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Journal Club

Journal Club. 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.

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Journal Club

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  1. Journal Club 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. ArteriosclerThrombVasc 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. 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

  2. 《REVERSAL》 社内資料 　プラーク体積の変化率（中央値）　 （%） **p=0.02 3.5 プラバスタチン ベースラインからの評価 3.0 *p=0.001 アトルバスタチン 2.5 * : 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 2.0 1.5 2.7 1.0 0.5 0 -0.4 -0.5 *p=0.98 -1.0 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。 Nissen SE.et al.:JAMA,291,1071,2004.

  3. （主要評価項目） %プラーク体積の変化 グリメピリド（n=181） ピオグリタゾン（n=179） （%） p=0.002 0.8 Least-square mean （95% CI） 0.73（0.33,1.12） 0.6 0.4 0.2 p=0.44 （対投与前） p<0.001 （対投与前） 0 -0.16（-0.57,0.25） -0.2 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。 Nissen S.E. et al.:JAMA,299,1561,2008.

  4. LDL-C値とプラークの進展の関係 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 （%） 1.8 CAMELOT プラセボ ％プラーク体積の変化 REVERSAL プラバスタチン 1.2 PERISCOPE グリメピリド ACTIVATE プラセボ 0.6 REVERSAL アトルバスタチン ILLUSTRATE アトルバスタチン 0 PERISCOPE ピオグリタゾン -0.6 ASTEROID ロスバスタチン -1.2 50 60 70 80 90 100 110 120 （mg/dL） LDL-C値 Nissen S.E. et al.:Association Corporate Counsel ,Mar,2008,Chicago.

  5. CHICAGO StudyにおけるIMT測定方法 総頸動脈 内頸動脈 外頸動脈 ≧2cm ≧2cm 関心領域 参考）日本での測定方法 • 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］ 内頸動脈 総頸動脈 外頸動脈 1cm 1cm max IMT 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）。

  6. mean IMT変化量の推移（主要評価項目） （mm） mean±SE 登録時mean IMT 0.016 グリメピリド 0.779±0.008 0.012 ピオグリタゾン 0.771±0.008 0.012 0.008 0.013mmp=0.02 0.004 0 -0.001 -0.004 -0.008 -0.012 （週）　 0 24 48 72 症例数 186 175 グリメピリド ピオグリタゾン 186 175 186 175 170 166 Mazzone T. et al.：JAMA,Published online,13 Nov,2006.

  7. Enrollment, Randomization, and Follow-up of Study Patients. ACTNOW研究 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 Participants initially received 30 mg of pioglitazoneper day or placebo. One month after randomization, the dose of pioglitazone was increased to 45 mg per day. 602 Underwent randomization 303 Were assigned to receive pioglitazone 299 Were assigned to receive placebo 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 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 213 Completed study 228 Completed study DeFronzo RAet al. N Engl J Med 2011;364:1104-15.

  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 RAet al. N Engl J Med 2011;364:1104-15.

  9. Kaplan–Meier Plot of Hazard Ratios for Time to Developmentof Diabetes. 0.4 Hazard ratio, 0.28 (95% CI, 0.16-0.49) P<0.001 Placebo 0.3 72%減少！ Cumulative Hazard 0.2 Pioglitazone 0.1 0 0 6 12 18 24 30 36 42 48 Months since Randomization No. at Risk Placebo Pioglitazone 299 303 259 262 228 244 204 228 191 218 134 140 83 87 17 24 DeFronzo RAet al. N Engl J Med 2011;364:1104-15.

  10. Placebo Pioglitazone 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). P<0.005 EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 6 5 4 I/G xMatsuda (0-120) 3 2 1 0 Pre Post Pre Post

  11. Effect of Thiazolidinediones on Fat Topography High FFA FFA TZD IntramuscularFat SubcutaneousFat IntrahepaticFat IntraabdominalFat Intra-arterialFat Artery Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..

  12. Effects of Pioglitazone as Compared with Placebo (CIMT) Carotid Intima-Media Thickness P=0.047 4.0 Placebo Mean Percent Change 2.0 Pioglitazone 0.0 0 12 24 36 Month 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. DeFronzo RAet al. N Engl J Med 2011;364:1104-15.

  13. 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.). ArteriosclerThrombVasc Biol. 2013;33:393-399

  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.

  16. 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).

  17. 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.

  18. 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

  19. 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: 2.39×10–3–7.14×10–3mm/year) compared with placebo (9.69×10–3mm/year; 95% CI: 7.24×10–3–12.15×10–3mm/ 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.

  20. 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.

  21. 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。

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

  23. 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.

  24. 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).

  25. 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.

  26. 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 血圧高くない：収縮障害？　ACEI 高血圧：拡張障害？(糖尿病で多い)ARB

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