ADVANCE ARTICLE:
THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

Increased Cardiovascular Risk in Hypertriglyceridemic Patients with Statin-Controlled LDL Cholesterol

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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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