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 2014 年 10 月 2 日 8:30-8:55 ８階 医局 Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, Arima H, Monaghan H, Joshi R, Colagiuri S, Cooper ME, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Lisheng L, Mancia G, Marre M, Matthews DR, Mogensen CE, Perkovic V, Poulter N, Rodgers A, Williams B, MacMahon S, Patel A, Woodward M; the ADVANCE-ON Collaborative Group. Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes. N Engl J Med. 2014 Sep 19. DOI: 10.1056/NEJMoa1407963 Ikramuddin S, Blackstone RP, Brancatisano A, Toouli J, Shah SN, Wolfe BM, Fujioka K, Maher JW, Swain J, Que FG, Morton JM, Leslie DB, Brancatisano R, Kow L, O'Rourke RW, Deveney C, Takata M, Miller CJ, Knudson MB, Tweden KS, Shikora SA, Sarr MG, Billington CJ. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA. 2014 Sep 3;312(9):915-22. doi: 10.1001/jama.2014.10540.

2. ACCORD HbA 1C の推移 主要評価項目 観察期間（年） 543210 5,109 5,119 4,774 4,768 4,588 4,585 3,186 3,165 1,744 1,706 455 476 436 471 通常療法 強化療法 中央値 バーは四分位範囲 6 症例数 通常療法 強化療法 HbA 1C （ % ） 8.0 9.0 7.0 9.0 0.0 6.0 8.5 7.5 9.5 6.5 良い 症例数 強化療法 通常療法 累積イベント発症率（ % ） 5 25 15 0 10 20 良い 観察期間（年） 543210 5,128 5,123 4,843 4,827 4,390 4,262 2,839 2,702 1,337 1,186 475 440 448 395 通常療法 強化療法 6 ハザード比 95% 信頼区間 p値p値 0.900.78, 1.040.16 差がない！

3. ハザード比 95% 信頼区間 p値p値 0.8450.704, 1.0160.0725VADT HbA 1C の推移 非致死性イベント HbA 1C （ % ） 9.5 10.5 7.5 5.5 8.5 6.5 9.0 7.0 10.0 8.0 6.0 0.0 観察期間（年） 54321 登録時 6  中央値 通常療法（ 8.4%  ） 強化療法（ 6.9%  ） 良い 非発症率（ % ） 80 100 40 良い 60 20 0 観察期間（年） 54321067 通常療法 強化療法 差がない！

4. ADVANCE HbA 1C の推移 観察期間（ヵ月） 660 HbA 1C 値 通常療法 強化療法 7.29 6.53 平均 HbA 1C （ % ） 8.0 5.0 10.0 7.0 9.0 0.0 6.0 8.5 5.5 7.5 9.5 6.5 良い 54484236302418126 7.32 7.01 60 7.30 6.93 7.29 6.70 7.29 6.53 7.31 6.50 7.33 6.52 通常療法 強化療法 P<0.001 大血管症 + 細小血管症への影響 症例数 強化療法 通常療法 累積イベント発症率（ % ） 観察期間（ヵ月） 660 447 470 5 25 15 0 10 20 良い 5,570 5,569 54484236302418126 5,457 5,448 60 5,369 5,342 5,100 5,065 4,867 4,808 4,599 4,545 1,883 1,921 通常療法 強化療法 5,256 5,240 4,957 4,903 4,756 4,703 4,044 3,992 ハザード比 95% 信頼区間 p値p値 0.900.82, 0.980.01 差があったが 10% 程度！

5. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8. ADVANCE Collaborative Group.

6. N Engl J Med. 2014 Sep 19. DOI: 10.1056/NEJMoa1407963

7. Background In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post- trial follow-up.

8. Methods We invited surviving participants, who had previously been assigned to perindopril– indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.

11. Figure 1. Cumulative Incidence of Events, According to Blood- Pressure–Lowering Study Group. Shown is the percentage of patients who had events at any time after the start of randomized treatment in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, according to assignment to the active-drug (perindopril–indapamide) group or the placebo group. Cumulative hazard ratios (active-drug group vs. placebo group) and P values are shown for a 12-year period from the start of randomized treatment to the end of the post-trial follow-up in the ADVANCE– Observational Study (ADVANCE-ON). The insets in Panels A and C (which show outcomes that were reduced significantly with the active drug) display the same data on an enlarged y axis.

12. Figure 2. Hazard Ratios for Events, According to Blood-Pressure– Lowering Study Group. Hazard ratios are shown for events that occurred from the start of randomized treatment to the end of the blood-pressuring–lowering comparison (2007), to the end of the glucose-control comparison (2008), and to the end of each year of post- trial follow-up (2010 through 2013). The hazard ratios are for the active- drug (perindopril–indapamide) group versus the placebo group. P values are for the between-group comparison at the final visit for the randomized trial in 2007 and at the end of the post-trial follow-up period. The data for 2013 include those obtained in the first 2 months of 2014, when follow-up was terminated. T1 indicates the final visit for the blood-pressure-comparison cohort, and T2 the final visit for the glucose-comparison cohort. Vertical lines indicate 95% confidence intervals.

13. Figure 3. Cumulative Incidence of Events, According to Glucose- Control Study Group. Shown is the percentage of patients who had events at any time after the start of randomized treatment, according to assignment to the intensive-glucose-control group or the standard-glucose-control group. Hazard ratios (intensive control vs. standard control) and P values are shown for the 12-year period from the start of randomized treatment to the end of the post-trial follow-up. The inset in Panel E (which shows an outcome that was reduced significantly with intensive glucose control) displays the same data on an enlarged y axis.

14. Figure 4. Hazard Ratios for Events, According to Glucose-Control Study Group. Hazard ratios are shown for events that occurred from the start of randomized treatment to the end of the glucose-control comparison (2008) and to the end of each year of post-trial follow-up (2010 through 2013). The hazard ratios are for the intensive-control group versus the standard-control group; values less than 1.00 represent better outcomes in the intensive-control group. P values are for the between-group comparison at the final visit for the randomized trial in 2008 and at the end of the post-trial follow-up period. The data for 2013 include those obtained in the first 2 months of 2014, when follow-up was terminated. Vertical lines indicate 95% confidence intervals.

15. Results The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure–lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood- pressure–lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive- glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.

16. Conclusions The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure–lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.)

17. Message 2 型糖尿病への降圧療法と血糖降下強化療法を評 価した ADVANCE 試験の参加者 8494 人の試験後 6 年追跡結果を報告（ ADVANCE-ON 試験）。降 圧療法による全死因死亡 / 心血管死抑制効果は減 弱したが、依然有意だった（ハザード比 0.91 、 0.88 ）。血糖降下の強化療法と標準療法では、 全死因死亡 / 大血管イベントリスクに差はなかっ た。

19. JAMA. 2014 Sep 3;312(9):915-22. doi: 10.1001/jama.2014.10540. 1 Department of Surgery, University of Minnesota, Minneapolis 2 University of Minnesota, Minneapolis; Scottsdale Healthcare Bariatric Center, Scottsdale, Arizona 3 Institute of Weight Control, Sydney, Australia 4 Adelaide Bariatric Centre, Adelaide, Australia 5 Department of Surgery, Tufts Medical Center, Boston, Massachusetts 6 Department of Surgery, Oregon Health & Science University, Portland 7 Scripps Clinic, San Diego, California 8 Division of General Surgery, Virginia Commonwealth University, Richmond 9 Department of Gastroenterologic and General Surgery, Mayo Clinic Rochester, Rochester, Minnesota 10 Division of General Surgery, Stanford University School of Medicine, Stanford, California 11 Department of Surgery, University of Michigan and Ann Arbor VA Hospital 12 North American Science Associates, Minneapolis, Minnesota 13 EnteroMedics Inc, St Paul, Minnesota 14 Division of General and Gastrointestinal Surgery, Brigham and Women’s Hospital, Boston, Massachusetts 15 Division of Endocrinology and Diabetes, Minneapolis VA Medical Center and University of Minnesota, Minneapolis

20. Importance Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. Objective To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment.

21. Design, Setting, and Participants A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity- related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. Interventions One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. Main Outcomes and Measures The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10- point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%.

22. VBLOC is a surgically implanted device that uses electrical pulses to target the multiple digestive functions under control of the vagus nerves and to affect the perception of hunger and fullness. Unlike pacemakers, patients power the EnteroMedics' VBLOC device on and off with a control belt worn around their waist. When VBLOC is on, patients are supposed to feel less hungry, eat less and therefore lose weight. According to the company, VBLOC is potentially less invasive and reversible, unlike gastric bypass surgery. But EnteroMedics is also developing VBLOC at a time when the obese have far easier treatment options. Recently approved pills from Vivus (NASDAQ:VVUS) and Arena Pharmaceuticals (NASDAQ:ARNA) are some of the examples.VVUSARNA http://seekingalpha.com/article/1168571-enteromedics-vbloc-obesity-device-fails?page=2

23. BMI indicates body mass index.

25. Abbreviation: LOCF, last observation carried forward.

26. Error bars indicate 95%CIs. BMI indicates body mass index.

27. Only adverse events attributed by the investigator to the device, procedure, or therapy that occurred in at least 3%of vagal nerve block group participants are displayed.

28. Results In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P =.71), although weight loss was statistically greater in the vagal nerve block group (P =.002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy–related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity.

29. Conclusion and Relevance Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. Trial Registration clinicaltrials.gov Identifier: NCT01327976

30. Message 病的肥満患者 239 人を対象に、間欠的可逆的な迷 走神経ブロック療法の効果と安全性を無作為化臨 床試験で検証（ ReCharge 試験）。平均過剰体 重減少率はブロック群 24.4 ％、偽治療群 15.9 ％ と、偽治療との差は当初の目標であった 10 ポイ ントを下回った。 12 カ月時の 20 ％減量達成率は それぞれ 52 ％、 32 ％、 25 ％達成率は 38 ％、 23 ％だった。 間欠的可逆的な迷走神経ブロック療法は一応減量 の効果はありそうだが．．．