Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial | Acute Coronary Syndromes | JAMA Neurology | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  CONSORT Diagram
CONSORT Diagram

IRIS indicates Insulin Resistance Intervention After Stroke.

aPrediabetes was defined by American Diabetes Association criteria: hemoglobin A1c 5.7% to 6.4% or fasting plasma glucose level 100 mg/dL to 125 mg/dL (to convert to millimoles per liter, multiply by 0.0555).

Figure 2.  Time to First Event for Participants With 80% or More Adherence
Time to First Event for Participants With 80% or More Adherence

A, Stroke or myocardial infarction (hazard ratio [HR] 0.57; 95% CI, 0.39-0.84; P = .004). B, Stroke (HR, 0.64; 95% CI, 0.42-0.99; P = .04). C, Acute coronary syndrome (HR, 0.47; 95% CI, 0.26-0.85; P = .01). D, Stroke/myocardial infarction (MI)/hospitalization for heart failure (HHR) (HR, 0.61; 95% CI, 0.42-0.88; P = .008). E, New-onset diabetes (HR, 0.18; 95% CI, 0.10-0.33; P < .001).

Table 1.  Baseline Characteristics of Participants With Adherence of 80% or More
Baseline Characteristics of Participants With Adherence of 80% or More
Table 2.  Hazard Ratios in Cox Regression for On-Treatment and Intention-to-Treat Analyses
Hazard Ratios in Cox Regression for On-Treatment and Intention-to-Treat Analyses
Table 3.  Adverse Events by Severity for Participants With Prediabetes by US/American Diabetes Association Criteria, by Treatment Group
Adverse Events by Severity for Participants With Prediabetes by US/American Diabetes Association Criteria, by Treatment Group
1.
Burchfiel  CM, Curb  JD, Rodriguez  BL, Abbott  RD, Chiu  D, Yano  K.  Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program.  Stroke. 1994;25(5):951-957. doi:10.1161/01.STR.25.5.951PubMedGoogle ScholarCrossref
2.
Janghorbani  M, Hu  FB, Willett  WC,  et al.  Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study.  Diabetes Care. 2007;30(7):1730-1735. doi:10.2337/dc06-2363PubMedGoogle ScholarCrossref
3.
Kernan  WN, Inzucchi  SE, Viscoli  CM,  et al.  Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.  Neurology. 2003;60(9):1447-1451. doi:10.1212/01.WNL.0000063318.66140.A3PubMedGoogle ScholarCrossref
4.
Mather  KJ, Steinberg  HO, Baron  AD.  Insulin resistance in the vasculature.  J Clin Invest. 2013;123(3):1003-1004. doi:10.1172/JCI67166PubMedGoogle ScholarCrossref
5.
Semenkovich  CF.  Insulin resistance and atherosclerosis.  J Clin Invest. 2006;116(7):1813-1822. doi:10.1172/JCI29024PubMedGoogle ScholarCrossref
6.
Kernan  WN, Inzucchi  SE, Viscoli  CM, Brass  LM, Bravata  DM, Horwitz  RI.  Insulin resistance and risk for stroke.  Neurology. 2002;59(6):809-815. doi:10.1212/WNL.59.6.809PubMedGoogle ScholarCrossref
7.
Spencer  M, Yang  L, Adu  A,  et al.  Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity.  PLoS One. 2014;9(7):e102190. doi:10.1371/journal.pone.0102190PubMedGoogle ScholarCrossref
8.
Zhang  MD, Zhao  XC, Zhang  YH,  et al.  Plaque thrombosis is reduced by attenuating plaque inflammation with pioglitazone and is evaluated by fluorodeoxyglucose positron emission tomography.  Cardiovasc Ther. 2015;33(3):118-126. doi:10.1111/1755-5922.12119PubMedGoogle ScholarCrossref
9.
Yki-Järvinen  H.  Thiazolidinediones.  N Engl J Med. 2004;351(11):1106-1118. doi:10.1056/NEJMra041001PubMedGoogle ScholarCrossref
10.
Berger  J, Moller  DE.  The mechanisms of action of PPARs.  Annu Rev Med. 2002;53:409-435. doi:10.1146/annurev.med.53.082901.104018PubMedGoogle ScholarCrossref
11.
Wilcox  R, Bousser  MG, Betteridge  DJ,  et al; PROactive Investigators.  Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).  Stroke. 2007;38(3):865-873. doi:10.1161/01.STR.0000257974.06317.49PubMedGoogle ScholarCrossref
12.
Kernan  WN, Viscoli  CM, Furie  KL,  et al; IRIS Trial Investigators.  Pioglitazone after ischemic stroke or transient ischemic attack.  N Engl J Med. 2016;374(14):1321-1331. doi:10.1056/NEJMoa1506930PubMedGoogle ScholarCrossref
13.
Lee  M, Saver  JL, Liao  HW, Lin  CH, Ovbiagele  B.  Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis.  Stroke. 2017;48(2):388-393. doi:10.1161/STROKEAHA.116.013977PubMedGoogle ScholarCrossref
14.
American Diabetes Association.  2: Classification and diagnosis of diabetes.  Diabetes Care. 2016;39(suppl 1):S13-S22. doi:10.2337/dc16-S005PubMedGoogle ScholarCrossref
15.
Punthakee  Z, Goldenberg  R, Katz  P; Diabetes Canada Clinical Practice Guidelines Expert Committee.  Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome.  Can J Diabetes. 2018;42(suppl 1):S10-S15. doi:10.1016/j.jcjd.2017.10.003PubMedGoogle ScholarCrossref
16.
Morris  DH, Khunti  K, Achana  F,  et al.  Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis.  Diabetologia. 2013;56(7):1489-1493. doi:10.1007/s00125-013-2902-4PubMedGoogle ScholarCrossref
17.
Simpson  SH, Eurich  DT, Majumdar  SR,  et al.  A meta-analysis of the association between adherence to drug therapy and mortality.  BMJ. 2006;333(7557):15. doi:10.1136/bmj.38875.675486.55PubMedGoogle ScholarCrossref
18.
Young  LH, Viscoli  CM, Curtis  JP,  et al; IRIS Investigators.  Cardiac outcomes after ischemic stroke or transient ischemic attack: effects of pioglitazone in patients with insulin resistance without diabetes mellitus.  Circulation. 2017;135(20):1882-1893. doi:10.1161/CIRCULATIONAHA.116.024863PubMedGoogle ScholarCrossref
19.
Yaghi  S, Furie  KL, Viscoli  CM,  et al; IRIS Trial Investigators.  Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke).  Circulation. 2018;137(5):455-463. doi:10.1161/CIRCULATIONAHA.117.030458PubMedGoogle ScholarCrossref
20.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 1958;53:457-481. doi:10.1080/01621459.1958.10501452Google ScholarCrossref
21.
Armstrong  EJ, Chen  DC, Westin  GG,  et al.  Adherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease.  J Am Heart Assoc. 2014;3(2):e000697. doi:10.1161/JAHA.113.000697PubMedGoogle ScholarCrossref
22.
Rawshani  A, Rawshani  A, Franzén  S,  et al.  Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2018;379(7):633-644. doi:10.1056/NEJMoa1800256PubMedGoogle ScholarCrossref
23.
Inzucchi  SE, Viscoli  CM, Young  LH,  et al. What mediated pioglitazone’s cardiovascular benefit in the iris trial? Paper presented at: American Diabetes Association 78th Scientific Sessions 2018; June 25, 2018; Orlando, FL.
24.
Fonville  S, Zandbergen  AA, Koudstaal  PJ, den Hertog  HM.  Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management.  Cerebrovasc Dis. 2014;37(6):393-400. doi:10.1159/000360810PubMedGoogle ScholarCrossref
25.
van Agtmaal  MJM, Houben  AJHM, de Wit  V,  et al.  Prediabetes is associated with structural brain abnormalities: the Maastricht Study.  Diabetes Care. 2018;41(12):2535-2543. doi:10.2337/dc18-1132PubMedGoogle ScholarCrossref
26.
Hernán  MA, Robins  JM.  Per-protocol analyses of pragmatic trials.  N Engl J Med. 2017;377(14):1391-1398. doi:10.1056/NEJMsm1605385PubMedGoogle ScholarCrossref
27.
Sheiner  LB, Rubin  DB.  Intention-to-treat analysis and the goals of clinical trials.  Clin Pharmacol Ther. 1995;57(1):6-15. doi:10.1016/0009-9236(95)90260-0PubMedGoogle ScholarCrossref
28.
Bełtowski  J, Rachańczyk  J, Włodarczyk  M.  Thiazolidinedione-induced fluid retention: recent insights into the molecular mechanisms.  PPAR Res. 2013;2013:628628. doi:10.1155/2013/628628PubMedGoogle ScholarCrossref
29.
Nakamura  A, Osonoi  T, Terauchi  Y.  Relationship between urinary sodium excretion and pioglitazone-induced edema.  J Diabetes Investig. 2010;1(5):208-211. doi:10.1111/j.2040-1124.2010.00046.xPubMedGoogle ScholarCrossref
30.
Adachi  H, Katsuyama  H, Yanai  H.  The low dose (7.5mg/day) pioglitazone is beneficial to the improvement in metabolic parameters without weight gain and an increase of risk for heart failure.  Int J Cardiol. 2017;227:247-248. doi:10.1016/j.ijcard.2016.11.126PubMedGoogle ScholarCrossref
31.
Akintunde  A, Nondi  J, Gogo  K,  et al.  Physiological phenotyping for personalized therapy of uncontrolled hypertension in Africa.  Am J Hypertens. 2017;30(9):923-930. doi:10.1093/ajh/hpx066PubMedGoogle ScholarCrossref
32.
Spence  JD, Rayner  BL.  Hypertension in blacks: individualized therapy based on renin/aldosterone phenotyping.  Hypertension. 2018;72(2):263-269. doi:10.1161/HYPERTENSIONAHA.118.11064PubMedGoogle ScholarCrossref
33.
Viswanathan  V, Mohan  V, Subramani  P,  et al.  Effect of spironolactone and amiloride on thiazolidinedione-induced fluid retention in South Indian patients with type 2 diabetes.  Clin J Am Soc Nephrol. 2013;8(2):225-232. doi:10.2215/CJN.06330612PubMedGoogle ScholarCrossref
Original Investigation
February 7, 2019

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

Author Affiliations
  • 1Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada
  • 2Department of Medicine, Yale School of Medicine, New Haven, Connecticut
  • 3Department of Neurology, Yale School of Medicine, New Haven, Connecticut
  • 4Radcliffe Department of Medicine, University of Oxford, United Kingdom
  • 5Department of Neurology, Maine Medical Center, Portland, Maine
  • 6Warren Alpert Medical School of Brown University, Providence, Rhode Island
JAMA Neurol. 2019;76(5):526-535. doi:10.1001/jamaneurol.2019.0079
Key Points

Question  Does pioglitazone reduce cardiovascular events in patients with prediabetes?

Findings  In this post hoc analysis of 2885 individuals with prediabetes enrolled in a randomized clinical trial, there was a significant reduction of cardiovascular events and new-onset diabetes. The association was amplified in participants with good adherence (≥80% of protocol dose taken), with stroke/myocardial infarction reduced by 40%, stroke by 33%, and new-onset diabetes by 80%.

Meaning  Pioglitazone may be an effective therapy for secondary stroke prevention in patients with prediabetes.

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

Introduction

Diabetes is an important risk factor for stroke.1,2 Adverse cardiovascular effects of diabetes are associated with insulin resistance, which is present in 50% of patients with stroke or transient ischemic attack who do not have diabetes.3 Insulin resistance is associated with increased blood pressure, serum low-density lipoprotein cholesterol, triglycerides, coagulation, inflammatory markers, platelet reactivity, reduced high-density lipoprotein cholesterol, and vascular reactivity.4-6

Pioglitazone also has antiatherosclerotic effects7,8; it reduces insulin resistance by activating peroxisome proliferator–activated receptors–γ and also causes partial minor activation of peroxisome proliferator–activated receptors–α,9 which promotes uptake, use, and catabolism of fatty acids.10

In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study, fatal/nonfatal stroke was reduced by 47%.11 In the Insulin Resistance Intervention After Stroke (IRIS) trial, pioglitazone reduced new-onset diabetes by half and reduced stroke or myocardial infarction (MI) by 24%.12

In a meta-analysis of studies in patients with stroke and insulin resistance, prediabetes, and diabetes mellitus, pioglitazone was associated with a 42% lower risk of recurrent stroke.13 Adverse events that were more common in individuals using pioglitazone in the IRIS trial included weight gain, edema, and bone fractures.

Inclusion in the IRIS trial was based on the homeostatic model assessment of insulin resistance (HOMA-IR) score, a measure of insulin resistance (fasting blood glucose in milligrams per deciliter × fasting insulin level in milliunits per liter/405). Homeostatic model assessment of insulin resistance is not commonly measured, so the IRIS results may be perceived as having limited application in clinical practice.

Therefore, to translate the IRIS trial results to real-world practice, we present analyses for patients with prediabetes, as defined by the American Diabetes Association. Results for participants with prediabetes by the more conservative definitions of the World Health Organization (WHO) are presented in eTable 3, eTable 4, and the eFigure in Supplement 1. Because we wished to assess the potential benefit of pioglitazone in real-world practice, we emphasized the results in participants who were adherent to therapy, with adherence defined as taking 80% or more of the protocol dose over the duration of the study.

Methods
Study Design

In the IRIS trial,12 insulin resistance was defined as a HOMA-IR score higher than 3. Participants without diabetes with ischemic stroke or transient ischemic attack who had insulin resistance were randomized 1:1 to placebo or pioglitazone. The dose of study drug was titrated up from 15 mg of pioglitazone per day or matching placebo to 45 mg per day over 3 months, and participants continued receiving the highest dose tolerated. The present study is a post hoc, exploratory subgroup analysis. Fasting glucose and hemoglobin A1c (HbA1c), 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. The statistical analysis plan is available in Supplement 2.

Trial Conduct and Ethics

The study was approved by the local ethics committee at each site. Participants gave written consent. The trial was monitored by an independent data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke, which funded the study.

Patient Population

Of 3876 participants in the IRIS trial, we analyzed results of pioglitazone therapy in patients with prediabetes based on the American Diabetes Association criteria.14 Selection of participants is shown in Figure 1. Results based on the WHO definition15,16 are presented in eTable 3, eTable 4, and the eFigure in Supplement 1.

Definitions

By the American Diabetes Association definition, patients are considered to have prediabetes if the glycosylated HbA1c level is 5.7% to 6.4% or the fasting plasma glucose level is 100 mg/dL to 125 mg/dL (to convert to millimoles per liter, multiply by 0.0555) or the 2-hour glucose tolerance test result is more than 140 mg/dL to 199 mg/dL.16 In the IRIS trial, patients were classified as having prediabetes for the current study based solely on HbA1c and fasting glucose measures.14 Prediabetes was defined by the WHO criteria as an HbA1c level of 6% to 6.4% or fasting glucose level of 110 mg/dL to 125 mg/dL.15

Good adherence was specified in the IRIS protocol as taking 80% or more of the protocol dose over the duration of the study as measured by pill counts on returned bottles. This is one of several common definitions of good adherence across trials.17

The primary end point was recurrent fatal or nonfatal stroke, or MI. Secondary outcomes were recurrent stroke; acute coronary syndrome; the composite of stroke/MI/hospitalization for heart failure; and the progression to diabetes. In these analyses, we used updated criteria for stroke and MI.18,19 Preselected safety events (ie, bone fracture, heart failure, and cancer) were adjudicated by the members of independent committees in a blinded fashion.

Statistical Methods

Categorical variables were summarized as percentage, and differences between groups were compared by the χ2 test. Continuous variables were summarized as mean (SD); differences between groups were analyzed by analysis of variance. Hazard analyses were completed by Cox regression. Relative risk reductions (RRRs) were calculated as percent reduction of events. Cumulative event-free rates were calculated by the Kaplan-Meier method.20 A 2-sided P value less than .05 was regarded as significant. Statistical tests were performed using SPSS, version 25 (IBM Corporation) and SAS software, version 9.4 (SAS Institute Inc). As it is known that patients with good adherence tend to have better outcomes,21 we compared participants with good adherence in both arms of the study.

Results

By the American Diabetes Association criteria, there were 2885 participants with prediabetes and 1410 with prediabetes by the more restrictive WHO criteria. Results presented here are for patients with prediabetes by the US criteria; Figure 1 shows the selection of the subgroups. Results for participants with prediabetes by the WHO criteria were very similar, although less statistically significant, and are presented in eTable 3, eTable 4, and the eFigure in Supplement 1.

Participants with prediabetes had higher levels of glycosylated HbA1c than those without prediabetes (mean [SD], 5.92% [0.34%] vs 5.47% [0.35%]) and higher HOMA-IR scores (mean [SD], 5.68 [2.87] vs 4.78 [2.19]), the latter indicating greater insulin resistance. Baseline characteristics of the participants with good adherence are shown in Table 1; characteristics of the participants in the intention-to-treat (ITT) analysis are shown in eTable 5 in Supplement 1.

Analyses for the Subgroup With Adherence of 80% or More

Among 1454 participants with prediabetes and good adherence to the protocol dose, 644 (44.3%) were in the pioglitazone group and 810 (55.7%) in the placebo group. The mean (SD) age of patients was 63 (10) years in the pioglitazone group and 64 (10) years in the placebo group. Patients with good adherence taking pioglitazone were more likely to be men (491 [76.2%] vs 572 [70.6%]), were more likely to be smokers (102 [15.9%] vs 95 [11.7%]), and had higher diastolic pressures and lower baseline high-density lipoprotein cholesterol (Table 1). Fasting blood glucose level, systolic and diastolic blood pressure, triglyceride level, and high-density lipoprotein cholesterol level were all significantly better during treatment with pioglitazone (eTable 2 in Supplement 1). Reductions in outcomes and RRRs with pioglitazone were for stroke/MI, from 83 (10.2%) to 39 (6.1%), RRR = 40%; for stroke, 61 (7.5%) to 32 (5%), RRR = 33%; for acute coronary syndrome, 39 (4.8%) to 15 (2.3%), RRR = 52%; and for stroke/MI/hospitalization for heart failure, 84 (10.4%) to 42 (6.5%), RRR = 38%. New-onset diabetes was reduced by pioglitazone from 82 (10.1%) to 13 (2.0%), RRR = 80%. Hazard ratios with 95% CI and numbers needed to treat (NNT) for statistically significant differences are shown in Table 2 and time-to-event curves in Figure 2.

Effects of pioglitazone were numerically greater among IRIS participants with prediabetes than in those without prediabetes; however, the differences were not significant (eTable 1 in Supplement 1). The results for patients with prediabetes by the WHO definition were similar to the results for prediabetes defined by US criteria but with the smaller sample size were not statistically significant except for new-onset diabetes (eTable 2, eTable 3, and eFigure in Supplement 1).

Intention-to-Treat Analyses

Among 2885 participants with prediabetes, 1456 (50.5%) were randomized to pioglitazone and 1429 (49.5%) to placebo. Baseline characteristics of the patients with prediabetes by randomized treatment group are shown in eTable 5 in Supplement 1. The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) were men in the pioglitazone group and placebo group, respectively. Reductions in outcomes and RRRs with pioglitazone were for stroke/MI, from 179 (12.5%) to 130 (8.9%), RRR = 29%; for stroke, 135 (9.4%) to 100 (6.9%), RRR = 27%; for acute coronary syndrome, 84 (5.9%) to 62 (4.3%), RRR = 27%; and for stroke/MI/hospitalization for heart failure, 193 (13.5%) to 154 (10.6%), RRR = 22%. New-onset diabetes was reduced by pioglitazone from 142 (9.9%) to 69 (4.7%), RRR = 53%. Hazard ratios and 95% CI as well as NNT for statistically significant results are shown in Table 2. For patients without prediabetes, effects of pioglitazone were attenuated but not statistically different compared with patients with prediabetes (eTable 1 in Supplement 1).

Adverse Outcomes

Among the participants with good adherence, serious bone fractures occurred in 23 patients (3.6%) in the pioglitazone group vs 23 patients (2.8%) in the placebo group. Weight gain of 10% or more occurred in 192 (29.8%) in the pioglitazone group vs 97 (12.0%) in the placebo group; edema occurred in 188 (29.2%) in the pioglitazone group vs 175 (21.6%) in the placebo group. There was a slight and nonsignificant reduction in all-cause mortality, cancer, and hospitalization with pioglitazone, and no significant increase in heart failure. Table 3 shows hazard ratio and 95% CI, and number needed to harm, for statistically significant differences. Adverse events for the ITT analysis followed the same pattern (eTable 5 in Supplement 1).

Discussion

Among IRIS study participants with prediabetes and good adherence, pioglitazone reduced stroke/MI by 40%, stroke by 33%, acute coronary syndrome by 52%, and new-onset diabetes by 80% over a median follow-up of 4.8 years. The effect sizes in the ITT analysis of those with prediabetes were smaller (29%, 27%, 27%, and 53%, respectively). These findings were observed despite a higher proportion of men and smokers, higher diastolic blood pressures, and lower high-density lipoprotein cholesterol levels among individuals with good adherence assigned to receive pioglitazone. These associations of pioglitazone in the cohort with good adherence were greater than the associations observed in the ITT cohort or in the full trial cohort probably because this was an analysis of participants with good adherence and also perhaps because participants with prediabetes had higher HbA1c level and HOMA-IR scores than those without prediabetes. As shown in Figure 2, the benefit of pioglitazone continued to increase over time, suggesting that even greater benefits might have been shown with longer follow-up. Some or much of this may have been due to prevention of diabetes over time. A 2018 study from the Swedish National Diabetes Register reported that in individuals with diabetes, the strongest predictor of cardiovascular adverse events was HbA1c.22

A question that arises from our findings is whether patients can be selected for pioglitazone therapy after stroke or transient ischemic attack based on prediabetes rather than the HOMA-IR test. It is not possible to provide a definitive answer to this question because all of the patients in our secondary analysis were enrolled in the study based on a HOMA-IR criterion. However, we believe such a strategy is reasonable for 3 reasons: (1) HbA1c level correlates well with measures of insulin resistance, (2) most patients with recent ischemic stroke and prediabetes have insulin resistance,3 and (3) in the IRIS Trial, HOMA-IR score was inversely and paradoxically correlated with magnitude of treatment effect.23 If a criterion based on HbA1c results in administration of pioglitazone to patients with lesser severity of insulin resistance, our data suggest this may not diminish the benefit of pioglitazone. Of course, the only way to provide a definitive answer would be to conduct a new trial with entry criteria based on HbA1c level rather than HOMA-IR score. An interim strategy might be to use pioglitazone for patients with a high threshold for HbA1c (eg, 6.0%) to select patients with a very high probability of advanced insulin resistance.

Participants with prediabetes had greater benefit from pioglitazone than those in the IRIS trial, although adherence was slightly less. In the IRIS trial, the percentage of participants with good adherence was 45.2% in the pioglitazone cohort vs 58.2% in the placebo cohort. In participants with prediabetes, 44.5% in the pioglitazone group had good adherence vs 57.3% in the placebo group. Notably, this is the first time, to our knowledge, that any glucose-lowering treatment has been demonstrated to reduce vascular events in a population with prediabetes. Prediabetes is a recognized risk factor for ischemic stroke,24 especially for recurrent stroke. A 2018 study also found that subclinical cerebral infarcts were more than 60% more common in individuals with prediabetes than in those with euglycemia and that this relative increase was nearly as high as observed in those with overt diabetes.25 Accordingly, our data support the notion of early treatment of prediabetes to improve clinical outcomes in those with established vascular disease.

Although ITT analysis is usually regarded as de rigeur, there are good reasons to also perform analyses that show the potential of a treatment among persons able to take it. Hernán and Robins26 discussed this issue, saying that ITT analysis may not be directly relevant for guiding decisions in clinical settings with different adherence patterns. Sheiner and Rubin27 made the distinction between “use effectiveness” (the result of prescribing a medication) and “method effectiveness” (the result of taking a medication). They pointed out that for the purpose of treating individual patients, method effectiveness was a more useful pharmacologic characteristic. This may be particularly true for drugs, which, like pioglitazone, have adverse effects that limit adherence in some patients but not in others. For patients who can take pioglitazone, it appears to be very beneficial; some patients may not be able to take it if fluid retention is excessive.

As seen in Table 3, a common adverse effect of pioglitazone is edema, which accounts for much (but not all) of the weight gain. Although we did not observe an increase in heart failure with pioglitazone in the IRIS trial, there have been concerns about heart failure as an adverse effect of pioglitazone. There appear to be 2 mechanisms contributing to edema: salt and water retention due to effects on the renal tubular epithelial sodium channel and other effects in the collecting duct28 and perhaps increased vascular permeability.29

There are maneuvers that can be implemented to minimize the problem of fluid retention. The simplest would be to use a lower dose of pioglitazone. The usual doses of pioglitazone are 15 mg, 30 mg, or 45 mg daily, but a 2017 review indicated that 7.5 mg daily confers much of the benefit of pioglitazone with less weight gain and fluid retention.30 Initiating the drug with dose titration, with a prescription that specifies repeats of the dose that did not cause a problem is 1 approach to mitigating the problem with fluid retention. Another is the use of amiloride, a specific antagonist of epithelial sodium channel. The centrality of the renal tubular epithelial sodium channel to salt and water retention and the importance of considering the use of amiloride, a seldom-used drug, were recently reviewed.31 It seems likely that amiloride, a specific antagonist of epithelial sodium channel,32 may be useful in counteracting the weight gain and fluid retention due to pioglitazone.33 (Vigilance should be exercised with regard to hyperkalemia in patients with impaired renal function.) Amiloride was reported to be more efficacious than spironolactone in reducing fluid retention with pioglitazone.33

From the perspective of the payer, with regard to direct cost of medication, what matters more is what happens when patients use a treatment since there are no medication costs for those who do not. Third-party payers who also cover the costs of costly complications such as stroke should also consider the cost of not taking medications. The economic benefits of pioglitazone with regard to prevention of MI/stroke (NNT, 24), stroke (NNT, 39), and diabetes (NNT, 12) may be offset somewhat by the cost of events such as fractures (number needed to harm, 125). Myocardial infarction and stroke are very costly, so the balance of NNTs for beneficial outcomes and numbers needed to harm for adverse outcomes would suggest cost utility for pioglitazone, but we have not yet conducted a cost-utility calculation. To achieve the greatest benefit of pioglitazone in prediabetes it would probably be better to use the US definition rather than the WHO definition.

Limitations

There are limitations to our analyses. All the participants in the IRIS trial had insulin resistance; these analyses pertain to the subgroup with prediabetes, who had significantly higher HOMA-IR scores. We cannot know the effectiveness of pioglitazone in patients with prediabetes and HOMA-IR scores less than or equal to 3, although this would be an infrequent scenario. Also, the diabetes end point was simply based on fasting glucose levels and patient reports. Hemoglobin A1c testing was not performed after the baseline visit, and oral glucose tolerance testing was not part of the protocol. As such, our diagnostic rate for new-onset diabetes was likely reduced, although this should not have introduced a bias.

Conclusions

Pioglitazone appears to reduce the risk of recurrent stroke or MI, recurrent stroke, acute coronary syndrome, and diabetes in patients with insulin resistance and prior stroke/transient ischemic attack and prediabetes, particularly in individuals who adhere to therapy. These benefits appear to outweigh the risks of fracture and fluid retention.

Back to top
Article Information

Corresponding Author: J. David Spence, MD, Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Rd, London, ON N6G 2V4, Canada (dspence@robarts.ca).

Accepted for Publication: October 26, 2018.

Published Online: February 7, 2019. doi:10.1001/jamaneurol.2019.0079

Correction: This article was corrected on March 18, 2019, to fix an error in the Discussion section.

Author Contributions: Drs Spence and Viscoli had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Spence, Inzucchi, Gorman, Young, Kernan.

Acquisition, analysis, or interpretation of data: Spence, Viscoli, Inzucchi, Dearborn-Tomazos, Ford, Gorman, Furie, Kernan.

Drafting of the manuscript: Spence, Furie.

Critical revision of the manuscript for important intellectual content: Spence, Viscoli, Inzucchi, Dearborn-Tomazos, Ford, Gorman, Young, Kernan.

Statistical analysis: Spence, Viscoli.

Obtained funding: Young, Kernan.

Administrative, technical, or material support: Furie.

Supervision: Young, Kernan.

Conflict of Interest Disclosures: The investigators (except for Dr Dearborn-Tomazos) were members of the Steering Committee of the IRIS trial. The authors have no connection with, nor have ever had any connection with, nor owned shares, nor received any funds of any kind from the manufacturer of pioglitazone. Dr Inzucchi reports grants from National Institute of Neurological Disorders and Stroke and nonfinancial support from Takeda during the conduct of the study and personal fees and nonfinancial support from Boehringer Ingelheim and personal fees from AstraZeneca, Novo Nordisk, Sanofi/Lexicon, vTv Therapeutics, Intarcia, Janssen, Daiichi Sankyo, Eisai, and Merck outside the submitted work. Dr Dearborn reports personal fees from Pfizer outside the submitted work. Dr Ford reports grants and personal fees from Medtronic and Pfizer and personal fees from Amgen, Stryker, Daiichi Sankyo, Bayer, and AstraZeneca outside the submitted work. Dr Young reported grants from National Institutes of Health during the conduct of the study. Dr Kernan reported nonfinancial support and other from Takeda Pharmaceuticals North America during the conduct of the study. No other disclosures were reported.

Funding/Support: The IRIS trial was supported by a grant (U01NS044876) from the National Institute of Neurological Disorders and Stroke. Takeda Pharmaceuticals International Inc donated pioglitazone and matching placebo for the trial and had the right to a delay of up to 6 weeks before submission of the paper for patent purposes.

Role of the Funder/Sponsor: Neither the funding agency nor Takeda had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Group Information: The IRIS Investigators are Christopher Bladin, MD (Monash University–Box Hill Hospital, Box Hill, Victoria); Stephen Davis, MD (Royal Melbourne Hospital, Parkville, Victoria); Tissa Wijeratne, BMed, FRACP, PhD (Western Hospital, University of Melbourne, Footscray, Victoria); Christopher Levi, MD (John Hunter Hospital, University of Newcastle, New Lambton Heights, Newcastle, NSW); Mark Parsons, MD (John Hunter Hospital, University of Newcastle, New Lambton Heights, Newcastle, NSW); Amy Brodtmann, MD (Austin Health, National Stroke Research Institute, Heidelberg Heights, Victoria); Steven Ng, MD (The Northern Hospital, Epping, Victoria); John Archer, MD (The Northern Hospital, Epping, Victoria); Candice Delcourt, MD (The George Institute for International Health-Royal Prince Alfred Hospital, Camperdown, Sydney, NSW); Toni R. Winder, MD (Center for Neurologic Research, Lethbridge, Alberta); Leo Berger, MD (Hopital Charles LeMoyne, Greenfield Park, Quebec); Jean-Martin Boulanger, MD (Hopital Charles LeMoyne, Greenfield Park, Quebec); Richard K. Chan, MD (Robarts Research Institute, London, Ontario); J. David Spence, MD (Robarts Research Institute, London, Ontario); Andre Durocher, MD (CHUM-Centre de recherche, Hopital Notre-Dame, Montreal, Quebec); Ariane Mackey, MD (CHU de Québec–Hôpital de l’Enfant-Jésus, Quebec); Steve Verreault, MD (CHU de Québec–Hôpital de l’Enfant-Jésus, Quebec); Jeffrey Minuk, MD (McGill University–Jewish General, Montreal, Quebec); Andrew M. Penn, MD (Vancouver Island Health Research Centre, Victoria, British Columbia); Ashfaq Shuaib, MD (University of Alberta, Edmonton, Alberta); Robert Cote, MD (McGill University–Montreal General, Montreal, Quebec); Daniel Selchen, MD, FRCP (St Michaels Hospital, University of Toronto, Toronto, Ontario); Neville Bayer, MD (St Michaels Hospital, University of Toronto, Toronto, Ontario); Margaret Sweet, MD (Intermountain Research Consultants, Thunder Bay, Ontario); Salim Malik, MD (Intermountain Research Consultants, Thunder Bay, Ontario); Grant Stotts, MD (Ottawa Hospital-General Campus, Ottawa, Ontario); Bernd Griewing, Dr med (Neurologische Klinik Bad Neustadt, Bad Neustadt); Hassan Soda, Dr med (Neurologische Klinik Bad Neustadt, Bad Neustadt); Renate Weinhardt, Dr med (Neurologische Klinik Bad Neustadt, Bad Neustadt); Jörg Berrouschot, Dr med (Klinikum Altenburger Land, Altenburg); Anett Stoll, Dr med (Klinikum Altenburger Land, Altenburg); Otto W. Witte, Dr med, PhD (Friedrich Schiller-University Jena, Jena); Albrecht Günther, Dr med (Friedrich Schiller-University Jena, Jena); Ulf Bodechtel, Dr med (University Hospital Dresden, Dresden); Ulf Schminke, Dr med (Ernst-Moritz-Arndt-University Greifswald, Greifswald); Carsten Hobohm, Dr med (Leipzig University, Leipzig); Andreas Hetzel, Dr med (Freiburg University, Freiburg); Johann Lambeck, Dr med (Freiburg University, Freiburg); Katja E. Wartenberg, Dr med, PhD (Martin-Luther-Universitaet Halle-Wittenberg, Halle); Hagen Huttner, Dr med (University of Erlangen, Erlangen); Ralf Dittrich, Dr med (University Hospital Münster, Münster); Darius G. Nabavi, Dr med (Neukolln Hospital, Berlin); Klaus Gröschel, Dr med (University Hospital Mainz, Mainz); Gotz Thomalla, Dr med (University Medical Center Hamburg-Eppendorf, Hamburg); M. Rosenkranz, Dr med (University Medical Center Hamburg-Eppendorf, Hamburg); Sebastian Jander, Dr med (University Düsseldorf/Heinrich-Heine University, Düsseldorf); Andreas Meisel, Dr med (Charite-Universitätsmedizin Berlin, Berlin); Albert Ludolph, Dr med (University of Ulm, Ulm); Katharina Althaus, Dr med (University of Ulm, Ulm); R. Huber, Dr med (University of Ulm, Ulm); Matthias Lorenz, Dr med (University Hospital Frankfurt, Frankfurt am Main); David Tanne, MD (Sheba Medical Center, Tel Hashomer); Oleg Merzlyak, MD (Sheba Medical Center, Tel Hashomer); Natan M. Bornstein, MD (Tel Aviv Medical Center, Tel Aviv); Gregory Telman, MD (Rambam Health Corporation, Haifa); Yair Lampl, MD (Wolfson Medical Center, Holon); Jonathan Streifler, MD (Rabin Medical Center-Golda Campus, Petach Tikva); Boaz Weller, MD (Bnai-Zion Medical Center, Haifa); Gal Ifergane, MD (Ben Gurion Medical Center, Beer-Sheva); Y. Wirgin, MD (Ben Gurion Medical Center, Beer-Sheva); Antonio Carolei, MD (University of Laquila, L'Aquila); Danilo Toni, MD, PhD (University of Rome La Sapienza, Rome); Paolo Stanzione, MD (University of Rome Tor Vergata, Roma); Giuseppe Micieli, MD (IRCCS Fondazione Istituto Neurologico C. Mondino, Pavia); Giancarlo Agnelli, MD (University of Perugia, Perugia); Valeria Caso, MD (University of Perugia, Perugia); Carlo Gandolfo, MD (Genoa University Hospital, Genoa); Giancarlo Comi, MD (Hospital San Raffaele S.r.l., Milan); Domenico Consoli, MD (Jazzolino Hospital, Vibo Valentia); Maurizia Rasura, MD (University of Rome (S. Andrea Hospital), Roma); Vincenzo Di Lazzaro, MD (Sacred Heart Catholic University, Rome); Anand Dixit, MBBS, MD, MRCP, DGM (Newcastle upon Tyne, Newcastle upon Tyne, Tyne and Wear, England); Becky Jupp, MD (Royal Bournemouth & Christchurch Hospitals, Bournemouth, England); Louise Shaw, MB, ChB, FRCP (Royal United Hospital, Avon, England); Isam Salih, MD (Torbay Hospital, South Devon Healthcare NHS Foundation Trust, Devon, England); Bernard Esisi, MD (Queen Elizabeth Hospital Gateshead, Sheriff Hill, Gateshead, England); Michael Power, MD (Ulster Hospital, Dundonald, Belfast, Northern Ireland); William D. Strain, BSc, MB ChB, MD (Royal Devon and Exeter, Exeter, England); Salim Elyas, MD (Royal Devon and Exeter, Exeter, England); Dulka Manawadu, MBBS, MD, MRCP, PhD, FRCP (Kings College London, London, England); Lalit Kalra, MD (Kings College London, London, England); Eoin O’Brien, MB, MRCPI, FRCP, MICGP (Addenbrookes Foundation NHS Trust Cambridge, Cambridge, England); Elizabeth Warburton, MD (Addenbrookes Foundation NHS Trust Cambridge, Cambridge, England); Kausik Chatterjee, MBBS, MRCP, MD (Countess of Chester Foundation Trust, Chester, England); David R. Hargroves, BSc, FRCP, MD (William Harvey Hospital, Ashford, Kent, England); Adrian Blight, MD (Royal Surrey County Hospital, Guildford, England); Barry Moynihan, MB, BCH, BAO, MD, MRCPI (Saint Georges University of London, Tooting, England); Hugh S. Markus, MD (Saint Georges University of London, Tooting, England); Mary Joan Macleod, MB CHB, PHD, FRCP (Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland); David Lance Broughton, MBBS, MRCP, MD (James Cook University Hospital, Middlesbrough, Cleveland, England); Helen Rodgers, MB ChB, MRCP, FRCH (North Tyneside General Hospital, Newcastle upon Tyne, Tyne and Wear, England); Thant Hlaing, MD (University Hospital Aintree, Liverpool, England); Scott Muir, MD (Western Infirmary, Glasgow, Scotland); Mahmud Sajid, MD (Chesterfield Hospital, Chesterfield, Derbyshire); Philip M.W. Bath, MD, MB, FRCP (University of Nottingham, Nottingham, England); Christopher Price, MB ChB, MD, FRCP, MclinEd (Wansbeck General Hospital, Ashington, Northumberland, England); Lakshmanan Sekaran, MBBS, MD, FRCP (Luton and Dunstable Hospital, Luton, England); Djamil Vahidassr, MD (Northern Trust, Co Antrim, N Ireland); Keith W. Muir, MB ChB, MSc, MD, MRCP, CCST, FRCP (Southern General Hospital, Glasgow, Scotland); James McIlmoyle, MB, BCh, MRCP, FRCP (Blackpool Victoria Hospital, Blackpool, England); Prabal K. Datta, MD, FRCP (Dewsbury District Hospital, Dewsbury, West Yorkshire, England); Richard Davey, MD (Dewsbury District Hospital, Dewsbury, West Yorkshire, England); Peter Langhorne, BSc, PhD, FRCP (Glasgow Royal Infirmary, Glasgow, Scotland); David Stott, MD (Glasgow Royal Infirmary, Glasgow, Scotland); Prabal K. Datta, MD, FRCP (Pinderfields Hospital, Wakefield, England); Timothy John England, MD (Royal Derby Hospital, Mickleover, Derby, England); K. Muhidden, MD (Royal Derby Hospital, Mickleover, Derby, England); Janice Elizabeth O’Connell, BSc, MBChB, MRCP, FRCP (Sunderland Royal Hospital, Sunderland, Tyne and Wear, England); Nikhil Majmudar, MD (Sunderland Royal Hospital, Sunderland, Tyne and Wear, England); Joseph Schindler, MD (Yale University, New Haven, CT); Wayne M. Clark, MD (Oregon Health & Science University, Portland, OR); Pramodkumar Sethi, MD (Guilford Neurologic Associates, Greensboro, NC); Guy Rordorf, MD, MPH (Massachusetts General Hospital/General Hospital Corp, Boston, MA); Dawn O. Kleindorfer, MD (University of Cincinnati, Cincinnati, OH); Scott L. Silliman, MD (University of Florida, Jacksonville, FL); Mark Gorman, MD (University of Vermont, Burlington, VT); Michael A. Kelly, MD (Hektoen Institute for Medical Research, LLC, Chicago, IL); Lafayette Singleton, MD (Hektoen Institute for Medical Research, LLC, Chicago, IL); Brett C. Meyer, MD (University of California, San Diego, San Diego, CA); Christy Jackson, MD (University of California, San Diego, San Diego, CA); James Walker, MD (Via Christi Regional Medical Center, Wichita, KS); As’ad Ehtisham, MD (Via Christi Regional Medical Center, Wichita, KS); Hewitt C. Goodpasture, MD (Via Christi Regional Medical Center, Wichita, KS); David Wang, DO (OSF Saint Francis Medical Center, Peoria, IL); Pierre Fayad, MD (University of Nebraska, Omaha, NE); Steve Cordina, MD (University of South Alabama, Mobile, AL); Dean Naritoku, MD (University of South Alabama, Mobile, AL); David Chiu, MD (Methodist Hospital Research Institute, Houston, TX); Timothy Lukovits, MD (Dartmouth, Lebanon, NH); Richard Goddeau, DO (Dartmouth, Lebanon, NH); Robin Clark-Arbogast, APRN (Dartmouth, Lebanon, NH); Richard Leigh, MD (Johns Hopkins University, Baltimore, MD); Robert J. Wityk, MD (Johns Hopkins University, Baltimore, MD); L. Creed Pettigrew, MD (University of Kentucky Research Foundation, Lexington, KY); Ashis H. Tayal, MD (Allegheny Singer Research Institute, Pittsburgh, PA); Judy Jarouse, NP (Allegheny Singer Research Institute, Pittsburgh, PA); Gary H. Friday, MD (Lankenau Institute for Medical Research, Wynnewood, PA); Souvik Sen, MD, MS, MPH, FAHA (University of South Carolina, Columbia, SC); Anthony S. Kim, MD (University of California, San Francisco, San Francisco, CA); S. Claiborne Johnston, MD, PhD (University of California, San Francisco, San Francisco, CA); Jacob S. Elkins, MD (University of California, San Francisco, San Francisco, CA); Anna M. Barrett, MD (Kessler Foundation, West Orange, NJ); Enrique C. Leira, MD (University of Iowa, Iowa City, IA); Adam Kelly, MD (University of Rochester, Rochester, NY); S. Burgin, MD (University of Rochester, Rochester, NY); David A. Rempe, MD (University of Rochester, Rochester, NY); Michael R. K. Jacoby, MD (Ruan Neuroscience Center/Mercy Medical Center, Des Moines, IA); Bruce Hughes, MD (Ruan Neuroscience Center/Mercy Medical Center, Des Moines, IA); Jennifer Majersik, MD (University of Utah, Salt Lake City, UT); Elaine J. Skalabrin, MD (University of Utah, Salt Lake City, UT); Jin-Moo Lee, PhD, MD (Washington University, St Louis, MO); Chung Hsu, MD (Washington University, St Louis, MO); Sophia Sundararajan, MD (Case Western Reserve University, Cleveland, OH); Andrew Slivka, MD (Ohio State University, Columbus, OH); Alireza Minagar, MD (LSU Health Sciences Center, Shreveport, LA); Radica Alicic, MD (Providence Medical Research Center, Spokane, WA); Madeleine Geraghty, MD (Providence Medical Research Center, Spokane, WA); Carlos S. Kase, MD (Boston Medical Center Corp, Boston, MA); Maartan Lansberg, MD (Stanford University, Stanford, CA); Greg Albers, MD (Stanford University, Stanford, CA); Dennis W Dietrich, MD (Advanced Neurology Specialists, Great Falls, MT); Joseph P. Hanna, MD (Metrohealth Medical Center, Cleveland, OH); Nina T. Gentile, MD (Temple University, Philadelphia, PA); Fernando Santiago, MD (University of Puerto Rico, San Juan, Puerto Rico); Irene Katzan, MD (Cleveland Clinic Foundation, Cleveland, OH); Marilou Ching, MD, MPH (Research Foundation SUNY, University of Buffalo, Buffalo, NY); Robert Sawyer, MD (Research Foundation SUNY, University of Buffalo, Buffalo, NY); Tanya Warwick, MD (UCSF (Fresno), Fresno, CA); Engin Yilmaz, MD (Ingalls Memorial Hospital, Harvey, IL); Laura Pedelty, MD, PhD (University of Illinois, Chicago, Chicago, IL); Michael J. Schneck, MD (Loyola University Chicago, Maywood, IL); Bruce M. Coull, MD (University of Arizona, Tucson, AZ); Nina J. Solenski, MD (University of Virginia, Charlottesville, VA); Karen Johnston, MD (University of Virginia, Charlottesville, VA); Vivien Lee, MD (Rush University, Chicago, IL); Shyam Prabhakaran, MD (Rush University, Chicago, IL); Mark D. Johnson, MD (University of Texas, Southwestern, Dallas, TX); Isaac E. Silverman, MD (Hartford Hospital, Hartford, CT); Miran W. Salgado, MD (New York Methodist Hospital, Brooklyn, NY); Robert Birkhahn, MD (New York Methodist Hospital, Brooklyn, NY); Richard Strawsburg, MD (Associates in Neurology, PC, Valparaiso, IN); Irfan Altafullah, MD (Minneapolis Clinic of Neurology, Golden Valley, MN); Daniel Aaron Cohen, MD (Sentara Neurology Specialists, Norfolk, VA); Richard Zweifler, MD (Sentara Neurology Specialists, Norfolk, VA); Peterkin Lee Kwen, MD (Southtowns Neurology of WNY, PC, West Seneca, NY); Maxim D. Hammer, MD (University of Pittsburgh, Pittsburgh, PA); Nirav Vora, MD (University of Pittsburgh, Pittsburgh, PA); Gretchen E. Tietjen, MD (University of Toledo, Toledo, OH); Erfan Albakri, MD (Florida Neurovascular Institute, Tampa, FL); Bhuvaneswari (Bo) K. Dandapani, MD (Health First Physicians, Inc., Melbourne, FL); Glen Jickling, MD (UC-Davis Medical Center, Sacramento, CA); Piero Verro, MD (UC-Davis Medical Center, Sacramento, CA); Matthew J. Roller, MD (Altru Health System, Grand Forks, ND); Richard L. Hughes, MD (Denver Health and Hospital Authority, Denver, CO); Jennifer Simpson, MD (Denver Health and Hospital Authority, Denver, CO); Thomas R. Vidic, MD, FAAN (Indiana Medical Research, Elkhart, IN); Stephanie Lash, MD (Penobscot Bay Neurology, Rockport, ME); Bruce Sigsbee, MD (Penobscot Bay Neurology, Rockport, ME); Daniel Rosenbaum, MD (SUNY Downstate, Brooklyn, NY); Pasquale Fonzetti, MD, PhD (Burke Medical Research Institute, White Plains, NY); James D. Fleck, MD (Indiana University, Indianapolis, IN); Adrian J. Goldszmidt, MD (Sinai Hospital of Baltimore, Baltimore, MD); Andrei V Alexandrov, MD (University of Alabama, Birmingham, AL); James H. Halsey, MD (University of Alabama, Birmingham, AL); Robert Hart, MD (University of Texas, San Antonio, San Antonio, TX); Justin A. Sattin, MD (University of Wisconsin, Madison, WI); Sandeep Kumar, MD (Beth Israel Deaconess, Boston, MA); Diane Book, MD (Medical College of Wisconsin, Milwaukee, WI); Michel Torbey, MD (Medical College of Wisconsin, Milwaukee, WI); James J. Poock, MD (Northeast Iowa Medical Education Foundation, Waterloo, IA); Molly K. King, MD (University of New Mexico, Albuquerque, NM); Glenn D. Graham, MD, PhD (University of New Mexico, Albuquerque, NM); Gene Yong Sung, MD, MPH (University of Southern California, Los Angeles, CA); Thomas Mirsen, MD (Cooper University Hospital, Camden, NJ); Alexander W. Dromerick, MD (National Rehabilitation Hospital, Washington, DC); Andreas D. Runheim, MD (Salem Neurological Center, Winston-Salem, NC); Christy M. Jackson, MD (Scripps Clinic, La Jolla, CA); Eliahu Feen, MD (St Louis University, St .Louis, MO); Raymond K. Reichwein, MD (Penn State-Hershey Medical Center, Hershey, PA); Michael F. Waters, MD (University of Florida, Gainesville, Gainesville, FL); Colum Amory, MD (Albany Medical Center, Albany, NY); Gary L. Bernardini, MD (Albany Medical Center, Albany, NY); Rodney D. Bell, MD (Thomas Jefferson University, Philadelphia, PA); B. Franklin Diamond, MD (Abington Memorial Hospital, Abington, PA); Daniel M. Rosenbaum, MD (Albert Einstein, Bronx, NY); David Palestrant, MD (Cedars-Sinai Medical Center, Los Angeles, CA); Alan Z. Segal, MD (Cornell University, New York, NY); Kathleen Burger, DO (George Washington University, Washington, DC); Ronald L. Schwartz, MD (Hattiesburg Clinic, Hattiesburg, MS); Panayiotis Mitsias, MD (Henry Ford Health Sciences Center, Detroit, MI); Jeffrey Kramer, MD (Jeffrey Kramer, MDSC [formerly Kramer/Mercy], Chicago, IL); David Robbins, MD (Pines Neurological Associates, Pembroke Pines, FL); Brian Silver, MD (Rhode Island Hospital, Providence, RI); J. Donald Easton, MD (Rhode Island Hospital, Providence, RI); Edward Feldmann, MD (Rhode Island Hospital, Providence, RI); Marilyn M. Rymer, MD (St Lukes Brain and Stroke Institute, Kansas City, MO); Joyce Dorssom, MD (St Lukes Brain and Stroke Institute, Kansas City, MO); Latisha Ali, MD (University of California, Los Angeles, Los Angeles, CA); Bruce Ovbiagele, MD (University of California, Los Angeles, Los Angeles, CA); Howard S. Kirshner, MD (Vanderbilt University, Nashville, TN); Walter N. Kernan, MD (Department of Medicine, Yale School of Medicine, New Haven, CT); L. Brass, MD (Yale School of Medicine, New Haven, CT) (deceased); K. Furie, MD (Warren Alpert Medical School of Brown University, Providence, RI); Anne M. Lovejoy, PA-C (Department of Medicine, Yale School of Medicine, New Haven, CT); R. Horwitz, MD (Yale School of Medicine, New Haven, CT); Silvio E. Inzucchi, MD (Department of Medicine, Yale School of Medicine, New Haven, CT); Catherine M. Viscoli, PhD (Department of Medicine, Yale School of Medicine, New Haven, CT); Lawrence H. Young, MD (Department of Medicine, Yale School of Medicine, New Haven, CT); Harold P. Adams, MD (University of Iowa, Iowa City, IA); Gary Ford, MB, Bchir (University of Oxford, Oxfordshire, UK); Peter Guarino, PhD (Yale School of Public Health, New Haven, CT); Peter N. Peduzzi, PhD (Yale School of Public Health, New Haven, CT); Peter Ringleb, MD (University Heidelberg, Heidelberg, Germany); Gregory Schwartz, MD (Denver VA Medical Center, Denver, CO); Phillip B. Gorelick, MD (University of Illinois at Chicago, Chicago, IL); Eugene J. Barrett, MD (University of Virginia, Charlottesville, VA ); Mark L. Dyken, MD (Indiana University Medical Center, Indianapolis, IN); Richard W. Nesto, MD (Lahey Clinic, Burlington, MA); William T. Longstreth Jr, MD (University of Washington, Seattle, WA); Dejuran Richardson, MD (Rush University, Chicago, IL); John O’Leary, MA (Yale School of Medicine, New Haven, CT); B. Zhou, PhD (Yale School of Medicine, New Haven, CT); Osama Abdelghany, PharmD (Yale-New Haven Hospital, New Haven, CT); Sandra L. Alfono, PharmD (Yale-New Haven Hospital, New Haven, CT); Lauren Golden, MD (Columbia University Medical Center, New York, NY); Dan Lorber, MD (New York Hospital Medical Center, Flushing, NY); Erin W. Hofstatter, MD (Yale School of Medicine, New Haven CT); Frederick S. Ling, MD (University of Rochester, Rochester NY); J. Dawn Abbott, MD (The Warren Alpert Medical School of Brown University, Providence, RI); Jeptha P. Curtis, MD (Yale School of Medicine, New Haven CT); JoAnne M. Foody, MD (Harvard Medical School, Boston, MA); Daniel Jacoby, MD (Yale School of Medicine, New Haven CT); Daniel M. Kolansky, MD (University of Pennsylvania Health System, Philadelphia, PA); Steven Pfau, MD (Yale School of Medicine, New Haven, CT); John M. Lasala, MD (Washington University in St Louis, St Louis, MO); Mary T. Korytkowski, MD (University of Pittsburgh, Pittsburgh, PA); Sam Engel, MD (Albert Einstein College of Medicine, Bronx, NY); Faramarz Ismail-Beigi, MD (Case Western University, Shaker Heights, OH); David McCulloch, MD (University of Washington, Seattle, WA); Richard E. Pratley, MD (Florida Hospital Diabetes Institute, Tampa, FL); Paulos Berhanu, MD (Wayne State University, Detroit, MI); Enrique Caballero, MD (Harvard University, Cambridge, MA); Sam Dagogo-Jack, MD (University of Tennessee, Memphis, TN); Mark H. Schutta, MD (University of Pennsylvania, Philadelphia, PA); Andy Haims, MD (Yale School of Medicine, New Haven CT); Karl Insogna, MD (Yale School of Medicine, New Haven, CT); Dieter Lindskog, MD (Yale School of Medicine, New Haven CT); Ron Adelman, MD (Yale School of Medicine, New Haven, CT); Scott Kasner, MD (University of Pennsylvania Medical Center, Philadelphia, PA); Joseph P. Broderick, MD (University of Cincinnati, Cincinnati, OH); Mark J. Alberts, MD (Northwestern University Medical School, Chicago, IL); Michael D. Walker, MD (NA, Sarasota, FL); John B. Buse, MD (University of North Carolina at Chapel Hill, Chapel Hill, NC); Lloyd Chambless, PhD (University of North Carolina at Chapel Hill, Chapel Hill, NC); David Faxon, MD (University of Chicago, Chicago, IL); Jennifer K. Pary, MD (Mercy Medical Center, Dakota Dunes, SD); Robin Conwit, MD (National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD); Claudia Scala Moy, MD (National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD); Scott Janis, PhD (National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD); Laurie Gutmann, MD (National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD); Barbara Radziszewska, MD (National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD).

Additional Contributions: We thank the study coordinators and site investigators.

References
1.
Burchfiel  CM, Curb  JD, Rodriguez  BL, Abbott  RD, Chiu  D, Yano  K.  Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program.  Stroke. 1994;25(5):951-957. doi:10.1161/01.STR.25.5.951PubMedGoogle ScholarCrossref
2.
Janghorbani  M, Hu  FB, Willett  WC,  et al.  Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study.  Diabetes Care. 2007;30(7):1730-1735. doi:10.2337/dc06-2363PubMedGoogle ScholarCrossref
3.
Kernan  WN, Inzucchi  SE, Viscoli  CM,  et al.  Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.  Neurology. 2003;60(9):1447-1451. doi:10.1212/01.WNL.0000063318.66140.A3PubMedGoogle ScholarCrossref
4.
Mather  KJ, Steinberg  HO, Baron  AD.  Insulin resistance in the vasculature.  J Clin Invest. 2013;123(3):1003-1004. doi:10.1172/JCI67166PubMedGoogle ScholarCrossref
5.
Semenkovich  CF.  Insulin resistance and atherosclerosis.  J Clin Invest. 2006;116(7):1813-1822. doi:10.1172/JCI29024PubMedGoogle ScholarCrossref
6.
Kernan  WN, Inzucchi  SE, Viscoli  CM, Brass  LM, Bravata  DM, Horwitz  RI.  Insulin resistance and risk for stroke.  Neurology. 2002;59(6):809-815. doi:10.1212/WNL.59.6.809PubMedGoogle ScholarCrossref
7.
Spencer  M, Yang  L, Adu  A,  et al.  Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity.  PLoS One. 2014;9(7):e102190. doi:10.1371/journal.pone.0102190PubMedGoogle ScholarCrossref
8.
Zhang  MD, Zhao  XC, Zhang  YH,  et al.  Plaque thrombosis is reduced by attenuating plaque inflammation with pioglitazone and is evaluated by fluorodeoxyglucose positron emission tomography.  Cardiovasc Ther. 2015;33(3):118-126. doi:10.1111/1755-5922.12119PubMedGoogle ScholarCrossref
9.
Yki-Järvinen  H.  Thiazolidinediones.  N Engl J Med. 2004;351(11):1106-1118. doi:10.1056/NEJMra041001PubMedGoogle ScholarCrossref
10.
Berger  J, Moller  DE.  The mechanisms of action of PPARs.  Annu Rev Med. 2002;53:409-435. doi:10.1146/annurev.med.53.082901.104018PubMedGoogle ScholarCrossref
11.
Wilcox  R, Bousser  MG, Betteridge  DJ,  et al; PROactive Investigators.  Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).  Stroke. 2007;38(3):865-873. doi:10.1161/01.STR.0000257974.06317.49PubMedGoogle ScholarCrossref
12.
Kernan  WN, Viscoli  CM, Furie  KL,  et al; IRIS Trial Investigators.  Pioglitazone after ischemic stroke or transient ischemic attack.  N Engl J Med. 2016;374(14):1321-1331. doi:10.1056/NEJMoa1506930PubMedGoogle ScholarCrossref
13.
Lee  M, Saver  JL, Liao  HW, Lin  CH, Ovbiagele  B.  Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis.  Stroke. 2017;48(2):388-393. doi:10.1161/STROKEAHA.116.013977PubMedGoogle ScholarCrossref
14.
American Diabetes Association.  2: Classification and diagnosis of diabetes.  Diabetes Care. 2016;39(suppl 1):S13-S22. doi:10.2337/dc16-S005PubMedGoogle ScholarCrossref
15.
Punthakee  Z, Goldenberg  R, Katz  P; Diabetes Canada Clinical Practice Guidelines Expert Committee.  Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome.  Can J Diabetes. 2018;42(suppl 1):S10-S15. doi:10.1016/j.jcjd.2017.10.003PubMedGoogle ScholarCrossref
16.
Morris  DH, Khunti  K, Achana  F,  et al.  Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis.  Diabetologia. 2013;56(7):1489-1493. doi:10.1007/s00125-013-2902-4PubMedGoogle ScholarCrossref
17.
Simpson  SH, Eurich  DT, Majumdar  SR,  et al.  A meta-analysis of the association between adherence to drug therapy and mortality.  BMJ. 2006;333(7557):15. doi:10.1136/bmj.38875.675486.55PubMedGoogle ScholarCrossref
18.
Young  LH, Viscoli  CM, Curtis  JP,  et al; IRIS Investigators.  Cardiac outcomes after ischemic stroke or transient ischemic attack: effects of pioglitazone in patients with insulin resistance without diabetes mellitus.  Circulation. 2017;135(20):1882-1893. doi:10.1161/CIRCULATIONAHA.116.024863PubMedGoogle ScholarCrossref
19.
Yaghi  S, Furie  KL, Viscoli  CM,  et al; IRIS Trial Investigators.  Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke).  Circulation. 2018;137(5):455-463. doi:10.1161/CIRCULATIONAHA.117.030458PubMedGoogle ScholarCrossref
20.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 1958;53:457-481. doi:10.1080/01621459.1958.10501452Google ScholarCrossref
21.
Armstrong  EJ, Chen  DC, Westin  GG,  et al.  Adherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease.  J Am Heart Assoc. 2014;3(2):e000697. doi:10.1161/JAHA.113.000697PubMedGoogle ScholarCrossref
22.
Rawshani  A, Rawshani  A, Franzén  S,  et al.  Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2018;379(7):633-644. doi:10.1056/NEJMoa1800256PubMedGoogle ScholarCrossref
23.
Inzucchi  SE, Viscoli  CM, Young  LH,  et al. What mediated pioglitazone’s cardiovascular benefit in the iris trial? Paper presented at: American Diabetes Association 78th Scientific Sessions 2018; June 25, 2018; Orlando, FL.
24.
Fonville  S, Zandbergen  AA, Koudstaal  PJ, den Hertog  HM.  Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management.  Cerebrovasc Dis. 2014;37(6):393-400. doi:10.1159/000360810PubMedGoogle ScholarCrossref
25.
van Agtmaal  MJM, Houben  AJHM, de Wit  V,  et al.  Prediabetes is associated with structural brain abnormalities: the Maastricht Study.  Diabetes Care. 2018;41(12):2535-2543. doi:10.2337/dc18-1132PubMedGoogle ScholarCrossref
26.
Hernán  MA, Robins  JM.  Per-protocol analyses of pragmatic trials.  N Engl J Med. 2017;377(14):1391-1398. doi:10.1056/NEJMsm1605385PubMedGoogle ScholarCrossref
27.
Sheiner  LB, Rubin  DB.  Intention-to-treat analysis and the goals of clinical trials.  Clin Pharmacol Ther. 1995;57(1):6-15. doi:10.1016/0009-9236(95)90260-0PubMedGoogle ScholarCrossref
28.
Bełtowski  J, Rachańczyk  J, Włodarczyk  M.  Thiazolidinedione-induced fluid retention: recent insights into the molecular mechanisms.  PPAR Res. 2013;2013:628628. doi:10.1155/2013/628628PubMedGoogle ScholarCrossref
29.
Nakamura  A, Osonoi  T, Terauchi  Y.  Relationship between urinary sodium excretion and pioglitazone-induced edema.  J Diabetes Investig. 2010;1(5):208-211. doi:10.1111/j.2040-1124.2010.00046.xPubMedGoogle ScholarCrossref
30.
Adachi  H, Katsuyama  H, Yanai  H.  The low dose (7.5mg/day) pioglitazone is beneficial to the improvement in metabolic parameters without weight gain and an increase of risk for heart failure.  Int J Cardiol. 2017;227:247-248. doi:10.1016/j.ijcard.2016.11.126PubMedGoogle ScholarCrossref
31.
Akintunde  A, Nondi  J, Gogo  K,  et al.  Physiological phenotyping for personalized therapy of uncontrolled hypertension in Africa.  Am J Hypertens. 2017;30(9):923-930. doi:10.1093/ajh/hpx066PubMedGoogle ScholarCrossref
32.
Spence  JD, Rayner  BL.  Hypertension in blacks: individualized therapy based on renin/aldosterone phenotyping.  Hypertension. 2018;72(2):263-269. doi:10.1161/HYPERTENSIONAHA.118.11064PubMedGoogle ScholarCrossref
33.
Viswanathan  V, Mohan  V, Subramani  P,  et al.  Effect of spironolactone and amiloride on thiazolidinedione-induced fluid retention in South Indian patients with type 2 diabetes.  Clin J Am Soc Nephrol. 2013;8(2):225-232. doi:10.2215/CJN.06330612PubMedGoogle ScholarCrossref
×