RESEARCH

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Rosuvastatin versus atorvastatin treatment in adults with
coronary artery disease: secondary analysis of the randomised
LODESTAR trial
Yong-Joon Lee,1 Sung-Jin Hong,1 Woong Chol Kang,2 Bum-Kee Hong,3 Jong-Young Lee,4
Jin-Bae Lee,5 Hyung-Jin Cho,6 Junghan Yoon,7 Seung-Jun Lee,1 Chul-Min Ahn,1 Jung-Sun Kim,1
Byeong-Keuk Kim,1 Young-Guk Ko,1 Donghoon Choi,1 Yangsoo Jang,8 Myeong-Ki Hong,1
on behalf of the LODESTAR investigators

For numbered affiliations see Abstract (standard deviation (SD) 5.2 mg) in the rosuvastatin
end of the article Objective group and 36.0 (12.8) mg in the atorvastatin group at
Correspondence to: M-K Hong To compare the long term efficacy and safety of three years (P<0.001). The primary outcome occurred
[email protected]
(ORCID 0000-0002-2090-2031)
rosuvastatin with atorvastatin treatment in adults with in 189 participants (8.7%) in the rosuvastatin group
Additional material is published
coronary artery disease. and 178 (8.2%) in the atorvastatin group (hazard
online only. To view please visit Design ratio 1.06, 95% confidence interval 0.86 to 1.30;
the journal online.
Randomised, open label, multicentre trial. P=0.58). The mean low density lipoprotein (LDL)
Cite this as: BMJ 2023;383:e075837 cholesterol level during treatment was 1.8 mmol/L
http://dx.doi.org/10.1136/ Setting
(SD 0.5 mmol/L) in the rosuvastatin group and 1.9
bmj‑2023‑075837 12 hospitals in South Korea, September 2016 to
(0.5) mmol/L in the atorvastatin group (P<0.001).
Accepted: 02 September 2023 November 2019.
The rosuvastatin group had a higher incidence of
Participants new onset diabetes mellitus requiring initiation of
4400 adults (age ≥19 years) with coronary artery antidiabetics (7.2% v 5.3%; hazard ratio 1.39, 95%
disease. confidence interval 1.03 to 1.87; P=0.03) and cataract
Interventions surgery (2.5% v 1.5%; 1.66, 1.07 to 2.58; P=0.02).
Participants were assigned to receive either Other safety endpoints did not differ between the two
rosuvastatin (n=2204) or atorvastatin (n=2196) using groups.
2×2 factorial randomisation. Conclusions
Main outcome measures In adults with coronary artery disease, rosuvastatin
The primary outcome was a three year composite and atorvastatin showed comparable efficacy for the
of all cause death, myocardial infarction, stroke, or composite outcome of all cause death, myocardial
any coronary revascularisation. Secondary outcomes infarction, stroke, or any coronary revascularisation at
were safety endpoints: new onset diabetes mellitus; three years. Rosuvastatin was associated with lower
hospital admissions due to heart failure; deep LDL cholesterol levels but a higher risk of new onset
vein thrombosis or pulmonary thromboembolism; diabetes mellitus requiring antidiabetics and cataract
endovascular revascularisation for peripheral artery surgery compared with atorvastatin.
disease; aortic intervention or surgery; end stage Trial registration
kidney disease; discontinuation of study drugs owing ClinicalTrials.gov NCT02579499.
to intolerance; cataract surgery; and a composite of
laboratory detected abnormalities. Introduction
Results Intensive reduction in low density lipoprotein (LDL)
4341 of the 4400 participants (98.7%) completed cholesterol levels is recommended in people with
the trial. Mean daily dose of study drugs was 17.1 mg coronary artery disease, who are regarded as being
at high risk or very high risk of future atherosclerotic
cardiovascular events.1 2 Among the various lipid
What is already known on this topic lowering drugs available, 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors (statins)
Low density lipoprotein (LDL) cholesterol lowering capacity varies by statin type
are the cornerstone of treatment, and high intensity
The comparative long term efficacy and safety between two potent statins
statins are generally the choice for LDL cholesterol
(rosuvastatin and atorvastatin) in people with coronary artery disease are
lowering treatment in people with coronary artery
unclear disease.1 2 Doctors make decisions not only about
What this study adds statin intensity (high, moderate, or low) but also about
statin type; however, although previous studies have
In people with coronary artery disease, rosuvastatin and atorvastatin showed
evaluated clinical outcomes according to different
comparable efficacy in terms of a composite of all cause death, myocardial
intensities of statins for managing dyslipidaemia in
infarction, stroke, or any coronary revascularisation within three years
people with coronary artery disease, clinical trials have
Rosuvastatin was associated with greater efficacy in reducing LDL cholesterol
not sufficiently evaluated the effects of different types
levels, but it incurred a higher risk of new onset diabetes mellitus requiring of statins.4-6 Furthermore, few randomised clinical
antidiabetics and cataract surgery than atorvastatin trials have directly compared the long term clinical

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outcomes of the two most potent statins—rosuvastatin dyslipidaemia in adults (age ≥19 years) with coronary
and atorvastatin—in people with coronary artery artery disease. The study design, protocol, and
disease. rationale for the LODESTAR trial are described in
In addition to statins’ efficacy in reducing LDL detail elsewhere.3 Adults with clinically diagnosed
cholesterol levels and the risk of future adverse coronary artery disease, including stable ischaemic
cardiovascular events, safety concerns, including heart disease and acute coronary syndrome (unstable
statin related adverse effects and intolerance, should angina and acute myocardial infarction), who required
also be considered in real world practice.7-10 Statin statin treatment to lower their LDL cholesterol levels
associated muscle symptoms and other concerning were eligible to participate in the trial.3 Supplementary
statin related adverse effects on glucose homeostasis table S1 shows the inclusion and exclusion criteria. All
or hepatic or renal function are more common with participants provided written informed consent before
high potency statins than with low potency statins.7-9 11 participation in the trial. Study coordination, data
However, although various statin related adverse management, and site management were performed
effects have been reported, it is not clear whether the at the Cardiovascular Research Centre (Seoul, South
adverse effects are due to the drug itself or to drug Korea). Those designated to monitor the trial reviewed
class effects.7-9 We therefore conducted the LODESTAR the data twice a year for accuracy and completeness
(Low-Density Lipoprotein Cholesterol-Targeting and ensured adherence to the protocol. A data and
Statin Therapy Versus Intensity-Based Statin Therapy safety monitoring board of independent doctors
in Patients With Coronary Artery Disease) trial, a oversaw the safety of the study. These doctors acted
multicentre, randomised trial for the management of in an advisory capability to check on safety of the
dyslipidaemia in people with coronary artery disease. participants, evaluate study progress, and review the
This secondary analysis of the LODESTAR trial focused study process.
on the efficacy and safety of rosuvastatin versus
atorvastatin treatment over three years in people with Randomisation
coronary artery disease. Participants were assigned to treatments using a
2×2 factorial randomisation. The factors were statin
Methods intensity strategy strategy versus high intensity
Study design and population statin strategy) and statin type (rosuvastatin versus
The LODESTAR trial, conducted at 12 centres in South atorvastatin).3 Eligible participants underwent
Korea, was an investigator initiated, prospective, randomisation using an interactive web response
multicentre, randomised, open label trial using 2×2 permuted block randomisation procedure (mixed
factorial randomisation.3 The trial evaluated statin blocks of 4 or 6) at each participating site, stratified by
intensity strategy and statin type for managing baseline LDL cholesterol levels of 2.6 mmol/L, acute

4400
Patients with coronary artery disease recruited* and randomised†

2204 2196
Assigned to receive rosuvastatin Assigned to receive atorvastatin
1935 Received rosuvastatin as randomised 1898 Received atorvastatin as randomised
49 Did not complete statin treatment 46 Did not complete statin treatment
40 Adverse events 37 Adverse events
9 Poor compliance 9 Poor compliance
220 Did not receive rosuvastatin 252 Did not receive atorvastatin
21 Adverse events 30 Adverse events
18 Patients’ request 16 Patients’ request
5 Doctors’ decision 11 Doctors’ decision
170 Did not comply with protocol 187 Did not comply with protocol
6 Other 8 Other

86 77
Excluded Excluded
57 Died 51 Died
16 Withdrew consent 14 Withdrew consent
13 Lost to follow-up 12 Lost to follow-up

2204 2196
Included in primary analysis Included in primary analysis

Fig 1 | Flow of participants through study. *Data on screening were not collected. †Randomisation was stratified by baseline low density lipoprotein
cholesterol levels ≥2.6 mmol/L, acute coronary syndrome, and presence of diabetes mellitus

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Table 1 | Baseline characteristics. Values are number (percentage) unless stated for titration or maintenance were identical for both
otherwise groups.3 Briefly, in the group assigned to receive
Rosuvastatin group Atorvastatin group the treat-to-target strategy, statin naïve participants
Characteristics (n=2204) (n=2196) were started on moderate intensity statin treatment
Mean (SD) age (years) 65 (10) 65 (10) (rosuvastatin 10 mg or atorvastatin 20 mg), and
Women 602 (27.3) 626 (28.5)
those already using a statin received a corresponding
Mean (SD) weight (kg) 67 (11) 67 (10)
Mean (SD) height (cm) 164 (8) 165 (8)
intensity of rosuvastatin or atorvastatin based on their
Mean (SD) body mass index 24.8 (3.0) 24.7 (2.8) LDL cholesterol levels at randomisation (equivalent
Current smoker 291 (13.2) 312 (14.2) intensity for those with LDL cholesterol levels <1.8
Comorbidities mmol/L or an up-titrated intensity for those with LDL
Hypertension 1498 (68.0) 1439 (65.5) cholesterol levels ≥1.8 mmol/L).3 During follow-up,
Diabetes mellitus 725 (32.9) 743 (33.8)
we titrated statin intensity based on the obtained LDL
Diabetes mellitus: insulin treatment 83 (3.8) 79 (3.6)
Chronic kidney disease* 149 (6.8) 170 (7.7)
cholesterol levels: up-titration for those whose LDL
End stage kidney disease: receiving dialysis 14 (0.6) 15 (0.7) cholesterol levels were ≥1.8 mmol/L, maintenance of
Mean (SD) eGFR (mL/min/1.73 m2) 88.1 (17.4) 87.9 (17.9) the same intensity without titration for those whose LDL
Medical history cholesterol levels were ≥1.3 mmol/L and <1.8 mmol/L,
Percutaneous coronary intervention 1258 (57.1) 1199 (54.6) and down-titration for those whose LDL cholesterol
Coronary artery bypass grafting surgery 167 (7.6) 167 (7.6) levels were <1.3 mmol/L.3 For participants assigned to
Stroke 140 (6.4) 123 (5.6)
receive the high intensity statin strategy, high intensity
Clinical presentation at randomisation:
Acute myocardial infarction <1 year 175 (7.9) 163 (7.4) statin treatment (rosuvastatin 20 mg or atorvastatin
Unstable angina or revascularisation <1 year 404 (18.3) 384 (17.5) 40 mg) was initiated and maintained irrespective
Myocardial infarction >1 year ago 322 (14.6) 353 (16.1) of patients’ LDL cholesterol levels at randomisation
Unstable angina or revascularisation >1 year ago 906 (41.1) 878 (40.0) and follow-up.3 Adding non-statin agents, such as
Detection of asymptomatic CAD at screening 397 (18.0) 418 (19.0) the cholesterol absorption inhibitor ezetimibe, was
Lipid lowering treatment before randomisation
strongly not recommended to focus on data for statin
Statin intensity:
High 533 (24.2) 572 (26.0) treatment and to prevent confounding.3 Data on the
Moderate 1277 (57.9) 1247 (56.8) use of the study drugs were collected from doctors’
Low 43 (2.0) 50 (2.3) records of prescriptions, and drug adherence was
None 351 (15.9) 327 (14.9) measured by participants’ self-reported pill count.3 For
Ezetimibe 259 (11.8) 220 (10.0) other medical treatments, guideline directed treatment
Mean (SD) lipids (mmol/L)
was strongly recommended, and modification of risk
LDL cholesterol 2.2 (0.9) 2.3 (0.8)
HDL cholesterol 1.2 (0.3) 1.2 (0.3)
factors, including blood pressure or glucose control,
Total cholesterol 4.1 (1.0) 4.1 (0.9) weight reduction, exercise, dietary changes, and
Triglycerides 1.6 (0.9) 1.6 (0.9) smoking cessation, was also encouraged.3
CAD=coronary artery disease; eGFR=estimated glomerular filtration rate; HDL=high density lipoprotein; LDL=low Follow-up visits to assess general health status, use
density lipoprotein; SD=standard deviation.
*Defined as eGFR <60 mL/min/1.73 m2 of body surface area.
of study drugs, and the occurrence of study outcomes
or adverse events took place at six weeks and 3, 6, 12,
24, and 36 months after study initiation.3 To confirm
coronary syndrome, and the presence of diabetes the obtained LDL cholesterol levels and monitor statin
mellitus.3 Participants were randomly assigned to related adverse effects, serial follow-up of patients’
receive a statin using either a treat-to-target strategy lipid profiles (total cholesterol, LDL cholesterol, high
or a high intensity statin strategy; participants were density lipoprotein cholesterol, and triglyceride levels),
also randomly assigned to receive either rosuvastatin aspartate aminotransferase, alanine aminotransferase,
or atorvastatin.3 The investigators and participants creatine kinase, and creatinine levels were performed
were blinded to the randomisation sequence. The at six weeks and 12, 24, and 36 months.3 Serial follow-
results of the analysis of the treat-to-target strategy up of plasma glucose and haemoglobin A1c levels was
using titrated intensity statin treatment to reach a carried out at 12, 24, and 36 months.3
target LDL cholesterol level of 1.3-1.8 mmol/L versus
high intensity statin strategy without a target goal were Study outcomes and definitions
recently reported.3 The primary outcome was major adverse cardiac
and cerebrovascular events, defined as a composite
Study procedures of all cause death, myocardial infarction, stroke, or
Adherence to the assigned statin type (rosuvastatin any coronary revascularisation within three years.3
or atorvastatin) was strongly recommended during Death was classified as cardiovascular death and
the entire follow-up period. The intensity of statin non-cardiovascular death. Cardiovascular death
treatment was classified on the basis of the 2013 was defined as death from myocardial infarction,
American College of Cardiology/American Heart heart failure, stroke, cardiovascular procedures or
Association guidelines on the management of haemorrhage, sudden cardiac death, and any case
dyslipidaemia.3 12 In each statin type group, the of death in which a cardiovascular cause could not
intensity of statin was titrated or maintained following be excluded, as adjudicated by a clinical endpoints
the assigned statin intensity strategy, and the principles committee.13 Myocardial infarction was defined on the

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Table 2 | Primary and secondary outcomes at three years in adults assigned to receive rosuvastatin or atorvastatin.* Values are number (percentage)
unless stated otherwise
Rosuvastatin group Atorvastatin group Absolute difference
Outcome (n=2204) (n=2196) (95% CI) Hazard ratio (95% CI) P value†
Primary outcome
Death, myocardial infarction, stroke, or any coronary 189 (8.7) 178 (8.2) 0.5 (−1.2 to 2.1) 1.06 (0.86 to 1.30) 0.58
revascularisation
Components of primary outcome
Death: 57 (2.6) 51 (2.3) 0.3 (−0.7 to 1.2) 1.12 (0.77 to 1.63) 0.57
Cardiac death (No) 14 15
Myocardial infarction 34 (1.5) 26 (1.2) 0.3 (−0.4 to 1.0) 1.27 (0.76 to 2.12) 0.37
Stroke: 24 (1.1) 20 (0.9) 0.2 (−0.4 to 0.8) 1.20 (0.66 to 2.17) 0.55
Ischaemic (No) 16 16
Haemorrhagic (No) 8 4
Coronary revascularisation‡ 115 (5.3) 111 (5.2) 0.2 (−1.2 to 1.5) 1.03 (0.80 to 1.34) 0.81
Secondary outcomes
New onset diabetes mellitus 152 (7.1) 119 (5.5) 1.5 (0.1 to 3.0) 1.29 (1.01 to 1.63) 0.04
New onset diabetes mellitus among participants without 152/1479 (10.4) 119/1453 (8.4) 2.1 (−0.0 to 4.2) 1.26 (0.99 to 1.60) 0.06
diabetes mellitus at baseline §
Initiation of antidiabetics among participants without diabetes 104/1479 (7.2) 74/1453 (5.3) 2.0 (0.2 to 3.7) 1.39 (1.03 to 1.87) 0.03
mellitus at baseline §
Hospital admission due to heart failure 12 (0.6) 8 (0.4) 0.2 (−0.2 to 0.6) 1.50 (0.61 to 3.66) 0.37
Deep vein thrombosis or pulmonary embolism: 7 (0.3) 2 (0.1) 0.2 (−0.0 to 0.5) 3.50 (0.73 to 16.84) 0.10
Deep vein thrombosis (No) 5 2
Pulmonary embolism (No) 3 0
Peripheral artery revascularisation 12 (0.5) 17 (0.8) −0.3 (−0.8 to 0.2) 0.65 (0.30 to 1.38) 0.25
Aortic intervention or surgery: 3 (0.1) 2 (0.1) 0.0 (−0.2 to 0.3) 1.50 (0.25 to 8.94) 0.66
Endovascular treatment (No) 3 0
Surgical treatment (No) 0 2
End stage kidney disease 9 (0.4) 4 (0.2) 0.2 (−0.1 to 0.6) 2.25 (0.69 to 7.30) 0.17
Discontinuation of statin treatment 40 (1.8) 37 (1.7) 0.1 (−0.7 to 0.9) 1.08 (0.69 to 1.69) 0.74
Cataract surgery 53 (2.5) 32 (1.5) 1.0 (1.4 to 1.8) 1.66 (1.07 to 2.58) 0.02
Composite of laboratory detected abnormalities¶: 26 (1.2) 22 (1.0) 0.2 (−0.4 to 0.8) 1.24 (0.70 to 2.20) 0.47
Increase in aminotransferase (No) 10 10
Increase in creatine kinase (No) 5 6
Increase in creatinine (No) 11 7
CI=confidence interval.
*Primary and secondary outcomes were evaluated in the intention-to-treat population three years after randomisation. The listed percentages were estimated using the Kaplan-Meier method, so
values might not calculate mathematically.
†Calculated using log rank test.
‡All coronary revascularisations were clinically indicated by a diameter stenosis ≥50% on invasive coronary angiography with ischaemic symptoms or signs or ≥70% even in the absence of
symptoms or signs.
§Data are number of patients/total number of patients (%).
¶An increase in aminotransferase level was defined as more than baseline level and >3 times the upper reference limit; an increase in creatine kinase level was defined as more than baseline
level and >5 times the upper reference limit; and an increase in creatinine level was defined as >50% increase from baseline and greater than the upper reference limit.

basis of symptoms, changes on electrocardiography, disease; aortic intervention or surgery; end stage
or abnormal findings on imaging studies, combined kidney disease; discontinuation of study drugs owing
with an increase in the creatine kinase myocardial to intolerance; cataract surgery; and a composite of
band fraction above the upper limit of normal or laboratory detected abnormalities.3 New onset diabetes
an increase in troponin T or troponin I level >99th mellitus was defined as a fasting plasma glucose level
centile of the upper limit of normal.14 Stroke was ≥7.0 mmol/L or new initiation of antidiabetics.11 16 A
defined as an acute cerebrovascular event resulting post hoc analysis of the trial database was performed to
in a neurological deficit at >24 hours or the presence identify and include participants with a haemoglobin
of acute infarction noted by imaging studies.15 Any A1c level ≥6.5% during the study period as having
coronary revascularisation included percutaneous new onset diabetes mellitus.16 17 The supplementary
coronary intervention and coronary artery bypass graft methods section provides definitions of the other
surgery, and clinically indicated revascularisation secondary outcomes. An independent clinical endpoint
was defined as a diameter stenosis ≥50% on invasive committee blinded to the treatment assignments
coronary angiography with ischaemic symptoms or and primary results of the trial adjudicated both the
signs, or as a percentage diameter stenosis ≥70% even primary and the secondary outcomes.3
in the absence of symptoms or signs.13 Staged coronary
revascularisations planned at randomisation were not Statistical analysis
considered as adverse events.3 The sample size estimation for the LODESTAR
The secondary outcomes were new onset diabetes trial was performed on the basis of the primary
mellitus; hospital admissions due to heart failure; deep objective of the study: to compare the treat-to-target
vein thrombosis or pulmonary thromboembolism; strategy with the high intensity statin strategy for
endovascular revascularisation for peripheral artery the occurrence of the primary outcome, a composite

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10 Categorical variables are reported as number
Cumulative incidence (%)

Hazard ratio 1.06 (95% CI 0.86 to 1.30); P=0.58 (percentage), and continuous variables are reported
8 as mean (standard deviation (SD) or median
Rosuvastatin group
Atorvastatin group (interquartile range)), depending on distribution.
6 Time-to-event curves were plotted using a Kaplan-
Meier survival analysis from the time of randomisation
4 to the occurrence of the first event of interest during
follow-up, and the event rates between the two groups
2
were compared using log rank tests. Hazard ratios
with 95% confidence intervals were estimated using a
0
0 12 24 36 Cox regression analysis. To assess whether treatment
Months aer randomisation effects (rosuvastatin versus atorvastatin) differed
No at risk
Rosuvastatin
according to statin intensity strategy (treat-to-target
2204 2126 2059 1984 strategy versus high intensity statin strategy), P values
for interaction between statin type and statin intensity
Atorvastatin
strategy were calculated using Cox proportional hazard
2196 2124 2051 1990
regression model. Additional subgroup analyses were
Fig 2 | Kaplan-Meier survival (time-to-event) curves for primary outcome (all cause performed according to age, sex, body mass index,
death, myocardial infarction, stroke, or any coronary revascularisation) in adults presence of diabetes mellitus, hypertension, chronic
assigned to rosuvastatin or atorvastatin. CI=confidence interval
kidney disease, clinical presentation at randomisation,
previous percutaneous coronary intervention, use of
of all cause death, myocardial infarction, stroke, or ezetimibe before randomisation, and baseline LDL
any coronary revascularisation within three years.3 cholesterol levels. To evaluate the association between
Additional details about the sample size estimation new onset diabetes mellitus as a time dependent
are published elsewhere.3 The sample size estimation variable and the primary outcome, a time dependent
was not performed for comparing the different Cox regression analysis was performed. No imputation
types of statin. This study focused on the clinical was used to infer missing values, and those with
outcomes at three years between rosuvastatin and missing data for primary or secondary outcomes were
atorvastatin treatment, and the analysis of this study censored at the time of withdrawal of consent or loss
was performed using an intention-to-treat approach, to follow-up. All tests were two sided, and P<0.05 was
with all participants randomly assigned to a treatment considered to indicate statistical significance, with
group. Sensitivity analyses were performed in the per no adjustment for multiple comparisons. Statistical
protocol population after excluding participants who analyses were performed using IBM SPSS, version 25.0
did not receive the assigned treatment (participants (IBM, Chicago, IL) and R 3.5.3 software (R Foundation
who discontinued statin treatment or those who did for Statistical Computing, Vienna, Austria).
not receive the assigned statin type).
Patient and public involvement
2.5 Although our study dealt with an important area for
LDL cholesterol (mmol/L)

Rosuvastatin group
Atorvastatin group public health and was of interest to patients given the
2.0 high percentage of people worldwide who take statins,
patient and public involvement and training could not
1.5 be managed for this study without additional funding,
particularly as the training would have needed to be
1.0
done across the 12 sites and coordinated. As a result,
no patients or members of the public were directly
0.5
involved in setting the research question or developing
plans for the design or implementation of the study or
0
0 1.5 3 6 12 24 36 in the interpretation or writing up of the results.
Months aer randomisation
No at risk Results
Rosuvastatin Between September 2016 and November 2019, 4400
2204 447 1098 1875 1673 1582
1570 adults with coronary artery disease were randomly
Atorvastatin assigned to receive either rosuvastatin (n=2204) or
2196 391 1068 1841 1660 1532
1629 atorvastatin (n=2196) (fig 1). Supplementary table S2
Absolute difference lists the reasons for withdrawal of consent and death.
-0.2 -0.1 -0.1 -0.1 -0.1
-0.1 The baseline characteristics of the participants were
well balanced between the two groups (table 1). Mean
Fig 3 | Serial mean values for LDL cholesterol over time in participants assigned to
age was 65 years (SD 10 years) and overall 27.9%
rosuvastatin or atorvastatin. The whiskers indicate 95% confidence intervals. The
absolute difference (mmol/L) in LDL cholesterol levels between the two groups is were women, 33.4% had diabetes mellitus, 55.8% had
presented under the graph. All differences were significant (P<0.001). LDL=low density undergone percutaneous coronary intervention, and
lipoprotein 74.3% had received their initial diagnosis or coronary

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Clinical safety

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revascularisation more than one year previously. In
the rosuvastatin group, 93.9% of patients were taking More participants in the rosuvastatin group than
the assigned statin type at six weeks, 93.3% at three atorvastatin group developed new onset diabetes
months, 93.4% at six months, 93.4% at one year, mellitus (7.1% v 5.5%; hazard ratio 1.29, 95%
92.0% at two years, and 91.1% at three years; the confidence interval 1.01 to 1.63; P=0.04) and
corresponding rates in the atorvastatin group were underwent cataract surgery (2.5% v 1.5%; 1.66,
93.8%, 92.6%, 92.5%, 92.5%, 91.3%, and 89.5%, 1.07 to 2.58; P=0.02) (table 2 and supplementary fig
respectively (see supplementary table S3). Although S2). Among participants without diabetes mellitus
the use of a high intensity statin did not differ between at baseline, the rosuvastatin group had a higher
the two groups at six weeks, three and six months, or incidence of new onset diabetes mellitus requiring
one year, it was lower in the rosuvastatin group than initiation of antidiabetics (7.2% v 5.3%; 1.39, 1.03 to
atorvastatin group at two years (71.9% v 74.7%; 1.87; P=0.03) and a trend towards a higher incidence
P=0.04) and three years (70.9% v 74.0%; P=0.02) of new onset diabetes mellitus (10.4% v 8.4%; 1.26,
(see supplementary tables S3 and S4). The mean 0.99 to 1.60; P=0.06) (table 2). The other secondary
daily dose at three years was 17.1 mg (SD 5.2 mg) outcomes did not differ between the two groups. These
in the rosuvastatin group and 36.0 (12.8) mg in the findings were consistent in the per protocol population
atorvastatin group (P<0.001). The use of ezetimibe was (see supplementary table S7). Supplementary table S9
lower in the rosuvastatin group than atorvastatin group lists the reasons for discontinuation of statin treatment.
from three months (all P<0.05) (see supplementary
tables S3 and S5). Supplementary table S6 presents Additional analyses
the use of other cardiovascular drugs. In a post hoc analysis using a definition of new onset
diabetes mellitus that incorporated a haemoglobin A1c
Clinical efficacy and LDL cholesterol levels level ≥6.5% during the study period, the incidence
The median follow-up duration was 3 years of new onset diabetes mellitus was still higher in the
(interquartile range 3-3 years), and 4341 participants rosuvastatin group than atorvastatin group (9.5% v
(98.7%) completed the clinical follow-up at three 7.7%; 1.25, 1.02 to 1.53; P=0.03).
years (table 2). The primary outcome occurred in 189 No significant interaction occurred between statin
participants (8.7%) in the rosuvastatin group and type and statin intensity strategy for the primary
178 (8.2%) in the atorvastatin group (hazard ratio outcome (P=0.77 for interaction) (supplementary
1.06, 95% confidence interval 0.86 to 1.30; P=0.58) table S10). Supplementary fig S3 shows the results of
(fig 2). All cause death occurred in 57 participants the subgroup analyses for the primary outcome. The
(2.6%) in the rosuvastatin group and 51 (2.3%) in the effect of rosuvastatin treatment versus atorvastatin
atorvastatin group (1.12, 0.77 to 1.63; P=0.57) (table treatment was consistent for the primary outcome
2). Myocardial infarction was observed in 34 (1.5%) across all subgroups.
and 26 (1.2%) participants, respectively (1.27, 0.76 New onset diabetes mellitus as a time dependent
to 2.12; P=0.37). The occurrence of stroke did not variable was not associated with increased risk of the
differ between the two groups (1.1% v 0.9%; 1.20, primary outcome (hazard ratio 1.16, 95% confidence
0.66 to 2.17; P=0.55). Any coronary revascularisation interval 0.51 to 2.64; P=0.73) and no significant
occurred in 115 (5.3%) and 111 (5.2%) participants, interaction occurred between statin type and new onset
respectively (1.03, 0.80 to 1.34; P=0.81). These diabetes mellitus for the primary outcome (P=0.08 for
findings were consistent in the per protocol population interaction).
(see supplementary table S7).
Figure 3 shows the serial changes in LDL cholesterol Discussion
levels during the study period (also see supplementary The main findings of this secondary analysis of the
table S8). The mean LDL cholesterol level during the randomised LODESTAR trial comparing clinical
overall study period was 1.8 mmol/L (SD 0.5 mmol/L) outcomes over three years between rosuvastatin and
in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin treatment in adults with coronary artery
atorvastatin group (P<0.001). The mean LDL cholesterol disease were that the risk of a three year composite
levels were consistently lower in the rosuvastatin of all cause death, myocardial infarction, stroke, or
group than atorvastatin group (1.7 v 1.8 mmol/L at six any coronary revascularisation did not differ between
weeks, three months, six months, one year, two years, the two groups; rosuvastatin treatment resulted in
and three years; all P<0.001) (fig 3). The proportion of lower LDL cholesterol levels and a higher proportion
participants with LDL cholesterol levels <1.8 mmol/L of participants achieving LDL cholesterol levels <1.8
was also consistently higher in the rosuvastatin group mmol/L throughout the study period, compared with
than atorvastatin group: at six weeks (62.9% v 54.6%; atorvastatin treatment; and rosuvastatin treatment
P<0.001), three months (66.7% v 58.8%; P=0.02), six was associated with a higher incidence of new onset
months (64.3% v 53.1%; P<0.001), one year (61.5% diabetes mellitus requiring initiation of antidiabetics
v 53.1%; P<0.001), two years (64.0% v 57.2%; and cataract surgery than atorvastatin treatment.
P<0.001), and three years (62.5% v 55.2%; P<0.001) In clinical practice, appropriate decisions for statin
(see supplementary fig S1). Supplementary table S8 type as well as statin intensity are important—however,
presents serial changes in the other lipid profiles. only rosuvastatin and atorvastatin can offer both the

6 doi: 10.1136/bmj-2023-075837 | BMJ 2023;383:e075837 | the bmj

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in the rosuvastatin group than atorvastatin group.19

BMJ: first published as 10.1136/bmj-2023-075837 on 18 October 2023. Downloaded from http://www.bmj.com/ on 25 October 2023 by guest. Protected by copyright.
high intensity and moderate intensity statin treatment
usually required by people with coronary artery That finding could be due to the low between group
disease to intensively lower their LDL cholesterol difference in reduction of LDL cholesterol levels, as
levels.1-3 12 The clinical benefits of using either of well as the difference in pharmacological properties
these two potent statins in people with coronary artery between the two statins. Whereas lipophilic statins
disease have been shown in previous studies.4 5 18 such as atorvastatin can cross cellular membranes
However, to our knowledge, only the SATURN (Study through passive diffusion and are therefore widely
of Coronary Atheroma by Intravascular Ultrasound: distributed in different tissues, hydrophilic statins such
Effect of Rosuvastatin versus Atorvastatin) trial directly as rosuvastatin are more liver selective owing to the
compared the effects of rosuvastatin and atorvastatin active carrier mediated uptake mechanism, and thus
treatment in people with coronary artery disease.19 they are more limited in their ability to have additional
Among people with coronary artery disease who were effects beyond cholesterol lowering (pleiotropic
randomised to either rosuvastatin 40 mg or atorvastatin effects) in extrahepatic tissues.23 24 In addition, the
80 mg in that study, the primary outcome—the change atorvastatin group’s higher use of ezetimibe, which can
in intravascular ultrasound defined percentage not only reduce LDL cholesterol levels but also inhibit
atheroma volume at 104 weeks—did not differ between platelet aggregation and activation, reduce oxidative
the two groups (−0.99% v −1.22%, P=0.17).19 In the stress, and accelerate plaque regression, could be
secondary outcomes of that study, the occurrence another explanation of our findings.25 26 Further study
of a composite of cardiovascular death, non-fatal is, however, required before any causative effect can be
myocardial infarction, non-fatal stroke, arterial established or rebutted.
revascularisation, or admission to hospital for unstable Although reducing LDL cholesterol levels and the
angina did not differ between the groups (7.5% v risk for future adverse cardiovascular events is the
7.1%), although the rosuvastatin group had lower LDL primary aim of statin treatment in people with coronary
cholesterol levels than the atorvastatin group (1.6 v artery disease, safety is also a major concern for long
1.8 mmol/L; P<0.001).19 However, the SATURN trial term statin treatment.7-9 JUPITER (Justification for
primarily evaluated the effects of the highest doses the Use of Statins in Prevention: an Intervention Trial
of rosuvastatin and atorvastatin on the progression Evaluating Rosuvastatin) was the first randomised trial
of coronary atherosclerosis by means of intravascular to report an increase in new onset diabetes mellitus
ultrasonography, rather than clinical outcomes, and among participants receiving statin treatment.27
it included fewer participants (n=1039) and a shorter Among participants who were randomised to either
follow-up time (two years) than the current study. Our rosuvastatin 20 mg or placebo, a 0.6% higher
randomised study, however, compared the effects of incidence of new onset diabetes mellitus was noted in
rosuvastatin and atorvastatin treatment in terms of a those receiving rosuvastatin.27 This finding was also
composite of all cause death, myocardial infarction, confirmed in a meta-analysis, which showed that statin
stroke, or any coronary revascularisation in 4400 treatment was associated with a 9% increased risk of
patients with coronary artery disease during three new onset diabetes mellitus.28 Whether statin related
years of follow-up. The results show that rosuvastatin new onset diabetes mellitus is a drug or a drug class
was associated with greater efficacy in reducing LDL effect remains controversial, however, and no head-to-
cholesterol levels throughout the study period, which head comparisons between the two most potent statins
is in line with a previous meta-analysis showing the (rosuvastatin and atorvastatin) regarding new onset
superiority of rosuvastatin over atorvastatin in lowering diabetes mellitus have been conducted previously.
LDL cholesterol levels.20 This difference in the LDL In this study, a higher incidence of new onset
cholesterol lowering capacity might have contributed diabetes mellitus was shown for rosuvastatin than for
to the higher use of a high intensity statin (from two atorvastatin. Even though the mechanisms of statin
years) and ezetimibe (from three months) in the treatment and new onset diabetes mellitus are not
atorvastatin group. Although the difference between yet fully understood, a meta-analysis of genetic data
these two potent statins is unclear, factors such as their from 223 463 individuals showed that the association
bonding capacity to HMG-CoA reductase and plasma could be related to the lowered activity of HMG-CoA
half-life might have contributed to the difference in reductase, the target of statin treatment.7 9 29 Two
LDL cholesterol lowering capacity.21-23 Although both single nucleotide polymorphisms (rs17238484-G and
rosuvastatin and atorvastatin have greater bonding rs12916-T) in the HMG-CoA reductase gene reduced
capacity to HMG-CoA reductase than other statin types, LDL cholesterol levels by 0.1 mmol/L and increased
rosuvastatin has the greatest bonding interaction with the risk of new onset diabetes mellitus by 2% and
HMG-CoA reductase.21-23 In addition, rosuvastatin 6%, respectively.29 Insofar as the risk of new onset
has a longer plasma half-life than atorvastatin (19 diabetes mellitus is related to the degree to which
hours v 15 hours).23 Nevertheless, in this study, the HMG-CoA reductase activity is inhibited, rosuvastatin,
pronounced reduction in LDL cholesterol levels with which has greater bonding interaction with HMG-
rosuvastatin did not translate into incremental benefit CoA reductase than atorvastatin, could be expected
in reducing three year composite outcomes, as in to be associated with the higher risk of new onset
the SATURN trial.19 In fact, in both trials, the rate of diabetes mellitus shown in this study.21 22 30 However,
composite clinical outcomes was numerically higher the higher incidence of new onset diabetes mellitus

the bmj | BMJ 2023;383:e075837 | doi: 10.1136/bmj-2023-075837 7

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did not translate into higher risk of the primary cataracts were not specified in the protocol. Sixthly,
outcome, and the use of ezetimibe was lower in the only Asian participants were included in this trial.
rosuvastatin group. Further studies evaluating the Finally, the study period was three years, which may
association between statin type, new onset diabetes have been relatively short to find longer term effects
mellitus, and future cardiovascular events, as well as of two statin types. Therefore, our findings should
those evaluating the effects of ezetimibe on new onset be interpreted with caution, and further dedicated
diabetes mellitus are required. investigation with longer follow-up is warranted.
In this study, the incidence of cataract surgery
differed according to statin type. Although statins’ Conclusions
antioxidant and anti-inflammatory effects on the lens In people with coronary artery disease, rosuvastatin
are expected to slow the aging process of the lens and atorvastatin treatment showed comparable
nucleus and epithelium, a concern has been that efficacy in terms of the composite of all cause death,
statin treatment could increase the risk of cataracts myocardial infarction, stroke, or any coronary
based on the hypothesis that statins inhibit proper revascularisation within three years. Rosuvastatin
epithelial cell development within the crystalline lens, treatment was associated with lower LDL cholesterol
where cholesterol biosynthesis is critical to maintain levels, but it also carried a higher risk of new onset
transparency and structure of the lens.9 31 A possible diabetes mellitus requiring antidiabetics and cataract
association between statin treatment and cataracts surgery, compared with atorvastatin treatment.
was shown in previous studies.32 33 In this study, 1.9%
Author affiliations
of patients underwent cataract surgery during the 1
Division of Cardiology, Severance Hospital, Yonsei University
median follow-up of 3.0 years, which is in line with College of Medicine, Seodaemun-gu, 03722, Seoul, Korea
the findings of the HOPE (Heart Outcomes Prevention 2
Gachon University College of Medicine, Incheon, Korea
Evaluation)-3 trial, which showed that 3.8% of patients 3
Gangnam Severance Hospital, Seoul, Korea
receiving statin treatment underwent cataract surgery 4
Kangbuk Samsung Hospital, Sungkyunkwan University School of
during a median follow-up of 5.6 years.33 Consistently, Medicine, Seoul, Korea
5
compared with atorvastatin, the incidence of cataract Daegu Catholic University Medical Centre, Daegu, Korea
6
Inje University Busan Paik Hospital, Busan, Korea
surgery with rosuvastatin was 1.0% higher. The greater 7
Wonju Severance Christian Hospital, Wonju, Korea
LDL cholesterol lowering capacity of rosuvastatin 8
CHA University College of Medicine, Seongnam, Korea
might have prevented epithelial cell development
Affiliations of the LODESTAR investigators: Myeong-Ki Hong,
within the crystalline lens. Therefore, when using Donghoon Choi, Young-Guk Ko, Byeong-Keuk Kim, Jung-Sun Kim, Chul-
rosuvastatin over atorvastatin as a statin regimen Min Ahn, Sung-Jin Hong, Seung-Jun Lee, Yong-Joon Lee (Severance
in people with coronary artery disease, a greater Hospital, Yonsei University College of Medicine, Seoul, Korea); Bum-
Kee Hong, Hyuck Moon Kwon, Jong-Youn Kim, Pil Ki Min, Young Won
reduction in LDL cholesterol levels can be expected; Yoon, Byoung Kwon Lee, Se-Joong Rim, Eui-Young Choi (Gangnam
however, meticulous monitoring and appropriate Severance Hospital, Seoul, Korea); Woong Chol Kang, Pyung Chun Oh
lifestyle interventions should be considered to mitigate (Gachon University College of Medicine, Incheon, Korea); Jong-Young
Lee (Kangbuk Samsung Hospital, Sungkyunkwan University School
the risk of new onset diabetes mellitus or cataracts. To
of Medicine, Seoul, Korea); Jin-Bae Lee, Kee Sik Kim, Ji Yong Choi,
determine whether the increase in new onset diabetes Jae Kean Ryu, Seung Pyo Hong, Chang Yeon Kim (Daegu Catholic
mellitus and cataract surgery is directly related to the University Medical Center, Daegu, Korea); Tae-Hyun Yang, Hyung-Jin
Cho (Inje University Busan Paik Hospital, Busan, Korea); Junghan Yoon,
statin treatment, the underpinning mechanism for
Min-Soo Ahn, Sung Gyun Ahn, Jun-Won Lee, Jung-Woo Son (Wonju
these relations and the possible mechanism for a drug Severance Christian Hospital, Wonju, Korea); Yangsoo Jang (CHA
effect still require further investigations. University College of Medicine, Seongnam, Korea); Hyuck-Jun Yoon,
Cheol Hyun Lee, Jongmin Hwang, Yun-Kyeong Cho, Seung-Ho Hur,
Seongwook Han, Chang-Wook Nam, Hyoungseop Kim, Hyoung-Seob
Limitations of this study Park, In-Cheol Kim (Keimyung University Dongsan Medical Center,
This study has several limitations. Firstly, although Daegu, Korea); Yun-Hyeong Cho, Hyeon-Ju Jeong, Jin-Ho Kim, Chewan
Lim, Yongsung Suh, Eui Seok Hwang, Ji Hyun Lee (Myongji Hospital,
a 2×2 factorial randomisation was prespecified, no
Hanyang University College of Medicine, Ilsan, Korean); Sung Yun Lee,
a priori sample size estimation was performed on Sung Uk Kwon (Inje University Ilsan Paik Hospital, Ilsan, Korea); Song-
the basis of testing the different statin types. At the Yi Kim (Jeju National University Hospital, Jeju, Korea); Keun-Ho Park,
Hyun Kuk Kim (Chosun University Hospital, Gwangju, Korea).
time of the trial design, data were limited to provide
Contributors: Y-JL and S-JH are joint first authors and contributed
evidence for the sample size estimation based on
equally to this work. S-JH, B-KK, and M-KH designed the study.
statin type. Secondly, this was an open label trial. Y-JL, S-JH, and M-KH participated in the final analyses and data
However, an independent clinical endpoint committee interpretation. All authors participated in the enrolment of
blinded to the treatment assignments adjudicated participants, performed clinical follow-up, and revised the draft
critically for important intellectual content. This report was drafted
all clinical outcomes. Thirdly, the comparison of by Y-JL, S-JH, B-KK, and M-KH. All authors approved the final version
individual components of the primary outcome was of the manuscript and ensured that the accuracy and integrity of all
hampered by the small number of events. Fourthly, parts of the work have been appropriately investigated and resolved.
All authors had full access to all the data in the study and share final
the initial definition for new onset diabetes mellitus responsibility for the decision to submit for publication. B-KK and
did not include haemoglobin A1c levels. However, M-KH are the guarantors. B-KK is the co-corresponding author and can
a post hoc analysis using a definition of new onset be reached at [email protected]. The corresponding authors (B-KK and
M-KH) attest that all listed authors meet authorship criteria and that
diabetes mellitus that incorporated the haemoglobin no others meeting the criteria have been omitted.
A1c level showed consistent results. Fifthly, regular Funding: This study was funded by Sam Jin Pharmaceutical, Seoul,
ophthalmological examinations for the detection of Korea, and Chong Kun Dang Pharmaceutical, Seoul, Korea, and

8 doi: 10.1136/bmj-2023-075837 | BMJ 2023;383:e075837 | the bmj

 RESEARCH

BMJ: first published as 10.1136/bmj-2023-075837 on 18 October 2023. Downloaded from http://www.bmj.com/ on 25 October 2023 by guest. Protected by copyright.
supported by the Cardiovascular Research Centre, Seoul, Korea. The 9 Mach F, Ray KK, Wiklund O, et al; European Atherosclerosis Society
funders had no role in considering the study design; the collection, Consensus Panel. Adverse effects of statin therapy: perception
analysis, or interpretation of data; the writing of the report; or the vs. the evidence - focus on glucose homeostasis, cognitive, renal
decision to submit the article for publication. and hepatic function, haemorrhagic stroke and cataract. Eur Heart
J 2018;39:2526-39. doi:10.1093/eurheartj/ehy182
Competing interests: All authors have completed the ICMJE uniform 10 Serban MC, Colantonio LD, Manthripragada AD, et al. Statin
disclosure form at www.icmje.org/disclosure-of-interest/ and declare: intolerance and risk of coronary heart events and all-cause mortality
the study was funded by a grant from Sam Jin Pharmaceutical and following myocardial infarction. J Am Coll Cardiol 2017;69:1386-95.
Chong Kun Dang Pharmaceutical. M-KH has received speaker’s doi:10.1016/j.jacc.2016.12.036
fees from Medtronic, Edward Lifesciences, and Viatris Korea, and 11 Dormuth CR, Filion KB, Paterson JM, et al; Canadian Network for
institutional research grants from Sam Jin Pharmaceutical and Observational Drug Effect Studies Investigators. Higher potency
Chong Kun Dang Pharmaceutical; no financial relationships with any statins and the risk of new diabetes: multicentre, observational study
organisations that might have an interest in the submitted work in the of administrative databases. BMJ 2014;348:g3244. doi:10.1136/
previous three years; no other relationships or activities that could bmj.g3244
appear to have influenced the submitted work. 12 Stone NJ, Robinson JG, Lichtenstein AH, et al; American College
of Cardiology/American Heart Association Task Force on Practice
Ethical approval: This study was conducted in accordance with the
Guidelines. 2013 ACC/AHA guideline on the treatment of blood
Declaration of Helsinki and was approved by the local institutional cholesterol to reduce atherosclerotic cardiovascular risk in
review boards or ethics committees of all participating centres (Yonsei adults: a report of the American College of Cardiology/American
University Health System, Institutional Review Board, 4-2015-0713). Heart Association Task Force on Practice Guidelines. J Am Coll
Data sharing: Data will be shared by the corresponding author upon Cardiol 2014;63(25 Pt B):2889-934. doi:10.1016/j.jacc.2013.11.002
reasonable request. 13 Hicks KA, Tcheng JE, Bozkurt B, et al; American College of
Cardiology, American Heart Association. 2014 ACC/AHA Key data
The manuscript’s guarantors (B-KK and M-KH) affirm that the
elements and definitions for cardiovascular endpoint events in
manuscript is an honest, accurate, and transparent account of the clinical trials: A report of the American College of Cardiology/
study being reported; that no important aspects of the study have American Heart Association task force on clinical data standards
been omitted; and that any discrepancies from the study as planned (Writing committee to develop cardiovascular endpoints data
and registered have been explained. standards). Circulation 2015;132:302-61. doi:10.1161/
Dissemination to participants and related patient and public CIR.0000000000000156
communities: There are no plans to communicate the results to the 14 Thygesen K, Alpert JS, Jaffe AS, et al; Joint ESC/ACCF/AHA/WHF Task
study participants. Our research findings will be disseminated to the Force for the Universal Definition of Myocardial Infarction. Third universal
public and healthcare professionals through press releases, interviews definition of myocardial infarction. Circulation 2012;126:2020-35.
with local and national media, social media posts on Twitter, doi:10.1161/CIR.0b013e31826e1058
15 Sacco RL, Kasner SE, Broderick JP, et al; American Heart Association
Facebook, and academic conferences.
Stroke Council, Council on Cardiovascular Surgery and Anesthesia,
Provenance and peer review: Not commissioned; externally peer Council on Cardiovascular Radiology and Intervention, Council
reviewed. on Cardiovascular and Stroke Nursing, Council on Epidemiology
This is an Open Access article distributed in accordance with the and Prevention, Council on Peripheral Vascular DiseaseCouncil on
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) Nutrition, Physical Activity and Metabolism. An updated definition of
license, which permits others to distribute, remix, adapt, build upon stroke for the 21st century: a statement for healthcare professionals
from the American Heart Association/American Stroke Association.
this work non-commercially, and license their derivative works on
Stroke 2013;44:2064-89. doi:10.1161/STR.0b013e318296aeca
different terms, provided the original work is properly cited and the
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