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 2009 年 12 月 17 日 8:30-8:55 ８階 医局 Kaku K, Daida H, Kashiwagi A, Yamashina A, Yamazaki T, Momomura S, Iwase T, Yamasaki Y, Nagatsuka K, Kitagawa K, Kawamori R. Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. Curr Med Res Opin. 2009 Dec;25(12):2925-32. Redelmeier DA, Kenshole AB, Ray JG. Motor vehicle crashes in diabetic patients with tight glycemic control: a population-based case control analysis. PLoS Med. 2009 Dec;6(12):e1000192. Epub 2009 Dec 8.

2. ADOPT N Engl J Med 2006;355:2427-43. A Diabetes Outcome Progression Trial

3. ADOPT N Engl J Med 2006;355:2427-43. A Diabetes Outcome Progression Trial

4. 長期間の血糖コントロール DeFronzo AR.ADA 68 th Scientific Session,2008.San Francisco SU 薬による長期血糖コントロール TZD による長期血糖コントロール -2 0 1 012345610 -2 0 1 012345610 HbA1c の変化率 期間（年） （％） ～～～～ ～～～～ Hanefeld (n=250) Tan (n=297) UKPDS (n=1573) CHICAGO (n=230) ADOPT (n=1441) PERISCOPE (n=181) Hanefeld (n=250) Tan (n=270) CHICAGO (n=232) ADOPT (n=1454) PERISCOPE (n=178) グリメピリド グリブリド グリクラジ ド ピオグリタゾン ロシグリタゾン ピオグリタゾン

5. HbA 1C 変化量の推移 観察・投与期間 195 211 276 256 290 278 従来治療群 11 ピオグリタゾン投与 群 ** p<0.01 （群 間） mean -0.5 0.0 0.5 （週） 01224364860728496108120132144156168180192 ** 加来浩平（川崎医科大）：第 51 回日本糖尿病学会年次学術集会（ 2008.5 東 京） ピオグリタゾン投与群 従来治療群 PROBE （%）（%） アクトス群では長期にわたり HbA 1C が低下して いる

6. Kohei Kaku Diabetes and Endocrine Division, Department of Medicine, Kawasaki Medical School, Okayama, Japan Hiroyuki Daida Department of Cardiovascular Medicine, Juntendo University School of Medicine, Tokyo, Japan Atsunori Kashiwagi Department of Medicine, Shiga University of Medical Science, Shiga, Japan Akira Yamashina Second Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan Tsutomu Yamazaki Department of Clinical Epidemiology & Systems, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Shin-ichi Momomura Saitama Medical Center, Jichi Medical University, Saitama, Japan Takashi Iwase Iwase Internal Medicine Cardiology Clinic, Tokyo, Japan Yoshimitsu Yamasaki Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan Kazuyuki Nagatsuka Cerebrovascular Division, Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan Kazuo Kitagawa Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan Ryuzo Kawamori Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan

7. Background and Aim To evaluate the efficacy of pioglitazone for the prevention of macrovascular outcomes in Japanese patients with type 2 diabetes, without a recent history of macrovascular morbidity.

8. Method This 2.5–4 year, prospective, randomized, open-label, blinded-endpoint study was conducted in 20 Japanese centers. Patients received pioglitazone ± other oral glucose- lowering drugs (excluding another thiazolidinedione) [n = 293] or oral glucose- lowering drugs excluding thiazolidinediones (n = 294). Treatment was adjusted to achieve HbA1c<6.5%. The primary endpoint was the time to onset of a macrovascular event.

15. Adverse events that occurred in at least 10% of the pioglitazone group and at a higher incidence than in the control group included peripheral (lower limb) edema (16.4% vs 4.1%), generalized edema (15.7% vs 1.0%) and hypoglycemia (15.7% vs 12.9%). The incidence of diabetic nephropathy was lower in the pioglitazone group than in the control group (8.9% vs 12.9%). Bone fractures occurred in 18 patients (6.1%) in each of the pioglitazone and control groups. Three patients in the pioglitazone group died (cerebral infarction, acute MI, acute cardiac failure) as did one in the control group (cardiogenic cause but not specified further). None of the deaths in the pioglitazone group were considered to be related to treatment.

16. Results Pioglitazone delayed the time to onset of macrovascular events and was associated with a lower cumulative incidence of such events (3.56% vs. 4.49% for controls). Neither finding achieved statistical significance. This was likely because of the type of patient included in the study (i.e. no recent history of cardiovascular events) and the high use of concomitant anti- diabetic agents. Reductions in HbA1c, fasting blood glucose and fasting blood insulin levels, and an increase in HDL-C were significantly greater with pioglitazone throughout most of the study ( p<.05). Fewer patients in the pioglitazone group commenced permanent treatment with insulin (3.3% vs. 13.7% in the control group). Adverse events were reported by 97.6% of the pioglitazone group and 96.9% of the control group (serious adverse events, including deaths, were 20.1 vs. 22.2%, respectively). The only notable difference between the two groups was a higher incidence of edema in the pioglitazone group. The main limitation of this study was that too few patients were included to identify statistically significant differences in the primary endpoint.

17. Conclusion Pioglitazone produced good glycemic control in Japanese patients with type 2 diabetes, and significantly fewer patients treated with pioglitazone needed long- term insulin therapy. These changes were associated with a trend towards delayed onset of macrovascular events.

18. Message ピオグリタゾンと ピオグリタゾンを含まない 処方の比較だと、 A1C が違うので、何を見てい るのか？ インスリン導入で大きな差があることがわかる。 ともかく、 PROBE 研究は症例が少なすぎる。

20. PLoS Med. 2009 Dec;6(12):e1000192. Epub 2009 Dec 8.

21. Background Complications from diabetes mellitus can compromise a driver’s ability to safely operate a motor vehicle, yet little is known about whether euglycemia predicts normal driving risks among adults with diabetes. We studied the association between glycosylated hemoglobin (HbA1c) and the risk of a motor vehicle crash using a population- based case control analysis.

22. Method We identified consecutive drivers reported to vehicle licensing authorities between January 1, 2005 to January 1, 2007 who had a diagnosis of diabetes mellitus and a HbA1c documented. The risk of a crash was calculated taking into account potential confounders including blood glucose monitoring, complications, and treatments.

24. Figure 1. Glycemic control and risk of a motor vehicle crash.

25. Figure 2. Crash risk in different subgroups. Each analysis examines correlation of lower HbA1c levels with higher risk of a crash. Results expressed as odds ratio (solid circle) and 95% confidence interval (horizontal line) per 1% point decrease in HbA1c. Analyses of chronic complication subgroups exclude patients reporting corresponding symptom. Results for full cohort appear at bottom and show an odds ratio of 1.26 with 95% confidence interval 1.03–1.54.

26. Results A total of 57 patients were involved in a crash and 738 were not involved in a crash. The mean HbA1c was lower for those in a crash than controls (7.4% versus 7.9%, unpaired t-test, p = 0.019), equal to a 26% increase in the relative risk of a crash for each 1% reduction in HbA1c (odds ratio = 1.26, 95% confidence interval 1.03–1.54). The trend was evident across the range of HbA1c values and persisted after adjustment for measured confounders (odds ratio = 1.25, 95% confidence interval 1.02–1.55). The two other significant risk factors for a crash were a history of severe hypoglycemia requiring outside assistance (odds ratio = 4.07, 95% confidence interval 2.35–7.04) and later age at diabetes diagnosis (odds ratio per decade = 1.29, 95% confidence interval 1.07–1.57).

27. Conclusion In this selected population, tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.

28. Message 血糖管理をする場合に インスリンを処方している人には 車を運転する。 低血糖が自覚可能。 ブドウ糖で対処可能。 カルテに書くようにしましょう！