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

2012年 12月 6日　 8:30-8:55８階　医局

Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; the ALTITUDE Investigators.Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. N Engl J Med. 2012 Nov 3. [Epub ahead of print]

Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012 Nov 29;367(22):2089-99. doi: 10.1056/NEJMoa1206797. Epub 2012 Nov 5.

P110

PI 3-kinase

P-Ser-

-Tyr-

P

-Tyr-

P

P-Ser-

AⅡ

AT-R

P-S

er-

-Tyr-P

-Tyr-P

-Tyr-P

αβ

InsulinReceptor

IRS-1

P85

Diagram of AⅡ signaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC

Folli et al: J. Clin. Invest. 100:2158–2169, 1997

Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA.: Effects of angiotensin-converting enzyme inhibitors, Ca2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes. 1995 Jun;44(6):665-71.

Insulin sensitivity after administration of ACE-I, CaCB, and alpha AB

Insulin-medicated glucose uptake, glucose oxidation, and non-oxidative glucose disposal during the euglycemic clamp before (open bars) and after (solid bars) 3 months of treatment with doxazossin.

Trial publicationfollow-

up, yeardrug

No. of newon-set of DM

No.(total)event

per 1000 person-years

controlNo. of new

on-set of DMNo.(total)

eventper 1000

person-years

antihypertensive drug

CAPPP 1999 6.1 ACEI 337 5183 10.7 β blocker 380 5230 11.9

STOP-2 1999 4.0 ACEI 93 1970 11.8β blockerDiuretic

CCB

97

95

1960

1935

12.4

12.1

HOPE 2001 4.5 ACEI 102 2837 8.0 Placebo 155 2883 11.9

ALLHAT 2002 4.0 ACE 119 4096 7.3 CCBDiuretic

154302

39546766

9.711.2

PEACE 2004 4.8 ACEI 335 3432 20.3 Placebo 399 3472 23.9

ANBP-2 2005 4.1 ACEI 138 2800 12.0 Diuretic 200 2826 17.3

AASK 2006 3.8 ACEI 45 410 28.9 β blockerCCB

7032

405202

45.541.7

*DREAM 2006 3.0 ACEI 449 2623 57.1 Placebo 489 2646 61.6

LIFE 2002 4.8 ARB 242 4020 12.5 β blocker 320 3979 16.8

*ALPINE 2003 1.0 ARB 1 196 5.1 Diuretic 8 196 40.8

CHARM 2003 3.1 ARB 163 2715 19.4 Placebo 202 2721 23.9

SCOPE 2003 3.7 ARB 93 2167 11.6 Placebo 115 2175 14.3

VALUE 2004 4.2 ARB 690 5087 32.3 CCB 845 5074 39.7

CASE-J 2007 3.2 ARB 38 1343 8.8 CCB 59 1342 13.7

*ProFESS 2008 2.5 ARB 125 7306 6.8 Placebo 151 7283 8.3

*ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 8576 9.2

*ONTARGET 2008 4.7 ARB+ACEI 323 8502 8.1 ACEI 366 8576 9.2

*TRANSCEND 2008 4.7 ARB 319 2954 26.4 Placebo 395 2972 28.8

*HIJ-CREATE 2009 4.2 ARB 7 645 2.6 Placebo 18 624 6.9

*Kyoto Heart 2009 3.27 ARB+X 58 1116 51.6 X 86 998 76.7

*NAVIGATOR 2010 6.5 ARB 1532 3748 62.9 Placebo 1722 3725 71.1

Matsuda M.; Endocrinology＆ Diabetology;26,1,35-41,2008.

Prevention of Diabetes Mellitus

Figure 1: The renin-angiotensin-aldosterone systemBlack arrows show stimulation and red arrows show inhibition. Dotted lines show alternative pathways mainly documented in experimental studies. β blockers, renin inhibitors, inhibitors of angiotensin-converting enzyme (ACE) and angiotensin II type-1 receptor blockers (ARB) reduce the activity of the renin-angiotensin system (RAS). AT-R=angiotensin receptor; EP=endopeptidases; EC=endothelial cells.

Lancet. 2006 Oct 21;368(9545):1449-56.

Lancet. 2006 Oct 21;368(9545):1449-56.

Figure 2: Chemical structure of orally active renin inhibitorsLancet. 2006 Oct 21;368(9545):1449-56.

Aliskiren is not metabolised by cytochrome P450, does not interfere with the action of warfarin, and shows no clinically relevant pharmacokinetic interactions with lovastatin, atenolol, celecoxib, or cimetidine.

Lancet. 2006 Oct 21;368(9545):1449-56.

Lancet. 2006 Oct 21;368(9545):1449-56.

the Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.), Faculty of Health Science, Aarhus University, Aarhus (H.-H.P.), and Steno Diabetes Center, Gentofte (F.P.) — all in Denmark; the Renal Division (B.M.B.) and Cardiovascular Division (S.D.S., A.S.D., M.A.P.), Brigham and Women’s Hospital and Harvard Medical School, Boston; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow ( J.J.V.M.), and Imperial College, London (N.C.) — both in the United Kingdom; the Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (D.Z.); the Department of Medicine and Clinical Epidemiology, University of Texas Health Science Center, San Antonio (S.M.H.); and Novartis Pharma, Basel, Switzerland (M.N., A.R., Z.X., P.B.).

N Engl J Med 2012. DOI: 10.1056/NEJMoa1208799

Background This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.

Methods In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting–enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.

The initial dose of aliskiren, 150 mg once daily, was increased to 300 mg once daily at 4 weeks after randomization if there were no safety concerns.

Eighty-two percent of patients in each group had had diabetes for at least 5 years

Solid line indicate aliskiren, dotted line placebo.

Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).

Conclusions The addition of aliskiren to standard therapy with renin–angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)

Message心血管および腎イベント発症リスクの高い2型糖尿病（ DM）患者 8561人を対象に、標準治療に加えたアリスキレンの効果を二重盲検試験で検討（ ALTITUDE試験）。心・腎イベント発生率はアリスキレン群で18.3％、プラセボ群で 17.1％（ハザード比 1.08）だった。高カリウム血症と血圧低下はアリスキレン群で有意に多かった。

ちなみにアリスキレンでは白髪が進みます！

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.)

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

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 MedVolume 357(21):2109-2122November 22, 2007

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

Figure 1: Trial profile

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

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 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.

the Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver (G.G.S.); Stockholm Heart Center, Stockholm and Linköping University, Linköping, Sweden (A.G.O.); F. Hoffmann–La Roche, Basel, Switzerland (M.A., J.B., D.K., H.M.); Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston (C.M.B.); Heart Research Institute, Sydney (P.J.B.); Saint Louis University, St. Louis (B.R.C.); Oslo University Hospital, Ulleval, Oslo (I.M.H.); Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, Toronto (L.A.L.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.L.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom ( J.J.V.M.); South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, SA, Australia (S.J.N.); Cedars–Sinai Heart Institute, Los Angeles (P.K.S.); Montreal Heart Institute, Université de Montréal, Montreal ( J.-C.T.); and Mayo Clinic, Rochester, MN (R.S.W.).

N Engl J Med 2012. DOI: 10.1056/NEJMoa1206797

Background In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes.

Methods We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation.

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.

Results At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons).

Conclusions In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.

(Funded by F. Hoffmann–La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.)

Message急性冠症候群（ ACS）を最近発症した患者1万 5871人を対象に、コレステリルエステル転送たんぱく（ CETP）阻害薬dalcetrapibの効果を第 3相試験で検討（ dal-OUTCOMES試験）。冠動脈疾患死、非致死性心筋梗塞などの複合評価項目の累積発生率は、プラセボ群8.0％、 dalcetrapib群 8.3％だった。

CETP欠損の日本人は HDL-Cが高値でも安全でないかもしれない。