow-up of 3.3 years (interquartile range, 2.8-3.6 years)
owing to a highly significant relative risk reduction (HR, 0.64;
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Original Investigation Research
95% CI, 0.50-0.83; P < .001) in favor of atorvastatin calcium
10 mg/d compared with placebo on the primary coronary end
point (eFigure 1 in the Supplement).12 During the trial, a total
of 212 incident major coronary events (the trial primary end
point) occurred among the 8270 participants who had fasting
and nonfasting lipids measured at baseline and were in-
cluded in the analysis (6791 men [82.1%] and 1479 women
[17.9%]; mean [SD] age, 63.4 [8.5] years). Compared with those
participants without coronary events, those who had a coro-
nary event were significantly older (mean [SD] age, 65.6 [8.7]
vs 63.3 [8.5] years; P < .001), were more likely to have a his-
tory of stroke or transient ischemic attack (30 of 212 [14.2%]
vs 801 of 8058 [9.9%]; P = .04) or diabetes (77 of 212 [36.3%]
vs 2123 of 8058 [26.3%]; P = .001), and had more cardiovas-
cular risk factors (median, 4 [interquartile range, 3-5] vs 3 [in-
terquartile range, 3-4]; P < .001) (Table 1). Compared with fast-
ing samples, nonfasting samples obtained from the same
individuals had modestly higher triglyceride levels and neg-
ligible differences in total, LDL, and HDL cholesterol levels
(Table 1 and eFigure 2 in the Supplement). Spearman correla-
tion coefficients between fasting and nonfasting lipids ranged
from 0.693 for triglyceride level to 0.878 for HDL cholesterol
level (P < .001 for all) (eTable 1 in the Supplement).
Nonfasting and fasting levels of LDL and non-HDL choles-
terol and the ratio of total to HDL cholesterol were positively
assoc iated and HDL cholesterol level was inversely
associated with coronary events in unadjusted and risk factor–
adjusted models (Figure and Table 2). Notably, the nonfasting
lipid associations were similar in magnitude to fasting lipid as-
sociations, including for participants with no prior vascular dis-
ease (ie, the exclusively primary prevention group), with no
significant interaction by fasting status noted for any
lipid variable. For example, adjusted HRs per 40 mg/dL for
Friedewald LDL cholesterol were 1.32 (95% CI, 1.08-1.61;
P = .007) for nonfasting and 1.28 (95% CI, 1.07-1.55; P = .008)
for fasting levels. For the exclusively primary prevention group,
adjusted HRs were 1.42 (95% CI, 1.13-1.78; P = .003) for non-
fasting levels and 1.37 (95% CI, 1.11-1.69; P = .003) for fasting
levels (P = .85 and P = .003, respectively, for interaction by fast-
ing status). Sensitivity analysis showed a similar significant
result in Friedewald LDL cholesterol level after excluding tri-
glyceride levels of greater than 400 mg/dL. We obtained simi-
lar results when LDL cholesterol level was calculated using the
novel Martin-Hopkins equation with some strengthening of
the magnitude of association for nonfasting LDL cholesterol (HR
for nonfasting level, 1.39 [95% CI, 1.11-1.73; P = .004]; HR for fast-
ing level, 1.31 [95% CI, 1.08-1.58; P = .007]). For the exclusively
primary prevention group, adjusted HR for nonfasting level was
1.53 (95% CI, 1.19-1.97; P = .001), and HR for fasting level was
1.41 (95% CI, 1.13-1.75; P = .002) (P = .69 and P = .62, respec-
tively, for interaction by fasting status). Similar results were ob-
tained for analyses by SD increments (eTable 2 in the Supple-
ment). We found no evidence of interaction between sex and
each of the study lipid levels in association with the risk of coro-
nary events (eTable 3 in the Supplement).
The associations of nonfasting and fasting lipid levels with
coronary events were similar according to randomized ator-
vastatin calcium therapy (10 mg/d) vs placebo and consistent
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 Research Original Investigation Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA

Table 1. Baseline Characteristics by Incident Coronary Events During Follow-up

Study Groupa
Coronary Event No Coronary Event
Characteristic (n = 212) (n = 8058) P Value
Age, mean (SD), y 65.6 (8.7) 63.3 (8.5) <.001
Male 182 (85.8) 6609 (82.0) .15
White 200 (94.3) 7574 (94.0) .83
Current smoking 79 (37.3) 2580 (32.0) .11
Body mass index, mean (SD)b 28.33 (4.31) 28.67 (4.69) .30
Blood pressure, mean (SD)
Systolic 166.92 (19.39) 163.88 (17.81) .01
Diastolic 94.07 (9.96) 94.74 (10.29) .35
Heart rate, mean (SD), bpm 70.99 (12.60) 71.16 (12.58) .85
Fasting glucose level, mean (SD), mg/dL 118 (45) 111 (37) .01
Creatinine level, mean (SD), mg/dL 1.1 (0.2) 1.1 (0.2) .41
Medical history
Previous stroke or TIA 30 (14.2) 801 (9.9) .04
Previous peripheral vascular disease 14 (6.6) 409 (5.1) .32
Other relevant vascular disease 11 (5.2) 286 (3.5) .21
Diabetes 77 (36.3) 2123 (26.3) .001
No. of risk factors, median (IQR) 4 (3-5) 3 (3-4) <.001
Family history of premature CHD 45 (21.2) 1978 (24.5) .27
Nonrandomized drug treatment
Antihypertensive 166 (78.3) 6637 (82.4) .13
Aspirin use 48 (22.6) 1477 (18.3) .11
Treatment to lower lipid levels 3 (1.4) 80 (1.0) .54
Lipid level, median (IQR), mg/dL
Total cholesterol
Nonfasting 218 (197-236) 216 (193-232) .13
Fasting 216 (193-236) 212 (193-232) .30 Abbreviations: CHD, coronary heart
LDL cholesterolc disease; HDL, high-density
lipoprotein; IQR, interquartile range;
Nonfasting 129 (113-147) 127 (108-144) .07
LDL, low-density lipoprotein;
Fasting 139 (120-155) 133 (114-152) .03 MH, Martin-Hopkins; TIA, transient
LDL cholesterol-MHd ischemic attack.
Nonfasting 134 (121-151) 132 (114-148) .06 SI conversion factors: To convert
cholesterol to millimoles per liter,
Fasting 139 (121-156) 135 (117-153) .02
multiply by 0.0259; creatinine to
HDL cholesterol micromoles per liter, multiply by
Nonfasting 46 (39-54) 46 (39-58) .15 88.4; glucose to millimoles per liter,
multiply by 0.0555; triglycerides to
Fasting 46 (41-54) 50 (42-58) .05
millimoles per liter, multiply
Triglycerides by 0.0113.
a
Nonfasting 159 (119-239) 159 (115-230) .97 Unless otherwise indicated, data are
Fasting 124 (97-177) 124 (88-177) .71 expressed as number (percentage)
of participants.
Non-HDL cholesterol b
Calculated as weight in kilograms
Nonfasting 166 (151-189) 162 (143-181) .04 divided by height in meters
Fasting 164 (147-185) 162 (139-181) .05 squared.
c
Ratio of total to HDL cholesterol Calculated using the Friedewald
equation.11,12
Nonfasting 4.50 (3.80-5.60) 4.40 (3.60-5.30) .04
d
Calculated using the Martin-Hopkins
Fasting 4.50 (3.80-5.40) 4.30 (3.60-5.20) .02
equation.13,14

with the overall study (eTable 4 in the Supplement). No sta-
tistically significant interactions were noted between random-
ized atorvastatin treatment and fasting status in association
with risk of coronary events. For consistency with clinical pre-
vention guidelines, we also examined fasting and nonfasting
lipid associations with incident ASCVD events (MI, stroke, or
ASCVD death [n = 315]) and found similar results to the
primary coronary end point.
The overall concordance of fasting and nonfasting lipid
levels for classifying participants into categories of ASCVD risk
was very high (Table 3), whether risk was calculated based on
the 2013 ACC/AHA pooled cohort risk equations (94.8%

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 Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA Original Investigation Research

Figure. Association of Nonfasting and Fasting Lipid Levels With Coronary Events

A All participants B Participants with no prior vascular disease

Adjusted HR Favors Favors Adjusted HR Favors Favors

Lipid Level (95% CI) Protection Harm Lipid Level (95% CI) Protection Harm
Total Total
Fasting 1.14 (0.96-1.35) Fasting 1.21 (1.00-1.47)
Nonfasting 1.26 (1.03-1.54) Nonfasting 1.36 (1.08-1.71)
LDLa LDLa
Fasting 1.28 (1.07-1.55) Fasting 1.37 (1.11-1.69)
Nonfasting 1.32 (1.08-1.61) Nonfasting 1.42 (1.13-1.78)
LDLb LDLb
Fasting 1.19 (1.04-1.37) Fasting 1.25 (1.07-1.46)
Nonfasting 1.21 (1.05-1.40) Nonfasting 1.30 (1.10-1.52)
LDL-MHc LDL-MHc
Fasting 1.31 (1.08-1.58) Fasting 1.41 (1.13-1.75)
Nonfasting 1.39 (1.11-1.73) Nonfasting 1.53 (1.19-1.97)
Triglycerides Triglycerides
Fasting 0.99 (0.73-1.34) Fasting 1.04 (0.74-1.45)
Nonfasting 1.03 (0.78-1.37) Nonfasting 1.05 (0.76-1.43)
HDL HDL
Fasting 0.59 (0.34-1.01) Fasting 0.54 (0.29-0.99)
Nonfasting 0.69 (0.40-1.18) Nonfasting 0.64 (0.35-1.16)
Non-HDL Non-HDL
Fasting 1.23 (1.04-1.46) Fasting 1.31 (1.09-1.58)
Nonfasting 1.33 (1.09-1.61) Nonfasting 1.44 (1.15-1.79)
Ratio of total to HDL Ratio of total to HDL
Fasting 1.98 (1.18-3.32) Fasting 2.37 (1.33-4.20)
Nonfasting 1.91 (1.14-3.20) Nonfasting 2.25 (1.26-4.02)

0.1 1 10 0.1 1 10
Adjusted HR (95% CI) Adjusted HR (95% CI)

a
Associations are measured among all participants (n = 8270) and participants Calculated using the Friedewald equation.11,12
with no prior vascular disease (n = 6855) per 40-mg/dL (1-mmol/L) increment b
Excludes participants with triglyceride levels greater than 400 mg/dL
using Cox proportional hazard regression. Hazard ratios (HRs) were adjusted for (n = 370).
age, sex, race (white vs other), randomized blood pressure treatment, c
Calculated using the Martin-Hopkins equation.13,14
randomized statin treatment, smoking, diabetes, and body mass index.
HDL indicates high-density lipoprotein; LDL, low-density lipoprotein.

concordance) or the QRISK2 algorithm (98.6% concordance).
We also found highly concordant results among the partici-
pants with fasting or nonfasting LDL cholesterol levels of
70 to 189 mg/dL, which is the LDL cholesterol range of the ACC/
AHA cholesterol guidelines that are used for statin eligibility.
Moreover, no differences occurred in the proportion of reclas-
sification from high-risk to lower-risk categories between fast-
ing and nonfasting lipids for the ACC/AHA guidelines (1.41%
vs 1.40%) or QRISK2 algorithms (0.42% vs 0.45%).
eTable 6 in the Supplement shows no statistically signifi-
cant differences comparing the 10-fold cross-validated differ-
ence in the C indices between fasting and nonfasting lipid lev-
els in multivariable models using bootstrapping methods.
Finally, to address the possibility that some individuals may
have substantial differences in fasting and nonfasting lipid lev-
els, which may affect treatment decisions, we classified par-
ticipants based on within-individual differences between their
nonfasting and fasting lipid levels as discordant in the top quar-
tile of the distribution of differences (fasting greater than
nonfasting lipid levels), concordant (25th to 75th percentile),
or discordant in the bottom quartile of the distribution (fast-
ing less than nonfasting lipid levels). For all lipid measures, the
HRs were not significantly different between the 2 discor-
dant groups (fasting greater than nonfasting and fasting less
than nonfasting lipid levels) (eTable 7 in the Supplement).
Moreover, no significant differences in risk associated with
coronary events occurred between fasting and nonfasting lipid
levels within each discordant group (eTable 8 in the Supple-
ment). Similar results were also noted between the 2 discor-
dant groups, except for the ratio of total to HDL cholesterol
(adjusted HRs for fasting less than nonfasting levels, 5.25 [95%
CI, 1.58-17.40; P = .02] for fasting and 4.00 [95% CI, 1.14-
14.00; P = .06]; P = .76 for nonfasting).
Discussion
In ASCOT-LLA, nonfasting lipid levels were similar to fasting
lipid levels measured in the same individuals for association
with incident coronary and vascular events. Results were simi-
lar by randomized allocation to atorvastatin calcium 10 mg/d
or placebo. Furthermore, the very high agreement (94.8%) of
ASCVD risk classification categories for fasting and nonfast-
ing samples suggests that risk assessment and treatment

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 Research Original Investigation Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA

Table 2. Associations of Fasting and Nonfasting Lipids With Incident Coronary Eventsa
All Participants Exclusively Primary Prevention
(n = 8270; Coronary Events = 212) (n = 6855; Coronary Events = 170)b
Unadjusted HR Adjusted HR Unadjusted HR Adjusted HR
Lipid Measured (95% CI) P Value (95% CI) P Value (95% CI) P Value (95% CI) P Value
Total cholesterol
Nonfasting 1.18 (0.96-1.44) .11 1.26 (1.03-1.54) .02 1.25 (1.00-1.57) .048 1.36 (1.08-1.71) .009
Fasting 1.08 (0.91-1.28) .36 1.14 (0.96-1.35) .13 1.15 (0.95-1.38) .16 1.21 (1.00-1.47) .051
LDL cholesterolc
Nonfasting 1.26 (1.03-1.54) .02 1.32 (1.08-1.61) .007 1.34 (1.07-1.67) .01 1.42 (1.13-1.78) .003
Fasting 1.24 (1.03-1.49) .02 1.28 (1.07-1.55) .008 1.30 (1.06-1.60) .01 1.37 (1.11-1.69) .003
LDL cholesterold
Nonfasting 1.17 (1.02-1.35) .03 1.21 (1.05-1.40) .008 1.24 (1.06-1.46) .009 1.30 (1.10-1.52) .002
Fasting 1.16 (1.01-1.33) .04 1.19 (1.04-1.37) .01 1.20 (1.03-1.41) .02 1.25 (1.07-1.46) .005
LDL cholesterol-MHe
Nonfasting 1.32 (1.05-1.65) .02 1.39 (1.11-1.73) .004 1.43 (1.11-1.84) .006 1.53 (1.19-1.97) .001
Fasting 1.25 (1.03-1.52) .02 1.31 (1.08-1.58) .007 1.33 (1.07-1.66) .009 1.41 (1.13-1.75) .002
HDL cholesterolf
Nonfasting 0.66 (0.40-1.09) .10 0.69 (0.40-1.18) .17 0.63 (0.36-1.11) .11 0.64 (0.35-1.16) .14
Fasting 0.57 (0.34-0.95) .03 0.59 (0.34-1.01) .06 0.55 (0.31-0.97) .04 0.54 (0.29-0.99) .046
Triglyceridesf
Nonfasting 1.02 (0.78-1.34) .88 1.03 (0.78-1.37) .83 1.04 (0.77-1.39) .82 1.05 (0.76-1.43) .78
Fasting 0.97 (0.73-1.29) .83 0.99 (0.73-1.34) .94 1.01 (0.74-1.39) .94 1.04 (0.74-1.45) .84
Non-HDL cholesterol
Nonfasting 1.26 (1.04-1.53) .02 1.33 (1.09-1.61) .004 1.35 (1.08-1.67) .007 1.44 (1.15-1.79) .001
Fasting 1.18 (1.00-1.40) .05 1.23 (1.04-1.46) .02 1.25 (1.04-1.51) .02 1.31 (1.09-1.58) .005
Total/HDL cholesterol ratiof
Nonfasting 1.80 (1.10-2.95) .02 1.91 (1.14-3.20) .01 2.02 (1.16-3.50) .01 2.25 (1.26-4.02) .006
Fasting 1.88 (1.14-3.08) .01 1.98 (1.18-3.32) .009 2.15 (1.23-3.74) .007 2.37 (1.33-4.20) .003
c
Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; Calculated using the Friedewald equation.11,12
MH, Martin-Hopkins. d
Calculated using the Friedewald equation and excluding those with
a
Values shown were obtained by using Cox proportional hazard regression triglyceride levels of greater than 400 mg/dL.
model per 40-mg/dL (1-mmol/L) increment adjusted for age, sex, race, e
Calculated using the Martin-Hopkins equation.13,14
smoking status, diabetes, randomized blood pressure treatment (atenolol or f
Log transformed.
amlodipine), randomized statin or placebo, and body mass index.
b
Includes participants with no prior vascular disease.

Table 3. Concordance of Nonfasting and Fasting Lipid Level Measurements for Classifying Participants
Into Categories of ASCVD Riska
Participants in 10-y Risk Categories
by Fasting Lipid Levels, No. (%)
10-y Risk Category (%)
Guideline by Nonfasting Lipid Levels Low Medium High
2013 ACC/AHA ASCVD pooled
cohorts risk equations
Low (<5.0) 1126 (13.62) 79 (0.96) 1 (0.01) Abbreviations: ACC/AHA, American
Medium (5.0 to <7.5) 117 (1.42) 638 (7.72) 116 (1.40) College of Cardiology/American Heart
Association; ASCVD, atherosclerotic
High (≥7.5) 2 (0.02) 114 (1.38) 6074 (73.47)
cardiovascular disease.
QRISK2 equations a
Concordance of risk categories for
Low (<10.0) 1230 (14.88) 28 (0.34) 1 (0.01) fasting and nonfasting lipids was
Medium (10.0 to <20.0) 17 (0.21) 338 (4.09) 34 (0.41) 94.8% for the ACC/AHA pooled
cohorts risk equations and 98.6%
High (≥20.0) 0 (0.00) 37 (0.45) 6580 (79.61)
for QRISK2.

decisions for statin and antihypertensive therapies would be
consistent whether lipid levels were measured in the fasting
or nonfasting state. Therefore, the present ASCOT-LLA re-
sults provide robust evidence and more impetus for physi-
cians to more broadly adopt nonfasting measurement of lipid
levels for routine practice, in a manner consistent with the re-
cent guideline recommendations that have endorsed measur-
ing nonfasting lipid levels. Such a strategy would be highly
effective and offer many advantages for cardiovascular risk
screening and treatment, including for initiating statin therapy
and for blood pressure assessment and management deci-
sions that rely on calculating ASCVD risk.
Since the 1970s, numerous well-conducted, large, repre-
sentative case-control and prospective studies with me-
dium- to long-term follow-up5-9 have found that the associa-
tions of lipid levels with cardiovascular events were generally

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 Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the ASCOT-LLA Original Investigation Research

consistent among groups of individuals who had fasting lipid
levels measured compared with groups of individuals (albeit
not the same individuals) who had nonfasting lipid levels mea-
sured. These studies have examined clinical outcomes rang-
ing from incident ASCVD events (MI, stroke, and revascular-
ization) to cardiovascular or all-cause mortality, finding
consistent associations for nonfasting lipid profiles with risk
of cardiovascular events. Moreover, some studies that in-
cluded fasting and nonfasting populations found stronger risk
associations for nonfasting lipid levels such as triglycerides.6,7
This evidence base prompted the 2016 and 2018 European
Atherosclerosis Society and the European Federation of Labo-
ratory Medicine Consensus Statements3,16,17 to recommend
using nonfasting lipid levels for routine cardiovascular care,
including for cardiovascular risk assessment and treatment
decisions. Nonfasting lipid levels have also been recently en-
dorsed by Canadian guidelines,18,19 several other interna-
tional guidelines,20,21 and more recently by the 2018 ACC/
AHA cholesterol guidelines.22
The present study is, to our knowledge, the first to com-
pare prospective associations of fasting and nonfasting lipid lev-
els measured in the same individuals with incident vascular
events. Consistent with prior studies that were performed in
populations of fasting and nonfasting individuals,5-7,9,23 we
found small, clinically nonmeaningful differences between
fasting and nonfasting lipid levels measured in the same indi-
viduals, with modestly greater nonfasting triglyceride levels,
slightly lower nonfasting LDL cholesterol levels, and no differ-
ences in HDL cholesterol levels. One major limitation to more
widespread acceptance of nonfasting lipid levels has been that
prior studies that evaluated ASCVD risk associations for fast-
ing and nonfasting lipids measured them in groups of fasting
and nonfasting individuals, but not in the same individuals.2,10
This potential concern is relevant because physicians treat
individual patients (not populations), and individual-level
variability in fasting vs nonfasting lipid levels may not be cap-
tured when looking at population-level risk associations. In this
regard, the present study provides new and robust evidence that,
even when measured in the same individuals, nonfasting lipid
levels are at least as good as fasting lipid levels for calculating
cardiovascular risk, including for guiding risk classification and
preventive treatment decisions.
Furthermore, recent studies suggest that fasting for lipid
level testing may be risky in elderly patients or those with
diabetes who use hypoglycemic medications. Approximately
1 of 4 patients with diabetes reported having an en-route
hypoglycemic event owing to fasting for blood tests.24,25 These
events are underreported and add to patient morbidity. Hence,
a strategy that measures lipid levels without requiring fasting
after normal food intake has numerous practical advantages
for clinical practice.4,10,20
Strengths and Limitations
Strengths of the present study include that nonfasting and fast-
ing lipid levels were measured in the same individuals 4 weeks
apart according to a centralized trial protocol with no inter-
vention or advice during the 4-week period. Other strengths
included the large ASCOT-LLA study population with indi-
viduals undergoing primary and secondary prevention and
detailed information collected on cardiovascular risk factors,
the prospectively adjudicated clinical outcomes in this clini-
cal trial, and the randomized allocation of statin therapy vs pla-
cebo. Potential limitations include that the ASCOT-LLA trial
inclusion criteria may limit generalizability of the findings,
although our results are consistent with prior population-
based studies that compared group differences in fasting and
nonfasting lipid levels. ASCOT-LLA included patients with and
without prior vascular disease, which may make the results
more generalizable. Because the Friedewald equation has re-
cently been recognized to have limitations,13 especially in in-
dividuals with higher triglyceride levels or lower LDL choles-
terol levels, we also repeated the analyses for LDL cholesterol
level calculated by the novel Martin-Hopkins equation,13,14
finding similar results. Finally, few nonwhite individuals were
enrolled in ASCOT-LLA, and future research should assess
potential ethnic and/or racial differences.
Conclusions
In ASCOT-LLA, association with cardiovascular risk was at least
as good for nonfasting as for fasting lipid levels measured in the
same individuals, and lipid level measurements had very high
concordance for cardiovascular risk categorization regardless
of fasting status. These results are consistent with prior popu-
lation-level studies that examined fasting and nonfasting lipid
levels and support the recent change in US guidelines22 to more
broadly adopt nonfasting lipids for routine cardiovascular risk
assessment. The results of this study suggest that such a strat-
egy would be highly effective and offer many advantages for car-
diovascular risk screening and treatment decisions, including
for initiating statin or antihypertensive therapy.

ARTICLE INFORMATION
Accepted for Publication: February 3, 2019.
Published Online: May 28, 2019.
doi:10.1001/jamainternmed.2019.0392
Author Contributions: Dr Sever had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Concept and design: Mora, Sever.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Mora, Chang, Sever.
Critical revision of the manuscript for important
intellectual content: Mora, Moorthy.
Statistical analysis: Chang, Moorthy.
Obtained funding: Sever.
Administrative, technical, or material support: Sever.
Supervision: Mora, Sever.
Conflict of Interest Disclosures: Dr Mora reported
receiving grants from Pfizer, the National Heart,
Lung, and Blood Institute, and the National Institute
of Diabetes and Digestive and Kidney Diseases
during the conduct of the study; personal fees from
Pfizer, Amgen, and Quest Diagnostics, and grants
from Atherotech Diagnostics Lab outside the
submitted work. Dr Sever reported receiving
research grant support and personal fees from
Pfizer and Amgen outside the submitted work.
No other disclosures were reported.
Funding/Support: This study was supported by an
investigator-initiated institutional research grant
from Pfizer; grants K24HL136852, R01HL134811,
and HL117861 from the National Heart, Lung, and
Blood Institute of the National Institutes of Health
(Dr Mora); a Senior Investigator Award from the
National Institute for Health Research (Dr Sever);

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 Research Original Investigation
and a Biomedical Research Centre Award to
Imperial College from the Healthcare National
Health Service Trust (Dr Sever). The ASCOT trial was
financially supported by Pfizer.
Role of the Funder/Sponsor: The sponsors had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The content and opinions expressed in
the manuscript are solely the responsibility of the
study authors and do not necessarily represent the
views of the US National Institutes of Health or the
UK National Health Service.
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