Download Relationship of HMGCR gene expression and statin efficacy

Global impact of ischemic heart disease
World Heart Federation, 2011
The Problems
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Despite recent advances in treatment, cardiovascular disease
(CVD) remains the leading cause of death in the US.
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From 1996 to 2006 the number of inpatient cardiovascular procedures
increased from 5,400,000 to 7,235,000 annually.
Costs of CVD in the U.S. – both direct and indirect – are estimated to
be $503 billion this year.
At the present rate, due in large part to the ticking time bomb of obesity
and poor nutrition in children, within 20 yr over 40% of the U.S.
population will have CVD, with a cost to our health care system of over
$1 trillion dollars per year.
While improved CVD prevention is of critical importance, there
are major barriers:
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Current screening does not identify many who are at risk.
Dietary and lifestyle guidance has failed to substantially impact risk
factors, particularly those related to overweight and obesity.
American Heart Association, Circulation 2010
Atherosclerotic cardiovascular disease is
a complex condition, involving:
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Lipid deposition
Inflammation
Shear stress
Arterial remodeling
Plaque rupture
Thrombosis
©2010 by American College of Physicians
Alsheikh-Ali et al. Ann Intern Med;153:387,2010
What are the major risk factors for CVD?
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Unmodifiable: age, family history, sex
Modifiable:
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Lipids: LDL (high) and HDL (low)
Elevated blood pressure
Smoking
Diabetes
Other factors
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Diet
Overweight/obesity
Physical activity
NHLBI Adult Treatment Panel 3, 2001
Risk of CHD after 4 yr
CHD Risk: HDL-Chol and LDL-Chol as Predictors
3.0
2.0
1.0
25
45
0.0
100
160
220
LDL Cholesterol mg/dL
65
85
HDL Cholesterol
mg/dL
Men aged 50–70 y in the Framingham Heart Study
Adapted with permission from Castelli WP. Can J Cardiol.4:5A. 1988
How well do standard cholesterol values
predict CVD risk?
LDL
cholesterol
HDL
cholesterol
mg/dL
MI Cases
(n=1575)
Controls
(n=1570)
146
44
139
48
Baseline values in Malmo Diet and Cancer Study
in myocardial infarction (MI) cases and controls at 15 year followup
I have some bad news. While your
cholesterol level has remained the same,
the research findings have changed.
• LDL and HDL are types of lipoprotein particles.
• Cholesterol is just one component of these partices.
• The particles are what influence heart disease risk.
Lipoprotein particles come in many sizes
Distinct LDL subclasses have differing properties
Very Small
Small
Medium
• Reduced blood clearance • Most abundant
• Greater entry in artery
subclass in healthy
• Faster oxidation
individuals
• Associated with
metabolic syndrome/
diabetes/obesity
• Genetic influences
Large
Lp (a)
• Multiple
atherogenic
effects
• Very strong
genetic influence
Distribution of subclasses varies widely among individuals and is
independent of total LDL cholesterol
LDL particle subclasses and CVD risk
Malmo Study (n=4,459; 312 CVD cases/12 years)
Ion mobility measurements
350
300
250
Particle conc.
nmol/L
†
*
†
*
3.5
Relation
to CVD risk
(Log1/p)
*
200
3.0
2.5
2.0
150
1.5
100
1.0
50
0.5
0
IDL large med small
LDL
v small
0
p<0.01
*
† Independent of LDL-C
Musunuru et al. ATVB 29:1975, 2009
Issues regarding HDL cholesterol as
a CVD biomarker and drug target
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There is strong epidemiologic and pathophysiologic
evidence for a relation of HDL cholesterol to CVD risk.
However, HDL is even more heterogeneous than LDL and
includes multiple subpopulations of particles with differing
functional properties and disparate effects on atherogenic
mechanisms.
HDL levels are regulated by pathways that also affect LDL
subclasses and other lipids; and Increases in HDL-C by
lifestyle and drug interventions can result from multiple
different metabolic effects.
There is as yet no conclusive evidence in humans for an
independent benefit of HDL increase on CVD outcomes.
Case study: AIM-HIGH study of HDL
raising with niacin added to statin
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All pts had CVD and most were on a statin at entry, with very
low LDL cholesterol during the study.
HDL cholesterol increased by ~22%.
During the 32 mo follow-up period, the rate of clinical events
was not different with niacin vs. placebo, and there was no
evidence that this would change by continuing the trial
(p<0.0001).
There was also an excess of strokes in the niacin group.
The study was terminated 5/26/11.
Thus, at least in the setting of maximal LDLreduction in
patients with CVD, there appears to be no benefit of raising
HDL-C with niacin.
New findings and issues involving
lipoproteins and CVD risk
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LDL
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There is considerable residual CVD risk with statins, the
drug class most widely used to reduce LDL levels
Statins are less effective in reducing small vs. large LDL
Genetic factors can contribute to variation in statin
efficacy
Effects of statin on inflammation appear to contribute to
CVD benefit, and are weakly correlated with LDL
reduction
New findings and issues involving
lipoproteins and CVD risk
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HDL
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There at least 30 different proteins in HDL particles that
may influence multiple functions.
One of these functions, the ability of HDL to promote
removal of cholesterol from arterial cells, is significantly
related to CVD risk benefit – and this effect is independent
of HDL cholesterol.
The specific features of HDL responsible for this effect are
poorly understood.
And, there appear to be some forms of HDL particles that
are pro-inflammatory, and hence may increase CVD risk.
Lipoproteins and CVD risk:
We've come a long way,
but have a long way to go….