Relationships Between Low-Density Lipoprotein Particle
Size, Plasma Lipoproteins, and Progression of Coronary
Artery Disease
The Diabetes Atherosclerosis Intervention Study (DAIS)
Juha Vakkilainen, MD; George Steiner, MD; Jean-Claude Ansquer, MD; Francois Aubin, MD;
Stephanie Rattier, MSc; Christelle Foucher, PhD; Anders Hamsten, MD; Marja-Riitta Taskinen, MD;
on behalf of the DAIS Group
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Background—The Diabetes Atherosclerosis Intervention Study showed that treatment with fenofibrate decreases
progression of coronary atherosclerosis in subjects with type 2 diabetes. We determined whether on-treatment plasma
lipid concentrations and LDL particle size contribute to the favorable effect of fenofibrate on the progression of coronary
artery disease (CAD).
Methods and Results—A total of 418 subjects with type 2 diabetes were randomly assigned to 200 mg micronized
fenofibrate daily or placebo. The mean follow-up time was 39.6 months. LDL peak particle diameter (LDL size) was
determined by polyacrylamide gradient gel electrophoresis from 405 subjects at baseline and at the end of the study.
Progression of CAD was measured with quantitative coronary angiography. LDL size increased significantly more in
the fenofibrate group than in the placebo group (0.98⫾1.04 versus 0.32⫾0.92 nm, P⬍0.001). In the combined group,
small LDL size was significantly associated with progression of CAD measured as the increase of percentage diameter
stenosis (r⫽⫺0.16, P⫽0.002) and decreases in minimum (r⫽⫺0.11, P⫽0.030) and mean (r⫽⫺0.10, P⫽0.045) lumen
diameter. High on-treatment LDL cholesterol, apolipoprotein B, and triglyceride concentrations were also associated
with the progression of CAD. In regression analyses, small LDL size added to the effect of LDL cholesterol and
apolipoprotein B on the progression of CAD. Similar associations were observed in the fenofibrate group, whereas in
the placebo group, lipoprotein variables were not significantly correlated with the progression of CAD.
Conclusions—Changes in LDL size and plasma lipid levels account for part of the antiatherogenic effect of fenofibrate in
type 2 diabetes. (Circulation. 2003;107:1733-1737.)
Key Words: coronary disease 䡲 fenofibrate 䡲 diabetes mellitus 䡲 lipoproteins 䡲 angiography
C
particles are associated with other metabolic disturbances,
and their significance in atherogenesis is still under debate.
In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), treatment with gemfibrozil significantly
reduced recurrence of CAD events without a significant
reduction in serum LDL cholesterol (LDL-C) concentration.6
Further analyses have suggested that although the beneficial
effects of gemfibrozil in VA-HIT were significantly associated with an increase in HDL-C, only a portion of this benefit
could be explained by changes in total HDL-C concentration
or other traditional lipid parameters.7 The results of the
Diabetes Atherosclerosis Intervention Study (DAIS) showed
ardiovascular disease is the major cause of death in
diabetic patients, and the risk of cardiovascular morbidity and mortality is significantly higher in subjects with
diabetes compared with nondiabetic subjects.1 Hypercholesterolemia, hypertension, and other traditional risk factors of
atherosclerosis are also important in diabetic patients, but
they do not explain the excess risk in diabetes. Hypertriglyceridemia, low HDL cholesterol (HDL-C), and a preponderance of small LDL particles are typical features of dyslipidemia in subjects with type 2 diabetes. Several cross-sectional
and prospective studies have linked small, dense LDL to
coronary artery disease (CAD).2–5 However, small LDL
Received November 11, 2002; revision received December 31, 2002; accepted January 7, 2003.
From the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., M.-R.T.); the University Health Network, Toronto,
Canada (G.S.); Laboratories Fournier, Daix, France (J.-C.A., F.A., S.R., C.F.); and the Atherosclerosis Research Unit, King Gustaf V Research Institute,
Karolinska Hospital, Stockholm, Sweden (A.H.).
The Diabetes Atherosclerosis Intervention Study was funded by an unrestricted grant from Laboratoires Fournier S.A., Daix, France, which
manufactures fenofibrate. Drs Ansquer, Aubin, Rattier, and Foucher are full-time employees of Laboratoires Fournier S.A. Dr Taskinen has received
honoraria for speaking engagements from Laboratoires Fournier S.A. Dr Steiner has received grant and research support from Abbott, Fournier, Merck,
and AstraZeneca. The study was conducted independently by academic investigators.
Correspondence to Professor Marja-Riitta Taskinen, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 700, 00029 HUS, Helsinki, Finland. E-mail
[email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000057982.50167.6E
1733
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Circulation
April 8, 2003
The participants (n⫽405) divided into
tertiles of mean on-treatment lipoproteins
and final LDL size. The greatest progression of coronary atherosclerosis was
observed in subjects with small LDL particles and highest LDL-C, apoB, and triglyceride (TG) levels. Left, Mean changes
in percentage diameter stenosis according to tertiles of final LDL size and mean
on-treatment LDL-C concentrations. LDL
size (nm): small tertile, ⬍24.61; medium
tertile, 24.61 to 26.03; large tertile,
⬎26.03. LDL-C concentration (mmol/L):
low tertile, ⬍3.019; medium tertile, 3.019
to 3.646; high tertile, ⬎3.646. Middle, Mean changes in percentage diameter stenosis according to tertiles of final LDL size and mean
on-treatment apoB concentrations. LDL size (nm): small tertile, ⬍24.61; medium tertile, 24.61 to 26.03; large tertile, ⬎26.03. ApoB concentration (g/L): low tertile, ⬍0.986; medium tertile, 0.986 to 1.170; high tertile, ⬎1.170. Right, Mean changes in percentage diameter
stenosis according to tertiles of final LDL size and mean on-treatment TG concentrations. LDL size (nm): small tertile, ⬍24.61; medium
tertile, 24.61 to 26.03; large tertile, ⬎26.03. TG concentration (mmol/L): low tertile, ⬍1.514; medium tertile, 1.514 to 2.218; high tertile,
⬎2.218.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
that fenofibrate treatment is associated with significantly less
progression of focal CAD (40% less progression of minimum
lumen diameter versus placebo treatment, P⫽0.029; 42% less
progression in percentage diameter stenosis versus placebo
treatment, P⫽0.02) and improved the plasma lipid profile in
subjects with type 2 diabetes.8 Fenofibrate causes a shift
toward larger, more buoyant LDL particles,9,10 which is a
potentially antiatherogenic change. Therefore, we examined
whether changes in LDL particle size may contribute to the
favorable effect of fenofibrate on CAD progression in DAIS
participants.
Methods
Subject inclusion and exclusion criteria have been described.11
Briefly, patients were men and women with type 2 diabetes, 40 to 65
years old, with or without previous coronary intervention (coronary
artery bypass grafting or percutaneous transluminal coronary angioplasty). The lipid entry criteria were a total cholesterol/HDL-C ratio
of ⱖ4, plus either LDL-C 3.5 to 4.5 mmol/L and triglyceride
concentration of ⱕ5.2 mmol/L, or a triglyceride concentration of 1.7
to 5.2 mmol/L and LDL-C ⱕ4.5 mmol/L. Each physician was
allowed to adjust the glucose-lowering treatment to optimize metabolic control in the individual participant. Eligible patients were
randomly assigned to micronized fenofibrate or placebo for ⱖ3
years.8 The average time between baseline and final angiograms was
39.6 months. Progression of coronary artery atherosclerosis was analyzed by quantitative angiograms as described.8 The study was approved
by local ethics committees, and all participants gave their informed
consent.
Of the 418 patients randomized, 405 (207 placebo, 198 fenofibrate) patients had LDL size measurements at baseline and either at
the end of the study or after ⱖ1 year of treatment. Of the 405
patients, 379 had a final angiogram. For the 26 (12 placebo, 14
fenofibrate) patients with a missing final angiogram, “worst-case”
imputed angiographic parameters were used as described to permit
analysis by intention to treat.8 Two subjects in the fenofibrate group
and 4 subjects in the placebo group were excluded from analyses that
required on-treatment plasma apolipoprotein B (apoB) levels because of missing data.
Biochemical Analyses
Plasma total and HDL-C, total triglycerides, and apoB were measured as described.12 LDL-C was determined by the Friedewald
formula.13 LDL peak particle diameter (LDL size) was measured
from serum samples with polyacrylamide gradient gel electrophoresis as described,14 with slight modifications. Specifically, gels were
stained with Coomassie brilliant blue protein stain instead of Sudan
black lipid stain. All available values during the treatment period
were used to calculate mean on-treatment lipid levels. For the LDL
size, only the baseline and 1 on-treatment value (obtained at the end
of the study and referred to as “final LDL size”) were available.
Because plasma triglyceride level is the major determinant of LDL
size and the effect of fenofibrate on triglyceride levels was stable
during the whole treatment period, it is likely that the final LDL size
is a good measure of mean on-treatment LDL size.
Statistical Analyses
The between-groups comparison of on-treatment lipid parameters
and final LDL size was performed by use of ANCOVA with baseline
value, center, sex, and history of previous coronary intervention as
covariates. Pearson’s correlation coefficients were used to analyze
associations between absolute changes in LDL size and other
lipoprotein parameters and associations between mean on-treatment
lipids or final LDL size and absolute changes in angiographic
variables. Absolute changes in percentage diameter stenosis are
presented according to tertiles of final LDL size and mean ontreatment lipid concentrations for illustrative purposes (Figure). R2
and probability values are provided for multivariate regression
analysis on changes in percentage diameter stenosis versus ontreatment lipid parameters and final LDL size, which were used as
continuous variables. Plasma triglycerides were logarithmically
transformed before the analyses. Results are given as mean⫾SD. All
statistical analyses were done with SAS software (version 8.1). A
probability value of P⬍0.05 was considered statistically significant.
Results
Baseline characteristics are shown in Table 1. No significant
differences in age, body mass index, supine systolic and
diastolic blood pressure, fasting plasma glucose, and HbA1c
TABLE 1.
Baseline Characteristics
Total
(n⫽405)
Fenofibrate
(n⫽198)
Placebo
(n⫽207)
Male/female
298/107
144/54
154/53
Age, y
56.8⫾5.9
57.3⫾5.7
56.3⫾6.2
BMI, kg/m2
28.8⫾3.2
28.9⫾3.2
28.7⫾3.2
SBP, mm Hg*
140.4⫾18.1
140.3⫾18.8
140.4⫾17.5
DBP, mm Hg*
81.7⫾8.7
82.2⫾8.8
81.3⫾8.6
Fasting glucose, mmol/L
8.79⫾2.45
8.54⫾2.24
9.03⫾2.61
7.5⫾1.2
7.5⫾1.1
7.5⫾1.3
HbA1c, %
BMI indicates body mass index; SBP, systolic blood pressure; and DBP,
diastolic blood pressure.
*For SBP and DBP: n⫽400 (all), n⫽205 (placebo), n⫽195 (fenofibrate).
Vakkilainen et al
TABLE 2.
Small LDL and CAD Progression
1735
Baseline and On-Treatment Lipids and Lipoproteins
Placebo,
Baseline
(n⫽207)
Placebo,
On-Treatment/Final
(n⫽207)
Fenofibrate,
Baseline
(n⫽198)
Fenofibrate,
On-Treatment/Final
(n⫽198)
Fenofibrate,
Absolute Change*
Fenofibrate,
Percentage Change, %
TG, mmol/L
2.51⫾1.23
2.33⫾1.05
2.59⫾1.24
1.71⫾0.75§
⫺0.89⫾1.05
⫺27.8⫾28.9
TC, mmol/L
5.58⫾0.72
5.56⫾0.62
5.56⫾0.74
5.02⫾0.66§
⫺0.54⫾0.64
⫺9.0⫾11.2
LDL-C, mmol/L
3.39⫾0.72
3.45⫾0.67
3.37⫾0.69
3.16⫾0.54§
⫺0.21⫾0.62
⫺3.5⫾20.4
HDL-C, mmol/L
1.04⫾0.21
1.05⫾0.21
1.01⫾0.19
1.08⫾0.24§
0.07⫾0.14
7.5⫾14.3
ApoB, g/L†
1.14⫾0.17
1.13⫾0.18
1.16⫾0.18
1.03⫾0.22§
⫺0.13⫾0.21
⫺10.0⫾18.0
LDL-C/apoB, mmol/g†
LDL size, nm
3.02⫾0.49
3.04⫾0.55
2.94⫾0.48
3.09⫾0.38‡
0.14⫾0.45
6.9⫾16.6
24.76⫾1.12
25.07⫾1.21
24.69⫾1.10
25.66⫾1.17§
0.98⫾1.04
4.0⫾4.4%
TG indicates total triglycerides; TC, total cholesterol.
*Mean⫾SD of per-patient change from baseline in the fenofibrate group.
†n⫽203 (placebo) and n⫽196 (fenofibrate).
‡P⬍0.05, §P⬍0.001, for between-group comparison on final assessment using ANCOVA with baseline values as covariates and center, sex, and previous coronary
intervention as other sources of variation.
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were observed between the placebo and fenofibrate groups.
Fenofibrate did not have relevant effects on blood pressure or
glycemic control, as described.8 Baseline and mean ontreatment lipid assessments are shown in Table 2. Fenofibrate
treatment significantly increased LDL particle size and
HDL-C concentration and decreased plasma triglycerides,
total cholesterol, LDL-C, and apoB concentrations compared
with placebo. The absolute change in LDL size was related to
the plasma triglyceride concentration achieved by fenofibrate
treatment. In subjects in the lowest tertile of on-treatment
triglycerides (⬍1.275 mmol/L), the increase in LDL size was
1.19⫾0.93 nm, but in the highest tertile (⬎1.805 mmol/L), it
was only 0.69⫾1.05 nm. In the combined group, the change
in LDL size was significantly associated with changes in
plasma triglycerides (r⫽⫺0.56, P⬍0.0001), HDL-C (r⫽0.34,
P⬍0.0001), total cholesterol (r⫽⫺0.30, P⬍0.0001), apoB
(r⫽⫺0.31, P⬍0.0001), and LDL-C/apoB ratio (r⫽0.29,
P⬍0.0001) but not with the change in LDL-C concentration
(r⫽⫺0.03). These associations were also observed when fenofibrate and placebo groups were analyzed separately (not shown).
The relationships between plasma lipoproteins and angiographic changes are shown in Table 3. In the combined group
and in the fenofibrate group alone, the final LDL particle size
was inversely correlated with the increase in percentage
diameter stenosis and the decreases in mean and minimum
lumen diameter, indicating that the greatest progression of
atherosclerosis occurred in subjects with small LDL particles.
On-treatment apoB, total and LDL-C, and triglyceride concentrations showed positive correlations with the angiographic changes, indicating that the greatest progression of
atherosclerosis occurred in subjects with the highest levels of
these lipoproteins. Interestingly, in the placebo group, ontreatment lipoproteins were not significantly associated with
angiographic changes.
We performed multivariate regression analyses to analyze
the combined effects of LDL particle size and lipoprotein
concentrations on the progression of coronary atherosclerosis
(Table 4). Both on-treatment LDL-C concentration and final
LDL particle size, as well as on-treatment apoB concentration
and final LDL particle size, contributed significantly to the
progression of CAD in the combined group. Addition of
triglyceride and HDL-C did not significantly improve the
model, which is probably explained by the intercorrelations
between these variables and LDL size. These associations
were a result of the changes observed in the fenofibrate group
alone, whereas no such associations were observed in the
placebo group.
Progression of focal coronary atherosclerosis (increase in
percentage diameter stenosis) in the combined group is
illustrated in the Figure. The 405 subjects were divided into
tertiles of mean on-treatment lipoproteins. The greatest deterioration was observed in patients with the highest LDL-C,
apoB, and triglyceride levels. Importantly, LDL size modulated the progression of CAD so that subjects with small LDL
particles had more progression of atherosclerosis than those
with large LDL particles. Again, the effect of LDL size and
other lipoproteins was because of the fenofibrate group alone
and was not observed in the placebo group (not shown).
Discussion
The Diabetes Atherosclerosis Intervention Study was the first
intervention trial that examined whether the correction of
moderate dyslipidemia by fenofibrate reduces the progression
of CAD in subjects with type 2 diabetes. The main result was
that the subjects receiving fenofibrate had significantly less
progression of focal atherosclerosis than the subjects receiving placebo.8 We have now investigated the effect of fenofibrate on LDL particle size and other components of diabetic
dyslipidemia and their effect on CAD progression. Fenofibrate significantly increased LDL size and HDL-C concentration and decreased plasma triglyceride, total and LDL-C,
and apoB concentrations. The on-treatment lipid values
explained a significant but relatively small proportion of the
changes in the coronary angiograms.
Two smaller angiography trials have examined the associations of small, dense LDL and progression of coronary
atherosclerosis in subjects without diabetes. In the Familial
Atherosclerosis Treatment Study, colestipol-lovastatin and
colestipol-niacin treatments decreased hepatic lipase activity
and increased LDL buoyancy. The increase in LDL buoyancy
explained 37% of the variance in the change in coronary
stenosis.15 In contrast, in the Bezafibrate Coronary Athero-
1736
Circulation
April 8, 2003
TABLE 3. Univariate Correlation Analyses Between On-Treatment Lipid Parameters and Progression of Coronary Atherosclerosis in
Total, Fenofibrate, and Placebo Groups
Decrease in Mean Lumen Diameter
All
(n⫽405)
Fenofibrate
(n⫽198)
Placebo
(n⫽207)
Decrease in Minimum Lumen Diameter
Increase in Percentage Diameter Stenosis
All
(n⫽405)
Fenofibrate
(n⫽198)
Placebo
(n⫽207)
All
(n⫽405)
Fenofibrate
(n⫽198)
Placebo
(n⫽207)
⫺0.10†
⫺0.21†
0.00
⫺0.11†
⫺0.16†
⫺0.03
⫺0.16‡
⫺0.20‡
0.08
ApoB*
0.15‡
0.24§
0.05
0.14‡
0.23‡
0.03
0.18§
0.26§
0.06
TC
0.10
0.23‡
⫺0.05
0.12†
0.25§
⫺0.05
0.14‡
0.24§
0.00
LDL size
LDL-C
0.11†
HDL-C
⫺0.13‡
TG
LDL-C/apoB†
0.20‡
⫺0.12
0.10†
⫺0.05
0.22‡
⫺0.10
0.03
0.11†
⫺0.13
⫺0.11†
⫺0.02
⫺0.02
0.10†
⫺0.05
0.23‡
⫺0.07
0.15†
⫺0.04
0.00
0.11†
⫺0.13
⫺0.11†
0.00
⫺0.05
0.14‡
⫺0.09
0.18†
⫺0.08
0.21‡
⫺0.12
0.02
⫺0.13
0.02
⫺0.07
Abbreviations as in Table 2. Values represent Pearson correlation coefficients.
*n ⫽399 (all), n⫽196 (fenofibrate), n⫽203 (placebo).
†P⬍0.05, ‡P⬍0.01, §P⬍0.001.
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sclerosis Intervention Trial, on-trial LDL size was not correlated with the progression of atherosclerosis in coronary
angiograms, whereas on-trial HDL3 cholesterol and apoB
explained a small proportion of the changes.16 In the present
study, LDL size and plasma lipoprotein concentrations
showed a statistically significant association with the progression of coronary atherosclerosis. In addition, we found
support for the combined effect of small LDL particle size
and other dyslipidemias on the progression of atherosclerosis.
Notably, especially in subjects with low LDL-C or apoB
levels, a preponderance of small, dense LDL particles increased the progression of coronary atherosclerosis. These
results indicate that both the quality and the quantity of LDL
modulate the development of atherosclerosis. Thus, focusing
only on LDL-C concentration as a therapeutic target may be
misleading in these subjects. Potential mechanisms for increased atherogenicity of small, dense LDL include enhanced
inflow into the arterial wall,17 increased binding affinity to
arterial wall proteoglycans,18 decreased binding affinity to the
LDL receptor compared with mid-sized LDL particles,19 and
increased susceptibility to oxidative modification.20
Case-control studies with clinical end points have suggested
that small LDL size is a risk factor for clinical CAD before but
not after adjustment for other lipid variables.3,4 In the Québec
Cardiovascular Study, a prospective follow-up study of 2057
TABLE 4. Multivariate Regression Analysis of the Change in
Percentage Diameter Stenosis in Total (nⴝ405), Fenofibrate
(nⴝ198), and Placebo (nⴝ207) Groups
Model R 2
All
(n⫽405)
Fenofibrate
(n⫽198)
Placebo
(n⫽207)
LDL size and LDL-C
0.039§
0.073§
0.008
LDL size and apoB*
0.041§
0.078§
0.008
LDL size and HDL-C
0.026‡
0.041†
0.016
LDL size and TG
0.027‡
0.056‡
0.007
LDL size, LDL-C, apoB, HDL-C, TG*
0.044‡
0.082‡
0.021
Abbreviations as in Table 2.
*n ⫽399 (all), n⫽196 (fenofibrate), n⫽203 (placebo).
†P⬍0.05, ‡P⬍0.01, §P⬍0.001.
men, Lamarche et al5 recently showed that small LDL particles
increase the probability of developing ischemic heart disease.
The effect of small LDL was independent of other lipid and
nonlipid risk factors and additive to the effects of high LDL-C
and apoB level. To the best of our knowledge, our study shows
for the first time that increasing LDL particle size and decreasing
LDL-C and apoB levels by fenofibrate provides antiatherogenic
benefit in subjects with type 2 diabetes and therefore extends the
previous data. Further analysis of the Québec Cardiovascular
Study data showed that the calculated cholesterol concentration
in small LDL particles was superior to the LDL particle size in
predicting the ischemic heart disease risk.21 Because we used
protein and not lipid staining in measuring LDL size, we could
not conduct a similar analysis. However, our finding that small
LDL peak particle diameter (indicating increased proportion of
small LDL particles) and LDL-C concentration have a combined
effect in predicting the progression of coronary atherosclerosis
supports the idea that both the amount and the quality of LDL-C
are important risk factors for atherosclerosis. Interestingly, in the
Cholesterol and Recurrent Events (CARE) trial, large LDL
particle size at baseline was associated with increased risk of
recurrence of coronary events in the placebo group but not in the
pravastatin group.22 The participants of the CARE trial were
survivors of myocardial infarction, but it is uncertain whether
this could have an influence on the result.
We used quantitative coronary angiography to measure
progression of atherosclerosis. The method has good reproducibility, and it was the accepted standard for the assessment
of progression of CAD when DAIS was initiated.23 The
weaknesses of angiography include the fact that it visualizes
only vessel lumen diameter and not the size of the atheroma
in the vessel wall24 and that vascular remodeling decreases its
accuracy in measuring the progression of coronary atherosclerosis.25 It is therefore likely that the actual associations
between plasma lipoproteins and progression of atherosclerosis are stronger than those found by us and others.16,26,27
The associations between plasma lipoprotein levels and
progression of CAD were observed only in subjects assigned
to fenofibrate but not in those assigned to placebo, which
diluted the findings in the combined group. The data imply
that significant changes in plasma lipoproteins must be
Vakkilainen et al
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obtained to decrease the progression of atherosclerosis. In a
recent follow-up study, LDL-C and C-reactive protein, a
marker of inflammation, had additive power in predicting
future cardiovascular events.28 Fibrates have antiinflammatory and plaque-stabilizing effects in addition to the lipidlowering effect.29 It is possible that these nonlipid actions
increase the clinical benefit of fibrates even beyond the
decreased progression of atherosclerosis that was detected in
DAIS. Our preliminary data suggest, however, that fenofibrate did not significantly influence serum C-reactive protein
levels (Hamsten et al, unpublished data). This implies that
lipoprotein levels are more important than markers of inflammation in predicting the progression of atherosclerosis measured with angiography. The results of larger trials, such as
the Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) trial,30 have to be awaited before the clinical benefit
of the nonlipid actions of fibrates can be determined.
We conclude that treatment with fenofibrate has a favorable
effect on the plasma lipid profile and reduces the progression of
coronary atherosclerosis. Changes in LDL size and plasma lipid
levels account for at least part of the beneficial action of
fenofibrate. Small LDL particles increase the atherogenicity of
hyperlipidemia in subjects with type 2 diabetes.
Acknowledgments
This study was financed in part by Laboratories Fournier, the
Helsinki University Central Hospital Research Foundation, the
Biomedicum Research Foundation, and the Aarne and Aili Turunen
Foundation. We thank Helinä Perttunen-Nio for the measurement of
LDL particle sizes.
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Relationships Between Low-Density Lipoprotein Particle Size, Plasma Lipoproteins, and
Progression of Coronary Artery Disease: The Diabetes Atherosclerosis Intervention Study
(DAIS)
Juha Vakkilainen, George Steiner, Jean-Claude Ansquer, Francois Aubin, Stephanie Rattier,
Christelle Foucher, Anders Hamsten and Marja-Riitta Taskinen
on behalf of the DAIS Group
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Circulation. 2003;107:1733-1737; originally published online March 24, 2003;
doi: 10.1161/01.CIR.0000057982.50167.6E
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