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, Maria Masulli, Antonio Nicolucci, Enzo Bonora, Stefano Del Prato, Aldo P Maggioni, Angela A Rivellese, Sebastiano Squatrito, Carlo B Giorda, Giorgio Sesti, Paolo Mocarelli, Giuseppe Lucisano, Michele Sacco, Stefano Signorini, Fabrizio Cappellini, Gabriele Perriello, Anna Carla Babini, Annunziata Lapolla, Giovanna Gregori, Carla GiordanoLaura Corsi, Raffaella Buzzetti, Gennaro Clemente, Graziano Di Cianni, Rossella Iannarelli, Renzo Cordera, Olga La Macchia, Chiara Zamboni, Cristiana Scaranna, Massimo Boemi, Ciro Iovine, Davide Lauro, Sergio Leotta, Elisabetta Dall'Aglio, Emanuela Cannarsa, Laura Tonutti, Giuseppe Pugliese, Antonio C Bossi, Roberto Anichini, Francesco Dotta, Antonino Di Benedetto, Giuseppe Citro, Daniela Antenucci, Lucia Ricci, Francesco Giorgino, Costanza Santini, Agostino Gnasso, Salvatore De Cosmo, Donatella Zavaroni, Monica Vedovato, Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group

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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.

Original languageEnglish
Pages (from-to)887-897
Number of pages11
JournalThe Lancet Diabetes and Endocrinology
Volume5
Issue number11
DOIs
Publication statusPublished - Sep 13 2017

Keywords

  • Journal Article

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