Transcript Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科

Journal Club
Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, Baxter
JD, Angelin B.
Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.
N Engl J Med. 2010 Mar 11;362(10):906-16.
Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH,
Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST.
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol
concentrations in patients with homozygous familial hypercholesterolaemia: a
randomised, double-blind, placebo-controlled trial.
Lancet. 2010 Mar 20;375(9719):998-1006.
2010年３月25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
From the Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins
University School of Medicine, Baltimore (P.W.L.); Karo Bio, Huddinge ( J.D.K., B.C.), the Faculty of
Health Sciences, Linkoping University and Stockholm Heart Center, Stockholm (A.G.O.), and the
Department of Endocrinology, Metabolism, and Diabetes, and Center for Biosciences, Department of
Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm (B.A.) — all in
Sweden; the Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of
Medicine, Aurora (E.C.R.); the Department of Medicine, North Shore University Hospital and the
Feinstein Institute for Medical Research, Manhasset, NY (I.K.); and the Center for Diabetes Research,
Methodist Hospital Research Institute, Houston (J.D.B.).
N Engl J Med 2010;362:906-16.
Background
Dyslipidemia increases the risk of
atherosclerotic cardiovascular disease and is
incompletely reversed by statin therapy alone
in many patients. Thyroid hormone lowers
levels of serum low-density lipoprotein (LDL)
cholesterol and has other potentially
favorable actions on lipoprotein metabolism.
Consequently, thyromimetic drugs hold
promise as lipid-lowering agents if adverse
effects can be avoided.
Method
We performed a randomized, placebo-controlled,
double-blind, multicenter trial to assess the safety
and efficacy of the thyromimetic compound
eprotirome (KB2115) in lowering the level of serum
LDL cholesterol in patients with
hypercholesterolemia who were already receiving
simvastatin or atorvastatin. In addition to statin
treatment, patients received either eprotirome (at a
dose of 25, 50, or 100 μg per day) or placebo.
Secondary outcomes were changes in levels of
serum apolipoprotein B, triglycerides, and Lp(a)
lipoprotein. Patients were monitored for potential
adverse thyromimetic effects on the heart, bone, and
pituitary.
Mechanism of Action
The reduction of LDL (in humans)
●
1) increased expression of the hepatic LDLreceptor gene.
Accelerate clearance of cholesterol by the liver (in
rodents) by
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●
●
1) increasing the high-density lipoprotein (HDL)
receptor called scavenger receptor B1 (SR-B1)
2) increasing the activity of cholesterol 7αhydroxylase
3) increasing fecal excretion of cholesterol and bile
acids
Study Design
Percentage changes in serum Lp(a) lipoprotein concentration as a
function of the baseline Lp(a) level for individual patients. Individuals with
baseline values above 70 mg/dL represented 34% of the study patients.
Study Patients’ Vital Signs
Female Study Patients
Male Study Patients
Results
The addition of placebo or eprotirome at a dose of
25, 50, or 100 μg daily to statin treatment for 12
weeks reduced the mean level of serum LDL
cholesterol from 141 mg per deciliter (3.6 mmol per
liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9,
2.6, and 2.4 mmol per liter), respectively, (mean
reduction from baseline, 7%, 22%, 28%, and 32%).
Similar reductions were seen in levels of serum
apolipoprotein B, triglycerides, and Lp(a) lipoprotein.
Eprotirome therapy was not associated with adverse
effects on the heart or bone. No change in levels of
serum thyrotropin or triiodothyronine was detected,
although the thyroxine level decreased in patients
receiving eprotirome.
Conclusion
In this 12-week trial, the thyroid
hormone analogue eprotirome was
associated with decreases in levels
of atherogenic lipoproteins in
patients receiving treatment with
statins.
(ClinicalTrials.gov number, NCT00593047.)
Message
甲状腺ホルモンでコレステロールが低下する。
甲状腺ホルモン類似物質で甲状腺機能に影響させず
にコレステロールのみを低下させることが可能とい
うことが分かった。
甲状腺機能異常でのコレステロール値変化は代謝状
態の変化による２次的変化というのではなさそう。
これまでezetimibeやtorcetrapib (CETP阻害剤)では
スタチンに上乗せでLDL-Cが低下したりHDL-Cが上昇
しても心血管障害減少には結びつかなかったが，新
しい候補ができた！
それにしても，骨代謝マーカーを測定したというの
だが記載がない？
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa (Prof F J Raal MD); Lipid
Clinic, Heart Institute (InCor) University of Sao Paulo Medical School, Sao Paulo, Brazil (R D Santos MD); Division
of Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa (D J Blom MD, Prof A D
Marais MD); Department of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University,
Taipei, Taiwan (M-J Charng MD); Division of Atherosclerosis and Lipoprotein Disorders, Presbyterian Center for
Preventative Cardiology, Charlotte, NC, USA (W C Cromwell MD); Charles Dent Metabolic Unit, University
College London Hospitals, London, UK (R H Lachmann MRCP); Universite de Montreal, ECOGENE-21 Clinical
Research Center and Lipid Clinic, Chicoutimi, Canada (D Gaudet MD); Department of Cardiology, National Heart
Centre, Singapore (J L Tan MB BS); Biomedical Data Sciences and Informatics, Genzyme Corporation, Cambridge,
MA, USA (S Chasan-Taber PhD); and Isis Pharmaceuticals, Carlsbad, CA, USA (D L Tribble PhD, J D Flaim PhD,
S T Crooke MD)
Lancet 2010; 375: 998–1006
Aim
Homozygous familial hypercholesterolaemia
is a rare genetic disorder in which both LDLreceptor alleles are defective, resulting in very
high concentrations of LDL cholesterol in
plasma and premature coronary artery
disease. This study investigated whether an
antisense inhibitor of apolipoprotein B
synthesis, mipomersen, is effective and safe
as an adjunctive agent to lower LDL
cholesterol concentrations in patients with
this disease.
Mipomersen (ISIS-301012) is a 20-mer antisense
oligonucleotide that specifically binds apolipoprotein B
mRNA and leads to inhibition of protein translation,
reducing the synthesis and secretion of lipoproteins LDL
and VLDL that contain apolipoprotein B.
Mipomersen binding to the mRNA sequence encoding
apolipoprotein B results in degradation of the
apolipoprotein B mRNA by ribonuclease H, an
endoribonuclease that specifically hydrolyses the
phosphodiester bonds of RNA when hybridised to DNA,
thereby inhibiting translation of the apolipoprotein B
protein, and effectively reducing concentrations of
apolipoprotein B100.
Mipomersen’s half life is about 30 days. (~3 to 6 months
to steady state)
Method
This randomised, double-blind, placebo-controlled, phase 3
study was undertaken in nine lipid clinics in seven countries.
Patients aged 12 years and older with clinical diagnosis or
genetic confi rmation of homozygous familial
hypercholesterolaemia, who were already receiving the
maximum tolerated dose of a lipid-lowering drug, were
randomly assigned to mipomersen 200 mg subcutaneously
every week or placebo for 26 weeks. Randomisation was
computer generated and stratified by weight (<50 kg vs ≥50
kg) in a centralised blocked randomisation, implemented with
a computerised interactive voice response system. All
clinical, medical, and pharmacy personnel, and patients were
masked to treatment allocation. The primary endpoint was
percentage change in LDL cholesterol concentration from
baseline. Analysis was by intention to treat.
This trial is registered with ClinicalTrials.gov, number NCT00607373.
Trial profile
The most frequent allele was
D206E (familial hypercholesterolaemia Afrikaner-1),
which was present in 24 patients,
14 of whom were true
homozygotes, which is consistent
with the fact that many of the
study population were from South
Africa.
All patients apart from one were
being treated with lipid-lowering
drugs (50/51, 98%), 12 (24%) of
whom were taking a statin alone
(six mipomersen, six placebo) and
38 (76%) of whom were taking a
statin in combination with at least
one other lipid-lowering agent (27
mipomersen, 11 placebo), most
commonly ezetimibe (37/50, 74%).
Most patients taking a statin (44/50,
88%) were receiving the maximum
dose.
LDL-C 10 mmol/L = 386 mg/dl 11.4 = 440mg/dl 8.4 ⇒ 325mg/dl
Triglyceride 1 mmol/L = 88.5 mg/dl
Figure 2: Mean percentage change
from baseline (week 0) to primary
efficacy time point for LDL
cholesterol (A), apolipoprotein B
(B), and lipoprotein(a) (C) Error
bars indicate 95% CI.
Figure 3: Percentage change in LDL cholesterol from baseline for individual patients
Response is shown graphically for individual patients in the mipomersen and placebo
treatment groups. Each vertical bar represents one patient, arranged in order of response.
No patients developed antibodies to mipomersen.
Hy’s Law cases have the following three components
1. The drug causes hepatocellular injury, generally shown
by more frequent 3-fold or greater elevations above the
ULN of ALT or AST than the (nonhepatotoxic) control
agent or placebo.
2. Among subjects showing such AT elevations, often with
ATs much greater than 3xULN, some subjects also show
elevation of serum TBL to >2xULN, without initial
findings of cholestasis (serum alkaline phosphatase
(ALP) activity >2xULN).
3. No other reason can be found to explain the
combination of increased AT and TBL, such as viral
hepatitis A, B, or C, preexisting or acute liver disease, or
another drug capable of causing the observed injury.
No cases of ALT more than eight times ULN were noted and
no patient met Hy’s law.
Results
34 patients were assigned to mipomersen and 17 to placebo;
data for all patients were analysed. 45 patients completed the
26-week treatment period (28 mipomersen, 17 placebo). Mean
concentrations of LDL cholesterol at baseline were 11・4
mmol/L (SD 3・6) in the mipomersen group and 10・4 mmol/L
(3・7) in the placebo group. The mean percentage change in
LDL cholesterol concentration was significantly greater with
mipomersen (–24・7%, 95% CI –31・6 to –17・7) than with
placebo (–3・3%, –12・1 to 5・5; p=0・0003). The most common
adverse events were injection-site reactions (26 [76%]
patients in mipomersen group vs four [24%] in placebo
group). Four (12%) patients in the mipomersen group but
none in the placebo group had increases in concentrations of
alanine aminotransferase of three times or more the upper
limit of normal.
Conclusion
Inhibition of apolipoprotein B synthesis
by mipomersen represents a novel,
effective therapy to reduce LDL
cholesterol concentrations in patients
with homozygous familial hyper
cholesterolaemia who are already
receiving lipid-lowering drugs, including
high-dose statins.
Funding ISIS Pharmaceuticals and Genzyme Corporation.
discussion
In a small, open-label, dose-escalation pilot
study in patients with homozygous familial
hypercholesterolaemia receiving maximum
tolerated lipid-lowering treatment, 300 mg
mipomersen administered once per week for
11 weeks after a 2-week loading period
produced a 45–51% reduction in LDL
cholesterol concentrations in three patients
not undergoing apheresis.
Message
アンチセンス治療は抗癌剤とかAIDSなど特殊な
感染症の治療かと思っていたら脂質異常症の治
療にも使える！
副作用はさすがにちょっと問題かもしれないが，
血漿交換が必要なくらいの高コレステロール血
症では評価されてくる可能性がある。