Review
Meta-analysis: Statin Therapy Does Not Alter the Association Between
Low Levels of High-Density Lipoprotein Cholesterol and Increased
Cardiovascular Risk
Haseeb Jafri, MD; Alawi A. Alsheikh-Ali, MD, MS; and Richard H. Karas, MD, PhD
Background: Low levels of high-density lipoprotein cholesterol
(HDL-C) are associated with an increased risk for myocardial infarc-
tion (MI). Although statins reduce the risk for MI, most cardiovas-
cular events still occur despite statin treatment.
Purpose: Using meta-analysis of large randomized, controlled trials
(RCTs) of statins to determine whether statins alter the relationship
between HDL-C level and MI.
Data Sources: MEDLINE search to February 2010, ClinicalTrials.gov,
and reference lists from eligible studies.
Study Selection: English-language RCTs of statin-treated patients
versus control participants with 1000 or more person-years of
follow-up and reported HDL-C levels and MI.
Data Extraction: Two independent investigators extracted data
from eligible RCTs.
Data Synthesis: Twenty eligible RCTs were identified (543 210
person-years of follow-up and 7838 MIs). After adjustment for
on-treatment LDL-C levels, age, hypertension, diabetes, and to-
bacco use, there was a significant inverse association between
L arge epidemiologic studies have demonstrated a signif-
icant and independent inverse relationship between
high-density lipoprotein cholesterol (HDL-C) level and the
risk for cardiovascular disease (CVD) (1– 4). Data from the
Framingham Heart Study and the Prospective Cardiovas-
cular Munster Study suggest that every 0.026-mmol/L (1-
mg/dL) decrease in HDL-C is associated with a 2% to 3%
higher risk for CVD (3, 5). However, current national
guidelines for CVD risk reduction are primarily focused on
strategies to reduce levels of low-density lipoprotein cho-
lesterol (LDL-C), with the most recent focus being on
“lower is better” (6). This focus on LDL-C lowering is well
supported by many lipid intervention trials demonstrating
that 3-hydroxy-3-methylglutaryl coenzyme A reductase in-
hibitor (statin) therapy significantly reduces risk for cardio-
vascular events (7).
Although clearly supporting the importance of LDL-C
lowering and statin therapy, careful examination of ran-
See also:
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800 © 2010 American College of Physicians
Annals of Internal Medicine
HDL-C levels and risk for MI in statin-treated patients and control
participants. In Poisson meta-regressions, every 0.26-mmol/L (10-
mg/dL) decrease in HDL-C was associated with 7.1 (95% CI, 6.8
to 7.3) and 8.3 (CI, 8.1 to 8.5) more MIs per 1000 person-years in
statin-treated patients and control participants, respectively. The
inverse association between HDL-C levels and MI did not differ
between statin-treated patients and control participants (P ⫽ 0.57).
Limitation: The observed associations may be explained by unmea-
sured confounding and do not imply causality in the relationship
between HDL-C level and cardiovascular risk.
Conclusion: Statins do not alter the relationship between HDL-C
level and cardiovascular risk, such that low levels of HDL-C remain
significantly and independently associated with increased risk de-
spite statin treatment. The remaining risk seen in statin-treated
patients may be partly explained by low HDL-C levels or other
factors associated with low levels of HDL-C.
Primary Funding Source: None.
Ann Intern Med. 2010;153:800-808. www.annals.org
For author affiliations, see end of text.
domized, controlled trials (RCTs) using statins demon-
strates that even with intensive statin therapy and intensive
LDL-C lowering, many cardiovascular events are not pre-
vented (8 –11). Recognition of these ongoing events has
focused attention on attempts to identify factors that con-
tribute to the cardiovascular risk that persists in statin-
treated patients.
The compelling epidemiologic evidence linking
HDL-C level to CVD risk supports the hypothesis that
low baseline levels of HDL-C may be associated with the
substantial cardiovascular risk that remains in statin-treated
persons. However, it remains unclear whether statin ther-
apy substantially alters the relationship between HDL-C
level and CVD risk (12). Because most of the evidence
supporting the importance of HDL-C levels in CVD risk
predates the widespread use of statins, and given the effi-
cacy of statins in reducing CVD risk, it remains unclear
whether the association of HDL-C level with cardiovascu-
lar risk in statin-treated patients differs from that observed
in the predominantly statin-naive patients of large epide-
miologic studies. Although some studies have demon-
strated a significant association between HDL-C level and
CVD risk in statin-treated patients, to our knowledge there
has been no direct comparison of the magnitude of associ-
ation between HDL-C level and CVD risk in statin-treated
patients versus similar control participants to date. There-
fore, by using data from large RCTs of statins, we exam-

ined and contrasted the association of HDL-C level and
cardiovascular outcomes in statin-treated patients versus
similar cohorts of control participants.
METHODS
We followed the PRISMA (Preferred Reporting Items
for Systematic Reviews and Meta-Analyses) guidelines dur-
ing all stages of the design, implementation, and reporting
of this meta-analysis (13).
Data Sources and Searches
A MEDLINE search identified RCTs of statin therapy
versus control participants published up to February 2010
in the English-language literature. Only trials with at least
1000 person-years of follow-up were included to ensure
that they possessed sufficient follow-up to allow for evi-
dence of a clinically meaningful relationship between base-
line variables and the outcome of interest. To be eligible,
trials had to report both baseline and on-treatment
HDL-C levels. The electronic search strategy included the
terms hydroxyl methyl glutaryl coenzyme A reductase inhibi-
tor, statin, lovastatin, pravastatin, simvastatin, atorvastatin,
cerivastatin, fluvastatin, and rosuvastatin. Citations were
limited using the terms human, English language, and ran-
domized controlled trial. In addition, we manually reviewed
the reference lists of eligible trials to ensure that all appro-
priate studies were included. Finally, a review of Clinical-
Trials.gov was conducted to identify trials that may be
eligible for inclusion.
Study Selection
Our search yielded 2239 citations, which were
screened at the abstract level (Figure 1). We excluded 2196
abstracts (1421 with follow-up ⬍1000 person-years, 290
were not statin studies, and 485 were not RCTs), resulting
in 43 full-text manuscripts retrieved for detailed evalua-
tion. Of these, 23 were eventually excluded (15
had ⬍1000 person-years of follow-up, 3 did not report
on-treatment HDL-C levels, and 5 were statin vs. statin
RCTs). Hence, we included a total of 20 statin RCTs in
the main analysis (Appendix Figure 1, available at www
.annals.org).
Data Extraction and Quality Assessment
Two investigators independently reviewed full manu-
scripts of eligible trials, and the relevant data were extracted
into electronic data tables. For each eligible study, the vari-
ables extracted from the published manuscript were the
statin used and the dose; the number of patients in the
intervention and control groups; duration of follow-up;
and baseline and on-treatment serum HDL-C, LDL-C,
total cholesterol, and triglyceride levels. Of note, for all
on-treatment lipid measurements, including HDL-C, we
extracted the last value reported in the trial. In addition, we
extracted the number of patients with any of the following
outcomes during follow-up, as defined in each study: myo-
cardial infarction (MI), coronary heart disease (CHD)
www.annals.org
HDL-C, Statins, and Cardiovascular Risk Review
Figure 1. Summary of evidence search and selection.
Potentially relevant articles identified and
screened for retrieval (n = 2239)
Reports excluded on the basis of title and abstract review
(n = 2196)
<1000 person-years of follow-up: 1421
Nonstatin trials: 290
Non-RCTs: 485
Reports retrieved for more detailed evaluation (n = 43)
Reports excluded on the basis of title and abstract review
(n = 23)
<1000 person-years of follow-up: 15
Did not report on-treatment HDL-C levels: 3
Statin vs. statin trials: 5
Potentially appropriate RCTs for meta-analysis (n = 20)
RCTs excluded from meta-analysis (n = 0)
RCTs included in meta-analysis with usable
information for overall analysis (n = 20)
HDL-C ⫽ high-density lipoprotein cholesterol; RCT ⫽ randomized,
controlled trial.
death, CVD, CVD death, and all-cause death. For each
trial group, we recorded mean or median values for age;
the proportion of men; and the proportion of persons
who used tobacco products, had diabetes mellitus, or
had hypertension at baseline. Person-years of follow-up
for each study group were calculated by multiplying the
reported follow-up in years by the number of persons in
each group.
We used the Jadad scale to score study quality (range,
0 to 5; higher scores indicated better quality) (14). Study
quality was sufficient for all included RCTs (Jadad
score ⱖ3), for a median score of 5 for all trials included.
Of the 20 trials included in our study, 4 were not double-
blind and 4 others did not provide adequate explanation
for patients who withdrew.
Data Synthesis and Analysis
Our prespecified primary analysis examined the asso-
ciation between on-treatment HDL-C levels and the risk
for MI. To account for variation in follow-up, risk for MI
in each group of an RCT was expressed as number of MIs
per 1000 person-years of follow-up. The regression model
for this association relates the risk for MI to the median
person-years of follow-up and the exponent of a constant
plus the slope multiplied by the on-treatment HDL-C
level. The association of HDL-C level and risk for MI was
examined separately in the statin and control cohorts and
then compared between the 2 groups. This offered the
21 December 2010 Annals of Internal Medicine Volume 153 • Number 12 801
Review HDL-C, Statins, and Cardiovascular Risk
opportunity to compare the relationship of HDL-C levels
with risk for MI in 2 similar groups (by virtue of random-
ization), except for the presence of statin therapy in 1.
Secondary analyses were done by examining CHD death,
CVD, CVD death, and all-cause death. We repeated these
analyses by using baseline HDL-C levels in place of on-
treatment HDL-C levels to evaluate the sensitivity of our
findings to our definition of on-treatment HDL-C levels.
In addition, we calculated the median difference for the
rates of MI and CVD between the statin and control
groups to assess the overall magnitude of benefit derived
from statin therapy in these trials.
In the main analyses, we did not assume that rates of
cardiovascular events were normally distributed. The asso-
ciation between on-treatment HDL-C level and the out-
comes of interest was examined by using Poisson meta-
regressions with robust standard error estimation during
the follow-up for each trial. We estimated univariate as
well as multivariate associations, controlling for on-
treatment LDL-C levels; age (mean or median as reported
in the RCT); and proportion of patients with hyperten-
sion, diabetes mellitus, and tobacco use. In addition, we
repeated this analysis, controlling for statin dose and type.
To do this, we segregated our analysis along the lines of
relative statin potency and designated the statins used in
the trials as low, intermediate, or high dose. To compare
the relationship of HDL-C level with outcomes in the
statin versus control cohorts, we considered the hypoth-
esis that the slopes of the 2 regression lines are equal
(that is, the regression lines for the statin and control
cohorts are parallel). If the regression lines are parallel,
then the effect of HDL-C levels on the outcome rate is
the same in each group. We tested the parallelism hy-
pothesis, using the Chow test, by fitting a single regres-
sion line to the pooled data of both cohorts indexed by
a variable indicating cohort type (statin vs. control) and
then testing the significance of the interaction term of
cohort type with HDL-C level (15). We used STATA,
version 11.0 (StataCorp, College Station, Texas), for
statistical analysis. A P value less than 0.05 was consid-
ered statistically significant.
Role of the Funding Source
No funding was received for this study.
RESULTS
Eligible Trials
We included 20 statin RCTs in the analysis (Table 1)
(16 –35). No evidence of publication bias was noted, as
assessed by examination of a funnel plot for asymmetry and
quantified by using the Egger and Begg regression tests to
calculate 2-tailed P values (Appendix Figure 2, available at
www.annals.org) (36). A total of 70 939 patients were al-
located to the statin groups and 66 068 patients were allo-
cated to the control groups. The median (25th, 75th per-
802 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12
centiles) duration of follow-up was 3.9 years (3.1, 5.0
years).
During the total of 543 210 person-years of follow-up,
7838 MIs, 12 220 CVD events, 3088 CHD deaths, 4967
CVD deaths, and 10 941 all-cause deaths occurred. In the
control groups, the median (25th, 75th percentiles) rates of
the outcomes of interest per 1000 person-years of
follow-up were 15.5 (11.1, 22.5) for MIs, 27.8 (19.9,
37.9) for CVD events, 6.5 (1.9, 13.5) for CHD deaths, 7.7
(3.6, 16.4) for CVD deaths, and 17.5 (12.9, 25.1) for
all-cause deaths. The corresponding rates in the statin
groups were 11.5 (6.9, 15.9) for MIs, 23.7 (14.6, 31.7) for
CVD events, 3.9 (1.3, 9.3) for CHD deaths, 7.8 (2.3,
12.4) for CVD deaths, and 11.7 (6.0, 18.6) for all-cause
deaths. Relative to control participants, statin therapy was
associated with a median relative reduction in the rate of
MI (26.2%), CVD (24.5%), CHD death (26.7%), CVD
death (20.0%), and all-cause death (16.1%) (P ⬍ 0.01 for
all comparisons). In these studies, the overall median de-
crease observed with statin therapy was approximately
4 MIs and 4.1 CVD events per 1000 person-years of
follow-up.
Among all the eligible RCTs, baseline and on-
treatment lipid measures varied widely from study to
study, with similar baseline levels in the statin versus con-
trol groups, and favorable on-treatment changes in the sta-
tin groups (Table 2). In the statin groups, median baseline
and on-treatment HDL-C levels were 1.2 mmol/L (45.0
mg/dL) (range, 1.1 to 1.3 mmol/L [range, 40.9 to 49.0
mg/dL]) and 1.2 mmol/L (48.2 mg/dL) (range, 1.2 to 1.3
mmol/L [range, 46.2 to 50.0 mg/dL]), respectively (P ⬍
0.001) (Table 2). Baseline and on-treatment HDL-C levels
did not differ in the control groups (Table 2).
Primary Analysis
In the control cohorts, there was a significant inverse
association between HDL-C level and the risk for MI, such
that every 0.26-mmol/L (10-mg/dL) decrease in HDL-C
was associated with 8.3 (95% CI, 8.1 to 8.5) more MIs per
1000 person-years (P ⬍ 0.001) (Figure 2, top, and Table
3). This relationship persisted after adjustment for on-
treatment LDL-C level, age, and proportion of patients
with hypertension, diabetes mellitus, and tobacco use (P ⬍
0.001). Likewise, in the statin groups, there was a signifi-
cant inverse association between HDL-C level and the risk
for MI, such that every 0.26-mmol/L (10-mg/dL) decrease
in HDL-C was associated with 7.1 (CI, 6.8 to 7.3) more
MIs per 1000 person-years (P ⬍ 0.001) (Figure 2, top, and
Table 3). This relationship persisted after adjustment for
on-treatment LDL-C level, age, and proportion of patients
with hypertension, diabetes mellitus, and tobacco use (P ⬍
0.001). In addition, this relationship persisted after con-
trolling for the relative potency of the statin used within
the trials (P ⬍ 0.001). Of importance, the slopes of the 2
regression lines of HDL-C levels and risk for MI were
similar in the 2 groups (statin vs. control), suggesting that
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 HDL-C, Statins, and Cardiovascular Risk Review

Table 1. Characteristics of Large Randomized, Controlled Statin Trials Included in the Analysis

Study, Year Follow-up, Study Target Potency* Participants, Mean Men, % Diabetes, Hypertension, Smokers,
(Reference) y Group Dose, mg/d n Age, y† % % %
EXCEL, 1991 (16) 1 Lovastatin 20 Low 1642 55.6 60.1 1.0 41.0 18.0
Lovastatin 40 Intermediate 1645 55.7 59 1.0 40.0 18.0
Lovastatin 20 BID Intermediate 1646 56.2 57.8 1.0 38.0 18.0
Lovastatin 40 BID High 1649 55.2 59.2 1.0 38.0 18.0
Placebo 1663 56 58.3 1.0 41.0 18.0
4S, 1994 (17) 5.4 Simvastatin 20–40 Intermediate 2221 58.6 82 24 26 5
Placebo 2223 58.6 81 4.0 26.0 27.0
WOSCOPS, 5.0 Pravastatin 40 Intermediate 3302 55 100 1.0 16.0 44.0
1995 (18) Placebo 3293 55 100 1.0 15.0 44.0
CARE, 1996 (19) 5.0 Pravastatin 40 Intermediate 2081 59 86 14.0 42.0 21.0
Placebo 2078 59 86 15.0 43.0 21.0
AFCAPS/TexCAPS, 5.2 Lovastatin 20–40 Intermediate 3304 58 85 3.0 22.0 13.0
1998 (20) Placebo 3301 58 85 2.0 22.0 12.0
LIPID, 1998 (21) 6.1 Pravastatin 40 Intermediate 4512 62 83 9.0 41.0 9.0
Placebo 4502 62 83 9.0 42.0 10.0
GISSI, 2000 (22) 1.9 Pravastatin 20 Low 2138 60 86.7 12.9 36.2 12.4
Placebo 2133 60 85.8 14.4 36.9 11.3
ALLHAT-LLT, 4.8 Pravastatin 40 Intermediate 5170 66.4 51.4 35.9 100.0 23.1
2002 (23) Usual care 5185 66.3 51 34.4 100.0 23.3
GREACE, 3 Atorvastatin 80 High 800 58 78 20.0 42.0 NR
2002 (24) Placebo 800 59 79 19.0 44.0 NR
HPS, 2002 (25) 5.0 Simvastatin 40 Intermediate 10 269 63 75 19.5 19.8 14.0
Placebo 10 267 63 75 11.0 25.2 14.0
LIPS, 2002 (26) 3.9 Fluvastatin 80 High 844 60 84.2 14.2 39.0 25.0
Placebo 833 60 83.4 9.8 38.1 28.2
PROSPER, 3.2 Pravastatin 40 Intermediate 2891 75.4 48.3 10.5 62.2 26.0
2002 (27) Placebo 2913 75.3 48.3 11.0 61.6 27.6
ASCOT-LLA, 3.3 Atorvastatin 10 Low 5168 63.1 81.1 24.3 100.0 33.2
2003 (28) Placebo 5137 63.2 81.3 24.8 100.0 32.2
CARDS, 2004 (29) 3.9 Atorvastatin 10 Low 1428 61.5 68 100.0 84.0 22.0
Placebo 1410 61.8 68 100.0 84.0 22.0
ASPEN, 2006 (30) 4.0 Atorvastatin 10 Low 1211 61.1 66 100.0 55.0 12.0
Placebo 1199 61 67 100.0 55.0 13.0
MEGA Study, 5.3 Pravastatin 20 Low 3866 58.2 32 21.0 42.0 21.0
2006 (31)
Diet 3966 58.4 31 21.0 42.0 20.0
SPARCL, 4.9 Atorvastatin 80 High 2365 63 60.3 16.7 62.4 19.1
2006 (32) Placebo 2366 62.5 59 16.9 61.4 19.3
CORONA, 2.7 Rosuvastatin 10 Intermediate 2497 73 76 30.0 63.0 9.0
2007 (33) Placebo 2514 73 76 29.0 63.0 8.0
JUPITER, 1.9 Rosuvastatin 20 High 8901 66 61.5 0.0 NR 15.7
2008 (34) Placebo 8901 66 62.1 0.0 NR 16.0
AURORA, 3.8 Rosuvastatin 10 Intermediate 1389 64.1 61.3 20.6 NR 14.5
2009 (35) Placebo 1384 64.3 63 18.0 NR 16.4

4S ⫽ Scandinavian Simvastatin Survival Study; AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT-LLT ⫽ Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-LLA ⫽ Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm; ASPEN ⫽ Atorvastatin
Study for Prevention of Coronary Heart Disease Endpoints in Non–Insulin-Dependent Diabetes Mellitus; AURORA ⫽ A Study to Evaluate the Use of Rosuvastatin in
Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; BID ⫽ twice a day; CARDS ⫽ Collaborative Atorvastatin Diabetes Study;
CARE ⫽ Cholesterol and Recurrent Events Trial; CORONA ⫽ Controlled Rosuvastatin Multinational Trial in Heart Failure; EXCEL ⫽ Expanded Clinical Evaluation of
Lovastatin; GISSI ⫽ Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico; GREACE ⫽ The Greek Atorvastatin and Coronary-heart-disease Evaluation
study; HPS ⫽ Heart Protection Study; JUPITER ⫽ Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin; LIPID ⫽ Long-Term
Intervention with Pravastatin in Ischaemic Disease; LIPS ⫽ Lescol Intervention Prevention Study; MEGA ⫽ Management of Elevated Cholesterol in the Primary Prevention
Group of Adult Japanese; NR ⫽ not recorded; PROSPER ⫽ Prospective Study of Pravastatin in the Elderly at Risk; SPARCL⫽ Stroke Prevention by Aggressive Reduction
in Cholesterol Levels; WOSCOPS ⫽ West of Scotland Coronary Prevention Study.
* Low potency is lovastatin, 20 mg; pravastatin, 20 mg; or atorvastatin, 10 mg (approximately a 20%–30% reduction in low-density lipoprotein cholesterol levels).
Intermediate potency is lovastatin, 40 mg; simvastatin, 20 – 40 mg; pravastatin, 40 mg; or rosuvastatin, 10 mg (approximately a 30%– 40% reduction in low-density
lipoprotein cholesterol levels). High potency is lovastatin, 80 mg; atorvastatin, 80 mg; fluvastatin, 80 mg; or rosuvastatin, 20 mg (⬎40% reduction in low-density lipoprotein
cholesterol levels).
† Mean age for the group reported in the trial.

the effect of HDL-C on MI risk is not altered by statin of CVD events in the control cohorts (5.4 [CI, 4.8 to 5.8]
therapy (P ⫽ 0.57) (Table 3). more CVD events per 1000 person-years of follow-up for
Secondary Analysis every 0.26-mmol/L [10-mg/dL] decrease in on-treatment
We obtained similar findings when we examined HDL-C level; P ⬍ 0.001) (Figure 2, bottom, and Table 3)
CVD outcomes. There was a significant inverse associ- as well as in the statin cohorts (4.1 [CI, 3.5 to 4.5] more
ation between on-treatment HDL-C levels and the rate CVD events per 1000 person-years of follow-up for ev-
www.annals.org 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12 803
Review HDL-C, Statins, and Cardiovascular Risk

Table 2. Lipid Levels and Outcomes From Large Randomized, Controlled Statin Trials Included in the Analysis

Study, Year Study Target Baseline On- Increase in P Baseline On- Decrease P MI Rate CVD Rate
(Reference) Group Dose, HDL-C Treatment HDL-C Value† LDL-C Treatment in LDL-C Value† Per Per 1000
mg/d Level, HDL-C Level, % Level, LDL-C Level, % 1000 Person-
mg/dL* Level, mg/dL* Level, Person- Years
mg/dL* mg/dL* Years
EXCEL, 1991 (16) Lovastatin 20 45.0 48.0 6.6 NR 180 136.8 24.0 NR 11 NR
Lovastatin 40 45.0 48.2 7.2 NR 180 126 30.0 NR 3 NR
Lovastatin 20 BID 45.0 48.9 8.6 NR 180 118.8 34.0 NR 12 NR
Lovastatin 40 BID 45.0 49.3 9.5 NR 180 108 40.0 NR 12 NR
Placebo 45 45.9 2.0 180 180.7 ⫺0.4 12.1 NR
4S, 1994 (17) Simvastatin 20–40 45.5 49 8.0 NR 188 122 35.0 NR 13.7 36.5
Placebo 45.9 46 1.0 188 190 ⫺1.0 22.5 52.5
WOSCOPS, Pravastatin 40 44 46 5.0 NR 192 142 26.0 NR 11 13.5
1995 (18) Placebo 44 44 0.0 192 192 0.0 15.5 18
CARE, 1996 (19) Pravastatin 40 39 41 5.0 ⬍0.001 139 100 28.0 ⬍0.001 15.3 20.5
Placebo 39 39 0.0 139 139 0.0 20.3 27.8
AFCAPS/TexCAPS, Lovastatin 20–40 36.6 39 6.5 ⬍0.001 150 115 23.3 ⬍0.001 9.5 11.3
1998 (20) Placebo 36.6 38 3.8 150 156 ⫺4.0 12.5 14.9
LIPID, 1998 (21) Pravastatin 40 36 38 5.0 ⬍0.001 150 113 25.0 ⬍0.001 12.2 18.3
Placebo 36 36 0.0 150 150 0.0 16.9 24.3
GISSI, 2000 (22) Pravastatin 20 45.7 48 4.2 NR 151.8 123 19.0 NR 11.1 24.9
Placebo 45.7 47 2.0 151.5 148 2.6 12.6 27.9
ALLHAT-LLT, Pravastatin 40 47.6 49 1.9 NR 145.6 104 28.6 NR 15.3 23.7
2002 (23) Usual care 47.4 45 ⫺5.3 145.5 121 16.7 16.9 26.2
GREACE, Atorvastatin 80 39 42 7.7 0.003 180 97 46.1 ⬍0.001 NR NR
2002 (24) Placebo 39 40 2.6 179 169 5.6 NR NR
HPS, 2002 (25) Simvastatin 40 40.9 42 2.8 NR 131.2 89 32.4 NR 17.5 26.1
Placebo 40.9 41 0.0 131.2 127 2.9 23.6 35
LIPS, 2002 (26) Fluvastatin 80 38 46 22.1 NR 131 96 27.0 ⬍0.001 41 NR
Placebo 37 45 21.6 132 132 0.0 57.6 NR
PROSPER, Pravastatin 40 50.2 53 5.0 NR 146.7 97 34.2 NR 34.2 44.1
2002 (27) Placebo 50.2 50 0.0 146.7 129 11.8 40.3 50.7
ASCOT-LLA, Atorvastatin 10 50.6 51 0.0 NR 132.8 90 32.6 NR 5.9 15.7
2003 (28) Placebo 50.6 50 ⫺1.5 132.8 126 4.9 9.1 21.7
CARDS, 2004 (29) Atorvastatin 10 53.7 49 ⫺9.4 ⬍0.001 117.3 81 30.6 ⬍0.001 5.9 24.1
Placebo 54.8 47 ⫺13.4 116.6 120 ⫺3.3 11.1 34.4
ASPEN, 2006 (30) Atorvastatin 10 47 48 2.2 ⬍0.001 113 91 19.8 ⬍0.001 10.1 17.1
Placebo 47 47 ⫺0.2 114 113 1.1 13.8 21.7
MEGA Study, Pravastatin 20 57.5 60 4.7 ⬍0.001 156.3 128 18.2 ⬍0.001 0.9 3.3
2006 (31)
Diet 57.5 59 2.1 156.3 151 3.7 1.6 4.5
SPARCL, Atorvastatin 80 50 52 4.2 0.006 132.7 73 45.1 ⬍0.001 7.2 30
2006 (32) Placebo 50 51 2.0 133.7 129 3.9 10.4 37.3
CORONA, Rosuvastatin 10 48 50 4.3 ⬍0.001 136.9 76 44.5 ⬍0.001 18.2 33.3
2007 (33) Placebo 136 138 0.0 47.6 47.6 ⫺1.5 21.7 38.4
JUPITER, Rosuvastatin 20 49 52 6.1 ⬍0.001 108 54 50.0 ⬍0.001 1.8 3.8
2008 (34) Placebo 49 50 2.0 108 108 0.0 4 7.8
AURORA, Rosuvastatin 10 45 46.3 2.9 0.045 99 56.5 42.9 ⬍0.001 55.9 74.3
2009 (35) Placebo 45 48.6 8.0 100 98.1 1.9 60.1 77.8

4S ⫽ Scandinavian Simvastatin Survival Study; AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT-LLT ⫽ Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-LLA ⫽ Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; ASPEN ⫽ Atorvastatin Study
for Prevention of Coronary Heart Disease Endpoints in Non–Insulin-Dependent Diabetes Mellitus; AURORA ⫽ A Study to Evaluate the Use of Rosuvastatin in Subjects
on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; BID ⫽ twice a day; CARDS ⫽ Collaborative Atorvastatin Diabetes Study; CARE ⫽
Cholesterol and Recurrent Events Trial; CORONA ⫽ Controlled Rosuvastatin Multinational Trial in Heart Failure; CVD ⫽ cardiovascular disease; EXCEL ⫽ Expanded
Clinical Evaluation of Lovastatin; GISSI ⫽ Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico; GREACE ⫽ The Greek Atorvastatin and Coronary-
heart-disease Evaluation study; HPS ⫽ Heart Protection Study; HDL-C ⫽ high-density lipoprotein cholesterol; JUPITER ⫽ Justification for the Use of Statins in
Prevention: An Intervention Trial Evaluating Rosuvastatin; LIPID ⫽ Long-Term Intervention with Pravastatin in Ischaemic Disease; LDL-C ⫽ low-density lipoprotein
cholesterol; LIPS ⫽ Lescol Intervention Prevention Study; MEGA ⫽ Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; MI ⫽
myocardial infarction; NR ⫽ not recorded; PROSPER ⫽ Prospective Study of Pravastatin in the Elderly at Risk; SPARCL⫽ Stroke Prevention by Aggressive Reduction in
Cholesterol Levels; WOSCOPS ⫽ West of Scotland Coronary Prevention Study.
* To convert values for HDL-C and LDL-C levels to mmol/L, multiply by 0.0259. All lipid levels are mean levels reported in the trial.
† P value is on-treatment values in statin groups compared with baseline values at follow-up.

ery 0.26-mmol/L [10-mg/dL] decrease in on-treatment
HDL-C level; P ⬍ 0.001) (Figure 2, bottom, and Table 3).
The inverse associations persisted in both groups after ad-
justment for on-treatment levels of LDL-C, age, and pro-
portion of patients with hypertension, diabetes mellitus,
804 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12
and tobacco use (P ⬍ 0.001 for both groups). This associ-
ation persisted after controlling for the relative potency of
the statin used within the trials (P ⬍ 0.001). The effect of
HDL-C levels on CVD risk was not altered by statin ther-
apy (P ⫽ 0.21) (Table 3). We found similar relationships
www.annals.org
 HDL-C, Statins, and Cardiovascular Risk Review

in the control and statin cohorts when the outcomes of participants. In addition to not being affected by statin
CHD death, CVD death, and all-cause death were ana- therapy, the association of HDL-C level with cardiovas-
lyzed, such that significant inverse associations between the cular risk persists after controlling for on-treatment
risk for events and HDL-C levels were observed (Table 3), LDL-C level, age, hypertension, diabetes mellitus, and
without significant differences in these relationships be- tobacco use. Consequently, the cardiovascular risk that
tween statin and control groups (Table 3). All findings persists in statin-treated patients may, at least in part, be
were unchanged when a sensitivity analysis was conducted attributed to low levels of HDL-C.
after excluding the EXCEL (Expanded Clinical Evaluation The magnitude of the association of low levels of
of Lovastatin [several intervention groups]), CORONA HDL-C with cardiovascular risk is likely to be prominent
(Controlled Rosuvastatin in Multinational Trial In Heart because of the estimated number of additional events for a
Failure [heart failure population]), and AURORA (A given decrease in HDL-C level. Based on the analysis de-
Study to Evaluate the Use of Rosuvastatin in Subjects on scribed herein, each 0.26-mmol/L (10-mg/dL) decrease in
Regular Hemodialysis [hemodialysis population]) trials. In HDL-C levels, even after adjustment for on-treatment
addition, all findings were unchanged when the analyses LDL-C, is associated with approximately 7 additional MIs
were repeated using baseline instead of on-treatment and 4 additional CVD events per 1000 person-years, de-
HDL-C levels (data not shown). spite statin therapy. To put this in context with the mag-
nitude of benefit from statin therapy, the present analysis
DISCUSSION suggests that statin therapy is associated with 4 fewer MIs
Our meta-analysis of large-scale statin trials demon- and 4 fewer CVD events per 1000 person-years of follow
strates that the independent and significant inverse as- up. In other words, the magnitude of a statin-mediated
sociation between HDL-C levels and cardiovascular out- reduction in MI and CVD events is approximately equiv-
comes is not altered by statin therapy. Statin-treated alent to the difference in MI or CVD events that is asso-
patients are subject to the same magnitude of risk asso- ciated with a 0.13- and 0.26-mmol/L (5- and 10-mg/dL)
ciated with lower levels of HDL-C as similar control increase in HDL-C, respectively.

Figure 2. Associations between HDL-C levels and cardiovascular outcomes.

80 80

75 75

70 70

65 65

60 60
CVD Rate (per 1000 Person-Years)
MI Rate (per 1000 Person-Years)

55 55

50 50

45 45

40 40

35 35

30 30

25 25

20 20

15 15

10 10

5 5

0 0

35 40 45 50 55 60 65 35 40 45 50 55 60 65

On-Treatment HDL-C Level, mg/dL On-Treatment HDL-C Level, mg/dL

Black circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control. The circles
represent the relative sizes of the group (that is, the weight of the group). The solid lines are the regression lines (weighted by the SE). To convert values
for HDL-C to mmol/L, multiply by 0.0259. CVD ⫽ cardiovascular disease; HDL-C ⫽ high-density lipoprotein cholesterol; MI ⫽ myocardial
infarction.
www.annals.org 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12 805
Review HDL-C, Statins, and Cardiovascular Risk
Table 3. Estimated Number of Additional Events for Every
0.26-mmol/L (10-mg/dL) Decrease in High-Density
Lipoprotein Cholesterol Levels*
Outcome Statin-Treated Control P Value†
Patients Participants
Myocardial infarction 7.1 (6.8, 7.3) 8.3 (8.1, 8.5) 0.57
Cardiovascular disease 4.1 (3.5, 4.5) 5.4 (4.8, 5.8) 0.21
Coronary heart 2.6 (2.5, 2.7) 2.3 (2.2, 2.4) 0.31
disease death
Cardiovascular death 9.1 (8.0, 10.1) 9.5 (8.5, 10.5) 0.36
All-cause death 2.9 (2.2, 3.4) 2.6 (1.7, 3.1) 0.10
* Values reported are medians (25th, 75th percentiles).
† P value compares the association between high-density lipoprotein cholesterol
levels and events in statin-treated patients with those observed in control partici-
pants by using the Chow test (see the Methods section for details).
The present findings complement previous observa-
tions about HDL-C levels and cardiovascular risk in statin-
treated patients, as well as the findings of a post hoc anal-
ysis from the TNT (Treating to New Targets) trial. The
TNT study was a randomized trial comparing the effects of
low-dose versus high-dose atorvastatin on clinical out-
comes, and a post hoc analysis of this study demonstrated
that low levels of HDL-C were predictive of higher rates of
major CVD events, even at very low levels of LDL-C (12).
Similarly, in a pooled analysis of 3 pravastatin RCTs, there
was a significant inverse relationship between baseline
HDL-C level and CHD risk (37). The current findings
extend these previous studies by being the first to system-
atically examine the association of HDL-C levels and car-
diovascular outcomes across all relevant large RCTs of
statins and, of importance, to compare that relationship in
statin-treated patients with that seen in similar control par-
ticipants. In doing so, we were able to demonstrate not
only that an inverse association exists between low HDL-C
levels and CVD risk in statin-treated patients, but that this
association is not altered or attenuated by statin therapy.
Even though the present findings support an associa-
tion between low levels of HDL-C and increased cardio-
vascular risk in statin-treated patients, it should be ac-
knowledged that HDL-C is not currently a target of
national cholesterol guidelines; rather, levels of LDL-C and
non–HDL-C, are the specified primary and secondary tar-
gets for therapy (6). Further, it is unclear whether inter-
ventions that increase HDL-C levels will further reduce
CVD risk. Such potential was explored in HATS (HDL-
Atherosclerosis Treatment Study), in which treatment with
simvastatin plus niacin over 3 years was associated with
approximately 90% relative reduction in cardiovascular
risk compared with placebo (38). Although it was a small
trial with relatively few clinical events, the magnitude of
risk reduction in HATS is approximately 3 times that seen
in statin-only trials and was accompanied by regression of
coronary atherosclerosis (38). Nonetheless, whether the fa-
vorable effects of niacin seen in HATS were directly related
to changes in HDL-C levels remains unclear. In a separate
806 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12
study, increasing HDL-C in patients with very low LDL-C
levels (mean LDL-C level ⬍1.94 mmol/L [⬍75 mg/dL];
most were receiving statins), was associated with significant
improvement in endothelial function, and on-treatment
HDL-C levels correlated with the favorable effect on the
endothelium (39). Furthermore, in a meta-analysis of 23
trials of various lipid-altering drugs, the sum of the per-
centage reduction in LDL-C levels and percentage increase
in HDL-C levels was a better predictor of benefit than the
change in either lipoprotein component alone, suggesting
that strategies that favorably alter both lipid parameters
may be more effective in preventing cardiovascular events
(40). Despite these findings, it is well recognized that fa-
vorable changes in biomarker outcomes may not necessar-
ily translate into cardiovascular prevention, and a few stud-
ies have indicated that some interventions that increase
HDL-C levels may not improve outcomes (41– 43). For
example, a recent meta-regression analysis concluded that
simply increasing the amount of circulating HDL-C does
not reduce the risk for CVD, although the magnitude of
increase in HDL-C levels in the included studies was min-
imal (43). Clearly, the potential for therapies that increase
HDL-C levels to reduce CVD risk requires additional clin-
ical outcomes data. Such data should be forthcoming in
the AIM-HIGH (Atherothrombosis Intervention in Meta-
bolic Syndrome with Low HDL/High Triglycerides and
Impact on Global Health Outcomes) study and in the
HPS2-THRIVE (Heart Protection Study 2 Treatment of
HDL to Reduce the Incidence of Vascular Events) study
(44, 45). If increasing HDL-C levels is found to reduce
CVD risk in these trials, a large population of patients may
benefit because some studies have reported that nearly 80%
of statin-treated patients with low LDL-C levels still have
low HDL-C levels (46).
The trials included in this analysis were not designed
to examine the effect of treatment on HDL-C levels, so
this analysis is subject to the limitations of observational
studies. In addition, our findings are limited by the use of
trial-level data, which may be subject to biases related to
confounding that has not been fully captured by the sum-
mary estimates from the trials. Access to individual patient
data would allow for a more robust analysis. Furthermore,
although the outcomes of interest were adjudicated in each
trial, there was no standardized adjudication across all
RCTs, and hence differences in definitions of the outcomes
cannot be excluded. Such differences, however, should not
invalidate the comparison of the 2 regression lines (statin-
treated patients vs. control participants). In addition, al-
though our analysis demonstrates that low levels of
HDL-C are associated with persistent cardiovascular risk in
statin-treated patients, other risk factors, including other
lipid parameters, such as the ratio of total cholesterol to
HDL-C, non–HDL-C, and LDL particle numbers, may
also contribute to the remaining risk in these patients.
Therefore, associations reported here may be due to un-
measured confounding and should not be interpreted as
www.annals.org

supporting cause and effect in the relationship between
HDL-C level and cardiovascular risk.
In conclusion, even after adjustment for on-treatment
LDL-C levels, age, hypertension, diabetes mellitus, and to-
bacco use, statin-treated patients are subject to the same
magnitude of risk associated with lower levels of HDL-C,
relative to similar patients not treated with statins. The
persistent cardiovascular risk in statin-treated patients may
be partly explained by low levels of HDL-C or other CVD
risk factors that are associated with low levels of HDL-C.
The findings underscore the importance of recognizing the
risk associated with low levels of HDL-C, even in statin-
treated patients, and highlight the need for additional
clinical investigation that targets levels of HDL-C in this
context.
From Molecular Cardiology Research Institute, Institute for Clinical Re-
search and Health Policy Studies, Tufts Medical Center, and Tufts Uni-
versity School of Medicine, Boston, Massachusetts, and Institute of Car-
diac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, United Arab
Emirates.
Acknowledgment: The authors thank Dr. Thomas Trikalinos for his
valuable advice and assistance with statistical analysis.
Potential Conflicts of Interest: Dr. Alsheikh-Ali: Grants received: Pfizer.
Grants received (money to institution): Pfizer. Dr. Karas: Consultancy: Ab-
bott Laboratories. Disclosures can also be viewed at www.acponline.org
/authors/icmje/ConflictOfInterestForms.do?msNum⫽M10-2091.
Reproducible Research Statement: Study protocol, statistical code, and
data set: Not available.
Requests for Single Reprints: Richard H. Karas, MD, PhD, Molecular
Cardiology Research Institute, Box 80, Tufts Medical Center, 750 Wash-
ington Street, Boston, MA 02111; e-mail, rkaras@tuftsmedicalcenter
.org.
Current author addresses and author contributions are available at www
.annals.org.
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Annals of Internal Medicine
Current Author Addresses: Drs. Jafri and Karas: Molecular Cardiology
Research Institute, Box 80, Tufts Medical Center, 750 Washington Appendix Figure 2. Funnel plot for myocardial infarction.
Street, Boston, MA 02111.
Dr. Alsheikh-Ali: Institute of Cardiac Sciences, Sheikh Khalifa Medical 0
City, PO Box 51900, Abu Dhabi, United Arab Emirates. Egger weighted
0.05 regression, P = 0.179
Author Contributions: Conception and design: H. Jafri, A.A. Alsheikh- Begg rank
Ali, R.H. Karas. 0.1 correlation, P = 0.179
Analysis and interpretation of the data: H. Jafri, A.A. Alsheikh-Ali, R.H.

Standard Error
Karas. 0.15
Drafting of the article: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas.
Critical revision of the article for important intellectual content: H. Jafri, 0.2
A.A. Alsheikh-Ali, R.H. Karas.
Final approval of the article: H. Jafri, A.A. Alsheikh-Ali, R.H. Karas. 0.25
Statistical expertise: H. Jafri, A.A. Alsheikh-Ali.
Administrative, technical, or logistic support: H. Jafri, A.A. Alsheikh-Ali.
0.3
Collection and assembly of data: H. Jafri, A.A. Alsheikh-Ali.
0.35
–1 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6
LN Relative Risk

Plots represent data from 20 randomized, controlled trials of statin ther-

apy evaluating the outcome of myocardial infarction. LN ⫽ log normal.

Appendix Figure 1. Forest plot of statin versus control for MI and RR (95% CI) for MI.

Study, Year (Reference) Statin Group Control Group RR (95% CI) Weight, %
(MI/Total), n/N (MI/Total), n/N

EXCEL, 1991 (16) 18/1642 20/1663 0.912 (0.484–1.717) 1.07

4S, 1994 (17) 164/2221 270/2223 0.608 (0.505–0.731) 6.45
WOSCOPS, 1995 (18) 181/3302 256/3293 0.705 (0.587–0.848) 6.48
CARE, 1996 (19) 159/2081 211/2078 0.753 (0.618–0.916) 6.08
AFCAPS/TexCAPS, 1998 (20) 163/3304 215/3301 0.757 (0.622–0.923) 6.04
LIPID, 1998 (21) 336/4512 463/4502 0.724 (0.633–0.828) 8.31
GISSI, 2000 (22) 45/2138 51/2133 0.88 (0.592–1.308) 2.40
ALLHAT-LLT, 2002 (23) 380/5170 421/5185 0.905 (0.792–1.034) 8.35
HPS, 2002 (25) 898/10 269 1212/10 267 0.741 (0.683–0.804) 10.39
LIPS, 2002 (26) 135/844 187/833 0.713 (0.584–0.87) 5.99
PROSPER, 2002 (27) 316/2891 376/2913 0.847 (0.736–0.975) 8.06
ASCOT-LLA, 2003 (28) 100/5168 154/5137 0.645 (0.503–0.828) 4.67
CARDS, 2004 (29) 33/1428 61/1410 0.534 (0.362–0.811) 2.20
ASPEN, 2006 (30) 49/1211 66/1199 0.735 (0.512–1.055) 2.78
MEGA Study, 2006 (31) 18/3866 33/3966 0.56 (0.316–0.992) 1.28
SPARCL, 2006 (32) 83/2365 121/2366 0.686 (0.522–0.902) 4.14
CORONA, 2007 (33) 124/2497 149/2514 0.838 (0.665–1.056) 5.09
JUPITER, 2008 (34) 31/8901 68/8901 0.456 (0.298–0.696) 2.15
AURORA, 2009 (35) 295/1389 316/1384 0.93 (0.809–1.07) 8.08
Overall (P < 0.001) 3528/65 199 4650/65 268 0.748 (0.698–0.801) 100

0.1 1 10
Favors Statin Favors Control
RR (Log Scale)

The size of the data markers (solid squares) represents the relative weight of the trial in random-effects meta-analysis. See footnote to Tables 1 and 2 for
full titles of studies. MI ⫽ myocardial infarction; RR ⫽ relative risk.
www.annals.org 21 December 2010 Annals of Internal Medicine Volume 153 • Number 12 W-249