Journal Club
Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA;
for the TESLA Investigators.
Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia
(TESLA Part B): a randomised, double-blind, placebo-controlled trial.
Lancet. 2014 Oct 1. pii: S0140-6736(14)61374-X. doi: 10.1016/S0140-6736(14)61374-X.
Zhao D, Cho J, Kim MH, Friedman DS, Guallar E.
Diabetes, Fasting Glucose, and the Risk of Glaucoma: A Meta-analysis.
Ophthalmology. 2014 Oct 2. pii: S0161-6420(14)00697-6. doi:
10.1016/j.ophtha.2014.07.051.
2014年10月23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
http://www.pcsk9forum.org/
Treatment of homozygous familial hypercholesterolaemia
•
•
•
•
•
•
•
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statins
ezetimibe
partial ileal bypass
portacaval shunt
liver transplantation
LDL apheresis
mipomersen
lomitapide
• (ALN-PCS)
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•
alirocumab
evolocumab
bococizumab
PCSK9 target
KYNAMROTM (mipomersen sodium)
KYNAMROTM is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis
Lancet 2010; 375: 998–1006
Lomitapide (INN, marketed as Juxtapid) is a drug for the treatment of familial hypercholesterolemia,
developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and
in combinations with atorvastatin, ezetimibe and fenofibrate.
The US Food and Drug Administration (FDA) approved lomitapide on 21 December 2012, as an
orphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density
lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia
(HoFH).
Lomitapide inhibits the
microsomal triglyceride transfer
protein (MTP or MTTP) which is
necessary for very low-density
lipoprotein (VLDL) assembly and
secretion in the liver.
http://en.wikipedia.org/wiki/Lomitapide
Proprotein convertase subtilisin/kexin type 9
PCSK9 (neural apoptosis-regulated convertase, NARC-1) is a 692-residue
extracellular protein representing the 9th member of the secretory subtilase
family expressed primarily in the kidneys, liver and intestines.
Genetic studies mapped PCSK9 along with LDLR and APOB to cause autosomal
dominant hypercholesterolemia (ADH). Gain-of-function mutations increased
plasma levels of low-density lipoprotein cholesterol (LDL-C), whereas nonsense or
missense (loss-of-function) mutations, which interfere with folding or secretion of
PCSK9, led to a reduction of plasma levels of LDL-C and an 88% decrease in the
risk of coronary heart disease (CHD).
http://caltagmedsystems.blogspot.jp/2012/04/pcsk9-attractive-drug-target-for.html
Lancet. 2014 Jan 4;383(9911):60-8.
Alirocumab SAR236553 (REGN727)
抗体治療！！
single ascending-dose studies of REGN727
N Engl J Med 2012;366:1108-18.
抗体治療+スタチン
Alirocumab SAR236553 (REGN727)
primary hypercholesterolemia
N Engl J Med 2012;367:1891-900. DOI: 10.1056/NEJMoa1201832
Effect of ALN-PCS treatment on serum LDL cholesterol
Lancet. 2014 Jan 4;383(9911):60-8.
ALN-PCS:a small interfering RNA that inhibits PCSK9 synthesis
Evolocumab (AMG 145)
Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of
Witwatersrand, Johannesburg, South Africa (Prof F J Raal PhD); Amgen Inc, One Amgen
Center Drive, Thousand Oaks, CA, USA (N Honarpour MD, F Xu MS, R Scott MD, S M
Wasserman MD); Division of Lipidology, Department of Medicine, University of Cape Town,
UCT Faculty Health Sciences, Cape Town, South Africa (D J Blom MD); Vascular Medicine,
Academic Medical Centre, Amsterdam, Netherlands (G Kees Hovingh MD); and Metabolic
and Atherosclerosis Research Center, Cincinnati, OH, USA (Prof E A Stein PhD)
www.thelancet.com Published online October 2, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61374-X
Background
Homozygous familial hypercholesterolaemia is a
rare, serious disorder caused by very low or
absent plasma clearance of LDL, substantially
raised LDL cholesterol, and accelerated
development of cardiovascular disease.
Conventional lipid-lowering treatments are
modestly effective. Evolocumab, a monoclonal
antibody to proprotein convertase subtilisin/kexin
type 9 (PCSK9), reduced LDL cholesterol by 16%
in a pilot study. We now report results with
evolocumab in a randomised, double-blind,
placebo-controlled phase 3 trial.
Methods
This randomised, double-blind, placebo-controlled phase 3 trial was
undertaken at 17 sites in ten countries in North America, Europe, the
Middle East, and South Africa. 50 eligible patients (aged ≥12 years)
with homozygous familial hypercholesterolaemia, on stable lipidregulating therapy for at least 4 weeks, and not receiving lipoprotein
apheresis, were randomly allocated by a computer-generated
randomisation sequence in a 2:1 ratio to receive subcutaneous
evolocumab 420 mg or placebo every 4 weeks for 12 weeks.
Randomisation was stratified by LDL cholesterol at screening (<11
mmol/L or ≥11 mmol/L) and implemented by a computerised
interactive voice-response system. Patients, study personnel, and the
funder were masked to treatment and to the efficacy results by the
central laboratory not returning LDL cholesterol or any lipid results to
the clinical sites after the baseline visit. The primary endpoint was
percentage change in ultracentrifugation LDL cholesterol from
baseline at week 12 compared with placebo, analysed by intentionto-treat. This trial is registered with ClinicalTrials.gov, number
NCT01588496.
Table 1: Baseline characteristics
LDL-C 8.7mmol/L=336mg/dL
LDL-C 9.2mmol/L=355mg/dL
LDL-C 9.0mmol/L=347mg/dL
HDL-C 1.0mmol/L=38.6mg/dL
TG 1.3mmol/L=115mg/dL
0.0259 for Cholesterol
0.0113 for TG
Data are mean (SD), range, n (%),
or median (IQR).
PCSK9=proprotein convertase
subtilisin/kexin type 9.*Ethnicity
was self-reported and some
patients did not answer this
question.
Table 2: Efficacy outcomes
Data are leastsquares mean
(95% CI) except
for hsCRP data,
which are
median (IQR).
Least-squares
mean is from the
repeated
measures model,
which includes
treatment group,
stratifi cation
factor, scheduled
visit, and
interaction of
treatment with
scheduled visits
as covariates for
all endpoints.
PCSK9=proprotei
n convertase
subtilisin/kexin
type 9.
hsCRP=highsensitivity Creactive protein.
NA=not applicable.
*Multiplicity
adjustments
following the
Hochberg
procedure were
used to control for
overall signifi
cance at the 0·05
level of signifi
cance for the
primary and
secondary
endpoints.
Table 4: Adverse events
ALT=alanine aminotransferase.
AST=aspartate aminotransferase.
ULN=upper limit of normal.
*Reported in at least one patient in
either or both treatment groups.
†Searched with use of high-level
term grouping, which includes
injection-site rash, infl ammation,
pruritus, reaction, or urticaria.
‡Searched with use of high-level
grouping, which includes deliria
(including confusion), cognitive
and attention disorders and
disturbances, dementia and
amnestic disorders, disturbances
in thinking and perception, and
mental impairment disorders.
§Excludes one patient who had a
positive binding antibody test at
baseline and negative antibody
testing at all other study
assessments.
Findings
Of the 50 eligible patients randomly assigned to the
two treatment groups, 49 actually received the study
drug and completed the study (16 in the placebo
group and 33 in the evolocumab group). Compared
with placebo, evolocumab significantly reduced
ultracentrifugation LDL cholesterol at 12 weeks by
30·9% (95% CI −43·9% to −18·0%; p<0·0001).
Treatment-emergent adverse events occurred in ten
(63%) of 16 patients in the placebo group and 12
(36%) of 33 in the evolocumab group. No serious
clinical or laboratory adverse events occurred, and
no anti-evolocumab antibody development was
detected during the study.
Interpretation
In patients with homozygous familial
hypercholesterolaemia receiving stable
background lipid-lowering treatment and not
on apheresis, evolocumab 420 mg
administered every 4 weeks was well
tolerated and significantly reduced LDL
cholesterol compared with placebo.
Funding
Amgen Inc.
Message
ホモ接合体家族性高コレステロール血症（FH）患者50人
を対象に、前駆たんぱく質転換酵素サブチリシン/ケキ
シン9型（PCSK9）に対するモノクローナル抗体
evolocumabのLDLコレステロール低下効果を第3相試験で
検討（TESLA Part B試験）。12週後、プラセボに比べて
evolocumabがLDLコレステロールを30.9%低下させた(Ｐ
＜0.0001)。
大規模臨床治験中(心血管障害リスク者)
ODYSSEY (NCT01663402) with alirocumab,
FOURIER (NCT01764633) with evolocumab, and
SPIRE-1 (NCT01975389) and SPIRE-2 (NCT01975376)
with bococizumab,
Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical
Research, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
2 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences
and Technology, Sungkyunkwan University, Seoul, Korea.
3 Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, School of
Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
4 Saevit Eye Hospital, Goyang, Gyeonggi-do, Korea.
5 Department of Epidemiology, Graduate School of Public Health, Seoul National University, Seoul,
Korea.
6 Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
Topic: We performed a systematic review to
summarize the association of diabetes and blood
glucose levels with glaucoma, intraocular
pressure (IOP), and ocular hypertension in the
general population.
Clinical Relevance: Diabetes has been
proposed as a risk factor for glaucoma, but
epidemiologic studies have been inconsistent,
and the association is still controversial.
Furthermore, no systematic reviews evaluated
other metabolic abnormalities, such as the
metabolic syndrome, with the risk of glaucoma.
Methods: We identified the studies by searching
the PubMed and EMBASE databases. We used
inversevariance weighted random-effects models
to summarize relative risks across studies.
http://www.genome.med.kyoto-u.ac.jp/func-gen-redirect/wiki/index.php/Heterogeneity%E3%81%AE%E6%A4%9C%E5%AE%9A
Results: We identified 47 studies including 2 981 342
individuals from 16 countries. The quality of evidence
generally was higher in the cohort compared with casecontrol or cross-sectional studies. The pooled relative risk
for glaucoma comparing patients with diabetes with those
without diabetes was 1.48 (95% confidence interval
[CI], 1.29-1.71), with significant heterogeneity across studies
(I2 = 82.3%; P < 0.001). The risk of glaucoma
increased by 5% (95% CI, 1%-9%) for each year since
diabetes diagnosis. The pooled average difference in IOP
comparing patients with diabetes with those without diabetes
was 0.18 mmHg (95% CI, 0.09-0.27; I2 = 73.2%),
whereas the pooled average increase in IOP associated with
an increase in 10 mg/dl in fasting glucose was 0.09
mmHg (95% CI, 0.05-0.12; I2 = 34.8 %)
Conclusions: Diabetes, diabetes duration, and
fasting glucose levels were associated with a
significantly increased risk of glaucoma, and
diabetes and fasting glucose levels were
associated with slightly higher IOP.
Message
PubMedとEMBASEからの既発表論文47件（被験者
約298万人）を対象に、糖尿病（DM）と緑内障リ
スクの関連をシステマティックレビューで検
証。非DM患者に対するDM患者のプールされた緑
内障相対リスクは1.48だったが、高い報告間の
異質性が見られた（I2＝82.3％）。緑内障リスク
はDM診断後1年経過ごとに5％増加した。
緑内障はあまり糖尿病の合併症として考えられ
たり管理されていないが．．．