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Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

2021; Elsevier BV; Volume: 398; Issue: 10313 Linguagem: Inglês

10.1016/s0140-6736(21)02188-7

1474-547X

Stefano Del Prato, Steven E. Kahn, Imre Pávó, Govinda J. Weerakkody, Zhengyu Yang, John Doupis, Diego Aizenberg, Alan Wynne, Jeffrey S. Riesmeyer, Robert J. Heine, Russell J. Wiese, Andrew Ahmann, Samir Arora, Eric Ball, Rafael Burgos-Calderón, David Butuk, Leila Chaychi, Michael C. Chen, Brian M. Curtis, Ronald H. Chochinov, Christopher Chow, Clancy Cone, Lisa Connery, Gregorio Cortes-Maisonet, José de Souza, Kathleen Dungan, David Bradley, Juan P. Frías, Nashwa Gabra, Linda Gaudiani, Luis Herandez-Vazquez, Stanley H. Hsia, Michael Jardula, E. Klein, Mark E Kutner, Juan Loy, Francisco G Miranda, Lazaro Nunez, Miguel Mujica-Baella, Alexander V. Murray, Michael Oliver, Ramon Oritz-Carrasquillo, Betsy Palal, Michael T Parke, Athena Philis‐Tsimikas, Raman Purighalla, Julio Rosenstock, Airani Sathananthan, Courtney Shelton, Kanagaratnam Sivalingam, Ehab Sorial, Joseph Soufer, Helen L Stacey, Larry D. Stonesifer, Stanley Stringam, Joanna Van, Jose Vazquez-Tanus, Ramón López de los Reyes, Michelle Welch, Najmuddin Karimjee, Earl E Martin, Ahmed A. Arif, Timothy W Jennings, Neil J. Fraser, Anuj Bhargava, Alan Wynne, Evelyne Davidson, Liana K. Billings, Elizabeth A Barranco-Santana, Michael Dever, Patrick Walsh, A.K. Cho, James W. Chu, Jay H. Shubrook, Albert B. Knouse, Venkatesh Nadar, Lorena Lewy-Alterbaum, Michael Lillestol, Daniel J Humiston, Alexander White, Ronald K. Mayfield, Fahed Bitar, Fernando Cereto, Carmen de la Cuesta, L. de Teresa Parreño, Esteban Jódar Gimeno, Pedro Mezquita‐Raya, Cristóbal Morales, Miguel Quesada Charneco, Francisco J. Tinahones, Santiago Tofé, Luis Alberto Vázquez, Carmen Fajardo, Alfonso González, Cristina Mistodie, Iosif Szilagyi, Adriana Filimon, Nicoleta Mîndrescu, Lavinia Pop, Marlena Pascu, Gabriela Negrişanu, Daniela Ciomos, Valentina Neacsu, Amalia Thury-Burileanu, Idit F. Liberty, Naftali Stern, Yael Sofer, Jessica Sack, Ilan Shimon, Amir Tirosh, Avraham Ishay, Ofri Mosenzon Ninio, Naim Shehadeh, Julio Wainstein, Mahmud Darawsha, Dasa Skripova, Eva Pavleova, Viera Doničová, Ludmila Kubincova, Dalibor Sosovec, Martina Merciakova, Fadia El Boreky, Eric St-Amour, Zeina Yared, François Blouin, Buki Ajala, Naresh Aggarwal, Harpreet S. Bajaj, Chetna Tailor, Alan Egan, John O’Mahony, Natasha St.Onge, James R. W. Conway, Gustavo Akerman Augusto, João Borges, Maria Cerqueira, Denise Reis Franco, Tatiana Franco Hirakawa, Filipe D Souza, Miguel Nasser Hissa, Luciana Muniz Pechmann, Camila P Calil Salim, Luis Augusto T Russo, Joselita Siqueira, Sonia A Sassone, Jorge Archibaldo Glenny, Martín Koretzky, Diego Aizenberg, Andrea Steinacher, Silvana E Solis, Lucrecia Nardone, Federico C. Pérez Manghi, Silvia Ines Orio, Elizabeth Gelersztein, Jose Osvaldo Fretes, Pedro Calella, Cesar Javier Zaidman, Alejandro Chertkoff, Susana Salzberg, Claudio Majul, Luis A Nevarez, R. Ortiz, R. Elizondo, R. Villicana, Guillermo González-Gálvez, C. Calvo, Andrzej Kościański, H Rudzki, Andrzej Stankiewicz, Dariusz Sowiński, Ewa Krzyżagórska, Małgorzata Józefowska, Beata Matyjaszek‐Matuszek, Edward Franek, Ewa Skokowska, Anna Modzelewska, Ewa Szyprowska, Richard W Simpson, Christopher Gilfillan, David Colquhoun, Timothy M. E. Davis, Claire Morbey, Shannon E McCarthy, Kamal Kaur, Laurence Kemp, Antony J Shea, Yuriy Khalimov, Olga A Miroshnichenko, I. V. Dvoryashina, И. А. Карпова, М. А. Куницына, Н. В. Ворохобина, G. R. Galstyan, Ирина Аркадьевна Бондарь, Evgeniy V Filippov, О. Б. Ершова, Horng‐Yih Ou, Shih-Ting Tseng, Jung‐Fu Chen, Kai‐Jen Tien, Chien‐Ning Huang, Ching‐Chu Chen, Chii‐Min Hwu, Te‐Lin Hsia, John Doupis, Emmanouil Pagkalos, Zadalla Mouslech, Αlexandra Bargiota, Kalliopi Kotsa,

Metabolism, Diabetes, and Cancer

Background We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. Methods This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Findings Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. Interpretation In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Funding Eli Lilly and Company.