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 - PubMed (original) (raw)

Randomized Controlled Trial

. 2017 Nov;5(11):887-897.

doi: 10.1016/S2213-8587(17)30317-0. Epub 2017 Sep 13.

Maria Masulli 2, Antonio Nicolucci 3, Enzo Bonora 4, Stefano Del Prato 5, Aldo P Maggioni 6, Angela A Rivellese 2, Sebastiano Squatrito 7, Carlo B Giorda 8, Giorgio Sesti 9, Paolo Mocarelli 10, Giuseppe Lucisano 3, Michele Sacco 3, Stefano Signorini 10, Fabrizio Cappellini 10, Gabriele Perriello 11, Anna Carla Babini 12, Annunziata Lapolla 13, Giovanna Gregori 14, Carla Giordano 15, Laura Corsi 16, Raffaella Buzzetti 17, Gennaro Clemente 18, Graziano Di Cianni 19, Rossella Iannarelli 20, Renzo Cordera 21, Olga La Macchia 22, Chiara Zamboni 23, Cristiana Scaranna 24, Massimo Boemi 25, Ciro Iovine 26, Davide Lauro 27, Sergio Leotta 28, Elisabetta Dall'Aglio 29, Emanuela Cannarsa 30, Laura Tonutti 31, Giuseppe Pugliese 32, Antonio C Bossi 33, Roberto Anichini 34, Francesco Dotta 35, Antonino Di Benedetto 36, Giuseppe Citro 37, Daniela Antenucci 38, Lucia Ricci 39, Francesco Giorgino 40, Costanza Santini 41, Agostino Gnasso 42, Salvatore De Cosmo 43, Donatella Zavaroni 44, Monica Vedovato 45, Agostino Consoli 46, Maria Calabrese 47, Paolo di Bartolo 48, Paolo Fornengo 49, Gabriele Riccardi 2; Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society

Collaborators, Affiliations

Randomized Controlled Trial

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

Olga Vaccaro et al. Lancet Diabetes Endocrinol. 2017 Nov.

Erratum in

Abstract

Background: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes.

Methods: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856.

Findings: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.

Interpretation: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events.

Funding: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Copyright © 2017 Elsevier Ltd. All rights reserved.

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