Transcript Document

Role of Fenofibrate in Diabetic
Dyslipidemia
Diabetic Dyslipidaemia
 Occurs in type 2 diabetes
mellitus
 High levels of triglycerides
Small,
dense
LDL
TG
 Low levels of HDL-C
 LDL-C not significantly
increased
HDL-C
 Small, dense LDL particles
increased
Atherogenic
dyslipidaemia
DM macrovascular complications
Statins reduce CHD risk by 25%
CV risk differs in DM , CHD and CHD and DM combined.
Do statins reduce CV risk similarly in all groups?
Is there a role for fibrates?
DM microvascular complications:
statins have no impact on retinopathy (HPS)
treatment of DM nephropathy includes lipid control
Main trials of statins in diabetics
 CV risk remains high when HDL is low despite
normal LDL
 ASCOT-LLA study showed less effective Atorvastatin
among DM subjects
 CARDS: CV event reduction by 37% stroke by 48%
but risk for major CV event at 10 years remained at
25%
 ASPEN study did not show significant CHD benefit
in low risk DM subjects.
Fenofibrate activates PPAR
PPAR
Effects on lipid
and lipoproteins
Other
effects
 Lipolysis






of TG-rich particles
Plasma clearance
of TG-rich particles
Oxidation
of fatty acids
TG synthesis
Levels of dense
LDL subfractions
HDL-c
Lp (a) level
Effects on
apolipoproteins
 Apo AI levels
 Apo AII levels
 Apo B levels
Keating GM, Ormrod D. Drugs 2002;62:1-35
Effects on
cholesterol
transporters
Up-regulates
the synthesis
of cholesterol
transporters
 Plasma
fibrinogen
levels
 C-reactive
protein
 Uric acid
levels
Outcomes in fibrate trials
Trial
n
Major CVD event
rate (%)
RRR
(%)
p-Value
control
drug
4,081
41.4
27.3
34
<0.02
292
13.0
3.9
71
<0.005
Overall:
3,090
15.0
13.6
9.4
0.26
Diabetes:
1,470
18.4
14.1
25
0.03
Overall:
2,531
21.7
17.3
22
0.006
769
29.4
21.2
32
0.004
Primary prevention
HHS1
Overall:
Diabetes:
Secondary prevention
BIP2
VA-HIT3
Diabetes:
BIP = Bezafibrate Infarction Prevention study; HHS = Helsinki Heart Study; RRR = relative risk
reduction; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.
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
Conclusions
 STATINS: patients with cardiovascular disease
receive significant (greater?) cardiovascular benefits from
statin therapy
 But STATINS do not remove the risk associated
with a low HDL-C or other features of the metabolic
syndrome
 Diabetic patients have not always been evaluated in the statin
trials. When they did, there always remained an important
residual risk factor.
 FIBRATES: appear to be specifically effective
in people with Type 2 Diabetes and/or the features
of the metabolic syndrome in whom the excess
coronary risk is significantly reduced.
The Fenofibrate Intervention
and Event Lowering in Diabetes
(FIELD) Trial
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD
A unique study in type 2 diabetes
 With 9,795 patients, FIELD is the largest clinical outcomes
study ever conducted in patients with type 2 diabetes
 With 7,664 patients without prior cardiovascular disease, FIELD
includes the largest group of primary prevention patients with
type 2 diabetes
 FIELD was designed to assess whether intervention
with fenofibrate could prevent cardiovascular events
in patients with type 2 diabetes, with or without dyslipidemia
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD: the largest clinical outcomes study ever
conducted in patients with type 2 diabetes(1)
1. FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 184961
2. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in
20536 high-risk individuals: a randomised placebo-controlled
trial. Lancet 2002; 360: 7-22.
3. Colhoun HM, Betteridge DJ, Durrington PN et al. Primary
prevention of cardiovascular disease with atorvastatin in type
2 diabetes in the Collaborative Atorvastatin Diabetes Study
(CARDS) multicentre randomised placebo-controlled trial.
Lancet 2004; 364 (9435): 685-96.
4. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary
and stroke events with atorvastatin in hypertensive patients
who have average or lower-than-average cholesterol
concentrations, in the Anglo-Scandinavian Cardiac Outcomes
Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre
randomised controlled trial. Lancet 2003; 361 (9364): 114958.
5. Rubins BH, Robins ST, Collins D et al. Gemfibrozil for the
secondary prevention of coronary heart disease in men with
low levels of high-density lipoprotein cholesterol. N Engl J Med
1999; 341: 410-8.
6. Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin
on coronary events after myocardial infarction in patients with
average cholesterol levels. N Engl J Med 1996; 335: 1001-9.
7. The Scandinavian Simvastatin Survival Study Group.
Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian Simvastatin Survival
Study (4S). Lancet 1994; 344: 1383-9.
Study design
 5-year, double-blind, placebo-controlled study
 All patients received usual care, including
the option to add other lipid-lowering therapies
Fenofibrate
200 mg/day
9,795
patients
(n = 4,895)
Placebo
(n = 4,900)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Average
follow-up:
5 years
and 500
CHD events
Outcomes
 Primary outcome
• First occurrence of nonfatal MI or CHD death
 Secondary outcomes
• Total CVD events*
(MI, stroke, CVD death, coronary
and carotid revascularisation)
• Coronary & peripheral revascularisation
•
•
•
•
Stroke
CHD deaths
CVD deaths
Total mortality
* Primary outcome for subgroup analyses
 Tertiary outcomes
• Progression of renal disease
• Laser treatment for diabetic retinopathy
• Nonfatal cancers
• Vascular & neuropathic amputations
• Hospitalisation for angina pectoris
• Hospital admissions
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Inclusion criteria
 Type 2 diabetes
 Age 50–75 years
 Total cholesterol 115–250 mg/dl (3.0–6.5 mmol/L),
plus either:
 Total cholesterol : HDL-cholesterol ratio ≥ 4, or
 Triglycerides > 89 mg/dl (1 mmol/L)
 No clear indication for lipid-lowering therapy
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Exclusion criteria
 Triglycerides > 443 mg/dl (5 mmol/L)
 Concurrent lipid-lowering therapy at baseline
 lipid-lowering agents could be added after randomization
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Baseline characteristics summary
Total population: 9,795
Male gender
No prior cardiovascular disease (%)
Diabetes management with diet plus
one oral antidiabetic agent (%)
Median duration of diabetes (years)
Median HbA1c (%)
Diabetic complications (%)
Retinopathy
Nephropathy
Lipid parameters (mg/dl [mmol/L])
Total cholesterol (mean)
LDL-cholesterol (mean)
HDL-cholesterol (mean)
Triglycerides (median)
Dyslipidemia (%)*
62.7
78.3
59.5
5
6.9
8.3
2.8
194 [5.0]
119 [3.1]
42 [1.1]
153 [1.7]
38
* 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
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD Main results
Effects of fenofibrate on lipid levels after
4 months (entire cohort)
10
TC
LDL-c
TG
5,1%
5
Percentage change
from baseline after 4 months
(corrected for placebo effect)
HDL-c
0
-5
-10
-15
-11,4%
-12,0%
-20
-25
-30
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
-28,6%
Effects of fenofibrate on lipid levels at
study close (entire cohort)
10
TC
LDL-c
Percentage change
from baseline after close-out
(corrected for placebo effect)
5
HDL-c
TG
1.2%
0
-5
-10
-6.9%
-5.8%
-15
-20
-25
-30
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
-21.9%
Compliance and use of other lipidlowering agents
100
Drop-outs
HR = 1.01
95% CI = 0.93–1.11
p = 0.76
Proportion (%)
80
60
Placebo
Fenofibrate
40
Drop-ins
HR = 0.47
95% CI = 0.44 – 0.51
p < 0.0001
20
0
0
1
2
3
4
years
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
5
6
Primary endpoint
CHD events (nonfatal MI, CHD death)
10
Cumulative risk (%)
8
6
Placebo
HR = 0.89
95% CI = 0.75–1.05
p = 0.16
4
2
Fenofibrate
0
0
1
2
3
4
5
6
Years from randomization
Placebo
4,900
4,835
4,741
4,646
4,547
2,541
837
Fenofibrate
4,895
4,837
4,745
4,664
4,555
2,553
850
Number of patients still followed-up at the given year
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Primary endpoint
CHD events (nonfatal MI, CHD death)
100
Nonfatal MI
HR = 0.76
95% CI = 0.62–0.94
p = 0.010
Cumulative risk (%)
80
60
Placebo
Fenofibrate
40
CHD death
HR = 1.19
95% CI = 0.90–1.57
p = 0.22
20
0
0
1
2
3
4
years
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
5
6
Secondary endpoint
Total CVD events
Cumulative risk (%)
15
10
Placebo
HR = 0.89
95% CI = 0.80–0.99
p = 0.035
NNT ≈ 70
Fenofibrate
5
0
0
1
2
3
4
Years after randomization
5
6
Placebo
4,900
4,762
4,586
4,419
4,257
2,340
750
Fenofibrate
4,895
4,771
4,604
4,469
4,307
2,370
775
Number of patients still followed-up at the given year
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Primary endpoint adjusted for new lipid
lowering therapy
CHD events (nonfatal MI, CHD death)
Primary
endpoint
Primary endpoint,
adjusted for new
lipid-lowering therapy
Relative risk reduction (%)
0
-5
-10
-11%
-15
p = 0.16
-20
-19%
-25
p = 0.01
-30
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Secondary endpoint adjusted for new
lipid lowering therapy
Total CVD events
Secondary
endpoint
Secondary endpoint,
adjusted for new
lipid-lowering therapy
Relative risk reduction (%)
0
-5
-10
-11%
-15
p = 0.035
-15%
p = 0.004
-20
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD sub-group analysis
Subgroup analysis: Secondary endpoint
Primary vs secondary prevention
p = 0.05*
5
2%
Relative risk reduction (%)
0
p = 0.85
-5
-10
-11%
-15
p = 0.035
-20
-19%
p = 0.004
-25
Overall
Primary
prevention
Secondary
prevention
(n = 9,795)
(n = 7,664)
(n = 2,131)
* P value for interaction
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD tertiary endpoints
Microvascular disease
Retinopathy
Need for laser treatment
for retinopathy
-30%
6
5.2%
P=0.0003
Percentage of patients
5
4
3.6%
3
2
1
0
Placebo
Fenofibrate
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
“This effect cannot
be explained by changes
in HbA1c or concomitant
medications, or by the minor
reduction in blood pressure
in the fenofibrate group”
Progression of microalbuminuria
(baseline to study close)
Placebo
(n=4900)
Fenofibrate
(n=4895)
Regression
No change
Progression
400
3654
539
(8.2%)
(74.6%)
(11.0%)
462
3583
466
(9.4%)
(73.2%)
(9.5%)
Mann-Whitney test:P=0.002
Albuminuria status categories:
Normal: <3.5 mg/mmol; microalbuminuria:3.5-<35 mg/mmol;
macroalbuminuria: > 35 mg/mol
“This effect cannot be explained by changes in HbA1c or concomitant
medications, or by the minor reduction in blood pressure in the
fenofibrate group”
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Other tertiary outcomes
Hospitalisations
for angina pectoris
Amputations
RR = 0.82 (95% CI = 0.69-1.00)
RR = 0.69 (95% CI = 0.48-0.99)
p=0.04
p=0.04
Number of hospitalisations
252
200
5.1%
100
-18%
209
4.3%
100
0
Number of hospitalisations
300
75
74
1.5%
50
-31%
51
1.0%
25
0
Placebo
Fenofibrate
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Placebo
Fenofibrate
FIELD Conclusions
FIELD study:
Conclusions (1)
 This landmark trial was the largest ever conducted
in patients with type 2 diabetes. It contains the
largest group of patients without a prior
cardiovascular event ever studied in type 2 diabetes
 FIELD enrolled a patient population with good
overall glycemic control, with and without
dyslipidemia
 Results must be interpreted while taking into
account the substantially higher level of statin use in
the placebo group
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD study:
Conclusions (2)
 Fenofibrate was associated with a non significant
11% reduction in the primary endpoint (first nonfatal MI
or CHD death; p = 0.16)
 After adjusting for statin use, fenofibrate was
associated with a significant 19% reduction in the
primary endpoint (p = 0.01)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD study:
Conclusions (3)
 Fenofibrate was associated with a significant 11%
reduction in total CVD events (p = 0.035)
 When adjusted for statin use, fenofibrate was
associated with a 15% reduction in total CVD events
(p = 0.004)
 In the subset of patients without a prior
cardiovascular event, fenofibrate significantly
reduced the primary endpoint
(total CHD events) by 25% (p = 0.014) and total CVD
events by 19% (p = 0.004)
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD study:
Conclusions (4)
 Treatment with fenofibrate also significantly
reduced microvascular events in all tertiary end
points
 progression to albuminuria
 need for laser treatment for retinopathy
 amputations*
 Fenofibrate was well tolerated alone and in
combination with statins
* An endpoint possibly related to micro and/or macrovascular disease
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
FIELD study:
Conclusions (5)
 This is the first time a lipid-lowering agent has
reduced rates of both macrovascular and
microvascular events in an endpoint study
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
“The results are likely to be of particular importance
among patients without previous cardiovascular
disease and in settings
where both the prevention of non-fatal
macrovascular events and microvascular complications
are judged important.”
FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Clinical implications of the FIELD
study
The FIELD study population
Parameter
Diabetes duration (y)
Age (y)
HbA1c (%)
Value
62.2 (6.2)
Optimal glucose control
- same HbA1c
at the end of the trial
6.9 (6.17.8)
LDL-c (mg/dl)
119
HDL-c (mg/dl)
42
Triglycerides (mg/dl)
Relatively early stage
of disease
5 (210)
Overall, 38%
dyslipidemic*
153
No prior CV disease (%)
78
Coronary event rate (5y)**
6%
Most patients
in primary prevention
 Moderate 10-year risk  12%
* Triglycerides > 150 mg/dl and HDL-c < 40 mg/dl (men) or < 50 mg/dl
(women). ** First nonfatal MI or CHD death
FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
The FIELD study population
Parameter
CARDS2
HPS3
(n = 9,795)
(n = 2,838)
(n = 5,963)
5
8
9
62.2
61.2
62.1
7.8
7.1
FIELD1
Diabetes duration (y)
Age (y)
HbA1c (%)
6.9
(6.17.8)
LDL-c (mg/dl)
119
118
124
HDL-c (mg/dl)
42
54
41
153
150
204
No prior CV disease (%)
78
100
50
Coronary event rate (10y, %)
12
15
25
Major CV events (RRR, %)
-11
-37*
-22*
Triglycerides (mg/dl)
RRR = relative risk reduction; * p < 0.001
1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
2. Colhoun HM et al. Lancet 2004;364:685–96;
3. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16
Primary endpoints – FIELD
 No significant benefit on major coronary events
(first nonfatal MI or CHD death)
 11%, p = 0.16
Secondary endpoints – FIELD
 Significant benefits on total cardiovascular events
 -11%, p = 0.035
FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
Clinical implications of the FIELD study in
patients Without previous CV disease
Prior CVD
No prior CVD
22%
78%
FIELD:1 significant benefit
on total cardiovascular events
(NNT= 50 pts for 5 years to prevent
one or more CVD events in 1 patient)
Why may fenofibrate be a therapeutic
option in diabetics without previous CVD?
No prior CVD 100%
CARDS:2 significant benefit
on major cardiovascular events
(NNT= 27 pts for 4 years to prevent
one CVD event in 1 patient)
1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
2. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16
Take home messages1
 This is the first time a lipid-modifying agent has reduced
rates of both macrovascular and microvascular events
 In early-stage type 2 diabetics:
 without previous CVD
 with optimal glycemic control
 with or without atherogenic dyslipidemia
(and no elevation of LDL-c)
 Fenofibrate may represent a therapeutic option (alone or
with a statin) to reduce both total cardiovascular events
and the progression of microangiopathy (retinopathy and
microalbuminuria)
FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
Take home messages2
 In patients with type 2 diabetes, the use of statins remains
the strategy of choice for reducing cardiovascular (CV) events,
particularly in those with previous CV disease
 Fenofibrate may provide additional benefits in reducing total
cardiovascular events in type 2 diabetes when used with statin
therapy
 Both fenofibrate monotherapy and combination
fenofibrate/statin therapy are safe and well tolerated
FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61
FENOFIBRATE
BIOAVAILABILITY
Fenofibrate Nanotechnology 145 mg
NANOTECHNOLOGY:
a question of scale…
molecule
0.1 nm
1 nm
protein
10 nm
DNA
100 nm
Hair
Cell
1 μm
10 μm
100 μm
Flea
1 mm
Nanoworld
Lipanthyl
145 NT
Lipanthyl
300mg / 100mg
Lipanthyl
200M / 160mg SUPRA
Butterfly
1 cm
10 cm
Human
being
1m
LIPANTHYL 145 NT entering into the Nanoworld
200M
STANDARD
Median Ø = 150µm
SUPRA
MICRONIZED
Median Ø < 15µm
145 NT
NanoCrystalTM Technology
Median Ø < 400 nm
NEW NanoCrystalTM Technology:
increased surface area leads to a more predictable
bioavailibility
 LIPANTHYL 145 NanoCrystalTM Technology means no difference
in bioavailability when Lipanthyl 145 is taken with or without
food
 Previous Lipanthyl formulation resulted in 35% difference in
absorption when the previous formulation was taken without a
meal
Micronized fenofibrate
Source: Elan Corp
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