Role of Fenofibrate in Diabetic Dyslipidemia

1
Role of Fenofibrate in Diabetic Dyslipidemia
2
Diabetic Dyslipidaemia

• Occurs in type 2 diabetes mellitus
• High levels of triglycerides
• Low levels of HDL-C
• LDL-C not significantly increased
• Small, dense LDL particles increased
• ?Atherogenic dyslipidaemia

3

• 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

4
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.

5
Fenofibrate activates PPAR?
Keating GM, Ormrod D. Drugs 2002621-35
6
Outcomes in fibrate trials
Trial Trial Trial n Major CVD event rate () Major CVD event rate () RRR () p-Value
Trial Trial Trial n control drug RRR () p-Value
Primary prevention Primary prevention Primary prevention
HHS1 Overall Overall 4,081 41.4 27.3 34 lt0.02
HHS1 Diabetes Diabetes 292 13.0 3.9 71 lt0.005
Secondary prevention Secondary prevention Secondary prevention Secondary prevention
BIP2 Overall 3,090 3,090 15.0 13.6 9.4 0.26
BIP2 Diabetes 1,470 1,470 18.4 14.1 25 0.03
VA-HIT3 Overall 2,531 2,531 21.7 17.3 22 0.006
VA-HIT3 Diabetes 769 769 29.4 21.2 32 0.004
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
1987317123745 2. The BIP Study Group.
Circulation 2000102217 3. Rubins HB et al. N
Engl J Med 19993414108
7
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.
8
The Fenofibrate Intervention and Event Lowering
in Diabetes (FIELD) Trial
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FIELDA 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

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FIELD the largest clinical outcomes study ever
conducted in patients with type 2 diabetes(1)
1. FIELD Study Investigators. Lancet 2005 366
(9500) 1849-61 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) 1149-58. 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.
11
Study design
? 5-year, double-blind, placebo-controlled
study ? All patients received usual care,
including the option to add other
lipid-lowering therapies
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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

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Inclusion criteria
? Type 2 diabetes ? Age 5075 years ? Total
cholesterol 115250 mg/dl (3.06.5 mmol/L),
plus either ? Total cholesterol
HDL-cholesterol ratio 4, or ? Triglycerides
gt 89 mg/dl (1 mmol/L) ? No clear indication for
lipid-lowering therapy
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Exclusion criteria
? Triglycerides gt 443 mg/dl (5 mmol/L) ? Concurren
t lipid-lowering therapy at baseline ?
lipid-lowering agents could be added after
randomization
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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
TG gt 150 mg/dl (1.7 mmol/L) and HDL-c lt 40
mg/dl (1 mmol/L) for men or lt 50 mg/dl (1.3
mmol/L) for women
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FIELD Main results
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Effects of fenofibrate on lipid levels after 4
months (entire cohort)
TC
LDL-c
HDL-c
TG
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Effects of fenofibrate on lipid levels at study
close (entire cohort)
TC
LDL-c
HDL-c
TG
Percentage change from baseline after
close-out (corrected for placebo effect)
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Compliance and use of other lipid-lowering agents
Drop-outs HR 1.01 95 CI 0.931.11 p 0.76
Placebo Fenofibrate
Proportion ()
Drop-ins HR 0.47 95 CI 0.44 0.51 p lt 0.0001
0
1
2
3
4
5
6
years
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Primary endpointCHD events (nonfatal MI, CHD
death)
HR 0.89 95 CI 0.751.05 p 0.16
Cumulative risk ()
Years from randomization
Number of patients still followed-up at the given
year
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Primary endpointCHD events (nonfatal MI, CHD
death)
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Secondary endpoint Total CVD events
15
Placebo
HR 0.89 95 CI 0.800.99 p 0.035 NNT 70
10
Fenofibrate
Cumulative risk ()
5
0
0
1
2
3
4
5
6
Years after randomization
Number of patients still followed-up at the given
year
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Primary endpoint adjusted for new lipid lowering
therapyCHD events (nonfatal MI, CHD death)
Primary endpoint, adjusted for newlipid-lowering
therapy
Primary endpoint
p 0.16
p 0.01
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Secondary endpoint adjusted for new lipid
lowering therapyTotal CVD events
Secondary endpoint, adjusted for
newlipid-lowering therapy
Secondary endpoint
p 0.035
p 0.004
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FIELD sub-group analysis
26
Subgroup analysis Secondary endpointPrimary vs
secondary prevention
p 0.05
p 0.85
p 0.035
p 0.004
Overall
Primary prevention
Secondary prevention
(n 9,795)
(n 7,664)
(n 2,131)
P value for interaction
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FIELD tertiary endpoints
28
Microvascular disease Retinopathy
Need for laser treatment for retinopathy
-30
P0.0003
This effect cannot be explained by changes in
HbA1c or concomitant medications, or by the minor
reduction in blood pressure in the fenofibrate
group
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29
Progression of microalbuminuria(baseline to
study close)
Regression No change Progression
Placebo (n4900) 400 (8.2) 3654 (74.6) 539 (11.0)
Fenofibrate (n4895) 462 (9.4) 3583 (73.2) 466 (9.5)
Mann-Whitney testP0.002 Albuminuria status
categories Normal lt3.5 mg/mmol
microalbuminuria3.5-lt35 mg/mmol macroalbuminuria
gt 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
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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)
p0.04
p0.04
300
100
-18
252
-31
74
5.1
75
209
200
1.5
4.3
51
50
Number of hospitalisations
Number of hospitalisations
1.0
100
25
0
0
Placebo
Fenofibrate
Placebo
Fenofibrate
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FIELD Conclusions
32
FIELD studyConclusions (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

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FIELD studyConclusions (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)

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FIELD studyConclusions (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)

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FIELD studyConclusions (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
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FIELD studyConclusions (5)

• This is the first time a lipid-lowering agent
  has reduced rates of both macrovascular and
  microvascular events in an endpoint study

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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.
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Clinical implications of the FIELD study
39
The FIELD study population
Parameter Value Value
Diabetes duration (y) Age (y) HbA1c () LDL-c (mg/dl) HDL-c (mg/dl) Triglycerides (mg/dl) No prior CV disease () Coronary event rate (5y) 5 (2?10) 62.2 (6.2) 6.9 (6.1?7.8) 119 42 153 78 6
Relatively early stage of disease
Optimal glucose control - same HbA1c at the
end of the trial
Most patients in primary prevention
? Moderate 10-year risk ? 12
Triglycerides gt 150 mg/dl and HDL-c lt 40 mg/dl
(men) or lt 50 mg/dl (women). First nonfatal MI
or CHD death
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266(9500) 1849-61
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The FIELD study population
Parameter FIELD1(n 9,795)
Diabetes duration (y) Age (y) HbA1c () LDL-c (mg/dl) HDL-c (mg/dl) Triglycerides (mg/dl) No prior CV disease () Coronary event rate (10y, ) 5 62.2 6.9 (6.1?7.8) 119 42 153 78 12
CARDS2 (n 2,838) HPS3 (n 5,963)
8 61.2 7.8 118 54 150 100 15 9 62.1 7.1 124 41 204 50 25
Major CV events (RRR, ) -11 -37 -22
RRR relative risk reduction p lt 0.001
1. FIELD Study Investigators. Lancet 2005 Nov 26
266(9500) 1849-61 2. Colhoun HM et al. Lancet
200436468596 3. Heart Protection Study
Collaborative Group. Lancet 20033612005-16
41
Primary endpoints FIELD
? No significant benefit on major coronary events
(first nonfatal MI or CHD death) ? 11, p
0.16
? Significant benefits on total cardiovascular
events ? -11, p 0.035
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Clinical implications of the FIELD study in
patients Without previous CV disease
22
Prior CVD
No prior CVD
78
Why may fenofibrate be a therapeutic option in
diabetics without previous CVD?
1. FIELD Study Investigators. Lancet 2005 Nov 26
266(9500) 1849-61 2. Heart Protection Study
Collaborative Group. Lancet 20033612005-16
43
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)
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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
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FENOFIBRATE BIOAVAILABILITY

• Fenofibrate Nanotechnology 145 mg

46
NANOTECHNOLOGY a question of scale
molecule
DNA
Hair
Butterfly
protein
Flea
Human being
Cell
1 µm
10 µm
0.1 nm
1 nm
10 nm
100 nm
100 µm
1 mm
1 cm
10 cm
1 m
Nanoworld
Lipanthyl 145 NT
Lipanthyl 300mg / 100mg
Lipanthyl 200M / 160mg SUPRA
47
LIPANTHYL 145 NT entering into the Nanoworld
200M
SUPRA
145 NT
STANDARD
MICRONIZED
NanoCrystalTM Technology
Median Ø 150µm
Median Ø lt 15µm
Median Ø lt 400 nm
48
NEW NanoCrystalTM Technologyincreased 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
9
Source Elan Corp