Confidential: For Review Only - The BMJ: leading general medical journal… · 2019-10-02 · Confidential: For Review Only 1 Effects of fenofibrate therapy on cardiovascular outcomes

Confidential: For Review OnlyEffects of fenofibrate therapy on cardiovascular outcomes in

metabolic syndrome patients on statins: propensity-matched cohort study

Journal: BMJ

Manuscript ID BMJ-2019-049269

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 12-Feb-2019

Complete List of Authors: Kim, Sin Gon; Korea University College of Medicine, Internal MedicineKim, Nam Hoon; Korea University College of Medicine and School of Medicine, Internal MedicineHan, Ki Hoon ; University of Ulsan College of Medicine, Internal MedicineChoi, Jimi; Korea University College of Medicine and School of Medicine, BiostatisticsLee, Juneyoung; Korea University College of Medicine, Biostatistics

Keywords: fenofibrate, peroxisome proliferator-activated receptor-alpha agonist, residual cardiovascular risk, statin, metabolic syndrome

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review Only

1

Effects of fenofibrate therapy on cardiovascular outcomes in metabolic

syndrome patients on statins: propensity-matched cohort study

Nam Hoon Kim1, Ki Hoon Han2, Jimi Choi3, Juneyoung Lee3, and Sin Gon Kim1

1Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

2Department of Internal Medicine, Ulsan University, Seoul, Korea

3Department of Biostatistics, Korea University College of Medicine, Seoul, South Korea

Corresponding author: Sin Gon Kim, MD, PhD

Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea

University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga,

Seongbuk-gu, Seoul 02841, Korea

Tel: 82-2-920-5890, Fax: 82-2-953-9355, E-mail: [email protected]

Page 1 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

mailto:[email protected]


2

Abstract

OBJECTIVE

To investigate the effects of fenofibrate on residual cardiovascular risk reduction in metabolic

syndrome patients on statin therapy within a real world database.

DESIGN

Propensity-matched cohort study.

SETTING

Nationwide population-based cohort in Korea.

PARTICIPANTS

29,771 patients with metabolic syndrome (≥ 40 years) receiving statin therapy were matched

1:5 by propensity score into combined therapy (statin plus fenofibrate) group (n=2,427) and

statin monotherapy group (n=10,723).

MAIN OUTCOME MEASURE

The primary outcome was occurrence of composite cardiovascular events including incident

coronary heart disease (CHD), ischemic stroke (IS), and death from cardiovascular causes.

RESULTS

Cumulative incidence for composite cardiovascular events at 6 years was 8.06% in combined

therapy group and 10.76% in statin monotherapy group. Combined therapy significantly

reduced risk of composite cardiovascular events (adjusted hazard ratio 0.73, 95% confidence

interval 0.60 to 0.90; P=0.003) compared to statin monotherapy. Fewer patients died from

Page 2 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


3

cardiovascular causes in the combined therapy group than in the statin monotherapy group

(0.50, 0.21 to 1.17; P=0.109). The rate of incident CHD (0.78, 0.61 to 1.00; P=0.053) and IS

(0.79, 0.55 to 1.15; P=0.227) was insignificantly lower in combined therapy group.

Comparable results were found in patients who achieved target low-density lipoprotein

cholesterol levels. The lower risk of composite cardiovascular events with combined therapy

was prominent in patients with low high-density lipoprotein cholesterol or high triglyceride

concentrations.

CONCLUSION

In this propensity weighted cohort study, addition of fenofibrate to statins was associated with

significantly lower risk of major cardiovascular events compared with statin therapy alone in

metabolic syndrome patients, especially for those with atherogenic dyslipidemia.

Page 3 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


4

WHAT IS ALREADY KNOWN ON THIS TOPIC

Randomized clinical trials of fenofibrate therapy failed to reduce the risk of major

cardiovascular events in diabetic populations, but significant cardiovascular risk reduction was

observed in subgroups with atherogenic dyslipidemia.

Meta-analyses of fibrates also indicated that patients with atherogenic dyslipidemia would be

benefited from fibrates therapy on cardiovascular events reduction.

Real world evidences were not sufficient to prove fenofibrate efficacy in cardiovascular risk

reduction especially for East Asians who are reported to be genetically susceptible to poor

ability to eliminate blood triglyceride.

WHAT THIS STUDY ADDS

Fenofibrate therapy additionally reduced the risk of major cardiovascular events, mainly by

preventing coronary heart disease, in metabolic syndrome patients who were already receiving

statin therapy.

The treatment effects of fenofibrate on cardiovascular risk reduction was prominent in patients

with combined metabolic syndrome and atherogenic dyslipidemia.

Page 4 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


5

Introduction

Metabolic syndrome is a cluster of interrelated risk factors for metabolic dysregulation

predisposing to the development of atherosclerotic cardiovascular diseases.1 The increased risk

of cardiovascular disease in people with metabolic syndrome has been well established by

observational studies and meta-analyses.2-4 Elevated cardiovascular risk in metabolic syndrome

is partly attributable to accompanying atherogenic dyslipidemia which is characterized by

elevated triglyceride (TG), small dense low-density lipoprotein particles with low level of high-

density lipoprotein cholesterol (HDL-C).5 6 There is abundant evidence showing that lowering

low-density lipoprotein cholesterol (LDL-C) concentrations with statins is the primary

therapeutic option for minimizing cardiovascular risk in people at risk of cardiovascular disease

including those with atherogenic dyslipidemia.7-9 However, substantial cardiovascular risk

persisted despite ongoing statin therapy (residual cardiovascular risk) in many clinical trials

and observational studies.10-12

Due to its effects on hypertriglyceridemia and low HDL-C concentrations, fenofibrate has

been suggested as one of important treatment options for dyslipidemia management.13

Although large randomized clinical trials of fenofibrate therapy including the FIELD trial and

the ACCORD-Lipid trial failed to reduce the primary outcome of major cardiovascular events

in diabetic populations, significant cardiovascular risk reduction was observed in subgroups

with atherogenic dyslipidemia. 14-16 A few meta-analyses of fibrates also indicated that patients

with atherogenic dyslipidemia would be benefited from fibrates therapy on cardiovascular

events reduction.17 18

However, the aforementioned studies were mainly conducted in Western populations with

Page 5 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


6

high cardiovascular risk which limits direct application of the results to other ethnic populations

or to people with a broader range of cardiovascular risk. Given that atherogenic dyslipidemia

is more prevalent in East Asians, who are reported to be genetically susceptible to poor ability

to eliminate blood TG,19 it is necessary to provide study-based evidence to evaluate fenofibrate

efficacy in cardiovascular risk reduction in this population.

The aim of this study was to evaluate the effects of fenofibrate therapy on major

cardiovascular events in metabolic syndrome patients on statin therapy in a real-world setting.

We additionally assessed the degree of benefit from combined therapy with statin and

fenofibrate in terms of residual cardiovascular risk reduction in the study patients. This study

was conducted as part of the Effectiveness of Fenofibrate Therapy in Residual Cardiovascular

Risk Reduction in the Real World Setting (ECLIPSE-REAL) study.

Methods

Data sources

We used the Korean National Health Insurance Service-Health Screening Cohort (NHIS-

HEALS), which included 514,866 Koreans. This represents 10% of a random selection of all

health screening participants aged 40 to 79 in the index year 2002 or 2003 and followed up to

2015. This database contains longitudinal information including subject’ demographics,

medical and pharmaceutical records including disease code records according to the

International Classification of Disease, Tenth Revision (ICD-10), medical procedures,

hospitalizations, information on prescribed drugs, health examination data including

anthropometric measures and laboratory data, and death records. The detailed cohort protocol

Page 6 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


7

has been previously described.20

Patient selection and propensity score matching

Figure 1 shows the flow of subject selection for the study. We firstly selected patients from the

original database who had received statins for at least 3 months from January 1, 2007 to

December 31, 2014, as the national health examination programs included lipid profiles from

January 2007. Patients without documented lipid profiles before initiation of statin therapy

were excluded. Next, patients who met the metabolic syndrome criteria as defined by the Adult

Treatment Panel III guidelines before the index date were selected.21 Waist circumference (WC)

cut-off points for metabolic syndrome were accordance with the Asian standard set by the

World Health Organization.22 Thus, subjects with metabolic syndrome were required to

meet three or more of the following criteria: WC ≥90 cm in men and ≥80 cm in women, serum

triglyceride level ≥150 mg/dl, HDL-C levels <40 mg/dl in men and <50 mg/dl in women,

fasting glucose ≥100 mg/dl or anti-diabetic treatment and blood pressure ≥130/85 mmHg or

treatment for hypertension. Of the selected patients, 2,457 had received fenofibrate therapy for

at least 3 months in the whole follow-up period, and the others (n=27,314) had not.

Propensity score matching (1:5) was done for those who had been treated with fenofibrate

(combined therapy with statin and fenofibrate) and those who had not (statin therapy only). We

derived propensity score model from a multiple logistic regression that included age, sex, waist

circumference, fasting glucose, systolic blood pressure, serum creatinine, smoking status

(current, former, or never), alcohol consumption (≥ 3 times/week, ≤ 2 times/week, or never),

physical activity (≥ 3 times/week, ≤ 2 times/week, or never), preexisting cardiovascular disease

including coronary heart disease (CHD), ischemic stroke (IS) and heart failure, anti-thrombotic

Page 7 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


8

agents, anti-hypertensive agents, statin intensity, and index date of statin therapy. Baseline

LDL-C level (<100, 100-129, 130-160, and ≥160 mg/dl), HDL-C level (<34, ≥34 mg/dl), and

TG (<204, ≥204 mg/dl) were also used as independent variables in the propensity score model.

We used a greedy nearest neighbor matching on the logit of propensity score using calipers of

width 0.2 of the standard deviation of the logit of the propensity score. The cut-off points of

HDL-C and TG concentration was derived from the subgroups benefited from fenofibrate

therapy on cardiovascular outcomes in previous randomized controlled trials including the

ACCORD-Lipid and the FIELD trials.15 23 Finally, 2,427 subjects from the combined therapy

group and 10,723 subjects from the statin monotherapy group were selected. Distribution of

propensity scores that indicated a balanced matching between the combined therapy group and

statin monotherapy group is described in the supplementary figure 1.

Outcome measures

The cardiovascular outcomes of interest were incident CHD (ICD-10 codes I20-I25 plus a

coronary artery angiography procedure), IS (ICD-10 codes I63-66 with an examination of brain

imaging studies or procedures), and death from cardiovascular disease (ICD codes I00-I99).

Composite cardiovascular disease events included any of the prespecified cardiovascular

events.

Each patient was followed up from the index date up to the earliest occurrence of any study

outcome, death, or end of the study period (Dec 31, 2015).

Statistical analysis

Page 8 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


9

Data are presented as mean (standard deviation) for continuous variables and number

(percentage) for categorical variables. Demographic and clinical characteristics between

groups were compared by generalized estimating equation for matched data. Cumulative

incidence at 6 years and 95% confidence interval (CI) for the individual outcomes were

calculated. Stratified Cox proportional hazards regression model for matched data was used to

evaluate the relationship between the treatments and the study outcomes. In the matched

sample all absolute standardized differences (ASD) in baseline covariates between two groups

were less than 0.1. Although the ASD in LDL-C category was 0.097 after matching, the p-

value from generalized estimating equation (GEE) was significant, so that we decided to adjust

LDL-C category further in the model. Characteristics for subgroup analysis included age (≥ 65,

< 65 years), sex (men, women), WC (≥ 90, < 90 cm), preexisting cardiovascular disease,

hypertension and type 2 diabetes, statin intensity (moderate to high intensity, low intensity),

pre-treatment HDL-C concentration (≥ 34, < 34 mg/dl), TG concentration (≥ 204, < 204 mg/dl),

non-HDL-C concentration (≥ 130, < 130 mg/dl), and on-treatment LDL-C concentration (≥

100, < 100 mg/dl).

To reduce survival bias associated with time-to-fenofibrate initiation after enrolment, we used

an alternative index date for follow-up; the date of first prescription of fenofibrate, not the date

of enrolment into the combined therapy group.24 The index date for subjects in the statin

monotherapy group was the index date of matched subjects in the combined therapy group.

All statistical analyses were performed using the SAS software, version 9.4 (SAS Institute

Inc., Cary, NC, USA), and a two-sided p-value of <0.05 was considered statistically significant.

Patient and public involvement

Patients were not involved in research design or the outcome measures. No patients were

Page 9 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


10

asked to advise on interpretation or writing up of results. There are no plans to disseminate

the results of the research to study participants.

Results

The mean age and mean body mass index (BMI) for the subjects were 60.9 years and 25.7

kg/m2, respectively, 7.5% had previous cardiovascular disease, and 33.4% had type 2 diabetes.

The mean duration of statin therapy was 27.3 months. Baseline characteristics of the combined

therapy group and matched control were well balanced between the groups after 1:5 propensity-

weighted matching. (Table 1) The only parameter that was not balanced was the LDL-C

category; therefore, all subsequent analyses adjusted for the baseline LDL-C concentrations.

HDL-C and TG were matched by prespecified cut-offs (HDL-C of 34 mg/dl, and TG of 204

mg/dl) for lower and higher levels of each parameter. According to the criteria, 6.5% had lower

HDL-C levels and 31.1% had hypertriglyceridemia at baseline. Mean duration of follow-up

was 30.9 (18.0) months.

Changes in serum lipid profiles with treatment

Supplementary Table 1 shows changes in individual lipid profiles in each treatment group. At

baseline, the mean LDL-C and HDL-C concentrations were lower while the mean TG and non-

HDL-C concentrations were higher in the combined therapy group than in the statin

monotherapy group. These discrepancies occurred because the propensity-weighted matching

was done using categories of individual lipid profiles. On-treatment LDL-C and HDL-C

concentrations were comparable between groups (mean LDL-C concentration; 80.7 vs. 80.6

Page 10 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


11

mg/dl, mean HDL-C concentrations; 48.8 vs. 49.4 mg/dl, in the combined therapy and statin

monotherapy groups, respectively). Combined therapy reduced TG concentration more than

statin monotherapy; however, achieved mean TG concentration was higher in the combined

therapy group than in the statin monotherapy group (178.8 vs. 154.7 mg/dl, respectively). On-

treatment mean non-HDL-C concentration was also slightly higher in the combined therapy

group than in the statin monotherapy group (115.7 vs. 111.1 mg/dl, respectively).

Risk of major cardiovascular events

Cumulative incidences of composite cardiovascular events were 101 (8.06%) in the combined

therapy group and 581 (10.76%) in the statin monotherapy group. All subtypes of

cardiovascular events including incident CHD (5.12% vs. 7.22%), incident IS (3.07% vs.

3.11%), and cardiovascular death (0.56% vs. 1.13%) occurred less frequently in the combined

therapy group than in the statin monotherapy group.

Table 2 and figure 2A show the risk of composite cardiovascular events during a 6-year

follow-up period. Combined therapy with statin and fenofibrate significantly reduced the risk

of composite endpoints (Hazard ratio HR, 0.73; 95% CI, 0.60–0.90; P=0.003). The significance

was maintained in on-treatment analysis (HR, 0.66; 95% CI, 0.47–0.93, P=0.018). There were

over 20% risk reductions in incident CHD (HR, 0.78; 95% CI, 0.61–1.00; P=0.053) and

incident IS (HR, 0.79; 95% CI, 0.55–1.15; P=0.227) although they were not statistically

significant. Death from any cardiovascular cause was also not significantly lower in the

combined therapy group compared to the statin monotherapy group. In the subsequent analysis

of only patients with on-treatment LDL-C concentrations less than 100 mg/dl, the same trends

were maintained (Supplementary Table 2). There was a significant (44%) reduction in incident

Page 11 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


12

CHD events (HR, 0.56; 95% CI, 0.34–0.94) and a 33% reduction in composite cardiovascular

events with borderline significance (HR, 0.67; 95% CI, 0.44–1.00) in the combined therapy

group.

Subgroup analysis for risk of composite cardiovascular events

To identify the characteristics associated with cardiovascular benefits of fenofibrate therapy,

we analysed the risk of composite cardiovascular outcomes in subgroups.(Figure 3) In most

subgroups, combined therapy was associated with a lower risk of composite cardiovascular

events compared to statin monotherapy. However, some clinical characteristics were associated

with more significant benefits of combined therapy. Specifically, treatment effect was larger

in older (≥ 65 years) patients than in younger patients, and in men rather than in women.

Subjects with high TG or low HDL-C levels benefited more from combined therapy than

subjects with low TG and high HDL-C levels (HR, 0.71; 95% CI, 0.55–0.92 and HR, 0.78;

95% CI, 0.56–1.09, respectively). The corresponding Kaplan-Meier curves are shown in Figure

2B and Figure 2C. The beneficial effects of combined therapy were also notable in subjects

with some components of metabolic syndrome such as hypertension and higher WC but not in

subjects without these components. However, it was not affected by pre-existing cardiovascular

disease, type 2 diabetes or achieved LDL-C concentrations.

Discussion

Statement of principal findings

In this real-world database analysis, we found that fenofibrate therapy additionally reduced

Page 12 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


13

the risk of major cardiovascular events, mainly by preventing CHD, in metabolic syndrome

patients who were already receiving statin therapy. The treatment effects of fenofibrate on

cardiovascular risk reduction was greater in patients with combined metabolic syndrome and

atherogenic dyslipidemia.

Interpretation and implications

With the adoption of statin therapy as management for dyslipidaemia and cardiovascular risk,

strategies for residual cardiovascular risk management beyond statin therapy have remained

important.10 11 Certain old and novel drugs such as ezetimibe and proprotein convertase

subtilisin/kexin type 9 (PCSK9) inhibitors have shown some promising results in residual

cardiovascular risk reduction in recent large randomized clinical trials; however, those trials

included only patients with high cardiovascular risk or established coronary diseases.25-27 There

have been few evidence of lipid-modifying agents indicating the residual cardiovascular risk

reduction over statins in patients with a broader range of cardiovascular risk such as

metabolic syndrome patients.

Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, has been

proposed as a potent therapeutic agent for dyslipidemia, especially hypertriglyceridemia and

low HDL-C. Its beneficial effects on atherogenesis have been demonstrated by numerous

preclinical and clinical studies, which include favorable effects on lipoprotein metabolism,

inflammation, and vascular dysfunction.13 28 29 However, the beneficial effects on hard

cardiovascular outcomes over statins have not been proven by randomized clinical trials. In the

ACCORD-Lipid trial, addition of fenofibrate to simvastatin did not reduce the rate of major

cardiovascular outcomes compared to simvastatin monotherapy. Only several subpopulations

Page 13 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


14

such as men and patients with high TG and low HDL-C concentrations at baseline seemed to

benefit from fenofibrate add-on therapy.15

In contrast, our study in a real-world setting showed that fenofibrate therapy may play a role

in residual cardiovascular risk reduction. The reason the cardiovascular benefits of fenofibrate

addition to statin therapy, observed in our cohort study, was not demonstrated in earlier

randomized controlled trials is unclear. Although there is a fundamental difference and an

inferiority in the evidence level of our cohort study compared to the randomized clinical trials,

a possible explanation for the difference in results should be offered. The population we studied

was a group of metabolic syndrome patients with a wide range of cardiovascular risk which

included 7.5% and 33.4% of patients suffering from pre-existing cardiovascular disease and

type 2 diabetes, respectively. Thus, the rate of primary outcome was lower in our study

(cumulative incidence rate of 10.76% at 6 years in the statin monotherapy group) than in the

ACCORD-Lipid trial (annual rate of 2.4% in placebo group). These differences in population

and risk of cardiovascular disease may have mitigated the effects of statins in our study so that

the benefits of fenofibrate in terms of the reduction of cardiovascular events became more

apparent. Furthermore, subjects with metabolic syndrome or its components were identified

and categorized into a responder group for fenofibrate therapy in the FIELD, ACCORD-Lipid,

and a meta-analysis comprising other fibrates,17 23 30 indicating that our study recruited a more

appropriate target population for fenofibrate therapy. In that context, it should be noted that the

median TG concentrations at baseline were substantially higher in our study (242.9 mg/dl) than

those in the FIELD and the ACCORD-Lipid trials (153 and 162 mg/dl, respectively).

The ethnicity of the patients should also be considered in the explanation of the treatment

effects of fenofibrate. As there are only a few available clinical trials of fenofibrate or other

PPAR-α agonists in Asians, we did not have enough data to compare fenofibrate effects in

Page 14 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


15

different ethnic groups. Nevertheless, Asians are metabolically more susceptible to

hypertriglyceridemia and metabolic syndrome than other ethnicities. For example, over 30%

of adults in Korea, with significantly lower BMIs, had metabolic syndrome of a similar degree

as adults in USA.31 In addition, a specific APOA5 gene polymorphism predisposing to high

fasting and postprandial TG levels were reported to be prevalent in Koreans, even in healthy

nonobese individuals,19 which is consistent with the high prevalence of hypertriglyceridemia

in this population.32 Furthermore, TG concentration as an independent risk factor of

cardiovascular disease, especially CHD, is well established in Asian populations.33 34

Considering that fibrates exert their anti-atherosclerotic action primarily by reducing the

secretion of TG-rich very low-density lipoprotein particles by enhancing fatty acid oxidation

and reducing hepatic lipogenesis,35 we posit that our subjects are good candidates for the

demonstration of the cardiovascular benefits of fenofibrate therapy.

The patient characteristics related to treatment effects of fenofibrate addition to statins were

noted by subgroup analyses. As expected, the HR of composite outcome was lower with

combined therapy in patients with low HDL-C or high TG concentrations than in those without

these characteristics, even though the p-value for interaction was not significant between pair

groups in individual subgroup analyses. Metabolic syndrome components including

hypertension and central obesity generally favoured the treatment effects of fenofibrate,

indicating that individual components of metabolic syndrome could provide information

related to beneficial treatment effects of fenofibrate, which has already been supported by other

previous studies. Compared to statin monotherapy, combined therapy with statin and

fenofibrate resulted in considerable reduction in composite cardiovascular events regardless of

the cardiovascular disease. This suggests that it can play a role in the primary and secondary

prevention of cardiovascular disease and needs to be verified by further studies.

Page 15 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


16

Strengths and weaknesses

Recently, immortal bias and time-lag bias have been critical issues in pharmacoepidemiologic

studies.36 37 Our study also had a component related to possible immortal bias in that entry date

was matched by initiation of statin therapy in comparable groups, not by date of fenofibrate

therapy. To exclude the bias, we set the index date to be the same as the date of initiation of

fenofibrate therapy in cases and matched controls for the outcome measures. In addition, we

also subsequently analysed the outcomes only during the fenofibrate therapy period in cases

and matched controls and found that the significant reduction in cardiovascular events with

combined therapy was maintained.

The other possible bias is that LDL-C concentrations were not balanced at baseline even after

1:5 matching. Therefore, we adjusted for LDL-C concentration in all further analyses.

Additional subgroup analyses for different LDL-C concentration categories indicated that

primary outcome results were not likely to be affected by imbalance in LDL-C concentrations

at baseline.

Conclusion

In summary, this real-world evidence showed the beneficial role of fenofibrate therapy in

cardiovascular risk reduction when added to ongoing statin therapy in metabolic syndrome

patients. The components of metabolic syndrome can help identify patients who would benefit

from fenofibrate therapy.

Page 16 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


17

Acknowledgments

We thank all the participants of the Korean Health Insurance Cohort study, and the National

Health Insurance Service who developed the NHIS-HEALS (2002–2015) database (NHIS-

2017-2-592). The views expressed in this article are those of the authors and do not necessarily

represent the official position of the department of Korean National Health Insurance Service.

Contributors: SGK and KHH contributed to the idea and design of the research. JC analysed

the data. JL supervised the data analysis. NHK wrote the manuscript. All authors contributed

to the review and revision of the manuscript.

Funding: This study was supported by the Abbott Laboratories Korea. The funders had no role

in the design and conduct of the study; analysis, preparation, review, and approval of the

manuscript.

Competing interests: All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: no financial relationships or activities that

could appear to have influenced the submitted work.

Ethical approval: This study was approved by the institutional review board of Korea

University Anam Hospital (IRB number: ED17181). All data from the NHIS cohort do not

involve any personally identifiable data such as name and personal ID. Thus, NHIS approved

the cohort study without informed consent from each person.

Data sharing: Additional data are available through approval and oversight by the Korean

National Health Insurance Service.

The lead author (NHK, SGK) affirms that the manuscript is an honest, accurate, and transparent

account of the study being reported; that no important aspects of the study have been omitted;

and that any discrepancies from the study as planned (and, if relevant, registered) have been

explained.

Page 17 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


18

This is an Open Access article distributed in accordance with the Creative Commons

Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute,

remix, adapt, build upon this work non-commercially, and license their derivative works on

different terms, provided the original work is properly cited and the use is noncommercial. See:

http://creativecommons.org/licenses/by-nc/4.0/.

Page 18 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


19

References

1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes

1988;37:1595-1607.

2. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated

with the metabolic syndrome. Diabetes Care 2001;24:683-689.

3. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and

cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-2716.

4. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident

cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies.

J Am Coll Cardiol 2007;49:403-414. doi: 10.1016/j.jacc.2006.09.032

5. Tenenbaum A, Fisman EZ, Motro M, et al. Atherogenic dyslipidemia in metabolic syndrome

and type 2 diabetes: therapeutic options beyond statins. Cardiovasc Diabetol 2006;5:20.

doi:10.1186/1475-2840-5-20

6. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome.

Am J Cardiol 1998;81:18b-25b.

7. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis

of randomized controlled trials. JAMA 1999;282:2340-2346.

8. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment

of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the

American College of Cardiology/American Heart Association Task Force on Practice

Guidelines. Circulation 2014;129:S1-45. doi: 10.1161/01.cir.0000437738.63853.7a

9. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management

of Dyslipidaemias. Eur Heart J 2016;37:2999-3058. doi: 10.1093/eurheartj/ehw272

Page 19 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


20

10. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to

action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol

2008;102:1k-34k. doi: 10.1016/s0002-9149(08)01833-x [published Online First: 2008/12/17]

11. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL

cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr

Atheroscler Rep 2012;14:1-10. doi: 10.1007/s11883-011-0219-7

12. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first

cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER

trial. Lancet 2010;376:333-339. doi: 10.1016/s0140-6736(10)60713-1

13. Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic

arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol

2012;11:125. doi: 10.1186/1475-2840-11-125

14. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on

cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study):

randomised controlled trial. Lancet 2005;366:1849-1861. doi: 10.1016/s0140-6736(05)67667-

2

15. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2

diabetes mellitus. N Engl J Med 2010;362:1563-1574. doi: 10.1056/NEJMoa1001282

16. Hermans MP. Impact of Fenofibrate on Type 2 Diabetes Patients with Features of the

Metabolic Syndrome: Subgroup Analysis From FIELD. Curr Cardiol Rev 2010;6:112-118. doi:

10.2174/157340310791162686

17. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic

review and meta-analysis. Lancet 2010;375:1875-1884. doi: 10.1016/s0140-6736(10)60656-3

18. Bruckert E, Labreuche J, Deplanque D, et al. Fibrates effect on cardiovascular risk is greater

Page 20 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


21

in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic

review and meta-analysis. J Cardiovasc Pharmacol 2011;57:267-272. doi:

10.1097/FJC.0b013e318202709f

19. Jang Y, Kim JY, Kim OY, et al. The -1131T-->C polymorphism in the apolipoprotein A5

gene is associated with postprandial hypertriacylglycerolemia; elevated small, dense LDL

concentrations; and oxidative stress in nonobese Korean men. Am J Clin Nutr 2004;80:832-

840. doi: 10.1093/ajcn/80.4.832

20. Seong SC, Kim YY, Park SK, et al. Cohort profile: the National Health Insurance Service

National Health Screening Cohort (NHIS-HEALS) in Korea. BMJ Open 2017;7:e016640. doi:

10.1136/bmjopen-2017-016640

21. Executive Summary of The Third Report of The National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In

Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

22. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint

interim statement of the International Diabetes Federation Task Force on Epidemiology and

Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World

Heart Federation; International Atherosclerosis Society; and International Association for the

Study of Obesity. Circulation 2009;120:1640-1645. doi: 10.1161/circulationaha.109.192644

23. Scott R, O'Brien R, Fulcher G, et al. Effects of fenofibrate treatment on cardiovascular

disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic

syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Diabetes care 2009;32:493-498. doi: 10.2337/dc08-1543

24. Zhou Z, Rahme E, Abrahamowicz M, et al. Survival bias associated with time-to-treatment

initiation in drug effectiveness evaluation: a comparison of methods. Am J Epidemiol

Page 21 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


22

2005;162:1016-1023. doi: 10.1093/aje/kwi307

25. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after

Acute Coronary Syndromes. N Engl J Med 2015;372:2387-2397. doi:

10.1056/NEJMoa1410489

26. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in

Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-1722. doi:

10.1056/NEJMoa1615664

27. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after

Acute Coronary Syndrome. N Engl J Med 2018;379:2097-2107. doi:

10.1056/NEJMoa1801174

28. Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the

crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009;205:1-8. doi:

10.1016/j.atherosclerosis.2009.03.008

29. Lee JM. Nuclear Receptors Resolve Endoplasmic Reticulum Stress to Improve Hepatic

Insulin Resistance. Diabetes Metab J 2017;41:10-19. doi: 10.4093/dmj.2017.41.1.10

30. Koopal C, Visseren FLJ, Westerink J, et al. Predicting the Effect of Fenofibrate on

Cardiovascular Risk for Individual Patients With Type 2 Diabetes. Diabetes Care

2018;41:1244-1250. doi: 10.2337/dc17-0968

31. Lim S, Shin H, Song JH, et al. Increasing prevalence of metabolic syndrome in Korea: the

Korean National Health and Nutrition Examination Survey for 1998-2007. Diabetes care

2011;34:1323-1328. doi: 10.2337/dc10-2109

32. Jeong JS, Kwon HS. Prevalence and Clinical Characteristics of Dyslipidemia in Koreans.

Endocrinol Metab (Seoul) 2017;32:30-35. doi: 10.3803/EnM.2017.32.1.30

33. Chen AH, Tseng CH. The role of triglyceride in cardiovascular disease in asian patients

Page 22 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


23

with type 2 diabetes--a systematic review. Rev Diabet Stud 2013;10:101-109. doi:

10.1900/rds.2013.10.101

34. Kim EH, Lee JB, Kim SH, et al. Serum Triglyceride Levels and Cardiovascular Disease

Events in Koreans. Cardiology 2015;131:228-235. doi: 10.1159/000380941

35. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARalpha and PPARgamma

activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein

lipase gene. EMBO J 1996;15:5336-5348.

36. Levesque LE, Hanley JA, Kezouh A, et al. Problem of immortal time bias in cohort studies:

example using statins for preventing progression of diabetes. BMJ 2010;340:b5087. doi:

10.1136/bmj.b5087

37. Suissa S. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or

Bias? Diabetes care 2018;41:6-10. doi: 10.2337/dc17-1223

Page 23 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


24

Figure legends

Figure 1. Flow diagram of subject selection for the study.

Figure 2. Kaplan-Meier curves for composite cardiovascular outcomes between treatment

groups in all subjects (A), subjects with high TG or low HDL-C concentrations (B), and

subjects with low TG and high HDL-C concentrations (C). TG=triglyceride, HDL-C=high-

density lipoprotein-cholesterol, CI=confidence interval

Figure 3. Risk of composite cardiovascular events in the subgroups. CI=confidence interval,

HDL-C=high-density lipoprotein-cholesterol, TG=triglyceride, LDL-C=low-density

lipoprotein-cholesterol

Page 24 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


25

Table 1. Baseline characteristics of subjects.

Combined therapy

with statin and

fenofibrate (n=2,427)

Statin monotherapy

(n=10,723)p- value*

Age (years) 60.6 (7.9) 60.9 (7.9) 0.920

Male, n(%) 1,325 (54.6) 5,661 (52.8) 0.275

Body mass index (kg/m2) 25.8 (2.8) 25.7 (2.8) 0.209

Waist circumference (cm) 87.4 (7.6) 87.3 (7.5) 0.607

Fasting glucose (mg/dl) 118.6 (37.5) 117.8 (39.0) 0.389

Systolic blood pressure (mmHg) 132.7 (15.2) 132.9 (15.0) 0.613

Creatinine (mg/dl) 1.0 (1.0) 1.0 (1.3) 0.515

Current smoker, n(%) 493 (20.3) 2,037 (19.0) 0.358

Alcohol consumption, n(%) 1,060 (43.7) 4,574 (42.7) 0.987

Regular exercise, n(%) 1,282 (52.8) 5,635 (52.6) 0.823

Coronary heart disease, n(%) 80 (3.3) 341 (3.2) 0.810

Ischemic stroke, n(%) 92 (3.8) 407 (3.8) 0.982

Heart failure, n(%) 28 (1.2) 107 (1.0) 0.357

Antithrombotic agents, n(%) 841 (34.7) 3,661 (34.1) 0.698

RAS inhibitor, n(%) 1,452 (59.8) 6,346 (59.2) 0.644

Calcium channel blocker, n(%) 1,220 (50.3) 5,309 (49.5) 0.636

Beta blocker, n(%) 761 (31.4) 3,257 (30.4) 0.397

Alpha blocker, n(%) 358 (14.8) 1,537 (14.3) 0.511

Vasodilator, n(%) 13 (0.5) 53 (0.5) 0.776

Diuretics, n(%) 1,042 (42.9) 4,569 (42.6) 0.969

Statin intensity, n(%) 0.460

High 62 (2.6) 289 (2.7)

Moderate 2,236 (92.1) 9,898 (92.3)

Low 129 (5.3) 536 (5.0)

LDL-C (mg/dl) , n(%) <.001

< 100 mg/dl 646 (26.6) 2,415 (22.5)

100–130 mg/dl 645 (26.6) 2,942 (27.4)

130–160 mg/dl 670 (27.6) 3,148 (29.4)

≥ 160 mg/dl 466 (19.2) 2,218 (20.7)

HDL-C (mg/dl) , n(%) 0.180

Page 25 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


26

< 34 mg/dl 217 (8.9) 862 (8.0)

≥ 34mg/dl 2,210 (91.1) 9,861 (92.0)

Triglyceride (mg/dl) , n(%) 0.992

< 204mg/dl 899 (37.0) 4,266 (39.8)

≥ 204mg/dl 1,528 (63.0) 6,457 (60.2)

RAS=renin-angiotensin-aldosterone system, LDL-C=low density lipoprotein-cholesterol, HDL-C=high-density lipoprotein-cholesterol

Values are presented by mean (standard deviation), or n (%)

*p-value by generalized estimating equation for matched data

Page 26 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


27

Table 2. Effects of treatment on cardiovascular outcomes.

Combined therapy

with statin and


Statin monotherapy

(n=10,723)

p-value

Coronary heart disease

Number of events 70 381

Cumulative incidence at 6 years (%) 5.12 (3.92–6.67) 7.22 (6.10–8.54)

HR (95% CI) 0.78 (0.61–1.00) 1.00 0.053

Non-fatal stroke



HR (95% CI) 0.79 (0.55–1.15) 1.00 0.227

Cardiovascular deaths



HR (95% CI) 0.50 (0.21–1.17) 1.00 0.109

Composite cardiovascular events



HR (95% CI) 0.73 (0.60–0.90) 1.00 0.003

Composite cardiovascular events (on

treatment)



HR (95% CI) 0.66 (0.47–0.93) 1.00 0.018

HR=hazard ratio, CI=confidence interval

Page 27 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 1

167x190mm (300 x 300 DPI)

Page 28 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 2A

Page 29 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 2B

Page 30 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 2C

Page 31 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 3

Page 32 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlySupplementary figure 1. Distribution of propensity score. (A: Density of propensity score before and after matching, B: Distribution of propensity score before and after matching)

A.

Before matching After matching

B.

Before matching After matching

Page 33 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlySupplementary table 1. Changes in serum lipid profiles with treatment.

Combined therapy with statin and

fenofibrate (n=2,427)Statin monotherapy (n=10,723)

Pretreatment On-treatment Pretreatment On-treatment

LDL-C (mg/dl), mean

(SD)125.5 (40.6) 80.7 (28.3) 129.5 (38.4) 80.6 (28.5)

<100 mg/dl, (n/%) 646 (26.6) 1,032 (76.8) 2,415 (22.5) 4,712 (78.3)

100-130 mg/dl, (n/%) 645 (26.6) 245 (18.2) 2,942 (27.4) 967 (16.1)

130-160 mg/dl, (n/%) 670 (27.6) 53 (3.9) 3,148 (29.4) 265 (4.4)

≥160 mg/dl, (n/%) 466 (19.2) 14 (1.0) 2,218 (20.7) 76 (1.3)

HDL-C (mg/dl), mean

(SD)46.7 (12.1) 48.8 (12.1) 47.8 (12.4) 49.4 (12.1)

<34 mg/dl, (n/%) 217 (8.9) 95 (7.1) 862 (8.0) 368 (6.1)

≥34mg/dl, (n/%) 2,210 (91.1) 1,252 (92.9) 9,861 (92.0) 6,657 (93.9)

Triglyceride (mg/dl),

mean (SD)272.4 (151.2) 178.8 (107.5) 236.2 (116.5) 154.7 (81.3)

<204mg/dl, (n/%) 899 (37.0) 924 (68.9) 4,266 (39.8) 4,844 (80.4)

≥204mg/dl, (n/%) 1,528 (63.0) 417 (31.1) 6,457 (60.2) 1,181 ()

Non-HDL-C (mg/dl),

mean (SD)179.2 (41.6) 115.7 (31.6) 176.0 (37.8) 111.1 (31.7)

<100mg/dl, (n/%) 40 (1.7) 463 (32.4) 175 (1.6) 2,363 (39.2)

100-130mg/dl, (n/%) 195 (8.0) 530 (39.3) 938 (8.8) 2,198 (36.5)

≥130mg/dl, (n/%) 2,192 (90.3) 381 (28.3) 9,609 (89.6) 1,464 (24.3)

SD=standard deviation, LDL-C=low density lipoprotein-cholesterol, HDL-C=high-density lipoprotein-cholesterol

Page 34 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlySupplementary Table 2. Effects of treatment on cardiovascular outcomes in patients with on-treatment LDL-C levels less than 100 mg/dl.

Combined therapy

with statin and


Statin monotherapy

(n=10,723)

p-value

Coronary heart disease



HR (95% CI) 0.56 (0.34–0.94) 1.00 0.029

Non-fatal stroke



HR (95% CI) 0.91 (0.45–1.82) 1.00 0.779

Cardiovascular deaths



HR (95% CI) 0.61 (0.08–4.93) 1.00 0.644

Composite cardiovascular events



HR (95% CI) 0.67 (0.44–1.004) 1.00 0.051

Composite cardiovascular events (on

treatment)



HR (95% CI) 0.53 (0.25–1.12) 1.00 0.095

LDL-C=low-density lipoprotein-cholesterol, HR=hazard ratio, CI=confidence interval

Page 35 of 35


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Documents

Confidential: For Review Only - The BMJ: leading general medical journal… · 2019-10-02 · Confidential: For Review Only 1 Effects of fenofibrate therapy on cardiovascular outcomes