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 2016 年 4 月 6 日 8:30-8:55 ８階 医局 Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Reaven PD, DeFronzo RA. Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW. J Clin Endocrinol Metab. 2016 Mar 16:jc20154202. [Epub ahead of print] Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, Hu N, Paterson JM, Targownik L, Turin TC, Udell JA, Ernst P; CNODES Investigators. A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. N Engl J Med. 206 Mar 24;374(2):45-54. doi: 0.056/NEJMoa5065.

2. Figure 1. Primary Outcome. By 5 years, the primary outcome (fatal or nonfatal stroke or fatal or nonfatal myocardial infarction) had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group. The inset shows the same data on an enlarged y axis. The numbers at risk were the numbers of patients who were alive without an event and still being followed at the beginning of each time point. February 17, 2016, at NEJM.org. DOI: 10.1056/NEJMoa1506930 Participants AUSTRALIA (108) CANADA (543) GERMANY (151) ISRAEL (178) ITALY (48) UNITED KINGDOM (256) UNITED STATES (2592) Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

3. Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22, 2010. Prevention of Diabetes Mellitus Trialpublication follow-up, year drug No. of new on-set of DM No.(total) event per 1000 person-years control No. of new on-set of DM No.(total) event per 1000 person-years Thiazolidine *DPP20050.9Troglitazone1038728.7 Placebo Metformin ILS 37 21 16 391 397 393 105.1 58.8 45.2 TRIPOD20022.5Troglitazone1711459.6Placebo37122121.3 PIPOD20063.0Pioglitazone118642.6- *DREAM20063.0Rosiglitazone306236543.1Placebo686263486.8 *ACTNOW20084.0Pioglitazone103038.3Placebo4529937.6 *CANOE20103.9Met+Rosi1410334.9Placebo41104101.1 Other (α-GI, statin, fibrate, glinide) WOSCOP20015Pravastation5729993.8Placebo8239755.5 *STOP- NIDDM20023.3Acarbose22168298.2Placebo285686125.9 BIP20046.2Bezafibrate6615668.2Placebo8014787.8 *VICTORY20094Voglibose5089713.9Placebo10688130.0 *NAVIGATOR20106.5Nateglinide1674372669.1Placebo1580374764.9

4. EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY 4 6 8 10 2 0 PlaceboPioglitazone PrePostPrePost Matsuda Index P<0.001 Insulin sensitivity as measured with the Matsuda index increased more with pioglitazone than with placebo (4.31±0.24 to 7.65±0.34 vs. 4.31±0.30 to 5.23±0.31, P<0.001).

5. N Engl J Med 2011;364:1104-15. 72 ％ reduction!

6. J Clin Endocrinol Metab. 2016 Mar 16:jc20154202. [Epub ahead of print]

7. Objective Thiazolidinediones have proven efficacy in preventing diabetes in high risk individuals. However, the effect of TZDs on glucose tolerance after cessation of therapy is unclear. We examined the effect of pioglitazone on incidence of diabetes after discontinuing therapy in ACT NOW.

11. Calculations. Incremental AUC for plasma glucose and insulin during OGTT was calculated according to trapezoidal rule. The primary stimulus for insulin secretion is the increment in plasma glucose concentration, and insulin section was calculated as the increment in plasma insulin concentration (ΔI) (AUC) divided by the increment in plasma glucose concentration (ΔG) (AUC) from 0 to 120 minutes (ΔI/ΔG). Insulin sensitivity during OGTT was calculated from the Matsuda index (MI). β-cell function was calculated as the insulin secretion (IS)/ insulin resistance (IR) index (Δ I 0–120 / Δ G 0–120 x (MI) during OGTT. We previously have shown that IS/IR index calculated with Δ I0–120 / Δ G 0–120 x MI yields values similar to those calculated with Δ Cpep 0–120 / Δ G 0–120 (5, 19).

15. Results Diabetes developed in 17/138 (12.3%) PLAC vs. 17/152 PIO (11.2%, pns PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7% vs 22.3%, p<0.005). After therapy was discontinued, 23.0% (35/152) of PIO remained NGT vs 13.8% (19/138) of PLAC (p<0.04). Insulin secretion/insulin resistance (IS/IR) index (ΔI 0–120 /ΔG 0–120 x MI) was markedly lower in IGT subjects who converted to diabetes during follow up versus those who remained IGT or NGT. The decline in beta-cell function (IS/IR index) was similar in IGT subjects who developed diabetes, irrespective of whether they were treated with PIO or PLAC.

16. CONCLUSION: (1) the protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, (2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than placebo and a greater number of PIO-treated individuals maintained NGT after median follow-up of 11.4 months; (3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

17. Message ACTNOW 研究について介入後の細かい解析がさ らに追加された。 Pioglitazone の位置付けは今後どうなるのだろ うか？

19. alogliptin Dipeptidyl peptidase-4 inhibitor ／ GLP-1 receptor agonist sitagliptin vildagliptin ExenatideLixisenatide linagliptin saxagliptinteneligliptin anagliptin trelagliptin LiraglutideDulaglutide omarigliptin Semaglutide M.M. edited

20. Number of Patients who were Prescribed an Oral Hypoglycemic Agent in our Center Sulfonylurea Metformin* DPP-4 inhibitor Thiazolidinedione Alpha-glucosidase inhibitor* Glinide SGLT2 inhibitor Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University One patient may received several agents. In type 2 diabetic patients, combination use with insulin has been approved if the indication of the agent is “type 2 diabetes mellitus” or the combination has been specifically approved. *: In type 1 diabetic patients, combination use with insulin may be accepted.

21. DPP4 阻害薬、 GLP-1 受容体作動薬、 SGLT2 阻害薬の心血管障害への影響 1.Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR- TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–1326. 2.White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335. European Heart Journal doi:10.1093/eurheartj/ehv239 12

22. N Engl J Med. 2013 Oct 3;369(14):1317-26. SAVOR-TIMI 53 ClinicalTrials

23. BMJ 2016;352:i581 http://dx.doi.org/10.1136/bmj.i581

24. From the Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital (K.B.F., L.A., P.E.), the Departments of Medicine (K.B.F., P.E.), Oncology (L.A.), Pediatrics (R.W.P.), and Epidemiology, Biostatistics, and Occupational Health (R.W.P.), McGill University, and the Research Institute of the McGill University Health Centre (R.W.P.), Montreal, the Manitoba Centre for Health Policy, Department of Community Health Sciences (M.D., L.T.), and the Section of Gastroenterology, Division of Internal Medicine (L.T.), University of Manitoba, Winnipeg, the Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver (C.R.D.), the Department of Medicine, Western University, London, ON (K.K.C.), the Health Quality Council, Saskatoon, SK (N.H.), the Institute for Clinical Evaluative Sciences (J.M.P., J.A.U.), Institute of Health Policy, Management and Evaluation, University of Toronto (J.M.P.), and the Cardiovascular Division, Women’s College Hospital, Peter Munk Cardiac Centre of the University Health Network, and the University of Toronto (J.A.U.), Toronto, the Department of Family Medicine, McMaster University, Hamilton, ON (J.M.P.), and the Department of Family Medicine, University of Calgary, Calgary, AB (T.C.T.) — all in Canada. N Engl J Med 2016; 374:1145-1154March 24, 2016DOI: 10.1056/NEJMoa1506115March 24, 2016

25. Background There is concern that antidiabetic incretin- based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue.

26. Methods We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case–control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models.

27. Figure 1. Numbers of Patients in the Base Cohort and Study Cohort. HAART denotes highly active antiretroviral therapy, and HIV human immunodeficiency virus.

29. Figure 2. Association between Treatment with Incretin-based Drugs and the Risk of Hospitalization for Heart Failure among Patients with and Those without a History of Heart Failure. The reference category was treatment with combinations of oral antidiabetic drugs. The size of the box surrounding the point estimate for each site is proportional to the weight of that site in the random-effects meta-analysis. The I 2 statistic represents the proportion of the total variance in the metaanalysis that was due to between-study heterogeneity rather than withinstudy variability. Tau 2 is an estimate of the between-study variance. A value of I2 greater than 50% indicates notable heterogeneity. 20

30. * Cases and controls were matched for sex, age, year of cohort entry, duration of treated diabetes, and duration of followup. Values that were based on five or fewer patients were withheld by the participating sites because of privacy restrictions; when data were collated across sites, a value of 3 was assigned in these instances. For this reason, the sums may differ slightly from the totals shown. DPP-4 denotes dipeptidyl peptidase 4, and GLP-1, glucagon-like peptide 1. † Data for current treatment with insulin and single oral antidiabetic drugs and data for no current treatment (i.e., data for those who discontinued treatment with antidiabetic drugs), accounting for 17,581 case patients and 341,103 controls, are not shown in the table but were considered in the regression model for proper estimation of treatment effects. ‡ Hazard ratios were adjusted for alcohol-related disorders, coexisting conditions (atrial fibrillation, cancer, chronic obstructive pulmonary disease, coronary artery disease, dyslipidemia, hypertension, peripheral vascular disease, previous coronary revascularization, previous myocardial infarction, and previous stroke), microvascular complications of diabetes (neuropathy, renal disease, retinopathy, and peripheral arteriopathy), number of hospitalizations, number of unique nondiabetic drugs in the prior year, number of antidiabetic drugs received before study-cohort entry, and treatment with the following drugs in the year before study-cohort entry: angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium-channel blockers, diuretics, statins, aspirin, and other nonsteroidal antiinflammatory drugs. For the CPRD data, hazard ratios were further adjusted for body-mass index, smoking status, and glycated hemoglobin level (≤7.0% [53 mmol per mole], 7.1 to 8.0% [54 to 64 mmol per mole], or >8.0% [64 mmol per mole]). § The I2 statistic represents the proportion of the total variance of the meta-analysis that is due to between-study heterogeneity rather than within-study variability.

31. * Cases and controls were matched for sex, age, year of cohort entry, duration of treated diabetes, and duration of followup. Values that were based on five or fewer patients were withheld by the participating sites because of privacy restrictions; when data were collated across sites, a value of 3 was assigned in these instances. For this reason, the sums may differ slightly from the totals shown. † Data for current treatment with insulin and single oral antidiabetic drugs and data for no current treatment (i.e., data for those who discontinued treatment with antidiabetic drugs), accounting for 4912 case patients and 77,478 controls, are not shown in the table but were considered in the regression model for proper estimation of treatment effects. ‡ Hazard ratios were adjusted for alcohol-related disorders, coexisting conditions (atrial fibrillation, cancer, chronic obstructive pulmonary disease, coronary artery disease, dyslipidemia, hypertension, peripheral vascular disease, previous coronary revascularization, previous myocardial infarction, and previous stroke), microvascular complications of diabetes (neuropathy, renal disease, retinopathy, and peripheral arteriopathy), number of hospitalizations, number of unique nondiabetic drugs in the prior year, number of antidiabetic drugs received before study-cohort entry, and treatment with the following drugs in the year before study-cohort entry: angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium-channel blockers, diuretics, statins, aspirin, and other nonsteroidal antiinflammatory drugs. For the CPRD data, hazard ratios were further adjusted for body-mass index, smoking status, and glycated hemoglobin level (≤7.0% [53 mmol per mole], 7.1 to 8.0% [54 to 64 mmol per mole], or >8.0% [64 mmol per mole]). § The I2 statistic represents the proportion of the total variance of the meta-analysis that is due to between-study heterogeneity rather than within-study variability.

32. Results The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues.

33. Conclusions In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02456428.)

34. Message ユダヤ総合病院（カナダ、モントリオール）の Kristian B. Filion 氏らは、カ ナダの 4 州、米国および英国における糖尿病患者の医療データを用いて、イン スリン関連薬と心不全リスクとの関連を検討した。このコホート内で心不全に よる入院患者と性や年齢などをマッチさせた対照者を比較する症例対照研究を 行った。データは約 150 万人の患者から収集し、そのうち心不全による入院は 約 2 万 9,000 件であった。 解析の結果、心不全既往患者と心不全既往がない患者ともに、経口の糖尿病 治療薬を併用投与した場合に比べて、インクレチン関連薬を使用した場合に心 不全による入院率は上昇していなかった〔ハザード比はそれぞれ 0.86 （ 95 ％ 信頼区間 0.62 ～ 1.19 ）、 0.82 （同 0.67 ～ 1.00 ）〕。 DPP-4 阻害薬と GLP- 1 受容体拮抗薬それぞれの解析でも同様の結果が得られた。 以上の結果から、同氏らは「大規模な糖尿病患者のコホート集団から得た データを解析した結果、一般に広く用いられている経口糖尿病治療薬の併用投 与と比べて、インクレチン関連薬は心不全による入院リスクを上昇させないこ とがわかった」と結論づけている。 http://dm-rg.net/news/2016/03/017578.html https://www.nejm.jp/abstract/vol374.p1145