Pioglitazone after ischemic stroke or Transient Ischemic attack

W. N. Kernan, C. M. Viscoli, K. L. Furie, L. H. Young, S. E. Inzucchi, M. Gorman, P. D. Guarino, A. M. Lovejoy, P. N. Peduzzi, R. Conwit, L. M. Brass, G. G. Schwartz, H. P. Adams, L. Berger, A. Carolei, W. Clark, Bruce M Coull, G. A. Ford, D. Kleindorfer, J. R. O'LearyM. W. Parsons, P. Ringleb, S. Sen, J. D. Spence, D. Tanne, D. Wang, T. R. Winder

Research output: Contribution to journalArticle

409 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1321-1331
Number of pages11
JournalNew England Journal of Medicine
Volume374
Issue number14
DOIs
StatePublished - Apr 7 2016

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pioglitazone
Transient Ischemic Attack
Stroke
Insulin Resistance
Placebos
Myocardial Infarction
Confidence Intervals
Weight Gain
Edema
Cerebrovascular Disorders
Fatal Outcome
Bone Fractures

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kernan, W. N., Viscoli, C. M., Furie, K. L., Young, L. H., Inzucchi, S. E., Gorman, M., ... Winder, T. R. (2016). Pioglitazone after ischemic stroke or Transient Ischemic attack. New England Journal of Medicine, 374(14), 1321-1331. https://doi.org/10.1056/NEJMoa1506930

Pioglitazone after ischemic stroke or Transient Ischemic attack. / Kernan, W. N.; Viscoli, C. M.; Furie, K. L.; Young, L. H.; Inzucchi, S. E.; Gorman, M.; Guarino, P. D.; Lovejoy, A. M.; Peduzzi, P. N.; Conwit, R.; Brass, L. M.; Schwartz, G. G.; Adams, H. P.; Berger, L.; Carolei, A.; Clark, W.; Coull, Bruce M; Ford, G. A.; Kleindorfer, D.; O'Leary, J. R.; Parsons, M. W.; Ringleb, P.; Sen, S.; Spence, J. D.; Tanne, D.; Wang, D.; Winder, T. R.

In: New England Journal of Medicine, Vol. 374, No. 14, 07.04.2016, p. 1321-1331.

Research output: Contribution to journalArticle

Kernan, WN, Viscoli, CM, Furie, KL, Young, LH, Inzucchi, SE, Gorman, M, Guarino, PD, Lovejoy, AM, Peduzzi, PN, Conwit, R, Brass, LM, Schwartz, GG, Adams, HP, Berger, L, Carolei, A, Clark, W, Coull, BM, Ford, GA, Kleindorfer, D, O'Leary, JR, Parsons, MW, Ringleb, P, Sen, S, Spence, JD, Tanne, D, Wang, D & Winder, TR 2016, 'Pioglitazone after ischemic stroke or Transient Ischemic attack', New England Journal of Medicine, vol. 374, no. 14, pp. 1321-1331. https://doi.org/10.1056/NEJMoa1506930
Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M et al. Pioglitazone after ischemic stroke or Transient Ischemic attack. New England Journal of Medicine. 2016 Apr 7;374(14):1321-1331. https://doi.org/10.1056/NEJMoa1506930
Kernan, W. N. ; Viscoli, C. M. ; Furie, K. L. ; Young, L. H. ; Inzucchi, S. E. ; Gorman, M. ; Guarino, P. D. ; Lovejoy, A. M. ; Peduzzi, P. N. ; Conwit, R. ; Brass, L. M. ; Schwartz, G. G. ; Adams, H. P. ; Berger, L. ; Carolei, A. ; Clark, W. ; Coull, Bruce M ; Ford, G. A. ; Kleindorfer, D. ; O'Leary, J. R. ; Parsons, M. W. ; Ringleb, P. ; Sen, S. ; Spence, J. D. ; Tanne, D. ; Wang, D. ; Winder, T. R. / Pioglitazone after ischemic stroke or Transient Ischemic attack. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 14. pp. 1321-1331.
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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.",
author = "Kernan, {W. N.} and Viscoli, {C. M.} and Furie, {K. L.} and Young, {L. H.} and Inzucchi, {S. E.} and M. Gorman and Guarino, {P. D.} and Lovejoy, {A. M.} and Peduzzi, {P. N.} and R. Conwit and Brass, {L. M.} and Schwartz, {G. G.} and Adams, {H. P.} and L. Berger and A. Carolei and W. Clark and Coull, {Bruce M} and Ford, {G. A.} and D. Kleindorfer and O'Leary, {J. R.} and Parsons, {M. W.} and P. Ringleb and S. Sen and Spence, {J. D.} and D. Tanne and D. Wang and Winder, {T. R.}",
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TY - JOUR

T1 - Pioglitazone after ischemic stroke or Transient Ischemic attack

AU - Kernan, W. N.

AU - Viscoli, C. M.

AU - Furie, K. L.

AU - Young, L. H.

AU - Inzucchi, S. E.

AU - Gorman, M.

AU - Guarino, P. D.

AU - Lovejoy, A. M.

AU - Peduzzi, P. N.

AU - Conwit, R.

AU - Brass, L. M.

AU - Schwartz, G. G.

AU - Adams, H. P.

AU - Berger, L.

AU - Carolei, A.

AU - Clark, W.

AU - Coull, Bruce M

AU - Ford, G. A.

AU - Kleindorfer, D.

AU - O'Leary, J. R.

AU - Parsons, M. W.

AU - Ringleb, P.

AU - Sen, S.

AU - Spence, J. D.

AU - Tanne, D.

AU - Wang, D.

AU - Winder, T. R.

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.

AB - 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.

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