Risk factors in heart disease
Optimizing patient care
William Cromwell, MD, FAHA, FNLA
Chief Medical Officer – LipoScience, Inc.
Chief – Lipoprotein and Metabolic Disorders Institute
Adjunct Associate Professor – Wake Forest University School of Medicine
Disclosures
William Cromwell, MD, FAHA, FNLA
Current Perspectives on LDL Management
1. The causal link between high levels of low-density lipoprotein (LDL)
and the development of CVD is well established 1

Increased numbers of circulating LDL particles accelerates development
of atherosclerotic cardiovascular disease

The longer the exposure to high LDL, the greater the risk of CVD events
2. Lowering LDL is a central tenet of clinical practice

2013 ACC/AHA guidelines recommend a two step approach to managing
LDL-related CVD risk 1
- Use moderate or high dose statin therapy in selected populations;
- Monitor LDL levels on therapy and use clinical judgment in determining
next steps in patient management.
1. Stone NJ, et al. Circulation 2014;129:S1-S45.
2. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.
3. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.
4. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.
5. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.
6. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.
7. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.
8. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.
Two Ways To Measure LDL Quantity
 LDL cholesterol (LDL-C) is the traditional measure of LDL, chosen
for historical, not analytic or clinical reasons.
 Alternatively, LDL can be measured by particle number (LDL-P), or
estimated by apolipoprotein B.
 Due to differences in the amount of cholesterol contained in LDL,
alternate LDL measures (LDL-C vs. LDL-P) frequently disagree
(discordance).1-7
Triglycerides
Triglycerides
LDL Particle
LDL Particle
LDL-P
LDL-P
LDL-C
LDL-C
Cholesterol
Cholesterol
1. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.
2. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.
3. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.
4. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.
5. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.
6. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.
7. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.
Alternate LDL Measures (LDL-C versus LDL-P)
Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697)
Otvos et al. J Clin Lipidol 2011;5:105-13
Alternate LDL Measures (LDL-C versus LDL-P)
Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697)
Discordant Measures
LDL-C (mg/dL)
79
LDL-C and LDL-P
Different
(50% Subjects)
90 100 108 116 123 131 141 157
LDL-P > LDL-C
LDL-P percentile
80
Concordant Measures
1750
Less Cholesterol
per Particle
1580
70
1460
60
1360
50
1270
40
1190
30
1100
20
LDL-P < LDL-C
1000
10
More Cholesterol
per Particle
880
LDL-C and LDL-P
Similar
(50% Subjects)
Otvos et al. J Clin Lipidol 2011;5:105-13
10
20
30
40
50 60
70
LDL-C percentile
80
90
LDL-P (nmol/L)
90
Alternate LDL Measures (LDL-C versus LDL-P)
Type II Diabetes Mellitus Subjects (n=2,355)
5th
20
1%
(n=19)
20th
24%
(n=364)
50th
43%
(n=631)
80th
21%
(n=307)
percentile
11%
(n=163)
15
Percent
of
Subjects
LDL-C
70-99 mg/dL
(5th – 20th
Percentile)
10
5
(n=1,484)
0
700
20
16%
(n=147)
1000
43%
(n=377)
1300
30%
(n=260)
1600 (nmol/L)
9%
(n=76)
2%
(n=15)
15
Percent
of
Subjects
40%
LDL-C
10
< 70 mg/dL
(< 5th Percentile)
5
(n=871)
0
700
Cromwell WC, Otvos JD. AJC 2006;98:1599-1602
1000
1300
1600 (nmol/L)
Alternate LDL Measures and Cardiovascular
Disease
1. Cardiovascular risk tracks with LDL particle number
– When alternate LDL measures (LDL-C vs LDL particle number) agree
(concordance) each measure is equally associated with CVD risk.
– When alternate measures are discordant (e.g., diabetes, metabolic
syndrome, statin therapy), risk tracks with LDL-P, not LDL-C.1-5
1. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.
2. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.
3. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.
4. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345.
5. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449.
Associations of Alternate LDL Measures with CHD
Framingham Offspring Study (n=3,066)
1.00
Better survival
Lower risk
0.98
0.96
Low LDL-C
Low LDL-P
(n=1,249)
0.94
Event-Free Survival
0.92
Worse survival
Higher risk
0.90
0.88
High LDL-C
Low LDL-P
(n=284)
High LDL-C
High LDL-P
(n=1,251)
0.86
0.84
Better Survival
Lower Risk
Worse Survival
Higher Risk
0.82
Low LDL-C
High LDL-P
(n=282)
0.80
0.78
Concordant
0.76
Discordant
0.74
0
1
2
3
4
5
6
7
8
9
Years of Follow-up
Cromwell WC et al. J Clin Lipidol 2007;1(6):583-592.
10 11 12 13 14 15 16
LDL-P and LDL-C Discordance in MESA
Relations with Incident CVD Events
0.08
Percent
Cumulative
Incidence
Cumulative
Incidence
MetSyn
LDL-P >> LDL-C
LDL-C
LDL-P
Concordant
Concordant
0.06
60.06
LDL-P << LDL-C
LDL-C
LDL-P
54%
33%
16%
LDL-C underestimates
LDL-attributable risk
0.04
40.04
0.02
20.02
3
4
22 2
3
4
3
Follow-up (years)
Follow-up (years)
Otvos et al. J Clin Lipidol 2011;5:105-13
4
5
5
5
104
1372
117
1249
1117
mg/dL
nmol/L
0
111
LDL-P
130
LDL-C overestimates
LDL-attributable risk
0
00
LDL-C
6
High LDL
Despite
Low LDL-C
Low LDL
Despite
High LDL-C
LDL-P and LDL-C Discordance in MESA
CVD Event Rates in Subgroups with Low LDL-C
Incidence
Cumulative
Incidence
Percent
Cumulative
0.08
Low: < 30th percentile
LDL-C < 100 mg/dL
LDL-P < 1060 nmol/L
0.06
60.06
LDL-P
LDL-C
(n)
Not Low
Low
(516)
Discordant
High LDL-P
0.04
40.04
Concordant
Low
0.02
20.02
00
0
0
Otvos et al. J Clin Lipidol 2011;5:105-13
1
1
2
3
4
2
3
4
Follow-up (years)
5
5
6
Low
(1115)
LDL-P and LDL-C Discordance in MESA
CVD Event Rates in Subgroups with Low LDL-P 1
Incidence
Cumulative
Incidence
Percent
Cumulative
0.08
Low: < 30th percentile
LDL-C < 100 mg/dL
LDL-P < 1060 nmol/L
0.06
60.06
LDL-P
LDL-C
(n)
Not Low
Low
(516)
Discordant
High LDL-P
ACC/AHA Threshold for
Considering Statin Therapy
(7.5% risk over 10 years) 2
0.04
4
0.04
Concordant
0.02
20.02
Low
Low
Low
Not Low (553)
00
0
0
1
1
1. Otvos et al. J Clin Lipidol 2011;5:105-13
2. Adapted from Stone et al. Circulation. 2013
2
3
4
4
3
2
Follow-up (years)
5
5
6
(1115)
A Meta-Analysis of Low-Density Lipoprotein
Cholesterol, Non-High-Density Lipoprotein
Cholesterol, and Apolipoprotein B as
Markers of Cardiovascular Risk
Allan D. Sniderman, MD; Ken Williams, MSc; John H.
Contois, PhD; Howard M. Monroe, PhD; Matthew J.
McQueen, MBChB, PhD; Jacqueline de Graaf, MD, PhD;
Curt D. Furberg, MD, PhD
Circulation. Cardiovascular quality and outcomes.
2011;4(3):337-345.
Meta-Analysis of LDL-C, Non-HDL-C, and ApoB
as Markers of Cardiovascular Risk
Study Design:
Meta-analysis of all published epidemiologic studies with estimates of
relative risks of fatal or nonfatal ischemic cardiovascular events and
measures of non-HDL-C and apoB.
12 independent reports, including 233,455 subjects and 22,950
events, were analyzed.
Major Findings:
Whether analyzed individually or in head-to-head comparisons, apoB
was the most potent marker of cardiovascular risk.
Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
Meta-Analysis of LDL-C, Non-HDL-C, and ApoB
as Markers of Cardiovascular Risk
Conclusions:
“The present analysis indicates that non-HDL-C is superior to LDL-C
as a marker of cardiovascular risk.”
“The conventional explanation would be that the gain in predictive
power is due to the cholesterol in VLDL.”
“The superiority of non-HDL-C over LDL-C is due to the fact that nonHDL-C is a better marker of LDL-P than LDL-C.”
“When apoB and non-HDL-C are concordant, they will predict risk
equally, whereas when they are discordant, apoB will be superior.”
Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
LDL Subclasses: 2011 National Lipid
Association Recommendations
“Many studies document links between
small dense LDL particles and
atherosclerotic CVD.”
“However, these statistical associations
between small, dense LDL and CV
outcomes are either significantly
attenuated or abolished when the
analyses are adjusted for the overall
number of circulating LDL particles
(LDL-P) either by adjustment for Apo B
levels or by adjustment for nuclear
magnetic resonance-derived LDL-P.”
Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.
LDL Subclasses: 2011 National Lipid
Association Recommendations
“To date, there is no evidence that the
shift in LDL subfractions directly
translates into change in disease
progression or improved outcome.”
“The NLA Biomarkers Expert Panel was
unable to identify any patient subgroups
in which LDL subfractionation is
recommended.”
Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.
Expectations for Novel Risk Tests versus
An Alternate Measure of an Established Target
Intended
Application
Type of Biomarker
Clinical Use
Impact on
Clinical Decision
Making
Evidence Needed to Support Use
Biomarker is
used to
enhance risk
assessment
Allocate patient to
different risk
category
Significant improvement in risk
stratification with the addition of new
biomarker (net reclassification) 1
Novel Biomarker
Risk
Assessment
(lipoprotein particle
size / subclasses,
Inflammatory
measures)
Novel Biomarker
(LDL particle size,
Inflammatory
measures)
Risk
Management
Newer Measure of
an Established
Target
Biomarker
serves as a
treatment goal
(e.g., LDL particle
number)
1, Ge Y, Wang TJ. J Intern Med. 2012;272(5):430-439.
2. Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822
Modify therapy
(different agents,
dosage, or
combinations) as
indicated to
achieve new
therapeutic goal
Outcome improvement established
independent of other risk factors
1. Newer measure consistently
outperforms the old measure in
the setting of discordance.2
2. Improved outcomes are noted
when subjects are treated to
equivalent levels of the new
versus old measure.
Recommendations for Using LDL Particle
Number Measures as Targets of Therapy
Recommendations for Using LDL Particle
Number Measures as Targets of Therapy
Step 1: Stratify ASCVD risk and initiate therapy
(Statin therapy if triglyceride levels < 500 mg/dL)
Step 2: Assess adequacy (laboratory testing) and tolerance of therapy
Risk Level
Moderate Risk
High Risk
DM but no other major risk
and/or age < 40
DM + major CVD risk(s)
(HTN, Family History, Low HDL-C,
smoking) or CVD
Desirable Level
LDL-P (nmol/L)
< 1200
< 1000
apoB (mg/dL)
< 90
< 80
Step 3: If not at desired level intensify therapeutic lifestyle, consider additional therapy
 Intensify statin therapy;
 Consider combination statin &/or ezetimibe &/or colesevelam &/or niacin
Step 4: Assess adequacy / tolerance of therapy with and consider additional
therapeutic adjustment.
Adapted from Garber AJ, et al. Endocr Pract 2013;19 (Suppl 2):1-48.
Recommendations for Using LDL Particle
Number Measures as Targets of Therapy
• “These data indicate that both Apo B and LDL-P were generally in
agreement in their association with diverse clinical outcomes (58.8%), but
with a substantial amount of discordance (21.2%) in which one biomarker
was statistically significant whereas the other was not.”
• “In these cases, LDL-P showed a significant association with a clinical
outcome more often than apo B alone, and the level of statistical
significance, as indicated by the P value, and the strength of association,
as indicated by the OR, RR, and HR, was more often higher for LDL-P
than it was for apo B.”
Cole TG, et al. Clinical Chemistry February 2013;59(5):752-770
2013 ACC / AHA Cholesterol Guidelines
2013 ACC / AHA Cholesterol Guidelines
Overview
1. Objective:
Produce treatment recommendations, based on randomized controlled
trial (RCT) data, to reduce atherosclerotic cardiovascular disease
(ASCVD) risk.
2. Based on RCT data significant emphasis was placed on identifying
populations most likely to benefit from statin therapy.
“Because the overwhelming body of evidence came from statin RCTs,
the Expert Panel appropriately focused on these statin RCTs to
develop evidence-based guidelines for the reduction of ASCVD risk.” 1
1. Stone et al. Circulation. 2013
ASCVD Statin Benefit Groups
No
Stone et al. Circulation. 2013
2013 ACC / AHA Cholesterol Guidelines
Role of LDL Testing
1.
While acknowledging the causal role of LDL in ASCVD, due to exclusive
reliance on RCT data no recommendation was made for LDL treatment goals.
“The panel makes no recommendations for or against specific LDL-C or nonHDL-C targets for the primary or secondary prevention of ASCVD.” 1
2. Although no goal is endorsed, LDL testing is advocated to aid clinical
management
– ATP III Recommendation:
LDL testing was used to achieve risk-based LDL goal
– 2013 ACC/AHA Recommendation:
LDL testing is used to monitor therapeutic response and adherence
3.
Modifying individual treatment requires clinical judgment.
“The ultimate decision about care of a particular patient must be made by the
healthcare provider and patient in light of the circumstances presented by that
patient.” 1
1. Stone et al. Circulation. 2013
Statin Therapy: Monitoring Therapeutic
Response and Adherence
Stone et al. Circulation. 2013
Integrating Population Based and
Individual Optimization Strategies in Practice
1. The 2013 ACC/AHA Guideline is a starting point for population management,
but is not an end point for individual care.
 This highlights two different opportunities to improve patient care:
- Population strategy (A) – treat population with generalized therapy to
achieve relative risk reduction among the group
- Individual optimization strategy (B) – monitor individual response with
a reliable LDL measure and adjust care as indicated.
 2013 Guidelines advise clinicians to integrate these options:
- Use of A and B (start with population care, followed by individual
optimization based on clinical judgment) is recommended;
- Use of A only (population strategy, “Fire and Forget”) is not advised.
2. Exclusive use of a population strategy is incapable of judging individual
response to statin therapy or optimizing individual management.
Heterogeneous Response to High Intensity
Statin Therapy
Cardiovascular Events In Treat to New Target “TNT”
Patients with major CVD events (%)
18
Atorva 10 mg
16
Atorvastatin 10 mg
(LDL-C on-trial 101 mg/dL)
Atorva 80 mg
14
Atorvastatin 80 mg
12
(LDL-C on-trial 77 mg/dL)
No Benefit
From Aggressive
Treatment (44 %)
10
22% Reduction in Major
cardiovascular events
(p=0.0002)
8
6
2
56% Benefited From
High Intensity Statin
Therapy
0
WHY?
4
0
1
2
3
# MetSyn Components
Deedwania P, et al. The Lancet. 2006;368:919-928
4
5
Potential Answer to TNT is Supplied by
Framingham
180
N=286
N=407
N=355
N=233
N=113
N=30
1800
LDL-C
170
1700
160
1600
150
1500
140
1400
130
1300
120
1200
110
1100
0
1
2
MetSyn (-)
Kathiresan S, et al. Circulation 2006;113:20-27
3
4
MetSyn (+)
2.3x risk
5
LDL-P (nmol/L)
LDL-C (mg/dL)
LDL-P
With Higher LDL-P,
Greater Benefit Is
Expected From
More Intensive LDL-P
Lowering.
Relations of Change in Plasma Levels of
LDL-C, Non-HDL-C and apoB With Risk
Reduction From Statin Therapy: A MetaAnalysis of Randomized Trials
George Thanassoulis, Ken Williams, Keying Ye, Robert
Brook, Patrick Couture, Patrick R. Lawler, Jecqueline de
Graaf, Curt D. Furgerg and Allan Sniderman
Journal of American Heart Association 2014;3
Meta-Analysis of LDL Measures and Risk
Reduction from Statin Therapy
Objective:
• To evaluate the relationship between the reduction in alternate LDL
measures (LDL-C, non-HDL-C, apoB) and observed cardiovascular
benefit produced by statin therapy in randomized, placebo controlled
trials.
– “The marker whose reduction relates most directly to benefit
should also be the marker that is best to identify those whose
outcome might be improved by further lipid lowering.”
• Meta-analysis was performed using both frequentist and Bayesian
methods.
Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759
Meta-Analysis of LDL Measures and Risk
Reduction from Statin Therapy
Studies Selected:
Analyzed all published, placebo-controlled studies, which have reported
baseline and on-treatment levels of LDL- C, non-HDL-C, and apoB.
Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759
Meta-Analysis of LDL Measures and Risk
Reduction from Statin Therapy
Findings:
Relative risk reduction from statin therapy in the 7 major placebocontrolled statin trials demonstrated:
– Risk reduction was more closely related to reductions in apoB
than to reductions in either non-HDL-C or LDL-C.
– Changes in non-HDL-C and LDL-C appeared to be statistically
indistinguishable with respect to risk reduction of statin therapy.
Within trial “head-to-head” comparisons of cardiovascular risk
relationship with individual LDL markers :
– LDL-C was 2.4% (- 3.6%, 8.4%) > non-HDL-C (P=0.445)
– apoB was 21.6% (12.0%, 31.2%) > LDL-C (P<0.001)
– apoB was 24.3% (22.4%, 26.2%) > non-HDL-C (P<0.001).
Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759
Cardiovascular Risk in Patients Achieving
Low-Density Lipoprotein Cholesterol and
Particle Targets
Peter P. Toth , MD, PhD Michael Grabner , PhD
Rajeshwari S. Punekar , PhD Ralph A. Quimbo , MA
Mark J. Cziraky , PharmD Terry A. Jacobson , MD
Atherosclerosis 2014;235(2):585-591
Study Design
• Claims data between 2006 and 2012 were used to identify eligible patients achieving
LDL-P <1000 nmol/L (LDL-P cohort) and patients achieving LDL-C<100 mg/dL (LDL-C
cohort) without LDL-P measurements.
• Demographic and comorbidity differences between the two cohorts were balanced
using propensity score matching however, treatment patterns were left intact.
Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.
Baseline Characteristics for Patients with
≥ 12 Months of Follow-Up
Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.
Baseline Characteristics for Patients with
≥ 12 Months of Follow-Up
Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.
Study Results
At every follow-up interval the LDL-P cohort
demonstrated:
Significant risk reduction (Hazard Ratio):
 24% at 12 months
 22% at 24 months
 25% at 36 months
Significant event reduction
(Number of patients with CHD/stroke events)
Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

1.8% (8.12% - 6.26%) at 12 months

2.9% (13.9% - 11.0%) at 24 months

4.4% (19.0% - 14.6%) at 36 months
Study Results
Another metric of event reduction is the “Number
Needed to Treat” (NNT).

NNT = 1 / Event Reduction

Represents the number of subjects
needed to treat to prevent 1 event. (i.e.,
number of subjects needed to attain LDLP <1000 vs LDL-C <100 to prevent 1
CHD/stroke event).
2.9
Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.
Number Needed to Treat
2014;235(2):585-591.
Approach to the Use of LDL in Clinical Practice
Step 1: Stratify ASCVD risk (does not require LDL-P)
Step 2: Institute appropriate course of treatment.
Step 3: Use a reliable, FDA cleared, outcome proven LDL measure to
monitor adherence and response among those treated.
Step 4: Use clinical judgment in considering the need to modify individual
therapy.
Step 5: After modifying therapy, use a reliable, FDA cleared, outcome
proven LDL measure to assess patient response.
Use clinical judgment to consider modifications of treatment as
indicated to optimize care.
Selected Strategies to Reduce Particle Number
Improve LDL Particle
Clearance
(remove more)
Reduce LDL Particle
Production
(make less)





Diet
Exercise
Weight Loss
Glycemic Control
Co-Morbidity
Management
(up to 30-50% 6 LDL-P)
 Marine Omega-3
o DHA + EPA
(no 6 LDL-P)
o EPA Only
(4-15 % 6 LDL-P)
LDL-P
Target
 Statins
(35-55% 6 LDL-P)
 Gut agents
o Ezetimibe
(15-30% 6 LDL-P)
o Resins / Bile Acid
Sequestrates
(15-30% 6 LDL-P)
 Statin + Gut
(50-70% 6 LDL-P)
 Statin + Gut + Niacin
(> 60% 6 LDL-P)
Adapted from Cromwell W, Dayspring T. Lipid and lipoprotein disorders: Current clinical solutions. Baltimore: International Guideline
Center; 2012.
Conclusions
1. Guidelines recommend a two step approach to managing LDL-related CVD
risk: 1


Use moderate or high dose statin therapy in selected populations;
Monitor LDL levels on therapy and use clinical judgment in determining
next steps in patient management.
2. Because CVD risk tracks with apoB and NMR LDL-P 2-6, and because
frequent discordance exists between LDL-C and measures of LDL-P 2-4,7-10,
many expert panels advocate use of LDL particle number to adjudicate
response and optimize individual therapy.11-13
3. Clinical utilization data confirms a significant reduction of CVD risk and
events among high risk patients attaining low NMR LDL-P (mean 860
nmol/L) versus statin treated subjects with low LDL-C (mean 79 mg/dL).14
1. Stone NJ, et al. Circulation 2014;129:S1-S45.
2. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.
3. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.
4. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.
5. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345.
6. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449.
7. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.
8. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.
9. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.
10. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.
11. Contois JH et al. Clin Chem. 2009;55:407-419.
12. Davidson MH et al. J Clin Lipidol. 2011;5:338-367.
13. Garber AJ, et al. Endocr Pract 2013;19(Suppl 2):1-48.
14. Toth PP, et al. Atherosclerosis 2014;235(2):585-591.