Summer 2018
Vol 116.1
ADVANCE ARTICLE:
THE JOURNAL OF CLINICAL
ENDOCRINOLOGY & METABOLISM
Increased Cardiovascular Risk in Hypertriglyceridemic Patients with Statin-Controlled LDL Cholesterol
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references to, products or publications do not imply endorsement of that product or publication.
Context: Real-world evidence of the relationship between high triglyceride (TG) levels and
increased cardiovascular disease (CVD) risk among statin-treated patients with LDL cholesterol
(LDL-C) control is lacking.
Objective: We aimed to compare the risk of CVD and mortality between patients with high vs.
normal TGs.
Design: Longitudinal observational cohort study.
Setting: Integrated delivery system.
Patients: Patients aged >45 whose TG level was either <150 mg/dL (normal) or between 200-
499 mg/dL (high) in 2010, were taking only statins, had LDL-C values 40-100 mg/dL, and had
diagnosed CVD.
Methods: Patients were followed through December 2016. Our primary outcomes were a
composite of non-fatal MI, non-fatal stroke, unstable angina, coronary revascularization, and allcause
mortality, and a second composite adding peripheral revascularization and aneurysm
repair. We compared multivariable adjusted incidence rates and rate ratios (RR) of the outcomes
and their components.
Results: A total of 14,481 patients comprised the normal TG group and 2,702 patients were in
the high TG group. Multivariable adjusted incidence of the second composite was 10% greater
in the high TG group (50.9/1,000 person-years, 95% CI 47.0-55.2 vs. 46.5, 44.8-48.2, RR 1.10,
95% CI 1.00-1.20, p=0.041). The difference was driven by non-fatal MI (RR 1.20, 95% CI 1.00-
1.45, p=0.045), coronary revascularization (RR 1.18, 95% CI 1.00-1.40, p=0.045) and peripheral
revascularization (RR 1.56, 95% CI 1.14-2.13, p=0.006).
Conclusions: CVD risk in statin-treated patients was associated with high TG levels. Ongoing
CV outcome trials of add-on therapies in statin treated high-risk patients with high TG levels are
testing this hypothesis.
Among high-risk ASCVD patients with well controlled LDL-C on statin therapy followed for over 5 years,
we found a significantly increased risk of CVD among those with high vs. normal TG levels.
Introduction
The large reductions in cardiovascular disease (CVD) event and mortality rates that have
occurred during the last 50+ years(1-4) are at least in part attributable to the clear-cut benefits of
increasingly aggressive management of low-density lipoprotein cholesterol (LDL-C) levels.(5)
Nevertheless, substantial cardiovascular risk remains among the estimated 92 million US adults
with CVD in one of its many forms,(6) and CVD continues to be the leading cause of mortality
in the US.(7) Elevated triglyceride (TG) levels, which is a common finding in clinic, may
identify individuals at increased CVD risk and represent an attractive target for additional CVD
risk reduction especially among patients with well-controlled LDL-C on statin therapy.(8) Posthoc
analyses of clinical trials of LDL-C lowering have suggested that TG levels are associated
with CVD and mortality in the context of statin treatment,(9-12) and a recent report shows a
causal relationship between TG levels and CVD.(13) However, real-world evidence of the
relationship between elevated TG levels and CVD among statin treated patients who have
succeeded in attaining LDL-C control is lacking. Therefore, we conducted an observational
longitudinal cohort study using the electronic health records (EHR) of patients in an integrated
delivery system who were at high risk for CVD events and who had statin-controlled LDL-C to
determine whether the presence of high TG levels influences CV risk in real-world clinical
practice.
Materials and Methods
Kaiser Permanente (KP) is an integrated delivery system that provides medical care to
individuals in eight semi-autonomous regions around the country. For this study, we combined
the EHR data of the Northwest (NW) and Southern California (SC) regions that collectively
serve approximately 4.5 million members. Both organizations use an EPIC®-based EHR that
combines seamlessly with enrollment, laboratory and pharmacy information systems to develop
a comprehensive dataset that is standardized into a common data model.(14) The KPNW
Institutional Review Board (IRB) approved the study with a waiver of informed consent; the
KPSC’s IRB ceded review to KPNW.
The sample for the current study was selected to simulate the inclusion and exclusion criteria
of patients with atherosclerotic CVD (ASCVD) participating in the Reduction of Cardiovascular
Events with EPA - Intervention Trial (REDUCE-IT), a Phase 3b trial evaluating the safety and
efficacy of 4 grams daily of pure eicosapentaenoic acid (EPA), a prescription omega-3 fatty acid,
as an adjunct to statin therapy in reducing CV events in a high-risk patient population with
persistent hypertriglyceridemia; details of the study design have been previously published.(15)
To mimic the REDUCE-IT population, we identified all KPNW and KPSC patients aged 45
and older with ASCVD who had a TG level <500 mg/dL in 2010, were receiving statin therapy
but no other anti-hyperlipidemic agent, had LDL-C values between 40 and 100 mg/dL, and had a
charted diagnosis of MI (ICD-9-CM 410.x or 412), stroke (434.x), acute coronary syndrome
(411.1), or PAD (443.8x, 443.9x). From the 48,141 who met these criteria, we identified high
(200-499 mg/dL, n=6,737) and normal (<150 mg/dL, n=34,095) TG groups. Again following
REDUCE-IT, we excluded individuals with a life-threatening illness (AIDS/HIV [ICD-9-CM
042.x, 043.x, 044.x], malignant cancer [140.xx-239.xx] or end-stage renal disease [585.6],
planned surgery (defined for this study as any surgery within 6 months of the date of TG testing),
and liver disease (cirrhosis, hepatitis, ALT or AST >3x ULN, bilirubin > 2x ULN), kidney
dysfunction (albumin level < 3.4 g/dL, blood urea nitrogen level > 20mg/dL, or a serum
creatinine >1.3 mg/dL in men or 1.1 mg/dL in women), or thyroid function abnormalities
(thyroid stimulating hormone values <0.4 mU/L or >4.2 mU/L with or without treatment).
Although REDUCE-IT excluded NYHA Class IV heart failure only, our data did not contain
heart failure class. Therefore, we excluded all individuals with a charted heart failure diagnosis
(ICD-9-CM 428.x). These criteria resulted in the exclusion of 4,035 patients from the high TG
group and 19,614 from the normal TG group for final sample sizes of 2,702 and 14,481 patients
in the high and normal TG group, respectively. A complete consort diagram of the inclusion and
exclusion criteria is provided in Figure 1.
Index Date and Follow-up Period
If multiple TG results were available in 2010, all had to be <150 mg/dL for a patient to qualify
for the normal TG group, and all had to be 200-499 mg/dL for a patient to qualify for the high
TG group. We used the first available TG level in 2010 as the index value. We defined the
baseline period (for baseline data collection) as six months before and six months after the index
TG. To avoid immortal time bias that would result from including the 6 months post index TG
level as follow-up time, we defined the index date for beginning follow-up as the date of the
index TG plus 182 days. Patients were followed from the index date through December 2016 for
a maximum follow-up period of 6.5 years. Data were censored on 31 December 2016 or when a
patient died or left the health plan.
Study Outcomes and Covariates
We pre-specified two composite outcomes. The first included all-cause mortality and first
occurrence of a non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina.
The second added peripheral revascularization and aneurysm repair to the first. In secondary
analyses, we evaluated each of the individual components of the composite outcomes separately.
We assessed baseline demographics (age, sex, race), clinical characteristics (smoking status,
body mass index [BMI], systolic and diastolic blood pressure, lipid fractions, and comorbidities)
as potential covariates and compared them between the high and normal TG groups using t-tests
for continuous variables and χ
2 tests for dichotomous and categorical variables. We also
compared the number of outcomes and the proportion of each group with each outcome that
occurred any time during follow-up using χ
2 tests.
We compared multivariable adjusted incidence rates and rate ratios of the outcomes between
the TG groups using generalized linear models with Poisson errors (log-link) with follow-up
time as an offset variable (to account for differential follow-up). We conducted univariate Cox
regression analyses of the association between all candidate variables (see Table 1) and the
primary composite outcome. Variables that were significant at p<0.05 were included as potential
covariates in multivariable models. From these, we used forward selection to define our
multivariable analyses; final incidence models were adjusted for age, sex, race/ethnicity, BMI,
smoking status, blood pressure, diabetes, use of insulin, history of MI, stroke or other ischemic
heart disease, serum creatinine, and study site. To explore the robustness of our results, we reestimated
the final models for pre-specified dichotomous stratifications of age (< 65 vs. > 65
years), sex, race (white vs. black), Hispanic ethnicity, smoking status, blood pressure (< 140/90
vs. > 140/90 mmHg), HDL-C (< 40 vs. > 40 mg/dL), diabetes, and chronic kidney disease (e
GFR< 60 vs. > 60 mL/min/1.73m2). All analyses were conducted using SAS version 9.4 (Cary,
North Carolina).
Results
Patients in the high TG group (n=2,702) were significantly different from patients in the normal
TG group (n=14,481); they were younger and more likely to be white or Hispanic, to smoke, to
have lower HDL-C levels, and to have a higher prevalence of diabetes and CKD (Table 1). The
crude prevalence of the composite outcomes at any time during follow-up did not differ between
groups (Table 2, 24.4% vs. 25.4%, p=0.272 for the first composite; 26.3% vs. 27.0%, p=0.478
for the second composite). However, patients in the high TG group were more likely to
experience a non-fatal MI (6.3% vs. 5.2%, p=0.023) and either coronary (7.7% vs. 5.9%,
p<0.001) or peripheral revascularization (2.1% vs. 1.6%, p=0.026) while more patients in the
normal TG group died (13.4% vs. 16.0%, p<0.001). All these significant findings were similarly
significant for men, but only prevalence of coronary revascularization was significantly different
among women.
After multivariable statistical adjustment and accounting for time to event (Table 3), the rate
ratio indicated that the high TG group was 10% more likely to experience the second composite
outcome compared with the normal TG group (RR 1.10, 95% CI 1.00-1.20, p=.041). The
difference was driven by the rates of non-fatal MI (RR 1.20, 95% CI 1.00-1.45, p=0.045),
coronary revascularization (RR 1.18, 95% CI 1.00-1.40, p=0.045) and peripheral
revascularization (RR 1.56, 95% CI 1.14-2.13, p=0.006). The incidence rate (per 1,000 person years)
of the second composite was greater among the high vs. normal TG group, but the
confidence intervals overlapped (50.9, 95% CI 47.0-55.2 vs. 46.5, 95% CI 44.8-48.2). Incidence
of the first composite outcome was not significantly different between groups with rates of 45.9
per 1,000 person-years (95% CI 42.2-49.9) in the high TG group and 42.8 per 1,000 person-years
(95% CI 41.1-44.5) in the normal TG group and a rate ratio of 1.07 (95% CI 0.98-1.18,
p=0.127). Rates of all-cause mortality, non-fatal stroke, unstable angina and aneurysm repair
were elevated among the high TG group but were not significantly different from patients with
normal TG levels.
With the exception of age, results for the second composite outcome were consistent across
stratifications (Table 4). Only the interaction between group and age was statistically significant
(p=0.001) with a larger effect observed among those under age 65 compared with 65 and older.
Discussion
In this observational longitudinal cohort study of 17,183 patients with ASCVD and statincontrolled
LDL-C, we found that TG levels in the 200-499 mg/dL range were significantly
associated with CVD events over a mean follow-up of 5 years when compared with otherwise
similar patients with TG levels <150 mg/dL. Because we controlled for a number of
demographic and clinical risk factors and both TG groups had LDL-C levels ranging 40-100
mg/dL while on statin therapy, our results reflect differences in CVD risk that can be explained
at least in part by the difference in TG levels.
Past research spanning several decades has repeatedly identified TG as an important CVD
risk factor,(16) yet the contribution of TG to CVD and peripheral vascular disease risk after
adjustment for other factors has been difficult to pinpoint. The Emerging Risk Factors
Collaboration, an analysis of over 300,000 individuals from 68 prospective studies, found that
the hazard ratio for coronary heart disease (CHD) attributed to elevated TG was 1.37 (95% CI
1.31-1.42) after adjustment for non-lipid factors and became non-significant (0.99, 0.94-1.05)
following adjustment for HDL-C and non-HDL-C.(17) Because VLDL particles are the main
carrier of TG and are a component of non-HDL-C, this biological correlation may have resulted
in statistical overcorrection.(18) Moreover, all subjects were free of vascular disease at baseline,
a decidedly different study population from ours. In any case, three other large meta-analyses of
studies of general populations found that TG levels remained highly significantly associated with
CVD after adjustment for HDL-C, suggesting that TG are indeed acting independently as CVD
risk factor.(16,19,20) Our results are unique in that we focused on statin-treated patients with
controlled LDL-C and established ASCVD, and TG levels may play a larger role in CVD risk in
this more selected high-risk population. Furthermore, in our study, neither HDL-C nor its
interaction with TG group was a significant predictor of our composite CVD outcome, further
demonstrating that elevated TG levels may confer independent CVD risk.
A composite outcome that includes mortality may overemphasize less serious events such as
revascularization, especially when mortality may not be the direct result of CVD. Because we
did not have access to specific causes of death, we could not determine whether mortality was
CV-related. Despite a higher proportion of subjects in the normal TG group dying during followup,
we did not find a significant difference between groups in the multivariable adjusted risk of
all-cause mortality that accounted for time to event. Older age and slightly longer follow-up
among patients with normal TG levels likely accounts for the difference in the crude and
adjusted results. Importantly, all-cause mortality comprised 51% of the second composite
outcome in the high TG group and 63% in the normal TG group. Given these findings, it may be
more appropriate to consider the individual components of the composite as the better measure
of CV events.
Our findings were driven by significantly increased risk non-fatal MI and coronary and
peripheral revascularization. In unadjusted data, non-fatal MI was significantly different
between the TG groups among men but not women. However, a higher (albeit nonsignificant)
proportion of women in the high TG group experienced an MI suggesting that the lack of
significance may have been due to fewer events rather than sex.
It must be noted that 50% of the high TG group had a diagnosis of diabetes at baseline (vs.
38% in the normal TG group), a variable we controlled for in our multivariable analyses. The
known increased risk of CV and peripheral artery disease among patients with diabetes,(21,22)
coupled with our findings, suggests that hypertriglyceridemia may be of particular importance in
predicting, and perhaps causing, CVD in patients with diabetes.(23,24) In addition, although
clinical trials have not established that tight glycemic control reduces CVD and may even
increase the risk of death,(25,26) the association between glycemic control and CVD and
mortality has been demonstrated in observational studies.(27,28) However, because less than
half of our study sample had diabetes, only 49% had a baseline measure of hemoglobin A1c, and
61% had a baseline fasting glucose recorded. The large amount of missing data precluded us
from including measures of glycemia in our analyses.
To our knowledge, our focus on comparing CVD events and mortality between statin-treated
patients with controlled LDL-C and moderately elevated vs. normal TG was novel. Prior studies
have included patients with the full range of TG levels and measured their effect either
continuously, after log transformation, or by comparing dichotomized cut-points or upper and
lower tertiles or quintiles of TG.(10-12,16,19,20,29) While these characterizations of TG levels
offer important evidence of an association with CVD risk, they are of limited clinical value
because they do not align with guideline-recognized elevated ranges of TG levels.(23,30,31) In
contrast, our study focused on a level of hypertriglyceridemia that represents approximately onefifth
of the US adult population.(32)
Whether elevated TG levels are a cause of or merely a biomarker for CVD cannot be
established from epidemiologic or observational studies. Nevertheless, there is now mounting
genetic evidence from mutational analyses, genome-wide association studies and Mendelian
randomization studies that TG abnormalities lie in the causal pathway of ASCVD.(33) The
elevated risk of CVD events that we observed among the statin-treated high TG group may be
amenable to reduction with some TG-lowering interventions. This hypothesis is currently being
tested in three large ongoing CV outcome trials in high CV risk patients on statin therapy with
specific agents that lower TG and other biomarkers.(15,34,35)
Although an early meta-analysis found that the summary estimate of TG-associated CVD
risk was greater among women than men,(16) two subsequent meta-analyses did not find
differences by sex.(17,19) We did not observe meaningful differences between sexes in our data.
Indeed, with the exception of age, we did not observe any statistically significant interactions
between TG group and the variables we tested. That the results differed by age suggests that the
TG levels among older adults are less causative of CV events than among younger adults.
Strengths of our study included adequate sample size and follow-up of up to six years that
allowed us to capture a sufficient number of events to find significant differences between
groups. The inclusion of a wide range of covariates allowed us to isolate the effect of the TG
grouping on CVD outcomes. Our study also has notable limitations. Despite the large sample
size, the detailed selection criteria could raise questions of generalizability. However, within our
source population, among statin-treated patients with at least one TG measurement and LDL-C
<100 mg/dL, 40% had a TG level >150 mg/dL and 23% had a TG level >200 mg/dL. These
findings are consistent with large CV outcomes trials in which approximately 25-40% of
participants had LDL-C < 100 mg/dL and TG >150 mg/dL and 15-20% had LDL-C <100 mg/dL
and TG >200 mg/dL.(10,11,36-38) We used observational laboratory data that does not contain a
reliable determination of fasting status at the time of the TG tests. Because we limited our data to
outpatient TG results, it is likely that a majority of the tests were non-fasting. Although fasting
TG may be preferred for diagnosing hypertriglyceridemia,(39) non-fasting values have
repeatedly been shown to better predict CVD risk.(40-42) Moreover, because non-fasting TG
are substantially higher than fasting TG,(39,43) the resulting misclassification of patients with
normal fasting but high post-prandial TG levels would have biased our results toward the null.
Our estimates of excess CVD risk in the high TG group may therefore be conservative. By
design, we assessed CVD risk factors (including TG levels) only in the baseline year. Whether
changes in TG or other lipid parameters during follow-up affected our results is not known.
Real-world studies may contain inaccurate recording of health events, missing data, and
uncertainty about internal validity. Despite these limitations, analysis of real-world data can by
definition provide important information about patient risk as seen in clinical practice.(44,45)
Conclusions
Despite statin-controlled LDL-C levels, CV events were greater among ASCVD patients with
high compared with normal TG levels, suggesting that persistent hypertriglyceridemia is
associated with risk of CV outcomes in high-risk patients.
This study was funded by Amarin Pharma, Inc. GAN has unrelated funding from Boehringer-
Ingelheim, Janssen Pharmaceuticals, and Sanofi. SP and CBG are employees of Amarin. KR
has unrelated funding from Amgen and Regeneron. SF has consulted for Amarin, Amgen,
Pfizer, Kowa, and Merck & Co.
Amarin Pharma, Inc, na, Gregory A Nichols
Corresponding Author (and request reprints from): Gregory A. Nichols, PhD, Center
for Health Research, 3800 N. Interstate Avenue, Portland, OR 97227-1098, Phone: (503)
335-6733 // Fax: (503) 335-6311, E-mail: greg.nichols@kpchr.org
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Gregory A. Nichols, PhD, Sephy Philip, RPh, PharmD, Kristi Reynolds, PhD, Craig B. Granowitz, MD, PhD, Sergio Fazio, MD, PhD
The Journal of Clinical Endocrinology & Metabolism
Endocrine Society
Submitted: Feb 26, 2018
Accepted: May 23, 2018
First Online: May 29, 2018
Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-00470/5005949
© 2018 New Jersey Association of Osteopathic Physicians and Surgeons
The Journal is the official magazine of the New Jersey Association of Osteopathic Physicians and Surgeons (NJAOPS). NJAOPS is the sixth largest state affiliate of the American Osteopathic Association. NJAOPS represents the interests of more than 4,700 active osteopathic physicians, residents, interns and medical students. Founded in 1901, NJAOPS is one of the most active medical associations in New Jersey with 12 county societies.