Management of

Hypertriglyceridemia
Sponsored by
ACCESS Medical Group
Department of Continuing Medical Education
Funded by an unrestricted educational grant from Abbott Laboratories.
2001 ACCESS Medical Group

Atherosclerosis
Prevention Trials

The Pyramid of Recent Trials

Relative Size of the Various Segments of the Population
4S
Very high cholesterol with
CHD or MI

LIPID

Moderately high cholesterol in

high risk CHD or MI
CARE
Normal cholesterol with
CHD or MI
WOSCOP
High cholesterol
without CHD or MI
AFCAPS/TexCAPS
No history of CHD or MI

4S: Evaluating Lowering

Cholesterol on Coronary Events
Patients with CHD and Hypercholesterolemia

Baseline total cholesterol levels: 210-310 mg/dL

High-risk group (high LDL, prior MI or angina)
Reduction of LDL levels: 35%
Reduction of major coronary events: 34%
Reduction of total mortality: 30%
End of the cholesterol controversy
4S Group. Lancet. 1994;344:1383-1389.

Coronary Events Defined

by Baseline LDL-C
Variable
LDL-C
125
mg/dL
125-150
mg/dL
150-175
mg/dL

N Patients

N (%) Patients with event

Change in Risk

Placebo

Pravastatin

Placebo

441

410

93 (21)

89 (22)

+3%

1172

1183

311 (27)

239 (20)

-26%

465

488

145 (31)

102 (21)

-35%

Pravastatin

95% (CI)

No risk reduction in patients with LDL levels under 125 mg/dL.

CARE suggests a lower boundary for a clinically

important influence of the LDL level on CHD.
Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

Reduction in LDL Cholesterol

1,2,3
and Coronary Events
Percent Reduction

0
-10

LDL
-20

Coronary
Events

-30
-40
-50
4S

WOSCOPS

Helsinki

1. 4S Group. Lancet. 1994;344:1383-1389. 2. WOSCOPS Group. Circulation. 1998;97:1440-1445.

3. Frick MH, et al. N Engl J Med. 1987;317:1237-1245.

Lowering cholesterol is effective and

safe in hypercholesterolemic patients
with evidence of CHD and leads to a
reduction in coronary events.

4S Group. Lancet. 1994;344:1383-1389.

LDL Reduction and CHD Risk

The latest studies have confirmed the positive correlation
between CAD risk and lowering cholesterol
LDL reduction in primary and secondary prevention can
significantly reduce clinical cardiac events
It can also significantly reduce the rate of
arteriographically defined disease progression

However, elevated LDL is only one of several factors

contributing to CAD risk

Beyond
LDL

Beyond LDL Reduction

There is something more than LDL
Control Group
Clinical Events

Treatment Group
Clinical Events

4S

622 (28.0%)

431 (19.4%)

30.6%

WOSCOPS

248 (7.5%)

174 (5.3%)

31.0%

Study

% Reduction
Clinical Events

Such a large number of poor responders implicates factors other

than just LDL in the development or progression of CHD (ie, low
HDL, small, dense LDL, fibrinogen, Lp(a), triglycerides)
Aggressively treating other important risk factors, such as low
HDL, may further benefit patients
Superko HR. Circulation. 1996;94:2351-2354.

CHD Risk Factors Beyond LDL

Triglycerides
HDL
Small, dense LDL
Apo CIII
Lp(a)
Homocysteine
Fibrinogen

The Role of

Triglycerides
as a CHD Risk Factor

Possible Atherogenic Changes

Accompanying Hypertriglyceridemia
Increased VLDL
cholesterol-rich
remnants

Low HDL

Small,
dense LDL

Hypertriglyceridemia

Coagulation
changes

Increased
chylomicron
remnants
Miller M. Eur Heart J. 1998;19(Suppl H):H18-H22.

Development of Hypertriglyceridemia
Chylomicron

VLDL

Liver

Defective
Lipolysis
Remnants
Intestine
Miller M. University of Maryland, unpublished data, 1998.

Risk of CHD by Triglyceride Level

(The Framingham Heart Study)
N=5127

3
Men

Relative Risk

2.5

Women

2
1.5
1
0.5
0
50

100

150
200
250
300
Triglyceride Level (mg/dL)

350

400

Castelli WP. Am J Cardiol. 1992;70: 3H-9H.

The Copenhagen Male Study

2906 white men

Age range: 53-74 years
Initially free of overt cardiovascular disease
8-year follow-up period
229 men had first IHD event
Triglyceride tertile cut points: 96.6 mg/dL and 141.8 mg/dL
Crude cumulative incidence rates of IHD: 4.6% for lowest,
7.7% for middle, 11.5% for highest third (for the trend,
P<0.001)
Jeppesen J, et al. Circulation. 1998;97:1029-1036.

The Copenhagen Male Study

Adjusted IHD Incidence Rates
N=2906
Compared With Lowest Tertile

2.5
Adjusted for
Age
Body mass index
Alcohol use
Smoking
Physical activity
Hypertension
NIDDM
Social class
LDL
HDL

2
1.5
1
0.5
0
Lowest

Middle

Highest

Tertile of Triglyceride Level

Jeppesen J, et al. Circulation. 1998;97:1029-1036.

Event Free Survival (%)

Baltimore Coronary Observational Long-Term Study

Triglycerides Compared With Survival Rates
TG <100 mg/dL (n=114)
TG >100 mg/dL (n=236)
P=0.008

Time (mo) Following 1977-78 Coronary Arteriogram

Miller M, et al. J Am Coll Cardiol. 1998;31:1252-1257.

Distribution of Adjusted Plasma Triglycerides

LDL Phenotype A and B

Cumulative Percent
Frequency

Phenotype A
Phenotype B

Triglyceride (mg/dL)
Austin M, et al. Circulation. 1990;82:495-506.

Increase in CVD Risk

Due to High Triglycerides
(Univariate Analysis)
100%
80%

75%

60%
40%
20%
0%

30%
Men
n=46,413

Women
n=10,864

Relative risks and 95% CI calculated and standardized with respect to a

1 mmol/L increase in triglyceride.
Hokanson JE, et al. J Cardiovasc Risk. 1996;3(2):213-219.

The Role of

HDL-Cholesterol
as a CHD Risk Factor

HDL: A Major Risk Factor for CHD

A low plasma HDL is an important risk factor for
CHD in the general population
A high level of HDL may confer cardioprotection
Reverse cholesterol transport by HDL may be the
principle cardioprotective mechanism
On average, a 10% decrease in CHD risk occurs for
each increase of 4 mg/dL in the HDL level.
The ILIB Lipid Handbook for Clinical Practice. 1995:26.

HDL: Major Factor

in Predicting Reduced CAD
N=4407

Incidence of CHD (per

1000 in 6 years)

120
100
80
60
40
20
0

<35

35 - 55
HDL-cholesterol (mg/dL)

>55

Assmann G, et al. Atherosclerosis. 1996;124(suppl):S11-S20.

HDL Predictive Value

(The Framingham Heart Study)
Men and women without CHD history

Incidence
(% in 4 years)

15
10
>260
)
L
231-260
d
g/
m
200-230
l(
o
r
<200
ste

5
0

<40

40-49

50-59

HDL-cholesterol (mg/dL)

>59

tal
o
T

le
o
-c h

Castelli WP. JAMA. 1986;256(20):2835-2838.

LDL and HDL Impact on CHD Risk

A Compounded Rather Than Additive Impact

Incidence per
1000 (in 6 years)

400
300

>195

200

155-195
135-154

100
0

<135
<35

35-55

>55

HDL-cholesterol (mg/dL)

LD

st
e
l
o
-ch

(m
l
e ro

)
L
d
g/

Assmann G, et al. Atherosclerosis. 1996;124(suppl):S11-S20.

HDL in Clinical Practice

Routinely measured in all adult patients
HDL-C <35 mg/dL is a major risk factor
Nonpharmacologic therapy (exercise, weight
loss, smoking cessation)
Pharmacologic therapy
Consider drug therapy that lowers LDL-C and
also increases HDL-C levels.
Expert Panel. JAMA. 1993;269:3015-3023.

The Role of

Small, Dense LDL

as a CHD Risk Factor

Small, Dense LDL

Dangerous: Small, dense LDL trait increases

heart disease risk up to three fold

Common: 40% to 50% of men with heart disease
have small, dense LDL
Measurable: Tests are now available to physicians
Treatable: Approaches can involve lifestyle
changes and/or drugs
The ILIB Lipid Handbook for Clinical Practice. 1995:26.
Austin MA, et al. JAMA. 1988;260(13):1917-1921.

Atherogenicity of Small, Dense LDL

Endothelial
Chemoattractants

LDL

Monocyte

Endothelium

Macrophage

LDL
Mildly oxidized

Macrophage

Smooth Muscle
Cell

Foam Cell
Highly oxidized

Evidence from in vitro studies suggests that large, buoyant LDL particles are more
resistant to oxidative stress and small, dense LDL particles more susceptible to oxidation.

Small, Dense LDL and Drug Therapy

In a trial measuring the effects of simvastatin on ApoB
metabolism and LDL subfraction distribution, it was found
that small, dense LDL were not significantly affected.
Gaw A, et al. Arterioscler Thromb. 1993;13:170-189.

In a study investigating the ability of pravastatin to affect

small, dense LDL, it was found that although this agent
favorably altered total cholesterol and LDL levels, the
abnormal LDL particle distribution and composition were not
affected.
Franceschini G, et al. Arterioscler Thromb. 1994;14:1569-1575.

The Role of

Fibrinogen
as a CHD Risk Factor

Elevated Plasma Fibrinogen

A Major, Independent Cardiovascular Risk Factor
Epidemiological studies
Cross-sectional analyses
Clinical cohort studies
There is a sizeable body of evidence identifying
fibrinogen as a major, independent cardiovascular
risk factor
Ernst E, et al. Eur Heart J. 1995;16(supplA):47-53.

Fibrinogen and Atherosclerosis

N=652 men

Presence or Absence
of Plaque

100%
Present

80%

Absent
60%
40%
20%
0%
Lower

Middle

Upper

Levenson J, et al. Arterioscler Thromb Vasc Biol. 1995;15:1263-1268.

Effects of Lipid-Lowering Agents

on Fibrinogen
Change in Fibrinogen (%)

30

20

20
10

0
-10

-10

-20
-30

-16
Diet*

Feno**

Beza**

Gem**

Simva*

Prava*

*Not significant
**P<0.01

Branchi A, et al. Thromb Haemost. 1993;70:241-243.

Fibrate Clinical Overview

Fibrates
O
Fenofibrate

Cl

CH3

CH3

O C

COO CH

CH3

CH3

H3C

Bezafibrate

OH
CH3

N
H
Cl
CH3

Gemfibrozil

O
CH3

CH3
CH2 CH2

CH2 CH2

C
CH3

COOH

Metabolic Action of Fibrates

Chylomicrons

Liver
Apo E
Apo C-III
FFA

VLDL
Lipoprotein
lipase

IDL
Apo C-II
Apo C-III

Packard CJ. Eur Heart J. 1998;19(suppl A):A62-A65.

Metabolic Action of Fibrates

The Peroxisome Proliferator Activator Receptor (PPAR)
Fibrate
Nucleus
PPAR

HNF-4 +ve factor

C3P

CIII Gene

Plasma Apo C-III

60%

Apo E/Apo C-III

Packard CJ. Eur Heart J. 1998;19(suppl A):A62-A65.

Mechanisms of Action of Fibrates

Inhibit triglyceride synthesis; reduces VLDL release into circulation
Increase lipoprotein lipase activity, which catabolizes chylomicrons
and VLDL
Increase catabolism of triglyceride-rich VLDL, thereby lowering
serum VLDL levels
Increase HDL through improved Apo A-I and Apo A-II synthesis

Fibrate

.
.......
.....
.
.
....

Serum VLDL
(Triglyceride-rich)

Lowered Serum VLDL

(Reduced triglycerides)

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study
Fenofibrate
Group A
Before
After
Percent
(350-499 mg/dL)

(mean SE)

( mean SE)

Changes*

Total cholesterol

251.8 5.3

227.4 6.7

-9.1

<0.001

VLDL-cholesterol

92.1 6.8

45.8 4.5

-44.7

<0.001

LDL-cholesterol

128.4 7.1

136.7 5.3

NS

0.8570

HDL-cholesterol

33.7 1.1

40.3 1.9

+19.6

0.0014

Total triglyceride

432.0 19.1

223.4 13.9

-46.2

<0.001

VLDL-triglyceride

349.8 34.3

177.8 24.6

-44.1

<0.001

*These are mean percentage changes, not percentage changes in means.

NS=Not statistically significant when compared with placebo (12% increase).

Goldberg AC, et al. Clin Ther. 1989;11:69-83.

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study
Fenofibrate
Before
After
Percent
Group B
(500-1500 mg/dL)

(mean SE)

( mean SE)

Changes*

Total cholesterol

261.0 6.7

223.3 6.6

-13.8

0.0001

VLDL-cholesterol

126.2 7.0

53.7 3.4

-49.4

0.0001

LDL-cholesterol

103.1 6.8

131.0 6.0

+45.0

0.0002

HDL-cholesterol

29.6 1.3

36.0 1.8

+22.9

0.0029

Total triglyceride

725.6 37.4

308.0 19.9

-54.5

0.0001

VLDL-triglyceride

543.3 50.8

204.7 23.0

-50.6

0.0001

*These are mean percentage changes, not percentage changes in means.

Goldberg AC, et al. Clin Ther. 1989;11:69-83.

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study

Many patients with markedly elevated triglycerides have

reduced LDL levels because of a derangement in the normal
composition of LDL
This derangement produces a triglyceride-rich and
cholesterol-depleted LDL
When triglycerides are reduced with therapy, the
composition of LDL normalizes; this change can elevate
LDL levels
Goldberg AC, et al. Clin Ther. 1989;11:69-83.

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study

Total Triglyceride - Group B

% Change from Baseline

20
10
0
-10
-20

Placebo

-30

Fenofibrate

-40
-50
-60
0

4
Week of Treatment

Goldberg AC, et al. Clin Ther. 1989;11:69-83.

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study

HDL-C - Group B
% Change from Baseline

30
25
20
15
10
5
0

Placebo
Fenofibrate

-5
-10
0

Week of Treatment
Goldberg AC, et al. Clin Ther. 1989;11:69-83.

Fenofibrate for the Treatment of

Type IV and V Hyperlipoproteinemias
A Double-Blind, Placebo-Controlled Multicenter US Study

[F]enofibrate is both safe and effective in the

treatment of primary type IV and V
hyperlipoproteinemias in patients in whom
dietary modifications have proved ineffective
in reducing plasma triglycerides.

Goldberg AC, et al. Clin Therapeut. 1989;11:69-83.

Effects of Fenofibrate on Plasma Lipids

Double-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia

Variable
Sample Size (n)

Age (yr SD)

Weight (lbs SD)
Sex (n)
Male
Female
Race (n)
Caucasian
Black
Hispanic
Other
Hyperlipoproteinemia (n)
Type IIa
Type IIb

N=227

Fenofibrate

Placebo

116

111

52.0 0.96
165.1 2.48

51.7 0.97
164.9 2.49

82
34

71
40

104
6
0
6

98
9
2
2

92
24

89
22

Brown WV, et al. Arteriosclerosis. 1986;6:670-678.

Effects of Fenofibrate on Plasma Lipids

Double-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia
Percentage Changes at Endpoint from Baseline Values after 24 Weeks of
Double Blind Study vs Placebo (Plb)
Type IIa (%)

Type IIb (%)

Feno

Plb

Feno

Plb

n=92

n=88

n=24

n=22

Total Cholesterol

-17.5

-0.4

-15.8

+4.6

LDL Cholesterol

-20.3

+0.4

-6.1

-0.5

HDL Cholesterol

+11.1

-1.2

+15.3

-3.5

Total Triglycerides

-37.9

-4.2

-44.6

+22.3

LDL/HDL Cholesterol

-27.1

-1.9

-13.3

0.0

VLDL Cholesterol

-38.4

-2.5

-52.7

+8.4

P<0.01 except for LDL-C in Type IIb, where P>0.10

Brown WV, et al. Arteriosclerosis. 1986; 6:670-678.

Effects of Fenofibrate on Plasma Lipids

Double-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia
Mean LDL Plasma Cholesterol Concentration
Type IIa

Mean Concentration (mg%)

Double-Blind Period
Placebo

230
210
190

Fenofibrate

170
150
0

12

18

24

Weeks on Study Medication

Brown WV, et al. Arteriosclerosis. 1986;6:670-678.

Effects of Fenofibrate on Plasma Lipids

Double-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia
Mean LDL Plasma Cholesterol Concentration
Type IIb
Double-Blind Period
Mean Concentration (mg%)

210

Placebo

200
190
180

Fenofibrate

170
160
150
0

12

18

24

Weeks on Study Medication

Brown WV, et al. Arteriosclerosis. 1986;6:670-678.

Comparative Efficacy and Safety of Micronized

Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
Study Design
Single-center, Double-blind, Crossover Trial
60 Patients (32 type IIa and 28 type IIb)
Randomized to treatment for 3 months
Single daily dose of fenofibrate 200 mg or simvastatin
20 mg
Changed to alternative treatment for a further 3 months
Farnier M, et al. Arch Int Med. 1994;154:441-449.

Comparative Efficacy and Safety of Micronized

Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
(Randomized, Crossover Study)

Group 1

Fenofibrate
200 mg/day

Simvastatin
20 mg/day

Type IIa, n=16

Type IIb, n=14

Group 2

Simvastatin
20 mg/day
I
I

Fenofibrate
200 mg/day
I
I

Type IIa, n=16

Type IIb, n=14

I
0

I
3
Months

I
6

Farnier M, et al. Arch Int Med. 1994;154:441-449.

Comparative Efficacy and Safety of Micronized

Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
Characteristic

Fenofibrate

Simvastatin

Sample Size (n)

30

30

41.5 11.4
149.6 23.5

46.1 10.2
159.1 27.9

16
14

21
9

16
14
315 50
234 48
50 18
1.82 1.19

16
14
323 45
241 50
48 11
1.91 1.17

Age (yr SD)

Weight (lbs SD)
Sex (n)
male
female
Hyperlipoproteinemia (n)
Type IIa
Type IIb
Total Cholesterol (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
Triglyceride (mmol/L)

Farnier M, et al. Arch Int Med. 1994;154:441-449.

Fenofibrate Versus Simvastatin

Effect on Overall Lipid Profile
(Type IIa)
NC NC

% Change from Baseline

NC

-10
-20
-30

-28 -28
-34

-40
-50

-36

Total-C
NC=No change

LDL-C

Fenofibrate
Simvastatin

HDL-C

-37
Trig

Farnier M, et al. Arch Int Med. 1994;154:441-449.

Fenofibrate Versus Simvastatin

Effect on Overall Lipid Profile
(Type IIb)
45
% Change from Baseline

30

Fenofibrate
Simvastatin

29
18

17

15
0
-15
-30

-23 -21

-25 -30

-45
-60

-52
Total-C

LDL-C

HDL-C

Trig

Farnier M, et al. Arch Int Med. 1994;154:441-449.

Fenofibrate and Plaque Regression

21 Patients with CHD had 98 narrowings
Mean duration of follow-up: 21 months (range
12 to 36 months)
Comparison with a similar untreated group of
21 patients with CHD presenting 98
narrowings
Quantitative coronary angiography (QCA)
Hahmann HW, et al. Am J Cardiol. 1991;67: 957-961.

Fenofibrate and Plaque Regression

70

Regression
Stabilization
Progression

Percent Patients

60
50
40
30
20
10
0
Fenofibrate

Untreated
Hahmann HW, et al. Am J Cardiol. 1991;67:957-961.

Micronized Fenofibrate
A Comprehensive Profile
N=1545 patients
45
Normal
High Risk*

Percent Change

30
15
0
-15
-30
TC

LDL

HDL

Fibrinogen

*High risk: TC 250 mg/dL, LDL 185 mg/dL, HDL 35 mg/dL, fibrinogen 300
mg/dL

Kornitzer M, et al. Atherosclerosis. 1994;110(suppl):S49-S64.

LDL Profile of Fenofibrate

60%
40%

Change

20%
0%
-20%
-40%
-60%

Total
Cholesterol

LDL-C

LDL Receptor
Uptake

Large,
Buoyant LDL

Small, Dense
LDL

Caslake MJ, et al. Arterioscler Thromb. 1993;13:702-711.

The Helsinki Heart Study

A 5-year trial that tested the efficacy of gemfibrozil for
decreasing the risk of coronary artery disease in
hypercholesterolemic men without coronary artery disease
The study involved 4081 men (40 to 55 years of age) with a
non-HDL cholesterol level >200 mg/dL
Gemfibrozil use was associated with a 34% reduction in
coronary artery events

Frick MH, et al. N Engl J Med. 1987:317:1237-1245.

Veterans Affairs High-Density Lipoprotein

Cholesterol Intervention Trial (VA HIT)
Study Design
Double-blind trial that compared gemfibrozil (1200 mg/day)
with placebo
Study of 2531 men with coronary heart disease, high-density
lipoprotein cholesterol levels 40 mg/dL, and low-density
lipoprotein cholesterol levels 140 mg/dL
The primary outcome was nonfatal myocardial infarction or
death from coronary causes

Rubins HB, et al. N Engl J Med. 1999;341:410-418.

The Veterans Affairs High-Density Lipoprotein Cholesterol

Intervention Trial (VA HIT): Baseline Characteristics
Characteristic

Placebo
(N=1267)

Gemfibrozil
(N=1264)

Age (yr)
Age >60 years (%)
Prior MI (%)
Time since MI (yr)
Diabetes (%)
Hypertension (%)
Low-density lipoprotein, mg/dL (mean)
High-density lipoprotein, mg/dL (mean)

64 7
77
61
66
25
57
112 23
32 5

64 7
76
61
66
24
57
111 22
32 5

Triglycerides, mg/dL (mean)

160 67

161 68

Rubins HB, et al. N Engl J Med. 1999;341:410-418.

% With Death, Myocardial

Infarction, or Stroke

The Veterans Affairs High-Density Lipoprotein Cholesterol

Intervention Trial (VA HIT) Results

30
25

20
15

* Risk reduction =
24% (P<0.001)

10
5
0

Placebo

Gemfibrozil

Rubins HB, et al. N Engl J Med. 1999;341:410-418.

The Veterans Affairs High-Density Lipoprotein

Cholesterol Intervention Trial (VA HIT): Summary
VA HIT compared treatment with gemfibrozil or placebo in
2531 men with coronary heart disease and low levels of
high-density lipoprotein cholesterol
There was a 24% reduction in risk of nonfatal myocardial
infarction, stroke, or death due to CHD in the group who
received gemfibrozil (P<0.001)
The findings suggest that the rate of coronary events is
reduced by raising HDL and lowering triglycerides without
lowering LDL
Rubins HB, et al. N Engl J Med. 1999;341:410-418.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Protocol
Double-blind, randomized, placebo-controlled angiographic study using
200 mg/day micronized fenofibrate
Population

305 men, 113 women, 40 to 65 years of age

Subjects had type 2 diabetes with good glycemic control, and at least one
visible coronary lesion
Mild dyslipoproteinemia typically seen in type 2 diabetes
Half of subjects had no previous clinical coronary disease
Treatment period at least 3 years
Primary Aim
To determine by quantitative angiography whether correcting lipid
abnormalities with fenofibrate in type 2 diabetes alters the progression of
coronary artery disease

Steiner G. Diabetologia. 1996;39:1655-1661.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Baseline Clinical Characteristics
Placebo
(n=211)

Fenofibrate
(n=207)

Demographics
Age (years SD)
Women (%)
Current smokers (%)

56 6
26
16

57 6
28
14

48
140 18
81 9

55
140 19
82 9

47
30

48
32

Blood pressure
History of Hypertension (%)
Systolic (mm Hg SD)
Diastolic (mm Hg SD)

Coronary Disease
History of CAD (%)
Prior intervention (%)

DAIS Investigators. Lancet. 2001;357:905-910.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Angiographic Changes from Baseline
%
Change
4.00

mm

Progression of CAD

-0.10

mm
-0.10

-42%

-40%

-0.08

-25%
-0.08

-0.06

-0.06
2.00

-0.04

-0.04
P = 0.020

P = 0.029

-0.02

-0.02

0.00

0.00

Minimum Lumen
Diameter
Placebo
Fenofibrate

P = 0.171

0.00

Percent Stenosis

Mean Segment
Diameter

DAIS Investigators. Lancet. 2001;357:905-910.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Combined Clinical Endpoints

Event Rate (%)

25

-23%*

20
15
10

Participants with at least

one clinical or
interventional endpoint,
including death, stroke,
MI, CABG, PTCA, and
hospitalization for
angina.

5
0

Placebo

Fenofibrate

* DAIS was not powered to examine clinical events. Even though the
results suggest a trend, they were not statistically significant.
DAIS Investigators. Lancet. 2001;357:905-910.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Clinical Implications

DAIS assessed the effects on coronary atherosclerosis of

correcting lipoprotein abnormalities in patients with type 2 diabetes

The study found that treatment with fenofibrate reduced the

angiographic progression of coronary artery disease in men and
women with type 2 diabetes; this effect was related, at least in part,
to the correction of lipoprotein abnormalities

DAIS findings suggest that people with type 2 diabetes should

have lipoproteins measured at diagnosis and annually thereafter

Existing evidence suggests that any lipoprotein abnormality should

be corrected, even if small, to reduce the risk of coronary disease
in patients with type 2 diabetes
DAIS Investigators. Lancet. 2001;357:905-910.

The Diabetes Atherosclerosis Intervention Study (DAIS)

Comparison to Clinical Trials With Diabetic Patients
Study

Agent

Event
Reduction

DAIS

Fenofibrate

23%

NS

CARE

Pravastatin

25%

0.05

LIPID

Pravastatin

19%

NS

VA HIT

Gemfibrozil

24%

<0.001

P Value

NS = Not statistically significant

DAIS Investigators. Lancet. 2001;357:905-910.