Journal Club 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 2015 年 6 月 25 日 8:30-8:55 ８階 医局 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, placebo- controlled phase 2 trial. Lancet Jun 2. pii: S (15) doi: /S (15)

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, NCT ) N Engl J Med 2007;356: the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial

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 N Engl J Med Volume 357(21): November 22, 2007 the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial

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 I bars represent 95% confidence intervals. N Engl J Med DOI: /NEJMoa dalcetrapib, at a dose of 600 mg daily

N Engl J Med DOI: /NEJMoa dalcetrapib, at a dose of 600 mg daily

a Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands b 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 Dr G Kees Hovingh a,,,G Kees Hovingh a Prof John J P Kastelein a, b,John J P Kastelein ab Prof Sander J H van Deventer b, c,Sander J H van Deventer bc Patrick Round bPatrick Round b, d,d John Ford bJohn Ford b, d,d Danish Saleheen e Danish Saleheen e, Prof Daniel J Rader e,Daniel J Rader e Prof H Bryan Brewer f,H Bryan Brewer f Prof Philip J Barter gPhilip J Barter g Lancet Jun 2. pii: S (15) doi: /S (15)

Background Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid- modifying 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, parallel- group 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 NCT

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 [NCT ] and ACCELERATE [NCT ]) in which investigators are studying CETP inhibitors that do not possess the adverse off-target effects of torcetrapib. 34NCT NCT mmol/L mg/dL factor=

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. Figure 1: Trial profile

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)

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 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 B- containing 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: Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima- media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (N Engl J Med, 364 (2011), pp. 127–135)

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.

Published online June 3, Currently evacetrapib and anacetrapib are being tested in two large cardiovascular disease outcome studies (NCT and NCT ).

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 TA 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 ％、 ％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 は薬物として使うようになるのだろうか？！