Journal Club
Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J,
Saleheen D, Rader DJ, Brewer HB, Barter PJ.
Cholesterol ester transfer protein inhibition by TA-8995 in patients
with mild dyslipidaemia (TULIP): a randomised, double-blind, placebocontrolled phase 2 trial.
Lancet. 2015 Jun 2. pii: S0140-6736(15)60158-1. doi: 10.1016/S01406736(15)60158-1.
2015年6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 Kawasaki Medical School Syllabus
A total of 1188 patients
(LDL) cholesterol to less than 100 mg per deciliter
atorvastatin monotherapy or atorvastatin plus 60 mg of
torcetrapib daily.
After 24 months,
The CETP inhibitor torcetrapib was associated with a
substantial increase in HDL cholesterol and decrease in LDL
cholesterol. It was also associated with an increase in blood
pressure, and there was no significant decrease in the
progression of coronary atherosclerosis. The lack of efficacy
may be related to the mechanism of action of this drug class
or to molecule-specific adverse effects. (ClinicalTrials.gov
number, NCT00134173.)
the Investigation of Lipid Level Management Using
Coronary Ultrasound to Assess Reduction of
Atherosclerosis by CETP Inhibition and HDL
Elevation (ILLUSTRATE) trial
N Engl J Med 2007;356:1304-16.
Kaplan-Meier Curves for
Death from Any Cause
and for the Primary
Composite Outcome
Torcetrapib therapy
resulted in an
increased risk of
mortality and
morbidity of unknown
mechanism
the Investigation of Lipid
Level Management to
Understand its Impact in
Atherosclerotic Events
(ILLUMINATE) trial
N Engl J Med
Volume 357(21):2109-2122
November 22, 2007
Figure 1.
Effects of the Study Drug on
Mean High-Density
Lipoprotein (HDL) Cholesterol
and Low-Density Lipoprotein
(LDL) Cholesterol Levels.
To convert the values for
cholesterol to millimoles per liter,
multiply by 0.02586. I bars
represent 95% confidence
intervals.
dalcetrapib,
at a dose of 600 mg daily
N Engl J Med 2012. DOI: 10.1056/NEJMoa1206797
dalcetrapib,
at a dose of 600 mg daily
N Engl J Med 2012. DOI: 10.1056/NEJMoa1206797
a
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
Dezima Pharma BV, Naarden, the Netherlands
c Department of Gastroenterology, Leiden University Medical Centre, Leiden, the Netherlands
d Xention, Cambridge, UK
e Department of Genetics, Perelman School of Medicine, University of Pennsylvania, PA, USA
f MedStar Research Institute, Washington Hospital Center, Washington DC, USA
g Centre for Vascular Research, University of New South Wales, Sydney, NSW, Australia
b
Dr G Kees Hovingha, , ,
Prof John J P Kasteleina, b,
Prof Sander J H van Deventerb, c,
Patrick Roundb, d,
John Fordb, d,
Danish Saleheene,
Prof Daniel J Radere,
Prof H Bryan Brewerf,
Prof Philip J Barterg
Lancet. 2015 Jun 2. pii: S0140-6736(15)60158-1. doi: 10.1016/S0140-6736(15)60158-1.
Background
Dyslipidaemia remains a significant risk factor for
cardiovascular disease and additional lipidmodifying treatments are warranted to further
decrease the cardiovascular disease burden. We
assessed the safety, tolerability and efficacy of a
novel cholesterol esterase transfer protein
(CETP) inhibitor TA-8995 in patients with mild
dyslipidaemia.
Methods
In this randomised, double-blind, placebo-controlled, parallelgroup phase 2 trial, we recruited patients (aged 18–75 years) from
17 sites (hospitals and independent clinical research
organisations) in the Netherlands and Denmark with fasting LDL
cholesterol levels between 2·5 mmol/L and 4·5 mmol/L, HDL
cholesterol levels between 0·8 and 1·8 mmol/L and triglyceride
levels below 4·5 mmol/L after washout of lipid-lowering treatments.
Patients were randomly allocated (1:1) by a computer-generated
randomisation schedule to receive one of the following nine
treatments: a once a day dose of 1 mg, 2·5 mg, 5 mg, or 10 mg
TA-8995 or matching placebo; 10 mg TA-8995 plus 20 mg
atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg
atorvastatin or 10 mg rosuvastatin alone. We overencapsulated
statins to achieve masking. The primary outcome was percentage
change in LDL cholesterol and HDL cholesterol from baseline at
week 12, analysed by intention to treat. This study is registered
with ClinicalTrials.gov, number NCT01970215.
Initial attempts to show cardioprotective effects of CETP
inhibition with torcetrapib and dalcetrapib in human
beings have failed.3 and 4 Nevertheless, the hypothesis of
a beneficial effect of CETP lowering is being tested in
two large clinical outcome trials (REVEAL
[NCT01252953] and ACCELERATE [NCT01687998]) in
which investigators are studying CETP inhibitors that do
not possess the adverse off-target effects of torcetrapib.
mmol/L mg/dL factor=0.0259
0.8 31
1.8 69
2.5 97
4.5 174
Figure 1: Trial profile
The primary efficacy dataset included all patients
who received at least one dose of study drug and
had lipid measurements at baseline and week 12.
All patients who received at least one dose of
study drug were included in the safety analyses.
193
154
116
77
39
193
154
116
77
39
Figure 2: Baseline and week 12 data for LDL (A) and HDL (B) Boxes show the 25th and 75th percentiles, whiskers show the minimum and
maximum values, horizontal lines show the median, and green circles show the mean. The data only include patients who had both baseline and
week 12 data. The changes from baseline for all active treatments showed signifi cant diff erences from placebo at week 12 (p<0·0001).
193
154
116
77
39
193
154
116
77
39
Figure 2: Baseline and week 12 data for LDL (A) and HDL (B) Boxes show the 25th and 75th percentiles, whiskers show the minimum and
maximum values, horizontal lines show the median, and green circles show the mean. The data only include patients who had both baseline and
week 12 data. The changes from baseline for all active treatments showed signifi cant diff erences from placebo at week 12 (p<0·0001).
Cholesterol efflux capacity from macrophages, a metric of HDL
function, has a strong inverse association with both carotid intimamedia thickness and the likelihood of angiographic coronary artery
disease, independently of the HDL cholesterol level. (N Engl J Med,
364 (2011), pp. 127–135)
Cholesterol efflux capacity measurement (N Engl J Med, 364 (2011), pp. 127–135)
The HDL fraction used in the cholesterol efflux capacity assay was obtained by depleting subject serum of apolipoprotein B particles
using polyethylene glycol (PEG) precipitation.
This method yielded recovery of more than 97% of apolipoprotein A-I-containing HDL particles and less than 2% of apolipoprotein Bcontaining low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) particles in pilot studies.
Reference: 1. Adorni MP, Zimetti F, Billheimer JT, et al. The roles of different pathways in the release of cholesterol from
macrophages. J Lipid Res. 2007;48:2453 - 62.
Findings
Between Aug 15, 2013, and Jan 10, 2014, 364 patients were
enrolled. At week 12, LDL cholesterol levels were reduced by
27·4% in patients assigned to the 1 mg dose, 32·7% in
patients given the 2·5 mg dose, 45·3% in those given the 5
mg dose, and 45·3% in those given the 10 mg dose
(p<0·0001). LDL cholesterol levels were reduced by 68·2%
in patients given 10 mg TA-8995 plus atorvastatin, and by
63·3% in patients given rosuvastatin plus 10 mg TA-8995
(p<0·0001). A daily dose of 1 mg TA-8995 increased HDL
cholesterol levels by 75·8%, 2·5 mg by 124·3%, 5 mg by
157·1%, and 10 mg dose by 179·0% (p<0·0001). In patients
receiving 10 mg TA-8995 and 20 mg atorvastatin HDL
cholesterol levels increased by 152·1% and in patients
receiving 10 mg TA-8995 and 10 mg rosuvastatin by 157·5%.
We recorded no serious adverse events or signs of liver or
muscle toxic effects.
Interpretation
TA-8995, a novel CETP inhibitor, is well tolerated
and has beneficial effects on lipids and
apolipoproteins in patients with mild
dyslipidaemia. A cardiovascular disease outcome
trial is needed to translate these effects into a
reduction of cardiovascular disease events.
Funding
Dezima.
Currently evacetrapib and anacetrapib are being tested in two large
cardiovascular disease outcome studies (NCT01687998 and NCT01252953).
www.thelancet.com Published online June 3, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60608-0
Message
軽度の脂質異常症患者364人を対象に、コレステ
リルエステル転送タンパク（CETP）阻害薬TA8995の効果をプラセボ対照第2相試験で検証
（TULIP試験）。12週時のLDL-C低下率は5mg群お
よび10mg群で45.3％、HDL-C増加率は157.1％、
179.0％だった。重篤な有害事象や肝/筋毒性は
見られなかった。
コレステリルエステル転送タンパク（CETP）阻害薬はこれま
での失敗（dalcetrapib, tracetrabip）にもめげず、evacetrapib，
anacetrapib や今回のTA-8995は薬物として使うようになる
のだろうか？！
http://www.m3.com/clinical/journal/15524