Original Article
Elevated Triglyceride Level Is Independently Associated
With Increased All-Cause Mortality in Patients
With Established Coronary Heart Disease
Twenty-Two–Year Follow-Up of the Bezafibrate Infarction Prevention
Study and Registry
Robert Klempfner, MD; Aharon Erez, MD; Ben-Zekry Sagit, MD; Ilan Goldenberg, MD;
Enrique Fisman, MD; Eran Kopel, MD; Nir Shlomo, MA; Ariel Israel, MD;
Alexander Tenenbaum, MD, PhD
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Background—The independent association between elevated triglycerides and all-cause mortality among patients with
established coronary heart disease is controversial. The aim of this study was to investigate this association in a large
cohort of patients with proven coronary heart disease.
Methods and Results—The study cohort comprised 15 355 patients who were screened for the Bezafibrate Infarction
Prevention (BIP) trial. Twenty-two–year mortality data were obtained from the national registry. Patients were divided
into 5 groups according to strata of fasting serum triglycerides: (1) low-normal triglycerides (<100 mg/dL); (2) highnormal triglycerides (100–149 mg/dL); (3) borderline hypertriglyceridemia triglycerides (150–199 mg/dL); (4) moderate
hypertriglyceridemia triglycerides (200–499 mg/dL); (5) severe hypertriglyceridemia triglycerides (≥500 mg/dL). Ageand sex-adjusted survival was 41% in the low-normal triglycerides group than 37%, 36%, 35%, and 25% in groups with
progressively higher triglycerides (P<0.001). In an adjusted Cox-regression for various covariates including high-density
lipoprotein cholesterol, each 1 unit of natural logarithm (Ln) triglycerides elevation was associated with a corresponding
6% (P=0.016) increased risk of 22-year all-cause mortality. The 22-year mortality risk for patients with severe
hypertriglyceridemia was increased by 68% when compared with patients with low-normal triglycerides (P<0.001).
Conclusions—In patients with established coronary heart disease, higher triglycerides levels are independently associated
with increased 22-year mortality. Even in patients with triglycerides of 100 to 149 mg/dL, the elevated risk for death
could be detected than in patients with lower triglycerides levels, whereas severe hypertriglyceridemia denotes a
population with particularly increased mortality risk. (Circ Cardiovasc Qual Outcomes. 2016;9:00-00. DOI: 10.1161/
CIRCOUTCOMES.115.002104.)
Key Words: cholesterol HDL ◼ coronary disease ◼ hypertriglyceridemia ◼ mortality ◼ triglycerides
T
he independent association between elevated triglyceride, cardiovascular risk, and mortality has long been
controversial.1,2 Although the majority of studies have shown
a significant association between elevated triglycerides with
adverse outcomes,3–11 this association sometimes became nonsignificant after multivariate adjustment including other lipid
levels and weight-related variables.12–15 For example, in the
largest meta-analysis to date,12 triglycerides were shown to
be independently associated with increased risk of coronary
heart disease (CHD) after adjustment for age and sex, but this
association became statistically nonsignificant after further
adjustment for high-density lipoprotein (HDL)-cholesterol
and non–HDL-C. As a result, the prognostic significance of
hypertriglyceridemia and its role as a plausible therapeutic
target is still a matter of active debates.
Editorial, see p 97
Accordingly, we undertook the present study in an attempt
to clarify the association between different triglyceride levels
and long-term all-cause mortality (>22 years) in a large cohort
of patients with proven CHD.
Methods
Study Population
The Bezafibrate Infarction Prevention (BIP) study and accompanying
large registry have been previously described.16,17 Briefly, the BIP trial
Received June 20, 2015; accepted December 17, 2015.
From The Heart Center, Sheba Medical Center, Tel-Hashomer, Israel (R.K., A.E., B.-Z.S., I.G., E.F., A.T.); Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel (B.-Z.S., I.G., E.F., A.T.); Heart Research Follow-up Program, University of Rochester Medical Center, NY (I.G.); Public Health
Department, Ministry of Health, Jerusalem, Israel (E.K.); and The Israeli Association for Cardiovascular Trials, Neufeld Cardiac Research Institute, Sheba
Medical Center, Tel Hashomer, Israel (N.S., A.I.).
The Data Supplement is available at http://circoutcomes.ahajournals.org/lookup/suppl/doi:10.1161/CIRCOUTCOMES.115.002104/-/DC1.
Correspondence to Aharon Erez, MD, The Leviev Heart Center, Chaim Sheba Medical Center, Tel Hashomer, Israel. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org
1
DOI: 10.1161/CIRCOUTCOMES.115.002104
2 Circ Cardiovasc Qual Outcomes March 2016
WHAT IS KNOWN
• Elevated triglyceride levels are associated with
adverse outcome.
• However, the independent association between elevated triglyceride and mortality is controversial.
WHAT THE STUDY ADDS
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• In a large cohort of secondary prevention-eligible
cardiac patients followed up for 22 years, elevated
triglyceride levels are associated with an independent risk of death.
• The association between elevated triglyceride levels
and death is graded in a dose–response manner.
• Even triglyceride levels of 100 to 149 mg/dL are
associated with an increased risk of death.
was a secondary prevention prospective multicenter randomized, placebo-controlled, double-blinded trial (RCT) aimed to assess the efficacy of long-term administration of bezafibrate in reduction of coronary
events. Screening and enrollment of patients were performed between
February 1, 1990, and October 30, 1992. Inclusion criteria for screening patients for the trial included the following: age 45 to 74 years, the
history of a verified myocardial infarction (MI) 6 months to 5 years
before inclusion, and stable angina pectoris with symptoms present
during the 2 years preceding inclusion, or an objective documentation
of related coronary artery disease, which was made by a positive exercise test, evidence of myocardial ischemia revealed by radionuclear
studies, or angiographic evidence of at least 60% stenosis of 1 major
coronary artery.18 Exclusion criteria included diabetes mellitus requiring the use of insulin, severe heart failure, unstable angina, hepatic or
renal failure, and current use of lipid-modifying drugs.
On the basis of these inclusion and exclusion criteria, the present
study sample comprised 15 446 patients who were either screened for
participation (12 324 patients) or eventually included in the BIP study
(3122 patients). All study patients underwent a complete medical examination and biochemical blood tests; historical medical data and data on
drug therapy were recorded. Median follow-up duration was 22.8 years.
The study was approved by the institute’s internal review board
and was performed according to the principles expressed in the
Declaration of Helsinki and the ethics policy of the institute.
Laboratory Methods
Blood samples were drawn after at least 12 hours of fasting.
Cooled samples, collected in the 18 participating centers using
standard equipment and procedures, were transferred to the
study’s central laboratory. All analyses were performed on a
Boehringer Hitachi 704 random access analyzer using Boehringer diagnostic kits. Detailed data on laboratory methods are
given in a previous report.19 Briefly, evaluation of triglycerides
was performed by determination of total values (glycerol-3-­
phosphate oxidase-phenol + aminophenazone high performance
method) using a BM/Hitachi 717/911 analyzer. Glucose values
were determined by the glucose oxidase-phenol + aminophenazone method. Cholesterol was determined by the cholesterol
­oxidase-phenol + aminophenazone method. The screening values
obtained on the first visit were used for all the described analysis.
Classification of Triglycerides and Outcomes
The patients were divided into 5 groups according to strata
of fasting serum triglycerides levels at screening. The
categorization is based on the ATP III 4 triglyceride categories,20 with further categorizing the normal triglyceride levels
(<150 mg/dL) into low-normal and high-normal triglyceride
levels. Accordingly, the 5 groups are (1) low-normal triglycerides (<100 mg/dL); (2) high-normal triglycerides (100–149
mg/dL); (3) borderline hypertriglyceridemia triglycerides
(150–199 mg/dL); (4) moderate hypertriglyceridemia (200–
499 mg/dL); (4) severe hypertriglyceridemia triglycerides
(≥500 mg/dL). HDL-C was defined as low for values <40 mg/
dL for men and 50 mg/dL for women.
Mortality data were obtained by matching the patients’
identification numbers with their vital status in the official National Population Registry. It should be stressed that
each matched record was checked for correct identification
by matching the study recorded date of birth, coded during
enrollment, to the date of birth stored at the National registry.
Patients with missing values or inconsistent matching were
excluded from the analysis.
In addition, we matched patients’ identification numbers
with the National Cancer Registry to obtain data on incidental
cancer during the time from enrollment. We used this data to
perform a sensitivity analysis in which patients with incidental
cancer were excluded.
Statistical Analysis
Variables were expressed as mean±SD, and categorical data
were summarized as percentages. The clinical characteristics
of the patients at baseline were compared among the subgroups, with the use of the Kruskal–Wallis test for continuous
variables and the χ2 test for dichotomous variables using Bonferroni adjusted P values for comparison. Spearman correlation was used to assess the relationship between HDL-C and
APO B to triglycerides.
Survival analysis was performed using standardized
Kaplan–Meier curves using the conditional approach balancing for sex and age confounders based on their distribution in
our entire cohort as detailed by Therneau et al.21 Multivariate
analysis was performed using the Cox-proportional hazards
regression method for the outcome of all-cause mortality.
Several models were constructed by introducing prespecified covariates using the best-subset method. Because the
distribution of triglyceride was skewed, a natural Log (Ln)
of triglycerides was introduced into the model that assessed
triglycerides as a continuous measure. The following models
were prespecified: model 1—Ln triglycerides only; model
2—Ln triglycerides, age, and sex; model 3—Ln triglycerides,
age, sex, and body mass index (BMI); model 4—Ln triglycerides, age, gender, BMI, low-density lipoprotein-cholesterol
(LDL-C); model 5—Ln triglycerides, age, sex, BMI, LDL-C,
and HDL-C; model 6—the fully adjusted Cox model included:
age, sex, BMI, serum creatinine level, presence or absence of
diabetes mellitus, chronic obstructive pulmonary disease, past
MI, cerebrovascular accident, New York Heart Association
functional class, systolic blood pressure, diagnosis of malignancy, heart failure, and serum concentrations of LDL-C and
HDL-C. A separate analysis (model 7) was performed including only subjects enrolled in the BIP RCT after the screening phase (n=3122). Similarly, we explored the association
of the different triglycerides groups against the group with
Klempfner et al Triglycerides Are Associated With Mortality 3
triglycerides <100 mg/dL serving as the reference in a Cox
model adjusted for age, diabetes mellitus, BMI, and HDL-C
levels. Regression models goodness-of-fit was assessed by
examination Schoenfeld and Cox-Snell residuals.
A sensitivity analysis was performed using the fully adjusted
model (model 6) after the exclusion of subjects that have been
diagnosed with cancer during the 22-year follow-up period.
The association of hypertriglyceridemia (defined as triglycerides ≥200 mg/dL) was further explored among prespecified patients’ subgroups by interaction term analysis. The
following subgroups were explored: sex, low HDL-C levels
(defined as <40 mg/dL for men and <50 mg/dL for women),
diabetics, BMI (dichotomized at 30 kg/m2), past and active
smokers, fasting glucose levels dichotomized at 100 mg/dL,
pervious MI, and inclusion in the BIP RCT. In addition to
the interaction term triglycerides ≥200 mg/dL and the specific subgroup, the following covariates were included in the
model: age, sex, serum creatinine level, presence or absence of
diabetes mellitus, chronic obstructive pulmonary disease, past
MI, cerebrovascular accident, New York Heart Association
functional class, systolic blood pressure, and serum concentrations of LDL-C and HDL-C. The associated risk is graphically presented in form of a Forest plot.
All statistical tests were 2 sided, and a P value of <0.05
was considered statistically significant. The P values for interaction are reported. Analyses were performed with the use of
SPSS software, version 22 (IBM Inc.), R statistical package
(version 3.1), and SAS, version 9.3.
Results
Baseline Characteristics
Of the 15 446 patients available from the BIP study and
screening registry, 91 subjects were excluded from the present
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Table 1. Baseline Patient Characteristics by Predefined TG Groups
Age, y
TG<100
(n=3794)
TG=100–149
(n=5095)
TG=150–199
(n=3103)
TG=200–499
(n=3221)
TG>500
(n=142)
P Value
61±7
60±7
59±7*
59±7*
57±8*
<0.001
Male sex, %
81
80.7
80.5
80.1
86.7
0.23
BMI, kg/m2
25.8±3.4
26.6±3.5
27±3.5*
27.6±3.7*
28.2±3.7*
<0.001
8.6
10*
13.4*
14.7*
17*
<0.001
Past smoker, %
50
53*
52
54
60
0.13
Past MI, %
71
72
73
73
81*
0.01
Current smoker, %
Hypertension, %
32
33*
34
36*
31
0.005
Diabetes mellitus, %
14
17*
20*
26*
44*
<0.001
CVA, %
1.9
1.7
1.4
1.9
2.1
0.44
TIA, %
0.8
1.2
1.0
0.8
0
0.46
COPD, %
2.9
3.1
2.9
3.0
0.7
0.44
PVD, %
3.8
4
4.0
4.6
6.4
0.19
Angina, %
59
59
60
63*
64*
<0.001
Angina CCS 3–4
4.0
4.2
4.4
6.0*
5.6
0.002
NYHA I, %
74
73
71
68*
64
<0.001
NYHA II, %
21
22
22
25*
29*
NYHA III–IV, %
5
6
6.5*
7*
7.3*
Heart rate, bpm
70±10
71±10
71±10*
72±10*
74±12*
<0.001
Systolic BP, mm Hg
133±19
135±19
135±120
136±20*
136±17
0.001
Creatinine, mg/dL
1.14±0.17
1.15±0.17
1.16±0.29
1.15±0.19
1.12±0.13
0.29
Cholesterol, mg/dL
206±35
222±35
230±37*
242±42*
279±57*
<0.001
Glucose, mg/dL
104±33
109±39
116±46*
128.9±58*
181±96*
<0.001
HDL-C, mg/dL
44±11
39±9
35±7.7*
32±7.3*
26±7.3*
<0.001
LDL-C, mg/dL
146±31
158±32*
161±35*
157±39*
NA
<0.001
No. of past MI
1.16±0.5
1.16±0.5
1.18±0.45
1.18±0.48
1.28±0.58
0.12
TG, mg/dL
78±15
124±14*
173±14*
267±63*
662±173*
<0.001
APO A
107±16
107±16
106.9±59.4
104.4±58.9*
107.1±6.3
<0.001
APO B
95±16
102±15*
105±16*
107±16*
122±6.2
<0.001
Ln TG
4.34±0.2
4.82±0.1*
5.15±5.0*
5.57±5.3*
6.50±6.2*
<0.001
APO indicates apolipoprotein; BMI, body mass index; BP, blood pressure; CCS, Canadian Cardiovascular Society; COPD, chronic obstructive pulmonary
disease; CVA, cerebrovascular accident; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; Ln, natural logarithm; MI,
myocardial infarction; NYHA, New York Heart Association; PVD, peripheral vascular disease; TG, triglycerides; and TIA, transient ischemic attack.
*Differs significantly from the TG <100-mg/dL group (P<0.05).
4 Circ Cardiovasc Qual Outcomes March 2016
directly correlated, with increasing levels of triglycerides
(correlation coefficients, −0.41 and 0.20, respectively; both
P<0.01). Comorbidities such as peripheral vascular disease,
chronic obstructive lung disease, and past cerebrovascular
accident or transient ischemic attack, as well as number of
pervious MI events did not differ significantly among groups.
Patients with greater triglycerides levels were more likely to
be classified as New York Heart Association functional class
>1 (Table 1). Although, some differences exist in the baseline
medication levels, the majority received no lipid-modifying
medication (>90%).
Long-Term Outcomes
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Figure 1. Long-term cumulative, age- and sex-adjusted, survival
probability of the entire study population by the prespecified
triglycerides (TG) groups. §P value for overall differences
between the TG groups.
analysis because of missing clinical, laboratory or follow-up
data. Distribution of excluded patients was similar among the
triglycerides groups.
Thus, 15 355 were included in the final analysis. Patients’
baseline characteristics by triglycerides groups are summarized in Table 1. Population comprised mostly of men (81%),
aged 60±7 years, the majority having a history of a previous
MI (72%).
Patients in the higher triglycerides groups were significantly younger but presented with a higher BMI, and
greater prevalence of diabetes mellitus and active smoking.
Consistently, HDL-C and APO B levels were inversely and
Age- and sex-adjusted survival differed significantly among
triglycerides groups: it was 41% in the low-normal triglycerides group (<100 mg/dL) than 37%, 36%, 35%, and 25% in
groups with progressively higher concentrations of triglycerides (100–149, 150–199, 200–499, ≥500 mg/dL, respectively;
log-rank P<0.001; Figure 1).
Multivariate Cox-proportional hazards regression modeling (after adjustment for age, HDL-C, BMI, and presence of
diabetes mellitus; Figure 2; Table I in the Data Supplement)
showed that triglycerides groups 150–200, 200–499, and ≥500
mg/dL were associated, respectively, with 16%, 29%, and
68% increased mortality risk when compared with the group
with triglycerides values <100 mg/dL (serving as the reference group). Notably, there was a marginally increased risk
mortality risk among triglycerides group 100 to 150 mg/dL
(hazard ratio [HR], 1.06; confidence interval [CI], 1.01–1.12).
When triglycerides were assessed as a continuous measure (normalized because of skewed distribution as Ln
Figure 2. Adjusted all-cause mortality risk associated with the prespecified triglyceride (TG) groups. Regression model adjusted for age,
high-density lipoprotein-cholesterol, body mass index, and diabetes mellitus. CI indicates confidence interval.
Klempfner et al Triglycerides Are Associated With Mortality 5
Table 2. Multivariate Models for the 22-Year All-Cause
Mortality Outcome by Log Unit TG Increment*
HR Per 1 Log TG
Increment
95% CI
P Value
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Model 1: Ln TG only
1.11
1.06–1.15 <0.001
Model 2: Ln TG, age, and sex
1.26
1.21–1.32 <0.001
Model 3: Ln TG, age, sex, and BMI
1.23
1.17–1.28 <0.001
Model 4: Ln TG, age, sex, BMI, LDL-C
1.21
1.15–1.27 <0.001
Model 5: Ln TG, age, sex, BMI,
LDL-C, and HDL-C
1.12
1.06–1.18 <0.001
Model 6: fully adjusted model†
1.06
1.01–1.12 0.016
Model 7: Ln TG, age, sex, and BMI
in subjects included in the BIP RCT
only (n=3122)
1.15
1.01–1.32 0.036
BIP indicates Bezafibrate Infarction Prevention; BMI, body mass index; CI,
confidence interval; HDL-C, high-density lipoprotein-cholesterol; HR, hazard
ratio; LDL-C, low-density lipoprotein-cholesterol; Ln, natural logarithm; RCT,
randomized, placebo-controlled, double-blinded trial; and TG, triglycerides.
*Consistent results were obtained when subjects with incident cancer during
the 22-year follow-up were excluded (n=3933; 25.4% of the entire study cohort).
†Adjusted for age, sex, HDL-C, LDL-C, blood glucose, BMI, angina, New
York Heart Association class, hypertension, diabetes mellitus, past myocardial
infarction, peripheral vascular disease, chronic obstructive pulmonary disease,
cerebrovascular accident, or transient ischemic attack.
triglycerides), each unit increment in Ln triglycerides was
shown to be independently associated with 26% greater mortality risk when adjusted for age and sex only (Table 2, model
2). This association remained statistically significant (HR,
1.12; CI, 1.06–1.18) after the introduction of HDL-C level into
the model (model 5). In a Cox-regression fully adjusted model
(Table 2, model 6; Table II in the Data Supplement), each 1 unit
of Ln triglycerides elevation was associated with a marginally
increased risk of all-cause mortality (HR, 1.06; CI, 1.01–1.12).
Consistent results were obtained when subjects participating
in the BIP RCT (n=3122) were separately analyzed (Table 2,
model 7). A sensitivity analysis showed consistent results after
excluding patients who developed incidental cancer during
follow-up (n=3933; 25.4% of entire cohort).
Subgroup Analysis
The age-adjusted effect of moderate and severe hypertriglyceridemia, defined as triglycerides ≥200 mg/dL was consistent
across the prespecified patient subgroups including diabetes
mellitus, low HDL-C levels, high BMI, and smoking. Subgroup analysis is presented in Figure 3. Thus, elevated triglycerides were similarly associated with mortality in all analyzed
subsets, with the exception of the relatively small group of
female patients (n=2962; 19% of all study population).
Discussion
Our study, performed in a large cohort of secondary prevention-eligible cardiac patients, who were followed up >22 years
for fatal events, has several important clinical implications:
(1) elevated triglycerides level is associated with increased
long-term mortality in patients with established CHD even
after full adjustment including HDL-C. This effect is graded:
the higher the triglycerides concentration the higher the independent mortality risk; (2) even triglycerides levels of 100 to
149 mg/dL are associated with a small increased risk for all
cause-mortality; (3) Severe hypertriglyceridemia (triglycerides >500 mg/dL) denotes a population at substantially greater
mortality risk. To our knowledge, the present study represents
the largest reported study with the longest follow-up period,
which explores the relationship between triglycerides levels
and mortality in patients with established CHD.
Comparison With Other Studies
Most previous studies have evaluated the role of triglycerides
in subjects free of CHD. The data on subjects with established
CHD are limited only to many small studies with relatively
short follow-up periods, which have shown inconclusive
results.22–24
For example, in a study by Cheng et al22 on 247 patients
with ST-segment–elevation MI who were treated with primary
PCI and followed up for a period of 1.23 to 1.4 years, higher
levels of triglycerides (>150 versus <150 mg/dL) were paradoxically associated with a lower rate of overall major adverse
cardiac events. This discrepancy could be explained by different study populations (acute versus stable CHD patients),
different outcome measures, and chance, reflecting a post hoc
finding. Yun et al24 showed in 325 patients who underwent PCI
and received statins, that high triglycerides levels (>150 mg/
dL), 4 weeks after PCI, are an independent predictor of major
adverse cardiac events (HR, 4.01; CI, 1.85–9.06). Similar to
our results, results by Sprecher et al23 showed that after coronary artery bypass grafting, triglycerides levels are predictive
of long-term all-cause mortality risk (mostly 5-year mortality), yet the results were not fully adjusted for HDL-C.
Kasai et al25 demonstrated in a study of 1836 patients
after complete revascularization that triglycerides levels
are independently associated with increased risk of cardiac
death but not with all-cause mortality, or was there a significant adjusted association with cardiovascular mortality in
the patient group with triglycerides ranging from 100 to 200
mg/dL. In a previous analysis from the BIP Registry including 11 532 patients26 with a shorter follow-up period, there
was a stepwise increase in age-adjusted 5-year mortality
with increasing triglyceride levels, yet after adjustment for
HDL-C and other covariates, this association failed to reach
statistical significance. In the current study, we included
15 355 patients with considerably longer follow-up period
and have shown that elevated triglycerides levels are associated with increased risk for 22-year mortality (HR, 1.06;
CI, 1.01–1.12), and the results are consistent in all subgroup
tested after adjustment for multiple covariates including
HDL-C. Our study encompassed markedly greater number
of end point events and thus had greater statistical power
than previous studies from the BIP registry and trial. The
risk associated with hypertriglyceridemia is attenuated after
adjustment for medical history, laboratory values, and risk
factors, probably denoting the complex association where
triglycerides exerts both direct biological effects, yet also
serve as a marker for more severe metabolic abnormalities,
comorbidities, and cardiovascular disease.
6 Circ Cardiovasc Qual Outcomes March 2016
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Figure 3. Associated risk of hypertriglyceridemia (triglyceride [TG] ≥200 vs TG <200 mg/dL) with long-term mortality in each prespecified
subset. Model adjusted for age, sex, serum creatinine level, presence or absence of diabetes mellitus (DM), chronic obstructive
pulmonary disease, past myocardial infarction (MI), cerebrovascular accident, New York Heart Association functional class, systolic blood
pressure, and serum concentrations of low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol (HDL-C). All P values
for interaction >0.05, with the exception of sex by TG ≥200 mg/d interaction; P value for interaction=0.03. BIP indicates Bezafibrate
Infarction Prevention; BMI, body mass index; HR, hazard ratio; HTN, hypertension; and RCT, randomized, placebo-controlled, doubleblinded trial.
Threshold for Elevated Triglycerides Level
Classification of serum triglyceride levels >150 mg/dL (1.7
mmol/L) as elevated is mainly based on large prospective
observational studies. However, the exact level at which
serum triglycerides start to confer risk is unknown.27 The triglycerides classification cut points have been lowered over
the years.21 Previous reports have shown an excessive risk for
cardiovascular disease even among subjects with triglycerides
levels within the so-called normal range.9 Epidemiological
data taken together raise the possibility that an optimal fasting
triglyceride level might be <100 mg/dL.
However, to the best of our knowledge, there were no
published reports on the relationship between low- and highnormal levels of triglycerides and long-term mortality in populations with established CHD. We demonstrated that even
triglyceride levels between 100 and 149 mg/dL (versus triglycerides <100 mg/dL) were associated with excessive risk
of 22-year all-cause mortality, yet this association is marginally significant and therefore warrants further validation.
Pendulum Moves From HDL-C to Triglycerides
High-density lipoprotein and triglycerides tend to vary
inversely. Traditional thought has focused on the benefits of
raising HDL-C as a protective factor against atherosclerosis.
The inverse association between HDL-C and triglycerides
complicates analysis designed to evaluate the independent contribution of elevated triglycerides levels to mortality. Although
the majority of studies found a substantial direct association
between triglycerides and adverse outcomes,3–11,28,29 triglycerides have received less attention as a causal risk factor, as
adjustment for HDL-C and other potential cofounders, tend to
attenuate or nullify the association between triglycerides concentration and cardiovascular risk.12–15,30,31 In a recent longitudinal observational study in out-patients with type 2 diabetes
mellitus, mean triglycerides levels were significantly associated with all-cause mortality after adjustment for several confounding factors including mean values of HDL-C.32 In our
report, triglycerides levels are significantly associated with
excessive risk for 22-year mortality, even after adjustment for
HDL-C and for other potential confounders. It is noteworthy
that the associated risk is attenuated after adjustment for other
risk factors and comorbidities, possibly denoting the complex
association between triglycerides levels and mortality, where
elevated triglycerides exert both a direct biological effect and
also represent a marker of more advanced atherosclerosis.
Multiple strategies to raise HDL-C levels as a primary goal
have failed to date to show clinical benefit. Moreover, recent
genetic studies have also cast doubt on HDL-C as a causal risk
factor.33 There is a growing evidence suggesting a causal role
between triglycerides and cardiovascular risk and that treating
Klempfner et al Triglycerides Are Associated With Mortality 7
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high triglycerides levels in addition to treating high LDL-C
may be beneficial.34 Contemporary genetic analyses indicate
that higher concentration of triglycerides contributes directly
to the pathogenesis of ischemic heart disease.35 Elevated apolipoprotein C3, a protein associates with triglyceride-rich lipoproteins, is associated with greater cardiovascular risk.36 Two
recently published independent large studies provide strong
evidence for the causal role of apolipoprotein C3 and triglycerides in atherosclerotic vascular disease.37,38 The results published in our report support the renewed interest in triglycerides
as a possible therapeutic target for cardiovascular risk reduction. An interesting lesson could be derived from the BIP study:
despite of a significant HDL-C increase in the bezafibrate treatment arm, the overall benefits were nonsignificant. However,
the benefit of bezafibrate in the subgroup of patients with high
triglycerides levels was impressive.39 In all the available 5 randomized control trials, the beneficial effects of fibrates were
highly significant in patients with hypertriglyceridemia.39–44
Limitations
Our study presents many limitations. First, we have limited
follow-up data of patients after screening visits (registry
group) or after the RCT BIP study completion (randomized
study group). Thus, we could not adjust for potentially confounders, such as morbidity and treatment given, during the
entire follow-up period. Second, we do not have information
on the cause of death. However, even after excluding patients
with incidental cancer, higher triglycerides levels remained
independently associated with increased all-cause mortality. In addition, some indirect estimation could be partially
derived from the experience with 3122 patients enrolled in the
BIP RCT. Their data have shown that after 8 years of followup, ≈58% of deaths were because of a cardiovascular cause
(similarly in both study arms).45 Therefore, our assumption
that the major reason for triglyceride-associated increased
mortality is cardiovascular disease seems logical.
Third, diabetes mellitus status was based on medical
records obtained at baseline for all participants. This fact can
cause a misclassification of diabetes mellitus and potentially
can lead to bias toward higher risk in the higher triglycerides groups. However, our fully multivariate adjusted model,
included adjustment for baseline glucose level >100 mg/dL.
Thus, it lessens the impact of a potential misclassification of
diabetes mellitus status.
Fourth, our analysis is based on a single measurement of
fasting triglyceride levels and cannot adjust for possible variations over time. Another important limitation of our report is
related to the lack of racial/ethnic diversity in patients who
participated in the BIP registry. This limits the generalizability
of our results. Moreover, the BIP study and registry enrolled
mostly men; thus, women were under-represented. Probably
because of a small sample size, the current analysis failed to
demonstrate a statistically significant triglyceride-associated
mortality risk in women.
The lack of clinical and laboratory data during the followup period may also limits the interpretation of the results
given the inability to adjust for confounders occurring during follow-up (ie, changes in management strategies since
the early 1980s, variations in the triglycerides levels in each
triglycerides group, and the possible effect of development of
time-dependent cardiovascular risk factors or diabetes mellitus on subsequently mortality).
Conclusions
Elevated triglycerides in patients with established CHD are
associated with a long-term mortality risk that is independent
of HDL-C levels. Even among subjects with triglycerides >100
mg/dL, the higher mortality risk could be detected. Severe
hypertriglyceridemia (triglycerides >500 mg/dL) denotes a
population with particularly increased mortality risk. The current threshold for the definition of elevated triglycerides level
for patients with CHD may be higher than desired. Prospective studies in appropriately selected subjects should further
clarify these important aspects.
Disclosures
None.
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Elevated Triglyceride Level Is Independently Associated With Increased All-Cause
Mortality in Patients With Established Coronary Heart Disease: Twenty-Two−Year
Follow-Up of the Bezafibrate Infarction Prevention Study and Registry
Robert Klempfner, Aharon Erez, Ben-Zekry Sagit, Ilan Goldenberg, Enrique Fisman, Eran
Kopel, Nir Shlomo, Ariel Israel and Alexander Tenenbaum
Circ Cardiovasc Qual Outcomes. published online March 8, 2016;
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SUPPLEMENTALMATERIAL
Table A – All cause long-term mortality risk by pre-specified TG groups
TG < 100 mg/dL
TG 100-149 mg/dL
TG 150-199 mg/dL
TG 200-499 mg/dL
TG > 500 mg/dL
BMI (per unit Kg/m2)
Age (per 1-year increment)
Diabetes Mellitus
HDL-C (per 1 mg/dL increment)
HR
1
1.06
1.16
1.29
1.68
1.02
1.07
1.78
0.992
95% CI
Lower
Upper
Reference value
1.01
1.12
1.09
1.23
1.22
1.37
1.38
2.06
1.02
1.03
1.07
1.08
1.70
1.87
0.990
0.994
P value
0.049
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
Abbreviations as in Table 1. HR – hazard ratio
Table B– Long-term independent mortality risk by TG increment (per 1
natural log increment)*
95% CI
Natural Log TG (per 1 increment)
Age (per year increment)
BMI (per unit increment)
Angina pectoris at baseline
COPD
Past CVA \ TIA
HDL-C mg/dL (per mg increment)
Hypertension
PVD
Past MI
Diabetes mellitus
Female gender
NYHA class III-IV
LDL-C
Baseline glucose > 100 mg/dL
HR
1.06
1.07
1.01
1.08
1.38
1.25
0.99
1.10
1.37
1.40
1.54
0.94
1.31
1.02
1.25
Lower
1.01
1.07
1.01
1.03
1.23
1.09
0.99
1.05
1.24
1.33
1.46
0.88
1.21
0.97
1.19
Upper
1.12
1.08
1.02
1.13
1.55
1.45
1.00
1.15
1.50
1.47
1.62
0.99
1.42
1.16
1.31
Adjusted P
value
0.016
< 0.001
< 0.001
0.001
< 0.001
0.002
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
0.02
< 0.001
0.11
< 0.001
Abbreviations as in Table 1