Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus
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Background: Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described. Methods: We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee. Results: The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54–0.94; P =0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40–0.96; log-rank P =0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58–1.91; P =0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22–0.87; P =0.02), but not smaller MIs. Conclusions: Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT00091949.
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In a post hoc analysis of IRIS, pioglitazone was associated with a 38% relative risk reduction in myocardial infarction (1.7% versus 2.7%).
“and 38% RRR in myocardial infarction (1.7% versus 2.7%)”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [213]
In a post hoc analysis of IRIS, pioglitazone was associated with a 29% relative risk reduction in acute coronary syndrome (4.3% versus 6.0%).
“pioglitazone was also associated with a 29% RRR in acute coronary syndrome (4.3% versus 6.0%)”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [213]
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Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,232 · see citing works
Regression Models and Life-Tables
Cox, D. R. (1972) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1972.tb00899.x · Cited by 39,793 · see citing works
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158 · see citing works
Regression Models and Life-Tables
Cox, D. R. (1992) · Springer Series in Statistics · doi:10.1007/978-1-4612-4380-9_37 · Cited by 26,297 · see citing works
Diagnosis and Classification of Diabetes Mellitus
American Diabetes Association (2010) · Diabetes Care · doi:10.2337/dc11-s062 · Cited by 14,019 · see citing works
Zhang, Q., Wang, C., Zheng, M., Li, Y., Li, J., Zhang, L., Shang, X., & Yan, C. (2014) · Cerebrovascular Diseases · doi:10.1159/000369778 · Cited by 11,609 · see citing works
A sharper Bonferroni procedure for multiple tests of significance
HOCHBERG, Y. (1988) · Biometrika · doi:10.1093/biomet/75.4.800 · Cited by 4,829 · see citing works
Antman, E. M., Bassand, J., Klein, W. W., Ohman, M. E., Sendón, J. L. L., Rydén, L., Simoons, M. L., & Tendera, M. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)00804-4 · Cited by 4,824 · see citing works
A comparison of rate control and rhythm control in patients with atrial fibrillation
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa021328 · Cited by 4,405 · see citing works
Dormandy, J. A., Charbonnel, B., Eckland, D. J., Erdmann, E., Massi-Benedetti, M., Moules, I. K., Skene, A. M., Tan, M. H., Lefèbvre, P. J., Murray, G. D., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67528-9 · Cited by 4,129 · see citing works
Thygesen, K. A. (2007) · Circulation · Cited by 3,132 · see citing works
Third Universal Definition of Myocardial Infarction
Thygesen, K., Alpert, J. S., Jaffe, A. S., Simoons, M. L., Chaitman, B. R., & White, H. D. (2012) · Circulation · doi:10.1161/cir.0b013e31826e1058 · Cited by 2,985 · see citing works
High-Dose Atorvastatin after Stroke or Transient Ischemic Attack
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061894 · Cited by 2,887 · see citing works
Comment on the provisional report from the WHO consultation
(1999) · Diabetic Medicine · doi:10.1046/j.1464-5491.1999.00059.x · Cited by 1,820 · see citing works
Toole, J. F., Malinow, M. R., Chambless, L. E., Spence, J. D., Pettigrew, L. C., Howard, V. J., Sides, E. G., Wang, C.-H., & Stampfer, M. (2004) · JAMA · doi:10.1001/jama.291.5.565 · Cited by 1,391 · see citing works
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., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1506930 · Cited by 1,127 · see citing works
Self-citationNissen, S. E., Nicholls, S. J., Wolski, K., Nesto, R., Kupfer, S., Perez, A., Jure, H., De Larochellière, R., Staniloae, C. S., Mavromatis, K., et al. (2008) · JAMA · doi:10.1001/jama.299.13.1561 · Cited by 850 · see citing works
Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure
Nesto, R. W., Bell, D. S. H., Bonow, R. O., Fonseca, V. A., Grundy, S. M., Horton, E. S., Winter, M. L., Porte, D., Semenkovich, C. F., Smith, S. E., et al. (2003) · Circulation · doi:10.1161/01.cir.0000103683.99399.7e · Cited by 831 · see citing works
Self-citationDiagnosis and Classification of Diabetes Mellitus
American Diabetes Association (2005) · Diabetes Care · doi:10.2337/diacare.28.suppl_1.s37 · Cited by 830 · see citing works
Effects of clopidogrel added to aspirin in patients with recent lacunar stroke
The SPS3 Investigators (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1204133 · Cited by 679 · see citing works
BARTNIK, M. (2004) · European Heart Journal · doi:10.1016/j.ehj.2004.07.027 · Cited by 617 · see citing works
Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes
Soccio, R. E., Chen, E. R., & Lazar, M. A. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.08.005 · Cited by 518 · see citing works
Ascaso, J. F., Pardo, S., Real, J. T., Lorente, R. I., Priego, A., & Carmena, R. (2003) · Diabetes Care · doi:10.2337/diacare.26.12.3320 · Cited by 490 · see citing works
Wilcox, R., Bousser, M.-G., Betteridge, D. J., Schernthaner, G., Pirags, V., Kupfer, S., & Dormandy, J. (2007) · Stroke · doi:10.1161/01.str.0000257974.06317.49 · Cited by 475 · see citing works
Dirks, M. L., Wall, B. T., van de Valk, B., Holloway, T. M., Holloway, G. P., Chabowski, A., Goossens, G. H., & van Loon, L. J. C. (2016) · Diabetes · doi:10.2337/db15-1661 · Cited by 391 · see citing works
Deeg, M. A., Buse, J. B., Goldberg, R. B., Kendall, D. M., Zagar, A. J., Jacober, S. J., Khan, M. A., Perez, A. T., Tan, M. H., & on behalf of the GLAI Study Investigators (2007) · Diabetes Care · doi:10.2337/dc06-1903 · Cited by 179 · see citing works
Pioglitazone Reduces Neointima Volume After Coronary Stent Implantation
Marx, N., Wöhrle, J., Nusser, T., Walcher, D., Rinker, A., Hombach, V., Köenig, W., & Höher, M. (2005) · Circulation · doi:10.1161/circulationaha.105.535484 · Cited by 165 · see citing works
Takagi, T., Yamamuro, A., Tamita, K., Yamabe, K., Katayama, M., Mizoguchi, S., Ibuki, M., Tani, T., Tanabe, K., Nagai, K., et al. (2003) · American Heart Journal · doi:10.1016/s0002-8703(03)00146-7 · Cited by 154 · see citing works
Risk of Myocardial Infarction or Vascular Death After First Ischemic Stroke
Dhamoon, M. S., Tai, W., Boden-Albala, B. M., Rundek, T., Paik, M. C., Sacco, R. L., & Elkind, M. S. V. (2007) · Stroke · doi:10.1161/strokeaha.106.480988 · Cited by 135 · see citing works
Wilcox, R., Kupfer, S., & Erdmann, E. (2008) · American Heart Journal · doi:10.1016/j.ahj.2007.11.029 · Cited by 129 · see citing works
Design & Rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
Downs, J. R., Beere, P. A., Whitney, E. J., Clearfield, M. B., Weis, S. E., Rochen, J., Stein, E. A., Shapiro, D. R., Langendörfer, A., & Gotto, A. M. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(97)00347-0 · Cited by 83 · see citing works
Nitta, Y., Tahara, N., Tahara, A., et al. (2013) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2013.09.004 · Cited by 62 · see citing works
Choi, K. M., Lee, K. W., Kim, S. G., Kim, N. H., Park, C. G., Seo, H. S., Oh, D. J., Choi, D. S., & Baik, S. H. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1795 · Cited by 60 · see citing works
Viscoli, C. M., Brass, L. M., Carolei, A., Conwit, R., Ford, G. A., Furie, K. L., Gorman, M., Guarino, P. D., Inzucchi, S. E., Lovejoy, A. M., et al. (2014) · American Heart Journal · doi:10.1016/j.ahj.2014.07.016 · Cited by 50 · see citing works
Self-citationOgasawara, D., Shite, J., Shinke, T., Watanabe, S., Otake, H., Tanino, Y., Sawada, T., Kawamori, H., Kato, H., Miyoshi, N., et al. (2009) · Circulation Journal · doi:10.1253/circj.cj-08-0699 · Cited by 46 · see citing works
Alpert, J., Antman, E., Apple, F., Armstrong, P. W., Bassand, J., de Luna, A. D., Beller, G., Breithardt, G., Chaitman, B., Clemmensen, P., et al. (2000) · European Heart Journal · doi:10.1053/euhj.2000.2305 · Cited by 37 · see citing works
Jørgensen, E. O., Kelbæk, H., Helqvist, S., et al. (2003) · American Heart Journal · doi:10.1067/mhj.2003.32 · Cited by 30 · see citing works
Stubbs, P. J., Alaghband-Zadeh, J., Laycock, J. F., et al. (1999) · Heart · doi:10.1136/hrt.82.4.443 · Cited by 28 · see citing works
Efird, J. T., & Nielsen, S. S. (2008) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph5050394 · Cited by 22 · see citing works
Mongan, J., Mieszczanska, H. Z., Smith, B. H., Messing, S. P., Phipps, R. P., & Francis, C. W. (2012) · Thrombosis Research · doi:10.1016/j.thromres.2011.12.019 · Cited by 14 · see citing works
Christoph, M., Herold, J., Berg-Holldack, A., Rauwolf, T., Ziemssen, T., Schmeißer, A., Weinert, S., Ebner, B., Said, S. M., Strasser, R. H., et al. (2014) · Heart and Vessels · doi:10.1007/s00380-014-0480-0 · Cited by 12 · see citing works
Huff, T. A., Lebovitz, H. E., HEYMAN, A., & Davis, L. (1972) · Stroke · doi:10.1161/01.str.3.5.543 · Cited by 10 · see citing works
Ogasawara, D., Shite, J., Shinke, T., et al. (2009) · Japanese Circulation Journal-english Edition · Cited by 5 · see citing works
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Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., & Cherney, D. Z. I. (2018) · Kidney International · doi:10.1016/j.kint.2017.12.027 · Cited by 393 · see citing works
Self-citationSamson, S. L., Vellanki, P., Blonde, L., Christofides, E. A., Galindo, R. J., Hirsch, I. B., Isaacs, S. D., Izuora, K. E., Low Wang, C. C., Twining, C. L., et al. (2023) · Endocrine Practice · doi:10.1016/j.eprac.2023.02.001 · Cited by 375 · see citing works
Arnold, S. V., Bhatt, D. L., Barsness, G. W., Beatty, A. L., Deedwania, P. C., Inzucchi, S. E., Kosiborod, M., Leiter, L. A., Lipska, K. J., Newman, J. D., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000766 · Cited by 304 · see citing works
Self-citationNonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management
Marjot, T., Moolla, A., Cobbold, J. F., Hodson, L., & Tomlinson, J. W. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnz009 · Cited by 228 · see citing works
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DeFronzo, R. A., Inzucchi, S., Abdul-Ghani, M., & Nissen, S. E. (2019) · Diabetes and Vascular Disease Research · doi:10.1177/1479164118825376 · Cited by 223 · see citing works
Self-citationMantovani, A., Byrne, C. D., & Targher, G. (2022) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00261-2 · Cited by 230 · see citing works
Spence, J. D., Viscoli, C. M., Inzucchi, S. E., Dearborn-Tomazos, J., Ford, G. A., Gorman, M., Furie, K. L., Lovejoy, A. M., Young, L. H., Kernan, W. N., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.0079 · Cited by 109 · see citing works
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Echouffo-Tcheugui, J. B., Xu, H., Matsouaka, R. A., Xian, Y., Schwamm, L. H., Smith, E. E., Bhatt, D. L., Hernandez, A. F., Heidenreich, P. A., & Fonarow, G. C. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy036 · Cited by 103 · see citing works
- Authors
- Young, L. H., Viscoli, C. M., Curtis, J. P., Inzucchi, S. E., Schwartz, G. G., Lovejoy, A. M., Furie, K. L., Gorman, M. J., Conwit, R., Abbott, J. D., Jacoby, D. L., Kolansky, D. M., Pfau, S. E., Ling, F. S., & Kernan, W. N.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- Circulation
- Published
- 2017-05-16
- Volume
- 135
- Issue
- 20
- Pages
- 1882-1893
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC5511545
- OpenAlex
- W2892426086
- Cited by
- 66
- References
- 43
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 9 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 11 · 2018: 13 · 2017: 10
- FWCI
- 8.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Institute of Neurological Disorders and Stroke (U01NS044876)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- pioglitazone, insulin resistance, ischemic stroke, transient ischemic attack, acute coronary syndrome, myocardial infarction, unstable angina, type 1 myocardial infarction, type 2 myocardial infarction, serum troponin, IRIS trial, secondary prevention, thiazolidinediones, cardiac outcomes, atherosclerosis, diabetes mellitus
- MeSH terms
- Pioglitazone, Aged, Ischemic Attack, Transient, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Cohort Studies, Treatment Outcome, Stroke, Internationality, Thiazolidinediones, Acute Coronary Syndrome
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