Presentation on theme: "Journal Club 2011年3月31日 8:30-8:55 ８階 医局"— Presentation transcript:
1 Journal Club 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):2011年3月31日 8:30-8:55８階 医局埼玉医科大学 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
2 Primary Prevention of Type 2 Diabetes Mellitus ● 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 DiabetesEDIT：Early Diabetes Intervention Trial,NAVIGATOR：Natglinide and Valsartan in Impaired Glucose Tolerance Outcome ReaserachDREAM：Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications
3 Prevention of Diabetes Mellitus Trialpublicationfollow-up, yeardrugNo. of newon-set of DMNo.(total)eventper 1000 person-yearscontrolThiazolidine*DPP20050.9Troglitazone1038728.7PlaceboMetforminILS372116391397393105.158.845.2TRIPOD20022.51711459.6122121.3PIPOD20063.0Pioglitazone118642.6-*DREAMRosiglitazone306236543.1686263486.8*ACTNOW20084.03038.34529937.6*CANOE20103.9Met+Rosi1410334.941104101.1Other (α-GI, statin, fibrate, glinide)WOSCOP20015Pravastation5729993.88239755.5*STOP- NIDDM3.3Acarbose22168298.2285125.9BIP20046.2Bezafibrate6615668.28014787.8*VICTORY20094Voglibose5089713.910688130.0*NAVIGATOR6.5Nateglinide1674372669.11580374764.9Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22,
4 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.BMJ 2011;342:d1309Meta-analysis of odds ratio for overall mortality with rosiglitazone versus pioglitazone
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 BACKGROUNDImpaired 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 METHODSWe 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.
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 10Insulin 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).P<0.00186Matsuda Index42PrePostPrePost
15 EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX 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<0.005654I/G xMatsuda (0-120)321PrePostPrePost
16 Effect of Thiazolidinediones on Fat Topography High FFAFFATZDIntramuscular FatHarold Bays, Lawrence Mandarino, and Ralph A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., Feb 2004; 89:Subcutaneous FatIntrahepatic FatIntra-arterial FatIntraabdominal FatArteryBays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:
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 RESULTSAnnual 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 CONCLUSIONSAs 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 )