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 2015 年 6 月 11 日 8:30-8:55 ８階 医局 Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jun 8. doi: 10.1056/NEJMoa1501352 Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266.

2. 試験名 TECOSEXAMINESAVOR-TIMI 53CAROLINA 対象 2 型糖尿病患者急性冠症候群を合併 した 2 型糖尿病患者 2 型糖尿病患者 薬剤名シタグリプチンアログリプチンサクサグリプチンリナグリプチン 対照薬プラセボ グリメピリド 登録例数 14,000 例 5,400 例 16,500 例 6,000 例 主要 エンドポイント 心血管死，非致死 的心筋梗塞，非致 死的脳卒中，不安 狭心症による複合 心血管死，非致死的 心筋梗塞，非致死的 脳卒中の複合 心血管死，非致死 的心筋梗塞，非致 死的虚血性脳卒中 の複合 心血管死，非致死 的心筋梗塞，非致 死的脳卒中，不安 狭心症による複合 観察期間 5 年間 4.75 年間 4 年間 8.33 年間 試験開始 2008 年 2009 年 2010 年 試験終了予定 2014 年 12 月 2013 年 12 月 2013 年 7 月 2018 年 9 月 綿田裕孝（順天堂大学大学院代謝内分泌内科学） Pharma Medica ;30,8,157-164.2012. clinicaltrials.gov （ http://clinicaltrials.gov/ ）をもとに一部改変 DPP-4 阻害薬の心血管アウトカム試験

3. N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684 SAVOR-TIMI53 BMI, HbA1c, FPG 推移

4. Scirica B.M. NEJM published on Sep. 2, 2013. SAVOR-TIMI53 事前に設定された評価項目 Saxagliptin [N=8,280] Placebo [N=8,212] ハザード比（ 95% Cl ） P値P値 主要評価項目 : 心血管死、心筋梗塞、脳卒 中 613[7.3]609[7.2] 1.00 （ 0.89~1.12 ） 0.99 副次評価項目： 主要評価項目 ＋不安定狭心症による入院 心不全による入院 冠動脈血行再建述 1,059[12.8]1,034[12.4] 1.02 （ 0.94~1.11 ） 0.66 総死亡 全ての心血管死 心筋梗塞 虚血性脳卒中 不安定狭心症による入院 心不全による入院 冠動脈血行再建術 血清クレアチニン倍化 / 血液透 析 / 腎移植 / 血清クレアチン >6 mg/dL 420[4.9] 269[3.2] 265[3.2] 157[1.9] 97[1.2] 289[3.5] 423[5.2] 194[2.2] 378[4.2] 260[2.9] 278[3.4] 141[1.7] 81[1.0] 228[2.8] 459[5.6] 178[2.0] 1.11 （ 0.96~1.27 ） 1.03 （ 0.87~1.22 ） 0.95 （ 0.80~1.12 ） 1.11 （ 0.88~1.39 ） 1.19 （ 0.89~1.60 ） 1.27 （ 1.07~1.51 ） 0.91 （ 0.80~1.04 ） 1.08 （ 0.88~1.32 ） 0.15 0.72 0.52 0.38 0.24 0.007 0.18 0.46 低血糖による入院 53[0.6]43[0.5] 1.22 （ 0.82~1.83 ） 0.33 No.[%] N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684

5. HbA1c の推移 2 0136912162024283236 追跡期間 （月） 1 0 -2 ベースライン HbA1 C 値 プラセボ : 8.03±1.11% アログリプチン : 8.03±1.09% 最終評価時におけるアログリプチン と プラセボとの差： -0.36%; P<0.001 2,6792,5832,4702,2992,1351,9321,6471,32098659328382 2,7002,6132,4952,3322,1571,9521,6931,34998461127181 アログリプチン （ N=2,701 ） プラセボ （ N=2,679 ） Mean±SD （%）（%） White W.B. 欧州心臓会議（ 2013 年 9 月 2 日、アムステルダム） NEJM published on Sep. 2, 2013. プラセボ： アログリプチン：

6. 1.3 未満を達成（非劣性を証 明） 0 0612182430 6 12 18 24 追跡期間（月） 2,6792,2991,8911,375805286 プラセボ： 2,7012,3161,8991,394821296 アログリプチン： イベント数 （ % ） プラセボ : 316 （ 11.8 ） アログリプチン : 305 （ 11.3 ） プラセボ アログリプチ ン （%）（%） ハザード比 0.96 （信頼区間上限 ; 1.16 ） α （ P ） =0.01 White W.B. 欧州心臓会議（ 2013 年 9 月 2 日、アムステルダム） NEJM published on Sep. 2, 2013. 主要評価項目（心血管死、非致死性心筋梗塞、非致死性脳卒中） （例）

7. www.thelancet.com Published online March 10, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62225-X

9. Duke Clinical Research Institute, Duke University School of Medicine, Durham (J.B.G., J.G., M.J.P., E.D.P.) and University of North Carolina School of Medicine, Chapel Hill (J.B.B.) — both in North Carolina; Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom (M.A.B., R.R.H.); Canadian VIGOUR Centre, University of Alberta, Edmonton, AB (P.W.A.) and St. Michael’s Hospital, University of Toronto, Toronto (R.J.) — both in Canada; Merck, Kenilworth, NJ (S.S.E., K.D.K., J.K., S.K., P.P.S., S.S.); George Washington University Biostatistics Center, Rockville, MD (J.M.L.); University of Texas Southwestern Medical Center, Dallas (D.K.M.); Munich Diabetes Research Group, Helmholtz Center, Neuherberg, Germany (E.S.); and University of Leuven, Leuven, Belgium (F.V.W.). June 8, 2015 DOI: 10.1056/NEJMoa1501352

10. Background Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.

11. Methods In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.

12. Figure 1. Enrollment, Follow-up, and Vital Status. GCP denotes Good Clinical Practice guidelines.

13. Figure 2. Glycated Hemoglobin Level. Data are shown as mean values. The I bars indicate standard deviations.

17. Figure S1. Forest Plot of All Prespecified Subgroup Analyses for the Primary Composite Cardiovascular Outcome.

19. Results During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, −0.29 percentage points; 95% confidence interval [CI], −0.32 to −0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

20. Conclusions Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.)

21. Message 単剤で比較した 1 つの RCT と、メトホルミン併用下で 両者を比較した 2 つの RCT の計 3 試験、 2451 人（シタグ リプチン群 1226 人、 SU 薬群 1225 人）のデータを解析 した。追跡期間はメトホルミン併用下の 1 試験が 30 週、 他の 2 試験が 104 週であり、その間に発生した主要な心 血管イベント（ MACE ： Major Adverse CV Event ） の発生率を比較した。 追跡期間内に発生した MACE は、シタグリプチン群が 0 件、 SU 薬群が 11 件で、 100 人・年当たりの発生件数 はそれぞれ 0 件、 0.9 件。心血管疾患による死亡件数は、 シタグリプチン群 0 件、 SU 薬群 5 件で、 100 人・年当た りの発生件数はそれぞれ 0 件、 0.4 件だった。 https://medical.nikkeibp.co.jp/leaf/all/gakkai/wdc2011/201112/522762.html 心不全について他と異なるのか？？？ HbA1c に差がない！

23. Changes in Median Glycated Hemoglobin Levels from Baseline through 78 Months Duckworth W et al. N Engl J Med 2009;360:129-139 VADT

24. Kaplan-Meier Curves for the Time until the First Occurrence of a Primary or Secondary Outcome Duckworth W et al. N Engl J Med 2009;360:129-139

25. 強化療法の通常療法に対する 心血管疾患発症におけるハザード比 0243691218 0.4 1.4 1.0 0.8 0.6 1.2 15 糖尿病罹病期間 21 2 型糖尿病 1,791 例を無作為にロシグリタゾンを中心とした治療により強化療法群（ HbA 1C 6.0% 未満）、または 通常療法（ HbA 1C 8.0 ～ 9.0% ）に割り付けた。そして、主要心血管イベント（心血管死、心筋梗塞、脳卒中、 うっ血性心不全、手術できない冠動脈疾患）、虚血部位の切断、冠動脈疾患へのインターベンション、末梢血管 疾患を主要評価項目とした。 Duckworth W. ： ADA 68th Scientific Sessions,2008,San Francisco. （年） VADT ～イベント発症リスクと糖尿病罹病期間の関 係～ p ＜ 0.0001

26. Veterans Affairs (VA) Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI (R.A.H., W.L.W.); Phoenix VA Health Care System, Phoenix, AZ (P.D.R., W.C.D.); and the Hines VA Cooperative Studies Program Coordinating Center and Edward Hines, Jr., VA Hospital (G.D.B., D.J.R., L.G., N.V.E.), and VA Pharmacy Benefits Management Services (M.M.) — all in Hines, IL. N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266.

27. Background The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants.

28. Methods After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality.

30. * Plus–minus values are means ±SD. Data are baseline values before randomization. The group numbers are participants who have complete follow- up data in the analyses (i.e., who were followed until the end of December 2013, had a primary-outcome event, or died during active follow-up). The complete cohort included follow-up data for 92.4% of participants in the original trial. The survey cohort included participants who agreed to additional data collection by means of annual surveys and periodic chart reviews, with follow-up data for 77.7% of trial participants. The P values are for the comparisons of the standard- therapy group with the intensive-therapy group. There were no significant differences between the complete cohort and survey cohort in any of the above characteristics. To convert the values for weight to pounds, multiply by 2.2. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. † Hypertension was defined as current treatment for hypertension or a blood pressure of 140/90 mm Hg or more. ‡ Race or ethnic group was self-reported. § The body-mass index is the weight in kilograms divided by the square of the height in meters. ¶ The estimated glomerular filtration rate (GFR) was calculated with the use of the Modification of Diet in Renal Disease equation. ‖ The estimated 10-year cardiovascular risk was calculated with the use of the United Kingdom Prospective Diabetes Study Risk Engine. 19

31. Figure 2. Changes in Median Glycated Hemoglobin Level, According to Year since the Start of the Study. Data are shown starting at year 3 because that was the point at which all the participants had been enrolled and had been in the study for at least 3 months. The I bars (slightly offset for better visibility) represent interquartile ranges. The vertical line represents the end of the interventional component of the trial and the beginning of the follow-up study period. The reason for the slight decline in the difference in glycated hemoglobin levels between the two groups that was observed in the last 6 months of the trial is unclear.

35. Figure 3. Probability Curves for Time to the First Major Cardiovascular Event and for Cardiovascular Mortality and Total Mortality. The primary outcome was the time to the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or death from cardiovascular causes).

37. Results The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard- therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive- therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years).

38. Conclusions After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person- years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.)

39. Message VADT では罹病期間が長い場合に血糖の保護作用 がなかった。 全体的に見ても長期観察になると効果があるよう である。