Transcript 2008 ADA ACC Lipoprotein Consensus

ADA & ACC Consensus Statement
Lipoprotein Management in Patients
with Cardiometabolic Risk
Thomas Dayspring, MD, FACP
Clinical Assistant Professor of Medicine
University of Medicine and Dentistry of New Jersey
New Jersey Medical School
Attending in Medicine: St Joseph’s Regional Medical Center,
Paterson and Wayne, NJ
Diplomate: American Board of Clinical Lipidology
Certified Menopause Clinician: North American Menopause Society
North Jersey Institute of Menopausal Lipidology Wayne, New Jersey
ADA and ACC Consensus Statement
on Lipoprotein Management
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Lipoproteins are the particles composed of cholesterol,
triglycerides, phospholipids and apolipoproteins and they
interact with the artery wall and set off the atherosclerotic
cascade
Within each category of lipoproteins, the size, density and
lipid composition vary
Atherosclerosis results from interactions between modifiedlipoproteins and monocyte-derived macrophages,
components of innate immunity and cellular elements of the
artery
There is a curvilinear relationship between increasing
plasma cholesterol and incidence of CVD
Measurements of cholesterol are indirect estimates of
lipoproteins transporting cholesterol
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
Overweight/Obesity
Genetics
• LDL
Age
Insulin Resistance
Insulin Resistance
Syndrome
Lipids
Abnormal Lipid Metabolism
BP
• ApoB
?
• HDL
Cardiometabolic Risk
• Triglycerides
Global Diabetes/CVD Risk
Glucose
Age, Race, Gender,
Family History
Smoking,
Physical Inactivity,
Unhealthy Eating
Hypertension
Inflammation,
Hypercoagulation
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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A plasma level of 25 mg/dL is sufficient to supply peripheral
cholesterol needs
Individuals with genetic mutations causing low LDL-C avoid
CVD and are free of other abnormalities that might
conceivably be linked to very low cholesterol levels
The dyslipoproteinemia of insulin resistance is
characterized by elevated VLDL, lower HDL-C and altered
distributions of all lipoprotein classes
• Increased VLDL production and decreased clearance causing
increased levels of large and intermediate VLDL particles
• Increased numbers of small, dense LDL particles which are easily
oxidized, glycated and able to bond to intimal proteoglycans
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Despite the usefulness of LDL-C for CVD prediction on a
population level, the measure has limitations for individual
risk assessment
LDL-C is estimated using the Friedewald Equation, but this
underestimates LDL-C as TG levels increase
• LDL-C = TC – [HDL-C + VLDL-C)
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VLDL-C = TG/5
However, the cholesterol content of LDL particles varies
from person to person and is influenced by insulin
resistance and hyperglycemia
Hence, LDL-C may not accurately
represent atherogenic burden in those
with cardiometabolic risk
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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A more accurate way to capture may be to measure LDL
particles directly using Nuclear Magnetic Resonance (NMR)
Cross-sectional and prospective studies show LDL-P is
a better discriminator of risk than is LDL-C
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MESA (Multiethnic Study of Atherosclerosis)
PLAC-1 (Pravastatin Limitation of Atherosclerosis in Coronary Arteries)
WHS (Women’s Health Study)
VA-HIT (Veteran’s Affairs HDL Intervention Trial)
EPIC-Norfolk Population Study
Framingham Offspring Study
LDL size can also be measured. The association of small
LDL and CVD may simply reflect the increased numbers of
LDL particles in patients with small LDL.
Hence it is unclear whether LDL size adds value
to measurement of LDL-P
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
Lipoprotein (a)
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There is little evidence the insulin resistance or diabetes
influences Lp(a) concentrations.
The utility of routine measurement of Lp(a) is unclear
More aggressive control of other lipoprotein parameters
may be warranted in those with high concentrations of Lp(a)
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Non HDL-C reflects the concentration of cholesterol within
lipoproteins considered atherogenic and adds no expense
and can be calculated from nonfasting specimens
Non-HDL-C = TC – HDL-C or VLDL-C + LDL-C
Many studies have demonstrated non-HDL-C is a better
predictor of risk than is LDL-C
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STRONG Heart Study
Physicians Health Study
Framingham Cohort and Offspring Studies
Multiple Risk Factor Intervention Trial (Mr FIT )
Lipid Research Clinics Prevalence Follow-up Study (LRCF)
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Each Chylomicrons, VLDL, IDL, LDL and Lp(a) contains a
single molecule of apolipoprotein B, making apoB
measurement a marker of atherogenic particles
• Does not require fasting and assay is standardized
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In several epidemiological and post-hoc analyses of clinical
trials apoB has been a better predictor of risk than LDL-C,
particularly the on-treatment level of LDL-C
Once LDL-C is lowered apoB may be a more effective way
to assess residual CVD risk and to determine the need for
medication adjustments
The differences between apoB, LDL-C and non-HDL-C are
more pronounced in patients with cardiometabolic risk,
suggesting apoB is a more useful predictor among these
patients
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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HDL-C levels are string inverse predictors of CVD events in
diabetic and nondiabetic populations
It has been difficult to determine whether raising HDL-C
independently reduces CVD events, because all such
interventions also affect concentrations of other lipoproteins
Strategies to raise HDL-C remain a promising area of
research that may be particularly valuable in patients with
cardiometabolic risk
Measurements of HDL subfractions or apoA-I appear to
provide little clinical value beyond HDL-C
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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In the fasting state most TG are found in VLDL, so plasma
TG are used as a surrogate measure of VLDL
TG are a univariate predictor of CVD in many studies but
often not an independent predictor in multivariate analyses
• This is because TG are linked to HDL and LDL abnormalities
• There are no clinical trial data establishing that lowering TG in
individuals with or without diabetes independently leads to lower
CVD event rates when one adjusts for HDL-C
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Chylomicron remnants may be atherogenic in a manner
similar to VLDL remnants, but there is little population
based evidence liking chylomicron remnants
(measurements of which are not available) to CVD
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management



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HDL-C levels are strong inverse predictors of CVD events
in diabetic and nondiabetic populations
It has been difficult to determine whether raising HDL-C
independently reduces CVD events, because all such
interventions also affect concentrations of other lipoproteins
Strategies to raise HDL-C remain a promising area of
research that may be particularly valuable in patients with
cardiometabolic risk
Measurements of HDL subfractions or apoA-I appear to
provide little clinical value beyond HDL-C
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Good clinical practice calls for a comprehensive evaluation
of current vascular health, factors related to
dyslipoproteinemia and other factors affecting global risk
• Determine to the extent possible magnitude of future risk
• Identify modifiable prognostic risk factors
• Establish a treatment plan in terms of scope and intensity
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Subclinical disease may be determined by
• Coronary Calcification
• Carotid intima-media thickness
• Ankle-brachial index
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Other metabolic risk factors include BP, smoking,
hyperglycemia, diet, inactivity, chronic renal disease
Family history of premature CAD in siblings is a powerful
risk predictor
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
Other markers
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The independent predictive power and clinical utility of
C-reactive protein, fibrinogen and homocysteine are still
unclear.
CRP is often elevated in patients with cardiometabolic risk,
but utility of its measurement in people already known to be
at risk is unknown
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Dyslipoproteinemia implies the presence of increased
number of atherogenic lipoproteins and/or a reduced
protective capacity of HDL beyond what is considered
optimal
• It is present when triglycerides are high, HDL-C is low, and/or there
is atherogenic particle excess (such as high LDL-C or small LDL-P)
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Lifestyle and pharmacologic therapy should be started
concurrently in subjects with CVD and those with diabetes
and multiple CVD risk factors regardless of baseline LDL-C
Pharmacologic therapy is recommended for moderately
high-risk primary prevention patients if LDL-C remains
> 100 after several months of lifestyle changes
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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For patients who cannot tolerate a statin or the maximum
statin therapy does not achieve treatment goals, other
LDL-C lowering drugs include ezetimibe, bile-acid
sequestrants or niacin. Each of these drugs enhance the
LDL-C lowering of statins.
• BAS or niacin with statins selectively decrease small LDL particles
• BAS used alone can aggravate TG
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NCEP-ATP III established Non-HDL-C as a secondary
target in those with hypertriglyceridemia or metabolic
syndrome but the use of this measure has not been widely
adopted
Both LDL-C and Non HDL-C focus on cholesterol which is
only a surrogate given that atherosclerosis is mediated by
lipoproteins
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Measurement of apoB or LDL-P by NMR may more closely
quantitate the atherogenic lipoprotein load
Studies suggest that both are better indices than LDL-C or
non-HDL-C and more reliable indexes of on-treatment
residual risk
• PLAC-1, WHS, AFCAPS-Tex-CAPS, AMORIS, INTER-HEART,
4S, LIPID
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Statins lower non-HDL-C more than they lower apoB and
several studies show reaching apoB target usually requires
more intensive therapy than achieving the equivalent level
for non-HDL-C
ApoB and LDL-P appear to be more closely associated with
cardiometabolic risk factors than LDL-C
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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When both non-HDL-C and apoB are measured, the two
are highly correlated, but only moderately concordant
At any given level of non-HDL-C there will be wide
variations of apoB levels and vice versa indicat9ing the
correlation is of limited value for assessing individual risk
• This lack of concordance is particularly marked in patients with
elevated triglyceride levels
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The panel concludes that routine use of non-HDL-C
constitute a better index than LDL-C for identifying high
risk patients
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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LDL-C should not be abandoned
• Many years of public and professional education geared towards
LDL-C has resulted in its successful integration into the fabric of
CVD prevention and treatment
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Non HDL-C should be provided on all laboratory reports
and should also be used to ascertain risk in patients with
low to moderate LDL-C levels (i.e., LDL-C < 130 mg/dL)
Measurement of apoB is warranted in patients with
cardiometabolic risk on pharmacologic treatment
In particular apoB should be used to guide adjustments to
therapy
LDL-P as measured by NMR appears equally informative
as apoB
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
Particle Quantification
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Measurement of apoB is warranted in patients with
cardiometabolic risk on pharmacologic treatment
In particular apoB should be used to guide
adjustments to therapy
LDL-P as measured by NMR appears equally
informative as apoB
The panel recommends that the apoB goal be
reached
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
TREATMENT GOALS
Highest-risk patients, including
those with 1) known CVD or
2) Diabetes plus one or more
additional CVD risk factor
High-risk patients, including
those with 1) no diabetes or
known clinical CVD but 2 or
more additional major CVD
risk factors or 2) Diabetes but
no other CVD risk factors
LDL-C Non-HDL-C ApoB
(mg/dL)
(mg/dL) (mg/dL)
< 70
< 100
< 100
< 130
< 80
< 90
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
TREATMENT GOALS:
LDL-C
non-HDL-C
ApoB
LDL-P
< 70
< 100
< 80
< 1000
< 100
< 130
< 90
< 1300
Highest-risk patients
•
known CVD or
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CMR plus one or
more additional
CVD risk factor
High-risk patients
•
no CMR or known
clinical CVD but 2
or more additional
major CVD risk
factors
•
CMR but no other
CVD risk factors
ADA and ACC Consensus Statement
on Lipoprotein Management
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Elevations of TG and reduced HDL-C are the most common
abnormalities of the standard lipid panel in subjects with
obesity and insulin resistance-related cardiometabolic risk
It has been difficult to demonstrate that lowering TG is
independently associated with a reduction in CVD events
Clinical trial evidence supporting treatment of low HDL-C is
modest compared with that for LDL-C lowering
For these reasons NCEP ATP-III recommended non HDL-C
as a secondary target of treatment with a goal 30 mg/dL
> than the LDL-C goal
The panel recommends that the apoB goal be reached
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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The exception to not targeting TG is the relatively small
proportion of patients with severe hypertriglyceridemia in
whom the initial treatment priority is to reduce the risk of
pancreatitis by combining fat restriction with fibrate, niacin
or high-dose n-3 FA therapy
A statin is the initial drug of choice for the vast majority of
people with cardiometabolic risk who have high TG
and low HDL-C
In patients on statins who continue to have low HDL-C or
elevated non-HDL-C, especially if apoB remains elevated,
combination therapy is recommended
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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The preferred agent to use in combination with a statin is
niacin because there is somewhat better evidence for
reduction in CVD events with niacin than there is for fibrates
Fibrates have been shown to reduce CVD events in some
studies but not mortality
N-3 fatty acid therapy lowers TG levels at high doses (≥ 4
grams/day) and may be another option to consider to lower
non HDL-C in patients on statin therapy, but CVD outcome
data are lacking for hypertriglyceridemic patients
In diabetic patients, enhanced glycemic control may
improve lipid and lipoprotein abnormalities, particularly
hypertriglyceridemia
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Niacin decreased CVD in the Coronary Drug Project and
total mortality in an extended follow up
Niacin in combination with bile-acid sequestrants was
associated with regression of atherosclerosis and CVD
events in several studies
• FATS, HATS, ARBITER 2, CLAS
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Although niacin has been associated with insulin
resistance, in diabetes the use of low dose niacin (1500
mg/day) does not significantly increase A1C levels
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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In observational studies, low HDL-C is a powerful predictor
of risk for CVD and remains a risk factor even in patients
with low HDL-C
Because a recent trial with a CETP inhibitor to raise HDL-C
was terminated because of excess CV risk, it remains
unclear if raising HDL-C per se reduces CV risk
It may be that by increasing HDL-C by modifying the
reverse cholesterol pathway may paradoxically increase
CV risk, while other mechanisms to increase HDL-C may
lead to a reduction in risk
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Monotherapy with statins, fibrates, niacin and bile acid
sequestrants have been shown to reduce CV events in
clinical trials but there is not yet robust evidence for
incremental benefits or risks of combination therapy
compared with those of monotherapy
Results of on-going and future trials of statin-niacin, statinfibrate, and statin-n-e fatty acids will answer these
questions
Although statin therapy is highly effective in reducing CVD
risk in primary and secondary prevention, there remain
subsets of patients regarding whom more data are needed
• These include elderly, chronic kidney disease and young patients
with cardiometabolic risk
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
on Lipoprotein Management
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Patients with cardiometabolic (CMR) risk factors have a
high lifetime risk for CVD.
• They have low HDL-C, increased TG and/or increased
numbers of small LDL particles
The panel recommends for patients with CMR risk
• Statin therapy for the majority
• Guide therapy with measurements of apoB and treat
to apoB goal
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
SUMMARY SLIDES
ADA and ACC Consensus Statement
In Patients with Cardiometabolic Risk
Summary
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Lipoprotein abnormalities are common findings in patients
with CMR. Measurement of LDL cholesterol may not
accurately reflect the true burden of atherogenic LDL
particles, especially in those with typical lipoprotein
abnormalities of CMR.
Even with adequate LDL cholesterol lowering, many
patients on statin therapy have significant residual CVD
risk. Treatment targets and the best approach for CVD risk
reduction in this population need to be better defined.
Some have advocated that assessment of other lipoprotein
parameters might be more helpful than assessment limited
to LDL-C or non-HDL cholesterol in these populations.
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
In Patients with Cardiometabolic Risk
Summary
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A more accurate way to capture the risk posed by LDL may
be to measure the number of LDL particles directly using
nuclear magnetic resonance (NMR)
“Many cross-sectional and prospective studies show that
LDL particle number is a better discriminator of risk than is
LDL cholesterol.”
Measurements of apoB or LDL particle number by NMR
may more closely quantitate the atherogenic lipoprotein
load.
Some studies suggest that both are better indices of CVD
risk than LDL cholesterol or non-HDL cholesterol and more
reliable indexes of on-treatment residual CVD risk.
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
ADA and ACC Consensus Statement
In Patients with Cardiometabolic Risk
Summary
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ApoB and LDL particle number also appear to be more
discriminating measures of the adequacy of LDL lowering
therapy than are LDL cholesterol or non-HDL cholesterol.”
ApoB and LDL particle concentration also appear to be
more closely associated with obesity, diabetes, insulin
resistance, and other markers of CMR than LDL cholesterol
or non-HDL cholesterol.”
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822
LIPOSCIENCE PRESS RELEASE
Quantitating Lipoprotein Particles
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Cardiometabolic Risk (CMR) is associated with Type 2
Diabetes and CVD – obesity, insulin resistance,
hyperglycemia and hypertension are risk factors that often
cluster together.
ApoB and LDL particle concentration appear to be more
closely associated with these markers of CMR than LDL
cholesterol or non-HDL cholesterol.
• Subsequently, lipoprotein abnormalities are commonly found in
patients with CMR.
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According to the consensus statement, ApoB and LDL
particle number by NMR appear to be more discriminating
measures of the adequacy of LDL lowering therapies than
are traditional LDL and HDL cholesterol measures.
Quantitating Lipoprotein Particles
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The American Diabetes Association (ADA) and the
American College of Cardiology (ACC) issued a consensus
statement today that states the measurement of LDL
particle number by nuclear magnetic resonance (NMR) is
one of the more accurate ways to evaluate cardiometabolic
risk (CMR).
The study, published in the April issue of Diabetes Care
2008;31:811-822, reinforces that LDL cholesterol may not
be the best way to quantify a patient’s risk for
cardiovascular disease (CVD).
Quantitating Lipoprotein Particles
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The NMR LipoProfile® test, developed by LipoScience, Inc.,
is the only test that quantifies LDL particle number (LDL-P)
using Nuclear Magnetic Resonance.
LDL particle information is used by clinicians to monitor the
effect of lipid altering interventions, such as statins, in the
management of a patient’s cardiovascular health by
lowering LDL particle number (LDL-P).