management of hypertriglyceridemia sponsored by access medical group department of continuing...
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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
4S
CARE
WOSCOP
Relative Size of the Various Segments of the Population
AFCAPS/TexCAPS
LIPID
Very high cholesterol with CHD or MI
Moderately high cholesterol in high risk CHD or MI
Normal cholesterol with CHD or MI
High cholesterol without CHD or MI
No history of CHD or MI
4S: Evaluating LoweringCholesterol on Coronary Events
• 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%
Patients with CHD and Hypercholesterolemia
End of the cholesterol controversy4S Group. Lancet. 1994;344:1383-1389.
Coronary Events Definedby Baseline LDL-C
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.
Change in RiskVariable N Patients N (%) Patients with event
LDL-C Placebo Pravastatin PravastatinPlacebo 95% (CI)
125-150 mg/dL
150-175 mg/dL
125 mg/dL
441
1172
465
410
1183
488
93 (21)
311 (27)
145 (31)
89 (22)
239 (20)
102 (21)
+3%
-26%
-35%
No risk reduction in patients with LDL levels under 125 mg/dL.
Reduction in LDL Cholesteroland Coronary Events1,2,3
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.
-50
-40
-30
-20
-10
0
4S WOSCOPS Helsinki
LDL
CoronaryEvents
Perc
ent R
educ
tion
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 in primary and secondary prevention can significantly reduce clinical cardiac events
• It can also significantly reduce the rate of arteriographically defined disease progression
LDL Reduction and CHD RiskThe latest studies have confirmed the positive correlation
between CAD risk and lowering cholesterol
However, elevated LDL is only one of several factors contributing to CAD risk
BeyondLDL
Beyond LDL ReductionThere is something more than LDL
• 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.
StudyControl GroupClinical Events
Treatment GroupClinical Events
% Reduction Clinical Events
622 (28.0%)
248 (7.5%)
431 (19.4%)
174 (5.3%) 31.0%
30.6%4S
WOSCOPS
CHD Risk Factors Beyond LDL
• Triglycerides
• HDL
• Small, dense LDL
• Apo CIII
• Lp(a)
• Homocysteine
• Fibrinogen
The Role of
Triglyceridesas a CHD Risk Factor
Possible Atherogenic Changes Accompanying Hypertriglyceridemia
Hypertriglyceridemia
Increasedchylomicron
remnants
Small,dense LDL
Coagulationchanges
Increased VLDL cholesterol-rich
remnantsLow HDL
Miller M. Eur Heart J. 1998;19(Suppl H):H18-H22.
Development of Hypertriglyceridemia
Liver
VLDLChylomicron
Intestine
DefectiveLipolysis
Remnants
Miller M. University of Maryland, unpublished data, 1998.
Risk of CHD by Triglyceride Level(The Framingham Heart Study)
N=5127
Castelli WP. Am J Cardiol. 1992;70: 3H-9H.
0
0.5
1
1.5
2
2.5
3
50 100 150 200 250 300 350 400
Men Women
Rel
ativ
e R
isk
Triglyceride Level (mg/dL)
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 StudyAdjusted IHD Incidence Rates
N=2906
Jeppesen J, et al. Circulation. 1998;97:1029-1036.
Adjusted for• Age• Body mass index• Alcohol use• Smoking• Physical activity• Hypertension• NIDDM• Social class• LDL• HDL
0
0.5
1
1.5
2
2.5
Lowest Middle Highest
Com
pare
d W
ith
Low
est T
erti
le
Tertile of Triglyceride Level
Baltimore Coronary Observational Long-Term StudyTriglycerides Compared With Survival Rates
Eve
nt F
ree
Surv
ival
(%
)
Time (mo) Following 1977-78 Coronary Arteriogram
TG <100 mg/dL (n=114)TG >100 mg/dL (n=236)P=0.008
Miller M, et al. J Am Coll Cardiol. 1998;31:1252-1257.
Cum
ulat
ive
Perc
ent
Freq
uenc
y
Triglyceride (mg/dL)
Phenotype A
Phenotype B
Austin M, et al. Circulation. 1990;82:495-506.
Distribution of Adjusted Plasma TriglyceridesLDL Phenotype A and B
Increase in CVD RiskDue to High Triglycerides
(Univariate Analysis)
0%
20%
40%
60%
80%
100%
Men Womenn=46,413 n=10,864
30%
75%
Hokanson JE, et al. J Cardiovasc Risk. 1996;3(2):213-219.
Relative risks and 95% CI calculated and standardized with respect to a1 mmol/L increase in triglyceride.
The Role of
HDL-Cholesterolas 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 Factorin Predicting Reduced CAD
0
20
40
60
80
100
120
<35 35 - 55 >55
HDL-cholesterol (mg/dL)
Inci
denc
e of
CH
D (
per
1000
in 6
yea
rs)
Assmann G, et al. Atherosclerosis. 1996;124(suppl):S11-S20.
N=4407
HDL Predictive Value(The Framingham Heart Study)
0
5
10
15
<40 40-49 50-59 >59
<200200-230
231-260>260
Men and women without CHD history
HDL-cholesterol (mg/dL) Total-ch
olester
ol (mg/dL)
Inci
denc
e (%
in 4
yea
rs)
Castelli WP. JAMA. 1986;256(20):2835-2838.
LDL and HDL Impact on CHD RiskA Compounded Rather Than Additive Impact
0
100
200
300
400
<35 35-55 >55
<135
135-154
155-195
>195
HDL-cholesterol (mg/dL)LDL-ch
olester
ol (mg/dL)
Inci
denc
e pe
r10
00 (
in 6
yea
rs)
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 LDLas 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
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.
EndothelialChemoattractants
Foam Cell
Highly oxidizedSmooth Muscle
Cell
Mildly oxidized
Macrophage
LDL
LDL
Endothelium Monocyte
Macrophage
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
Fibrinogenas a CHD Risk Factor
Elevated Plasma FibrinogenA 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 AtherosclerosisN=652 men
0%
20%
40%
60%
80%
100%
Lower Middle Upper
Present
Absent
Pres
ence
or
Abs
ence
of P
laqu
e
Levenson J, et al. Arterioscler Thromb Vasc Biol. 1995;15:1263-1268.
Effects of Lipid-Lowering Agents on Fibrinogen
1
-16
-10
20
40
-30
-20
-10
0
10
20
30
Diet* Feno** Beza** Gem** Simva* Prava*
Cha
nge
in F
ibri
noge
n (%
)
Branchi A, et al. Thromb Haemost. 1993;70:241-243.
*Not significant
**P<0.01
Fibrate Clinical Overview
Fenofibrate
Bezafibrate
Gemfibrozil
CH3
CH3
O CH2 CH2 CH2 CH2
CH3
COOH
CH3
C
C O
O
C
CH3
COO CH
CH3
CH3
Cl
CH3
Fibrates
OO
O
OH
CH3H3C
Cl
NH
Metabolic Action of Fibrates
Lipoprotein lipase
VLDLIDL
Apo C-II Apo C-III
Chylomicrons
Liver
Packard CJ. Eur Heart J. 1998;19(suppl A):A62-A65.
Apo EApo C-III
FFA
Fibrate
PPAR
Nucleus
HNF-4 +ve factor
CIII GeneC3P
Plasma Apo C-III 60%
Apo E/Apo C-III
Packard CJ. Eur Heart J. 1998;19(suppl A):A62-A65.
Metabolic Action of FibratesThe Peroxisome Proliferator Activator Receptor (PPAR)
-
-
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
Serum VLDL(Triglyceride-rich)
Fibrate
......... ..
.. . .....
Lowered Serum VLDL(Reduced triglycerides)
Before After Percent(mean ± SE) ( mean ± SE) Changes* P
Fenofibrate for the Treatment of Type IV and V HyperlipoproteinemiasA Double-Blind, Placebo-Controlled Multicenter US Study
Goldberg AC, et al. Clin Ther. 1989;11:69-83.
Fenofibrate
251.8 ± 5.3
92.1 ± 6.8
128.4 ± 7.1
33.7 ± 1.1
432.0 ± 19.1
349.8 ± 34.3
227.4 ± 6.7
45.8 ± 4.5
136.7 ± 5.3
40.3 ± 1.9
223.4 ± 13.9
177.8 ± 24.6
-9.1
-44.7
NS
+19.6
-46.2
-44.1
*These are mean percentage changes, not percentage changes in means.
NS=Not statistically significant when compared with placebo (12% increase).
Total cholesterol
VLDL-cholesterol
LDL-cholesterol
HDL-cholesterol
Total triglyceride
VLDL-triglyceride
<0.001
<0.001
0.8570
0.0014
<0.001
<0.001
Group A(350-499 mg/dL)
Fenofibrate for the Treatment of Type IV and V HyperlipoproteinemiasA Double-Blind, Placebo-Controlled Multicenter US Study
Goldberg AC, et al. Clin Ther. 1989;11:69-83.
Fenofibrate
261.0 ± 6.7
126.2 ± 7.0
103.1 ± 6.8
29.6 ± 1.3
725.6 ± 37.4
543.3 ± 50.8
223.3 ± 6.6
53.7 ± 3.4
131.0 ± 6.0
36.0 ± 1.8
308.0 ± 19.9
204.7 ± 23.0
-13.8
-49.4
+45.0
+22.9
-54.5
-50.6
*These are mean percentage changes, not percentage changes in means.
Total cholesterol
VLDL-cholesterol
LDL-cholesterol
HDL-cholesterol
Total triglyceride
VLDL-triglyceride
Before After Percent (mean ± SE) ( mean ± SE) Changes* P
0.0001
0.0001
0.0002
0.0029
0.0001
0.0001
Group B(500-1500 mg/dL)
Fenofibrate for the Treatment of Type IV and V HyperlipoproteinemiasA 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 ofType IV and V HyperlipoproteinemiasA Double-Blind, Placebo-Controlled Multicenter US Study
Week of Treatment
-60
-50
-40
-30
-20
-10
0
10
20
0 2 4 6 8
Placebo
Fenofibrate
% C
hang
e fr
om B
asel
ine
Goldberg AC, et al. Clin Ther. 1989;11:69-83.
Total Triglyceride - Group B
Fenofibrate for the Treatment ofType IV and V HyperlipoproteinemiasA Double-Blind, Placebo-Controlled Multicenter US Study
Week of Treatment
Goldberg AC, et al. Clin Ther. 1989;11:69-83.
-10
-5
0
5
10
15
20
25
30
0 2 4 6 8
Placebo
Fenofibrate% C
hang
e fr
om B
asel
ine
HDL-C - Group B
Fenofibrate for the Treatment ofType IV and V HyperlipoproteinemiasA 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 LipidsDouble-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia
Brown WV, et al. Arteriosclerosis. 1986;6:670-678.
N=227Variable Fenofibrate PlaceboSample Size (n) 116 111
Age (yr ± SD)Weight (lbs ± SD)Sex (n)
MaleFemale
Race (n)CaucasianBlackHispanicOther
Hyperlipoproteinemia (n)Type IIaType IIb
52.0 ± 0.96 51.7 ± 0.97 165.1 ± 2.48 164.9 ± 2.49
8234
7140
104606
98922
9224
8922
Percentage Changes at Endpoint from Baseline Values after 24 Weeks of Double Blind Study vs Placebo (Plb)
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
Feno Plb Feno Plbn=92 n=88 n=24 n=22
Type IIa (%) Type IIb (%)
Effects of Fenofibrate on Plasma LipidsDouble-Blind, Multicenter Study in Patients
with Type IIa or IIb Hyperlipidemia
Brown WV, et al. Arteriosclerosis. 1986; 6:670-678. P<0.01 except for LDL-C in Type IIb, where P>0.10
Effects of Fenofibrate on Plasma LipidsDouble-Blind, Multicenter Study in Patients
with Type IIa or IIb HyperlipidemiaMean LDL Plasma Cholesterol Concentration
Brown WV, et al. Arteriosclerosis. 1986;6:670-678.
Type IIa
150
170
190
210
230
0 2 4 8 12 18 24
Fenofibrate
Placebo
Double-Blind PeriodM
ean
Con
cent
rati
on (
mg%
)
Weeks on Study Medication
Effects of Fenofibrate on Plasma LipidsDouble-Blind, Multicenter Study in Patients
with Type IIa or IIb HyperlipidemiaMean LDL Plasma Cholesterol Concentration
Brown WV, et al. Arteriosclerosis. 1986;6:670-678.
Type IIb
150
160
170
180
190
200
210
0 2 4 8 12 18 24
Fenofibrate
Placebo
Double-Blind Period
Mea
n C
once
ntra
tion
(m
g%)
Weeks on Study Medication
Comparative Efficacy and Safety of Micronized Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
Study Design
Farnier M, et al. Arch Int Med. 1994;154:441-449.
• 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
Comparative Efficacy and Safety of Micronized Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
(Randomized, Crossover Study)
Farnier M, et al. Arch Int Med. 1994;154:441-449.
Fenofibrate200 mg/day
Simvastatin20 mg/day
Simvastatin20 mg/day
Fenofibrate200 mg/day
Type IIa, n=16Type IIb, n=14
Type IIa, n=16Type IIb, n=14
Group 1
Group 2
I I I I I I I0 3 6
Months
Comparative Efficacy and Safety of Micronized Fenofibrate and Simvastatin in Patients with
Primary Type IIa or IIb Hyperlipidemia
Characteristic Fenofibrate SimvastatinSample Size (n) 30 30
Age (yr ± SD)Weight (lbs ± SD)Sex (n)
malefemale
Hyperlipoproteinemia (n)Type IIaType IIb
Total Cholesterol (mg/dL)LDL-C (mg/dL)HDL-C (mg/dL)Triglyceride (mmol/L)
41.5 ± 11.4 46.1 ± 10.2 149.6 ± 23.5 159.1 ± 27.9
1614
219
1614
1614
315 ± 50 323 ± 45234 ± 48 241 ± 5050 ± 18 48 ± 11
1.82 ± 1.19 1.91 ± 1.17
Farnier M, et al. Arch Int Med. 1994;154:441-449.
-28 -28
-34-36 -37
-50
-40
-30
-20
-10
0
Total-C LDL-C HDL-C Trig
FenofibrateSimvastatin
Fenofibrate Versus SimvastatinEffect on Overall Lipid Profile
Farnier M, et al. Arch Int Med. 1994;154:441-449.
(Type IIa)%
Cha
nge
from
Bas
elin
e
NC NC NC
NC=No change
-23 -21 -25 -30
29
17
-52
18
-60
-45
-30
-15
0
15
30
45
Total-C LDL-C HDL-C Trig
FenofibrateSimvastatin
Fenofibrate Versus SimvastatinEffect on Overall Lipid Profile
Farnier M, et al. Arch Int Med. 1994;154:441-449.
(Type IIb)%
Cha
nge
from
Bas
elin
e
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 RegressionPe
rcen
t Pat
ient
s
Hahmann HW, et al. Am J Cardiol. 1991;67:957-961.
0
10
20
30
40
50
60
70
Fenofibrate Untreated
RegressionStabilizationProgression
Micronized Fenofibrate A Comprehensive Profile
Kornitzer M, et al. Atherosclerosis. 1994;110(suppl):S49-S64.
-30
-15
0
15
30
45
TC LDL HDL Fibrinogen
NormalHigh Risk*
Perc
ent C
hang
eN=1545 patients
*High risk: TC 250 mg/dL, LDL 185 mg/dL, HDL 35 mg/dL, fibrinogen 300 mg/dL
LDL Profile of Fenofibrate
-60%
-40%
-20%
0%
20%
40%
60%
Caslake MJ, et al. Arterioscler Thromb. 1993;13:702-711.
Cha
nge
Total Cholesterol
LDL-C LDL Receptor Uptake
Large, Buoyant LDL
Small, Dense LDL
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
Rubins HB, et al. N Engl J Med. 1999;341:410-418.
• 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.
Age (yr) 64 ± 7 64 ± 7Age >60 years (%) 77 76Prior MI (%) 61 61Time since MI (yr) 6 ± 6 6 ± 6Diabetes (%) 25 24Hypertension (%) 57 57Low-density lipoprotein, mg/dL (mean) 112 ± 23 111 ± 22 High-density lipoprotein, mg/dL (mean) 32 ± 5 32 ± 5
Triglycerides, mg/dL (mean) 160 ± 67 161 ± 68
Placebo GemfibrozilCharacteristic (N=1267) (N=1264)
The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA HIT): Baseline Characteristics
Rubins HB, et al. N Engl J Med. 1999;341:410-418.
The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA HIT) Results
0
5
10
15
20
25
30
Placebo Gemfibrozil
*
* Risk reduction = 24% (P<0.001)
% W
ith D
eath
, M
yoca
rdia
l In
farc
tion,
or
Str
oke
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.
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) Protocol
The Diabetes Atherosclerosis Intervention Study (DAIS)Baseline Clinical Characteristics
Placebo Fenofibrate
(n=211) (n=207)Demographics Age (years ± SD) 56 ± 6 57 ± 6 Women (%) 26 28 Current smokers (%) 16 14
Blood pressure History of Hypertension (%) 48 55 Systolic (mm Hg ± SD) 140 ± 18 140 ± 19 Diastolic (mm Hg ± SD) 81 ± 9 82 ± 9
Coronary Disease History of CAD (%) 47 48 Prior intervention (%) 30 32
DAIS Investigators. Lancet. 2001;357:905-910.
The Diabetes Atherosclerosis Intervention Study (DAIS)Angiographic Changes from Baseline
Minimum LumenDiameter
0.000.00
-0.02-0.02
-0.04-0.04
-0.06-0.06
-0.08-0.08
-0.10-0.10
mmmm
-40%-40%
P = 0.029Prog
ress
ion
of C
AD
% % ChangeChange
Percent Stenosis
4.004.00
2.002.00
0.000.00
P = 0.020
-42%-42%
Mean Segment Diameter
0.000.00
-0.02-0.02
-0.04-0.04
-0.06-0.06
-0.08-0.08
-0.10-0.10
mmmm
-25%-25%
P = 0.171
DAIS Investigators. Lancet. 2001;357:905-910.PlaceboFenofibrate
The Diabetes Atherosclerosis Intervention Study (DAIS)Combined Clinical Endpoints
Placebo Fenofibrate 0
5
15
Eve
nt R
ate
(%)
Eve
nt R
ate
(%)
25
20
10
-23%*
* DAIS was not powered to examine clinical events. Even though the results suggest a trend, they were not statistically significant.
Participants with at least one clinical or interventional endpoint, including death, stroke, MI, CABG, PTCA, and hospitalization for angina.
DAIS Investigators. Lancet. 2001;357:905-910.
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
The Diabetes Atherosclerosis Intervention Study (DAIS)Clinical Implications
DAIS Investigators. Lancet. 2001;357:905-910.
The Diabetes Atherosclerosis Intervention Study (DAIS)Comparison to Clinical Trials With Diabetic Patients
Study AgentEvent
Reduction
DAIS Fenofibrate 23%
CARE Pravastatin 25%
LIPID Pravastatin 19%
VA HIT Gemfibrozil 24%
P Value
NS
NS = Not statistically significant
0.05
NS
<0.001
DAIS Investigators. Lancet. 2001;357:905-910.