Journal Club

1. Journal Club Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011 Mar 10;364(10):907-17. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011 Mar 3;364(9):829-41. 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3月17日8:30-8:55 ８階　医局

2. Randomized Olmesartan and DiabetesMicroalbuminuriaPrevention (ROADMAP) study From the Department of Nephrology and Hypertension, Hannover Medical School, Hannover (H.H., J.M.); the Department of Nephrology, University of Heidelberg, Heidelberg (E.R.); and the Department of Nephrology, Heinrich- Heine-University Düsseldorf (L.C.R.) — all in Germany; the Department of Clinical Medicine, Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai (S.I.); and the Department of Endocrinology and Diabetes, Saitama Medical School, Iruma, Saitama (S.K.) — both in Japan; the Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo ( J.L.I.); the Institute of Cardiology, Department of Hypertension, Warsaw, Poland (A.J.); Hospital Lapeyronie, Montpellier, France (A.M.); the Department of Nephrology and Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands (T.J.R.); the Division of Hypertension, Hospital 12 de Octubre, Madrid (L.M.R.); and King’s College London School of Medicine, Guy’s Hospital, London (G.V.). N Engl J Med 2011;364:829-41.

3. Background Microalbuminuriais an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria.

4. Methods In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting–enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points.

6. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of more than 35 in women or more than 25 in men. Any single elevation in the urinary albumin-to-creatinine ratio required confirmation by at least one additional positive result from two separate tests of urine samples performed within 2 weeks after the initial test. If microalbuminuria was confirmed, the patient was assigned to an open-label phase in which he or she received olmesartan at a dose of 40 mg daily

8. 163mg/dl

9. 0.88mg/dl 201mg/dl 120mg/dl 46mg/dl 186mg/dl

12. Figure 2. Event Rate of the Primary End Point in the Two Study Groups, According to Subgroups. The restricted full analysis set was used for this analysis. This set comprises all patients from the full analysis set (i.e., patients in the intention-to-treat population) with the exception of patients who had confirmed microalbuminuria at baseline (visit 1) and patients without any follow-up measurements of microalbuminuria that could be evaluated. All the results are based on adjudicated end points. The primary efficacy end point (the time to the onset of microalbuminuria) was analyzed with the use of a Cox proportional-hazards regression model, with study treatment as the fixed effect and the log10-transformed baseline urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) as the covariate. Owing to a prespecified interim analysis performed by the data and safety monitoring board, the significance level for the final confirmatory analysis was adjusted to 0.049, resulting in a twosided 95.1% confidence interval. For all other analyses, two-sided 95% confidence intervals are shown. The sensitivity analyses were performed by extending the main model by an additional covariate. The exploratory subgroup analyses were performed with the use of the main model, with the exception of the subgroup analysis of urinary albumin-to-creatinine ratio. In this last analysis, the Cox proportionalhazards regression model with study treatment as the fixed effect was used.

16. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET; NCT00153101)24 and the International Verapamil SR Trandolapril Study (INVEST; NCT00133692),25 an increase in the rate of death from cardiovascular causes was observed among patients with known coronary heart disease if the systolic blood pressure was below 120 mm Hg during the time the patient was receiving therapy with ACE inhibitors or ARBs (in ONTARGET) or calcium-channel blockers or beta-blockers (in INVEST); thus, any adverse effect appears to be related more closely to the achieved blood pressure than the class of drug that was used. The concern about potential overtreatment is reflected in the guidelines published by the European Society of Hypertension, which state that physicians should avoid lowering blood pressure excessively (i.e., to values below 120/70 mm Hg) in persons with underlying cardiovascular disease.

17. Results The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P = 0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events — 81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P = 0.37) — but a greater number had fatal cardiovascular events — 15 patients (0.7%) as compared with 3 patients (0.1%) (P = 0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P = 0.02).

18. Conclusions Olmesartanwas associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.)

19. Message/Comments Olmesartanは糖尿病患者の微量アルブミン尿減少に効果があった。（血圧で補正すると有意差はないようなのだが） しかし、心血管障害の進んでいる場合には血圧の下げすぎも問題かもしれない。 2型糖尿病患者4447人を対象に、オルメサルタンの微量アルブミン尿抑制効果を無作為化二重盲検プラセボ対照試験で検討。微量アルブミン尿が発現した患者の割合は、オルメサルタン群8.2％、プラセボ群9.8％だった（ハザード比0.77）。また、オルメサルタン群では微量アルブミン尿発現までの時間が23％延長した。

21. SreenivasaRaoKondapallySeshasai, M.D., Stephen Kaptoge, Ph.D., Alexander Thompson, Ph.D., Emanuele Di Angelantonio, M.D., Pei Gao, Ph.D., and NadeemSarwar, Ph.D., University of Cambridge, Cambridge, United Kingdom; Peter H. Whincup, F.R.C.P., St. George’s University of London, London; Kenneth J. Mukamal, M.D., Harvard University, Boston; Richard F. Gillum, M.D., Centers for Disease Control and Prevention, Atlanta; IngarHolme, Ph.D., Ulleval University Hospital, Oslo; IngerNjolstad, M.D., University of Tromso, Tromso, Norway; Astrid Fletcher, Ph.D., London School of Hygiene and Tropical Medicine, London; Peter Nilsson, M.D., Lund University, Lund, Sweden; Sarah Lewington, D.Phil., and Rory Collins, F.Med.Sci., University of Oxford, Oxford, United Kingdom; VilmundurGudnason, M.D., Icelandic Heart Association and the University of Iceland, Reykjavik; Simon G. Thompson, D.Sc., Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; NaveedSattar, F.R.C.P., University of Glasgow, Glasgow, United Kingdom; Elizabeth Selvin, Ph.D., Johns Hopkins University, Baltimore; Frank B. Hu, M.D., Harvard University, Boston; and John Danesh, F.R.C.P., University of Cambridge, Cambridge, United Kingdom N Engl J Med 2011;364:829-41.

22. Background The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

23. Methods We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

26. * Plus–minus values are means ±SD. Data are shown for the 715,061 of the 820,900 participants without known preexisting cardiovascular disease at baseline and for whom there was complete information about age, sex, smoking status (current smoker vs. any other status) and body-mass index. Information about the other characteristics in the table was not available for all participants. Diabetes was ascertained on the basis of self-report, medication use, fasting glucose level of 126 mg per deciliter (7.0 mmol per liter) or more, or a combination of these. To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. To convert values for triglycerides to milligrams per deciliter, divide by 0.01129. To convert values for fibrinogen to grams per deciliter, divide by 29.41. To convert values for insulin to microunits per milliliter, divide by 6.945. To convert values for fasting glucose to milligrams per deciliter, divide by 0.05551. HDL denotes high-density lipoprotein. † Physical activity was defined as any form of aerobic or anaerobic exercise. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Estimated glomerular filtration rate was calculated with the use of the Modification of Diet in Renal Disease equation.

29. Figure 1. Hazard Ratios for Death from Cancer and from Noncancer, Nonvascular Causes among Participants with Diabetes as Compared with Those without Diabetes at Baseline. Panel A shows hazard ratios for deaths from cancer, and Panel B shows hazard ratios for deaths from noncancer, nonvascular causes. With the exception of the classifications “site unspecified or other” in Panel A and “other noncancer, nonvascular deaths” in Panel B, causes of death are presented in descending order according to their estimated hazard ratios. All analyses were stratified on the basis of study, sex, and trial group (where applicable) and adjusted for baseline age, smoking status (current smoker vs. any other status), and body-mass index. There was evidence of heterogeneity in hazard ratios among cancer sites and among the noncancer, nonvascular causes of death (P<0.001 for both comparisons). Participants with known preexisting cardiovascular disease at baseline were excluded from all analyses. The sizes of the data markers are proportional to the inverse of the variance of the loge hazard ratios. In Panel A, risk estimates for cancer of the colorectum were broadly similar to those for cancer at subsites (i.e., colon cancer vs. cancer of the rectosigmoid and anus). In Panel B, death from endocrine disorders does not include death coded as being due to diabetes. Other noncancer, nonvascular deaths are those that could not be attributed to a major organ or system. COPD denotes chronic obstructive pulmonary disease.

30. Figure 1. Hazard Ratios for Death from Cancer and from Noncancer, Nonvascular Causes among Participants with Diabetes as Compared with Those without Diabetes at Baseline. Panel A shows hazard ratios for deaths from cancer, and Panel B shows hazard ratios for deaths from noncancer, nonvascular causes. With the exception of the classifications “site unspecified or other” in Panel A and “other noncancer, nonvascular deaths” in Panel B, causes of death are presented in descending order according to their estimated hazard ratios. All analyses were stratified on the basis of study, sex, and trial group (where applicable) and adjusted for baseline age, smoking status (current smoker vs. any other status), and body-mass index. There was evidence of heterogeneity in hazard ratios among cancer sites and among the noncancer, nonvascular causes of death (P<0.001 for both comparisons). Participants with known preexisting cardiovascular disease at baseline were excluded from all analyses. The sizes of the data markers are proportional to the inverse of the variance of the loge hazard ratios. In Panel A, risk estimates for cancer of the colorectum were broadly similar to those for cancer at subsites (i.e., colon cancer vs. cancer of the rectosigmoid and anus). In Panel B, death from endocrine disorders does not include death coded as being due to diabetes. Other noncancer, nonvascular deaths are those that could not be attributed to a major organ or system. COPD denotes chronic obstructive pulmonary disease.

31. 5mM= 90mg/dl

32. Figure 3. Diabetes and Survival, According to Sex and Diabetes Status. Panel A shows estimated survival curves that were plotted by applying hazard ratios for death from any cause (specific for sex and age at risk) from the present analyses to mortality data for the European Union in 2000. Panel B shows the estimated numbers of years of life lost owing to diabetes. Participants with known preexisting cardiovascular disease at baseline were excluded from both analyses.

33. Results After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional selfharm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

34. Conclusions In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional selfharm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)

35. Message/Comments 糖尿病になると２～４倍脳梗塞や心筋梗塞が増加すると言われている。癌ではリスクが増えるもの（肝、膵など）と減るもの（前立腺）もある。この解析では全死亡では80%増だった。 前向き試験97件中の死亡12万3205例を対象に、糖尿病と死因別死亡リスクのハザード比を算出。糖尿病患者の死亡ハザード比は、全死因1.80、癌1.25、血管疾患2.32、その他1.73で、糖尿病により複数の癌・感染症・外的要因・自傷・変性疾患による死亡リスクが上昇し、死亡との関連は空腹時血糖100mg/dL超で見られた。