O
Cl
CH3
C
O
C
CH3
COO
CH
CH3
Fenofibrate
CH3
CH3
Cl
O
Clofibrate
C
COOC2H5
CH3
CH3
CH3
O
CH3
CH2
CH2
Gemfibrozil
CH2
CH2
C
CH3
COOH
Slide Source
LipidsOnline
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Fibric Acid Derivatives
Indications: Adjunctive therapy to diet
Hypertriglyceridemia (Type IV and V)
Combined hyperlipidemia (Type IIb) with low HDL
who do not respond to NA
Mechanism of Action: Increases peripheral lipolysis and decreases hepatic
TG production
Efficacy: Decreases TG 25-50%
LDL decreases, remains the same or increases
Increases HDL 15-25% in hypertriglyceridemia
Side Effects: GI upset (8%), cholelithiasis, myositis, abn LFTs
Contraindications: Hepatic or renal dysfunction
Pre-existing gallbladder disease
Intervention Trials: Helsinki Heart Study, LOCAT, BECAIT, VA-HIT, BIP
Slide Source
LipidsOnline
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Helsinki Heart Study
 Primary-prevention, placebo-controlled trial to determine
whether increasing HDL-C levels and decreasing LDL-C
levels would reduce incidence
of CHD
 4,081 dyslipidemic men, aged 40–55 y
 Subjects randomized to gemfibrozil (600 mg BID) or
placebo
 Study duration: 5 y
Frick MH et al. N Engl J Med. 1987;317:1237–1245
Slide Source
LipidsOnline
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Helsinki Heart Study
Incidence of CHD Events
Incidence of cardiac events
(per 1,000 person-years)
20
Gemfibrozil
15
Placebo
10
5
0
mg/dL:
27
36
7
9
TG  200 TG  200
HDL-C  42
14
16
8
23
TG  200 TG  200
HDL-C  42
Numbers inside bars indicate number of cardiac events in each subgroup
Slide Source
LipidsOnline
Manninen V et al. Circulation. 1992;85:37–45
www.lipidsonline.org
Angiographic and Clinical Event Trials
Summary
 In angiographic trials, benefits were related to
reductions in LDL-C (apoB-100) and increases in
HDL-C (apoA-I).
 Fibrates have shown benefits in patients with:
 High TG and low HDL-C (Helsinki, BIP)
 Normal LDL-C and low HDL-C (VA-HIT)
 Statins have consistently shown the greatest
benefits in patients with low HDL-C and average
LDL-C (CARE, LIPID, AFCAPS/TexCAPS) or high LDLC (4S, WOSCOPS).
Slide Source
LipidsOnline
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LDL Particle Size and Apolipoprotein B Predict
Ischemic Heart Disease: Quebec Cardiovascular
Study
6
6.2
5
(p<0.001)
4
3
2.0
2
1
0
1.0
Apo B
1.0
>120 mg/dl
<120 mg/dl
>25.64
<25.64
LDL Peak Particle Diameter (nm)
Lamarche B et al. Circulation 1997;95:69-75.
Slide Source
LipidsOnline
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CHD Prevention Trials with Fibrates in
Diabetic Subjects: Subgroup Analyses
Drug
Dose
Study
Baseline
LDL-C,
mg/dl
No. (mmol/L)
LDL-C
Lowering
CHD
Reduction
203
(5.2)
6%
68%
NS
112
(2.9)
–
24%
Primary Prevention
Helsinki
Heart Study
Gemfibrozil 135
(1200 mg/d)
Secondary Prevention
VA-HIT
Gemfibrozil 627
(1200 mg/d)
Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825;
Rubins HB et al. N Engl J Med 1999;341:410-418.
p=0.05
Slide Source
LipidsOnline
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5-Year Incidence of CHD (%)
Primary CHD* Prevention in Type 2 Diabetic
Patients: The Helsinki Heart Study
15
P=0.19
10.5
P<0.02
10
7.4
5
0
3.4
3.3
Type 2
(n=135)
Others
(n=3946)
Type 2 on
Placebo
(n=76)
*Myocardial infarction or cardiac death
Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825.
Type 2 on
Gemfibrozil
(n=59)
Slide Source
LipidsOnline
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hs-CRP as a Risk Factor for Future CVD
MRFIT (Kuller 1996)
CHD Death
PHS
(Ridker 1997)
MI
PHS
(Ridker 1997)
Stroke
CHS/RHPP
PHS
(Tracy 1997)
(Ridker 1998)
WHS
(Ridker 1998, 2000)
MONICA
Helsinki
(Koenig 1999)
CHD
PVD
CVD
CHD
(Roivainen 2000)
CHD
Caerphilly(Mendall 2000)
CHD
Britain
CHD
(Danesh 2000)
0
1.0
2.0
3.0
4.0
5.0
Relative Risk (upper vs lower quartile)
Slide Source
LipidsOnline
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6.0
% CHD Death/Nonfatal MI
Trials of Fibrates: Effects on Cardiac Events
42%
30
Rx
25
Placebo
10
5
0
Deaths
22.3
9%
21.7***
17.3
20
15
22%
66%
34%
2.7
2.2 2.1
13.0
8.0
4.1***
HHS
13.6
15.0
2.7
HHS
(Post Hoc)*
PRIMARY PREVENTION
BIP
10.4 9.9
BIP
(Post Hoc)**
VA-HIT
15.7 17.4
SECONDARY PREVENTION
* Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL.
** Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL.
*** Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05).
Frick MH et al. N Engl J Med 1987;317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45.
Slide Source |
LipidsOnline
BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418.
www.lipidsonline.org
CHD Prevention Trials with Fibrates in
Diabetic Subjects: Subgroup Analyses
Drug
Study
(dose)
Baseline
LDL-C,
LDL-C
mg/dl
No. (mmol/L) Lowering
CHD
Reduction
Primary Prevention
Helsinki Heart Study
Gemfibrozil
135
(1200 mg/d)
203
6%
(5.2)
68%
NS
Secondary Prevention
VA-HIT
DAIS
Gemfibrozil 627
(1200 mg/d)
Fenofibrate
(200 mg/d)
418
112*
(2.9*)
–
24%
P=.05
130
6%
23%
NS
*Median value
Koskinen P et al. Diabetes Care 1992;15:820-825. | Rubins HB et al. N Engl J Slide
MedSource
LipidsOnline
1999;341:410-418. | DAIS Investigators. Lancet 2001;357:905-910.
www.lipidsonline.org
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LipidsOnline
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