role of fenofibrate in diabetic dyslipidemia. diabetic dyslipidaemia occurs in type 2 diabetes...

Role of Fenofibrate in Diabetic

Dyslipidemia

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

Small,denseLDL

HDL-C

TG

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

Keating GM, Ormrod D. Drugs 2002;62:1-35

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 lipidand lipoproteins

Plasma fibrinogenlevels

C-reactive protein

Uric acidlevels

Other effects

Apo AI levels

Apo AII levels

Apo B levels

Effects onapolipoproteins

Up-regulatesthe synthesis of cholesterol transporters

Effects oncholesterol

transporters

PPAR

Trial n

Major CVD event rate (%) RRR

(%) p-Valuecontrol drug

Primary prevention

HHS1Overall: 4,081 41.4 27.3 34 <0.02

Diabetes: 292 13.0 3.9 71 <0.005

Secondary prevention

BIP2Overall: 3,090 15.0 13.6 9.4 0.26

Diabetes: 1,470 18.4 14.1 25 0.03

VA-HIT3Overall: 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;317:1237–452. The BIP Study Group. Circulation 2000;102:21–73. 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.

Outcomes in fibrate trials

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

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.

Diabetic patients have not always been evaluated in the statin trials. When they did, there always remained an important

residual risk factor.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Trial

FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

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

FIELDA unique study in type 2 diabetes


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.

Study design

5-year, double-blind, placebo-controlled study

All patients received usual care, including the option to add other lipid-lowering therapies

9,795patients

Fenofibrate 200 mg/day(n = 4,895)

Placebo(n = 4,900)

Average follow-up:

5 yearsand 500

CHD events


• First occurrence of nonfatal MI or CHD death

Outcomes

Primary outcome

• Total CVD events* (MI, stroke, CVD death, coronary and carotid revascularisation)

• Coronary & peripheral revascularisation

Secondary outcomes

Tertiary outcomes

• Progression of renal disease• Laser treatment for diabetic retinopathy• Nonfatal cancers• Vascular & neuropathic amputations• Hospitalisation for angina pectoris• Hospital admissions

• Stroke

• CHD deaths

• CVD deaths

• Total mortality

* Primary outcome for subgroup analyses


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


Exclusion criteria

Triglycerides > 443 mg/dl (5 mmol/L)

Concurrent lipid-lowering therapy at baseline lipid-lowering agents could be added after randomization


* 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 62.7No prior cardiovascular disease (%) 78.3

Diabetes management with diet plus one oral antidiabetic agent (%) 59.5Median duration of diabetes (years) 5Median HbA1c (%) 6.9

Diabetic complications (%)

Retinopathy 8.3Nephropathy 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 Main results

-11,4% -12,0%

5,1%

-28,6%-30

-25

-20

-15

-10

-5

0

5

10

Perc

enta

ge

chan

ge

from

bas

elin

e af

ter

4 m

onth

s(c

orr

ecte

d f

or

pla

cebo e

ffec

t)TC LDL-c HDL-c TG

Effects of fenofibrate on lipid levels after 4 months (entire cohort)


Effects of fenofibrate on lipid levels at study close (entire cohort)


-21.9%

1.2%

-5.8%-6.9%

-30

-25

-20

-15

-10

-5

0

5

10 TC LDL-c HDL-c TGPerc

enta

ge c

hang

efr

om

base

line a

fter

close

-out

(corr

ect

ed

for

pla

ceb

o e

ffect

)

Drop-outs

HR = 1.0195% CI = 0.93–1.11p = 0.76

Drop-ins

HR = 0.4795% CI = 0.44 – 0.51p < 0.0001

PlaceboFenofibrate

100

80

60

40

20

0

0 1 2 3 4 5 6

years

Pro

port

ion (

%)

Compliance and use of other lipid-lowering agents


Cum

ula

tive r

isk (

%)

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 endpointCHD events (nonfatal MI, CHD death)

HR = 0.8995% CI = 0.75–1.05p = 0.16

Number of patients still followed-up at the given year


Nonfatal MI

HR = 0.7695% CI = 0.62–0.94p = 0.010

CHD death

HR = 1.1995% CI = 0.90–1.57p = 0.22

PlaceboFenofibrate

100

80

60

40

20

0

0 1 2 3 4 5 6

years

Cum

ula

tive r

isk (

%)

Primary endpointCHD events (nonfatal MI, CHD death)


Cum

ula

tive r

isk (

%)

HR = 0.8995% CI = 0.80–0.99p = 0.035NNT ≈ 70

15

10

5

0

0 1 2 3 4 5

Fenofibrate

Placebo

6

Secondary endpoint 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


-11%

-19%

-30

-25

-20

-15

-10

-5

0

Rela

tive r

isk r

educt

ion (

%)

p = 0.16

Primaryendpoint

Primary endpoint, adjusted for new

lipid-lowering therapy

p = 0.01

Primary endpoint adjusted for new lipid lowering therapyCHD events (nonfatal MI, CHD death)


Secondary endpoint adjusted for new lipid lowering therapyTotal CVD events

-11%

-15%

-20

-15

-10

-5

0

Rela

tive r

isk r

educt

ion (

%)

p = 0.035

Secondaryendpoint

Secondary endpoint, adjusted for new

lipid-lowering therapy

p = 0.004


FIELD sub-group analysis

-11%

-19%

2%

-25

-20

-15

-10

-5

0

5R

ela

tive r

isk r

educt

ion (

%) p = 0.85

p = 0.004

p = 0.035

Subgroup analysis: Secondary endpointPrimary vs secondary prevention

(n = 9,795) (n = 7,664) (n = 2,131)

p = 0.05*

Overall Primary prevention

Secondary prevention

* P value for interaction


.

RichardShould this p-value be <0.001 ? See Figure 4 in e-publication

FIELD tertiary endpoints

5.2%

3.6%

0

1

2

3

4

5

6

Placebo Fenofibrate

Perc

enta

ge

of

pat

ients

Need for laser treatment for retinopathy

“This effect cannot be explained by changes in HbA1c or concomitant

medications, or by the minor reduction in blood pressure

in the fenofibrate group”

P=0.0003

-30%

Microvascular diseaseRetinopathy


Progression of microalbuminuria(baseline to study close)

Regression No change Progression

Placebo(n=4900)

400(8.2%)

3654(74.6%)

539(11.0%)

Fenofibrate(n=4895)

462(9.4%)

3583(73.2%)

466(9.5%)

Mann-Whitney test:P=0.002Albuminuria 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”


Other tertiary outcomes

300

0

Num

ber

of

hosp

italis

ati

ons

200

100

Placebo Fenofibrate

Hospitalisations for angina pectoris

RR = 0.82 (95% CI = 0.69-1.00)

p=0.04

100

0

Num

ber

of

hosp

italis

ati

ons

50

Placebo Fenofibrate

Amputations

RR = 0.69 (95% CI = 0.48-0.99)

p=0.04

252

75

25

5.1% 209

4.3%

74

1.5%51

1.0%


-18%

-31%

FIELD Conclusions

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:Conclusions (1)


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)



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)



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


This is the first time a lipid-lowering agent has reduced rates of both macrovascular and

microvascular events in an endpoint study



“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.”


Clinical implications of the FIELD study

Parameter 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 (210)

62.2 (6.2)

6.9 (6.17.8)

119

42

153

78

6%

Relatively early stage of disease

Optimal glucose control - same HbA1c at the end of the trial

Overall, 38% dyslipidemic*

Most patients in primary prevention

The FIELD study population

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

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

The FIELD study population

RRR = relative risk reduction; * p < 0.001

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 (6.17.8)

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*

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


22%Prior CVD

Why may fenofibrate be a therapeuticoption in diabetics without previous CVD?

Clinical implications of the FIELD study in patients Without previous CV disease

No prior CVD 100%

No prior CVD 78%

1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-612. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16

FIELD:1 significant benefiton total cardiovascular events(NNT= 50 pts for 5 years to prevent one or more CVD events in 1 patient)

CARDS:2 significant benefiton major cardiovascular events(NNT= 27 pts for 4 years to preventone CVD event in 1 patient)

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)

Take home messages1

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)


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

Take home messages2


FENOFIBRATE BIOAVAILABILITY

Fenofibrate Nanotechnology 145 mg

NANOTECHNOLOGY: a question of scale…

0.1 nm 1 nm 10 nm 100 nm 1 μm 10 μm 100 μm 1 mm 1 cm 10 cm 1 m

Nanoworld

moleculeprotein

DNACell

Hair Flea Butterfly Humanbeing

Lipanthyl300mg / 100mg

Lipanthyl200M / 160mg SUPRA

Lipanthyl145 NT

LIPANTHYL 145 NT entering into the Nanoworld

STANDARD MICRONIZED NanoCrystalTM Technology

200M SUPRA

Median Ø = 150µm Median Ø < 15µm Median Ø < 400 nm

145 NT

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

9Source: Elan Corp

Micronized fenofibrate

role of fenofibrate in diabetic dyslipidemia. diabetic dyslipidaemia occurs in type 2 diabetes...

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