***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background and Purpose — Very recent subgroup analysis from the PROspect i ve pioglitAzone Clinical Trial In macroVascular Events has shown that pioglitazone reduces the risk of recurrent stroke in type 2 diabetic patients . However , the underlying mechanism of stroke prevention by pioglitazone is unknown . Our aim was to examine the effect of pioglitazone on hypertension-based stroke in rats . Methods — Pioglitazone ( 1 mg · kg−1 · d−1 ) was orally administered to stroke-prone spontaneously hypertensive rats ( SHRSP ) to examine the effect on incidental stroke , cerebrovascular injury , brain inflammation , oxidative stress , and vascular endothelial dysfunction induced by hypertension . Results — Treatment of SHRSP  with pioglitazone for 4 weeks , without affecting blood pressure and blood glucose values , improved vascular endothelial dysfunction ( P<0.05 ) , suppressed remodeling of the middle cerebral artery ( P<0.05 ) and brain microvessels ( P<0.05 ) , and inhibited brain macrophage infiltration ( P<0.05 ) and the upregulation of brain monocyte chemoattractant protein-1 and tumor necrosis factor-&agr ; expression ( P<0.01 ) . Furthermore , pioglitazone treatment significantly delayed the onset of stroke signs and death in SHRSP ( P<0.05 ) . These beneficial effects of pioglitazone on cerebrovascular injury and stroke in SHRSP were associated with a reduction of brain and vascular superoxide via the inhibition of NADPH oxidase activity . Conclusions — Our work provides the first evidence that pioglitazone significantly protects against hypertension-induced cerebrovascular injury and stroke by improving vascular endothelial dysfunction , inhibiting brain inflammation , and reducing oxidative stress . These beneficial effects of pioglitazone were independent of blood pressure or blood sugar values . Thus , pioglitazone appears to be a potential therapeutic agent for stroke in type 2 diabetes with hypertension OBJECTIVE The PROspect i ve pioglitAzone Clinical Trial In macroVascular Events ( PROactive ) assesses the effect of pioglitazone , a peroxisome proliferator-activated receptor agonist , with anti-inflammatory and vascular properties , on the secondary prevention of macrovascular events in type 2 diabetes . RESEARCH DESIGN AND METHODS PROactive is an on-going r and omized , double-blind outcome study in patients with type 2 diabetes managed with diet and /or oral blood glucose-lowering drugs (  combination of oral agents with insulin is permitted ) who have a history of macrovascular disease . Patients are r and omized to receive pioglitazone ( forced titration from 15 to 30 to 45 mg , depending on tolerability ) or placebo in addition to existing therapy . The primary end point is the time from r and omization to occurrence of a new macrovascular event or death . Follow-up is estimated to span 4 years . RESULTS A total of 5238 patients have been r and omized from 19 countries . At entry into the study , patients enrolled are a mean age of 61.8 years , with type 2 diabetes for a mean of 9.5 years ; 60.9 and 61.5 % are taking metformin or a sulfonylurea , respectively ; and 33.6 % are using insulin in addition to oral glucose-lowering drugs . The majority of patients are men ( 66.1 % ) . Patients are required to meet one or more of entry criteria , as follows : > 6 months ' history of myocardial infa rct ion ( 46.7 % ) ; coronary artery revascularization ( 30.8 % ) , stroke ( 18.8 % ) , or acute coronary syndrome for > 3 months ( 13.7 % ) ; other evidence of coronary artery disease ( 48.1 % ) ; or peripheral arterial occlusive disease ( 19.9 % ) . One-half ( 48.5 % ) of the patients have two or more of these risk factors . Three-quarters ( 75.4 % ) have hypertension  , and 58.8 % are current or previous  smokers . CONCLUSIONS The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events . The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes Background —Therapeutic strategies to stabilize advanced arteriosclerotic lesions may prevent plaque rupture and reduce the incidence of acute coronary syndromes .  Thiazolidinediones ( TZDs ) , like rosiglitazone , are oral antidiabetic drugs with additional antiinflammatory and potential antiatherogenic properties . In a r and omized , placebo-controlled , single-blind trial , we examined the effect of 4 weeks of rosiglitazone therapy on histomorphological characteristics of plaque stability in artery specimen of nondiabetic patients scheduled for elective carotid endarterectomy . Methods and Results —A total of 24 nondiabetic patients with symptomatic carotid artery stenosis were r and omly assigned to rosiglitazone ( 4 mg BID ) or placebo in addition to st and ard therapy . In this population of nondiabetic patients , rosiglitazone treatment did not significantly change fasting blood glucose , fasting insulin , or lipid parameters . In contrast , rosiglitazone significantly reduced CD4-lymphocyte content as well as macrophage HLA-DR expression in the shoulder region , reflecting less inflammatory activation of these cells by lymphocyte interferon-&ggr;. Moreover , rosiglitazone significantly increased plaque collagen content ( 7.7±1.6 % versus 3.7±0.7 % of plaque area ; P=0.036 ) compared with placebo , suggesting that TZD treatment may stabilize arteriosclerotic lesions . In addition , rosiglitazone  reduced serum levels of 2 inflammatory arteriosclerosis markers : C-reactive protein and serum amyloid A. Conclusions —Four weeks of treatment with rosiglitazone significantly reduces vascular inflammation in nondiabetic patients , leading to a more stable type of arteriosclerotic lesion OBJECTIVE Thiazolidinediones , such as rosiglitazone , have been shown to retard atherosclerosis disease progression in diabetic subjects . These agents may have anti-atherosclerotic effects through direct inhibition of inflammatory processes in the vessel wall , and so their benefit may extend to patients with atherosclerotic disease , even in the absence of diabetes . In this study , we assessed the effect of rosiglitazone on common carotid intima-media thickness ( IMT ) progression in nondiabetic coronary artery disease ( CAD ) patients . METHODS AND RESULTS Consecutive subjects ( n=92 ) with clinical ly stable , angiographically documented CAD and without diabetes mellitus were r and omized in a double-blind manner to receive placebo or rosiglitazone for 48 weeks . They received single-dose placebo and rosiglitazone 4 mg daily for the initial 8 weeks , and the doses were doubled for the remainder of the study . Common carotid IMT together with fasting glucose , insulin , and lipid profile were measured at baseline and repeated after 24 and 48 weeks . Rosiglitazone-treated patients showed reduced IMT progression compared with the placebo group , -0.012 mm/48 weeks versus 0.031 mm/48 weeks ( P=0.03 ) . Rosiglitazone treatment significantly reduced insulin resistance , estimated by homeostasis model of insulin resistance index , compared with placebo ( P=0.01 ) . CONCLUSIONS Rosiglitazone reduces common carotid IMT progression in nondiabetic CAD patients , and insulin-sensitization may be one contributory mechanism The TRoglitazone In the Prevention Of Diabetes ( TRIPOD ) trial is a single-center , r and omized , placebo-controlled , double-masked study . The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus ( GDM ) will improve whole-body insulin sensitivity and reduce the incidence of non-insulin-dependent diabetes ( NIDDM ) . Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM , an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention . In addition , since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance , we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis . In this article we describe the experiment 's design , the study 's endpoints and methods for determining those endpoints , methods for assessing quality of life , and proposed methods for statistical analyses . The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes , but also of the clinical question about whether early intervention is superior to late intervention . Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM OBJECTIVE The Insulin Resistance Intervention after Stroke ( IRIS ) trial recently found that pioglitazone reduced risk for stroke and myocardial infa rct ion in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack ( TIA ) . This report provides detailed results on the metabolic effects of pioglitazone and the trial ’s prespecified secondary aim of diabetes prevention . RESEARCH DESIGN AND METHODS A total of 3,876 patients with recent ischemic stroke or TIA , no history of diabetes , fasting plasma glucose ( FPG ) < 126 mg/dL , and insulin resistance by homeostasis model assessment of insulin resistance ( HOMA-IR ) score > 3.0 were r and omly assigned to pioglitazone or placebo . Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing . RESULTS At baseline , the mean FPG , HbA1c , insulin , and HOMA-IR were 98.2 mg/dL ( 5.46 mmol/L ) , 5.8 % ( 40 mmol/mol ) , 22.4 μIU/mL , and 5.4 , respectively . After 1 year , mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL ( 5.28 mmol/L ) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL ( 5.54 mmol/L ) , in the placebo group ( all P < 0.0001 ) . Over a median follow-up of 4.8 years , diabetes developed in 73 ( 3.8 % ) participants assigned to pioglitazone compared with 149 ( 7.7 % ) assigned to placebo ( hazard ratio [ HR ] 0.48 [ 95 % CI 0.33–0.69 ] ; P < 0.0001 ) . This effect was predominately driven by those with initial impaired fasting glucose ( FPG > 100 mg/dL [ 5.6 mmol/L ] ; HR 0.41 [ 95 % CI 0.30–0.57 ] ) or elevated HbA1c ( > 5.7 % [ 39 mmol/mol ] ; HR 0.46 [ 0.34–0.62 ] ) . CONCLUSIONS Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA  , pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events . Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial AIMS To conduct a 10-year , observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time . METHODS Macrovascular endpoints and malignancies were compared based on original r and omization to pioglitazone or placebo and ' any ' versus ' no ' pioglitazone use for bladder and prostate cancer . RESULTS Of 4873 patients completing the PROactive trial , 74 % entered the follow-up . During follow-up ( mean 7.8 years ) , there were no statistically significant differences in the primary [ all-cause mortality , myocardial infa rct ion ( MI ) , cardiac intervention , stroke , major leg amputation , leg revascularization ] or main secondary ( death , MI , stroke ) endpoints for subjects originally r and omized to pioglitazone and placebo , except for leg amputations during follow-up [ 4.1 % pioglitazone , 5.6 % placebo ; hazard ratio 0.74 , 95 % confidence interval ( CI ) 0.55 - 0.99 ; p = 0.046 ] . During follow-up , the incidence of total malignancies was similar between groups ; bladder cancer 
    Output:
    
Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death , non-fatal myocardial infa rct ion or non-fatal stroke , and may improve insulin sensitivity and the stabilisation of carotid plaques .
Their effects on adverse events are uncertain .