Insulin Resistance Intervention After Stroke Research Articles

Effect of pioglitazone on vascular events in post-stroke cognitive impairment: Post hoc analysis of the IRIS trial.

In stroke patients with insulin resistance (IR), post-stroke cognitive impairment (PSCI) is associated with higher risk of recurrent stroke, but the effect of pioglitazone on that risk has not been explored. The goal of this study was to compare the secondary stroke prevention effect of pioglitazone against placebo in patients with versus without PSCI. We studied patients enrolled in the Insulin Resistance Intervention after Stroke (IRIS) trial with a post-stroke modified Mini-Mental State Examination (3MS) cognitive assessment (mean time of assessment: 79 days post-stroke). We considered a baseline score of ⩽ 88 on the 3MS to indicate global PSCI, and domain-specific summary scores in the lowest quartile to indicate attention, language, memory, orientation, and visuospatial impairments. In n = 3338 patients with IR, the effect of pioglitazone versus placebo on secondary stroke significantly differed by initial post-stroke global (interaction p = 0.0127) and memory impairment status (interaction p = 0.0003). Hazard ratios (HRs) were time-dependent such that, among those with either global or memory impairment, pioglitazone has an increasingly stronger protective effect at later timepoints. There was no statistically significant effect of pioglitazone among those without either global or memory impairment. The effect of pioglitazone versus placebo on myocardial infarction (MI) also significantly differed by global impairment status (interaction p = 0.030). Pioglitazone was protective among those with global impairment (HR = 0.23 [95% CI: 0.08, 0.71]) but not among those without (HR = 0.88 [95% CI: 0.59, 1.31]). These data indicate that pioglitazone treatment may be more effective at reducing risk of recurrent stroke and MI in stroke patients with PSCI. Simple cognitive testing 2-3 months post-stroke may identify patients for whom treatment would be most beneficial.

An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized clinical trials

Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate’s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: −14.8% ± 3.1%, pone-sample t-test = 0.001; SPRINT: −17.6% ± 3.6%, pone-sample t-test < 0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all simulations with Cox regression-derived p value of < 0.01 for the effect of the intervention on the respective primary outcome). This adaptive framework has the potential to maximize RCT enrollment efficiency.

Study on insulin resistance and ischemic cerebrovascular disease: A bibliometric analysis via CiteSpace.

It is reported that insulin resistance widely exists in non-diabetic patients with a recent history of transient ischemic attack (TIA) or ischemic stroke. There is currently strong evidence to prove the bidirectional effect of glucose metabolism disorders and stroke events. Therefore, it is necessary to retrospectively tease out the current status, hotspots, and frontiers of insulin resistance and ischemic cerebrovascular disease through CiteSpace. We searched the Web of Science (WOS) for studies related to insulin resistance and ischemic cerebrovascular disease from 1999 to April 2022, then downloaded the data into CiteSpace to generate a knowledge visualization map. A total of 1,500 publications relevant to insulin resistance and ischemic cerebrovascular disease were retrieved. The USA had the most articles on this topic, followed by PEOPLES R CHINA and JAPAN. WALTER N KERNAN was the most prolific author, whose research mainly focused on insulin resistance intervention after stroke (IRIS) trial. The most common keywords were myocardial ischemia, metabolic syndrome, ischemic stroke, cerebral ischemia, association, oxidative stress, inflammation, and adipose tissue. Major ongoing research trends include three aspects: (1) the association between insulin resistance and ischemic cerebrovascular disease in non-diabetic patients, (2) the intrinsic pathological mechanism between insulin resistance and ischemic cerebrovascular disease, and (3) early intervention of insulin resistance to improve the prognosis of stroke. The results of this bibliometric study provide the current status and trends of clinical research publications in the field of insulin resistance and ischemic cerebrovascular disease. Insulin resistance is strongly associated with the occurrence of ischemic stroke, early neurological deterioration in stroke patients, post-stroke depression, and cerebral small vessel disease. Early treatment of insulin resistance can be an effective way to prevent the onset of ischemic stroke and improve stroke prognosis. This study may help researchers to identify hot topics and explore new research directions.

Abstract TMP26: Effect Of Pioglitazone On Recurrent Stroke Risk In Patients With Post-stroke Cognitive Impairment And Insulin Resistance: Subgroup Analysis Of IRIS Trial

Patients with post-stroke cognitive impairment are at higher risk of recurrent stroke but the effect of pioglitazone on that risk has not been explored. The goal of this study was to determine the effect of pioglitazone on the risk of recurrent vascular events in patients with post-stroke cognitive impairment (PSCI) and insulin resistance (IR). We studied patients enrolled in Insulin Resistance Intervention after Stroke (IRIS) trial with a baseline Modified Mini-Mental State Examination (3MS) cognitive exam at median of 79 days after their stroke. We considered a baseline score of ≤ 88 on the 3MS to indicate global PSCI, and domain-specific summary scores in the lowest quartile to indicate language, attention, orientation, memory and visuospatial impairments. The primary endpoint of the study was recurrent stroke and MI. We studied n=3,338 patients. In fully adjusted Cox proportional hazards models for recurrent stroke, the hazard ratio (HR) for the effect of pioglitazone compared to placebo differed by post-stroke memory impiarment status (interaction p = 0.01). Pioglitazone was associated with 51% lower risk of recurrent stroke in patients with post-stroke memory impairment [HR = 0.49 (95% CI: 0.30 - 0.81); p = 0.005], but not in those without it [HR = 1.01 (95% CI: 0.75- 1.36); p = 0.942]. In fully adjusted Cox proportional hazards models for MI, the HR for the effect of pioglitazone compared to placebo differed by global PSCI status (interaction p = 0.03). Pioglitazone was associated with 77% lower risk of MI in patients with post-stroke global PSCI [HR = 0.23 (95% CI: 0.08, 0.71); p = 0.01], but not in those without it [HR = 0.88 (95% CI: 0.59, 1.31); p = 0.53]. These data indicate that simple cognitive testing after 3 months from stroke may serve as a precision medicine tool to identify patients at higher risk who may benefit from pioglitazone treatment. This approach can be tested in secondary stroke prevention clinical trials.

Abstract 13661: An Adaptive Strategy of Predictive Enrichment to Increase Efficiency of Randomized Clinical Trials Using Machine Learning: A Simulation of the IRIS Trial

Introduction: Randomized controlled trials (RCT) represent the cornerstone of evidence-based medicine but often carry high financial costs and lengthy time frames. Hypothesis: We hypothesized that a machine learning (ML) strategy of predictive enrichment can reduce the size of RCTs through adaptive enrollment based on projected response profiles. Methods: We conducted a post-hoc analysis of individual patient data from the Insulin Resistance Intervention after Stroke (IRIS) trial using dynamic computational trial phenomapping. After a study period of 36 months, we performed serial annual interim analyses ( A ). For this, we designed an algorithm that used a phenotypic trial representation using 59 baseline variables to predict personalized effects of pioglitazone on fatal/nonfatal stroke or myocardial infarction (study outcome). Compared with a complete trial enrollment (100%), in an adaptive fashion, we a priori restricted enrollment to two thirds (66.7%) of eligible participants between each interim analysis based on the projected treatment benefit. Since this was defined by their baseline phenotypic profile, treatment randomization was preserved. We employed these patient subsets as comparators and assessed the effect of pioglitazone on the study outcome through Cox regression models. Results: Compared to the unrestricted enrollment of participants ( blue line ), an ML-guided adaptive strategy of predictive enrichment ( green line ) was associated with defining the same treatment effect size with a lower trial size - 3876 vs 2946 participants ( B-C ). Both approaches appeared to meet statistical significance at 6 years after the trial onset ( D-E ). In contrast, a strategy of random patient selection ( orange line ) did not show significant benefit at the same population size. Conclusions: We developed an adaptive strategy for predictive enrichment to increase efficiency of RCTs using machine learning.

Central vs site outcome adjudication in the IRIS trial

BackgroundCentral adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. MethodsIRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. ResultsThe hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DiscussionCentral stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

Abstract TP183: Risk And Predictors Of Relapse After Smoking Cessation In Patients With Ischemic Stroke And Transient Ischemic Attack

Introduction: Smoking cessation is an integral part of secondary prevention after stroke and TIA. Relapse after successful smoking cessation in this population is poorly understood. Methods: This is a retrospective cohort analysis of patients enrolled in the international Insulin Resistance Intervention After Stroke (IRIS) trial, which included 3,876 nondiabetic patients with ischemic stroke or TIA. In IRIS, patients were asked about smoking status at the time of the index event, at randomization, and annually thereafter for 5 years. For this analysis, we included patients who quit smoking by randomization. Patients with active smoking at any follow-up visit were categorized as relapsed. We used time-to-event analysis to estimate cumulative relapse rates. We used univariate Cox proportional hazards regression to assess possible predictors of relapse: demographics, index event type (stroke vs TIA), country of origin, cardiovascular comorbidities, and duration/intensity of smoking. Results: At the time of stroke/TIA, 1,072 patients were active smokers. By randomization, a median of 3 (IQR, 2-5) months later, 450 (42%) had quit smoking. The mean age of the 450 quitters was 58 years, and 35% were women. They had smoked a median of 20 (IQR, 10-25) cigarettes/day for a median of 40 (IQR, 34-46) years. Over a mean follow-up of 3.8 years, 156 patients relapsed. The 5-year cumulative relapse rate was 38% (95% CI, 34-43%), with 21% (95% CI, 18-25%) relapsing within 1 year (Figure). Age, sex, index event type, duration and intensity of smoking were not associated with relapse. However, patients at US sites (vs non-US sites) were more likely to relapse (HR, 1.46; 95% CI, 1.01-2.10), as were patients with more cardiovascular comorbidities (HR, 1.28; 95% CI, 1.05-1.55; for each additional condition). Conclusion: Stroke/TIA survivors with early smoking cessation have a high rate of relapse, highlighting a need to engage this at-risk population in sustained cessation interventions.

Adherence to study drug in a stroke prevention trial"?>

ObjectiveStandards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. If applied to clinical trial research in patients with stroke, these improvements have the potential to identify when in the sequence of trial operations participants are at risk for non-adherence and opportunities to safeguard adherence. MethodsWe analyzed three phases of adherence according to the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient prematurely and permanently discontinue drug). IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug. ResultsDuring 2005-2013, 3876 participants were enrolled from 179 sites in seven countries and followed for a mean of 4.8 years. Less than 1% of participants in each group did not initiate study drug. 20% of patients assigned to pioglitazone and 17% assigned to placebo took at least one drug holiday. 36% and 30%, respectively, discontinued the study drug prematurely with or without a prior holiday. The risk for stopping the study drug (temporarily or permanently) in the first year after randomization was twice the risk in each of the subsequent four years. This was true both for patients assigned to active therapy and placebo. More participants assigned to pioglitazone, compared to placebo, took a drug holiday or permanently stopped study drug, but the difference in rates of discontinuation was only evident in year one. In years two through five, rates of discontinuation were similar in the two treatment groups. The difference in rates during year one was the result of adverse effects related to the active study drug, pioglitazone. During the remainder of the trial, the attribution of discontinuations to adverse effects potentially related to pioglitazone was reduced but still higher in those assigned to active drug. Other reasons for discontinuation were similar between treatment groups and were largely unrelated to pharmacodynamic effects of the study drug. Rates of discontinuation varied widely among research sites. ConclusionPatients in a drug trial for stroke prevention are at greatest risk for premature drug discontinuation early after randomization. Reasons for discontinuation change over time. Variable discontinuation rates among sites suggests that adherence can be improved by using best practices from high-performing sites.

PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic disturbances that include disrupted bone morphogenetic protein receptor (BMPR2)-peroxisome proliferator-activated receptor gamma (PPARγ) axis and DNA damage. Activation of PPARγ improves many of these mechanisms, although erroneous reports on potential adverse effects of thiazolidinedione (TZD)-class PPARγ agonists reduced their clinical use in the past decade. Here, we review recent findings in heart, lung, and kidney research related to the pathobiology of vascular remodeling and tissue fibrosis, and also potential therapeutic effects of the PPARγ agonist pioglitazone. Independent of its metabolic effects (improved insulin sensitivity and fatty acid handling), PPARγ activation rescues BMPR2 dysfunction, inhibits TGFβ/Smad3/CTGF and TGFβ/pSTAT3/pFoxO1 pathways, and induces the PPARγ/apoE axis, inhibiting vascular remodeling. PPARγ activation dampens mtDNA damage via PPARγ/UBR5/ATM pathway, improves function of endothelial progenitor cells (EPCs), and decrease renal fibrosis by repressing TGFβ/pSTAT3 and TGFβ/EGR1. Pharmacological PPARγ activation improves many hallmarks of PAH, including dysfunction of BMPR2-PPARγ axis, PAEC, PASMC, EPC, mitochondria/metabolism, and inflammation. Recent randomized controlled trials, including IRIS (Insulin Resistance Intervention After Stroke Trial), emphasize the beneficial effects of PPARγ agonists in PAH patients, leading to recent revival for clinical use.

Activation of the Metabolic Master Regulator PPARγ: A Potential PIOneering Therapy for Pulmonary Arterial Hypertension.

Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.

Pioglitazone Therapy in Patients With Stroke and Prediabetes

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. 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. 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. Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. 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. 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. Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. ClinicalTrials.gov identifier: NCT00091949.

Abstract TMP92: Pioglitazone for Secondary Stroke Prevention in Pre-diabetes: Implications for Real-world Practice

Pioglitazone reduces insulin resistance and cardiovascular risk among patients with type 2 diabetes. The Insulin Resistance Intervention after Stroke (IRIS) trial randomized 3876 non-diabetic participants with recent stroke/TIA and insulin resistance based on the Homeostasis Model of Insulin Resistance (HOMA-IR) score to pioglitazone (PIO) vs. placebo (PLA). Over 4.8 years, the relative risk reduction (RRR) with PIO was 27% for stroke/myocardial infarction, 25% for stroke, 29% for acute coronary syndrome (ACS), and 52% for new-onset diabetes. PIO could therefore be considered a new therapy for secondary stroke prevention before diabetes onset. However, it is not in widespread use, not only because of increased fracture risk, but perhaps also because HOMA-IR is not commonly assessed in clinical practice. In contrast, the presence of prediabetes is often identified in this population. We therefore analyzed the intention-to-treat (ITT) and the on-treatment effect of PIO (defined as adherence of &gt; 80%) in IRIS participants with prediabetes by the American Diabetes Association criteria: HbA1C 5.7%-6.4%, or fasting glucose 100-125 mg/dL (n=2885; PIO 1456, PLA 1429). By ITT, for pioglitazone the hazard ratio and 95% confidence interval in Cox regression for stroke/MI was 0.70 (0.56-0.88, p=0.002), for stroke 0.72 (0.56-0.93, p=0.013), for ACS 0.72 (0.52-1.00, p = 0.052), for stroke/MI/hospitalized heart failure (HHF) 0.78 (0.63-0.96, p=0.02), and for new-onset diabetes HR 0.46 (0.34-0.61, p &lt;0.0001). Among participants with good adherence, pioglitazone participants (n=644) were more likely to be men (76.2% vs 70.6%, p=0.02) and more likely to be smokers (15.9% vs. 11.7%, p=0.02) compared to PLA participants (n=810). In this subgroup, the HR for stroke/MI was 0.57 (0.39-0.84, p=0.004), for stroke 0.64 (0.42-0.99, p=0.04), for ACS 0.47 (0.26-0.85, p=0.01), for stroke/MI/HHF 0.61 (0.42-0.88, p=0.008), and for new-onset diabetes HR 0.18 (0.10-0.33, p&lt;0.0001) Conclusion: Pioglitazone should be considered efficacious for secondary prevention in stroke/TIA participants with prediabetes, simply assessed by fasting plasma glucose or A1C.

Abstract WP525: Adherence and Adherence Recovery in a Stroke Trial

Objective: Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. We report adherence in a stroke trial using the EMERGE guidelines and demonstrate how support of patients can lead to adherence recovery during therapy implementation. Methods: We analyzed 3 phases of adherence according to current taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient permanently and prematurely discontinue drug). IRIS was a randomized, placebo controlled trial testing pioglitazone to prevent stroke or MI in patients with ischemic stroke/TIA and insulin resistance. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug. Results: During 2005-2013, 3876 participants were enrolled from 179 sites in 7 countries. Mean age was 63.5 years; 65% were male, 11% Black race, and 4% Hispanic ethnicity. A total of 26 patients (&lt;1%) did not start study drug. During implementation, 706 (18%) patients took a drug holiday: 587 took 1 holiday, 97 took 2, and 22 took ≥3. Study drug was discontinued early in 1275 (33%). Major reasons for holidays and discontinuations are shown below by treatment. Conclusion: For the first time in a stroke trial, we report adherence according to internationally recommended guidelines. Results show that holidays are common, but participants will resume drug with coaching. Among reasons for drug cessation, only those secondary to study protocol were unavoidable and misattributions of AEs to study drug were common as seen in the placebo group. Our findings have implications for trials that require high drug adherence to successfully answer scientific hypotheses.

Decrease of cardiovascular risk in patients with type 2 diabetes: review of the common strategies and clinical studies

Military Medical Academy of S.M. Kirov, Saint-Petersburg, Russia&#x0D; Recent clinical trials about the cardiovascular safety of empagliflozin and liraglutide demonstrated a convincing lowering effect on mortality from cardiovascular causes among the patients with type 2 diabetes. These findings resulted in many questions about why this phenomenon was seen in two drugs with widely different mechanisms of functioning. It is important to note that the glucose-lowering effect was moderate, although a feature seen in both empagliflozin and liraglutide was their ability to increase insulin sensitivity. In many fundamental studies, this feature was associated with a reduction of cardiovascular risks. Insulin resistance, which has always been a pathophysiological base for the development of cardiovascular disease in patients with type 2 diabetes, is a topic for this report. Different methods to manage insulin resistance, including lifestyle changes, drug treatment and metabolic surgery, are discussed. Furthermore, the most common features of glucose-lowering drugs are analysed, including protective effects for cardiovascular outcomes in patients with type 2 diabetes presented in randomised clinical trials. Studies include the United Kingdom Prospective Diabetes Study (UKPDS), PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), Insulin Resistance Intervention After Stroke (IRIS), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). The current study shows that the potential to reduce the risk of cardiovascular disease is determined not only by effective lowering of glucose but also by the ability to lower insulin resistance, which causes a paradigm shift in the management of type 2 diabetes.

What Mediated Pioglitazone's Cardiovascular (CV) Benefit in the IRIS Trial?

In the Insulin Resistance Intervention after Stroke (IRIS) trial, pioglitazone (PIO) reduced the risk of fatal/nonfatal stroke/MI by 24% vs. placebo (PLA) in 3876 nondiabetic patients with insulin resistance (IR) and recent stroke or transient ischemic attack (TIA). We sought to determine which factor(s) modified by PIO were associated with its CV benefit. The effect of PIO was quantified using Cox models. Starting with a bivariate model, change from baseline at year 1 in a single factor (Table) was included as a covariate for stroke/MI events beyond year 1. The resulting percent change in log HR for PIO towards the null was defined as the percent mediation of PIO’s effect by that factor. The combined effect was assessed in a model using all factors identified in bivariate models as potential mediators. The factor with the largest impact (26%) was HDL-C, with smaller mediating effects (&amp;lt;15%) from CRP, TG, BP and glucose. Together, these factors accounted for 43% of the treatment benefit. We could not confirm any mediating effect from the reduction in measures of IR. Findings were similar in several sensitivity analyses. In summary, no single factor explained the majority of PIO’s CV benefit in IRIS. PIO’s favorable effects in patients with IR and stroke/TIA is likely mediated through multiple and combined benefits on lipids, BP, glucose, and inflammation.Table. Change in log HR (percent mediation) after controlling for individual factors and their combination.FactorMean (SE) for FactorTreatment Effect, Adjusted for Factor%Δ log(HR)BaselineΔ at Year 1ALLPLAPIOHR95% CINone----0.779(0.59, 1.02)--HDL-C (mg/dL)46.8 (0.2)2.3 (0.2)5.5 (0.3)0.831(0.63, 1.09)25.9%CRP (mg/L)*4.6 (0.2)-0.3 (0.3)-1.2 (0.3)0.805(0.61, 1.06)13.1%TG (mg/dL)*137.5 (1.1)-1.7 (1.3)-16.2 (1.2)0.799(0.61, 1.05)10.2%Glucose (mg/dL)98.1 (0.2)1.3 (0.4)-2.9 (0.3)0.792(0.60, 1.04)6.6%SBP (mm Hg)133.0 (0.3)-0.8 (0.5)-2.1 (0.5)0.792(0.60, 1.04)6.6%DBP (mm Hg)79.1 (0.2)-1.0 (0.3)-3.0 (0.3)0.781(0.59, 1.03)1.0%LDL-C (mg/dL)87.5 (0.6)2.3 (0.7)3.2 (0.8)0.772(0.59, 1.01)-3.6%HOMA-IR*5.4 (0.1)0.3 (0.1)-1.3 (0.1)0.709(0.53, 0.94)-37.7%Insulin (μU/mL)*22.1 (0.2)0.4 (0.4)-5.1 (0.3)0.707(0.53, 0.94)-38.8%Combined model (HDL-C, CRP, glucose, SBP, DBP)0.868(0.66, 1.15)43.3%*Skewed distributions; values were log transformed before analysis.HDL-C= high density lipoprotein cholesterol; CRP=high-sensitivity C-reactive protein; TG=triglycerides; SBP=systolic blood pressure; DBP=diastolic blood pressure; LDL-C=low density lipoprotein cholesterol; HOMA-IR=homeostatic model assessment of insulin resistance. Disclosure S.E. Inzucchi: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Sanofi, Lexicon Pharmaceuticals, Inc.. Consultant; Self; VTV Therapeutics. Other Relationship; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc., Alere Inc.. C.M. Viscoli: None. L.H. Young: Research Support; Self; Merck &amp; Co., Inc., NovaTarg Therapeutics, Mifcor. Consultant; Self; Portage. M.J. Gorman: None. R.A. Conwit: None. G.G. Schwartz: Research Support; Self; Roche Pharma, Sanofi, Resverlogix Corp.. W. Kernan: None.

Abstract 101: Pioglitazone Prevents Stroke in Patients With a Recent TIA or Ischemic Stroke: a Secondary Analysis of the IRIS Trial

Background: The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone reduced risk for the composite outcome of stroke or myocardial infarction among non-diabetic patients with insulin resistance and a recent ischemic stroke or TIA. The drug also reduced risk for stroke alone, but the finding did not reach statistical significance. During the trial, the Data &amp; Safety Monitoring Board approved a secondary analysis using updated 2013 consensus criteria for ischemic stroke. Our objective is to examine the effect of pioglitazone, compared with placebo, on risk for stroke alone defined by the 2013 criteria. Methods: Participants were randomized to pioglitazone (45 mg per day target dose) or placebo and followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. The primary outcome was any stroke, but we also examined type of stroke (ischemic or hemorrhagic), and ischemic stroke subtype. Results: Among 3876 IRIS participants (mean age 63 years, 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years (329 stroke events by the original trial criteria plus 48 new events identified by applying the 2013 stroke criteria). Pioglitazone was associated with a 25% risk reduction for any stroke (8.0% compared to 10.7%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60 to 0.94) and a 28% reduction for ischemic stroke (HR, 0.72; 95% CI, 0.57 to 0.9) but not hemorrhagic stroke (HR, 1.00; 95% CI, 0.50-2.00). Pioglitazone was associated with fewer numbers of all subtypes of ischemic stroke, but the difference from placebo reached or approached significance only for lacunar (HR, 0·46; 95% CI, 0·22-0·93; p=0·03) and large vessel (HR, 0·59; 95% CI, 0·33-1·04; p=0·07) strokes. Conclusion: Pioglitazone prevents recurrent ischemic stroke among non-diabetic patients with insulin resistance.

Abstract TP389: Achievement of Healthy Weight Loss Among Patients With Recent Ischemic Stroke or TIA and Obesity

Introduction: Approximately 30% of patients with a recent ischemic stroke or TIA are obese as defined by a body mass index (BMI) ≥30 kgs/m 2 . Guidelines from professional and governmental organizations recommend that patients with obesity lose weight to improve cardiovascular risk factors including glucose control, diabetes risk, blood pressure, and lipid metabolism. In this study, we examined the proportion of patients with a recent ischemic stroke or TIA who achieve these recommendations and meet two common goals for weight reduction within two years: 1) reduction of weight by 5% from baseline and reduction to a BMI &lt;27 kgs/m 2 . Methods: Participants were men and women assigned to placebo treatment in the Insulin Resistance Intervention after Stroke (IRIS) Trial who were obese at the time of enrollment. The IRIS trial was a randomized trial that examined the effectiveness of pioglitazone compared with placebo for prevention of stroke or MI among non-diabetic patients with a recent ischemic stroke or TIA and insulin resistance. The trial enrolled participants from 2005 to 2012. Participants were followed for a minimum of 28 months and were seen in-person and weighed annually. Results: Of the 1937 participants in the placebo arm of IRIS, 855 (44%) had BMI≥30 kgs/m 2 at entry. Mean age was 61 years (standard deviation, 10) and 59% were male. At one year, 788 patients with obesity at baseline remained in the trial with weight measured (10 died, 14 dropped-out, and 43 were missing weight). Among these patients, 133 (17%) had lost 5% of their body weight and 12 (2%) had achieved a BMI &lt; 27 kgs/m 2 at 12 months. Two years from randomization, 22% had lost 5% of their body weight and 3% had achieved a BMI &lt;27 kgs/m 2 . Conclusion: In this cohort of patients with ischemic stroke or TIA and obesity, less than a quarter achieved even modest goals for weight loss after one or two years. Clinical trials will be required to determine if failure to lose weight represents a lost opportunity for secondary stroke prevention. Trials can determine 1) if weight loss is effective for preventing recurrent stroke, cardiovascular disease and diabetes and for improving function after ischemic stroke or TIA and 2) the amount of weight loss that must be achieved to realize meaningful benefit.

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial

IntroductionPatients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function.MethodsIn the Insulin Resistance Intervention after Stroke...

Smoking cessation and outcome after ischemic stroke or TIA.

To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes

Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM.