From Cornell University Medical College, New York, NY.
Correspondence to Antonio M. Gotto, MD, DPhil, Cornell University Medical College, Olin Hall, Room 205, 445 E 69th St, New York, NY 10021. E-mail jjou{at}mail.med.cornell.edu
The
relation of serum TG concentrations and risk for CHD has been an issue
of great interest and controversy. Unlike analyses with LDL-C
and HDL-C, for which very strong and consistent relations with
CHD risk have been demonstrated in observational and interventional
studies, those with TG are ambiguous. Thus, TG represents a
clinical conundrum: should it be measured, what does it mean, and
should it be treated if elevated? In the past, the lack of an
independent effect led one authority to advise against measuring TG or
taking the serum TG concentration into account when assessing CHD
risk.1 Also, TG measurement was fraught with
problems, such as the confounding effect of free glycerol. In recent
years, both analytic methods and biostatistical analysis have
improved, and this forgotten risk factor has arisen again.
A number of factors have contributed to the conflicting views
concerning TG concentration and CHD risk, including a weakening of the
effect in multivariate analyses that control
for HDL-C compared with univariate analyses. The
inverse metabolic relation between HDL and the TG-rich
lipoproteins may contribute to this weakening.
An important confounder of TG and CHD risk is the
heterogeneity of the TG-rich lipoproteins. TG-rich
particles derived from dietary lipid intake are not thought to be
associated with increased risk for CHD, although extreme elevations of
TG (TG >11.29 mmol/L) carry the risk of pancreatitis. Chylomicron
remnant particles, on the other hand, are thought to be atherogenic.
Through the action of lipoprotein lipase, VLDLs, the TG-rich
lipoproteins secreted by the liver from endogenously
produced lipids, are converted to IDLs, which are also believed to be
atherogenic.2,3 The relation between the
concentration of the larger VLDL particles and atherogenicity is
unclear at this time. Protocols for measuring remnant lipoproteins have
been developed only recently. If these become generally available, they
should be of assistance to the physician in refining lipid profile
assessment.
Some studies have reported that the degree of postprandial lipemia is a
better indicator of atherogenicity than fasting serum TG levels. In
some studies, the degree of postprandial lipemia was associated with
risk for CHD or with the extent of coronary
blockage.4,5 Furthermore, postprandial lipemia is
associated with insulin resistance and
hyperinsulinemia and may be an important marker for
CHD independent of elevations of LDL-C.
Whether isolated hypertriglyceridemia in
the absence of either an increased LDL-C or a decreased HDL-C is
atherogenic has been a matter of dispute. Existing evidence suggests
that TG is an important risk factor in subgroups of the population. In
a 14-year follow-up of the Framingham Heart Study, TG was an
independent risk factor in women between the ages of 50 and 69
years.6 Also, data from the Paris Prospective
Study support the significance of
hypertriglyceridemia as a risk factor in
patients with non–insulin-dependent diabetes
mellitus.7 In this issue of
Circulation,8 the 8-year follow-up to
the Copenhagen Male Study by Jeppesen et al adds support by showing
increased CHD risk in middle-aged and elderly men in the middle and
highest thirds of TG levels and a gradient of risk for TG levels even
when stratified for HDL-C. In fact, TG levels increased within each
level of HDL-C. In this report, fasting
hypertriglyceridemia was a strong predictor
of CHD independent of other risk factors, including HDL-C. This finding
represents an important addition to our understanding of the
complex association between CHD risk and TG.
In a recent meta-analysis of 17 population-based prospective
studies, Hokanson and Austin9 present a
strong case for TG as an independent risk factor for CHD. On the basis
of data from a total of 46 413 men and 10 864 women, elevated TG was
associated with an
Furthermore, TG as a synergistic risk factor with other lipid risk
factors is becoming accepted. In the Helsinki Heart Study, the group of
patients who benefited the most from treatment with gemfibrozil were
those who had what is described as the lipid triad: a combination of
high LDL-C, relatively low HDL-C, and high TG.11
This subgroup accounted for
More recent trials that used the HMG-CoA reductase
inhibitors, or statins, have provided interesting insights
into the atherogenicity of TG-rich lipoproteins. In the Monitored
Atherosclerosis Regression Study (MARS) of
lovastatin, the progression of mild to moderate
coronary lesions correlated best with lipoprotein remnant
particles and was correlated with a high ratio of apolipoprotein C3 in
VLDL and LDL as contrasted with HDL, suggesting impaired
metabolism of lipoprotein remnant
particles.14,15 Baseline TG levels were
predictors of CHD risk in the West of Scotland Coronary
Prevention Study (WOSCOPS) (personal communication, James Shepherd, MD,
1997). Also, as reported at the European Society of
Cardiology meeting (Stockholm, Sweden, August 24–28,
1997), the increased risk in the Scandinavian Simvastatin
Survival Study (4S) associated with increased TG levels appeared to be
abolished by lipid-lowering treatment with simvastatin.
Interestingly, a subgroup analysis from the
Cholesterol and Recurrent Events (CARE) trial suggested
that patients whose baseline TG concentration was <1.62 mmol/L
experienced significant benefit (32% risk reduction,
P<.001), whereas those whose baseline TG was
Whether lowering isolated
hypertriglyceridemia can reduce
coronary morbidity and mortality rates cannot be examined until
a trial that manipulates only TG concentration can be designed, if such
a design is even possible, given that available drugs that reduce TG
also alter the concentrations of other lipoprotein families. However,
the current evidence makes a compelling argument for including TG in
the lipoprotein profile in the evaluation of patient risk for
coronary disease. For the present, a measurement of a
fasting TG and its assessment in conjunction with LDL-C and HDL-C
concentrations and other risk factors would seem to be the most
practical way of assessing any additional risk posed by
hypertriglyceridemia.
HDL-C and LDL-C are well established as strong, independent CHD
risk factors. However, it seems that TG continues to struggle to prove
its credentials. The growing attention to
hypertriglyceridemia and increased CHD risk
is encouraging to veterans of the "triglyceride wars"
and congruent with another trend in CHD risk management, namely, the
concept of global risk assessment, in which TG and other risk factors
are considered in the context of patients' global risk for developing
CHD.
Selected Abbreviations and Acronyms
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorial
Triglyceride
The Forgotten Risk Factor
Key Words: : Editorials • lipids • lipoproteins • risk factors
30% increase in cardiovascular
risk in men and a 75% increase in cardiovascular risk
in women. Adjustment for HDL-C and other risk factors attenuated these
risks but did not render them nonsignificant. Although the status of TG
as an independent risk factor is controversial, elevated TG is
increasingly recognized as a marker among metabolic and
clinical conditions that are associated with increased risk for
atherosclerosis. These include postprandial lipemia;
insulin resistance; hyperinsulinemia; low HDL-C;
small, dense LDL particles; increased oxidizability of LDL; poorly
controlled diabetes; and central obesity.10 70% of the event reduction in the
Helsinki Heart Study. Similarly, in the observational PROCAM study, the
combination of an increased ratio of LDL-C to HDL-C in combination with
an elevated TG carried the highest risk for
CHD.12 Of >4000 subjects with an LDL-C:HDL-C
ratio of >5 and a TG level >2.26 mmol/L, 5% accounted for
25% of the cardiovascular disease in this
population.13 
1.62
mmol/L did not.16
CHD
=
coronary heart disease
HDL-C
=
HDL cholesterol
LDL-C
=
LDL cholesterol
TG
=
triglyceride
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