SummaryBackground: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor 7 (PPAR 7) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.

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OBJECTIVE -Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucoseand lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone.RESEARCH DESIGN AND METHODS -We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n ϭ 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n ϭ 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals.RESULTS -Triglyceride levels were reduced by 51.9 Ϯ 7.8 mg/dl with pioglitazone, but were increased by 13.1 Ϯ 7.8 mg/dl with rosiglitazone (P Ͻ 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 Ϯ 0.5 vs. 2.4 Ϯ 0.5 mg/dl; P Ͻ 0.001) and the increase in LDL cholesterol was less (12.3 Ϯ 1.6 vs. 21.3 Ϯ 1.6 mg/dl; P Ͻ 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P Ͻ 0.001). LDL particle size increased more with pioglitazone (P ϭ 0.005).CONCLUSIONS -Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size. Diabetes Care 28:1547-1554, 2005T wo core metabolic defects contribute to the development of type 2 diabetes: relative insulin insufficiency and insulin resistance. Approximately 92% of patients with type 2 diabetes demonstrate insulin resistance (1). Even in the absence of overt hyperglycemia, insulin resistance is associated with a cluster of abnormalities that increase the risk for cardiovascular disease (CVD), including dyslipidemia, increased expression of inflammatory markers, activation of procoagulants, hemodynamic changes, and endothelial dysfunction (2,3).The dyslipidemia associated with insulin resistance and type 2 diabetes is characterized by elevated triglycerides and decreased HDL cholesterol (4 -6). Although LDL cholesterol may not be elevated in type 2 diabetes, an increase in the proportion of small, dense, and potentially more atherogenic LDL cholesterol particles is observed (7). In addition to LDL cholesterol, elevated triglyceride levels and reduced HDL cholesterol levels are both risk factors for coronary heart disease (CHD) (8 -11). Compared with nondiabetic individuals, patients with type 2 diabetes have a two-to fourfold high...

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Background Stroke thrombolysis with alteplase is currently recommended 0-4•5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4•5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4•5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FindingsWe identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1•86, 95% CI 1•15-2•99, p=0•011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9•7, 95% CI 1•23-76•55, p=0•031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1•55, 0•81-2•96, p=0•66).Interpretation Patients with ischaemic stroke 4•5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.