Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial

Summary

Background: In patients with type 2 diabetes inadequately controlled with metformin, two main therapeutic options are equally plausible: add-on a sulfonylurea (SU) or a thiazolidinedione (TZD). Since the two classes of drugs clearly differ in terms of mechanisms of action, side effects, economic costs and cardiovascular risk factors profile, a direct comparison of the two therapeutic strategies would be most appropriate. Aims: 1) To evaluate the effects of add-on pioglitazone as compared with add-on a SU on the incidence of cardiovascular events in type 2 diabetic patients inadequately controlled with metformin; 2) To compare the two treatments in terms of glycemic control, safety, and economic costs. Methods: multicentre, randomised, open label, parallel group trial of 48 months duration. Eligible participants (type 2 diabetic males and females, aged 50-75 years, BMI 20-45 Kg/m2, in treatment for the last two months with metformin 2 gr/die in monotherapy and with HbA1c \> =7.0% and \<= 9.0%) will be randomized to add-on: a SU - glibenclamide (5-15 mg/die), gliclazide (30-120 mg/die), glimepiride (2-6 mg/die), chosen according to local practice - or pioglitazone (15-45 mg/die). A HbA1c value \> 8.0 % on two consecutive occasions will lead to addition of insulin to ongoing oral therapy. Primary efficacy outcome: a composite endpoint of all-cause mortality, non fatal MI (including silent MI), non fatal stroke, and unplanned coronary revascularization. Secondary outcomes. Principal secondary outcome: a composite ischemic endpoint of sudden death, fatal and non fatal acute MI (including silent MI), fatal and non fatal stroke, major amputations (above ankle), endovascular or surgical intervention on the coronary, leg or carotid arteries. Other secondary outcomes \- a composite cardiovascular end point including the primary end point plus hospitalization for heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries, silent MI, angina - by WHO criteria and confirmed by a new electrocardiogram abnormality - intermittent claudication with an ankle/brachial index lower than 090; events of heart failure; a microvascular endpoint including: plasma creatinine increase of 2 times above the baseline value or creatinine clearance reduction of 20ml/min/1. 73m2 or development of overt nephropathy (dialysis or plasma creatinine \>3,3 mg/dl) or macroalbuminuria; glycemic control (changes from baseline in HBA1c, time to failure of glycemic control, i.e., HBA1c \>8.0% on two consecutive occasions three months apart); major CV risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference); safety and side effects; direct and indirect costs. Data regarding CV endpoints, safety, tolerability, and study conduct will be monitored and analyzed by an independent committee, and will be not available to the study investigators until the closing of data collection. Efficacy end points will be analyzed on an intention-to-treat basis.

Timeline

Start

2008-09

Primary completion

2018-12

Completion

2018-12

Publications

• Background Vaccaro O, Masulli M, Bonora E, Del Prato S, Nicolucci A, Rivellese AA, Riccardi G; TOSCA.IT Study Group. The TOSCA.IT trial: a study designed to evaluate the effect of pioglitazone versus sulfonylureas on cardiovascular disease in type 2 diabetes. Diabetes Care. 2012 Dec;35(12):e82. doi: 10.2337/dc12-0954. No abstract available.
• Background Vaccaro O, Masulli M, Bonora E, Del Prato S, Giorda CB, Maggioni AP, Mocarelli P, Nicolucci A, Rivellese AA, Squatrito S, Riccardi G; TOSCA.IT study group (Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents. Intervention Trial). Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2012 Nov;22(11):997-1006. doi: 10.1016/j.numecd.2012.09.003. Epub 2012 Oct 11.
• Della Pepa G, Carli F, Sabatini S, Pezzica S, Russo M, Vitale M, Masulli M, Riccardi G, Rivellese AA, Vaccaro O, Bozzetto L, Gastaldelli A. Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control. Diabetes Metab Res Rev. 2024 May;40(4):e3798. doi: 10.1002/dmrr.3798.
• Masulli M, Lucisano G, Bonora E, Del Prato S, Rivellese AA, Signorini S, Mocarelli P, Riccardi G, Vaccaro O, Nicolucci A; TOSCA.IT Investigators. A few clinical features improve the prediction of mortality and cardiovascular outcomes in patients with type 2 diabetes. Eur J Prev Cardiol. 2022 Feb 9;28(18):e1-e3. doi: 10.1093/eurjpc/zwaa002. No abstract available.
• Masulli M, Della Pepa G, Cocozza S, Capasso M, Pignataro P, Vitale M, Gastaldelli A, Russo M, Dolce P, Riccardi G, Rivellese AA, Vaccaro O. The Pro12Ala polymorphism of PPARgamma2 modulates beta cell function and failure to oral glucose-lowering drugs in patients with type 2 diabetes. Diabetes Metab Res Rev. 2021 Mar;37(3):e3392. doi: 10.1002/dmrr.3392. Epub 2020 Sep 2.
• Sartore G, Chilelli NC, Seraglia R, Ragazzi E, Marin R, Roverso M, Cosma C, Vaccaro O, Burlina S, Lapolla A. Long-term effect of pioglitazone vs glimepiride on lipoprotein oxidation in patients with type 2 diabetes: a prospective randomized study. Acta Diabetol. 2019 May;56(5):505-513. doi: 10.1007/s00592-018-01278-2. Epub 2019 Feb 10.
• Vaccaro O, Masulli M, Nicolucci A, Bonora E, Del Prato S, Maggioni AP, Rivellese AA, Squatrito S, Giorda CB, Sesti G, Mocarelli P, Lucisano G, Sacco M, Signorini S, Cappellini F, Perriello G, Babini AC, Lapolla A, Gregori G, Giordano C, Corsi L, Buzzetti R, Clemente G, Di Cianni G, Iannarelli R, Cordera R, La Macchia O, Zamboni C, Scaranna C, Boemi M, Iovine C, Lauro D, Leotta S, Dall'Aglio E, Cannarsa E, Tonutti L, Pugliese G, Bossi AC, Anichini R, Dotta F, Di Benedetto A, Citro G, Antenucci D, Ricci L, Giorgino F, Santini C, Gnasso A, De Cosmo S, Zavaroni D, Vedovato M, Consoli A, Calabrese M, di Bartolo P, Fornengo P, Riccardi G; Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):887-897. doi: 10.1016/S2213-8587(17)30317-0. Epub 2017 Sep 13.
• Vitale M, Vaccaro O, Masulli M, Bonora E, Del Prato S, Giorda CB, Nicolucci A, Squatrito S, Auciello S, Babini AC, Bani L, Buzzetti R, Cannarsa E, Cignarelli M, Cigolini M, Clemente G, Cocozza S, Corsi L, D'Angelo F, Dall'Aglio E, Di Cianni G, Fontana L, Gregori G, Grioni S, Giordano C, Iannarelli R, Iovine C, Lapolla A, Lauro D, Laviola L, Mazzucchelli C, Signorini S, Tonutti L, Trevisan R, Zamboni C, Riccardi G, Rivellese AA; TOSCA.IT Study Group. Polyphenol intake and cardiovascular risk factors in a population with type 2 diabetes: The TOSCA.IT study. Clin Nutr. 2017 Dec;36(6):1686-1692. doi: 10.1016/j.clnu.2016.11.002. Epub 2016 Nov 14.
• Vitale M, Masulli M, Cocozza S, Anichini R, Babini AC, Boemi M, Bonora E, Buzzetti R, Carpinteri R, Caselli C, Ceccarelli E, Cignarelli M, Citro G, Clemente G, Consoli A, Corsi L, De Gregorio A, Di Bartolo P, Di Cianni G, Fontana L, Garofolo M, Giorda CB, Giordano C, Grioni S, Iovine C, Longhitano S, Mancastroppa G, Mazzucchelli C, Montani V, Mori M, Perriello G, Rinaldi ME, Ruffo MC, Salvi L, Sartore G, Scaranna C, Tonutti L, Zamboni C, Zogheri A, Krogh V, Cappellini F, Signorini S, Riccardi G, Vaccaro O; TOSCA.IT Study Group. Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):879-85. doi: 10.1016/j.numecd.2016.04.006. Epub 2016 Apr 16.

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Indications