Philip BarterSchool of Medical Sciences

University of New South WalesSydney, Australia

LDL, HDL and CVD:Epidemiology and Clinical Trials

Received honorariums for participating as a consultant or as a member of advisory boards for AMGEN, AstraZeneca, CSL-Behring, Lilly, Merck, Novartis, Pfizer and Roche and for giving lectures for AMGEN, AstraZeneca, Merck and Pfizer.

Disclosures

Lipoprotein fractions in plasma

Chylomicrons,VLDLs, and theircatabolic remnants

LDLs HDLs

Pro-atherogenic Anti-atherogenic

Fact

The concentration of non-HDL cholesterol is a positive predictor of the risk of having an atherosclerotic cardiovascular event.

The Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000.

Lipoproteins and Coronary Heart Diseasen = 302,430

Fact

The concentration of HDL cholesterol is an inverse predictor of the risk of having an atherosclerotic cardiovascular event.

The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000.

Coronary heart disease and HDL

0.8

1.0

1.5

2.0

2.5

3.0

3.5H

azar

d R

atio

N = 302,430

Adjusted for age and gender

Adjusted for multiple factors

40 60 80

HDL-C (mg/dL)30 50 70

Question

Does the level of HDL-C matter if the level of LDL-C is very low?

5 y

risk

of M

CV

Es (%

)

(<37) (37-42) (42-47) (47-55) (>55)

No of EventsNo of Patients

57 50 34 34 35473 525 550 569 544

10

8

6

4

2

0

HR (95% CI) vs Q1Q2 0.85 (0.57-1.25)Q3 0.57 (0.36-0.88)Q4 0.55 (0.35-0.86)Q5 0.61 (0.38-0.97)

Quintile of HDL-C (mg/dL)

TNT Trial: MCVE Frequency by HDL level in people with LDL-C < 1.8 mmol/L (70 mg/dL)

Barter et al, NEJM 2007, 357; 13, 1301-1310

What about plasma triglyceride?

The Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000.

Lipoproteins and Coronary Heart Diseasen = 302,430

CLINICAL INTERVENTION TRIALS TARGETING LDL-C

010

2030

400

40 80

50

CLINICAL INTERVENTION TRIALS: LDLR

ED

UC

TIO

N IN

MC

VE

s EV

ENTS

(%

)

REDUCTION IN LDL CHOLESTEROL(mg/dL)

JAMA. 1984; 251:365

LRC (cholestyramine)

010

2030

400

40 80

(mg/dL)

50

Posch

RE

DU

CTI

ON

IN M

CV

Es

EVEN

TS (

%)

(surgical ileal bypass)

JAMA. 1984; 251:365; Buchwald et al. Arch Intern Med. 1998;158:1253

REDUCTION IN LDL CHOLESTEROL

LRC (cholestyramine)

CLINICAL INTERVENTION TRIALS: LDL

Question

Is the reduction in CHD risk related to the magnitude of decrease in LDL-C?

010

2030

400

40 80

(mg/dL)

50

Posch

RE

DU

CTI

ON

IN M

CV

Es

EVEN

TS (

%)

LRC (cholestyramine)

(surgical ileal bypass)

JAMA. 1984; 251:365; Buchwald et al. Arch Intern Med. 1998;158:1253

REDUCTION IN LDL CHOLESTEROL

CLINICAL INTERVENTION TRIALS: LDL

010

2030

400

40 80

(mg/dL)

4SWOS

CARELIPID

AFCAPS

50

HPS

ASCOT

ALLHAT

CARDS

JUPITER

TNT

SEARCH

IDEAL

RE

DU

CTI

ON

IN M

CV

Es

EVEN

TS (

%)

LRC

Posch

REDUCTION IN LDL CHOLESTEROL

IMPROVE-IT

CLINICAL INTERVENTION TRIALS: LDL

End pointTreatment-arm

(n=84573)Control-arm (n=84565)

Relative risk(95% CI)

Any major vascular event

10973 13350 0.78 (0.76-0.80)

Any major coronary event

5105 6512 0.75 (0.70-0.82)

Any stroke 2302 2680 0.82 (0.74-0.92)

All statin clinical outcome trialsRelative risk reduction in major vascular events per 40 mg/dL

reduction in LDL-cholesterol

(26 Trials; 169,138 subjects; 24,323 events)

CTT Collaborators. Lancet. 2010; 376:1670-1681.

Number of Events

Any coronaryrevascularisation

5353 6807 0.71 (0.65-0.78)

What are the effects on CVD risk of lowering LDL-C with ezetimibe?

IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial

Ezetimibe 10 mg + simvastatin 40-80 mg

Simvastatin 40-80 mg18 000 patients• Men and

women • Aged 18 years• High-risk ACS

Continue until 5250 subjects have a primary event. Minimum 2.5-year follow-up

Study completed in 2014

Primary End Point Composite of CV death, major coronary

events, and stroke

010

2030

400

40 80

(mg/dL)

4SWOS

CARELIPID

AFCAPS

50

HPS

ASCOT

ALLHAT

MAJOR INTERVENTION TRIALS

CARDS

JUPITER

TNT

SEARCH

IDEAL

RE

DU

CTI

ON

IN M

CV

Es

EVEN

TS (

%)

LRC

Posch

REDUCTION IN LDL CHOLESTEROL

IMPROVE-IT

So, it is now proven beyond any doubt that LDL-C causes atherosclerotic CVD and that lowering the level of LDL-C reduces this risk

CLINICAL INTERVENTION TRIALS TARGETING TRIGLYCERDE AND HDL-C

The combination of a high triglyceride and low level of HDL cholesterol is associated with an increased risk of having a CV event

Fibrates lower triglyceride while raising HDL-C

Fibrates have potentially beneficial effects on all plasma lipoprotein

fractions

Effects of fibrates on plasma lipids

Plasma TG -35 to -40%

HDL-C +2 to +15%

LDL-C +5% to -15%

Lp(a) 0%

Clinical trials with fibrates

The results of CV clinical outcome trials with fibrates have been mixed

Fibrate On a statin• WHO: clofibrate No• HHS: gemfibrozil No• VA-HIT: gemfibrozil No• BIP: bezafibrate No• FIELD: fenofibrate No• ACCORD: fenofibrate Yes

Human Clinical Endpoint Studies with Fibrates

Fibrate Trial Positive•WHO: clofibrate No• HHS: gemfibrozil Yes• VA-HIT: gemfibrozil Yes• BIP: bezafibrate No• FIELD: fenofibrate No• ACCORD: fenofibrate No

Human Clinical Endpoint Studies with Fibrates

But while BIP with bezafibrate and FIELD and ACCORD with fenofibrate failed to achieve their primary endpoints, treatment with these fibrates significantly reduced ASCVD events in people with elevated plasma triglyceride and low HDL-C, especially if associated with obesity.

So, what are the effects of fibrates in subgroups with elevated plasma triglyceride, low HDL-C and obesity in the fibrate trials?

Helsinki Heart Study

A randomized, placebo-controlled trial of gemfibrozil in people with elevated levels of non-HDL-C

Treatment with gemfibrozil produced a significant 34% reduction in the incidence of nonfatal MI and CHD death

Frick et al. N Engl J Med. 1987;317:1237-45

Totalpopulation

0

10

20

30

40

50

60

70

G34%

Helsinki Heart Study: Total population

CH

D e

vent

s/10

00

Frick et al. N Engl J Med. 1987;317:1237-45

P

The reduction in events in this trial were even greater in people with elevated plasma TG, low HDL-C.

Helsinki Heart Study: effects of baseline TG on CHD Events

P

P

P

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Totalpopulation

TG ≤ 200 mg/dl

TG > 200 mg/dl

Manninen et al, Circulation, 1992

Helsinki Heart Study: effects of baseline TG on response to treatment

P

P

PG

34%

Totalpopulation

TG ≤ 200 mg/dl

TG > 200 mg/dl

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Manninen et al, Circulation, 1992

Helsinki Heart Study: effects of baseline TG on response to treatment

P

P

PG GG

34% 20% 56%

Totalpopulation

TG ≤ 200 mg/dl

TG > 200 mg/dl

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Manninen et al, Circulation, 1992

PP

Helsinki Heart Study: effects of baseline HDL-C on CHD events

P

Totalpopulation

HDL-C ≥ 40 mg/dl

HDL-C < 40 mg/dl

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Manninen et al, Circulation, 1992

PP

G G

34% 23%

Helsinki Heart Study: effects of baseline HDL-C on response to treatment

P

G44%

Manninen et al, Circulation, 1992

Totalpopulation

HDL-C ≥ 40 mg/dl

HDL-C < 40 mg/dl

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Totalpopulation

BMI ≤ 26 BMI > 26

G34%

Helsinki Heart Study: effects of BMI on response to treatment

Tenkanen et al, Circulation, 1995

P PP

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Totalpopulation

BMI ≤ 26 BMI > 26

GG

G34%16%

48%

Helsinki Heart Study: effects of BMI on response to treatment

Tenkanen et al, Circulation, 1995

P PP

0

10

20

30

40

50

60

70

CH

D e

vent

s/10

00

Tenkanen et al, Circulation, 1995

Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events

70

0

10

20

30

40

50

60

CH

D e

vent

s/10

00 P80

Totalpopulation

P

BMI > 26 kg/m2 plus TG>200, HDL-C<40)

G34%

Tenkanen et al, Circulation, 1995

Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events

70

0

10

20

30

40

50

60

CH

D e

vent

s/10

00 P80

Totalpopulation

P

BMI > 26 kg/m2 plus TG>200, HDL-C<40)

G34%

G78%

BIP Study

A randomized, placebo-controlled trial of bezafibrate in people with manifest ASCVD.

Treatment with bezafibrate produced a non-significant 9% reduction in the incidence of nonfatal MI and CHD death

BIP Study Group, Circulation, 2000;102:21-7

Totalpopulation

0

10

20

PB

9%

CH

D e

vent

s/10

00

BIP Study Group, Circulation, 2000;102:21-7

BIP Study: Total population

But there was a significant reduction in events in people with features of the metabolic syndrome

Totalpopulation

0

10

20

P

P

B9%

CH

D e

vent

s/10

00

TG > 200 mg/dl

BIP Study: effects of baseline TG on response to treatment

BIP Study Group, Circulation, 2000;102:21-7

Totalpopulation

0

10

20

P

P

B B

9%39%

CH

D e

vent

s/10

00

TG > 200 mg/dl

BIP Study: effects of baseline TG on response to treatment

BIP Study Group, Circulation, 2000;102:21-7

FIELD Study

A randomized, placebo-controlled trial of fenofibrate in people with type-2 diabetes

Treatment with fenofibrate produced a non-significant 11% reduction in the incidence of nonfatal MI and CHD death

Keech et al. Lancet. 2005;366:1849-61.

0

5

10

15

F11%

CH

D e

vent

s %

Totalpopulation

P

FIELD Study: Result in Total Population

Keech et al. Lancet. 2005;366:1849-61.

But there was a significant reduction in events in people with elevated levels of plasma triglyceride

0

5

10

15

CV

D e

vent

s %

P

P

FIELD Study: effects of baseline TG on CHD Events

Scott et al. Diabetes Care 32:493–498, 2009

Normal TG, normal HDL-C

High TG, low HDL-C

0

5

10

15

F

6%

CV

D e

vent

s %

P

P

FIELD Study: effects of baseline TG on response to treatment

Scott et al. Diabetes Care 32:493–498, 2009

Normal TG, normal HDL-C

High TG, low HDL-C

0

5

10

15

CV

D e

vent

s %

Normal TG, normal HDL-C

P

F

27%

High TG, low HDL-C

P

FIELD Study: effects of baseline TG on response to treatment

Scott et al. Diabetes Care 32:493–498, 2009

F

6%

ACCORD Study

The lipid arm of the ACCORD study was randomized, placebo-controlled trial of fenofibrate in statin-treated people with type-2 diabetes

Treatment with fenofibrate produced a non-significant 8% reduction in the incidence of nonfatal MI and CHD death

Totalpopulation

0

10

20

P F

8%

CH

D e

vent

s/10

00

ACCORD Study: Results in Total Population

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

But, again, there was a significant reduction in events in people with the combination of high plasma triglyceride and low HDL-C

Totalpopulation

0

10

20

P F

8%

CH

D e

vent

s/10

00ACCORD Study: effects of baseline TG and HDL-C on response to treatment

P

TG > 204HDL-C < 34

mg/dl

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

Totalpopulation

0

10

20

P

P

F F8%

29%

CH

D e

vent

s/10

00

TG > 204HDL-C < 34

mg/dl

ACCORD Study: effects of baseline TG and HDL-C on response to treatment

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

Subgroup analyses of fibrate studies

Trial (treatment)

Primary endpoint:

All patients

Lipid subgroup criteria (mg/dL)

Primary endpoint: Subgroup

ACCORD Lipid

(fenofibrate)

-8%

(p=0.32)

TG ≥ 200 +

HDL-C ≤ 34

-31%

(p=0.05)

FIELD

(fenofibrate)

-11%

(p=0.16)

TG ≥ 200 +

Low HDL-C

-27%

(p=0.005)BIP

(bezafibrate)

-7.3%

(p=0.24)

TG ≥ 200 -39.5%

(p=0.02)Helsinki Heart Study

(gemfibrozil)

-34%

(p=0.02)

TG> 200 -56%

(p<0.005)

Conclusions from Fibrate Trials

There is a consistent finding in the fibrate trials of a reduction in ASCVD events in people with high TG and low HDL-C, whether or not they are treated with a statin

There is a clear need to conduct a trial with fibrates in such a population.

Other HDL raising agents, including niacin and CETP inhibitors will be considered in a later lecture.