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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.

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Presentation on theme: "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."— Presentation transcript:

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 2011 年 3 月 31 日 8:30-8:55 8階 医局 DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, Mack WJ, Mudaliar S, Ratner RE, Williams K, Stentz FB, Musi N, Reaven PD; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med Mar 24;364(12):

2 ● Life style modification ・ Malmö feasibility study(Eriksson, 1991) ・ Malmö Prfevention Trial(Eriksson, 1998) ・ DaQing IGT and Diabetes Study(Pan, 1997) ・ Finnish Diabetes Prevnetion Study(Tuomilehto, 2001) ・ Japan Diabetes Prevention Study(Kuzuya) ・ Stockholm Diabetes Prevention Program(Bjärås) ● Drug intervention ・ Diabetes Prevention Program(DPP Research Group, 2002) ・ STOP-NIDDM(Chiasson, 2002) ・ TRIPOD(Buchanan, 2001) ・ EDIT(Holman, 2003) ・ NAVIGATOR(Rury R. Holman, 2010) negative ・ DREAM(Boche, 2006) ・ ACT NOW(DeFronzo , 2008) ・ ONTARGET(ONTARGET group, 2008) STOP-NIDDM : Study To Prevent NDDM, TRIPOD : Troglitazone In Prevention of Diabetes EDIT : Early Diabetes Intervention Trial, NAVIGATOR : Natglinide and Valsartan in Impaired Glucose Tolerance Outcome Reaserach DREAM : Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications Primary Prevention of Type 2 Diabetes Mellitus

3 Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22, 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 *DPP Troglitazone Placebo Metformin ILS TRIPOD Troglitazone Placebo PIPOD Pioglitazone *DREAM Rosiglitazone Placebo *ACTNOW Pioglitazone Placebo *CANOE Met+Rosi Placebo Other (α-GI, statin, fibrate, glinide) WOSCOP20015Pravastation Placebo *STOP- NIDDM Acarbose Placebo BIP Bezafibrate Placebo *VICTORY20094Voglibose Placebo *NAVIGATOR Nateglinide Placebo

4 Meta-analysis of odds ratio for overall mortality with rosiglitazone versus pioglitazone BMJ 2011;342:d1309 Cardiovascular outcomes from 16 observational studies (4 case- control studies and 12 retrospective cohort studies), including thiazolidinedione users, were evaluated after a detailed review of 189 citations.

5 the Texas Diabetes Institute and University of Texas Health Science Center (R.A.D., D.T., N.M.) and KenAnCo Biostatistics (K.W.) — both in San Antonio; Phoenix Veterans Affairs (VA) Health Care System, Phoenix, AZ (D.C.S., P.D.R.); College of Nursing and Health Innovation, Arizona State University, Phoenix (D.C.S.); SUNY Health Science Center at Brooklyn, Brooklyn, NY (M.B.); Pennington Biomedical Research Center– Louisiana State University, Baton Rouge (G.A.B.); University of Southern California Keck School of Medicine, Los Angeles (T.A.B., H.N.H., W.J.M.); Division of Endocrinology and Metabolism, Georgetown University, Washington, DC (S.C.C.); VA San Diego Healthcare System and University of California at San Diego, San Diego (R.R.H., S.M.); University of Tennessee, Division of Endocrinology, Diabetes, and Metabolism, Memphis (A.E.K., F.B.S.); and Medstar Research Institute, Hyattsville, MD (R.E.R.) N Engl J Med 2011;364:

6 BACKGROUND Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.

7 METHODS We conducted a randomized, double-blind, placebo- controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.

8 Figure 1. Enrollment, Randomization, and Follow-up of Study Patients. FPG denotes fasting plasma glucose, and OGTT oral glucose-tolerance test.

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12 Figure 3. Incidence Rates, Hazard Ratios, and Tests for Heterogeneity for All Patients and Selected Subgroups. The figure shows incidence rates per 100 person-years and corresponding hazard ratios and confidence intervals for the effects of pioglitazone as compared with placebo on the conversion of impaired glucose tolerance to diabetes. The x axis is interrupted to allow for better visual presentation. BMI denotes body-mass index (the weight in kilograms divided by the square of the height in meters), IFG impaired fasting glucose, and IGT impaired glucose tolerance. To convert the values for glucose to millimoles per liter, multiply by

13 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), and carotid intima–media thickness (Panel I). 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.) 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. P values are shown for the interaction between time and study group, indicating whether the slopes differ significantly over time.

14 EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY 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).

15 EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 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).

16 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: Intra-arterial Fat Artery

17 *For the comparison of placebo and pioglitazone regarding frequency of edema, cardiovascular events, and total events, P = 0.007, P = 0.80, and P = 0.03, respectively. The total number of adverse events — excluding edema — did not differ significantly between groups (P = 0.52). †Edema was defined as an increase above baseline by two or more grades on one or more distinct study visits. ‡Weight gain was defined as a gain of more than 1 kg.

18 RESULTS Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima–media thickening (31.5%, P = 0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P = 0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P = 0.007).

19 CONCLUSIONS As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT )

20 Message/Comments ACTNOW 研究の結果の報告がかなり遅れ ていたが今回発表された。 ピオグリタゾンの糖尿病発症予防は 72% である。

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22 2009_294 臨床研究: FMD と ARB 2009_307 臨床研究:プロインスリン 2010_334 臨床研究: DPP4I と OGTT 2010_342 臨床研究: DPP4I 長期介入 2010_350 臨床研究: DPP4I 抗 GAD 陽性者 2010_351 臨床研究:インスリン作用指標と血糖管 理 2011_398 臨床研究: DPP4I 獨協プロトコール

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24 Message/Comments 過去2年、埼玉医科大学総合医療センター内分 泌・糖尿病内科で行う臨床研究の準備を進めて きたが、やっと倫理委員会の承認や検査会社と の契約ができ開始できそうである。

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