Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Walter N Kernan; Catherine M Viscoli; Karen L Furie; Lawrence H Young; Silvio E Inzucchi; Mark Gorman; Peter D Guarino; Anne M Lovejoy; Peter N Peduzzi; Robin Conwit; Lawrence M Brass; Gregory G Schwartz; Harold P Adams Jr; Leo Berger; Antonio Carolei; Wayne Clark; Bruce Coull; Gary A Ford; Dawn Kleindorfer; John R O'Leary; Mark W Parsons; Peter Ringleb; Souvik Sen; J David Spence; David Tanne; David Wang; Toni R Winder; IRIS Trial Investigators

doi:10.1056/NEJMoa1506930

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

N Engl J Med. 2016 Apr 7;374(14):1321-31. doi: 10.1056/NEJMoa1506930. Epub 2016 Feb 17.

Authors

Walter N Kernan¹, Catherine M Viscoli¹, Karen L Furie¹, Lawrence H Young¹, Silvio E Inzucchi¹, Mark Gorman¹, Peter D Guarino¹, Anne M Lovejoy¹, Peter N Peduzzi¹, Robin Conwit¹, Lawrence M Brass¹, Gregory G Schwartz¹, Harold P Adams Jr¹, Leo Berger¹, Antonio Carolei¹, Wayne Clark¹, Bruce Coull¹, Gary A Ford¹, Dawn Kleindorfer¹, John R O'Leary¹, Mark W Parsons¹, Peter Ringleb¹, Souvik Sen¹, J David Spence¹, David Tanne¹, David Wang¹, Toni R Winder¹; IRIS Trial Investigators

Collaborators

IRIS Trial Investigators:
C Bladin, Z Ross, S Davis, T Wijeratne, C Levi, M Parsons, M Russell, A Brodtmann, L Walker, S Ng, J Archer, A Rodda, R Wong, C Delcourt, E Ray, T R Winder, J Elliott, C Walker, L Berger, J Boulanger, R K Chan, J D Spence, L Fleming, K Ford, A Durocher, A Mackey, S Dubé, A Hache, C Lessard, J Minuk, C Schanz, A M Penn, L Atkins, A Shuaib, Y Gable, B Schwindt, R Cote, L Wadup, D Selchen, N Bayer, P Kostyrko, M Sweet, S Malik, G Stotts, S Robert, B Griewing, H Soda, R Weinhardt, B Behringer, M Kirchner, A Märkert, J Berrouschot, A Stoll, O W Witte, U Bodechtel, I Dzialowski, K Haase, J Kepplinger, T Siepmann, U Schminke, C Hobohm, A Hetzel, J Lambeck, U Bergmann, K E Wartenberg, D Herale, H Huttner, R Dittrich, D G Nabavi, D Seraphin, O Crome, K Gröschel, G Thomalla, M Rosenkranz, C Beck, S Jander, B Cullman, A Meisel, S Hoffmann, A Ludolph, K Althaus, R Huber, C Adldinger, M Lorenz, I M Dos Santos, D Tanne, O Merzlyak, C Sasson, N M Bornstein, L Shopin, T Ulanovsky-Selinger, G Telman, Y Lampl, M Israelson, J Streifler, N Roizen, B Weller, E Aubhanov, L Mazareb, A Mahagney, O Nicola, S Sabetay, G Ifergane, Y Wirgin, A Carolei, D Degan, M Mantenuto, S Sacco, D Toni, M DiMascio, P Stanzione, G Micieli, I Canavero, A Persico, G Agnelli, V Caso, C D'Amore, C Gandolfo, D Sassos, G Sivori, G Comi, D Consoli, F Galati, P Postorino, M Rasura, F Di Lisi, A Spalloni, S La Starza, V Di Lazzaro, F Pilato, A Dixit, A Barkat, G Ford, K Storey, B Jupp, D Jenkinson, L Shaw, B Madigan, I Salih, D Kelly, B Esisi, M Power, D Wilson, B Wroath, W D Strain, S Elyas, S Keenan, H Kingwell, D Manawadu, L Kalra, K Anderson, B Mistry, E O'Brien, E A Warburton, E Amis, N Butler, J Mitchell, K Chatterjee, S Leason, D R Hargroves, L Cowie, A Blight, C Peixoto, K Pasco, B Moynihan, H Markus, S Trippier, M Macleod, J Furnace, H Gow, A Joyson, D L Broughton, L Dixon, K Chapman, H Rodgers, A Smith, T Hlaing, S Muir, B Manak, L McDonald, M Sajid, R Gascoyne, P M Bath, J Clarke, K Krishnan, C Price, L Sekaran, F Justin, D Vahidassr, A Thompson, K W Muir, A Welch, J McIlmoyle, P K Datta, R Davey, G Bateman, A Needle, P Langhorne, D Stott, R Graham, P K Datta, R Davey, T J England, K Muhiddin, J E O'Connell, N Majmudar, S Crawford, E Osborne, J Schindler, N Finch, W Kernan, B Mendes, K Shrauger, W M Clark, J Foley, P Sethi, S Hammonds, D Parker, G Rordorf, M Amatangelo, D O Kleindorfer, A Hodge, J Osborne, E Goodall, S L Silliman, Y Shabbir, M Varghese, M Gorman, C Gregory, S Kenney, M A Kelly, L Singleton, M Ohprecio, B C Meyer, C Jackson, R Chavez, N Kelly, K Rapp, J Walker, A Ehtisham, H Goodpasture, D Collie, S Miller, D Wang, J Beck, A Bogner, P Fayad, A Colburn, M Phillips, S Cordina, D Naritoku, R Backlin, D Chiu, T Lukovits, R Goddeau, R Clark-Arbogast, E Clough, M Notestine, D Sherman, R Leigh, R J Wityk, S Rice, L Pettigrew, D Taylor, A H Tayal, M Tian, G H Friday, J Brown, A Whittington-Gordon, S Sen, J Burdine, H Kowalczyk, R Sumner, A S Kim, J S Elkins, S C Johnston, T Yi, P Buekea, K Fukuda, A Teng, T Yi, A M Barrett, J Feriod, J R Masmela, K Sandefur, E C Leira, H Olalde, J Sieren, A Kelly, S Burgin, D Rempe, H Finley, J Zentner, M R Jacoby, B Hughes, J Majersik, E J Skalabrin, J Austin, S Niu, J Lee, J Naylor, J Newgent, R Sargent, S Sundararajan, D Korosec, A Slivka, A Green, P Notestine, C Heckman, A Minagar, R Alicic, M Geraghty, R Franks, K Worrell, C S Kase, H Lau, V Babikian, M Lansberg, G Albers, M Garcia, D W Dietrich, L Armstrong, J P Hanna, D Cook, N T Gentile, H Reimer, F Santiago, P Fuste, I Katzan, A Richmond, L Strozniak, M Ching, A Crumlish, D Holler, T Warwick, R Garcia, E Yilmaz, D Lawrence, L Pedelty, M Hillman, M J Schneck, T Lynch, J Ray, B M Coull, N Malekniazi, N J Solenski, K Johnston, C Harman, V Lee, S Prabhakaran, T Cole, S Dahl, M D Johnson, J Cameron-Watts, J Wright, I E Silverman, M Ahlquist, M W Salgado, R Birkhahn, R Strawsburg, I Altafullah, D A Cohen, R Zweifler, S Bright, P Hollsten, P Lee Kwen, N Kamuda, M D Hammer, J Oakley, G E Tietjen, A Korsnack, E Albakri, I Antonek, B K Dandapani, B Anthony, G Tirschner, G Jickling, P Verro, M J Roller, R Hendrickson, R Sperle, R L Hughes, J Simpson, T R Vidic, M Quakenbush, K Stanley, S Lash, B Sigsbee, J Sigsbee, D Rosenbaum, S Cherian, L Thomas, P Fonzetti, D Zondorak, J D Fleck, S Guingrich, A J Goldszmidt, A V Alexandrov, J H Halsey, M Taylor, R Hart, L Moreno, J A Sattin, A Harris, S Kumar, D Book, M Torbey, B Blaney, J J Poock, P Trenkamp, M K King, G D Graham, J Harnar, G Y Sung, M Fernandez, T Mirsen, C Hackmyer, A W Dromerick, M Giannetti, L Priestley, A D Runheim, C M Jackson, S Abel, G Moore, C Sanchez, E Feen, C Morefield, R K Reichwein, K Hitz, M F Waters, E Brooks, C Amory, G L Bernardini, S Rauch, R D Bell, B Diamond, D M Rosenbaum, D Palestrant, A Z Segal, K Burger, R L Schwartz, P Mitsias, B Stalling, J Kramer, D Robbins, B Silver, J D Easton, E Feldmann, M M Rymer, J McIntire, L Ali, B Ovbiagele, G Avila, S Pineda, H S Kirshner, D Brown, W Kernan, L Brass, K Furie, M Gorman, A Lovejoy, R Horwitz, S Inzucchi, C Viscoli, L Young, H Adams, A Carolei, W Clark, B Coull, G Ford, P Guarino, M Parsons, P Peduzzi, P Ringleb, G Schwartz, J Spence, D Tanne, P Gorelick, E Barrett, M Dyken, R Nesto, W Longstreth Jr, D Richardson, P Guarino, J O'Leary, P Peduzzi, B Zhou, O Abdelghany, Sandra Alfano, L Golden, D Lorber, E Hofstatter, F Ling, J Abbott, J Curtis, J Foody, D Jacoby, D Kolansky, S Pfau, J Lasala, M Korytkowski, S Engel, F Ismail-Beigi, D McCulloch, R Pratley, P Berhanu, E Caballero, S Dagogo-Jack, M Schutta, A Haims, K Insogna, D Lindskog, R Adelman, S Kasner, J Broderick, R Cote, C Kase, M Alberts, M Walker, J Buse, L Chambless, D Faxon, J Pary, R Conwit, C S Moy, L S Janis, L Gutmann, B Radziszewska

Affiliation

¹ From the School of Medicine (W.N.K., C.M.V., L.H.Y., S.E.I., A.M.L., L.M.B., J.R.O.) and the School of Public Health (P.D.G., P.N.P., J.R.O.), Yale University, New Haven, and the Cooperative Studies Program Coordinating Center, Veteran Affairs (VA) Connecticut HealthCare System, West Haven (P.D.G., P.N.P.) - all in Connecticut; Alpert Medical School, Brown University, Providence, RI (K.L.F.); Vermont College of Medicine, Burlington (M.G.); the National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); the VA Medical Center and the University of Colorado School of Medicine, Denver (G.G.S.); the University of Iowa, Iowa City (H.P.A.); Hôpital Charles LeMoyne, Greenfield Park, QC (L.B.), the University of Western Ontario, London (J.D.S.), and the Center for Neurological Research, Lethbridge, AB (T.R.W.) - all in Canada; University of L'Aquila, L'Aquila, Italy (A.C.); Oregon Health Sciences University, Portland (W.C.); the University of Arizona, Tucson (B.C.); the University of Oxford and Oxford University Hospitals NHS Foundation Trust, Oxfordshire, United Kingdom (G.A.F.); the University of Cincinnati, Cincinnati (D.K.); John Hunter Hospital, University of Newcastle, New Lambton Heights, NSW, Australia (M.W.P.); the University of Heidelberg, Heidelberg, Germany (P.R.); the University of South Carolina School of Medicine, Columbia (S.S.); Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (D.T.); and the Illinois Neurological Institute-OSF Saint Francis Medical Center and the Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria (D.W.).

Abstract

Background: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.

Methods: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.

Results: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).

Conclusions: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Aged
Brain Ischemia / drug therapy
Double-Blind Method
Female
Fractures, Bone / chemically induced*
Humans
Hypoglycemic Agents / adverse effects
Hypoglycemic Agents / therapeutic use*
Insulin Resistance*
Ischemic Attack, Transient / drug therapy*
Male
Middle Aged
Myocardial Infarction / prevention & control*
Peroxisome Proliferator-Activated Receptors / metabolism
Pioglitazone
Secondary Prevention
Stroke / drug therapy*
Stroke / prevention & control
Thiazolidinediones / adverse effects
Thiazolidinediones / therapeutic use*
Weight Gain / drug effects

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Authors

Collaborators

Affiliation

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding