1. 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 2010 年３月 11 日 8:30-8:55 ８階 医局 Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J, Brancati FL. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010 Mar 4;362(9):800-11. Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K, Velazquez EJ, Staikos-Byrne L, Kelly RY, Shi V, Chiang YT, Weber MA; for the ACCOMPLISH Trial investigators. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010 Feb 17. [Epub ahead of print]

3. From the Department of Epidemiology and the Welch Center for Prevention, Epidemiology, and Clinical Research (E.S., K.M., J.C., F.L.B.), and the Department of Biostatistics (H.Z., J.C.), Johns Hopkins Bloomberg School of Public Health; and the Division of General Internal Medicine, Department of Medicine, Johns Hopkins University (E.S., J.C., F.L.B.) — all in Baltimore; the Department of Laboratory Medicine and Pathology, Medical School (M.W.S.), and the Division of Epidemiology and Community Health ( J.P.), University of Minnesota, Minneapolis; and the Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (L.W.). N Engl J Med 2010;362:800-11.

4. Background Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose.

5. Method We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990–1992 period) of the Atherosclerosis Risk in Communities (ARIC) study.

7. * Plus–minus values are means ±SD. To convert the values for fasting glucose to millimoles per liter, multiply by 0.05551. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein. † The 699 persons (6.3%) with a fasting glucose level of 126 mg per deciliter (7 mmol per liter) or higher at baseline (8, 56, 112, 185, and 338 persons with a glycated hemoglobin category of <5.0%, 5.0 to <5.5%, 5.5 to <6.0%, 6.0 to <6.5%, and ≥6.5%, respectively) were excluded from the visit-based analysis examining the risk of diabetes with the use of fasting glucose levels during the first 6 years of follow-up but were included in the interview-based analysis of diagnosed diabetes during the 15 years of follow-up. ‡ Race was self-reported. § The body-mass index is the weight in kilograms divided by the square of the height in meters. ¶ Baecke’s physical-activity index is measured with the use of a questionnaire about leisure-time sports activities developed by Baecke et al. 20 The scale ranges from 1 to 4, with a score of 4 indicating the greatest activity.

9. Model 1a was adjusted for age, sex, and race (black or white). Model 2a was adjusted for the variables in model 1a plus low-density and high-density lipoprotein cholesterol levels, log-transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family history of diabetes (yes or no), education (less than high school, high school or equivalent, or college or above), alcohol use (currently, formerly, or never), physical-activity index score, and smoking status (current smoker, former smoker, or never smoked). Model 3a was adjusted for all variables in model 2a plus the baseline fasting glucose level. Model discrimination was assessed with the use of Harrell’s C statistic. Model assessment: C = 0.5: not good, C > 0.8: good, C = 1: perfect.

10. Self-report (Diagnosis or Use of medication)

13. Figure 2. Adjusted Hazard Ratios for Self-Reported Diagnosed Diabetes and Coronary Heart Disease, Ischemic Stroke, and Death from Any Cause, According to the Baseline Glycated Hemoglobin Value. The hazard ratios are per each absolute increase of 1 percentage point in the glycated hemoglobin value at baseline. The shaded area is the 95% confidence interval from the restricted-cubic-spline model. Both models are centered at the median (5.4%) and the plot was truncated at the 2.5th and 97.5th percentiles of glycated hemoglobin (4.7% and 6.8%, respectively). The hazard ratios were adjusted for age, sex, and race (black or white), low- density and high-density cholesterol levels, log-transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family history of diabetes (yes or no), education (less than high school, high school or equivalent, or college or above), alcohol use (currently, formerly, or never), physical-activity index score, and smoking status (current smoker, former smoker, or never smoked). The data are shown on a natural-log scale.

17. Results The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable- adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose.

18. Conclusion In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.

19. Message A1C を糖尿病の診断基準とすることを支持す るデータ： 糖尿病はともかく， FPG より虚血性心臓疾患 や脳卒中や死亡についても予後が A1C が 6.5% 以上だと悪くなる。 ( あと 黒人では A1C の影響が少ないらしい ) 日本は血糖を診断基準に入れているけれど， A1C だけでもよいかもしれない？

21. ACEI/ARB + CaB ACEI/ARB + 利尿薬 どちらを選びますか？

22. Hypertensive Diseases Unit, Department of Medicine, University of Chicago-Pritzker School of Medicine, Chicago, IL, USA (Prof G L Bakris MD); Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece (P A Sarafi dis MD); University of Maryland School of Medicine, Baltimore, MD, USA (Prof M R Weir MD); Sahlgrenska University Hospital, Gothenburg, Sweden (Prof B Dahlof MD); University of Michigan Health System, Ann Arbor, MI, USA (Prof B Pitt MD, K Jamerson MD); Duke University School of Medicine, Durham, NC, USA (E J Velazquez MD); Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (L Staikos-Byrne PhD, R Y Kelly MS, V Shi MD, Y-T Chiang PhD); and SUNY Downstate Medical College, Brooklyn, NY, USA (Prof M A Weber MD) Published Online February 18, 2010 DOI:10.1016/S0140- 6736(09)62100-0

23. Objective The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease.

24. Method ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12 ・ 5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1 ・ 73 m 2 or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950.

25. Patients were randomly assigned to receive either a single pill combination of benazepril (20 mg) plus amlodipine (5 mg) or a combination of benazepril (20 mg) plus hydrochlorothiazide (12 ・ 5 mg) daily, without washout of previous medications. 1 month after randomisation, the benazepril component in both groups was force titrated to 40 mg. 2 months after randomisation, investigators could titrate doses of either drug to the maximum, if needed, to achieve a target blood pressure of less than 140/90 mm Hg (or <130/80 mm Hg for patients with diabetes or chronic kidney disease). 3 months after randomisation and until the end of the trial, add-on antihypertensive agents, consisting of β blockers, α blockers, clonidine, and spironolactone, were allowed. β blockers were recommended as a second agent in both groups to achieve blood pressure targets. Once-daily loop diuretics could be given for volume management. After the initial 3-month titration period, patients returned at 6 months and then at 6-month intervals until the end of the trial.12 Patient follow-up for assessment of endpoints continued until the end of the trial, even if study medication had been permanently discontinued.

26. Endpoints The primary endpoint of the main ACCOMPLISH trial was time to first event of composite cardiovascular morbidity and mortality (sudden cardiac death, myocardial infarction, stroke, coronary intervention, congestive heart failure, or other cardiovascular causes). The prespecified, intention-to-treat, chronic kidney disease endpoint was time to first event of doubling of serum creatinine concentration or end- stage renal disease, defined as eGFR less than 15 mL/min/1 ・ 73 m 2 or need for chronic dialysis. This endpoint was defined before the data and safety monitoring board recommended early termination of the trial. (Because of this early termination, the follow-up period in this trial is about 1 year shorter than that in previous trials reporting chronic kidney disease outcomes. ) Other endpoints were progression of chronic kidney disease plus death (all-cause or cardiovascular), change in albuminuria, and change in eGFR. Additionally, progression of chronic kidney disease was assessed in the subset of patients with more advanced chronic kidney disease at baseline.

27. Patients with chronic kidney disease had a similar rate of diabetes to those without the disease (58 ・ 9% vs 60 ・ 5%; p=0 ・ 302). 60% ： diabetes mellitus

33. Results The trial was terminated early (mean follow-up 2 ・ 9 years [SD 0 ・ 4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2 ・ 0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3 ・ 7%) in the benazepril plus hydrochlorothiazide group (HR 0 ・ 52, 0 ・ 41–0 ・ 65, p<0 ・ 0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33 ・ 7%; benazepril plus hydrochlorothiazide, 85 of 532, 16 ・ 0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.

34. Conclusion Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent.

35. Message ACEI と Ca 拮抗薬が ACEI と利尿薬より腎臓に対 してよかった という結果。 ARB でもおそらく Ca 拮抗薬 との併用から？ 一応 糖尿病があると ABCD 研究では 差はな し。 また， GUARD 研究では 利尿薬の方が微量ア ルブミンは減少効果はよいとされた。

36. CARTER 試験概要 デザイン 対象患者 方法 : 多施設無作為化オープン比較試験 :1. 尿蛋白 300mg/gCr 以上 2. 血清クレアチニン 3.0mg/dL 以下 3. 血圧 130/85mmHg 以上 4.2 ～ 3 ヵ月間 RAS 阻害薬で治療中 : ●●●●●● エンドポイ ント : 尿蛋白 / クレアチニン比の変化 ● 目標血圧 : 130/85mmHg 未満 ※シルニジピン又はアムロジピンにて降圧目標値に到達しない場合は、 RAS 阻害薬又は Ca 拮抗薬以外の第三の薬剤を追加投与。 前観察期間 治療期間 1 年間 339 例 179 例 RAS 阻害薬 + シルニジピン （ 5-20mg/ 日） 160 例 RAS 阻害薬 + アムロジピン （ 2.5-7.5mg/ 日） RAS 阻害薬 ● Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal Disease Fujita T, et al. Kidney Int 2007; 72: 1543-9

37. 0 500 1000 1500 2000 2500 投与前 13612  観察期間（月） 160 179 147 168 142 168 137 160 130 146 ｱﾑﾛｼﾞﾋﾟﾝ群 ｼﾙﾆｼﾞﾋﾟﾝ群 観察期間（月） アムロジピン群シルニジピン群 -25 -20 -15 -10 -5 0 5 10 15 20 13612  ††  ： p<0.05 vs シルニジピン群  ： p<0.05 ， ： p<0.01 vs シルニジピン群 † 尿蛋白・クレアチニン比（ mg/gCr ） 変化率 （ % ） Fujita T, et al. Kidney Int 2007; 72: 1543-9 試験期間中の尿蛋白／ Cr 比の変化