1. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017
Jun 12.

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, 
Desai M, Matthews DR; CANVAS Program Collaborative Group.

Collaborators: Arias P, Ulla MR, Alvarisqueta A, Maffei L, Fretes JO, De
Lapertosa SG, Visco V, Sposetti G, Farias J, Farias EF, Cantero MC, Feldman R,
Ridruejo MC, Calella P, Zaidman C, Stranks S, Mah PM, Nankervis A, Topliss D,
Soldatos G, Simpson R, Gerstman M, Colquhoun D, Moses R, Suranyi M, Hocking S,
Packham D, Cooke D, Kostner K, Weber E, Vercammen C, Van Gaal L, Tits J,
Keymeulen B, Mathieu C, Aggarwal N, Dattani D, Blouin F, Dumas R, Henein S, Ma P,
Najarali A, Omahony M, Pella T, Rodger W, Shu D, Woo V, Zidel B, Pliamm L,
Ramjattan B, Akhras R, Belle-Isle J, Ross S, Molnar G, Arteaga JM, Jarava I,
Andresova A, Komrskova M, Mucha C, Brychta T, Bartaskova D, Urbanova R, Spousta
T, Havelkova J, Sedlacek T, Kvapil M, Jakovlev Ü, Fogel V, Viitas L, Soots M,
Lubi M, Past M, Krasnopejeva J, Alawi H, Busch K, Pröpper FK, Thron A, Jacob S,
Pfützner A, Rose L, Segiet T, Kosch C, Moelle A, Davies M, Courtney H, Gibson M, 
Gnudi L, Game F, Wilding J, Sathyapalan T, Fisher M, Ramtoola S, Rajbhandari S,
Okane M, Beke E, Poor F, Nagy K, Kocsis G, Oroszlan T, Faludi P, Gurzo M,
Srikanta S, Dharmalingam M, Murugan B, Gandhi P, Sethi B, Aravind S,
Ardhanareeshwaran S, Bhattacharyya A, Bantwal G, Viswanathan V, Shamanna P, Saboo
B, Mohan V, Parmaj R, Modi KK, Joshi S, Jain S, Kalra S, Somasekharan AC,
Adhikari P, Kumar A, Kudalkar H, Passey R, John M, Yalamanchi S, Parikh K, Rajesh
KP, Nair R, Kumar S, Rodrigues L, Gangwal P, Agarwal P, Gupta SK, Mutha AA, Kale 
SD, Kulkarni RL, Chudasama S, Sharma K, Nambiar A, Tangaonkar A, Deshmukh V,
Majumdar B, Veerappan R, Namjoshi D, Raz I, Weinstein J, Boehm IH, Vishlitzky V, 
Dadoun F, Shah RP, Hooi LS, Tan A, Wan Bebakar WM, Mohamed M, Khir AS, Sukor N,
Kadir KA, Morales E, Zuñiga S, Alpizar M, Calvo C, Zamarripa R, Rosas J, Vargas
A, Nieuwdorp M, Kose V, Kentgens S, Rojas G, Van Kempen W, Hoogendijk J, Alhakim 
M, Gerdes V, Hovens M, Berends J, Woittiez A, Smit CJ, Dekkers B, Spiering W, Van
Dijk-Okla MK, Imholz BPM, Van Leendert RJM, Ten Wolde M, Smak Gregoor PJH, Scott 
R, Krebs J, Baker J, Singh J, Young C, Langslet G, Hoivik HO, Kjaernli T, Elle S,
Gjertsen E, Risberg K, Tandberg A, Solnoer L, Sirnes PA, Derezinski T,
Arciszewska M, Franek E, Szyprowska E, Sowinski D, Petryka R, Czakanska-Dec B,
Pulka G, Jusiak K, Dabrowski M, Kubalski P, Wojciechowska M, Madej A,
Pupek-Musialik D, Blinova N, Kondratjeva L, Kuzin A, Boyarkin M, Gomova T,
Khokhlov A, Vorobjev S, Mirolyubova O, Boldueva S, Ershova O, Ballyzek M,
Smolenskaya O, Yakushin SS, Zateyshchikov D, Arkhipov M, Kuzmenko A, Maksimov I, 
Motylev I, Rafalskiy V, Strongin L, Treshkur T, Volkova N, Barbarash O, Raskina
T, Bartosh L, Nikolskaya I, Shutemova E, Gurevich V, Burova N, Vorobyeva E,
Andreev D, Bart B, Khlevchuk T, Gapon L, Gordeev I, Gratsiansky N, Zalevskaya A, 
Sayganov S, Solovyev O, Reshedko G, Shilkina N, Chizhov P, Shapovalova J,
Sherenkov A, Reshetko O, Simanenkov V, Garcia Puig J, Saban J, Pascual J,
Dominguez J, Delgado E, Calvo C, Vida M, Duran S, Tinahones F, Salas J, Gonzalez 
JM, Monreal M, Grau A, Nubiola A, Alvarez P, Stenlöf K, Koskinen P, Lindholm CJ, 
Mathiesen U, Blom KB, Tengmark BO, Jul-Nielsen H, Larin O, Panina S, Kovalenko S,
Voloshyna O, Tseluyko V, Gyrina O, Vizir V, Barna O, Dolzhenko M, Mostovoy Y,
Korpachev V, Mankovskiy B, Vatutin M, Arena C, Akpunonu B, Zerikly R, Baker C,
Briskin T, Bartilucci D, Barzilay J, Breton C, Buse J, Cherlin R, Cobble M, Ellis
C, Fink R, Forker A, Garcia R, Hollander P, House A, Hyman D, Ingebretsen R, Jack
D, Kirstein J, Kissell K, Lorber D, McNeil D, Miers W, Murray A, Call R, Ong ST, 
Ovalle F, Pearlstein R, Piziak V, Pomposini D, Robertson D, Rosenstock J,
Schubart U, Shah S, Stout R, Turner M, Wallace J, Chuck L, Claxton E, Morawski E,
Wynne A, Wysham C, Alderman M, Patton W, Pogue B, Silva A, Guthrie R, Lerman S,
Madder R, Miller W, Weiss D, Kereiakes D, Graf RJ, Rassouli N, Greenwald J,
Abu-Nassar H, Muse D, Kalen V, Hegedosh N, Dobrusin R, Johnson G, Bruce T,
Gleason G, Vico M, Hermida S, Nardone L, Gelersztein E, Sicer M, Orio S, Nolan C,
de Looze F, Sinha A, Davis T, Russell A, Shamasunder A, MacIsaac R, Warling X,
Behets J, Scheen A, T’Sjoen G, Verhaegen A, Dumont I, Taes Y, Duyck F, Lienart F,
Sparenberg A, Costa e Forti A, Leitao A, di Siqueira Chrisman CJ, Hayashida C,
Panarotto D, dos Sanos FR, Filho FF, Maia FC, Reis G, Lisboa H, Felicio J,
Siqueira J, Nigro Maia L, Andreotti Turatti LA, Cerqueira MJ, Zanella MT, Muszkat
P, Hissa MN, Bonansea T, Wilderman I, Filteau P, Tsoukas G, Milne P, Godin C,
Friars D, Gupta A, Nemtean T, Steele A, Li ZQ, Ma C, Ji L, Pang S, Jing Y, Zhao
R, Bu R, Souckova T, Kyselova P, Raclavska L, Malicherova E, Zaoui P, Gouet D,
Courreges JP, Fendri S, Hadjadj S, Verges B, Catargi BN, Clavel S, Altman JJ,
Hartemann A, Prevost G, Tschöpe D, Henkel E, Göbel R, Seufert J, Haller H, Behnke
T, Klausmann G, Hirschhaeuser B, Andrews R, Annamalai N, Bellary S, Blagden M,
Clark J, Creely S, Darzy K, Idris I, Falk R, Summers L, Asamoah N, Johnson A,
Kwok S, Rayman G, Smith J, Baranyai M, Csomos K, Harcsa E, Kanakaridisz N,
Késmárki N, Pátkay J, Peterfai E, Gaszner B, Jozsef I, Genovese S, Pontiroli AE, 
Bonora E, Giugliano D, Cucinotta D, Sesti G, Ponzani P, Pugliese G, Reggiani GM, 
Pozzilli P, Leotta S, Orsi E, Giorda C, Di Bartolo P, Park TS, Cho CG, Kim IJ,
Nam-Goong IS, Chung CH, Cho HC, Choi DS, Yoon KH, Kim NH, Choi KM, Ahn KJ, Mok
JO, Yoo SJ, Oh TK, Lee KW, Jang HC, Park JH, Lee IK, Kim BJ, Kim DM, Shon HS, Lee
MK, Kim S, Vengadasalam P, Tan ATB, Wan Mohamed WMI, Yusoff K, Mohd Khir AS, Tan 
F, Yahya M, Violante R, De los Rios MO, Alcocer M, González M, Martinez E,
Aldrete JA, Gonzalez G, Rocha CM, Sauque L, Frenk P, Arenas JL, Tichelaar P, Kooy
A, Van de Wiel A, Lochorn G, De Vries P, Feenstra H, Imholz B, van Leendert R,
Gregoor PS, Brussen J, Pijl H, Castro Cabezas M, Gonkel F, Smits P, Lansdorp D,
Veenendaal A, Richmond J, Williams M, Quinn D, Crawford V, Jedynasty K,
Polaszewska-Muszynska M, Zytkiewicz-Jaruga D, Wasilewska K, Romanczuk P,
Ocicka-Kozakiewicz A, Marcisz C, Okopien B, Bochenek A, Wojnowski L, Sliwinska T,
Rewerska B, Zmuda W, Klodawska K, Skokowska E, Fabisiak J, Danilkiewicz C, Perez 
Vargas E, Barranco Santana E, Kuzin A, Zykova T, Balyzek M, Rafalsky V, Nosova N,
Lysenko T, Ipatko I, Vorobyev S, Obrezan A, Esip V, Paltsman Z, Verbovoy A,
Khetagurova F, Shvarts Y, Alvarez-Garcia P, Martinez Deben F, Grinyo JM, Suarez
C, Pascual JM, Oliveras A, Gómez Peralta F, Alvarez-Sala L, Francisco C, Gómez
Cerezo J, Trescolí C, Fuentes Jimenez FJ, Tofé S, López J, Nieto Iglesias J,
Vigil L, Duran Garcia S, Gorriz JL, Saavedra Vallejo P, Tinahones Madueno F,
Blanco Coronado JL, Soto A, De Teresa L, Rodriguez Botaro A, Cuesta C, Bragée B, 
Moris L, Huss F, Jennersjö P, Berndtsson-Blom K, Liu B, Jendle J, Pei D, Shue WH,
Chiang CE, Chen CC, Chien MN, Liu P, Lin CL, Sheen YJ, Reshotko D, Rishko N,
Samoylov O, Serkova V, Smirnov I, Sokolova L, Tseluyko V, Vizir V, Zlova T,
Maslyanko V, Velichko V, Prystupa L, Yarema N, Mishanich G, Bondarets I, Virstyuk
N, Serhiyenko O, Pavlyk S, Levchenko O, Abrahamovych O, Botsurko V, Chernikova V,
Karachentsev Y, Katerenchuk V, Korpachov V, Malynovsky Y, Mankovsky B, Pererva L,
Pertseva N, Conrad V, Fox K, Buynak R, Dever M, Kirby J, Odekirk L, Wijewardane
P, Carson R, Seaton B, Mohart AE, Bianco S, Cox MR, Kim A, Geller S, Reddy J,
Bays H, Riser J, Arif A, Barbel-Johnson K, Bedel G, Blemur P, Chang A, Naccari B,
Coburn NJ, Cohen L, Dedeke E, Diederich C, Earl J, George A, Gilbert M, Haase G, 
Ison R, Jain M, Alam I, Levinson L, Lynn LD, Oliver M, Kusnick B, Plevin S,
Mujica Trenche S, Young V, Jutovsky M, Wade R, Weisbrot A, Wombolt D, Taslimi J, 
Anderson JL, Campbell IW, Lachin J, Scharfstein D, Solomon SD, Uzzo RG, Amerena
J, Chow C, Figtree G, French J, Hillis G, Hlatky MA, Jenkins B, Leeper NJ,
Lindley R, McGrath B, Street A, Watson J, Shahinfar S, Chang T, Sinha AD, August 
P, Cheifetz A, Sheth S, Feuerstein J.

Comment in
    N Engl J Med. ;377(21):2097-8.
    N Engl J Med. ;377(21):2098.
    N Engl J Med. ;377(21):2098-9.
    Ann Transl Med. 2017 Dec;5(23 ):473.

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that
reduces glycemia as well as blood pressure, body weight, and albuminuria in
people with diabetes. We report the effects of treatment with canagliflozin on
cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated
data from two trials involving a total of 10,142 participants with type 2
diabetes and high cardiovascular risk. Participants in each trial were randomly
assigned to receive canagliflozin or placebo and were followed for a mean of
188.2 weeks. The primary outcome was a composite of death from cardiovascular
causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age 
of the participants was 63.3 years, 35.8% were women, the mean duration of
diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The
rate of the primary outcome was lower with canagliflozin than with placebo
(occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio,
0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority;
P=0.02 for superiority). Although on the basis of the prespecified hypothesis
testing sequence the renal outcomes are not viewed as statistically significant, 
the results showed a possible benefit of canagliflozin with respect to the
progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the
composite outcome of a sustained 40% reduction in the estimated glomerular
filtration rate, the need for renal-replacement therapy, or death from renal
causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were
consistent with the previously reported risks associated with canagliflozin
except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000
patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were
primarily at the level of the toe or metatarsal. Conclusions In two trials
involving patients with type 2 diabetes and an elevated risk of cardiovascular
disease, patients treated with canagliflozin had a lower risk of cardiovascular
events than those who received placebo but a greater risk of amputation,
primarily at the level of the toe or metatarsal. (Funded by Janssen Research and 
Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and
NCT01989754 , respectively.).

DOI: 10.1056/NEJMoa1611925 
PMID: 28605608  [Indexed for MEDLINE]