Editorial
Slippery Slope of Triglycerides
They Are Associated With Risk, But in the Statin Era,
Does Targeting Them Confer Benefit?
Karol E. Watson, MD, PhD; Philipp Wiesner, MD
F
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or years, the scientific and medical communities have
pondered the role of triglycerides in cardiovascular disease (CVD) and mortality risk. Although several studies have
shown a relationship between elevated triglyceride levels and
CVD, the degree to which triglycerides are independently
associated and whether triglycerides directly cause CVD has
been hotly debated.1 This is in contradistinction to the role of
low-density lipoprotein cholesterol (LDL-c) where the direct
relationship between LDL-c and CVD is clear.2 During the
years, several pieces of evidence have suggested an independent association between elevated serum triglycerides
and CVD; however, the firmness of this conclusion has been
seen as tenuous.1 In fact, a recent large study (>300 000 participants) did not find triglycerides to be an independent risk
factor for CAD when adjusted for high-density lipoprotein
cholesterol and non–high-density lipoprotein cholesterol.3
Most likely, the confusion comes because it can be difficult
to know whether the triglycerides themselves are the cause of
the increased risk or merely a marker of increased risk. High
triglycerides usually occur in conjunction with a host of other
abnormalities, such as insulin resistance, diabetes mellitus,
low high-density lipoprotein cholesterol obesity, and hypertension, thus it is difficult to disentangle which is the true
causal factor.
reducing cardiovascular events. The parent trial found a 9.4%
reduction in the primary end point (fatal and nonfatal myocardial infarction plus sudden death) with bezafibrate, but this
was not statistically significant.5 In this study, the investigators
report 22-year mortality data on 15 355 patients screened for
the BIP trial (whether they were enrolled) and found that successively higher fasting triglyceride levels led to successively
higher age- and sex-adjusted mortality rates. When triglyceride
levels were plotted against mortality, the investigators clearly
showed an increase in mortality with increasing triglyceride
levels and in multivariate analysis (controlling for multiple
potential confounders) each unit of natural logarithm triglycerides elevation was associated with a 26% increase in all-cause
mortality. In this study, even high normal triglyceride levels
(100–149 mg/dL) were associated with increased mortality
when compared with low normal triglyceride levels (<100
mg/dL). The 22-year survival rate for patients with the highest triglyceride levels (>500 mg/dL) was only 25%, whereas
the survival rate for those with low normal triglyceride levels
(<100 mg/dL) was significantly higher at 41%. It is important
to note that mortality data for this study were obtained from the
official National population registry. The authors excluded participants who developed incidental cancers during follow-up
(as determined from the National Cancer registry), thus most
of the deaths were presumed to be cardiovascular. This seems
to be a valid assumption, but it is an assumption nonetheless
and is one of the limitations of the study. Other limitations
of this study which temper enthusiasm are the lack of adjudication of deaths, the lack of follow-up lipid values, lack of
follow-up ascertainment of important comorbidities, such as
diabetes mellitus, and lack of follow-up medication use. These
limitations notwithstanding, this work adds to our scientific
knowledge about the potential role of elevated triglycerides in
cardiovascular risk, especially given the large numbers of individuals studied and the long follow-up.
Furthermore, this research takes on special importance
given that elevations in triglycerides are increasingly common in current day society. National Health and Nutrition
Examination Survey (NHANES) has collected data on cardiovascular risk factors during the 3 decades, and these data
reveal that the average triglyceride levels are increasing in
the US population. During the period 1988 to 2010, 47%
of the US population had triglyceride levels >150 mg/dL.6
Although extremely high triglycerides are less common,
NHANES did find that 1% of the US population had triglyceride levels >500 mg/dL. In comparison, cholesterol
levels have been declining during this time period, which
is likely the result of more awareness, better screening, and
improved therapies.7
Article, see p 100
In this issue of Circulation: Cardiovascular Quality and
Outcomes, the article by Klempfner et al4 adds further support
for a role of triglycerides in promoting mortality, likely via an
increase in CVD mortality. The article “Elevated Triglyceride
Level is Independently Associated With Increased All-Cause
Mortality in Patients With Established Coronary Heart Disease:
A 22-Year Follow-Up of the BIP Study and Registry” reported
long-term mortality data on 15 355 patients who were screened
for the Bezafibrate Infarction Prevention (BIP) trial. The BIP
study was a randomized, placebo-controlled secondary prevention trial designed to assess the efficacy of bezafibrate in
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Division of Cardiology, David Geffen School of Medicine at
University of California, Los Angeles.
Correspondence to Karol Watson, MD, PhD, Division of Cardiology,
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
E-mail [email protected]
(Circ Cardiovasc Qual Outcomes. 2016;9:00-00.
DOI: 10.1161/CIRCOUTCOMES.116.002675.)
© 2016 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at
http://circoutcomes.ahajournals.org
DOI: 10.1161/CIRCOUTCOMES.116.002675
1
2 Circ Cardiovasc Qual Outcomes March 2016
But How Should We Incorporate These Findings
into Our Practice?
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Putting this study into the context of present day clinical care,
it is important to remember that this trial was conducted at a
time when standard of care lipid management was considerably different from current practices. The authors point out
that >90% of the patients in the BIP trial did not receive any
lipid modifying medication at the time of enrollment. This is
not surprising since at the time that BIP was enrolling, there
were no clear guidelines for this population and suboptimal
awareness and acceptance of the benefit of lipid-lowering
therapy.8 Lovastatin and simvastatin, Food and Drug Administration approved in 1987 and 1991, respectively, had only
recently entered the US market, and trials on their benefits
were ongoing.9
Currently, statins are the most widely used class of lipid
altering medications and also reveal the most robust clinical
event reduction.10 In addition to efficacy in LDL-c lowering, statins have moderate efficacy in triglycerides lowering;
however, we still see increased cardiovascular risk in patients
with elevated triglycerides, despite statin therapy. Subgroup
analysis of the statin secondary prevention trial, Prove-It
TIMI 22, revealed that in patients with recent acute coronary syndromes treated with statin therapy to an LDL-c <70
mg/dL, there was still a higher risk for recurrent coronary
events if triglycerides were elevated >150 mg/dL.11 Thus, we
clearly see evidence that patients with elevated triglycerides
are at increased cardiovascular risk, even with statin therapy.
Because statins are the mainstay of current lipid management,
an important question is what, if any, additional lipid modifying agents on top of statins should be used to target elevated
triglycerides. Unfortunately, the largest trials that evaluated
this question, The Action to Control Cardiovascular Risk in
Diabetes (ACCORD), the Atherothrombosis Intervention in
Metabolic Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes (AIM-HIGH) trial, and
the Heart Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascular Events (HPS-2 THRIVE) study did not
show benefit of adding additional agents (that primarily target
triglycerides lowering) on top of statins.12–14 In addition, there
are potential harms seen with the medication combinations
studied.2 The results of these outcome trials fail to support the
hypothesis that a triglyceride-lowering drug reduces the risk
for cardiovascular events among statin-treated patients—or
at least the drugs that were studied in those trials. The Food
and Drug Administration has publicly stated that it no longer
considers a change in serum triglyceride levels sufficient to
establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels
<500 mg/dL.15 Also, current US cholesterol guidelines do
not advocate routinely adding triglyceride-lowering medications to statin therapy in patients with elevated triglycerides.
The 2013 American College of Cardiology/American Heart
Association cholesterol guidelines rightly focus on LDL-c
reduction to reduce cardiovascular risk. These guidelines say
“As of yet, there are no data to show that adding a nonstatin
drug(s) to high-intensity statin therapy will provide incremental ASCVD risk reduction benefit with an acceptable
margin of safety.”2
So, if moderately elevated triglycerides increase cardiovascular risk, but intervention trials fail to show benefit of
adding agents that reduce triglycerides, are we simply lacking
the right agents to lower triglycerides safely and effectively
or is the hypothesis flawed? Triglyceride-rich lipoproteins,
mainly chylomicrons and very low–density lipoprotein, contain a small glycoprotein apolipoprotein C-III, which has been
shown to induce proinflammatory processes which are known
to cause vascular inflammation, a key step in the formation
of atherosclerosis.16,17 Two recent Mendelian randomization
studies discovered a loss of function mutation in apolipoprotein C-III, resulting in low-triglyceride levels and dramatic
reduction in overall cardiovascular risk.18,19 This started the
development of a new target and a class of therapeutic agents,
antisense inhibitors of apolipoprotein C-III. In early clinical trials, these agents have been shown to be effective and
safe in lowering triglycerides.20 Whether these agents will be
able to improve cardiovascular outcomes remains to be seen.
Currently, lifestyle interventions remain an effective way in
lowering triglycerides. In the Diabetes Prevention Program,
3234 nondiabetic persons with pre–diabetes mellitus were
randomly assigned to placebo, metformin, or a lifestyle-modification program with the goals of at least a 7% weight loss
and at least 150 minutes of physical activity per week.21 The
lifestyle intervention was found to be most successful at preventing progression to diabetes mellitus, and in addition after
10 years of follow-up there was a sustained 12% reduction in
triglycerides with lifestyle.22
Although we search for the true significance of elevated
triglycerides in cardiovascular risk and potentially the optimal
method to lower triglycerides, we congratulate Klempfner et
al4 on an important study, which provides support for the idea
that triglycerides should be considered more seriously as a
future target to improve our patients’ outcomes. Be reminded,
however, that we currently do not know if triglyceride elevations will hold similar predictive value in patients whose
LDL-c is optimally controlled. And we must always remember that simply because something may or may not be a cardiovascular risk factor, altering it pharmacologically does not
always mean that we will lower risk.
Disclosures
None.
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Key Words: Editorials ◼ cholesterol ◼ risk factor ◼ survival rate
◼ triglycerides
Slippery Slope of Triglycerides: They Are Associated With Risk, But in the Statin Era,
Does Targeting Them Confer Benefit?
Karol E. Watson and Philipp Wiesner
Downloaded from http://circoutcomes.ahajournals.org/ by guest on June 15, 2017
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