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N Engl J Med. 2013 Oct 3;369(14):1317-26. doi: 10.1056/NEJMoa1307684. Epub 2013 Sep 2.

Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.

Collaborators (951)

Braunwald E, Bhatt DL, Scirica BM, Udell JA, Cavender MA, Desai N, Abrahamsen T, Grossman M, Morin S, Im K, Hoffman E, Gabovitch D, Pricken A, Raz I, Mosenzon O, Buskila A, Ohman P, Hirshberg B, Stahre C, Price D, Billing-Clason S, Sabel K, Monyak J, Sjöstrand M, Wei C, Lu J, Miller E, Raichlen J, Fitt S, Frederich R, Iqbal N, Donovan M, Braunwald E, Bhatt DL, Raz I, Davidson JA, Frederich R, Hirshberg B, Steg PG, Steg P, Davidson JA, Aguilar-Salinas C, Alvarsson M, Amerena J, Ardissino D, Averkov O, Avogaro A, Barnett A, Bretzel R, Chiang CE, Codoceo V, Corbalan R, Dalby A, Darius H, Deerochanawong C, Dellborg M, Eliaschewitz F, Garcia-Castillo A, Gomis R, Henry P, Hoekstra J, Jermendy G, Kastelein J, Keech A, Kiss R, Krempf M, Laakso M, Leiter L, Leitersdorf E, Lewis B, Litwak L, Lopez-Sendon J, Ma R, McGuire D, Medina F, Moses R, Nicolau JC, Opolski G, Oude Ophuis T, Paolasso E, Ray KK, Ruda M, Kumar KM, Shestakova M, Sheu WH, Smahelova A, Soma Raju Bhupathiraju B, Spinar J, Sritata P, Strojeck K, Villena-Chavez JE, Jia W, Huo Y, Wiviott SD, Lowe C, Awtry E, Berger C, Desai AS, Gelfand E, Leeman D, Link M, Ruberg F, Vita J, Rost N, Silverman S, Greenberger NJ, Lerch MM, Gersh B, Nesto R, Del Prato S, Tuomilehto J, Kelsey S, Litwak L, Paolasso E, Alvarisqueta A, Cuadrado J, Rista L, Hermida S, Baccaro C, Luquez C, Lagrutta M, Maffei L, Bartolacci I, Montaña O, Cutuli H, Berli M, Lorenzatti A, Frechtel G, La Greca R, Fretes O, Diaz M, Papini N, Farías E, Issa C, Elbert A, Amerena J, Moses R, Lehman R, Amerena J, Arya M, Singh B, Colquhoun D, Jayasinghe R, de Looze F, Blombery P, de Looze F, Ward G, Szto G, Abhayaratna W, Eliaschewitz F, Nicolau J, Borges J, Russo L, Eliaschewitz F, Felício J, Santos F, Guimarães Filho F, Castro M, Rossi P, Armaganijan D, Leães P, Bandeira F, Franken M, Rassi N, Réa R, Zanella M, Amodeo C, César L, Betti R, Chacra A, Schmid H, Leiter L, Bell A, Syan G, Zadra R, Conter H, Dumas R, Borts D, Dattani I, Poirier P, Cha J, Dzongowski P, Labonte R, St Pierre B, Gaudet D, Kouz S, Lamy A, Tishler S, Chehayeb R, Bedard J, Hramiak I, Teitelbaum I, Fortin C, Woo V, Conway J, Mehta P, Robinson S, Sussex B, Chiasson J, Muirhead N, Bose S, Ouellet A, Yale J, Bhargava R, Lau D, Tobe S, Perron P, Sigalas J, Bilodeau L, Tytus R, Achyuthan G, Pearce M, Steele A, Bailey G, Ma P, St-Maurice F, Rupka D, Houlden R, Bailey A, Rewa G, Sohal P, Ting R, Codoceo V, Corbalan R, Prieto J, Rodriguez M, Godoy G, Larenas G, Pincetti C, Cobos L, Saavedra V, Varleta P, Lucero F, Kuzmanic O, Acevedo M, Aguirre M, Florenzano F, Jia W, Huo Y, Ma J, Bao Y, Jiang M, Xu W, Shi Y, Zheng M, Li Y, Dong Y, Zhao W, Sun M, Lei M, Li Y, Wang J, Smahelova A, Spinar J, Píštěk Z, Řiháček I, Kučera D, Brada M, Náplava R, Špinar J, Karasová J, Vlašicová H, Skopeček J, Špinarová L, Šmahelová A, Raclavská L, Šarbochová R, Okénka L, Račická E, Urbancová K, Oznerová M, Lorenc Z, Wasserburger B, Záhumenský E, Grünfeldová H, Hradec J, Lukáč M, Svačina Š, Podzimek J, Hemžský L, Mikulková I, Pavlíčková J, Brychta T, Chochola J, Henry P, Krempf M, Henry P, Couffinhal T, Krempf M, Elbaz M, Petit C, Faller B, Marechaud R, Moulin P, Fendri S, Nazeyrollas P, Bretzel R, Darius H, Wendisch U, Busch K, Klausmann G, Duengen H, Appel K, Toursarkissian N, Jung T, Ott P, Schenkenberger I, Kuesters D, Landers B, Nischik R, Fischer H, Tschoepe D, Paschen B, Krause K, Derwahl K, Wenzl-Bauer V, Hamann A, Strotmann H, Milek K, Mueller S, Bretzel R, Ma R, Ma R, Chu D, Tan K, Kung K, Chu D, Tsang C, Chu D, Tomlinson B, Kung K, Jermendy G, Kiss R, Korányi L, Kerényi Z, Benczúr B, Illyés L, Hidvégi T, Somogyi A, Valcó J, Jermendy G, Ferenczi S, Rapi J, Vörös P, Winkler G, Sydó T, Hetey M, Simon K, Pénzes J, Kempler P, Bakó B, Lengyel Z, Witmann I, Dudás M, Vándorfi G, Takács J, Matoltsy A, Kiss R, Ladányi E, Gyimesi A, Somaraju B, Kumar K, Sadikot S, Parikh K, Jain S, Yajnik C, Sosale A, Shamanna P, Srikanta S, Shah S, Srinivas A, Kumar KM, Banker D, Shah P, Sharda A, Makkar B, Desai N, Rais N, Mardikar H, Mishra A, Bhupati S, Menon J, Sathe S, Gupta R, Sharma V, Lewis B, Raz I, Darawsha M, Herskovits T, Hamoud S, Nikolsky E, Raz I, Adawi F, Zimlichman R, Tsalihin D, Wainstein J, Klainman E, Mosseri M, Yerushalmi Y, Karnieli E, Knobler H, Zimlichman R, Benchetrit S, Tsur A, Yagil Y, Lewis B, Atar S, Beberashvili I, Fuchs S, Stern N, Pollak A, Chajek-Shaul T, Rozenman Y, Biton A, Ardissino D, Avogaro A, Ardissino D, Bramucci E, Fiscella A, Grassia V, Piatti P, De Cosmo S, Di Lorenzo L, Merlini P, Mannucci E, Frontoni S, Trevisan R, Zenari L, Avogaro A, Lambiase C, Salvioni A, Silvestri O, Ambrosio G, Di Bartolo P, Fattore L, Presbitero P, Calabrese M, Evola R, Aguilar-Salinas C, Garcia-Castillo A, Gamba MA, Ibarra MO, Muñoz E, Sánchez D, Herrera C, Ríos J, Llamas E, Esperon G, Cantú E, Fragoso J, González J, Martinez G, Padilla F, Mier G, Marmolejo D, Ruiz J, Portilla N, Rosas E, Salinas C, Machado G, Ramos J, Briones I, Hoekstra J, Oude Ophuis T, van Hessen MW, Strikwerda S, The SH, Kooy A, Ronner E, Nierop PR, Remmen JJ, Groenemeijer BE, Hamer BJ, Basart DC, van Lennep HW, Nieuwdorp M, van Dijk MP, Kentgens S, van Kempen WW, Hoogendijk J, Spiering W, Voors-Pette C, Köse V, de Waard DE, Gonkel F, Kaasjager HA, Lingan GM, Agous I, Kruik HJ, Imholz BP, Pieterse M, Medina F, Villena-Chavez J, Manrique H, Medina F, Villena J, Leon L, Kundert K, Minchola J, Pinto M, Heredia J, Rodriguez A, Guerreros C, Berrospi P, Zubiate C, Allemant A, Arbanil H, Ponciano W, Calderon J, Lisson R, Segura L, Opolski G, Strojek K, Sidorowicz-Bialynicka A, Sciborski R, Fares I, Mader P, Skierkowska J, Stasinska T, Pomiecko W, Skorski M, Krzyzagorska E, Polaszewska-Muszynska M, Sowinski D, Strojek K, Rosinska-Migda J, Romanczuk P, Golebiowski G, Kubica J, Mazurek T, Wojnowski L, Pasternak D, Stachlewski P, Trzepla E, Bogdanowicz G, Uzunow A, Potakowska I, Miszczyszyn Z, Waszyrowski T, Averkov O, Ruda M, Shestakova M, Smolenskaya O, Lukyanov Y, Vorokhobina N, Khalimov Y, Orlikova O, Rebrov A, Kukharchuk V, Boldueva S, Arkhipov M, Zhelninova T, Pavlysh E, Antsiferov M, Panov A, Pavlova M, Shustov S, Demchenko E, Galyavich A, Malakhina E, Semenova O, Kobalava Z, Shestakova M, Kotova S, Gavrisheva I, Oschepkova E, Karpov Y, Sidorenko B, Kislyak O, Ametov A, Dreval A, Grineva E, Mkrtumyan A, Tyurina T, Sazonova O, Bonnici F, Dalby A, Ranjith N, Burgess L, Nortje H, Distiller L, Mitha I, Moore R, Conradie M, Horak A, Pillay S, Wellmann H, Berg E, Pillai P, Padayachee T, Corbett C, Makan H, Wing J, Vawda Z, Ebrahim I, Dalby A, Mitha E, Bhorat A, Lopez-Sendon J, Gomis R, Fernández J, Muñoz C, Cortada J, Conde A, Calvo C, Extremera B, Delgado E, Masmiquel L, Puig J, Parreño Lde T, Mauricio D, Redón J, Brito M, Lopez C, de la Morera J, Alvarsson M, Dellborg M, Linderfalk C, Larnefeldt H, Olsson A, Lönneborg L, Ekelund M, Samad B, Borgencrantz B, Nilsson J, Berglund O, Svensson M, Mooe T, Alvarsson M, Curiac D, Albin J, Angesjö E, Lannemyr O, Dellborg M, Chiang C, Sheu W, Chiang C, Sheu W, Chen J, Tien K, Ueng K, Lai W, Yin W, Hung Y, Shyu K, Hou J, Lam H, Deerochanawong C, Sritara P, Laothavorn P, Sritara P, Kuanprasert S, Deerochanawong C, Khovidhunkit W, Benjasuratwong Y, Chotinaiwattarakul C, Mamanasiri S, Suraamornkul S, Pratipanawatr T, Nitiyanant W, Heller S, Barnett A, Ray K, Pieters R, Strang C, Bodalia B, Middleton A, Hall T, Chapman G, Calvert J, Reed R, Tam D, Butcher G, Jones N, Takhar A, Turner W, McNally D, Corey O, Chapman J, Mohr S, Edwards S, Bhatt D, Davidson J, Ocampo A, Kandath D, Aude Y, Ervin W, Savin V, Anderson R, Littlefield R, Oberoi M, Platt G, Yazdani S, Mangoo-Karim R, Walder J, Gogia H, Chandrashekhar Y, Boccalandro F, Rogers W Jr, Bilazarian S, Zieve F, Siage Y, O'Connor T, Mudaliar S, Nikas A, Giusti R, Glover R, Chilka S, French W, Roth E, Singh N, Christofferson R, Stich M, Dagogo-Jack S, Allison J 3rd, Zengotita G, Ison R, Iteld B, Sulistio M, Gonzalez E, Gorman T, Hage-Korban E, Reddy R, Byars W, Antonishen M, Benjamin S, First B, Rosado J, Bruschetta H, Mehta P, Poling T, Rosendorff C, Kerstein H, Saba F, Willis J, Adams K, Camilo Vazquez E, Ellison H, Kahn B, Kereiakes D, Powell S, Raskin P, Smith K, Varma S, Whittier F, Casanova R, Isserman S, Kaye W, McGuinn W 2nd, Bartkowiak A Jr, Dworkin L, Labrador C, Podlecki D, Popovtzer M, Aronoff S, Ballantyne C, Gonzalez Ortiz E, Mora A 3rd, Pitts T, Reinhardt S, Soucie G, Wainwright W, Henson B, Sklaver N, Arakaki R, Brown J, Chalavarya G, Chochinov R, Dixon T, Kutner M, Perlman R, Raisinghani A, Salacata A, Awasty V, Elinoff V, George W, LaRochelle-Gryseels A, Mercado A, Miller G, Qureshi M, Steljes A, Wefald F, Wilson J, Chinn J, Chuang R, Comulada-Rivera A, Hartman I, Narayan P, Pacheco T, Weiss R, Beavins J, Creevy J, Hamroff G, Hodson R, Kosinski E, Krichmar P, Patel R, Schneider R, Shapiro J, Sharp D, Speer J, Stegemoller R, Waxman F, Young Chang F, Braun E, Eder F, Minor S, Albert M, Carr K, Diaczok B, Gastman I, Gupta V, Longshaw K, Gonzalez-Campoy J, Raikhel M, Thomas J, Wood K, Diab I, Furda J, Gelernt M, Halter M, House B, Kaster S, Raad G, Stamatin R, Barker B, Blonder R, Bloomberg R, Calderon R, Carrol A, Comerota A, Feinglos M, Henderson D, Kastelic R, Stonesifer L, Talano J, Ver Lee P, Brosseau J, Clark W, Cohen E, Fialkow J, Horton K, Kozman H, McGill J, Mihills C, Poonawala R, Shore K, Tejada L, Torres R, Wright W, Calatayud G, Chandna H, Drozdiak R, Fink R, Gill R, Glandt M, Gottlieb D, Hack T, Kay J, Mansouri V, McKnight T, Mostel E, Schmidt L, Seide H, Sonel E, Taylor R, Velasquez M, Bretton E, Feldman R, Hartman A, Hershon K, Leach C, Martin E, Mohiuddin F, Naygandhi Y, Riske T, Schima S, Uzoaga E, Ward H, Weinstock R, Williams T, Altschuller A, Aoki T, Blumenthal S, Cash A, Eisner G, Gutmann J, Hagan M, Kabour A, Markus T, McKenzie W, Moursi M, Mystkowski P, Ovalle F, Perkins R, Popeil L, Saniuk R, Sierra Y, Alvarado O, Anderson J, Bajaj M, Blank R, Chu A, Levinsky L, 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Author information

  • 1TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, USA.

Abstract

BACKGROUND:

The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.

METHODS:

We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.

RESULTS:

A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).

CONCLUSIONS:

DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.).

Comment in

PMID:
23992601
[PubMed - indexed for MEDLINE]
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