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HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular

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Article in The New-England Medical Review and Journal · October 2007

DOI: 10.1056/NEJMoa064278 · Source: PubMed

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 The n e w e ng l a n d j o u r na l of m e dic i n e

original article

HDL Cholesterol, Very Low Levels of LDL

Cholesterol, and Cardiovascular Events
Philip Barter, M.D., Ph.D., Antonio M. Gotto, M.D., D.Phil., John C. LaRosa, M.D.,
Jaman Maroni, M.D., Michael Szarek, M.S., Scott M. Grundy, M.D., Ph.D.,
John J.P. Kastelein, M.D., Ph.D., Vera Bittner, M.D., M.S.P.H.,
and Jean-Charles Fruchart, Pharm.D., Ph.D.,
for the Treating to New Targets Investigators*

A BS T R AC T

BACKGROUND
High-density lipoprotein (HDL) cholesterol levels are a strong inverse predictor of From the Heart Research Institute, Sydney
cardiovascular events. However, it is not clear whether this association is main- (P.B.); the Joan and Sanford I. Weill Medi-
cal College of Cornell University, New York
tained at very low levels of low-density lipoprotein (LDL) cholesterol. (A.M.G.); the State University of New
York Downstate Medical Center, Brooklyn
METHODS (J.C.L.); Pfizer, New York (J.M., M.S.);
the Center for Human Nutrition, Univer-
A post hoc analysis of the recently completed Treating to New Targets (TNT) study sity of Texas Southwestern Medical Cen-
assessed the predictive value of HDL cholesterol levels in 9770 patients. The primary ter, Dallas (S.M.G.); the Academic Medi-
outcome measure was the time to a first major cardiovascular event, defined as cal Center, University of Amsterdam,
Amsterdam (J.J.P.K.); the Division of Car-
death from coronary heart disease, nonfatal non–procedure-related myocardial in- diovascular Disease, University of Ala-
farction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The predictive bama, Birmingham (V.B.); and the Insti-
relationship between HDL cholesterol levels at the third month of treatment with tut Pasteur, Lille, France (J.-C.F.). Address
reprint requests to Dr. Barter at the Heart
statins and the time to the first major cardiovascular event was assessed in univariate Research Institute, 145 Missenden Rd.,
and multivariate analyses and was also assessed for specific LDL cholesterol strata, Camperdown, NSW 2050, Australia, or at
including subjects with LDL cholesterol levels below 70 mg per deciliter (1.8 mmol barterp@hri.org.au.
per liter). *Participants in the Treating to New Targets
(TNT) study are listed in the Appendix.
RESULTS
N Engl J Med 2007;357:1301-10.
The HDL cholesterol level in patients receiving statins was predictive of major cardio- Copyright © 2007 Massachusetts Medical Society.
vascular events across the TNT study cohort, both when HDL cholesterol was con-
sidered as a continuous variable and when subjects were stratified according to
quintiles of HDL cholesterol level. When the analysis was stratified according to LDL
cholesterol level in patients receiving statins, the relationship between HDL choles-
terol level and major cardiovascular events was of borderline significance (P = 0.05).
Even among study subjects with LDL cholesterol levels below 70 mg per deciliter,
those in the highest quintile of HDL cholesterol level were at less risk for major car-
diovascular events than those in the lowest quintile (P = 0.03).

CONCLUSIONS
In this post hoc analysis, HDL cholesterol levels were predictive of major cardiovascu-
lar events in patients treated with statins. This relationship was also observed among
patients with LDL cholesterol levels below 70 mg per deciliter. (ClinicalTrials.gov
number, NCT00327691.)

n engl j med 357;13 www.nejm.org september 27, 2007 1301

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 The n e w e ng l a n d j o u r na l of m e dic i n e

P
opulation studies have consistent- the American College of Cardiology guidelines
ly shown that high-density lipoprotein (HDL) as a reasonable target for therapy in patients with
cholesterol levels are a strong, independent coronary heart disease or other forms of athero-
inverse predictor of cardiovascular disease.1-5 In sclerotic disease.18
the Framingham Heart Study, HDL cholesterol This post hoc analysis of the TNT trial exam-
level was more potent as a risk factor for coronary ined the relationship between the frequency of
heart disease than was the level of low-density major cardiovascular events and HDL cholesterol
lipoprotein (LDL) cholesterol.4 An analysis of data levels in a population of patients with clinically
from four large studies concluded that each in- evident coronary heart disease who were being
crease of 1 mg per deciliter (0.03 mmol per liter) treated with statins. It also investigated whether
in HDL cholesterol is associated with a decrease any observed relationship was maintained when
of 2 to 3% in the risk of future coronary heart LDL cholesterol was reduced below 70 mg per
disease.6 deciliter.
Intervention trials using statins to lower LDL
cholesterol have consistently shown substantial Me thods
reductions in major cardiovascular events in the
treated groups.7-13 Furthermore, the magnitude of The TNT trial was a randomized, double-blind,
the reduction in events is a function of the extent parallel-group, multicenter clinical trial, the de-
of LDL cholesterol lowering, with each decrease sign of which has been described in detail previ-
of 40 mg per deciliter (1.0 mmol per liter) in LDL ously.16,19 The trial was sponsored by Pfizer and
cholesterol corresponding to a 24% reduction in developed by the steering committee (see the Ap-
major cardiovascular events.13 However, in all the pendix) in collaboration with the sponsor. The
statin trials, there remains a substantial residual trial data were retained by the sponsor.
risk in the treated groups. The steering committee proposed and designed
One explanation for this may relate to the pres­ the analysis of HDL cholesterol data. The analysis
ence of a low baseline level of HDL cholesterol, was performed by one of the authors, who was em­
which has been shown in several trials to remain ployed by the sponsor. All the data and analyses
predictive of major cardiovascular events, even dur­ were made available to the steering committee
ing treatment with statins.14 In a recent pooled without restriction. All steering-committee mem-
analysis of four trials of statins, the moderate bers participated in the writing and critical ap-
increase in HDL cholesterol levels seen with these praisal of the manuscript. The steering committee
drugs correlated with regression of coronary assumes overall responsibility for the integrity of
atherosclerosis.15 These findings have added sup- the data, the accuracy of the data analyses, and
port to the proposition that HDL cholesterol lev- the completeness of the material reported.
els should be considered as therapeutic targets
independent of the lowering of LDL cholesterol Patient Population
levels. However, it could also be argued that if Subjects eligible for inclusion were men and wom-
LDL cholesterol levels are reduced to very low en aged 35 through 75 years with clinically evident
levels, low HDL cholesterol levels may no longer coronary heart disease, defined as a previous myo-
be relevant. To date, this view has remained un- cardial infarction, previous or current angina with
tested. objective evidence of atherosclerotic coronary
In the Treating to New Targets (TNT) trial heart disease, or a previous coronary revascular-
(ClinicalTrials.gov number, NCT00327691), 2661 ization procedure. The major exclusion criteria
subjects achieved an LDL cholesterol level below were statin hypersensitivity, current liver disease,
70 mg per deciliter (1.8 mmol per liter) while nephrosis, pregnancy, uncontrolled risk factors
receiving statin therapy.16 This target originally for coronary heart disease, a coronary heart dis-
was proposed as an optional treatment goal in ease event or revascularization procedure within
very-high-risk patients with coronary heart dis­ the preceding month, congestive heart failure, un-
ease in an update to the National Cholesterol explained creatine kinase levels greater than six
Education Program Adult Treatment Panel III times the upper limit of normal, any non-skin
(NCEP-ATP III) guidelines,17 and it has now been cancer, malignant melanoma, other survival-limit­
proposed by the American Heart Association and ing disease, and immunosuppressive treatment.

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 HDL cholesterol, Very Low Levels of LDL Cholesterol, and cardiovascular events

Study Protocol A stratified regression analysis was performed

Any previously prescribed lipid-regulating drugs to determine the interaction between HDL and
were discontinued at screening, and all subjects LDL cholesterol levels in patients receiving statins,
underwent a washout period of 1 to 8 weeks using specific LDL cholesterol cutoff points (<70,
(8 weeks for those who had previously received 70 to 100, and >100 mg per deciliter [<1.8, 1.8 to
lipid-regulating drugs and 1 week for those who 2.6, and >2.6 mmol per liter]). This analysis was
had not). To ensure that all subjects at baseline adjusted for treatment, sex, age as a continuous
achieved LDL cholesterol levels consistent with variable, smoking status, body-mass index, systol­
then-current guidelines for the treatment of stable ic blood pressure, fasting glucose level, the tri-
coronary heart disease, patients with LDL choles- glyceride level at month 3, and the presence or
terol levels between 130 and 250 mg per deciliter absence of a history of diabetes, myocardial infarc­
(3.4 and 6.5 mmol per liter) and triglyceride levels tion, cardiovascular disease, and hypertension.
of 600 mg per deciliter (6.8 mmol per liter) or less A separate analysis of patients receiving statins
entered an 8-week open-label period with 10 mg in the lowest LDL stratum (<70 mg per deciliter)
of atorvastatin per day. At the end of the run-in was performed according to quintile of HDL cho-
phase (baseline), subjects with a mean LDL cho- lesterol level during statin therapy, likewise adjust­
lesterol level of less than 130 mg per deciliter ed for the variables listed above.
(3.4 mmol per liter) (determined 4 weeks and The relationships between the quintile of the
2 weeks before randomization) were randomly ratio of LDL cholesterol to HDL cholesterol at
assigned to double-blind therapy with 10 mg or month 3, the quintile of the ratio of total choles-
80 mg of atorvastatin per day, as previously de- terol to HDL cholesterol at month 3, and the in-
scribed.16 The primary efficacy outcome measure cidence of major cardiovascular events were also
was the time to first occurrence of a major cardio- summarized overall and according to treatment
vascular event, defined as death from coronary group. Finally, the relationship between continu-
heart disease; nonfatal non–procedure-related ous HDL cholesterol levels (both at baseline and
myocardial infarction; resuscitation after cardiac at 3 months) and time to a first major cardiovas-
arrest; or fatal or nonfatal stroke. cular event was determined in univariate and
multivariate Cox regression models, including
Statistical Analysis all covariates listed above as well as treatment
For this study, the 9770 subjects in the TNT trial assignment.
for whom HDL cholesterol data were available
were stratified into quintiles based on their HDL R e sult s
cholesterol levels determined at month 3 of the
double-blind treatment phase. The baseline clini- Baseline Characteristics
cal characteristics of these five patient groups were The baseline characteristics and lipid levels of the
compared. subjects in each of the quintiles of HDL choles-
Cox regression models were fitted to deter- terol level during statin treatment (month 3) are
mine the expected 5-year risk of a first major shown in Table 1. Subjects with higher HDL cho-
cardiovascular event from nonparametric survivor lesterol levels were older, more likely to be female,
function estimates determined by quintile of HDL and leaner than those with lower HDL choles-
cholesterol level at month 3 of the trial, unadjust­ terol levels. Current smokers were less common
ed and after adjustment for important covariates. in the higher quintiles of HDL cholesterol levels,
The covariates considered in the analyses were and subjects with higher HDL cholesterol levels
sex, age, smoking status, body-mass index, systol­ were more likely to have never smoked. The propor­
ic blood pressure, fasting glucose level, LDL cho- tion of past smokers was similar in all quintiles.
lesterol level, triglyceride level, ratio of apolipo- As expected, subjects with higher HDL cho-
protein B to apolipoprotein A-I, LDL cholesterol lesterol levels during statin treatment (month 3)
and triglyceride levels at month 3 of the trial, and had higher concentrations of apolipoprotein A-I
the presence or absence of a history of diabetes, (a structural component of HDL) and lower plas-
myocardial infarction, cardiovascular disease, and ma triglyceride levels. The concentration of apo-
hypertension. lipoprotein B (a structural component of the non-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Baseline Characteristics of the Patients According to Quintile of HDL Cholesterol Level at Month 3.*

Quintile 1, Quintile 2, Quintile 3, Quintile 4, Quintile 5,

<38 mg/dl 38 to <43 mg/dl 43 to <48 mg/dl 48 to <55 mg/dl ≥55 mg/dl
Characteristic (N = 1710) (N = 1981) (N = 1959) (N = 1998) (N = 2122)
No. receiving 10 mg of atorvastatin 834 937 989 1043 1093
No. receiving 80 mg of atorvastatin 876 1044 970 955 1029
Male sex — % 91.5 89.4 83.7 78.0 65.0
White race — %† 94.0 93.7 94.1 94.2 94.4
Age — yr 58.9±9.1 59.9±8.8 61.2±8.7 61.6±8.6 62.9±8.4
Age ≥65 yr — % 29.4 33.3 38.4 40.7 46.7
Body-mass index‡ 29.9±4.7 29.1±4.9 28.6±4.4 28.0±4.1 27.2±4.3
Never smoked — no. (%) 317 (18.5) 419 (21.2) 486 (24.8) 505 (25.3) 561 (26.4)
Former smoker — no. (%) 1041 (60.9) 1251 (63.1) 1239 (63.2) 1291 (64.6) 1353 (63.8)
Current smoker — no. (%) 352 (20.6) 311 (15.7) 234 (11.9) 202 (10.1) 208 (9.8)
Lipids — mg/dl§
LDL cholesterol 96.7±17.7 97.3±17.4 97.6±17.2 98.4±17.6 97.2±17.8
HDL cholesterol 35.7±4.5 41.1±4.6 45.2±4.8 50.4±5.8 61.5±10.1
Total cholesterol 169.2±24.1 171.3±24.0 172.1±22.6 176.4±22.8 183.1±23.0
Total triglycerides 185.6±81.7 166.1±76.5 146.7±63.9 138.7±59.5 122.0±54.1
Apolipoprotein A-I 123.1±14.9 134.1±14.8 142.4±15.4 152.9±17.7 173.1±24.1
Apolipoprotein B 116.2±19.5 113.3±19.3 110.6±18.5 109.8±18.7 106.4±18.7
Cardiovascular history — no. (%)
Myocardial infarction 1077 (63.0) 1202 (60.7) 1141 (58.2) 1128 (56.5) 1150 (54.2)
Coronary-artery bypass grafting 855 (50.0) 972 (49.1) 921 (47.0) 887 (44.4) 916 (43.2)
Coronary angioplasty 921 (53.9) 1071 (54.1) 1068 (54.5) 1083 (54.2) 1145 (54.0)
Cerebrovascular accident 100 (5.8) 114 (5.8) 94 (4.8) 101 (5.1) 95 (4.5)
Angina 1402 (82.0) 1618 (81.7) 1621 (82.7) 1607 (80.4) 1715 (80.8)
Peripheral vascular disease 248 (14.5) 238 (12.0) 229 (11.7) 208 (10.4) 222 (10.5)
Hypertension 973 (56.9) 1060 (53.5) 1069 (54.6) 1060 (53.1) 1127 (53.1)
Arrhythmia 347 (20.3) 327 (16.5) 379 (19.3) 355 (17.8) 380 (17.9)
Congestive heart failure 177 (10.4) 169 (8.5) 145 (7.4) 127 (6.4) 134 (6.3)
Diabetes 363 (21.2) 338 (17.1) 286 (14.6) 256 (12.8) 224 (10.6)

* Plus–minus values are means ±SD.

† Race was determined by the investigator.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ To convert values for LDL, HDL, and total cholesterol to millimoles per liter, multiply by 0.02586. To convert values
for triglycerides to millimoles per liter, multiply by 0.01129.

HDL lipoproteins) declined slightly with increasing Cardiovascular Events According to Quintile
HDL cholesterol levels (P<0.001). The prevalence of HDL Cholesterol Level
of diabetes in the lowest quintile of HDL choles- The expected 5-year risk of major cardiovascular
terol levels was double that in the highest quin- events was determined for each quintile of HDL
tile. There were no significant differences in any cholesterol level in patients receiving statins across
of these baseline characteristics between the two the entire TNT trial cohort. In the univariate mod-
atorvastatin treatment groups within each HDL el, the event rate was reduced by 40% in the high-
cholesterol group. est quintile relative to the lowest. When the anal-

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 HDL cholesterol, Very Low Levels of LDL Cholesterol, and cardiovascular events

ysis included adjustments for covariates (Fig. 1A),

A
the quintile of HDL cholesterol level remained Hazard ratio (95% CI) versus Q1
a significant predictor of major cardiovascular 12
Q2 1.00 (0.82–1.21)
Q3 0.80 (0.65–0.99)
events, with a reduction in major cardiovascular

5-Yr Risk of Major Cardiovascular

Q4 0.92 (0.74–1.13)
events from 95% in the lowest quintile to 7.1% in 10 Q5 0.75 (0.60–0.95)
the highest quintile, a 25% reduction in risk (haz-
8
ard ratio, 0.75; 95% confidence interval [CI], 0.60

Events (%)
to 0.95). The risk of major cardiovascular events 6
differed significantly across HDL cholesterol quin-
4
tiles (P = 0.04).
The relationship between HDL cholesterol lev- 2
els in patients receiving statins and the frequency
of major cardiovascular events seen in the overall 0
Q1 Q2 Q3 Q4 Q5
cohort was also apparent in each of the two ator- (<38) (38 to <43) (43 to <48) (48 to <55) (≥55)
vastatin treatment groups. The incidence of major Quintile of HDL Cholesterol Level (mg/dl)
cardiovascular events was substantially lower in No. of Events 204 220 169 188 157
the group receiving 80 mg of atorvastatin per day
than in the group receiving 10 mg per day in all B
quintiles. However, in each treatment group, the 12 10 mg of atorvastatin 80 mg of atorvastatin

frequency of major cardiovascular events increased 5-Yr Risk of Major Cardiovascular 10

with decreasing levels of HDL cholesterol (Fig. 1B).
After adjustment for covariates, among subjects 8
Events (%)

assigned to 10 mg of atorvastatin, those in the

6
highest quintile were significantly less likely to
have a major cardiovascular event than those in 4
the lowest quintile (hazard ratio, 0.71; 95% CI,
0.52 to 0.96). In subjects assigned to 80 mg of 2

atorvastatin, the difference in cardiovascular risk 0

between the highest and the lowest quintile did Q1 Q2 Q3 Q4 Q5
(<38) (38 to <43) (43 to <48) (48 to <55) (≥55)
not reach significance (hazard ratio, 0.81; 95% CI,
0.58 to 1.14). Quintile of HDL Cholesterol Level (mg/dl)
No. of Events 113 91 125 97 102 68 103 86 87 71
Effect of LDL Cholesterol Level
Figure 1. Multivariate Analysis of the Relationship between HDL Cholesterol
We performed a stratified regression analysis to Levels at Month AUTHOR: Barter RETAKE
ICM3 and the Risk of Major Cardiovascular Events.
1st
determine the interaction between HDL and LDL REG F FIGURE: 1 of 3
Panel A shows the results for all patients. Quintile 1 is the reference
2nd
group.
3rd
cholesterol levels in patients receiving statins. In a The adjusted 5-year
CASE risk reflects the expected risk of aRevisedfirst major cardio-
Line 4-C
multivariate model (Fig. 2A), the quintile of HDL vascular eventEMail
for a cohort with the following
ARTIST: ts
characteristics:
SIZE female sex,
H/T H/T
cholesterol level was of borderline significance as Enon 61.0 years; past smoker, 63.2%; current22p3
19.0%; mean age, smoker, 13.4%;
Combo
mean body-mass index, 28.5; mean systolic blood pressure, 130.7 mm Hg;
a predictor of major cardiovascular events (P = 0.05), history of diabetesFigure
mellitus,AUTHOR, PLEASE NOTE:
15.0%; history of myocardial infarction, 58.3%;
with no evidence of interaction with the quintile has been redrawn and type has been reset.
history of cardiovascular disease,
Please5.2%;
checkhypertension
carefully. (systolic blood pres-
of LDL cholesterol level (P = 0.67). The hazard sure, >140.0 mm Hg or patient receiving antihypertensive therapy), 54.1%;
ratios and 95% confidence intervals for quintiles mean fasting glucose
JOB: 35713 level, 107.7 mg per deciliter (6.0 mmol
ISSUE: per liter);
09-27-07
2 through 5 of HDL cholesterol level (with quin- mean LDL cholesterol level at month 3, 85.8 mg per deciliter (2.2 mmol
per liter); and mean triglyceride level at month 3, 140.1 mg per deciliter
tile 1 as a reference) were 1.00 (95% CI, 0.82 to (1.6 mmol per liter). Panel B shows the results for the 10-mg and 80-mg
1.21), 0.80 (95% CI, 0.65 to 0.99), 0.92 (95% CI, atorvastatin groups. The lipid levels at month 3 in the 10-mg atorvastatin
0.74 to 1.13) and 0.75 (95% CI, 0.60 to 0.95). group were 98.9 mg of LDL cholesterol per deciliter (2.6 mmol per liter)
A separate analysis was conducted to evaluate and 151.8 mg of triglycerides per deciliter (1.7 mmol per liter). The lipid
the influence of HDL cholesterol on outcome levels at month 3 in the 80-mg atorvastatin group were 72.6 mg of LDL
cholesterol per deciliter (1.9 mmol per liter) and 128.2 mg of triglycerides
among subjects in the lowest LDL cholesterol stra- per deciliter (1.4 mmol per liter). To convert values for HDL cholesterol to
tum (<70 mg per deciliter). In this group, accord- millimoles per liter, multiply by 0.02586.
ing to multivariate analysis (Fig. 2B), the risk of a
major cardiovascular event differed significantly

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 The n e w e ng l a n d j o u r na l of m e dic i n e

among quintiles of HDL cholesterol levels (P = 0.03).

A
Subjects in the highest HDL cholesterol quintile
LDL Cholesterol Level
<70 mg/dl 70–100 mg/dl >100 mg/dl
had a lower risk of major cardiovascular events
12 than subjects in the lowest quintile (hazard ratio,
5-Yr Risk of Major Cardiovascular

0.61; 95% CI, 0.38 to 0.97).

10

8 Ratios of LDL Cholesterol and Total

Events (%)

Cholesterol to HDL Cholesterol

6
The ratio of LDL cholesterol to HDL cholesterol
4 at month 3 of the trial was also highly predictive
of major cardiovascular events. There were major
2 differences at the extremes: the event rate of 5.8%
0
in subjects with the lowest ratio was less than half
Q1 Q2 Q3 Q4 Q5 that in subjects with the highest ratio (13.5%).
(<38) (38 to <43) (43 to <48) (48 to <55) (≥55) The ratio of LDL cholesterol to HDL cholesterol
Quintile of HDL Cholesterol Level (mg/dl) among patients receiving statins (month 3) re-
mained highly predictive (P = 0.006) of major car-
B diovascular events, even after adjustment (Fig. 3A).
10 Hazard ratio (95% CI) versus Q1 Subjects in the quintile with the highest ratio of
5-Yr Risk of Major Cardiovascular

9 Q2 0.85 (0.57–1.25)
8 Q3 0.57 (0.36–0.88) LDL cholesterol to HDL cholesterol had a signifi-
7
Q4 0.55 (0.35–0.86) cantly greater risk of major cardiovascular events
Q5 0.61 (0.38–0.97)
than did subjects in the lowest quintile (hazard
Events (%)

6
5 ratio, 1.82; 95% CI, 1.32 to 2.51).
4 The ratio of total cholesterol to HDL choles-
3 terol at month 3 was also predictive of major
2 cardiovascular events (Fig. 3B). After adjustment,
1 subjects in the quintile with the highest ratio
0 were at significantly greater risk of major cardio-
Q1 Q2 Q3 Q4 Q5
(<37) (37 to <42) (42 to <47) (47 to <55) (≥55) vascular events than were those in the quintile
Quintile of HDL Cholesterol Level (mg/dl)
with the lowest ratio, with a hazard ratio after
adjustment for potential confounders of 1.72
No. of Events 57 50 34 34 35
No. of Patients 473 525 550 569 544 (95% CI, 1.26 to 2.35).
Figure 2. Multivariate Analysis of the Relationship ­between Major Continuous HDL Cholesterol Levels
­ ardiovascularICM
C Events and Quintiles
AUTHOR: Barter of HDL CholesterolRETAKELevels.
1st

In Panel A, patients FIGURE:

were 2 of 3
stratified according to specific cutoff2nd
points of
The risk of a major cardiovascular event was also
REG F
LDL cholesterol levels in patients receiving statins (<70
CASE
3rd
mg per deciliter determined for each increment of 1 mg per deci-
Revised
[2661 patients], 70 to 100 mg per deciliter
EMail Line[45374-C
patients], and
SIZE >100 mg per liter (0.03 mmol per liter) in HDL cholesterol level
ARTIST: ts
deciliter [2571 Enon
patients]). Multivariate analysis
H/T included
H/T the22p3
following covari- at baseline and during statin treatment (Table 2).
Combo
ates: treatment, sex, age treated as a continuous variable, smoking status, In a model adjusted for covariates, an increase of
body-mass index, systolic blood AUTHOR, PLEASE
pressure, NOTE:glucose level, triglyceride
fasting
Figure has been redrawn and type has been reset.
level at month 3, and the presence or absence of diabetes, myocardial infarc-
1 mg per deciliter in the HDL cholesterol level at
Please check carefully.
tion, cardiovascular disease, and hypertension. In Panel B, patients in the month 3 could be expected to reduce the risk of
lowest stratumJOB: of LDL cholesterol during statin treatment
35713 (<70 mg per deci­
ISSUE: 09-27-07
major cardiovascular events by 1.1% (P = 0.003)
liter) were analyzed according to quintile of HDL cholesterol level during (Table 2).
treatment. Multivariate analysis included the same covariates as those listed In the multivariate analysis, the relationship
for Panel A, plus the baseline LDL cholesterol level. The adjusted 5-year risk
reflects the expected risk of a first major cardiovascular event for a cohort
between baseline HDL cholesterol level and the
with the following characteristics: female sex, 17.5%; mean age, 61.6 years; risk of major cardiovascular events was almost
past smoker, 63.0%; current smoker, 12.6%; mean body-mass index, 28.1; identical to that observed between HDL choles-
mean systolic blood pressure, 130.1 mm Hg; history of diabetes mellitus, terol level and the risk of major cardiovascular
16.2%; history of myocardial infarction, 59.0%; history of cardiovascular dis- events during statin treatment. However, inclu-
ease, 4.7%; hypertension, 53.3%; mean fasting glucose level, 108.0 mg per
deci­liter (6.0 mmol per liter); mean LDL cholesterol level at month 3, 57.8 mg
sion of the baseline ratio of apolipoprotein B to
per deciliter (1.5 mmol per liter); and mean triglyceride level at month 3, apolipoprotein A-I in the analysis model reduced
126.3 mg per deciliter (1.4 mmol per liter). the predictive relationship to nonsignificance
(P = 0.46).

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 HDL cholesterol, Very Low Levels of LDL Cholesterol, and cardiovascular events

Interaction tests indicated that relationships

A
between HDL cholesterol levels at baseline or dur-
12 10 mg of atorvastatin 80 mg of atorvastatin Total
ing statin treatment and the risk of major cardio-

5-Yr Risk of Major Cardiovascular

vascular events did not depend on sex (P = 0.11 10
for baseline levels, P = 0.34 for levels during statin
8
treatment), age (P = 0.75 for baseline levels, P = 0.31

Events (%)
for levels during statin treatment), smoking sta- 6
tus (P = 0.55 for baseline levels, P = 0.64 for levels
during statin treatment), body-mass index (P = 0.13 4

for baseline levels, P = 0.09 for levels during statin 2

treatment), or any of the other covariates consid-
ered in the analysis (all P>0.10 for levels at base- 0
Q1 Q2 Q3 Q4 Q5
line and during statin treatment). (<1.33) (1.33 to <1.66) (1.66 to <1.98) (1.98 to <2.41) (≥2.41)
Quintile of the Ratio of LDL Cholesterol to HDL Cholesterol
Dis cus sion
B
It has long been known that a low level of HDL 12 10 mg of atorvastatin 80 mg of atorvastatin Total
cholesterol is a powerful predictor of increased
5-Yr Risk of Major Cardiovascular
10
cardiovascular risk,1-6 but it has not been clear
whether a low HDL cholesterol level would remain 8
a significant risk factor in people whose LDL cho-
Events (%)

lesterol was reduced to very low levels. Indeed, it 6

has been argued hypothetically that if the LDL 4

cholesterol level were reduced sufficiently, the lev­
el of HDL cholesterol might become irrelevant. 2
In this post hoc analysis from the TNT trial,
0
HDL cholesterol level was a significant predictor Q1 Q2 Q3 Q4 Q5
of major cardiovascular events across the entire (<2.76) (2.76 to <3.19) (3.19 to <3.63) (3.63 to <4.23) (≥4.23)
study cohort, even after all other baseline risk Quintile of the Ratio of Total Cholesterol to HDL Cholesterol
factors, including baseline LDL cholesterol level,
Figure 3. Relationship between Major Cardiovascular Events and Ratio
had been taken into account. This effect was of LDL Cholesterol
ICM to HDL Cholesterol at Month 3 (Panel A) and Ratio
AUTHOR: Barter RETAKE 1st
more pronounced in the analyses using HDL cho­ of Total Cholesterol
REG F to HDL Cholesterol
FIGURE: 3 of 3 at Month 3 (Panel B). 2nd
lesterol level as a continuous variable than in The adjusted 5-year
CASE risk reflects the expected risk of a Revised
3rd
first major cardio-
those using quintiles of HDL cholesterol levels vascular eventEMail Line
for a cohort with the following 4-C
characteristics:
SIZE female sex,
ARTIST: ts
at month 3 of the trial, a result suggesting that 19.0%; mean age, H/T H/T
Enon 61.0 years; past smoker, 63.2%; current22p3
Combo
smoker, 13.4%;
outlier HDL cholesterol levels may have had an body-mass index, 28.5; mean systolic blood pressure, 130.7 mm Hg; history
of diabetes mellitus, 15.0%; AUTHOR,
history ofPLEASE NOTE:infarction, 58.3%; history
myocardial
important role in the relationship we observed. Figure has been redrawn and type has been reset.
of cardiovascular disease, 5.2%; hypertension, 54.1%; and mean fasting
Please check carefully.
The effect of LDL cholesterol levels during glucose level, 107.7 mg per deciliter. The lipid levels at month 3 were 85.8 mg
statin treatment on the predictive value of HDL of LDL cholesterol per deciliter and 140.1 mg of triglycerides
JOB: 35713 per deciliter for
ISSUE: 09-27-07
cholesterol was examined. After adjustment for all subjects, 98.9 mg of LDL cholesterol per deciliter and 151.8 mg of triglyc-
covariates, the predictive value of HDL cholesterol erides per deciliter for those receiving 10 mg of atorvastatin, and 72.6 mg
of LDL cholesterol per deciliter and 128.2 mg of triglycerides per deci­liter for
levels was of borderline significance, a result con- those receiving 80 mg of atorvastatin.
sistent with a suggestion that in patients with
coronary heart disease, higher HDL cholesterol
levels may offset the increased risk associated
with higher LDL cholesterol levels. cular events was reduced in those with higher
In a further analysis, we examined the rela- rather than lower HDL cholesterol levels.
tionship between the quintile of HDL cholesterol Given that HDL and LDL cholesterol levels dur-
level during statin treatment with risk in those ing statin treatment were both independently
patients in the lowest stratum of LDL cholesterol predictive of major cardiovascular events across
level (<70 mg per liter). This analysis demonstrat­ the whole range of HDL and LDL cholesterol lev-
ed that even among patients in this very low LDL els in this analysis, it was not surprising to find
cholesterol stratum, the risk of major cardiovas- that the ratio of LDL to HDL cholesterol was also

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Relationship between HDL Cholesterol Levels and the Risk of Major Cardiovascular Events.

Relative Risk
Variable No. of Subjects No. of Events (95% CI)* P Value
Baseline HDL cholesterol†
Model 1 9956 974 1.1 (0.4 to 1.8) 0.002
Model 1 and baseline ratio of apolipoprotein B 9917 971 0.4 (−0.7 to 1.5) 0.46
to apolipoprotein A-I
Model 2‡ 9732 938 1.1 (0.4 to 1.7) 0.003

* The relative risk is for changes in HDL cholesterol levels in increments of 1 mg per deciliter.
† Model 1 is adjusted for treatment, sex, age, smoking status, body-mass index, systolic blood pressure, baseline LDL
cholesterol level, baseline triglyceride level, glucose level measured after an overnight fast, and the presence or absence
of a history of diabetes, myocardial infarction, cardiovascular disease, and hypertension.
‡ Model 2 is for HDL cholesterol levels at month 3 of the trial and is adjusted for treatment, sex, age, smoking status,
body-mass index, systolic blood pressure, fasting glucose level, LDL cholesterol level at month 3, triglyceride level at
month 3, and the presence or absence of a history of diabetes, myocardial infarction, cardiovascular disease, and hy-
pertension.

highly predictive of the risk of major cardiovascu- the effect of the LDL cholesterol level achieved in
lar events. A similar result was observed for the patients receiving therapy was taken into account,
ratio of total cholesterol to HDL cholesterol. These the role of HDL cholesterol was less marked,
results are consistent with previous studies.20-23 though still of borderline significance. The rela-
There are several limitations of this study that tionship remained significant even in patients
should be considered when evaluating our find- whose LDL cholesterol level was less than 70 mg
ings. The groups of patients defined by quintile per deciliter.
of HDL cholesterol level were not similar with re­ Supported by Pfizer.
spect to other cardiovascular risk factors (Table 1), Dr. Barter reports receiving consulting fees from Pfizer and
AstraZeneca, lecture fees from Pfizer, AstraZeneca, and Merck,
and there may have been other differences that and grant support from Pfizer. Dr. Gotto reports receiving con-
were not evaluated but that could have influenced sulting fees from Aegerion Pharmaceuticals, Arisaph Pharma-
the results of the analysis. We did not measure ceuticals, DuPont, Johnson & Johnson, Merck, Kowa, Schering-
Plough, Novartis, and Reliant Pharmaceuticals, receiving lecture
waist circumference or insulin levels in our study fees from Pfizer, Merck, Schering-Plough, Reliant Pharmaceu-
population, and thus we cannot determine to ticals, and Sanofi-Aventis, and testifying before the Food and
what degree the observed effect of HDL choles- Drug Administration on behalf of Johnson & Johnson–Merck.
Dr. LaRosa reports receiving consulting fees from Pfizer, Bayer,
terol level may be due to the coincidence of a low and Merck and lecture fees from Pfizer. Dr. Maroni and Mr.
HDL cholesterol level with the metabolic syn- Szarek report being employees of Pfizer and owning equity in
drome. This relationship is suggested in our data Pfizer. Dr. Grundy reports receiving consulting fees from
Pfizer, Merck, Kos Pharmaceuticals, Abbott, Schering-Plough,
by the fact that most of our study subjects who Fournier Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Sanofi-
had low HDL cholesterol levels were also obese Aventis, GlaxoSmith­Kline, Eli Lilly, and AstraZeneca and grant
and had elevated plasma triglyceride levels. support from Kos Pharmaceuticals, Abbott, and Merck. Dr.
Kastelein reports receiving consulting fees and lecture fees
In summary, this analysis from the TNT trial from Pfizer, Merck, Schering-Plough, AstraZeneca, Bristol-Myers
evaluated the effect of HDL cholesterol levels in Squibb, and Daiichi Sankyo. Dr. Bittner reports receiving con-
patients with clinically evident coronary heart sulting fees from Pfizer, Reliant Pharmaceuticals, CV Thera-
peutics, and Novartis and grant support from Pfizer, Athero-
disease who were receiving statin therapy to re- Genics, Kos Pharmaceuticals, and Merck. Dr. Fruchart reports
duce LDL cholesterol levels. Across the entire receiving consulting fees from Pfizer, Sanofi-Aventis, and
study cohort in multivariate analysis, HDL choles- Fournier Pharma and lecture fees from Pfizer, Merck, Schering-
Plough, Reliant Pharmaceuticals, and Sanofi-Aventis. No oth-
terol levels were a significant inverse predictor er potential conflict of interest relevant to this article was re-
of subsequent major cardiovascular events. When ported.

1308 n engl j med 357;13 www.nejm.org september 27, 2007

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 HDL cholesterol, Very Low Levels of LDL Cholesterol, and cardiovascular events

APPENDIX
The following persons participated in the TNT Study: Steering Committee: J. LaRosa (chair), Brooklyn, NY; P. Barter, Sydney; J.-C.
Fruchart, Lille, France; A.M. Gotto, New York; H. Greten, Hamburg, Germany; S.M. Grundy, Dallas; D. Hunninghake, Minneapolis; J.
Kastelein, Amsterdam; J. Shepherd, Glasgow, Scotland; D. Waters, San Francisco; N. Wenger, Atlanta; End-Points Committee: L. Cohen
(chair), New Haven, CT; J.-M. LaBlanche, Lille, France; H. Levine, Boston; U. Sechtem, Stuttgart, Germany; F. Welty, Boston; Data and
Safety Monitoring Board: C. Hennekens (chair), Miami; V. Brown, Atlanta; R. Carmena, Valencia, Spain; R. D’Agostino, Boston; S.
Haffner, San Antonio, TX; E. Leitersdorf, Jerusalem, Israel; Investigators (numbers of patients undergoing randomization in parenthe-
ses): Australia (608) — C. Aroney, P. Barter, J. Bradley, D. Colquhoun, A. Dart, M. d’Emden, J. Lefkovits, R. Minson, G. Nelson, R.
O’Brien, P. Roberts-Thomson, A. Thomson, D. Sullivan, P. Thompson; Austria (29) — H. Drexel, H. Sinzinger, F. Stockenhuber; Belgium
(300) — P. Chenu, G. Heyndrickx, J. Van Cleemput, A. Van Dorpe, W. Van Mieghem, P. Vermeersch; Canada (1052) — M. Arnold, R.
Baigrie, J. Bergeron, C. Gagné, J. Davignon, J. Ducas, J. Genest, L. Higginson, G. Hoag, J. Bonet, A. Ignaszewski, L. Leiter, S. LePage,
P. Ma, M. McQueen, D. Mymin, B. O’Neill, B. Sussex, P. Theroux, G. Tremblay, W. Tymchak, J. Warnica; France (207) — P. Attali, J.
Bonnet, L. Caster, R. Constans, J. Demarcq, I. Ginon, J. Leymarie, J. Mansourati, J. Ollivier, F. Paillard, J. Ponsonnaille; Germany (144)
— U. Beil, H. Fritz, D. Hüwel, W. Huppertz, W. Liebscher, K. Schussmann, E. Steinhagen-Thiessen; Ireland (53) — B. Buckley, P. Crean;
Italy (75) — A. Branzi, P. Fioretti, G. Gensini, N. Mininni, G. Pinelli, E. Uslenghi; the Netherlands (788) — R. Anthonio, J. Bonnier, H.
Crijns, H. Dohmen, P. Dunselman, M. Galjee, B. Hamer, J. Hoorntje, J. Jukema, A. Oude-Ophuis, H. Plokker, J. Posma, J. Ruiter, M.
Trip, A. van Boven; South Africa (523) — A. Dalby, L. Disler, A. Doubell, J. King, E. Lloyd, J. Marx, P. Roux; Spain (525) — M. Anguita, C.
Brotons, C. Calvo, J. Cruz-Fernandez, F. Fernandez-Aviles, A. Fernandez-Cruz, I. Ferreira, E. Gonzalez, E. Lage, P. Mata, J. Mostaza, R.
Muñoz-Aguilera, E. Lopez de Sa, G. Pedro, G. Permanyer, A. Pozuelo, R. Querejeta, J. Ribera, E. Ros-Rahola, M. Vela; Switzerland (91)
— W. Angehrn, L. Kappenberger, T. Moccetti, H. Saner; United Kingdom (299) — D. Brydie, A. Chauhan, R. Greenbaum, H. Kadr, C.
Kaski, R. Mattu, W. McCrea, J. McMurray, D. Mikhailidis, A. Salmasi, N. Samani, M. Shiu, A. Timmis, S. Turley, J. Wictome; United
States (5309) — R. Abadier, S. Alexander, B. Asbill, J. Bagdade, B. Beard, J. Becker, V. Bittner, R. Blumenthal, M. Bolton, W. Bremner,
D. Brewer, C. Brown, K. Browne, J. Carstens, W. Cefalu, J. Chambers, J. Cohen, M. Collins, S. Crespin, M. Cressman, R. Curry, M.
Davidson, G. De Gent, J. de Lemos, P. Deedwania, D. Dixon, J. Duncan, C. East, D. Edmundowicz, B. Effron, M. Elam, M. Ettinger, R.
Feldman, D. Fiske, J. Forrester, G. Fraser, Z. Freedman, S. Freeman, V. Fonseca, D. Frid, K. Friday, J. Geohas, H. Ginsberg, A. Goldberg,
E. Goldenberg, D. Goldner, D. Goldscher, B. Gordon, S. Gottlieb, M. Grayson, R. Guthrie, J. Guyton, J. Haas, F. Handel, R. Hartman,
J. Henry, M. Hepp, R. Heuser, D. Herrington, M. Hibbard, C. Hjemdahl-Monsen, G. Hopkins, V. Howard, J. Hsia, D. Hunninghake, S.
Jafri, P. Jones, P. Kakavas, J. Kane, L. Keilson, E. Kerut, R. Kloner, R. Knopp, J. Kostis, L. Kozlowski, R. Krasuski, A. Kugelmass, K.
LaBresh, J. Larry, C. Lavie, B. Lewis, S. Lewis, M. Linton, P. Linz, R. Lloret, V. Lucarella, J. Maciejko, D. McElroy, J. McGhee, M. Mc-
Gowan, W. McGuinn, M. Melucci, J. Merillat, M. Michalski, D. Miller, L. Miller, M. Miller, M. Mirro, V. Miscia, J. Mossberg, B. Musa,
S. Nash, R. Nesto, M. Neustel, T. Noonan, J. O’Keefe, B. Olafsson, S. Oparil, T. Pearson, C. Pepine, G. Peterson, G. Pogson, K. Powers,
D. Rader, R. Reeves, J. Reusch, G. Revtyak, D. Robertson, J. Robinson, W. Robinson, M. Rocco, J. Robinson, J. Rodgers, R. Rosenson,
E. Roth, S. Sadanandan, K. Salisbury, D. Sato, J. Saucedo, E. Schaefer, H. Schrott, L. Seman, G. Schectman, C. Schmalfuss, D. Sch-
neider, B. Sobel, R. Schneider, S. Schwartz, P. Seigel, M. Seyal, S. Sharp, D. Shindler, D. Smith, D. Sprecher, L. Solberg, E. Sontz, J.
Stamper, E. Stein, V. Subbarao, A. Susmano, A. Talle, P. Thompson, J. Torelli, F. Torres, D. Triffon, G. Vetrovec, N. Vijay, W. Wicker-
meyer, K. Wool, M. Zakrzewski, S. Zarich, J. Zavoral, F. Zieve.

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