Does combination therapy with statinsand fibrates prevent cardiovascular diseasein diabetic patientswith atherogenic mixed dyslipidemia?

3. Diabetics have increased
CVD risk
3 6 9 12 15 18 21 24
0.25
0.20
0.15
0.10
0.05
0.0
Months 
Event
rate
RR = 2.88 (2.37-3.49)
RR=1.99 (1.52-2.60)
RR=1.71 (1.44-2.04)
RR=1.00
Malmberg K, et al. Circulation 2000;102:1014–1019.
Diabetes/CVD +, (n = 1148)
No Diabetes/CVD +, (n = 3503)
Diabetes/CVD -, (n = 569)
No Diabetes/CVD -, (n = 2796)

4. Current treatment guidelines focus on statins and
LDL cholesterol reduction in diabetes

5. Major statin trials or sub-studies in diabetic patients
Lancet 2004;364:685
Diabetes Care 2006;29:1220
Lancet 2003;361:2005
Diabetes Care 2006;7:1478
Diabetes Care 1997;20:614
*Num. needed to treat (NNT) for moderate-high risk DM to avoid one death or MI: 3-50
ADA Standards of Care; Diabetes Care, January 2011

6. 6
LDL-C < 160 mg/dl

8. N 4,444 9,014 4,159 20,536 6,595 6,605
∆LDL -36% -25% -28% -29% -26% -27%
TxLDL 119 154 98 90 113 112
secondary high risk primary
%
CHD
events
on
statin
J Am Coll Card 2005;46:1225-8
LDLc lowering and residual risk – more is needed
The majority of CVD events still occur: CVD events occurring in the on-
treatment groups in major statin trials

9. • Elevated TG
• Reduced HDL
• Small, dense LDL
Mixed Dyslipidemia in DM
9

10. HDL-C &TG remain predictive of CVD events even when
LDL-C < 1.8 mmol/L:TNT & PROVE-IT
Barter P et al. NEJM 357:1301-10, 2007
On-Treatment Quintile of HDL-C
In Pts with LDL-C < 1.8 mmol/L
5
Yr
Risk
of
Major
CV
Events
(%)
12
10
8
6
4
2
0
Q1 Q2 Q3 Q4 Q5
(<38) (38<42) (42<46) (46<50) (>50)
Hazard Ratio vs Q1
Q2 0.85
Q3 0.57
Q4 0.55
Q5 0.61
+64%
≥2.3 mM/L
(n=603)
< 2.3 mM/L
(n=2796)
On-Treatment TG
In Pts with LDL-C < 1.8 mmol/L
20.3
13.5
30-day
risk
of
death,
MI
or
recurrent
ACS
(%)
RR 1.56 (1.28-1.89)
p= 0.001
+56
%
Miller et al. 2008

12. Residual CVD risk
Hypothesis

13. …
Duval C, et al. Trends Mol Med. 2002;8:422-430.
Lee CH, et al. Endocrinology. 2003;144:2201-2207.
Acyl-CoA
Synthase
AcetylCoA
FFA
apo A-I
apo A-II
ABCA1
apo C-III
Apo A-V
TG
Liver Circulation
… by
controlling
the
expression
of PPAR
target
genes
Results
LPL
Reversal of
CETP formation
of small and
dense LDL
particles
LDL
IncreasedVLDL
Clearance
DecreasedVLDL
Production
VLDL
Increased HDL
Production
HDL
ABCG1
DecreasedTG
levels

14.  Reversal of CETP formation of small dense LDL particles

15. Trial n
Major CVD event
rate (%) RRR
(%)
p-Value
control drug
Primary prevention
HHS1
Overall: 4,081 41.4 27.3 34 <0.02
Diabetes: 292 13.0 3.9 71 <0.005
Secondary prevention
BIP2
Overall: 3,090 15.0 13.6 9.4 0.26
Diabetes: 1,470 18.4 14.1 25 0.03
VA-HIT3
Overall: 2,531 21.7 17.3 22 0.006
Diabetes: 769 29.4 21.2 32 0.004
1. Frick MH et al. N Engl J Med 1987;317:1237–45
2. The BIP Study Group. Circulation 2000;102:21–7
3. Rubins HB et al. N Engl J Med 1999;341:410–8
BIP = Bezafibrate Infarction Prevention study; HHS = Helsinki Heart Study; RRR = relative risk
reduction; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.
Relative risk reduction in diabetic
subgroups in previous fibrate trials

16. Fibrate trials in diabetic patients

17. DAIS Investigators. Lancet 2001;357:905-910.
DAIS
mean + SD
TG LDL-C HDL-C
Placebo
Fenofibrate
mg/dL
0
177
354
531
TG
0
77
155
232
Chol
213–228
mg/dl
135–137
mg/dl
40–42
mg/dl

18. LDL-C
DAIS Investigators. Lancet 2001;357:905-910.
Reprinted with permission from Elsevier Science.
TC TG
HDL-C
Placebo
Fenofibrate
Percent
Change
10
0
-10
-20
-30
-5%
-29%
+5%

19. DAIS: Slower progression in coronary angiograms
Minimum lumen
diameter
-0.10
-0.08
-0.06
-0.04
-0.02
0.00
-40%
Percent
Stenosis
-42%
Mean Segment
Diameter
-25%
DAIS Investigators. Lancet 2001;357:905-910.
4.00
2.00
0.00
p = 0.029 p = 0.020 p = 0.171
-0.10
-0.08
-0.06
-0.04
-0.02
0.00
mm
%
change mm
Progression
of
CAD

20. FenofibrateIntervention
andEventLoweringinDiabetes
A randomised trial of the effects of fenofibrate
on coronary morbidity and mortality
in people with diabetes

21. Study design
 5-year, double-blind, placebo-controlled study
 All patients received usual care, including
the option to add other lipid-lowering therapies
9,795
patients
Fenofibrate
200 mg/day
(n = 4,895)
Placebo
(n = 4,900)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

22. * TG > 150 mg/dl (1.7 mmol/L) and HDL-c < 40 mg/dl (1 mmol/L) for men
or < 50 mg/dl (1.3 mmol/L) for women
Baseline characteristics summary
Total population: 9,795
Male gender 62.7
No prior cardiovascular disease (%) 78.3
Diabetes management with diet plus
one oral antidiabetic agent (%) 59.5
Median duration of diabetes (years) 5
Median HbA1c (%) 6.9
Diabetic complications (%)
Retinopathy 8.3
Nephropathy 2.8
Lipid parameters (mg/dl [mmol/L])
Total cholesterol (mean) 194 [5.0]
LDL-cholesterol (mean) 119 [3.1]
HDL-cholesterol (mean) 42 [1.1]
Triglycerides (median) 153 [1.7]
Dyslipidemia (%)* 38
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

23. Effects of fenofibrate on lipid levels at
study close (entire cohort)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
-21.9%
1.2%
-5.8%
-6.9%
-30
-25
-20
-15
-10
-5
0
5
10 TC LDL-c HDL-c TG
Percentage
change
from
baseline
after
close-out
(corrected
for
placebo
effect)

24. Cumulative
risk
(%)
Years from randomization
4,900
4,895
4,835
4,837
4,741
4,745
4,646
4,664
4,547
4,555
2,541
2,553
Placebo
Fenofibrate
837
850
10
8
6
4
2
0
0 1 2 3 4 5
Fenofibrate
Placebo
6
Primary endpoint
CHD events (nonfatal MI, CHD death)
HR = 0.89
95% CI = 0.75–1.05
p = 0.16
Number of patients still followed-up at the given year
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

25. Cumulative
risk
(%)
HR = 0.89
95% CI = 0.80–0.99
p = 0.035
15
10
5
0
0 1 2 3 4 5
Fenofibrate
Placebo
6
Total CVD events
Years after randomization
4,900
4,895
4,762
4,771
4,586
4,604
4,419
4,469
4,257
4,307
2,340
2,370
Placebo
Fenofibrate
750
775
Number of patients still followed-up at the given year
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

26. Coronary revascularisations
0 1 2 3 4 5 6
Years from randomisation
0
5
10
15
Cumulative
risk
(%)
Placebo 4900 4818 4693 4567 4423 2457 796
Fenofibrate 4895 4817 4698 4592 4445 2476 820
HR = 0.79
95% CI = 0.68–0.93
P=0.003
Placebo
Fenofibrate

27. Drop-outs
HR = 1.01
95% CI = 0.93–1.11
p = 0.76
Drop-ins
HR = 0.47
95% CI = 0.44 – 0.51
p < 0.0001
Placebo
Fenofibrate
100
80
60
40
20
0
0 1 2 3 4 5 6
years
Proportion
(%)
Compliance and use of other lipid-
lowering agents
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Non-study medications (mainly statins)
Placebo: 17 %
Fenofibrate: 8%
p < 0.0001

28. -11%
-19%
-30
-25
-20
-15
-10
-5
0
Relative
risk
reduction
(%)
p = 0.16
Primary
endpoint
Primary endpoint,
adjusted for new
lipid-lowering therapy
p = 0.01
Primary endpoint adjusted for new lipid
lowering therapy
CHD events (nonfatal MI, CHD death)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

30. Fibrate trials

38. HR 0.69
95% CI 0.49-0.97
p = 0.03