ORIGINAL CONTRIBUTION
Nonfasting Triglycerides and Risk
of Ischemic Stroke in the General Population
Jacob J. Freiberg, MD
Anne Tybjærg-Hansen, MD, DMSc
Jan Skov Jensen, MD, DMSc
Børge G. Nordestgaard, MD, DMSc
T
HE ROLE OF TRIGLYCERIDES IN
risk of ischemic stroke re-
mains controversial.1-8 Two re-
cent cohort studies reported a
strong association between elevated lev-
els of nonfasting, but not fasting, tri-
glycerides and increased risk of myo-
cardial infarction, ischemic heart
disease, and death9 and total cardio-
vascular events,10 respectively. It is
therefore possible that nonfasting tri-
glyceride levels are also associated with
increased risk of ischemic stroke.
Increased levels of nonfasting tri-
glycerides indicate the presence of
increased levels of remnants from chy-
lomicrons and very low-density lipo-
proteins.9 These cholesterol-contain-
ing, triglyceride-rich lipoproteins
penetrate the arterial endothelium11,12
and may get trapped within the suben-
dothelial space,13-16 potentially lead-
ing to the development of atheroscle-
rosis.17,18
Triglyceride levels are usually mea-
sured after an 8- to 12-hour fast,19 thus
excluding most remnant lipoproteins;
however, except for a few hours be-
fore breakfast, most individuals are in
the nonfasting state most of the time.
Therefore, by mainly studying fasting
rather than nonfasting triglyceride lev-
els, several previous studies1,4,6,7 may
have missed an association between tri-
glycerides and ischemic stroke. Also,
because former studies1-7 mainly fo-
cused on moderately elevated levels of
triglycerides, an association of very high
2142 JAMA, November 12, 2008—Vol 300, No. 18 (Reprinted)
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Context The role of triglycerides in the risk of ischemic stroke remains controversial.
Recently, a strong association was found between elevated levels of nonfasting tri-
glycerides, which indicate the presence of remnant lipoproteins, and increased risk of
ischemic heart disease.
Objective To test the hypothesis that increased levels of nonfasting triglycerides are
associated with ischemic stroke in the general population.
Design, Setting, and Participants The Copenhagen City Heart Study, a prospec-
tive, Danish population–based cohort study initiated in 1976, with follow-up through
July 2007. Participants were 13 956 men and women aged 20 through 93 years. A
cross-sectional study included 9637 individuals attending the 1991-1994 examina-
tion of the prospective study.
Main Outcome Measures Prospective study: baseline levels of nonfasting triglyc-
erides, other risk factors at baseline and at follow-up examinations, and incidence of
ischemic stroke. Cross-sectional study: levels of nonfasting triglycerides, levels of rem-
nant cholesterol, and prevalence of ischemic stroke.
Results Of the 13 956 participants in the prospective study, 1529 developed ische-
mic stroke. Cumulative incidence of ischemic stroke increased with increasing levels
of nonfasting triglycerides (log-rank trend, P⬍.001). Men with elevated nonfasting
triglyceride levels of 89 through 176 mg/dL had multivariate-adjusted hazard ratios
(HRs) for ischemic stroke of 1.3 (95% CI, 0.8-1.9; 351 events); for 177 through 265
mg/dL, 1.6 (95% CI, 1.0-2.5; 189 events); for 266 through 353 mg/dL, 1.5 (95% CI,
0.9-2.7; 73 events); for 354 through 442 mg/dL, 2.2 (95% CI, 1.1-4.2; 40 events);
and for 443 mg/dL or greater, 2.5 (95% CI, 1.3-4.8; 41 events) vs men with non-
fasting levels less than 89 mg/dL (HR, 1.0; 85 events) (P ⬍ .001 for trend). Corre-
sponding values for women were 1.3 (95% CI, 0.9-1.7; 407 events), 2.0 (95% CI,
1.3-2.9; 135 events), 1.4 (95% CI, 0.7-2.9; 26 events), 2.5 (95% CI, 1.0-6.4; 13 events),
and 3.8 (95% CI, 1.3-11; 10 events) vs women with nonfasting triglyceride levels less
than 89 mg/dL (HR, 1.0; 159 events) (P⬍.001 for trend). Absolute 10-year risk of
ischemic stroke ranged from 2.6% in men younger than 55 years with nonfasting tri-
glyceride levels of less than 89 mg/dL to 16.7% in men aged 55 years or older with
levels of 443 mg/dL or greater. Corresponding values in women were 1.9% and 12.2%.
In the cross-sectional study, men with a previous ischemic stroke vs controls had non-
fasting triglyceride levels of 191 (IQR, 131-259) mg/dL vs 148 (IQR, 104-214) mg/dL
(P⬍.01); corresponding values for women were 167 (IQR, 121-229) mg/dL vs 127
(IQR, 91-181) mg/dL (P⬍.05). For remnant cholesterol, corresponding values were
38 (IQR, 26-51) mg/dL vs 29 (IQR, 20-42) mg/dL in men (P⬍.01) and 33 (IQR, 24-
45) mg/dL vs 25 (IQR, 18-35) mg/dL in women (P⬍.05).
Conclusion In this study population, nonfasting triglyceride levels were associated
with risk of ischemic stroke.
JAMA. 2008;300(18):2142-2152 www.jama.com
Author Affiliations: Department of Clinical Biochem- Hospitals; and Faculty of Health Sciences, University
istry, Herlev Hospital (Drs Freiberg and Nordest- of Copenhagen, Copenhagen, Denmark.
gaard), Copenhagen City Heart Study, Bispebjerg Hos- Corresponding Author: Børge G. Nordestgaard, MD,
pital (Drs Tybjærg-Hansen, Jensen, and Nordestgaard), DMSc, Department of Clinical Biochemistry, Herlev
Department of Clinical Biochemistry, Rigshospitalet (Dr Hospital, Copenhagen University Hospital, Herlev
Tybjærg-Hansen), and Department of Cardiology, Ringvej 75, DK-2730 Herlev, Denmark (brno@heh
Gentofte Hospital (Dr Jensen), Copenhagen University .regionh.dk).
©2008 American Medical Association. All rights reserved.

levels with risk of ischemic stroke could
have gone unnoticed.
We tested the hypothesis that in-
creased levels of nonfasting triglycer-
ides are associated with risk of ische-
mic stroke in men and women in the
general population. For this purpose,
we studied 13 956 individuals from the
Copenhagen City Heart Study with up
to 31 years of follow-up, during which
time 1529 developed ischemic stroke.
METHODS
The prospective and cross-sectional
studies were approved by Herlev Hos-
pital and a Danish ethical committee
(Nos. 100.2039/91 and 01-144/01, Co-
penhagen and Frederiksberg commit-
tee) and were conducted according to
the Declaration of Helsinki. Partici-
pants provided written informed con-
sent.
Prospective Study
The Copenhagen City Heart Study is a
prospective cardiovascular study of the
Danish general population initiated in
1976.20 We invited 19 329 white women
and men of Danish descent, stratified
into 5-year age groups from 20 to 80
years and older and drawn randomly
from the national Danish Civil Regis-
tration System. Of those invited, 14 223
(74%) attended and 13 956 (72%) had
nonfasting triglyceride levels deter-
mined using fresh plasma samples;
women with triglyceride levels greater
than 266 mg/dL (to convert to mmol/L,
multiply by 0.0113) and men with lev-
els greater than 310 mg/dL were re-
ferred to their general practitioners for
further evaluation.
Participants underwent follow-up
from baseline at the 1976-1978 exami-
nation through July 2007. Follow-up
was complete; ie, we did not lose track
of any individuals during the up to 31
years of follow-up. Eighty-three indi-
viduals who emigrated from Denmark
during follow-up were censored at the
date of emigration. The present pro-
spective study on ischemic stroke com-
prised 13 956 individuals, 1529 with is-
chemic stroke and 12 697 without.
Multiple events in the same individual
©2008 American Medical Association. All rights reserved.
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NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE
were not considered in the statistical
analysis, because the first event led to
censoring of the individual.
Cross-sectional Study
We also studied cross-sectionally those
participants in the Copenhagen City
Heart Study who attended the 1991-
1994 examination, because levels of
nonfasting remnant lipoprotein cho-
lesterol as well as a lipid profile were
measured at this examination. Of the
16 563 individuals invited to this ex-
amination, 10 135 (61%) attended and
9637 (58%) had nonfasting lipid pro-
files measured on fresh plasma samples.
End Points
Diagnoses of cerebrovascular disease,
including ischemic stroke (Interna-
tional Classification of Diseases, 8th Re-
vision codes 431 through 438 and In-
ternational Statistical Classification of
Diseases, 10th Revision codes I61
through I69⫹G45) were gathered from
the national Danish Patient Registry and
the national Danish Causes of Death
Registry. For each person registered
with cerebrovascular disease, hospital
records were requested. To also in-
clude nonhospitalized patients with
nonfatal ischemic stroke, participants
were asked at 3 study examinations
(conducted 1976-1978, 1981-1983, and
1991-1994) whether they had previ-
ously had a stroke. If affirmative, fur-
ther information was obtained from that
person’s general practitioner. Experi-
enced neurologists blinded to triglyc-
eride values reviewed all potential
cases.21
Possible stroke events (among hos-
pitalized as well as nonhospitalized pa-
tients) were validated using the World
Health Organization definition of
stroke, ie, an acute disturbance of fo-
cal or global cerebral function with
symptoms lasting longer than 24 hours
or leading to death, with presumably
no other reasons than of vascular ori-
gin.22 To distinguish among stroke sub-
types—ie, infarction (ischemic stroke),
intracerebral hemorrhage, and sub-
arachnoid hemorrhage—either com-
puted tomography or magnetic reso-
(Reprinted) JAMA, November 12, 2008—Vol 300, No. 18
nance imaging scan, autopsy, spinal
fluid examination, or surgical descrip-
tion was necessary. The event was di-
agnosed as ischemic stroke if the scan
did not visualize an infarction or hem-
orrhage but the person had symptoms
that met the criteria of the stroke defi-
nition. The diagnosis of stroke was not
applied to persons in whom a scan re-
vealed signs of prior cerebrovascular
disease but who had no history of any
symptoms.
Cerebrovascular Risk Factors
Alcohol drinkers were defined as per-
sons consuming 4 units or more of al-
cohol weekly (12 g of alcohol per unit).
Smokers were defined as active smok-
ers. Hypertension was defined as use of
antihypertensive medication, a sys-
tolic blood pressure of 140 mm Hg or
greater, or a diastolic blood pressure of
90 mm Hg or greater. Atrial fibrilla-
tion was diagnosed from electrocardio-
graphic recordings obtained at study ex-
aminations in 1976-1978, 1981-1983,
and 1991-1994.23 Furthermore, infor-
mation on atrial fibrillation (Interna-
tional Classification of Diseases, Eighth
Revision codes 427.93 and 427.94 and
International Statistical Classification of
Diseases, 10th Revision code I48.9) was
gathered from the national Danish Pa-
tient Registry and the national Danish
Causes of Death Registry. Women re-
ported menopausal status and use of
hormone therapy. Body mass index
(BMI) was calculated as weight in ki-
lograms divided by height in meters
squared. Diabetes mellitus was de-
fined as self-reported disease, use of in-
sulin or oral hypoglycemic agents, or
nonfasting plasma glucose level greater
than 198 mg/dL (to convert to mmol/L,
multiply by 0.0555).
Lipids and Lipoproteins
Enzymatic methods (Boehringer Man-
nheim, Mannheim, Germany) were used
on fresh samples to measure plasma lev-
els of nonfasting triglycerides, total cho-
lesterol, and high-density lipoprotein
cholesterol (HDL-C). Levels of HDL-C
were not measured at baseline but at the
1981-1983, 1991-1994, and 2001-
2143
 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE
2003 examinations. The coefficient of
variation for measurement of triglycer-
ides at the levels of 89 mg/dL and 283
mg/dL were 5% and 2%, respectively.
Remnant lipoprotein cholesterol was
calculated as total cholesterol minus cho-
lesterol in high- and low-density lipo-
proteins. Levels of low-density lipopro-
tein cholesterol were calculated using the
Friedewald equation if triglyceride lev-
els were below 443 mg/dL and were
measured directly if levels were 443
mg/dL or greater (Thermo Fisher Sci-
entific, Waltham, Massachusetts).
All blood samples were drawn
between 8 AM and 4 PM, and 82% of
participants had eaten a meal within
the last 3 hours of blood sampling.
The remaining 18% had eaten their
most recent meal more than 3 hours
prior to blood sampling. We estimated
that at most 3% of participants had
eaten their most recent meal more
than 8 hours prior to blood sampling,
ie, were fasting.
Statistical Analysis
Data were analyzed using Stata ver-
sion 9.2 (StataCorp, College Station,
Texas). Two-sided P⬍.05 was consid-
ered significant. Analyses were strati-
fied a priori by sex, because we previ-
ously found large risk differences
between men and women for myocar-
dial infarction by levels of nonfasting
triglycerides.9
In the prospective study, to exam-
ine the association of very high levels
of nonfasting triglycerides with ische-
mic stroke, we preplanned stratifica-
tion at each 89-mg/dL increase until the
top group became too small for statis-
tically meaningful comparison with the
less than 89-mg/dL group. Thus, base-
line nonfasting triglyceride levels were
stratified into 6 groups: less than 89 mg/
dL, 89 through 176 mg/dL, 177 through
265 mg/dL, 266 through 353 mg/dL,
354 through 442 mg/dL, and 443 mg/dL
or greater. Also, age and multivariate
adjustment were prespecified; in mul-
tivariate adjustment, we included
known cardiovascular risk factors not
by themselves highly associated with el-
evated levels of nonfasting triglycer-
2144 JAMA, November 12, 2008—Vol 300, No. 18 (Reprinted)
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ides and remnant lipoprotein choles-
terol. For comparison we also
performed adjustment for BMI and dia-
betes mellitus and for HDL-C levels.
Cumulative incidence differences be-
tween strata of nonfasting triglyceride
levels were determined using log-rank
trend tests. Cox regression models using
triglyceride levels in strata or on a con-
tinuous scale estimated hazard ratios
(HRs) for ischemic stroke. Proportion-
ality of hazards over time for nonfast-
ing triglyceride levels was assessed
by plotting −ln[−ln(survival)] vs ln
(analysis time). Suspicion of nonpar-
allel lines was further tested using
Schoenfeld residuals. No major viola-
tions of the proportional hazard as-
sumption were detected. For all sur-
vival statistics, age was the time scale
using left truncation (or delayed en-
try), which implies that age is auto-
matically adjusted for. Hazard ratios
were adjusted for age alone and for age
and other traditional cerebrovascular
risk factors (total cholesterol level, al-
cohol consumption, smoking, hyper-
tension, atrial fibrillation, and lipid-
lowering therapy [in women, HRs were
also adjusted for postmenopausal sta-
tus and hormone therapy]). Addi-
tional adjustment for BMI and diabe-
tes mellitus and for HDL-C levels was
performed separately on both the age-
adjusted model and the multivariate-
adjusted model.
For analysis of the association be-
tween triglyceride levels (in strata and
on a continuous scale) and risk of is-
chemic stroke, we stratified analysis on
sex, age at study entry, hypertension,
BMI, physical activity, and hormone
therapy (in women). For each strati-
fied analysis we tested for interactions
between levels of nonfasting triglycer-
ides on a continuous scale and the di-
chotomized stratifying covariate on risk
of ischemic stroke. Evidence for step-
wise increases in risk of ischemic stroke
for increasing levels of nonfasting tri-
glycerides was tested for by using a like-
lihood ratio test between models using
triglyceride levels on a continuous scale
and models using levels in strata of 89-
mg/dL increases.
©2008 American Medical Association. All rights reserved.
Information on baseline covariates
was more than 99% complete; indi-
viduals with incomplete information on
covariates were excluded from multi-
variate analysis. Data from the 1976-
1978, 1981-1983, 1991-1994, and
2001-2003 examinations were used as
time-dependent covariates for multi-
variate adjustments. Because HDL-C
levels were not measured at the 1976-
1978 examination, adjustment for
HDL-C was based only on measure-
ments from the 1981-1983, 1991-
1994, and 2001-2003 examinations.
This reduced the number of partici-
pants from 13 956 in the main analy-
ses to 11 416 (82%) in analyses ad-
justed for levels of HDL-C.
Hazard ratios including confidence
intervals (CIs) were corrected for re-
gression dilution bias using a nonpara-
metric method.24 For this correction, we
used nonfasting triglyceride values from
6709 individuals without lipid-
lowering therapy attending both the
baseline 1976-1978 examination and
the 1991-1994 examination; how-
ever, the main analyses were con-
ducted on 13 956 individuals. These 2
measurements were 15 years apart,
equivalent to roughly halfway through
the observation period, the ideal time
difference for this correction.24 A re-
gression dilution ratio of 0.57 was com-
puted for women and of 0.60 for men.
Correction for regression dilution bias
increases the effect size for risk esti-
mates and increases the range of CIs but
does not change significance levels.
In the cross-sectional study among
all 9637 participants attending the
1991-1994 examination approxi-
mately 15 years after the first exami-
nation, we compared levels of nonfast-
ing triglycerides and lipoprotein
cholesterol in those who developed and
did not develop (controls) ischemic
stroke between the examinations. We
used general linear models adjusting for
total cholesterol level, alcohol con-
sumption, smoking, hypertension, atrial
fibrillation, and lipid-lowering therapy;
in women, models also adjusted for
postmenopausal status and hormone
therapy. Participants receiving lipid-
 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

lowering therapy were excluded from
analysis.
For levels of nonfasting triglycer-
ides on a continuous scale in the pro-
spective study with 13 956 partici-
pants and 1529 ischemic stroke events,
we had 90% statistical power at a
2-sided P⬍ .05 to detect an HR of 1.07
per 89-mg/dL increase in both men and
women.
RESULTS
Baseline characteristics of individuals
from the general population of the Co-
penhagen City Heart Study are shown
in TABLE 1. The study included 13 956
individuals (6375 men, 7581 women)
aged 20 to 93 years with up to 31 years
of follow-up; of these, 1529 (779 men,
750 women) developed ischemic
stroke. At the 1976-1978, 1981-1983,
1991-1994, and 2001-2003 examina-
tions, 0%, 0%, 1%, and 2%, respec-
tively, of the participants were receiv-
ing lipid-lowering therapy.
Prospective Study: Nonfasting
Triglycerides and Ischemic Stroke
In both sexes, the cumulative inci-
dence of ischemic stroke increased with
increasing levels of nonfasting triglyc-
erides (P ⬍ .001 by log-rank tests for
trend). Men with elevated nonfasting
triglyceride levels had age-adjusted HRs
for ischemic stroke ranging from 1.4
(95% CI, 0.9-2.1) for triglyceride lev-
els of 89 through 176 mg/dL to 3.2
(95% CI, 1.7-6.2) for levels of 443
mg/dL or greater vs men with nonfast-
ing triglyceride levels of less than 89
mg/dL (P⬍.001 for trend) (FIGURE 1).
Corresponding values for women
ranged from 1.3 (95% CI, 1.0-1.8) for
triglyceride levels of 89 through 176
mg/dL to 5.1 (95% CI, 1.7-14.8) for lev-
els of 443 mg/dL or greater vs women
with nonfasting triglyceride levels of less
than 89 mg/dL (P ⬍.001 for trend).
After multivariate adjustment, cor-
responding HRs (95% CIs) ranged from
1.3 (0.8-1.9) to 2.5 (1.3-4.8) in men
(P ⬍.001 for trend) and 1.3 (0.9-1.7)
to 3.8 (1.3-11.1) in women (P ⬍.001
for trend). With adjustment for sys-
tolic or diastolic blood pressures rather
than the dichotomized variable hyper-
tension, the results were similar. Ad-
ditional adjustment for BMI and dia-
betes mellitus attenuated risk estimates
in both the age- and multivariate-
adjusted models (Figure 1). Addi-
tional adjustment for HDL-C levels like-
wise attenuated risk estimates in both
the age- and multivariate-adjusted mod-
els; however, nonfasting triglyceride
levels were still associated with risk of
ischemic stroke (Figure 1).
The HR for ischemic stroke for each
89-mg/dL increase in nonfasting tri-
glyceride levels was 1.24 (95% CI, 1.19-
1.29; 1529 events; 52 events/10 000 per-
son-years) after age adjustment and
1.15 (95% CI, 1.09-1.22) after multi-
variate adjustment (TABLE 2). After
stratifying for sex, age-adjusted HRs for
ischemic stroke were 1.14 (95% CI,
1.07-1.21; 779 events; 44 events/
10 000 person-years) for men and 1.33
(95% CI, 1.20-1.48; 750 events; 64
events/10 000 person-years) for wom-
en; corresponding multivariate-
adjusted HRs (95% CIs) were 1.12
(1.04-1.20) and 1.28 (1.15-1.43). There
was statistical evidence for interaction
between nonfasting triglyceride levels
and sex on risk of ischemic stroke (age-
adjusted P=.01; multivariate-adjusted
P =.03), as anticipated by our a priori
stratification. We found no evidence for
nonlinearity between increasing lev-
els of triglycerides and increasing risk
of ischemic stroke in women (P⬎.99)
or in men (P=.14).

Table 1. Baseline Characteristics of Individuals From the General Population—Copenhagen City Heart Study (Prospective Study)
Quartile of Nonfasting Triglyceride Level, Median (Range), mg/dL

Men Women

1 2 3 4 1 2 3 4
Characteristic 85 (16-106) 127 (107-150) 180 (151-219) 298 (220-2716) 69 (19-83) 97 (84-112) 131 (113-157) 202 (158-1301)
No. of observations 1610 1586 1600 1579 1901 1931 1856 1893
No. with ischemic stroke 162 185 198 234 133 170 203 244
Age, median (IQR), y 52 (41-61) 54 (44-62) a 55 (46-62) a 54 (45-60) a 48 (39-56) 53 (44-59) a 55 (48-62) a 57 (51-64) a
Total cholesterol, 208 221 232 247 216 232 244 259
median (IQR), mg/dL (183-234) (196-247) a (206-258) a (221-277) a (188-244) (205-263) a (215-277) a (230-293) a
Alcohol drinker, No. (%) b 1122 (71) 1036 (67) c 1114 (72) 1136 (73) 718 (38) 661 (34) c 662 (36) a 605 (32) a
Smoker, No. (%) b 1047 (67) 1078 (70) 1093 (70) c 1135 (73) a 1013 (54) 1099 (57) a 1113 (61) a 1127 (60) a
Hypertension, No. (%) b 731 (47) 805 (52) c 875 (57) a 1024 (66) a 559 (30) 764 (40) a 861 (47) a 1072 (58) a
Atrial fibrillation, No. (%) b 27 (2) 33 (2) 32 (2) 24 (2) 18 (1) 35 (2) 28 (2) 42 (2) c
Lipid-lowering therapy, 0 0 0 0 0 0 0 0
No.
Postmenopausal, No. (%) 938 (50) 1228 (65) 1353 (74) 1511 (82)
Postmenopausal with 276 (15) 352 (18) a 322 (18) a 364 (20) a
hormone therapy, No. (%)
Abbreviation: IQR, interquartile range.
SI conversion factor: To convert triglyceride values to mmol/L, multiply by 0.0113; cholesterol values to mmol/L, multiply by 0.0259.
a P ⬍ .001.
b See “Methods” for definition.
c P ⬍ .05 by t test or Pearson ␹2 test comparing individuals with those in the first quartile of nonfasting triglyceride levels.

©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, November 12, 2008—Vol 300, No. 18 2145

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 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

Figure 1. Hazard Ratios (HRs) for Ischemic Stroke by Increasing Levels of Nonfasting Triglycerides, Stratified by Adjustment

Age-Adjusted Multivariate-Adjusted
Events/10 000
No. of No. of Person-Years P for P for
Triglycerides, mg/dL Participants Events (95% CI) HR (95% CI) Trend HR (95% CI) Trend
(mmol/L)
Men
<89 (<1) 905 85 45 (36-55) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3019 351 61 (55-68) 1.4 (0.9-2.1) 1.3 (0.8-1.9)
177-265 (2-2.99) 1410 189 74 (64-85) 1.8 (1.2-2.9) 1.6 (1.0-2.5)
<.001 <.001
266-353 (3-3.99) 545 73 72 (57-90) 1.9 (1.1-3.3) 1.5 (0.9-2.7)
354-442 (4-4.99) 238 40 94 (69-128) 2.9 (1.5-5.6) 2.2 (1.1-4.2)
≥443 (≥5) 258 41 87 (64-118) 3.2 (1.7-6.2) 2.5 (1.3-4.8)
Women
<89 (<1) 2210 159 28 (24-33) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3987 407 46 (42-50) 1.3 (1.0-1.8) 1.3 (0.9-1.7)
177-265 (2-2.99) 985 135 69 (58-81) 2.2 (1.5-3.3) 2.0 (1.3-2.9)
<.001 <.001
266-353 (3-3.99) 241 26 57 (39-84) 1.6 (0.8-3.3) 1.4 (0.7-2.9)
354-442 (4-4.99) 96 13 69 (40-119) 2.6 (1.0-6.6) 2.5 (1.0-6.4)
≥443 (≥5) 62 10 94 (51-175) 5.1 (1.7-14.8) 3.8 (1.3-11.1)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Age, BMI, and diabetes Multivariate, BMI, and diabetes

P for P for
HR (95% CI) Trend HR (95% CI) Trend
Men
<89 (<1) 903 85 45 (36-55) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3012 351 61 (55-68) 1.3 (0.8-2.0) 1.2 (0.8-1.8)
177-265 (2-2.99) 1408 189 74 (64-85) 1.6 (1.0-2.5) 1.4 (0.9-2.2)
.002 .05
266-353 (3-3.99) 544 73 72 (57-90) 1.6 (0.9-2.8) 1.3 (0.7-2.2)
354-442 (4-4.99) 238 40 94 (69-128) 2.1 (1.1-4.2) 1.6 (0.8-3.1)
≥443 (≥5) 258 41 87 (64-118) 2.4 (1.2-4.7) 1.8 (0.9-3.6)
Women
<89 (<1) 2206 158 28 (24-33) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3981 407 46 (42-51) 1.3 (0.9-1.8) 1.2 (0.9-1.7)
177-265 (2-2.99) 984 134 68 (57-81) 1.9 (1.3-2.8) 1.7 (1.1-2.6)
.002 .01
266-353 (3-3.99) 240 26 57 (39-84) 1.3 (0.7-2.7) 1.2 (0.6-2.4)
354-442 (4-4.99) 96 13 69 (40-119) 2.0 (0.8-5.2) 2.0 (0.8-5.3)
≥443 (≥5) 62 10 94 (51-175) 3.1 (1.0-9.2) 2.1 (0.7-6.3)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Age and HDL cholesterol Multivariate and HDL cholesterol

P for P for
HR (95% CI) Trend HR (95% CI) Trend
Men
<89 (<1) 729 63 37 (29-47) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 2377 257 50 (44-56) 1.2 (0.7-2.0) 1.1 (0.7-1.9)
177-265 (2-2.99) 1086 150 66 (56-77) 1.8 (1.0-3.0) 1.6 (0.9-2.7)
<.001 .005
266-353 (3-3.99) 436 59 66 (51-85) 1.9 (1.0-3.6) 1.6 (0.8-3.0)
354-442 (4-4.99) 195 34 89 (63-124) 2.9 (1.4-6.1) 2.2 (1.0-4.7)
≥443 (≥5) 196 30 73 (51-105) 2.7 (1.2-5.9) 2.1 (0.9-4.6)
Women
<89 (<1) 1962 141 27 (23-32) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3331 335 42 (38-47) 1.2 (0.8-1.6) 1.1 (0.8-1.6)
177-265 (2-2.99) 799 109 62 (51-75) 1.8 (1.1-2.7) 1.7 (1.1-2.6)
.001 .006
266-353 (3-3.99) 190 21 52 (34-80) 1.2 (0.6-2.7) 1.0 (0.5-2.3)
354-442 (4-4.99) 75 11 68 (38-122) 2.2 (0.8-6.3) 2.2 (0.8-6.2)
≥443 (≥5) 40 9 116 (60-223) 6.7 (2.1-20.9) 5.1 (1.6-16.2)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Values are from 13 956 individuals from the Copenhagen City Heart Study with up to 31 years of follow-up, during which time 1529 developed ischemic stroke.
Multivariate adjustment was for total cholesterol level, alcohol consumption, smoking, hypertension, atrial fibrillation, and lipid-lowering therapy, with further adjust-
ment in women for postmenopausal status and hormone therapy. P values for trend examine whether increased levels of triglycerides are associated with increased
HRs (triglyceride strata were coded 0, 1, 2, 3, 4, and 5 for increasing triglyceride levels). BMI indicates body mass index (calculated as weight in kilograms divided by
height in meters squared); CI, confidence interval (shown as error bars in the plots); HDL, high-density lipoprotein.

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 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

No consistent evidence for statisti-
cal interaction on risk of ischemic
stroke was found between nonfasting
triglyceride levels and age at study
entry (⬍55 years vs ⱖ55 years),
hypertension (normotensive vs
hypertensive), BMI (⬍25 vs ⱖ25),
physical activity (active vs inactive),
and hormone therapy in women (no
vs yes) (Table 2). Hazard ratios for
ischemic stroke for increasing strata
of nonfasting triglyceride levels
stratified for age at study entry,
hypertension, BMI, and physical
activity are shown in FIGURE 2 and
FIGURE 3. Increasing levels of non-
fasting triglycerides were associated
with increasing risk of ischemic
stroke in all subgroups examined
(Table 2 and Figures 2 and 3).
In both sexes, absolute 10-year risk
of ischemic stroke increased with in-
creasing levels of nonfasting triglycer-
ides and with increasing age (TABLE 3).
Absolute 10-year risk of ischemic stroke
ranged from 2.6% in men younger than
55 years with nonfasting triglyceride
levels less than 89 mg/dL to 16.7% in
men 55 years or older with triglycer-
ide levels of 443 mg/dL or greater. Cor-
responding values in women were 1.9%
and 12.2%.
Cross-sectional Study: Nonfasting
Triglycerides, Remnant
Cholesterol, and Ischemic Stroke
Among individuals who participated
in the 1991-1994 examination of the
Copenhagen City Heart Study, men
with a previous ischemic stroke vs
controls had nonfasting triglyceride
levels of 191 (interquartile range
[IQR], 131-259) mg/dL vs 148 (IQR,
104-214) mg/dL (P ⬍ .01); corre-
sponding values for women were 167
(IQR, 121-229) mg/dL vs 127 (IQR,
91-181) mg/dL (P ⬍ .05) (FIGURE 4).
For remnant cholesterol, correspond-
ing values were 38 (IQR, 26-51)
mg/dL vs 29 (IQR, 20-42) mg/dL in
men (P ⬍ .01) and 33 (IQR, 24-45)
mg/dL vs 25 (IQR, 18-35) mg/dL in
women (P ⬍ .05). In contrast, levels
of low-density lipoprotein choles-
terol and HDL-C did not differ
between these groups.
COMMENT
By using levels of nonfasting rather than
fasting triglycerides1,4,6,7 and by having
more statistical power than any previ-
ous study,1-8 we detected a previously
unnoticed association between linear in-
creases in levels of nonfasting triglycer-
ides and stepwise increases in risk of is-
chemic stroke, with no threshold effect.
The notion of linear increases is sup-
ported both by the risk estimates for lev-
els of triglycerides on a continuous scale
and by the direct test for nonlinearity
using increasing 89-mg/dL strata of tri-
glyceride levels. The highest levels of
nonfasting triglycerides (ⱖ443 mg/dL)
were associated with a 3- and 4-fold risk
of ischemic stroke in 4% of men and 1%
of women, respectively, in the general
population. Even the most recent Eu-
ropean and North American guidelines
on stroke prevention do not recognize
elevated triglyceride levels as a risk fac-
tor for stroke.8,25

Table 2. Hazard Ratios for Ischemic Stroke per 89-mg/dL Increase in Nonfasting Triglyceride Levels on a Continuous Scale a
Age-Adjusted Multivariate-Adjusted b
Events/10 000
No. of No. of Person-Years Interaction Interaction
Group Participants Events (95% CI) HR (95% CI) P Value c HR (95% CI) P Value c
All 13 956 1529 52 (50-55) 1.24 (1.19-1.29) 1.15 (1.09-1.22)
Sex
Men 6375 779 64 (60-69) 1.14 (1.07-1.21) 1.12 (1.04-1.20)
.01 .03
Women 7581 750 44 (41-47) 1.33 (1.20-1.48) 1.28 (1.15-1.43)
Age at study entry, y
⬍55 7385 525 28 (26-31) 1.24 (1.18-1.30) 1.16 (1.08-1.25)
.94 .29
ⱖ55 6571 1004 93 (87-99) 1.25 (1.14-1.36) 1.13 (1.03-1.24)
Hypertension
No 7078 496 30 (27-32) 1.36 (1.21-1.53) 1.16 (1.01-1.34)
.03 .38
Yes 6822 1026 82 (77-87) 1.17 (1.11-1.23) 1.12 (1.05-1.20)
Body mass index d
⬍25 7495 665 40 (37-43) 1.30 (1.16-1.46) 1.18 (1.04-1.35)
.18 .56
ⱖ25 6437 862 68 (63-72) 1.19 (1.13-1.25) 1.11 (1.04-1.19)
Physical activity
Active 9504 1004 47 (44-50) 1.23 (1.17-1.29) 1.14 (1.07-1.22)
.41 .85
Inactive 4450 524 65 (59-70) 1.28 (1.16-1.42) 1.18 (1.05-1.32)
Hormone therapy (women)
No 6247 599 42 (39-46) 1.33 (1.19-1.49) 1.29 (1.15-1.45)
.96 .80
Yes 1326 149 49 (42-58) 1.35 (1.00-1.82) 1.21 (0.89-1.66)
Abbreviations: CI, confidence interval; HR, hazard ratio.
a Values are from 13 956 individuals from the Copenhagen City Heart Study with up to 31 years of follow-up, during which time 1529 developed ischemic stroke. The number of partici-
pants varies slightly from covariate to covariate due to availability of data.
b Adjusted for age, total cholesterol level, alcohol consumption, smoking, hypertension, atrial fibrillation, and lipid-lowering therapy (0% in 1976-1978, 0% in 1981-1983, 1% in 1991-
1994, and 2% in 2001-2003); in women, also adjusted for postmenopausal status and use of hormone therapy.
c Interaction between nonfasting triglyceride levels and the stratifying covariate.
d Calculated as weight in kilograms divided by height in meters squared.

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 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

Mechanistically, the explanation for
these findings is straightforward. El-
evated levels of nonfasting triglycer-
ides mark elevated levels of remnant
from chylomicrons and very low-
density lipoproteins that likely pro-
mote atherosclerosis.17,18 Because all hu-
man cells can degrade triglycerides but
not cholesterol, it may not be the tri-
glyceride content of remnants that cause
atherosclerosis but rather the choles-
terol content of these particles. Rem-
nant lipoproteins can penetrate into the
arterial intima11,12 and may preferen-
tially get trapped within the subendo-
thelial space.13-16 Since cholesterol in
remnant particles cannot be degraded
when taken up by intimal macro-
phages, these cells are transformed into
cholesterol-laden foam cells, leading to
fatty streak formation and eventually
the development of atherosclerosis,
myocardial infarction, ischemic heart
disease,9,10 and—as demonstrated in the
present study—ischemic stroke.
Some former studies have overad-
justed for potential confounders, ie,
have adjusted for covariates that them-
selves are associated with elevated lev-
els of nonfasting triglycerides and rem-
nant lipoproteins. The classic example
is adjustment for levels of HDL-C: when
levels of triglycerides and remnant li-
poproteins are elevated, levels of HDL-C
are reduced—and vice versa for low lev-
els of triglycerides. As a consequence,
many researchers and even several large
pharmaceutical companies have fo-
cused research solely on HDL-C levels
and the so-called “reverse cholesterol
transport” and have largely ignored lev-
els of triglycerides and remnant lipo-
proteins. The strong association of
HDL-C with risk of cardiovascular dis-
ease may be explained in part by the as-
sociation between elevated levels of
nonfasting triglycerides or remnant
cholesterol and cardiovascular dis-
ease.9 In support of this idea, we re-
cently observed that loss-of-function
mutations in the adenosine triphos-
phate–binding cassette transporter 1
gene are associated with low HDL-C
levels without elevated levels of

Figure 2. Hazard Ratios (HRs) for Ischemic Stroke by Increasing Levels of Nonfasting Triglycerides, Stratified by Age at Study Entry and
Hypertension

Age-Adjusted Multivariate-Adjusted

No. of No. of Events/10 000 P for P for

Triglycerides, mg/dL Participants Events Person-Years HR (95% CI) Trend HR (95% CI) Trend
(mmol/L) (95% CI)
Age <55 y at
Study Entry
<89 (<1) 2054 94 17 (14-21) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3525 234 27 (23-30) 1.8 (1.2-2.7) 1.3 (0.8-2.0)
177-265 (2-2.99) 1063 109 44 (36-53) 4.2 (2.6-6.9) 2.3 (1.4-3.9)
<.001 <.001
266-353 (3-3.99) 385 34 39 (28-54) 3.6 (1.8-7.2) 1.6 (0.8-3.4)
354-442 (4-4.99) 165 28 78 (54-113) 12.0 (5.7-25.3) 4.8 (2.2-10.5)
≥443 (≥5) 193 26 64 (44-95) 9.0 (4.2-19.5) 3.6 (1.6-8.0)
Age ≥55 y at
Study Entry
<89 (<1) 1061 150 78 (66-91) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3481 524 90 (82-98) 1.3 (0.9-1.8) 1.2 (0.9-1.7)
177-265 (2-2.99) 1332 215 106 (93-121) 1.8 (1.3-2.6) 1.5 (1.0-2.2)
<.001 .02
266-353 (3-3.99) 401 65 109 (86-139) 2.1 (1.2-3.4) 1.5 (0.9-2.5)
354-442 (4-4.99) 169 25 98 (66-145) 1.8 (0.8-3.7) 1.2 (0.6-2.5)
≥443 (≥5) 127 25 144 (98-214) 4.0 (1.9-8.4) 2.2 (1.0-4.8)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Normotensive
<89 (<1) 2008 95 18 (15-22) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3618 276 33 (29-37) 1.9 (1.2-2.8) 1.5 (1.0-2.3)
177-265 (2-2.99) 984 80 38 (31-47) 2.2 (1.3-3.7) 1.4 (0.8-2.3)
<.001 .06
266-353 (3-3.99) 270 22 38 (25-58) 2.3 (1.0-5.3) 1.3 (0.5-2.9)
354-442 (4-4.99) 120 12 48 (27-85) 3.8 (1.3-11.0) 2.1 (0.7-6.2)
≥443 (≥5) 78 11 74 (41-133) 9.4 (3.1-28.5) 3.6 (1.2-11.2)
Hypertensive
<89 (<1) 1095 148 66 (56-78) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3360 476 77 (70-84) 1.2 (0.8-1.6) 1.1 (0.8-1.5)
177-265 (2-2.99) 1402 244 101 (89-115) 2.0 (1.4-2.9) 1.7 (1.2-2.5)
<.001 <.001
266-353 (3-3.99) 511 77 87 (69-109) 1.9 (1.2-3.1) 1.5 (0.9-2.4)
354-442 (4-4.99) 214 41 112 (82-152) 2.9 (1.6-5.3) 2.0 (1.1-3.7)
≥443 (≥5) 240 40 94 (69-128) 3.0 (1.6-5.5) 2.1 (1.1-4.0)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Values are from 13 956 individuals from the Copenhagen City Heart Study with up to 31 years of follow-up during which time 1529 developed ischemic stroke. See
Figure 1 legend for details on multivariate adjustment and P values. CI indicates confidence interval (shown as error bars in the plots).

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 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

Figure 3. Hazard Ratios (HRs) for Ischemic Stroke by Increasing Levels of Nonfasting Triglycerides, Stratified by BMI and Physical Activity

Age-Adjusted Multivariate-Adjusted
Events/10 000
No. of No. of Person-Years P for P for
Triglycerides, mg/dL Participants Events (95% CI) HR (95% CI) Trend HR (95% CI) Trend
(mmol/L)
BMI <25
<89 (<1) 2267 151 27 (23-32) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3952 374 44 (40-49) 1.6 (1.1-2.2) 1.4 (1.0-1.9)
177-265 (2-2.99) 921 106 59 (49-71) 2.4 (1.6-3.8) 1.8 (1.2-2.9)
<.001 .03
266-353 (3-3.99) 219 16 40 (24-65) 1.4 (0.6-3.5) 1.0 (0.4-2.6)
354-442 (4-4.99) 79 8 51 (25-101) 1.5 (0.4-5.3) 1.1 (0.3-3.8)
≥443 (≥5) 57 10 93 (50-172) 7.0 (2.2-21.6) 3.4 (1.1-10.6)
BMI ≥25
<89 (<1) 842 92 48 (39-59) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 3041 384 63 (57-69) 1.3 (0.9-2.0) 1.1 (0.7-1.7)
177-265 (2-2.99) 1471 217 80 (70-91) 2.1 (1.4-3.2) 1.5 (1.0-2.4)
<.001 .001
266-353 (3-3.99) 565 83 78 (63-96) 2.3 (1.4-3.9) 1.5 (0.8-2.5)
354-442 (4-4.99) 255 45 98 (73-132) 4.0 (2.1-7.4) 2.2 (1.2-4.3)
≥443 (≥5) 263 41 87 (64-119) 4.0 (2.1-7.6) 2.2 (1.1-4.3)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Physically active
<89 (<1) 2284 183 32 (28-37) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 4694 481 46 (42-50) 1.4 (1.0-1.9) 1.1 (0.8-1.5)
177-265 (2-2.99) 1547 203 65 (56-74) 2.4 (1.7-3.5) 1.6 (1.1-2.3)
<.001 <.001
266-353 (3-3.99) 536 66 62 (49-79) 2.6 (1.6-4.2) 1.4 (0.8-2.3)
354-442 (4-4.99) 218 36 86 (62-120) 4.7 (2.5-8.8) 2.3 (1.2-4.4)
≥443 (≥5) 225 35 81 (58-113) 5.3 (2.8-10.0) 2.4 (1.3-4.7)
Physically inactive
<89 (<1) 831 61 34 (27-44) 1 (Reference) 1 (Reference)
89-176 (1-1.99) 2311 277 66 (59-74) 2.0 (1.2-3.3) 1.8 (1.1-2.9)
177-265 (2-2.99) 847 120 87 (73-104) 3.0 (1.7-5.2) 2.4 (1.4-4.2)
<.001 .002
266-353 (3-3.99) 250 33 81 (58-114) 3.0 (1.4-6.3) 2.2 (1.0-4.7)
354-442 (4-4.99) 116 17 86 (53-138) 3.4 (1.3-8.9) 2.4 (0.9-6.2)
≥443 (≥5) 95 16 109 (67-178) 7.2 (2.7-19.1) 3.8 (1.4-10.4)

0.5 1 2 4 8 16 0.5 1 2 4 8 16
Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Values are from 13 956 individuals from the Copenhagen City Heart Study with up to 31 years of follow-up during which time 1529 developed ischemic stroke. See
Figure 1 legend for details on multivariate adjustment and P values. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters
squared); CI, confidence interval (shown as error bars in the plots).

Table 3. Absolute 10-Year Risk for Ischemic Stroke for Increasing Levels of Nonfasting Triglycerides by Age and Sex a
Men Women

Absolute Absolute Absolute Absolute

Triglycerides, No. of No. of 10-Year 10-Year Risk No. of No. of 10-Year 10-Year Risk
mg/dL (mmol/L) Participants Events Risk, % b Difference, % Participants Events Risk, % b Difference, %
Age ⬍55 y at Study Entry
⬍89 (⬍1) 529 27 2.6 1525 67 1.9
89-176 (1-1.99) 1543 127 3.3 0.7 1982 107 2.4 0.5
177-265 (2-2.99) 676 65 4.1 1.5 387 44 2.9 1.1
266-353 (3-3.99) 290 27 3.9 1.3 95 7 2.8 0.9
354-442 (4-4.99) 120 21 4.8 2.2 45 7 3.5 1.6
ⱖ443 (ⱖ5) 166 25 5.5 2.9 27 1 4.0 2.1
Age ⱖ55 y at Study Entry
⬍89 (⬍1) 376 58 8.1 5.5 685 92 5.8 4.0
89-176 (1-1.99) 1476 224 10.2 7.6 2005 300 7.4 5.5
177-265 (2-2.99) 734 124 12.5 9.9 598 91 9.1 7.2
266-353 (3-3.99) 255 46 11.9 9.3 146 19 8.6 6.8
354-442 (4-4.99) 118 19 14.6 12.0 51 6 10.6 8.8
ⱖ443 (ⱖ5) 92 16 16.7 14.1 35 9 12.2 10.3
a Values are from 13 956 individuals from the Copenhagen City Heart Study with up to 31 years of follow-up, during which time 1529 developed ischemic stroke.
b By Poisson regression.

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 NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE

nonfasting triglycerides or remnant
cholesterol but are not associated with
the expected increased risk of ische-
mic heart disease.26 Furthermore, torce-
trapib, a cholesteryl ester transfer pro-
tein inhibitor that increases plasma
levels of HDL-C, failed to protect against
the progression of atherosclerosis and
even increased the risk of cardiovascu-
lar disease, cardiovascular mortality,
and overall mortality.27 Likewise, ad-
justment for diabetes mellitus and over-
weight also tends to mask the associa-
Figure 4. Levels of Nonfasting Triglycerides and Lipoprotein Cholesterol for Individuals With
Previous Ischemic Stroke vs Controls
Triglycerides
Men
500
400
tion between elevated levels of
nonfasting triglycerides and cardiovas-
cular disease. 9 This is because el-
evated levels of remnants may contrib-
ute to the increased cardiovascular risk
observed in overweight individuals,
those with diabetes mellitus, or both.18
In accordance with this, adjustment for
age, BMI, and diabetes mellitus or for
age and HDL-C level slightly attenu-
ated risk estimates for ischemic stroke
for increasing levels of nonfasting tri-
glycerides.
Remnant cholesterol
Women
6.0
Men Women
80
5.0
60
4.0
mmol/L
Patients with familial forms of hy-
pertriglyceridemia have increased risk
of cardiovascular death,28 while pa-
tients with remnant hyperlipidemia
have premature atherosclerosis.29 In ac-
cordance with this, those with ische-
mic stroke in the Copenhagen City
Heart Study who attended the 1991-
1994 examination had elevated levels
of nonfasting triglycerides and rem-
nant cholesterol. Also, heterozygosity
for genetic defects in lipoprotein li-
pase, the plasma enzyme that de-
grades triglycerides, is associated with
elevated triglyceride levels as well as
with increased risk of ischemic heart
disease.30-32 Furthermore, subanalyses
of 3 randomized double-blind trials sug-
gest that among patients with elevated
2.0 triglyceride levels, a 20% to 40% re-
duction in triglyceride levels achieved
using fibrates was associated with a 30%
1.5
to 40% reduction in risk of ischemic
heart disease.33-35 Finally, in the Coro-

300

mmol/L
mg/dL

mg/dL

3.0
40 1.0 nary Drug Project, a 26% reduction in
200
2.0 triglyceride levels achieved using nia-
20 0.5 cin was associated with a 24% reduc-
100 1.0 tion in cerebrovascular events.36
An association between elevated tri-
0 0 0 0
Controls Ischemic Controls Ischemic Controls Ischemic Controls Ischemic glyceride levels and risk of cardiovas-
Stroke Stroke Stroke Stroke
cular disease has previously been ques-
tioned, since extremely high levels of
triglycerides (⬎2200 mg/dL), as seen
LDL cholesterol HDL cholesterol
in familial lipoprotein lipase defi-
Men Women Men Women
ciency with the chylomicronemia syn-
250 100
6.0
2.5 drome, does not lead to accelerated ath-
200 80
erosclerosis.30 The simple and
5.0 2.0
straightforward explanation for this ap-
150 4.0 60
parent paradox is that at such extreme
1.5
mmol/L
mg/dL

mg/dL

triglyceride levels, lipoproteins are very

mmol/L

3.0
100 40 1.0
large37 and consequently not able to
2.0 penetrate the intima of arteries.38 In sup-
50 20 0.5 port of this explanation, patients with
1.0
lipoprotein lipase deficiency who, dur-
0 0 0 0 ing part of their lives because of lipid-
Controls Ischemic Controls Ischemic Controls Ischemic Controls Ischemic
Stroke Stroke Stroke Stroke lowering treatment, have triglyceride
Observations, 4136 69 5377 55 4136 69 5377 55 levels as low as 266 to 616 mg/dL—
No. and thus much smaller triglyceride-
rich lipoproteins—do develop prema-
Values were measured in 9637 individuals participating in the 1991-1994 examination of the Copenhagen
City Heart Study; these individuals were not treated with lipid-lowering therapy. Boxes indicate interquartile ture atherosclerosis.39
range; horizontal lines, median; error bars, 95% confidence intervals. P values (triglycerides: P⬍.01 for ische- Another argument often presented
mic stroke vs controls in men and P⬍.05 in women; remnant cholesterol: P⬍.01 for ischemic stroke vs con- against using nonfasting triglyceride
trols in men and P⬍.05 in women) are from general linear models adjusting for age, total cholesterol level,
alcohol consumption, smoking, hypertension, and atrial fibrillation, with further adjustment in women for levels for assessment of cardiovascu-
postmenopausal status and hormone therapy. HDL indicates high-density lipoprotein; LDL, low-density lar risk is that triglyceride levels vary
lipoprotein.
greatly after intake of fatty meals. How-
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ever, this is mainly based on informa-
tion from fat-tolerance tests in which
participants ingest 1 g of fat per kilo-
gram of body weight and in which tri-
glycerides may increase up to a level of
176 to 353 mg/dL 4 hours after fat in-
take.9,40 In contrast, triglyceride levels
only increased to 140 mg/dL 4 hours
after normal intake of food in individu-
als in the general population.9
The potential difficulty in using non-
fasting triglyceride levels in clinical
practice without standardization of the
time since the most recent meal and the
content of that meal should also be con-
sidered. First, because lipid profiles usu-
ally are measured in fasting individu-
als, nonfasting levels would require yet
another blood sampling, unless non-
fasting lipid levels were to become the
standard in the future. Second, our re-
sults show that even random levels of
triglycerides are associated with ische-
mic stroke; however, whether standard-
ization of the time since the most re-
cent meal and the content of that meal
would further improve the associa-
tion between nonfasting triglyceride lev-
els and risk of ischemic stroke needs to
be studied.
In support of our findings, the Wom-
en’s Health Study showed that el-
evated nonfasting triglyceride levels, but
not fasting levels, are associated with
increased risk of ischemic stroke.10 An-
other study also found an association
between elevated levels of nonfasting
triglycerides and increased risk of is-
chemic stroke,3 while 2 others found no
association.2,5 Regarding fasting triglyc-
erides, some inconsistency exists; for
example, a large Asian-Pacific meta-
analysis with fasting lipid measure-
ments in 90% of participants reported
a positive association with risk of is-
chemic stroke,7 while other studies
found no association.1,4,6,10 None of
these former studies on fasting as well
as on nonfasting triglyceride levels at-
tempted to associate very high levels of
triglycerides with risk of ischemic stroke
and therefore were not able to detect
our result that nonfasting triglyceride
levels of 443 mg/dL or greater are as-
sociated with a 3- and 4-fold in-
©2008 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 06/30/2022
NONFASTING TRIGLYCERIDES AND ISCHEMIC STROKE
creased risk of ischemic stroke in men
and women, respectively.
Limitations include that we only
studied white individuals, and there-
fore our results may not necessarily
apply to other racial groups. Also, be-
cause we did not measure levels of rem-
nant lipoproteins at baseline, we can-
not implicate these lipoproteins directly
in risk of ischemic stroke; however, the
finding at the 1991-1994 examination
that participants with previous ische-
mic stroke had elevated levels of non-
fasting triglycerides and remnant lipo-
proteins supports this hypothesis.
Moreover, because 82% of our partici-
pants ate within 3 hours of the blood
sampling and at least 97% ate within 8
hours of sampling, we could not com-
pare fasting and nonfasting triglycer-
ide levels for association with ische-
mic stroke. This does not diminish the
finding that nonfasting triglyceride lev-
els are associated with ischemic stroke,
but it makes it difficult to know if fun-
damental differences exist between the
fasting and nonfasting states. How-
ever, results from the Women’s Health
Study suggested that levels of nonfast-
ing, but not fasting, triglycerides are as-
sociated with increased risk of ische-
mic stroke.10
Our study has several strengths. We
studied a homogeneous white general
population of 100% Danes; we had up
to 31 years of complete follow-up; end
points were validated using records
from hospitals, general practitioners, or
both; nonfasting triglyceride levels were
measured at baseline in 1976-1978
using fresh samples; less than 1% of
study participants were given lipid-
lowering therapy; we corrected for re-
gression dilution bias; and we had suf-
ficient statistical power to examine even
the association of very high levels of tri-
glycerides with ischemic stroke in men
as well as women.
Our results, together with those from
2 previous studies,9,10 suggest that el-
evated levels of nonfasting triglycerides
and remnant lipoprotein cholesterol
could be considered together with el-
evated levels of low-density lipoprotein
cholesterol for prediction of cardiovas-
(Reprinted) JAMA, November 12, 2008—Vol 300, No. 18
cular risk. However, these findings re-
quire replication in other populations.
Author Contributions: Drs Freiberg and Nordest-
gaard had full access to all of the data in the study
and take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Freiberg, Tybjærg-
Hansen, Jensen, Nordestgaard.
Acquisition of data: Tybjærg-Hansen, Jensen,
Nordestgaard.
Analysis and interpretation of data: Freiberg, Tybjærg-
Hansen, Nordestgaard.
Drafting of the manuscript: Freiberg.
Critical revision of the manuscript for important in-
tellectual content: Tybjærg-Hansen, Jensen,
Nordestgaard.
Statistical analysis: Freiberg, Nordestgaard.
Obtained funding: Tybjærg-Hansen, Nordestgaard.
Administrative, technical, or material support: Freiberg,
Nordestgaard.
Study supervision: Tybjærg-Hansen, Jensen,
Nordestgaard.
Financial Disclosures: Dr Nordestgaard reported
serving as a consultant for AstraZeneca and BG
Medicine and receiving lecture honoraria from
Boehringer Ingelheim, Merck, Pfizer, Sanofi-Aventis,
and AstraZeneca. No other disclosures were reported.
Funding/Support: This study was supported by the Uni-
versity of Copenhagen, the Danish Heart Founda-
tion, the Danish Medical Research Council, the Re-
search Fund at Rigshospitalet, Copenhagen University
Hospital, and the European Union, Sixth Framework
Programme Priority (FP-2005-LIFESCIHEALTH-6), con-
tract 037631.
Role of the Sponsor: The study sponsors had no role
in the conduct of the study; the collection, manage-
ment, analysis, and interpretation of data; or the prepa-
ration, review, or approval of the manuscript.
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