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

2011 年 10 月 6 日　 8:30-8:55８階　医局

Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A; for the dal-PLAQUE Investigators.Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.Lancet. 2011 Sep 9. [Epub ahead of print]

Boggs DA, Rosenberg L, Cozier YC, Wise LA, Coogan PF, Ruiz-Narvaez EA, Palmer JR.General and abdominal obesity and risk of death among black women.N Engl J Med. 2011 Sep 8;365(10):901-8.

From Kawasaki Medical School Syllabus

N Engl J Med 2007;356:1304-16.

the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial

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.)

Original Article Effects of Torcetrapib in Patients at High Risk for

Coronary Events

Philip J. Barter, M.D., Ph.D., Mark Caulfield, M.D., M.B., B.S., Mats Eriksson, M.D., Ph.D., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Michel

Komajda, M.D., Jose Lopez-Sendon, M.D., Ph.D., Lori Mosca, M.D., M.P.H., Ph.D., Jean-Claude Tardif, M.D., David D. Waters, M.D., Charles L. Shear, Dr.P.H., James H. Revkin, M.D., Kevin A. Buhr, Ph.D., Marian R. Fisher, Ph.D., Alan R. Tall, M.B.,

B.S., Bryan Brewer, M.D., Ph.D., for the ILLUMINATE Investigators

N Engl J MedVolume 357(21):2109-2122

November 22, 2007

the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) 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

DOI:10.1016/S0140- 6736(11)61383-4

Translational and Molecular Imaging Institute and Department of Radiology, Mount Sinai School of Medicine, New York, NY, USA (Prof Z A Fayad PhD, V Mani PhD); Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA (Prof Z A Fayad, Prof V Fuster MD, M E Farkouh MD); George Institute, University of Sydney, Sydney, Australia (Prof M Woodward PhD); F Hoff mann-La Roche Ltd, Basel, Switzerland (D Kallend MB BS, M Abt PhD); Hoff mann-La Roche Inc, Nutley, New Jersey, NJ, USA (T Burgess MSc); Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (Prof V Fuster); Baylor College of Medicine, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA (Prof C M Ballantyne MD); Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA (Prof E A Stein MD); Montreal Heart Institute, Universite de Montreal, Montreal, QC, Canada (Prof J-C Tardif MD); Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (J H F Rudd MD); Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, Toronto, ON, Canada (M E Farkouh); and Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA (A Tawakol MD)

Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.

Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 1⁸F-fl uorodeoxyglucose (1⁸F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.

Figure 1: Trial profile

Table 1: Baseline demographic and clinical characteristics

Data are n (%) or mean (SD) unless otherwise stated. IQR=interquartle range. HDL-C=high-density lipoprotein-cholesterol. LDL-C=low-density lipoprotein-cholesterol. *Race or ethnic group was determined by the investigators. †Total number of patients with MRI vessel parameter measurements was 56 for placebo and 58 for dalcetrapib. Includes all patients with measurements available. ‡Total number of patients with PET/CT data was 56 for placebo and 57 for dalcetrapib. §Total number of patients with target-to-background ratio measurements was 56 for placebo and 56 for dalcetrapib.

Figure 2: Mean carotid total vessel area and percent increase in average carotid total vessel area (by MRI) (A) Raw mean data (90% CI) for total vessel area at baseline, 6, 12, and 24 months. Total vessel area increased after 24 months in the placebo group: model-derived, corrected average absolute change (24 months–baseline) was 5 ・ 72 mm2 (90% CI 3 ・ 30–8 ・14), p=0 ・ 0002. However, in the dalcetrapib group, total vessel area did not change in the same period (1 ・ 71 [–0 ・ 68 to 4 ・ 10], p=0 ・ 24). The average reduction in total vessel area on dalcetrapib (versus placebo), after correction of baseline, was –4 ・ 01 (–7 ・ 23 to –0 ・ 80), p=0 ・ 04. (B) Group mean data for percent change in total vessel area at 6, 12, and 24 months (relative to baseline). In patients assigned placebo, model-derived, corrected total vessel area increased in the initial 24 months: percent change total vessel area was 10 ・ 8 (90% CI 5 ・ 8–15 ・ 8), p=0 ・001. However, in patients assigned dalcetrapib, total vessel area did not increase in the same period (4 ・ 0% [0 ・ 6–7 ・ 3], p=0 ・ 16). The average percent change in total vessel area in the dalcetrapib group (versus placebo), after correction of baseline, was –7 ・ 1% (–12 ・ 8 to –1 ・ 3), p=0 ・ 04.

SE=standard error. TBR=target-to-background ratio. *p values (2-sided) are presented for the diff erence between groups. †For total vessel area, wall area, and normalised wall index, n=39 for placebo and n=44 for dalcetrapib at baseline and month 24; n=37 for placebo and n=44 for dalcetrapib at month 6; and n=40 for placebo and n=45 for dalcetrapib at month 12. ‡Baseline based on patients having 24 months (6 months) assessment for MRI (PET/CT). Comparisons between timepoints were restricted to patients with data available at both timepoints. §For most diseased segment mean of maximum TBR: n=52 for placebo and n=54 for dalcetrapib at baseline and month 6 and n=55 for placebo and n=56 for dalcetrapib at month 3.

Table 4: Absolute and percent change from baseline in MRI measurements of plaque burden after 6, 12, and 24 months (average carotid) and PET/CT measurements of inflammation after 3 and 6 months (index vessel)

Figure 3: Mean carotid MDS TBR and percent increase in average carotid most-diseased-segment TBR (by PET). MDS=most-diseased-segment. TBR=target-to-background ratio. (A) Raw mean data for average carotid MDS TBR at baseline, and at 3 and 6 months. In the placebo group, MDS TBR did not change after 6 months: model-derived, corrected average absolute change for MDS TBR (6 months–baseline) was –0 ・ 043 (90% CI –0 ・ 14 to 0 ・ 06), p=0 ・ 48. However, in the dalcetrapib group, MDS TBR decreased in the same period (–0 ・ 19 [–0 ・ 29 to –0 ・ 09], p=0 ・ 001). The average reduction in MDS TBR on dalcetrapib (versus placebo), after correction for baseline, was –0 ・ 150 (–0 ・ 29 to –0 ・ 01), p=0 ・ 08. (B) Group mean (90% CI) data for percent change in average carotid MDS TBR after 3 and 6 months (relative to baseline). In the placebo group, model-derived, corrected average MDS TBR did not change over the initial 6 months: percent change in MDS TBR was 3 ・ 24 (90% CI –2 ・ 18 to 8 ・ 66), p=0 ・71. However, in the dalcetrapib group, MDS TBR decreased in the same period (–7 ・26% [–12 ・ 50 to –2 ・ 02], p=0 ・ 003). The estimated average percent change in MDS TBR on dalcetrapib (versus placebo), after correction for baseline, was –7 ・ 35% (90% CI –13 ・ 49 to –0 ・ 76), p=0 ・ 07.

Figure 4: Association between HDL-C and arterial inflammation as measured by MDS TBR on PET/CT and arterial inflammation and atherosclerotic burden

HDL-C=high-density lipoprotein cholesterol. MDS=most-diseased-segment. TBR=target-to-background ratio. (A) Change in arterial inflammation (MDS TBR) over 6 months versus change in HDL-C over the same period grouped in tertiles (third tertile represents the greatest increase in HDL-C). (B) Early increases in arterial inflammation associated with subsequent increases in atherosclerotic burden. The change in carotid inflammation at 6 months was compared within subjects that were classified into tertiles according to the subsequent rate of change in total vessel area at 24 months.

Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was –4 ・ 01 mm2 (90% CI –7 ・ 23 to –0 ・ 80; nominal p=0 ・ 04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7 ・ 3 [90% CI –13 ・ 5 to –0 ・ 8]; nominal p=0 ・ 07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.

Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed

Message/Comments冠動脈疾患とその高リスク患者 130 人を対象に、コレステロールエステル輸送蛋白質（ CETP ）阻害薬 dalcetrapib の 24 カ月間投与の効果を二重盲検プラセボ対照試験で検証。画像診断法 MRI と PET/CT による評価の結果、本剤の動脈壁への有害な影響は見られず、また総血管面積拡大抑制を含む有益な効果が示唆された。

　 (1) 皮下脂肪厚計測 ( 上腕背側部，肩甲骨下部 )　 (2) ウエスト / ヒップ比　 (3) 腹部 CT スキャン

内臓脂肪型肥満／皮下脂肪型肥満　 (4) 電気インピーダンス法（ BIA)　 (5) dual-energy x-ray absorptiometry (DXA) 　 (6) 全身：比重測定，水分測定： BW = FFM(LBM) + FM

BW:body weight, LBM:lean body mass (73% 水 ), FFM:fat free mass, FM:fat mass,%FM ：脂肪含有率%FM = FM/BWx100 [%]

肥満 ( 脂肪蓄積 ) の質的評価

皮下脂肪を基準にして画像上で脂肪を決定する

赤：脂肪

全体の脂肪：皮下脂肪と同じ CT 値の範

囲

全体の非脂肪= 全体−全体の脂

肪

皮下脂肪を基準にして画像上で脂肪を決定する

赤：脂肪

皮下脂肪

皮下非脂肪

腹腔内脂肪

腹腔内非脂肪

腹腔内脂肪の差異

腹腔内脂肪の差異

V:174cm2, S:76cm2V:260cm2, S:310cm2

V:96cm2, S:209cm2V:81cm2, S:100cm2

体重が 73kg の男性。ある方法で体内の水分を測定したところ水分含量は 60% と測定された。この男性の脂肪含有率は何％か？

( 参考 )BW = LBM （ FFM ） + FM

BW:body weight, LBM:lean body mass (73% 水 ), FFM:fat free mass, FM:fat mass,%FM ：脂肪含有率%FM = FM/BWx100 [%]

肥満 ( 脂肪蓄積 ) の質的評価　例

FFM = LBM = 73 ｘ 0.6÷0.73 = 60[kg]FM = BW - FFM = 73 - 60 = 13[kg]%FM = FM / BW x 100 = 13 / 73 x 100 = 17.8[%]

肥満は体脂肪が過剰に蓄積された状態であり、日本人では BMI 25≧ を肥満とする。

肥満には単純性肥満（肥満の 95 ％以上）と症候性肥満とがある。症候性肥満は、視床下部疾患、内分泌疾患、薬物によるもの、遺伝性疾患を含む。

肥満に基づく健康障害を合併している場合、または合併が予測されるハイリスクな肥満は「肥満症」と呼び、治療が必要な疾患として扱う。

ハイリスク肥満とは上半身肥満（腹囲が男性≧ 85cm 、女性≧ 90cm ）または内臓脂肪型肥満（内臓脂肪面積≧ 100cm2 ）のことであり、上半身肥満＝内臓脂肪型肥満である。

肥満症は「脂肪細胞の質的異常によるもの」（ BMI 25 ～ 30 ）と「脂肪細胞の量的異常によるもの」（ BMI 30≧ ）に大別される。

肥満と肥満症の診断 BMI

肥満 非肥満

肥満による 健康障害

スクリーニング検査 (ウエスト周囲系計測)

内臓脂肪

型

皮下脂肪

型

肥満症 肥満症 肥満 肥満

腹部 CT検査 (内臓脂肪面積)

25以上 25未満

なし

あり

男性: 85 cm 以上，女性 90 cm 以上 男性: 85 cm 未満，女性 90 cm 未満

100 cm2 未満

(日本肥満学会肥満症診断基準検討委員会作成資料より)

100 cm2 以上

0

50

100

150

200

250

300

15 20 25 30 35 40

２型糖尿病患者の BMI と内臓脂肪面積

n (M/F) 429(M/F 244/185)年齢　 ( 歳 ) 61.0±13.1罹病期間 ( 年 ) 11.9±9.7BMI (kg/m2) 24.6±4.6HbA1c (%) 9.1±2.2FPG (mg/dl) 180±76TG (mg/dl) 166±85 T-chol (mg/dl) 208±54HDL-chol (mg/dl) 48±16収縮期血圧（ mmHg ）

133±18 　拡張期血圧（ mmHg ）

75±9

内臓脂肪面積

(cm2)

BMI(kg/m2)

male

female

male

femalep<0.0001r=0.60

内蔵脂肪面積が100cm2 以上BMI 25 kg/m≧ 2

男性患者の 89% 女性患者の 88%

BMI ＜ 25 kg/m2

男性患者の 50% 女性患者の 32% 川崎医科大学附属病院糖尿病内分泌内科　入院患者

the Slone Epidemiology Center at Boston University, Boston.

N Engl J Med 2011;365:901-8.

Background Recent pooled analyses show an increased risk of death with increasing levels of the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 25.0 or higher in populations of European ancestry, a weaker association among East Asians, and no association of an increased BMI with an increased risk of death among South Asians. The limited data available on blacks indicate that the risk of death is increased only at very high levels of BMI (≥35.0).

Methods We prospectively assessed the relation of both BMI and waist circumference to the risk of death among 51,695 black women with no history of cancer or cardiovascular disease who were 21 to 69 years of age at study enrollment. Our analysis was based on follow-up data from 1995 through 2008 in the Black Women’s Health Study. Multivariable proportional-hazards models were used to estimate hazard ratios and 95% confidence intervals.

Hazard ratios for death from any cause, with 95% confidence intervals, are shown for BMI (the weight in kilograms divided by the square of the height in meters) (Panel A) and waist circumference (Panel B). Vertical lines indicate 95% confidence intervals. To convert inches to centimeters, multiply by 2.54. The analyses were adjusted for age, questionnaire cycle, educational level, marital status, vigorous physical activity, and alcohol intake.

Figure 1. Estimated Hazard Ratios for Death from Any Cause According to Body-Mass Index (BMI) and Waist Circumference among Women Who Never Smoked.

Hazard ratios for death from any cause, with 95% confidence intervals, are shown for BMI (the weight in kilograms divided by the square of the height in meters) (Panel A) and waist circumference (Panel B). Vertical lines indicate 95% confidence intervals. To convert inches to centimeters, multiply by 2.54. The analyses were adjusted for age, questionnaire cycle, educational level, marital status, vigorous physical activity, and alcohol intake.

Figure 1. Estimated Hazard Ratios for Death from Any Cause According to Body-Mass Index (BMI) and Waist Circumference among Women Who Never Smoked.

* The BMI is the weight in kilograms divided by the square of the height in meters. To convert inches to centimeters, multiply by 2.54. † All hazard ratios were adjusted for age, questionnaire cycle, level of education, marital status, vigorous physical activity, and alcohol intake. Hazard ratios for waist circumference were additionally adjusted for BMI. CI denotes confidence interval.

Results Of 1773 deaths identified during follow-up, 770 occurred among 33,916 women who had never smoked. Among nonsmokers, the risk of death was lowest for a BMI of 20.0 to 24.9. For a BMI above this range, the risk of death increased as the BMI increased. With a BMI of 22.5 to 24.9 as the reference category, multivariable-adjusted hazard ratios were 1.12 (95% confidence interval [CI], 0.87 to 1.44) for a BMI of 25.0 to 27.4, 1.31 (95% CI, 1.01 to 1.72) for a BMI of 27.5 to 29.9, 1.27 (95% CI, 0.99 to 1.64) for a BMI of 30.0 to 34.9, 1.51 (95% CI, 1.13 to 2.02) for a BMI of 35.0 to 39.9, and 2.19 (95% CI, 1.62 to 2.95) for a BMI of 40.0 to 49.9 (P<0.001 for trend). A large waist circumference was associated with an increased risk of death from any cause among women with a BMI of less than 30.0.

Conclusions The risk of death from any cause among black women increased with an increasing BMI of 25.0 or higher, which is similar to the pattern observed among whites. Waist circumference appeared to be associated with an increased risk of death only among nonobese women. (Funded by the National Cancer Institute.)

Message/Comments癌および心血管疾患の既往のない 21-69 歳の黒人女性 5万 1695 人を対象に、体格指数（ BMI ）および腹囲の両者と死亡の関連を前向きに評価。 BMI25.0 以上では、 BMI 値の上昇に伴い全死因死亡リスクの上昇が見られ、白人で見られる傾向と類似していた。 BMI30.0未満では、腹囲が大きいほど全死因死亡リスクが上昇した。