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Lancet. 2018 Oct 27;392(10157):1519-1529. doi: 10.1016/S0140-6736(18)32261-X. Epub 2018 Oct 2.

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.

Collaborators (795)

Del Prato S, McMurray JJV, D'Agostino RB, Granger CB, Hernandez AF, Janmohamed S, Leiter LA, Califf RM, Holman R, DeMets D, Riddle M, Goodman S, McGuire D, Alexander K, Devore A, Melloni C, Patel C, Kong D, Bloomfield G, Roe M, Tricoci P, Harrison R, Lopes R, Mathews R, Mehta R, Schuyler Jones W, Vemulapalli S, Povsic T, Eapen Z, Dombrowski K, Kolls B, Jordan D, Ambrosy A, Greene S, Mandawat A, Shavadia J, Cooper L, Sharma A, Guimaraes P, Friedman D, Wilson M, Endsley P, Gentry T, Collier J, Perez K, James K, Roush J, Pope C, Howell C, Johnson M, Bailey M, Cole J, Akers T, Vandyne B, Thomas B, Rich J, Bartone S, Beaulieu G, Brown K, Chau T, Christian T, Coker R, Greene D, Haddock T, Jenkins W, Haque G, Marquess M, Pesarchick J, Rethaford R, Stone A, Al Kawas F, Anderson M, Enns R, Sinay I, Mathieu C, Yordanov V, Hramiak I, Haluzik M, Galatius S, Guerci B, Nauck M, Migdalis I, Tan CBK, Kocsis G, Giaccari A, Lee MK, Muñoz EGC, Cornel J, Birkeland K, Pinto M, Tirador L, Olesinska-Mader M, Shestakova M, Distiller L, Lopez-Sendon J, Eliasson B, Chiang CE, Srimahachota S, Mankovsky B, Bethel MA, Dungan K, Kosiborod M, Alvarisqueta A, Baldovino J, Besada D, Calella P, Cantero MC, Castaño P, Chertkoff A, Cuadrado J, De Loredo L, Dominguez A, Español MV, Finkelstein H, Frechtel G, Fretes J, Garrido Santos N, Gonzalez J, Litvak M, Loureyro J, Maffei L, Maldonado N, Mohr Gasparini D, Orio S, Perez Manghi F, Rodriguez Papini N, Sala J, Schygiel P, Sposetti G, Ulla M, Verra F, Zabalua S, Zaidman C, Crenier L, Debroye C, Duyck F, Scheen A, Van Gaal L, Vercammen C, Damyanova V, Dimitrov S, Kovacheva S, Lozanov L, Margaritov V, Mihaylova-Shumkova R, Nikolaeva A, Stoyanova Z, Akhras R, Beaudry Y, Bedard J, Berlingieri J, Chehayeb R, Cheung S, Conway J, Cusson J, Della Siega A, Dumas R, Dzongowski P, Ferguson M, Gaudet D, Grondin F, Gupta A, Gupta M, Halperin F, Houle PA, Jones M, Kouz S, Kovacs C, Landry D, Lonn E, O'Mahony W, Peterson S, Reich D, Rosenbloom A, St-Maurice F, Tugwell B, Vizel S, Woo V, Brychta T, Cech V, Dvorakova E, Edelsberger T, Halciakova K, Krizova J, Lastuvka J, Piperek M, Prymkova V, Raclavska L, Silhova E, Urbanek R, Vrkoc J, Andersen U, Brønnum-Schou J, Hove J, Jensen JS, Kober L, Kristiansen OP, Lund P, Melchior T, Nyvad O, Schou M, Boye A, Cadinot D, Gouet D, Henry P, Kessler L, Lalau JD, Petit C, Thuan JF, Voinot C, Vouillarmet J, Axthelm C, Berger D, Bieler T, Birkenfeld A, Bott J, Busch K, Caca K, Chevts J, Donaubauer T, Erlinger R, Funke K, Grosskopf J, Hagenow A, Hamann M, Hartard M, Heymer P, Huppertz W, Illies G, Jacob S, Jung T, Kahrmann G, Kast P, Kellerer M, Kempe HP, Khariouzov A, Klausmann G, Klein C, Kleinecke-Pohl U, Kleinertz K, Koch T, Kosch C, Lorra B, Luedemann J, Luttermann M, Maxeiner S, Milek K, Moelle A, Neumann G, Nischik R, Oehrig-Pohl E, Plassmann G, Pohlmeier L, Proepper F, Regner S, Rieker W, Rose L, Samer H, Sauter J, Schaper F, Schiffer C, Schmidt J, Scholz BM, Schulze J, Segner A, Seufert J, Sigal H, Steindorf J, Stockhausen J, Stuebler P, Taeschner H, Tews D, Tschoepe D, Wilhelm K, Zeller-Stefan H, Avramidis I, Bousboulas S, Bristianou M, Dimitriadis G, Elisaf M, Kotsa K, Melidonis A, Mitrakou A, Pagkalos E, Papanas N, Pappas A, Sampanis C, Tentolouris N, Tsapas A, Tzatzagou G, Ozaki R, Hajdú C, Harcsa E, Konyves L, Mucsi J, Pauker Z, Petró G, Plés Z, Revesz K, Sándor V, Vass V, Avogaro A, Boemi M, Bonadonna R, Consoli A, De Cosmo S, Di Bartolo P, Dotta F, Frontoni S, Galetta M, Gambineri A, Gazzaruso C, Giorgino F, Lauro D, Orsi E, Paolisso G, Perriello G, Piatti P, Pontiroli A, Ponzani P, Rivellese AA, Sesti G, Tonolo G, Trevisan R, Ahn CW, Baik SH, Cha BS, Chung CH, Jang HC, Kim CJ, Kim HS, Kim IJ, Lee EY, Lee HW, Lee KW, Moon KW, Namgung J, Park KS, Yoo SJ, Yu J, Llamas EB, Cervantes-Escárcega JL, Flota-Cervera LF, González-González JG, Pascoe-Gonzalez S, Pelayo-Orozco ES, Ramirez-Diaz SP, Saldana-Mendoza A, Jerjes-Díaz CS, Torres-Colores JJ, Vidrio-Velázquez M, Villagordoa-Mesa J, Beijerbacht HP, Groutars RGEJ, Hoek BA, Hoogslag PAM, Kooy A, Kragten JA, Lieverse AG, Swart HP, Viergever EP, Ahlqvist J, Cooper J, Gulseth H, Guttormsen G, Wium C, Arbañil H, Calderon J, Camacho L, Espinoza AD, Garrido E, Luna A, Manrique H, Revoredo FM, Gonzales RV, Rincon LZ, Zubiate C, Ebo G, Morales-Palomares E, Arciszewska M, Banach M, Bijata-Bronisz R, Derezinski T, Gadzinski W, Gajek J, Klodawska K, Krzyzagorska E, Madej A, Miekus P, Opiela J, Romanczuk P, Siegel A, Skokowska E, Stankiewicz A, Stasinska T, Trznadel-Morawska I, Witek R, Aksentyev S, Bondar I, Demidova I, Dreval A, Ershova O, Galstyan G, Garganeeva A, Izmozherova N, Karetnikova V, Kharakhulakh M, Khokhlov A, Kobalava Z, Koshelskaya O, Kosmacheva E, Kostin V, Koziolova N, Kuzin A, Lesnov V, Lysenko T, Markov V, Mayorov A, Moiseev S, Myasoedova S, Petunina N, Rebrov A, Ruyatkina L, Samoylova J, Sazonova O, Shilkina N, Sokolova N, Vasilevskaya O, Verbovaya N, Vishneva E, Vorobyev S, Vorokhobina N, Zanozina O, Zhdanova E, Zykova T, Burgess L, Coetzee K, Dawood S, Lombard L, Makotoko E, Moodley R, Oosthuysen W, Sarvan M, Calvo Gómez C, Cano Rodríguez I, Castro Conde A, Cequier Fillat A, Cuatrecasas Cambra G, de Álvaro Moreno F, De Teresa Parreño L, Delgado Lista J, Domínguez Escribano JR, Durán García S, Elvira González J, Fernández Rodríguez JM, Goday Arno A, Gomez Huelgas R, González Juanatey JR, Hernandez Mijares A, Jiménez Díaz VA, Jodar Gimeno E, Lucas Morante T, Marazuela M, Martell Claros N, Mauricio Puente D, Mena Ribas E, Merino Torres JF, Mezquita Raya P, Nubiola Calonge A, Ordoñez Sánchez X, Pascual Izuel JM, Perea Castilla V, Pérez Pérez A, Perez Soto I, Quesada Charneco M, Quesada Simón A, Redón Mas J, Rego Iraeta A, Rodriguez Alvarez M, Rodríguez Rodríguez I, Sabán Ruiz J, Soto González A, Tinahones Madueno F, Trescoli Serrano C, Ulied Armiñana A, Bachus E, Berndtsson Blom K, Eliasson K, Koskinen P, Larnefeldt H, Lif-Tiberg C, Linderfalk C, Lund G, Lundman P, Moris L, Olsson Å, Salmonsson S, Sanmartin Berglund J, Sjöberg F, Söderberg S, Torstensson I, Chen JF, Tien KJ, Tseng ST, Tu ST, Wang CY, Wang JH, Phrommintikul A, Yamwong S, Jintapakorn W, Hutayanon P, Sansanayudh N, Bazhan L, Fushtey I, Grachova M, Katerenchuk V, Korpachev V, Kravchun N, Larin O, Mykhalchyshyn G, Myshanych H, Oleksyk O, Orlenko V, Pashkovska N, Pertseva N, Petrosyan O, Smirnov I, Vlasenko M, Zlova T, Aye M, Baksi A, Balasubramani M, Beboso R, Blagden M, Bundy C, Cookson T, Copland A, Emslie-Smith A, Green F, Gunstone A, Issa B, Jackson-Voyzey E, Johnson A, Maclean M, McKnight J, Muzulu S, O'Connell I, Oyesile B, Patterson C, Pearson E, Philip S, Smith P, Sukumaran U, Abbas J, Aggarwala G, Akhter F, Andersen J, Anglade M, Argoud G, Ariani M, Ashdji R, Bakhtari L, Banerjee S, Bartlett A, Baum H, Bays H, Beasley R, Belfort de Aguiar R, Benjamin S, Bhagwat R, Bhargava A, Bode B, Bratcher C, Briskin T, Brockmyre A, Broughton R, Brown J, Budhraja M, Cannon K, Carr J, Cathcart H, Cavale A, Chaykin L, Cheung D, Childress R, Cohen A, Condit J, Cooksey E, Cornett GM, Dauber I, Davila W, De Armas L, Dean J, Detweiler R, Diaz E, Di Giovanna M, Dor I, Drummond W, Eagerton D, Earl J, Eaton C, Ellison H, Farris N, Fiel T, Firek A, First B, Forgosh L, French W, Gandy W, Garcia R, Gill S, Gordon M, Guice M, Gummadi S, Hackenyos J, Hairston K, Hanson L, Harrison L, Hartman I, Heitner J, Hejeebu S, Hermany P, Hernandez-Cassis C, Hidalgo H, Higgins A, Ibrahim H, Jacobs S, Johnson D, Joshi P, Kaster S, Kellum D, Kim C, Kim E, Kirby W, Knouse A, Kulback S, Kumar M, Kuruvanka T, Labroo A, Lasswell W, Lentz J, Lenzmeier T, Lewis D, Li Z, Lillestol M, Little R, Lorraine R, McKeown-Biagas C, McNeill R, Mehta A, Miller A, Moran J, Morawski E, Nadar V, O'Connor T, Odio A, Parker R, Patel R, Phillips L, Raad G, Rahman A, Raikhel M, Raisinghani A, Rajan R, Rasouli N, Rauzi F, Rohr K, Roseman H, Rovner S, Saba F, Sachson R, Schabauer A, Schneider R, Schuchard T, Sensenbrenner J, Shlesinger Y, Singh N, Sivalingam K, Stonesifer L, Storey D, Suh D, Tahir M, Tan A, Tan M, Taylon A, Thakkar M, Tripathy D, Uwaifo G, Vedere A, Venugopal C, Vo A, Welch M, Welker J, White A, Willis J, Wynne A, Yazdani S, Green JB, Rosenberg A, Price L, Sigmon K, Lokhngina Y, Xing W, Overton R, Stewart M, Stead J, Lindsay A, Patel V, Ross J, Soffer J, Daga S, Sowell M, Patel P, Garvey L, Ackert J, Abraham S, Sabol MB, Altobelli D, Ha J, Kulkarni M, Somerville M, Noronha D, Casson E, Zang E, Sandhu C, Kumar R, Chen D, Taft L, Patel R, Ye J, Shannon J, Wilson T, Babi C, Miller D, Jones NP, Thorpe K, Russell R, Bull G, Hereghty B, Fernandez-Salazar E, Longley T, Donaldson J, Jarosz M, Murphy K, Adams P, Smith P, James R, Richards J, Sedani S, Althouse D, Watson D, Lorimer J, Lauder S, Schultheis R, Womer T, Wraight E, Li W, Price-Olsen E, Watson A, Kelly A, McLaughlin P, Fleming J, Schubert J, Schleiden D, Harris T, Prakash R, Breneman J, Deshpande S, Saswadkar A, Kumari A, Shitut A, Raorane A, Karmalkar A, Mhambrey A, Bhosale A, Vaphare A, Patil AP, Khandelwal C, Shaik F, Nadar M, Karka M, Kadgaonkar N, Gupta N, Aher N, Potnis O, Naicker P, Shinde R, Sharma R, Godse R, Solanki S, Sahu S, Dumbre S, Kumar S, Patil S, Mandal T.

Abstract

BACKGROUND:

Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.

METHODS:

We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30-50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.

FINDINGS:

Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68-0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.

INTERPRETATION:

In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.

FUNDING:

GlaxoSmithKline.

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