DECLARATION OF CONFLICT OF
INTEREST
Honorariums from
• MSD,Boehringer,Eli-Lilly,SanofiAventis,Takeda
Research Funding from
• MSD,Eli-Lilly and Takeda
Elevated triglycerides and normal lowdensity lipoprotein – do drugs improve
outcomes ?
Professor Marja-Riitta Taskinen
Department of Medicine, Division of Cardiology
Helsinki University Hospital, Finland
The common high TG states
Obesity
Elevated VLDL1
concentrations
The Metabolic Syndrome
Type 2 diabetes
Insulin resistance
Patients with CAD
”Familial” low HDL
Familial combined
hyperlipidemia (FCH)
Familial high TG
Visceral obesity
The
atherogenic
triad
Low HDL
Small, dense
LDL particles
TG > 1.7- 2.26 mmol/l - borderline high
TG 2.26 – 5.69 mmol/l – high
TG > 5.65 mmol/l
- very high
Prevalence of elevated TG (>1.7 mmol/l)
by country in EUROASPIRE III
50
40
30
20
10
Kotseva K et al. Eur J Cardiovasc Prev Rehabil 2009;16;121-137
Evidence for the causality between
elevated TRLs and CVD
Epidemiology
Prospective studies
Meta-analysis
Genetic Studies
Lipoprotein lipase - Mutations
Proof of concept
animal studies
Various models - Positive
Clinical Intervention
Trials
The Coronary Drug Project
Stockholm IHD, HATS
AFREGS, ARBITER
HHS, VA-HIT, BIP
DAIS
FIELD, ACCORD
Triglyceride controversy
Triglyceride rich particles (TRLs) are
heterogeneous
The specific association of triglycerides with
risk for CHD has been at the best modest –
1.12 for men and 1.37 for women per/mmol/l
(88.6 mg/dl) of triglycerides (Hokanson JE and
Austin MA. J Cardiovasc Risk 1996)
The relative risk for CHD is variable in
different subgroups
Recent studies have rediscovered triglycerides
as CVD risk factor
Triglycerides and risk for coronary
heart disease
Sarwar N et al. Triglycerides and the risk
of Coronary Heart Disease. Circulation 2007;
115:450-458
Bansal S et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular
events in women. JAMA 2007;298:309-316
Nordestgaard BG et al. Non-fasting
triglycerides and risk of Myocardial Infarction,
Ischemic Heart Disease, and Death in Men
and Women. JAMA 2007;298:299-308
Association of major lipids with CHD in
a meta-analysis of 302430 subjects
Event
HR (95% Cl) per 1 SD change
HDL-C
CHD
TG
0.71 (0.68-0.75)
1.37 (1.31-1.42)
Non-HDL-C
1.56 (1.47-1.66)
0.78 (0.74-0.82)* 0.99 (0.94-1.05)* 1.50 (1.39-1.61)*
Ischemic Stroke 0.93 (0.84-1.02)* 1.02 (0.94-1.11)* 1.12 (1.04-1.20)*
*adjusted for lipid risk factors
CHD risk was increased by 37% per SD increase in
TG adjusted for non-lipid risk factors but adjustment
for HDL-C and non-HDL-C nullified the association
The Emerging Risk Factors Collaboration JAMA 2009;302;1993-2000
Hypertriglyceridemic waist phenotype in men
associates with CAD risk in EPIC-Norfolk study
12
Hazard ratio
Event-free survival
1.0
0.95
Normal waist/
normal TG
Normal waist/
elevated TG
Increased waist/
normal TG
Increased waist/
elevated TG
0.90
0.85
0.80
0
3
6
10
Hypertriglyceridemic
-waist phenotype
Absent
Present
8
6
4
2
9
Follow-up, years
12
0
Bottom
tertile
Middle
tertile
Top
tertile
Framingham risk score
Arsenault BJ. et al. CMAJ. 182:1427-1432, 2010.
Incidence of CHD by presence or absence of
IR at higher values of plasma triglycerides
IR
TG
HR (95% Cl)
age adjusted
P
value
HR (95% Cl)
multiadjusted
P
value
2.50 (1.52,4.11) <0.001
Yes ≥Median
3.01 (1.94,4.66) <0.001
Yes <Median
1.75 (0.89,3.47)
0.11
1.60 (0.79,3.25)
0.19
≥Median
1.18 (0.72,1.92)
0.51
0.96 (0.58,1.57)
0.86
No
Incident CHD risk associates with triglycerides
only in the presence of insulin resistance
Robins SJ. et al. ATVB 31:1208-1214, 2011.
Association of APOA5-1131T>C with
circulating lipid concentration per C allele
Mean difference per C allele
(95% Cl)
P value
l2 (95% Cl)
0.25 mmol/l
4.4x10-2.4 76% (67-83)
HDL cholesterol
-0.053 mmol/l
3.0x10-12 71% (59-86)
LDL cholesterol
-0.010 mmol/l
0.76
82% (74-87)
-0.023 g/L
0.01
42% (0-72)
9.0x10-4
37% (0-70
Triglyceride
Apolipoprotein AI
Apolipoprotein B
0.027 g/L
-5%
0
5% 15% 10% 20%
Carriers of two C alleles had 32.6% or 0.51mmol/l
higher mean TG level than did non-carriers
ERFC et al. Lancet 2010;375:1634-1639
1131T>C genotypes of APOA5 gene is strongly
related to CHD risk (20842 cases/35206 controls)
Risk ratio (95% Cl)
1.8
1.6
1.4
1.2
1.0
0.8
T/T
Genotype
T/C
C/C
The odds ratio for CHD was 1.18 (95% Cl 1.08-1.12)
per C allele. The data suggest a causal association between
TRL mediated pathways and CHD.
ERFC et al. Lancet 2010;375:1634-1639
Does high triglycerides in patients with
normal or low LDL-cholesterol matter?
● On-treatment TG level was not associated with CVD risk in
AFCAPS/ TexCAPS and not predictive of CVD event rate in VA-HIT
(Gotto AM. Circulation 2000;101:477-484; Robins SJ et al. JAMA 2001;285;1585-1591)
● In lipid trial each 89mg/dl decrease in on-treatment TG level in
patients given pravastatin significantly decreased CVD risk by 14%
(Simes RJ. et al. Circulation 2002;105:1162-1169)
● High risk statin treated patients with elevated TG levels display an
increased risk for CVD in pooled analysis of IDEAL and TNT
(Faergenan O. et al. Am J Cardiol. 2009;104:459-463)
Limited data exists on the benefits of lowering TG levels
by adding drugs on top of statin in high risk patients
www.escardio.org
Impact of triglycerides beyond LDL-chol on
CVD risk after ACS in the PROVE-IT TIMI
Ref.
P=0.180
%
Event Rate
20
15
10
5
0
15.0%
HR
0.85
P=0.017
P=0.191
17.9%
16.5%
11.7%
HR
0.84
HR
0.72
TG<1.7
LDL-C≥1.8
LDL-C<1.8
mmol/l
TG≥1.7
mmol/l
mmol/l
mmol/l
Miller et al. J Am Coll Cardiol 2008; 51:1724-30
CVD event rates and HRs over 5 years
according to lipid profile in the FIELD study
%
Placebo
Fenofibrate
20
15
10
15.4 0.87
0.86
0.84
0.77
p<0.05
17.8
% 0.73
p<0.05
17.3
% 0.69
p=0.06
%
5
0
mmol/l
TG>1.7
Low
TG>2.3
TG>1.7 TG>2.3
ACCORD
HDL-c* Low HDL-c*
Low HDL-c* High TG and
low HDL-chol
*Low HDL-c: < 1.03 mmol/l for men
< 1.29 mmol/l for women
Scott R et al. Diabetes Care 2009;32;493-498
Primary Outcome By Treatment Group and Baseline Subgroups
NEJM 2010;362:1563-1574
Meta-analysis of fibrate trials in subjects with
(n=2428) and without (n=2298) dyslipidemia
Subgroups with Dyslipidemia
Study
Complementary subgroups
Odds Ratio (95%Cl)
Study
Odds Ratio (95% Cl)
ACCORD
ACCORD
FIELD
FIELD
BIP
BIP
HHS
HHS
VA-HIT
VA-HIT
Summary
Summary
0.65 (0.54-0.78)
0.16
0.25
0.40
0.63
1.00
1.58
0.16
0.94 (0.84-1.05)
0.25
0.40
0.63
1.00
1.58
ACCORD lipid criteria TG ≥ 2.30 mmol/l, HDL-chol ≤ 0.88 mmol/l
Fibrate treatment may reduce CVD among patients with dyslipidemia
Sacks FM et al. NEJM 2010;363:692-694
Effects of fibrates on
cardiovascular and other outcomes
Event
Relative risk
(95% Cl)
P-value
Composite CVD event
0.90 (0.82-1.00)
0.048
Coronary event
0.87 (0.81-0.93)
<0.0001
Non-fatal coronary event
0.81 (0.75-0.89)
<0.0001
All cause mortality
1.00 (0.93-1.08)
0.918
Cardiac death
0.93 (0.85-1.02)
0.116
Cardiovascular death
0.97 (0.88-1.07)
0.587
Fibrates reduced the risk of major CV events by
having favorable effect on the risk of coronary events
Jun M. et al. Lancet 2010;375;9729:1875-1984
Impact of niacin on atherosclerosis
and clinical outcomes
Anti-atherosclerotic effects of niacin in combination
with a statin have been extensively documented in
plaque imaging studies
Meta-analysis of niacin trials, several of which involved
small patient numbers, is indicative of clinical benefit in
patients with cardiometabolic disease
AIM-HIGH and HPS2-THRIVE trials were designed to
evaluate whether ER niacin on top of statin therapy can
reduce the CV risk
HPS2-THRIVE will hopefully reveal whether niacinstatin therapy is effective across a wide spectrum
of dyslipidemic patients or only in those with high
triglycerides/ low HDL-C dyslipidemia
Chapman J. et al. Eur Heart J. 32;11:1345.1361, 2011
Recommendations for drug treatment of HTG
Classa
Levelb
I
B
Ila
B
- Niacin + laropiprant
IIa
C
- n-3 fatty acids
IIa
B
- Statin + nicotinic acidd
IIa
A
- Statin + fibrated
IIa
C
- combinations
with n-3 fatty acidse
IIb
B
Recommendations
In particular high risk patients (see above),
lowering of HTG by using the following drugs:
Is recommended:
- Fibrates
Should be considered: - Niacin
May be considered:
a Class of recommendation; b Level of evidence.
d Evidence for additional lipid lowering, compared with monotherapy.
e The evidence for prevention of CVD using combination therapy is in general limited.
CVD: cardiovascular disease; HTG: hypertriglyceridaemia.
www.escardio.org
Key messages and guidance
for clinical practice
● High-risk individuals with cardiometabolic disease
who achieve LDL-goal remain at high risk of CV
events
● Appraisal of evidence implicates elevated
triglycerides as a marker of TRL and their remnants
and low levels of HDL-C in this excess CV risk
● Elevated triglycerides (≥ 1.7 mmol/L or 150mg/ dL)
and/ or low HDL-C levels (<1.6 mmol/L or 40mg/dL)
should be triggers for concidering further treatment
in high-risk individuals
Chapman MJ et al. Eur Heart J 2011, Published ahead of print, doi:10.1093/eurheartj/ehr112
www.escardio.org
Evidence for the causality between
high
triglyceride and CHD events
Data from human epidemiological studies have
established the positive association between
triglyceride-mediated pathways and CHD events
Human genetic studies suggest a causal
association with triglyceride-mediated pathways
and CHD
Data from randomized trials of triglyceride
lowering agents support causality between
TRLs and the development of CHD
Risk of MI, IHD and Total Death by a 1 mmol/l
increase in nonfasting triglyceride levels
Hazard Ratio
(95% Confidence Interval)
Women
MI
IHD
Total death
Men
MI
IHD
Total death
Age-adjusted
Adjusted for age
and HDL Chol
Adjusted
multifactorially
Women
1.46 (1.34-1.59)
1.30 (1.22-1.40)
1.26 (1.20-1.32)
Men
1.18 (1.13-1.23)
1.14 (1.10-1.19)
1.10 (1.06-1.13)
Women
1.41 (1.26-1.57)
1.25 (1.14-1.37)
1.18 (1.11-1.26)
Men
1.16 (1.10-1.22)
1.12 (1.07-1.18)
1.10 (1.06-1.15)
Women
1.20 (1.05-1.37)
1.10 (0.99-1.21)
1.18 (1.10-1.27)
Men
1.04 (0.98-1.11)
1.00 (0.95-1.06)
1.08 (1.03-1.13)
Nordestgaard BG et al. JAMA 2007;298:299-308
Incidence of myocardial infarction by
levels of non-fasting Tg
Cumulative Incidence %
Women
100
90
80
70
Myocardial infarction
Triglycerides,mmol/l
<1
1-1.99
2-2.99
3-3.99
4-4.99
>5
100
90
70
Log-rank overall,P<0.001
60
50
Log-rank trend,P<0.001
50
40
40
30
30
20
20
10
10
0
0
Age, y
Log-rank overall,P<0.001
Log-rank trend,P<0.001
80
60
45 50 55 60 65 70 75 80 85 90 95 100
Men
45 50 55 60 65 70 75 80 85 90 95 100
Age, y
Nordestgaard BG et al. JAMA 2007;298:299-308
Association of Tg levels with cardiovascular
end points, according to fasting status
Fasting
Non-fasting
Myocardial infarction
Ischemic stroke
Revascularization
Cardiovascular death
All cardiovascular events
0.5 1.0
10
Fully adjusted HR (95% CI)
0.5 1.0
10
Fully adjusted HR (95% CI)
Non-fasting Tg levels are strongly associated with future CVD
events independent of traditional risk factors and other lipids
Bansal S et al. JAMA 2007;298:309-316
The achieved lipid concentration and effectiveness
of fibrate therapy on coronary events
Studies
(n)
Scale
per difference
Proportional
change in risk
ratio (95% Cl)
P value
LDL
7
0.1 mmol/L
0.98 (0.95-1.00)
0.086
HDL
7
0.02 mmol/L
0.97 (0.92-1.01)
0.127
TG
10
0.1 mmol/L
0.95 (0.90-0.99)
0.026
Tot chol
10
0.1 mmol/L
0.97 (0.91-1.02)
0.267
Fibrate therapy produced most benefit when
serum triglycerides were improved
Jun M. et al. Lancet 2010;375;9729:1875-1984
The Atherogenic Lipoprotein Profile
Lifestyle
Large
VLDL
Insulin resistance
Type 2 Diabetes
FCH subjects
Low HDL subjects
Genes
Small
dense
LDL
Increased
CAD Risk
HDL
HRs for future CHD according to NonHDL-C in the EPIC-Norfolk study (n=21448)
Non-HDL-C
Non-HDL-C
LDL-C
<130 mg/dl
≥130 mg/dl
LDL-C
<160 mg/dl
LDL-C
<190 mg/dl
<100 mg/dl
100-129 mg/dl
130-159 mg/dl
LDL-C
≥160 mg/dl
1.00
1.00
1.00
<160 mg/dl
1.00
1.84 (1.12-3.04)
≥130 mg/dl
1.26 (0.97-1.64)
≥180 mg/dl
1.38 (1.12-1.69)
≥190 mg/dl
1.78 (1.40-2.28)
Individuals with low LDL-C (<100mg/dl) with Non-HDL
chol >130mg/dl had HR of 1.84 for future CHD
Arsenault BJ. JACC 55; 35-41, 2009
Impact of triglycerides beyond LDL-chol on
CVD risk after ACS in the PROVE-IT TIMI
Ref.
P=0.180
%
Event Rate
20
15
10
5
0
15.0%
HR
0.85
P=0.017
P=0.191
17.9%
16.5%
11.7%
HR
0.84
HR
0.72
TG<1.7
LDL-C≥1.8
LDL-C<1.8
mmol/l
TG≥1.7
mmol/l
mmol/l
mmol/l
Miller et al. J Am Coll Cardiol 2008; 51:1724-30
Risk of CVD events as a function of triglycerides
and Non-HDL-c in Gopenhagen City Heart Study
Triglycerides mmol/l
Hazard Ratios
(95%/Cl)
Lowest
Middle
Higher
0.1-1.1
1.2-1.7
1.8-24.4
1
1.0
1.7
(0.7-1.6)
0.7-3.8
3.9-5.0
5.1-13.4
1
1.6
2.3
(1.0-2.4)
(1.2-2.7)
P
for trend
<0.001
Non-HDL-c
Lowest
Middle
Higher
(1.5-3.4)
<0.001
Langsted A et al. Circulation 2008;118:2047-2056
Associations of major lipids and
apoproteins with CHD
HR
95% Cl
LDL-C, per 33mg/dl
1.38
1.09 - 1.73
Non-HDL-C, per 43mg/dl
1.59
1.36 – 1.85
Apo B, per 29mg/dl
1.58
1.36 – 1.79
HDL-C, per 15mg/dl
0.77
0.72 – 0.83
Apo A-I, per 29mg/dl
0.78
0.72 – 0.86
Non HDL-C/HDL-C, per 1.53 Unit
1.50
1.38 – 1.62
Apo B/ Apo A-I, per 0.27 Unit
1.49
1.39 – 1.60
Adjusted for confounding factors and lipid markers
The Emerging Risk factors Collaboration JAMA 2009;302;1993-2000
Association of Tg levels with future
cardiovascular events, stratified by
time since last meal
Time from
last meal, h
No. of
No. of
participants events
Hazard Ratio
(95% CI)
2 to <4
2797
98
4.48 (1.98-10.15)
4 to <8
2594
92
1.50 (0.72-3.13)
8 to <12
4846
177
1.31 (0.73-2.36)
15272
609
1.04 (0.79-1.38)
> 12
0.5
1.0
10
Fully adjusted HR (95% CI)
Bansal S et al. JAMA 2007;298:309-316