Journal Club
Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F,
Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E,
Melander O, Kathiresan S, Sabatine MS.
Genetic risk, coronary heart disease events, and the clinical benefit of statin
therapy: an analysis of primary and secondary prevention trials.
Lancet. 2015 Mar 3. pii: S0140-6736(14)61730-X. doi: 10.1016/S01406736(14)61730-X.
Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK.
Association between familial hypercholesterolemia and prevalence of type 2
diabetes mellitus.
JAMA. 2015 Mar 10;313(10):1029-36.
2015年3月19日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
• TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
• Cardiovascular Division, Department of Medicine and Division of Statistical Genomics, Washington University School of
Medicine, St Louis, MO, USA
• Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
• Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital
and Harvard Medical School, Boston, MA, USA
• William Harvey Research Institute, Queen Mary University of London and Barts NIHR CV Biomedical Research Institute, London,
UK
• Quest Diagnostics, Alameda, CA, USA
• Pfizer Research Laboratory, Groton, CT, USA
• Department of Nutrition, Harvard School of Public Health and Channing Division of Network Medicine, Brigham and Women's
Hospital, Boston, MA, USA
• International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, UK
• Department of Clinical Sciences, Faculty of Medicine, Lund University and Department of Internal Medicine, Skåne University
Hospital, Malmö, Sweden
• Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Center for Human Genetic Research and
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Published online March 4, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61730-X
Background
Genetic variants have been associated with the
risk of coronary heart disease. In this study, we
tested whether or not a composite of these
variants could ascertain the risk of both incident
and recurrent coronary heart disease events and
identify those individuals who derive greater
clinical benefit from statin therapy.
coronary heart disease was defined as a composite
of coronary heart death, myocardial infarction, or
unstable angina.
Methods
A community-based cohort study (the Malmo Diet and
Cancer Study) and four randomised controlled trials of
both primary prevention (JUPITER and ASCOT) and
secondary prevention (CARE and PROVE IT-TIMI 22)
with statin therapy, comprising a total of 48 421
individuals and 3477 events, were included in these
analyses. We studied the association of a genetic risk
score based on 27 genetic variants with incident or
recurrent coronary heart disease, adjusting for traditional
clinical risk factors. We then investigated the relative and
absolute risk reductions in coronary heart disease
events with statin therapy stratified by genetic risk. We
combined data from the different studies using a metaanalysis.
Primary prevention populations
The Malmo Diet and Cancer Study (MDCS) is a communitybased prospective epidemiological cohort of middle-aged (45–64 years old)
individuals from southern Sweden. Genetic samples were available from 27 817 people without documented coronary heart disease at baseline.
JUPITER was a primary prevention trial that tested rosuvastatin 20 mg daily versus placebo in 17 802 individuals with LDL cholesterol level
lower than 3·37 mmol/L, high-sensitivity C-reactive protein of 2 mg/L or higher, and no known cardiovascular disease. Genetic samples were
available in 8749 individuals for this analysis.
ASCOT tested the clinical benefi t of diff erent classes of antihypertensive therapy in 19 342 high-risk individuals without documented coronary
heart disease. The lipidlowering group (ASCOT-LLA) randomly assigned individuals from the main trial with a total cholesterol level of up to 6·5
mmol/L to either atorvastatin 10 mg daily or placebo. In total, 4219 individuals from ASCOTLLA were included in the treatment-related analyses.
Additionally, 2759 participants from the blood pressurelowering group of ASCOT who were not receiving a statin drug were assessed in the nontreatment-related analyses.
Secondary prevention populations
CARE was a secondary prevention trial that investigated the clinical benefi t of pravastatin 40 mg daily versus placebo in 4159 individuals with
previous myocardial infarction who had total cholesterol level of up to 6·2 mmol/L and LDL cholesterol level between 3·0 and 4·5 mmol/L.
Genetic samples were available for 2878 individuals in this study.
PROVE IT-TIMI 22, investigated the clinical benefi t of moderate statin therapy (pravastatin 40 mg daily) versus intensive statin therapy
(atorvastatin 80 mg daily) in 4162 patients after an acute coronary syndrome who had total cholesterol level of up to 6·2 mmol/L.21 A genetic
substudy included 1999 individuals. In PROVE IT-TIMI 22, the control group is moderate-intensity statin therapy (pravastatin 40 mg) and the
statin group is high-intensity statin therapy (atorvastatin 80 mg).
G Berglund, S Elmstahl, L Janzon, SA Larsson
The Malmo Diet and Cancer Study. Design and feasibility
J Intern Med, 233 (1993), pp. 45–51 Citing articles (252)
PM Ridker, E Danielson, FA Fonseca, et al.
Rosuvastatin to prevent vascular events in men and women
with elevated C-reactive protein
N Engl J Med, 359 (2008), pp. 2195–2207 Citing articles
(2781)
PS Sever, B Dahlof, NR Poulter, et al.
Prevention of coronary and stroke events with atorvastatin in
hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
(ASCOT-LLA): a multicentre randomised controlled trial
The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels.
Cholesterol and Recurrent Events Trial investigators
N Engl J Med, 335 (1996), pp. 1001–1009 Citing articles
(6246)
CP Cannon, E Braunwald, CH McCabe, et al.
Intensive versus moderate lipid lowering with statins after
acute coronary syndromes
N Engl J Med, 350 (2004), pp. 1495–1504 Citing articles
(2927)
Construction of the Genetic Risk Score
In each locus comprising the genetic risk score, the lead SNP or a proxy in
linkage disequilibrium (r2 > 0.8) was directly genotyped in MDCS, ASCOT,
CARE, and PROVE IT-TIMI 22 (see Supplemental Table 2 for details). In
JUPITER, genotypes for 11 of the loci were directly assessed using the Omni1Quad platform as previously described.1 Genotypes for the remaining loci were
statistically imputed using 1000 Genomes Project data as previously
described.2 All imputed SNPs had an imputation Rsq≥0.88. Quality control (QC)
procedures were applied to remove variants with missing genotypes in >5% of
individuals and samples missing >5% of genotypes. A linear sum of the risk
alleles weighted by the log of the odds ratio observed for each SNP in the
original report comprised the genetic risk score. In JUPITER, the 1000
Genomes imputation data were used to infer any missing genotypes in
individuals. In the other studies, missing genotypes in individuals were
assigned the mean genotype value observed within the study.
1 Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic
determinants of statin-induced low-density lipoprotein cholesterol reduction: the
Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012; 5(2): 257-64.
2 Chu AY, Guilianini F, Barratt BJ, Nyberg F, Chasman DI, Ridker PM. Pharmacogenetic
determinants of statin-induced reductions in C-reactive protein. Circ Cardiovasc Genet.
2012; 5(1): 58-65.
Scaling Factor
A scaling factor was created for each trial by which to multiply the event
rate difference for statin versus placebo and upper and lower bounds of
the 95% CI so that the event rate difference in the intermediate genetic
risk score category for each trial was 1%. Then within each trial, metaregression was performed across the genetic risk score categories to
determine how the relative magnitude of absolute risk reduction with
statin therapy varied by genetic risk score category. The coefficient
represents the relative degree by which the absolute risk reduction with
statin therapy varies when one shifts genetic risk score category. Metaanalysis was then performed combining the regression coefficients from
the 4 trials.
In terms of the clinical interpretation of the resultant number, a value of
0.50, for example, would indicate a 50% greater absolute risk reduction
with statin therapy in patients with a high vs. an intermediate genetic risk
score. If statin therapy in the average or intermediate population
followed for a certain amount time would be expected to yield an 8%
absolute risk reduction, enriching for patients with a high genetic risk
score should yield a 12% absolute risk reduction.
low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5)
Figure 2: Hazard
ratios for coronary
heart disease with
statin therapy across
genetic risk score
categories The boxes
indicate the point
estimates, and the size
of each box represents
the weight of a trial’s
data within that
subgroup. The
horizontal lines are the
95% CIs. The
diamonds provide
summary data. In
PROVE IT-TIMI 22, the
control group is
moderate-intensity
statin therapy
(pravastatin 40 mg)
and the statin group is
high-intensity statin
therapy (atorvastatin
80 mg).
Findings
When individuals were divided into low (quintile 1), intermediate
(quintiles 2–4), and high (quintile 5) genetic risk categories, a significant
gradient in risk for incident or recurrent coronary heart disease was
shown. Compared with the low genetic risk category, the multivariableadjusted hazard ratio for coronary heart disease for the intermediate
genetic risk category was 1·34 (95% CI 1·22–1·47, p<0·0001) and that
for the high genetic risk category was 1·72 (1·55–1·92, p<0·0001). In
terms of the benefit of statin therapy in the four randomised trials, we
noted a significant gradient (p=0·0277) of increasing relative risk
reductions across the low (13%), intermediate (29%), and high (48%)
genetic risk categories. Similarly, we noted greater absolute risk
reductions in those individuals in higher genetic risk categories
(p=0·0101), resulting in a roughly threefold decrease in the number
needed to treat to prevent one coronary heart disease event in the
primary prevention trials. Specifically, in the primary prevention trials,
the number needed to treat to prevent one such event in 10 years was
66 in people at low genetic risk, 42 in those at intermediate genetic risk,
and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20,
respectively, in ASCOT.
Interpretation
A genetic risk score identified individuals at
increased risk for both incident and recurrent
coronary heart disease events. People with the
highest burden of genetic risk derived the largest
relative and absolute clinical benefit from statin
therapy.
Funding
National Institutes of Health.
Heribert Schunkerta, Nilesh J Samanib: Statin treatment: can genetics sharpen the focus?
doi:10.1016/S0140-6736(14)61931-0
www.thelancet.com Published online March 4, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61931-0
Message
遺伝子やCRPを検索するコストとスタチン使
用のコストが割にあうかは気になるが、大
規模臨床試験では遺伝子も検査していたと
は！
スタチンで糖尿病が増えるリスクも考慮に
入れると薬物治療の対象選択をしてから処
方するようになるのであろうか？
1Department
of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands
2Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the
Netherlands
3Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Centre,
Amsterdam, the Netherlands
JAMA. 2015;313(10):1029-1036. doi:10.1001/jama.2015.1206.
Importance Familial hypercholesterolemia is
characterized by impaired uptake of cholesterol in
peripheral tissues, including the liver and the
pancreas. In contrast, statins increase the
cellular cholesterol uptake and are associated
with increased risk for type 2 diabetes mellitus.
We hypothesize that transmembrane cholesterol
transport is linked to the development of type 2
diabetes.
Objective To assess the association between
type 2 diabetes prevalence and familial
hypercholesterolemia.
Design, Setting, and Participants Cross-sectional
study in all individuals (n = 63 320) who underwent DNA
testing for familial hypercholesterolemia in the national
Dutch screening program between 1994 and 2014.
Exposures Deleteriousness and nondeleteriousness of
familial hypercholesterolemia mutations were based on
literature or laboratory function testing. Low-density
lipoprotein (LDL) receptor mutations were considered
more severe than apolipoprotein B gene (APOB)
mutations, and receptor-negative LDL receptor
mutations were considered more severe than receptordeficient mutations.
Main Outcomes and Measures Prevalence of type 2
diabetes.
aData
may not sum because participants
could be excluded for more than 1 reason.
bMeasurement of lipid profile became
customary after 2004.
The diagnosis of type 2 diabetes was self-reported and might therefore not be
accurate. However, a study by Okura et al37 found substantial agreement between
questionnaire responses and medical records for type 2 diabetes (total agreement,
97.2% [κ, 0.76; 95% CI, 0.70-0.82]) in a well-characterized, population-based
cohort with a long record archival period. Additionally, the type of diabetes was not
specified by our questionnaire. We considered patients with age younger than 30 at
time of diabetes diagnosis, or younger than 40 in combination with insulin use, as
having type 1 diabetes and classified them as non–type 2 diabetes patients. Since
type 2 diabetes rarely occurs before the age of 30 and type 1 diabetes is seldom
first diagnosed in patients older than 30,15 we think we adequately addressed this
issue. Moreover, the fact that insulin is initiated in patients with type 2 diabetes on
average 10 years after the diagnosis supports the age limit of 40 years in
combination with the use of insulin.16 Our sensitivity analyses, in which all patients
with diabetes were classified as type 2 diabetes patients, showed consistent results
(eAppendix 1, eTable 5 in the Supplement).
Results The prevalence of type 2 diabetes was 1.75% in
familial hypercholesterolemia patients (n = 440/25 137) vs
2.93% in unaffected relatives (n = 1119/38 183) (P < .001;
odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted
prevalence of type 2 diabetes in familial
hypercholesterolemia, determined using multivariable
regression models, was 1.44% (difference, 1.49% [95% CI,
1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P < .001). The
adjusted prevalence of type 2 diabetes by APOB vs LDL
receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.480.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence
for receptor-deficient vs receptor-negative mutation carriers
was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR,
0.38 [95% CI, 0.29-0.49]), respectively (P for trend <.001 in
both comparisons).
Conclusions and Relevance In a crosssectional analysis in the Netherlands, the
prevalence of type 2 diabetes among patients
with familial hypercholesterolemia was
significantly lower than among unaffected
relatives, with variability by mutation type. If this
finding is confirmed in longitudinal analysis, it
would raise the possibility of a causal relationship
between LDL receptor-mediated transmembrane
cholesterol transport and type 2 diabetes.
Message
作業仮説はコレステロールの肝臓への取り込み
が悪い高コレステロール血症とコレステロール
を肝臓への取り込みを促進するスタチンとが糖
尿病発症に関しては逆に作用するという面白い
論文である。膵臓へのコレステロール蓄積がイ
ンスリン分泌を低下させるかはよくわからない
が、機序もふくめて今後も検討されるであろう。
ただし、高コレステロールがあればスタチンで
の治療という臨床選択は揺るがない。
David Preiss, MD, PhD; Naveed Sattar, MD, PhD: Does the LDL Receptor Play a
Role in the Risk of Developing Type 2 Diabetes? JAMA. 2015;313(10):1016-1017.
doi:10.1001/jama.2015.127.