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 2013 年 2 月 14 日 8:30-8:55 ８階 医局 Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, Bray GA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Tripathy D, Defronzo RA, Reaven PD. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):393-9. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta- analysis of randomised trials. BMJ. 2013 Jan 28;346:f360. doi: 10.1136/bmj.f360.

2. Nissen SE.et al.:JAMA,291,1071,2004. 0 -0.5 0.5 1.0 1.5 2.0 2.5 3.0 3.5 （%）（%） *p=0.001 *p=0.98 2.7 -0.4 **p=0.02 プラバスタチ ン アトルバスタチ ン * : vs ベースライン 1 標本 Wilcoxon 検定 **: vs プラバスタチン 2 標本 Wilcoxon 検定 プラーク体積の変化率（中央値） 米国の 34 施設において冠動脈造影法で 1 枝以上に血管径 20 ％以上の狭窄が認められ、 4 ～ 10 週間の スタチン wash out 期間後の LDL-C が 125 ～ 210mg/dL の 502 例を対象に、プラバスタチン 40mg/ 日 とアトルバスタチン 80mg/ 日に割り付け 18 ヵ月間投与し、 IVUS による評価を投与前後に行った。 社内資料 《 REVERSAL 》

3. 社内資料 ピオグリタゾン （ n=179 ） % プラーク体積の変化 （主要評価項 目） p=0.002 0.73 （ 0.33,1.12 ） p<0.001 （対投与前） 0.4 0 0.6 0.8 -0.2 0.2 （%）（%） Nissen S.E. et al.:JAMA,299,1561,2008. 冠動脈造影で少なくとも 1 枝病変に 20% 以上の狭窄を認める 2 型糖尿病患者 547 例を二重盲検下でピオグリタ ゾン（ 15 ～ 45mg/ 日）またはグリメピリド（ 1 ～ 4mg ）に分け、 IVUS を用いて「％プラーク体積」の変化率 を主要評価項目として 18 ヵ月にわたり、比較検討した。 グリメピリド （ n=181 ） -0.16 （ -0.57,0.25 ） p=0.44 （対投与前） Least-square mean （ 95% CI ）

4. 社内資料 -1.2 -0.6 0 0.6 1.2 1.8 5060708090100110120 REVERSAL プラバスタチン REVERSAL アトルバスタチン CAMELOT プラセボ ACTIVATE プラセボ ASTEROID ロスバスタチン （ mg/d L ） （%）（%） LDL-C 値 IVUS を用いてプラーク体積に及ぼす影響を検討した他の試験との比 較 ILLUSTRATE アトルバスタチン PERISCOPE グリメピリド PERISCOPE ピオグリタゾン LDL-C 値とプラークの進展の関係 Nissen S.E. et al.: Association Corporate Counsel,Mar,2008,Chicago.

5. CHICAGO Study における IMT 測定方法 参考）日本での測定方法 max IMT ならびにその左右 1cm の IMT を測定し、 3 つの平均値を mean IMT と する（プラークを含む）。 総頸動脈 内頸動脈 max IMT 1cm 外頸動脈 総頸動脈 内頸動脈 外頸動脈 ≧ 2cm 関心領域  分岐部から 2cm 以上離れた領域を関心領域 （ 2cm 以上）と設定する［赤囲み部分］  総頸動脈 1cm あたり IMT を 70 ～ 100 の測定値 を得る  mean IMT は得られた IMT 測定値全ての平均 値とする  IMT の測定において、プラーク（血管内腔に 突出した病変）は IMT 測定値から除く［青部 分］

6. mean IMT 変化量の推移 （主要評価項目） グリメピリド ピオグリタゾン 186 175 170 166 186 175 186 175 Mazzone T. et al. ： JAMA,Published online,13 Nov,2006. 0244872 0 0.004 0.016 0.012 -0.001 （週 ） （ mm ） グリメピリ ド ピオグリタゾン 0.012 0.008 -0.012 -0.004 -0.008 mean±SE 登録時 mean IMT 0.779±0.008 0.771±0.008 0.013mm p=0.02 症例数

7. 1827 Patients were assessed for eligibility 1225 Were excluded 277 Had FPG out of range 187 Declined to participate 118 Had medical exclusions 12 Had too few risk factors 4 Had behavioral or logistic problems 627 Had OGTT–FPG or 2-hr glucose out of range 602 Underwent randomization 303 Were assigned to receive pioglitazone 90 Did not have a final visit for the following reasons: 9 Had weight gain 6 Relocated 12 Had work or schedule conflict 18 Had lack of interest 7 Did not give reason 28 Were lost to follow-up 5 Had unrelated illness or adverse events 5 Had other reason 213 Completed study 299 Were assigned to receive placebo 71 Did not have a final visit for the following reasons: 3 Had weight gain 17 Relocated 1 Had work or schedule conflict 9 Had lack of interest 10 Did not give reason 22 Were lost to follow-up 3 Had unrelated illness or adverse events 6 Had other reason 228 Completed study DeFronzo RA et al. N Engl J Med 2011;364:1104-15. Enrollment, Randomization, and Follow-up of Study Patients. Participants initially received 30 mg of pioglitazone per day or placebo. One month after randomization, the dose of pioglitazone was increased to 45 mg per day. ACTNOW 研究

8. Figure 4. Effects of Pioglitazone as Compared with Placebo. Over the course of the study, mean percentage changes and standard errors in continuous measures were calculated with the use of a linear, mixed- repeated-measures model fit to all available data for each measure. As compared with placebo, treatment with pioglitazone (dashed lines) had beneficial effects on fasting plasma glucose levels (Panel A), 2-hour plasma glucose levels (Panel B), and HbA1c levels (Panel C) and on systolic and diastolic blood pressure (Panels E and F, respectively), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (Panels G and H, respectively). Weight gain was greater with pioglitazone than with placebo (Panel D). (Body-mass index was calculated at each examination with the use of height measured at baseline; as a result, the percentage change in BMI is identical to the percentage change in weight.) P values are shown for the interaction between time and study group, indicating whether the slopes differ significantly over time. DeFronzo RA et al. N Engl J Med 2011;364:1104-15.

9. 0 0 61830423648 0.4 0.3 0.1 0.2 Cumulative Hazard Months since Randomization 1224 299 303 259 262 204 228 134 140 17 24 83 87 228 244 191 218 Placebo Pioglitazone No. at Risk Placebo Pioglitazone Hazard ratio, 0.28 (95% CI, 0.16-0.49) P<0.001 DeFronzo RA et al. N Engl J Med 2011;364:1104-15. Kaplan–Meier Plot of Hazard Ratios for Time to Development of Diabetes. 72% 減少！

10. EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 3 4 5 6 2 1 0 PrePostPrePost  I/  G xMatsuda (0-120) PlaceboPioglitazone P<0.005 The index of insulin secretion factored by insulin resistance, calculated on the basis of the oral glucose-tolerance test (I0–120/ΔG0–120 × Matsuda index), increased more with pioglitazone than with placebo (3.43±0.12 to 5.44±0.31 vs. 3.81±0.30 to 4.20±0.20, P<0.005).

11. Intramuscular Fat Intrahepatic Fat Intraabdominal Fat Subcutaneous Fat Effect of Thiazolidinediones on Fat Topography High FFA FFA TZD Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78.. Intra-arterial Fat Artery

12. Carotid Intima-Media Thickness Mean Percent Change Month 01224 4.0 2.0 0.0 36 P=0.047 Placebo Pioglitazone DeFronzo RA et al. N Engl J Med 2011;364:1104-15. Effects of Pioglitazone as Compared with Placebo (CIMT) A total of 365 patients (placebo group, 186; pioglitazone group, 179) completed the follow-up examination at 15 to 18 months for measurement of carotid intima–media thickness, and 336 patients (placebo group, 173; pioglitazone group, 163) completed the final examination for measurement of carotid intima–media thickness.

13. Arterioscler Thromb Vasc Biol. 2013;33:393-399 From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center- Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).

14. Objective—To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes.

15. Methods—CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial.

18. Figure. Annual carotid intima media thickness (CIMT) progression rates, mm/year ×103 by intention to treat groups. White bars represent those randomized to placebo. Black bars represent those randomized to piogitazone treatment. Error bars represent 95% CI. The difference in progression rate between treatment groups was significant in all models (P < 0.01). All models include random subject effects representing individual differences from the group mean for baseline CIMT and rate of CIMT progression. Model 1: Unadjusted. Model 2: Adjusted for age, study center, sex, race/ethnicity (non-Hispanic Whites vs others) and prior cardiovascular disease (CVD). Model 3: Adjusted for Model 2+HbA1c, systolic and diastolic blood pressure, body mass index, triglyceride/ high-density lipoprotein cholesterol (HDL-C) ratio, and Matsuda index. The results were not different when adjusted for other lipid values, such as total cholesterol/HDL-C ratio, or total cholesterol, triglycerides, low-density lipoprotein cholesterol, and HDL-C, individually or in combination. Model 4: Adjusted for Model 3+adiponectin, leptin, C-reactive protein, tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1, plasminogen activator inhibitor-1. Model 5: Adjusted for Model 4+concomitant medications (lipid-lowering agents, antihypertensives, and drugs containing salicylic acid; all parameterized as yes vs no). Model 6: Parsimonious model fitted, including all covariates from Model 5 that were P<0.1 (age, study center, prior CVD, HbA1c, and total cholesterol/HDL-C ratio).

19. Supplemental Figure I Frequency of participants with improved risk factors at the end of the study. Placebo (white bars), Pioglitazone (black bars); * After Bonferroni adjustment, P-values < 0.003 for differences between groups are considered significant. Abbreviations: BMI, body mass index; HDL-C, high density lipoprotein cholesterol; TC/HDL-C, total cholesterol/HDL-C ratio; TG/HDL-C, triglyceride/HDL-C ratio; G0, fasting glucose; G120, 2-hour glucose; HbA1c, glycosylated hemoglobin; SI, insulin sensitivity index by frequently sampled intravenous glucose tolerance test; IL-6, interleukin 6; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor-α.

20. Supplemental Figure II Annual CIMT progression rate during pioglitazone treatment as compared with placebo and stratified by change (decrease or increase) in risk factors. Placebo is set at zero CIMT progression. All models are adjusted for fixed effects age, gender, race/ethnicity (non- Hispanic Whites vs. Others), study site and prior CVD. Models also included random subject effects representing subject differences in baseline CIMT and rate of CIMT progression. Abbreviations: BMI, body mass index ; HDL-C, high density lipoprotein cholesterol; G0, fasting glucose; G120, 2-hour glucose; HbA1c, glycosylated hemoglobin; SI, insulin sensitivity index by frequently sampled intravenous glucose tolerance test; IL-6, interleukin 6 ; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor-α. O Decrease in risk factor during treatment ▲Increase in risk factor during treatment

21. Results—During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10 –3 mm/year; 95% CI: 2.39×10 –3 –7.14×10 –3 mm/year) compared with placebo (9.69×10 –3 mm/year; 95% CI: 7.24×10 –3 –12.15×10 –3 mm/ year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.

22. Conclusion—Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

23. Message ACTNOW 研究で IMT の改善の関与因子を 解析しているが不明。 IMT が改善しても生命予後がよくなるかは 別かもしれないが、不思議な現象である。

27. Objective To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy.

28. Design Systematic review and meta-analysis. Data sources PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012. Study selection Randomised controlled trials comparing dual blockers of the renin- angiotensin system with monotherapy, reporting data on either long term efficacy (≥1 year) or safety events (≥4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure.

40. Results 33 randomised controlled trials with 68 405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79).

41. Conclusion Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.

42. Message 無作為化比較試験 33 件を対象に、レニン - アン ジオテンシン系（ RAS ）阻害薬の併用による二 重阻害（ dual blockers ）の有効性をメタ解析 で検証。単剤療法に比べ、二重阻害は全死因お よび心血管死亡率への有意な効果と関連せず （相対リスク 0.97 、 0.96 ）、高カリウム血症 55 ％、低血圧症 66 ％、腎不全 41 ％などの有害 リスク増加と関連した。 ACEI か ARB かの選択 ACEI 血圧高くない：収縮障害？ ACEI ARB 高血圧：拡張障害？ ( 糖尿病で多い ) ARB