Actos Now for the prevention of diabetes (ACT NOW) study

Ralph A Defronzo, Maryann Banerji, George A Bray, Thomas A Buchanan, Stephen Clement, Robert R Henry, Abbas E Kitabchi, Sunder Mudaliar, Nicolas Musi, Robert Ratner, Peter D Reaven, Dawn Schwenke, Frankie B Stentz, Devjit Tripathy, Ralph A Defronzo, Maryann Banerji, George A Bray, Thomas A Buchanan, Stephen Clement, Robert R Henry, Abbas E Kitabchi, Sunder Mudaliar, Nicolas Musi, Robert Ratner, Peter D Reaven, Dawn Schwenke, Frankie B Stentz, Devjit Tripathy

Abstract

Background: Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

Methods/design: 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140-199 mg/dl). In addition, IGT subjects were required to have FPG = 95-125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2-3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.Primary endpoint is conversion of IGT to T2DM based upon FPG >or= 126 or 2-hour PG >or= 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.

Conclusion: ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.

Trial registration: clinical trials.gov identifier: NCT00220961.

References

    1. Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM, Saydah SH, Williams DE, Geiss LS, Gregg EW. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999–2002. Diabetes Care. 2006;29:1263–1268. doi: 10.2337/dc06-0062.
    1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–1053. doi: 10.2337/diacare.27.5.1047.
    1. World Health Organization . Diabetes Programme Facts and Figures, 2007. World Health Organisation; Geneva, Switzerland;
    1. UK Prospective Diabetes Study Group Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37) Diabetes Care. 1999;22:1125–1136. doi: 10.2337/diacare.22.7.1125.
    1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR, Prospective Diabetes Study Group Association of glycaemia with macrovascular and microvascular complications on type 2 dia betes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412. doi: 10.1136/bmj.321.7258.405.
    1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998. pp. 837–853.
    1. Klein R, Barrett-Connor EL, Blunt BA, Wingard DL. Visual impairment and retinopathy in people with normal glucose tolerance, impaired glucose tolerance, and newly diagnosed NIDDM. Diabetes Care. 1991;14:914–918. doi: 10.2337/diacare.14.10.914.
    1. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23:B21–29.
    1. American Diabetes Association Economic costs of diabetes in the US in 2007. Diabetes Care. 2008;31:1–20. doi: 10.2337/dc08-S001.
    1. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37:667–687.
    1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–794. doi: 10.1172/JCI7231.
    1. Festa A, Williams K, D'Agostino R, Jr, Wagenknecht LE, Haffner SM. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes. 2006;55:1114–1120. doi: 10.2337/diabetes.55.04.06.db05-1100.
    1. Lyssenko V, Almgren P, Anevski D, Perfekt R, Lahti K, Nissen M, Isomaa B, Forsen B, Homstrom N, Saloranta C, Taskinen MR, Groop L, Tuomi T. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes. 2005;54:166–174. doi: 10.2337/diabetes.54.1.166.
    1. Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Kawakubo M, Buchanan TA. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006;55:517–522. doi: 10.2337/diabetes.55.02.06.db05-1066.
    1. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–1350. doi: 10.1056/NEJM200105033441801.
    1. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403. doi: 10.1056/NEJMoa012512.
    1. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096–1105. doi: 10.1016/S0140-6736(06)69829-2.
    1. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51:2796–2803. doi: 10.2337/diabetes.51.9.2796.
    1. Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, Khunti K. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007;334:299–308. doi: 10.1136/bmj.39063.689375.55.
    1. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Beta cell function in subjects spanning the range from normal glucose tolerance to over diabetes: A new analysis. J Clin Endocrinol Metab. 2005;90:493–500. doi: 10.1210/jc.2004-1133.
    1. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006;55:1430–1435. doi: 10.2337/db05-1200.
    1. Abdul-Ghani A, Tripathy D, DeFronzo RA. Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–1139. doi: 10.2337/dc05-2179.
    1. Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferrannini E, Cusi K, Mandarino LJ, DeFronzo RA. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care. 2001;24:710–719. doi: 10.2337/diacare.24.4.710.
    1. Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes. 2003;52:1943–1950. doi: 10.2337/diabetes.52.8.1943.
    1. Kim YB, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar S, Henry RR, Kahn BB. Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110 beta protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes. 2002;51:443–448. doi: 10.2337/diabetes.51.2.443.
    1. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128:176–185.
    1. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab. 2007;292:E871–883. doi: 10.1152/ajpendo.00551.2006.
    1. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443. doi: 10.1056/NEJMoa066224.
    1. American Diabetes Association Diagnosis and Classification of Diabetes. Diabetes Care. 2008;31:S55–S60. doi: 10.2337/dc08-S055.
    1. Roberts LJ, 2nd, Morrow JD. The generation and actions of isoprostanes. Biochim Biophys Acta. 1997;1345:121–135.
    1. Papamichael CM, Lekakis JP, Stamatelopoulos KS, Papaioannou TG, Alevizaki MK, Cimponeriu AT, Kanakakis JE, Papapanagiotou A, Kalofoutis AT, Stamatelopoulos SF. Ankle-brachial index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease. Am J Cardiol. 2000;86:615–618. doi: 10.1016/S0002-9149(00)01038-9.
    1. Bergman RN. Toward physiologic understanding of glucose tolerance. Diabetes. 1989;38:1512–1517. doi: 10.2337/diabetes.38.12.1512.
    1. Hodis HN, Mack WJ, Barth J. Carotid intima-media thickness as a surrogate end point for coronary artery disease. Circulation. 1996;94:2311–2312.
    1. Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 1992;41:368–377. doi: 10.2337/diabetes.41.3.368.
    1. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Beta cell dysfunction and glucose intolerance: Results from the San Antonio Metabolism (SAM) study. Diabetologia. 2004;47:31–39. doi: 10.1007/s00125-003-1263-9.
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic glucose clamp. Diabetes Care. 1999;22:1462–1470. doi: 10.2337/diacare.22.9.1462.
    1. Mathews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883.
    1. Groop LC, Bonadonna RC, Shank M, Petrides AS, DeFronzo RA. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest. 1991;87:83–89. doi: 10.1172/JCI115005.
    1. Peduzzi P, Wittes J, Detre K, Holford T. Analysis as-randomized and the problem of non-adherence: an example from the Veterans Affairs Randomized Trial of Coronary Artery Bypass Surgery. Statistics in Medicine. 1993;12:1185–1195. doi: 10.1002/sim.4780121102.
    1. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: John Wiley; 1980.
    1. Lachin JM, Wei LJ. Estimators and tests in the analysis of multiple nonindependent 2 × 2 tables with partially missing observations. Biometrics. 1988;44:513–528. doi: 10.2307/2531864.
    1. The Diabetes Prevention Program Research Group The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care. 2000;23:1619–1629. doi: 10.2337/diacare.23.11.1619.
    1. Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorking JD, Muller DC, Collins VR, Hamman RF. Predictors of progression from impaired glucose tolerance to NIDDM: An analysis of six prospective studies. Diabetes. 1997;46:701–710. doi: 10.2337/diabetes.46.4.701.
    1. Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang AN, Buchanan TA, for the TRIPOD Study Group TRIPOD (TRoglitazone In the Prevention Of Diabetes): A randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus. Controlled Clin Trials. 1998;19:217–231. doi: 10.1016/S0197-2456(97)00151-7.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren