CoChat
Sign Up
Cited by 109Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsAcute Ischemic Stroke Management

Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial

Open access
Spence, J. David, Viscoli, Catherine M., Inzucchi, Silvio E., Dearborn-Tomazos, Jennifer, Ford, Gary A., Gorman, Mark, Furie, Karen L., Lovejoy, Anne M. +3 more·2019·JAMA Neurology
DOI 10.1001/jamaneurol.2019.0079PMC PMC6515584
Open this paper in CoChat — free accountOpen PDF

Abstract

Importance: In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. Objective: To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. Design, Setting, and Participants: The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Interventions: Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. Main Outcomes and Measures: The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Results: Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Conclusions and Relevance: Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. Trial Registration: ClinicalTrials.gov identifier: NCT00091949.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1001/jamaneurol.2019.0079

Cites

38 of 39 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Another meta-analysis of 8 randomized controlled trials comprising 56,251 participants found that GLP-1 receptor agonists reduced nonfatal strokes (OR 0.84, 95% CI 0.76-0.94; P=.002) compared with placebo.

    “Another meta-analysis evaluated the efficacy and safety of GLP-1 RAs for stroke prevention in 8 RCTs comprising 56,251 participants and found that compared with placebo, GLP-1 RAs reduced nonfatal strokes (OR, 0.84; 95% CI, 0.76–0.94; P = .002) and all strokes (OR, 0.84; 95% CI, 0.75–0.93; P = .001).661”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [661]

    Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Side effects of TZDs can be mitigated by using lower doses and combining TZD therapy with other medications (SGLT2i and GLP-1 RA) that promote weight loss and sodium excretion.

    “Side effects can be mitigated by using lower doses and combining TZD therapy with other medications (SGLT2i and GLP-1 RA) that promote weight loss and sodium excretion (199,206).”

    From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [199]

    The Discussion (page unavailable in our copy) says a lower pioglitazone dose may reduce weight gain and fluid retention. It also suggests amiloride for fluid retention, but does not support the specified combination with SGLT2 inhibitors or GLP-1 receptor agonists. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • TZDs are associated with possible side effects of fluid retention and congestive heart failure, weight gain, and bone fracture.

    “However, these bene fi ts must be balanced against possible side effects of fl uid retention and congestive HF (196,197,202), weight gain (196 -198,202,203), and bone fracture (204,205).”

    From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [199]

  • In the IRIS study, in adults without diabetes but with insulin resistance and recent history of stroke or transient ischemic attack, there was a lower risk of stroke or myocardial infarction with pioglitazone versus placebo.

    “In the Insulin Resistance Intervention After Stroke (IRIS) study in adults without diabetes but with insulin resistance (HOMA of insulin resistance > 3.0) and recent history of stroke or transient ischemic attack, there was a lower risk of stroke or myocardial infarction with pioglitazone versus placebo (198,199).”

    From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [199]

  • The same meta-analysis found that GLP-1 receptor agonists reduced all strokes (OR 0.84, 95% CI 0.75-0.93; P=.001) compared with placebo.

    “Another meta-analysis evaluated the efficacy and safety of GLP-1 RAs for stroke prevention in 8 RCTs comprising 56,251 participants and found that compared with placebo, GLP-1 RAs reduced nonfatal strokes (OR, 0.84; 95% CI, 0.76–0.94; P = .002) and all strokes (OR, 0.84; 95% CI, 0.75–0.93; P = .001).661”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [661]

    The Results and Table 2 report stroke outcomes for pioglitazone versus placebo in patients with prediabetes, not a meta-analysis of GLP-1 receptor agonists. Searches for GLP-1 agonists, the eight-trial meta-analysis, and the stated odds ratio found no passage addressing the attributed result in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. [28]28. Eoin O'Brien, MB, MRCPI, FRCP, MICGP (Addenbrookes Foundation NHS Trust Cambridge, Cambridge, England);
  2. [29]29. Elizabeth Warburton, MD (Addenbrookes Foundation NHS Trust Cambridge, Cambridge, England);
  3. [183]183. Gary Ford, MB, Bchir (University of Oxford, Oxfordshire, UK);
  4. [210]210. Enrique Caballero, MD (Harvard University, Cambridge, MA);

Cited by

Sorted by citations

Related

Authors
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., & for the IRIS Investigators
Affiliations
  • Western University (CA)
  • Yale University (US)
  • Department of Neurology, Yale School of Medicine, New Haven, Connecticut
  • University of Oxford (GB)
  • Maine Medical Center (US)
  • Brown University (US)
Corresponding author
Spence, J. David
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2019-05-01
Volume
76
Issue
5
Pages
526
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2019.0079
PMC
PMC6515584
OpenAlex
W2912548489
Cited by
109
References
37
Citations by year
2026: 6 · 2025: 8 · 2024: 12 · 2023: 19 · 2022: 14 · 2021: 21 · 2020: 18 · 2019: 11
FWCI
12.98
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Scholarship@Western (Western University) (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
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 Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
pioglitazone, prediabetes, insulin resistance, stroke, stroke recurrence, myocardial infarction, acute coronary syndrome, heart failure hospitalization, progression to diabetes, medication adherence, insulin sensitizers, IRIS trial, transient ischemic attack, HbA1c, fasting blood glucose, intention-to-treat effect, post hoc analysis, subgroup analysis
MeSH terms
Pioglitazone, Aged, Diabetes Mellitus, Type 2, Female, Heart Failure, Glycated Hemoglobin, Hospitalization, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Myocardial Infarction, Prediabetic State, Recurrence, Proportional Hazards Models, Disease Progression, Stroke, Acute Coronary Syndrome, Medication Adherence, Secondary Prevention

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review