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Lancet Diabetes Endocrinol. 2017 Nov;5(11):887-897. doi: 10.1016/S2213-8587(17)30317-0. Epub 2017 Sep 13.

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.

Collaborators (384)

Vaccaro O, Masulli M, Nicolucci A, Maggioni AP, Sesti G, Mocarelli P, Lucisano G, Sacco M, Signorini S, Cappellini F, Riccardi G, Boemi M, D'Angelo F, Giansanti R, Tanase L, Lanari L, Testa I, Ricci L, Pancani F, Ranchelli A, Vagheggi P, Scatona A, Fontana L, Giorgino F, Laviola L, Tarantino L, Ippolito C, Gigantelli V, Manicone M, Conte E, Trevisan R, Scaranna C, Rota R, Corsi A, Dodesini AR, Reggiani GM, Montesi L, Mazzella N, Forlani G, Caselli C, Di Luzio R, Mazzotti A, Aiello A, Barrea A, Musto A, D'Amico F, Squatrito S, Sinagra T, Longhitano S, Trowpea V, Sparti M, Italia S, Lisi E, Grasso G, Pezzino V, Insalaco F, Gnasso A, Carallo C, Scicchitano C, De Franceschi MS, Santini C, Mazzotti A, Caselli C, Calbucci G, Ripani R, Corsi L, Cuneo G, Corsi S, Giorda CB, Romeo F, Lesina A, Comoglio M, Bonetto C, Robusto A, Nada E, Asprino V, Cetraro R, Impieri M, Lucchese G, Donnarumma G, Tizio B, Clemente G, Lenza L, Paraggio P, Tomasi F, Zamboni C, Dozio N, Scalambra E, Mannucci E, Lamanna C, Cignarelli M, Macchia O, Fariello S, Sorrentino MR, Franzetti I, Radin R, Cordera R, Annunziata F, Bonabello LA, Durante A, Dolcino M, Gallo F, Mazzucchelli C, Aleo A, Melga P, Briatore L, Maggi D, Storace D, Cecoli F, Antenucci D, D'Ugo E, Pupillo M, Baldassarre MPA, Salvati F, Minnucci A, De Luca A, Zugaro A, Santarelli L, Bosco A, Petrella V, La Verghetta GG, Iannarelli R, De Gregorio A, D'Andrea S, Giuliani AE, Polidoro WL, Sperandio A, Sciarretta F, Pezzella A, Buzzetti R, Carlone A, Potenziani S, Venditti C, Foffi C, Carbone S, Cipolloni L, Moretti C, Leto G, Serra R, Petrachi F, Romano I, Di Cianni G, Lacaria E, Russo L, Goretti C, Sannino C, Gregori G, Dolci M, Bruselli L, Mori ML, Baccetti F, Del Freo M, Fontana L, Di Benedetto A, Cucinotta D, Giunta L, Ruffo MC, Cannizzaro D, Pintaudi B, Perrone G, Pata P, Ragonese F, Lettina G, Mancuso T, Coppolino A, Piatti PM, Monti L, Stuccillo M, Lucotti P, Setola M, Crippa GV, Loi C, Oldani M, Bottalico ML, Pellegata B, Bonomo M, Menicatti LSM, Resi V, Bertuzzi F, Disoteo EO, Pizzi G, Rivellese AA, Annuzzi G, Capaldo B, Nappo R, Auciello SM, Turco AA, Costagliola L, Iovine C, Corte GD, Vallefuoco P, Nappi F, Vitale M, Cocozza S, Ciano O, Massimino E, Garofalo N, Avogaro A, Vedovato M, Guarneri G, Lapolla A, Fedele D, Sartore G, Chilelli NC, Burlina S, Bonsembiante B, Giordano C, Galluzzo A, Torregrossa V, Dall'Aglio E, Mancastroppa G, Arsenio L, Cioni F, Caronna S, Papi M, Babini M, Perriello G, Santeusanio F, Calagreti G, Timi A, Tantucci A, Marino C, Consoli A, Ginestra F, Di Biagio R, Taraborelli M, Del Prato S, Miccoli R, Bianchi C, Garofolo M, Politi KS, Penno G, Zavaroni D, Livraga S, Calzoni F, Mancastroppa GLF, Anichini R, Corsini E, Tedeschi A, Gaglianò MS, Ippolito G, Salutini E, Citro G, Cervellino F, Natale M, Salvatore V, Zampino A, Sinisi R, Calabrese M, Arcangeli A, Zogheri A, Guizzotti S, Longo R, Di Bartolo P, Caselli C, Pellicano F, Scolozzi P, Termine S, Luberto A, Ballardini G, Babini AC, Ripani R, Trojani C, Mazzuca P, Bruglia M, Ciamei M, Genghini S, Zannoni C, Pugliese G, Vitale M, Rangel G, Salvi L, Zappaterreno A, Cordone S, Simonelli P, Meggiorini M, Frasheri A, Di Pippo C, Maglio C, Mazzitelli G, Lauro D, Rinaldi ME, Galli A, Romano M, D'Angelo P, Leotta S, Suraci C, De Cosmo S, Bacci S, Palena AP, Genovese S, Mancino M, Rondinelli M, Capone F, Calabretto E, Bulgheroni M, Bucciarelli L, Dotta F, Ceccarelli E, Fondelli C, Santacroce C, Guarino E, Nigi L, Lalli C, Di Vizia G, Scarponi M, Montani V, Di Bernardino P, Romagni P, Dolcetti K, Cannarsa E, Forte E, Potenziani S, Tamburo L, Fornengo P, Perin PC, Prinzis T, Gruden G, Bruno G, Zucco C, Perotta M, Marena S, Monsignore S, Panero F, Ponzi F, Bossi AC, Carpinteri R, Casagrande ML, Coletti MF, Menicatti LSM, Balini A, Filopanti M, Madaschi S, Pulcina A, Grimaldi F, Tonutti L, Venturini G, Agus S, Pagnutti S, Guidotti F, Cavarape A, Casagrande ML, Bonora E, Cigolini M, Pichiri I, Brangani C, Fainelli G, Tomasetto E, Zoppini G, Galletti A, Perrone D, Capra C, Bianchini F, Ceseri M, Di Nardo B, Sasso E, Bartolomei B, Suliman I, Fabbri G, Romano G, Maturo N, Nunziata G, Capobianco G, De Simone G, Villa V, Rota G, Pentangelo C, Carbonara O, Caiazzo G, Cutolo M, Sorrentino T, Mastrilli V, Amelia U, Masi S, Corigliano G, Gaeta I, Armentano V, Calatola P, Capuano G, Angiulli B, Auletta P, Petraroli E, Iodice CE, Agrusta M.

Author information

1
Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. Electronic address: ovaccaro@unina.it.
2
Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
3
Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.
4
Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy.
5
Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.
6
National Association of Hospital Cardiologists (ANMCO) Research Center, Florence, Italy.
7
Diabetes Unit, University Hospital Garibaldi-Nesima of Catania, Catania, Italy.
8
Diabetes Unit, Azienda Sanitaria Locale (ASL) Torino 5, Torino, Italy.
9
Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy.
10
University Department Laboratory Medicine, Hospital of Desio, Monza, Italy.
11
Endocrinology and Metabolism, University of Perugia, Perugia, Italy.
12
Medical Division, Rimini Hospital, Rimini, Italy.
13
Dipartimento di Medicina, Università di Padova, Padova, Italy.
14
Diabetes Unit, Massa Carrara, Azienda Unità Sanitarie Locali (USL) Toscana Nord Ovest, Carrara, Italy.
15
Section of Endocrinology, Diabetology and Metabolic Diseases, University of Palermo, Palermo, Italy.
16
Diabetes Unit, ASL 4 Chiavarese, Chiavari, Italy.
17
Department of Experimental Medicine, Sapienza University, Rome, Italy.
18
Institute for Research on Population and Social Policies-National Research Council, Penta di Fisciano, Italy.
19
Diabetes and Metabolism, Livorno Hospital, Livorno, Italy.
20
Diabetes Unit, Department of Medicine, San Salvatore Hospital, L'Aquila, Italy.
21
Diabetes Unit, School of Medicine, University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Hospital, Genova, Italy.
22
Endocrinology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Foggia, Italy.
23
Diabetes Unit, University of Ferrara, Ferrara, Italy.
24
Endocrinology and Diabetology, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.
25
Diabetes and Metabolism Unit, IRCCS Istituto Nazionale Riposo e Cura Anziani, Ancona, Italy.
26
Diabetes Unit, University of Naples Federico II, Naples, Italy.
27
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
28
UOC Diabetologia Ospedale Sandro Pertini, Rome, Italy.
29
Clinical and Experimental Medicine, University of Parma, Parma, Italy.
30
Diabetes Unit, San Liberatore Hospital, Atri Teramo, Italy.
31
Endocrinology, Diabetes, Metabolism and Clinical Nutrition Unit, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.
32
Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.
33
ASST Bergamo Ovest, Treviglio, Italy.
34
Diabetes Unit, USL 3, Pistoia, Italy.
35
Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
36
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
37
Endocrinology and Diabetes Unit, Azienda Sanitaria Locale di Potenza, Potenza, Italy.
38
Diabetes Unit, Renzetti Hospital, ASL 2 Abruzzo, Lanciano, Italy.
39
Diabetes Unit, USL Sud Est, Toscana, Italy.
40
Department of Emergency and Organ Transplantation, Endocrinology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Apulia, Italy.
41
Department Endocrinology and Diabetology, Cesena Hospital, Cesena, Italy.
42
Department of Clinical and Experimental Medicine, Magna Graecia University of Catanzaro, Italy.
43
Unit of Internal Medicine, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
44
Diabetes Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy.
45
Metabolism Unit, Azienda Ospedaliera di Padova, Padova, Italy.
46
Department of Medicine and Aging Sciences, and Aging and Translational Medicine Research Center (CeSI-Met), D'Annunzio University, Chieti-Pescara, Italy.
47
Diabetes Unit, USL Toscana Centro, Prato, Italy.
48
Diabetes Unit, Ravenna Internal Medicine Department, Romagna Local Health Unit, Ravenna, Italy.
49
Department of Medical Sciences, University of Turin, Turin, Italy.

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.

PMID:
28917544
DOI:
10.1016/S2213-8587(17)30317-0
[Indexed for MEDLINE]

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