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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.