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This on-treatment analysis was conducted to facilitate understanding of mechanisms underlying the increased risk of all-cause and cardiovascular mortality in heart failure patients with reduced ejection fraction and predominant central sleep apnoea randomised to adaptive servo ventilation versus the control group in the SERVE-HF trial.Time-dependent on-treatment analyses were conducted (unadjusted and adjusted for predictive covariates). A comprehensive, time-dependent model was developed to correct for asymmetric selection effects (to minimise bias).The comprehensive model showed increased cardiovascular death hazard ratios during adaptive servo ventilation usage periods, slightly lower than those in the SERVE-HF intention-to-treat analysis. Self-selection bias was evident. Patients randomised to adaptive servo ventilation who crossed over to the control group were at higher risk of cardiovascular death than controls, while control patients with crossover to adaptive servo ventilation showed a trend towards lower risk of cardiovascular death than patients randomised to adaptive servo ventilation. Cardiovascular risk did not increase as nightly adaptive servo ventilation usage increased.On-treatment analysis showed similar results to the SERVE-HF intention-to-treat analysis, with an increased risk of cardiovascular death in heart failure with reduced ejection fraction patients with predominant central sleep apnoea treated with adaptive servo ventilation. Bias is inevitable and needs to be taken into account in any kind of on-treatment analysis in positive airway pressure studies., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Background: Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea., Methods: We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure., Results: In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006)., Conclusions: Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).

Background: Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications., Study Design: ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar., Results: At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012)., Conclusions: Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes., Methods: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo. Relationships among treatment, outcome (time to first event of all-cause mortality, myocardial infarction and stroke) and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variable measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Log-linear models were fitted to multiway tables of discrete data and analysis of deviance used to summarize sources of variation in the data., Results: Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol (HDL-C), only the change from baseline HDL-C predicted the outcome (χ(2) = 28.89, p < 0.0001). No other variables, including HbA1c, triglycerides and systolic blood pressure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-C changes., Conclusions: This post hoc analysis suggests that HDL-C, but probably not HbA1c, is a driver of pioglitazone's favourable influence on CV outcome., (© 2011 Blackwell Publishing Ltd.)

Aim: Microalbuminuria (MAU) and heart rate are established predictors of an adverse cardiovascular outcome. Recently, heart rate was described as an independent predictor of MAU in hypertensive patients, raising the question of a causal link., Methods: In post-hoc analysis of the PROactive trial we examined the association of the baseline heart rate and MAU in diabetic patients with cardiovascular disease (n = 5,110, mean age 62 ± 8, 66% male) using logistic regression. Cox regression analysis was used to examine the independent impact of heart rate and MAU on the composite endpoint of all-cause mortality, myocardial infarction and stroke., Results: Baseline heart rate was not associated with a significantly increased risk for MAU at baseline (OR 1.01 per 10 bpm, 95% CI 0.97-1.06, p = 0.48) or MAU at the final visit (OR per 10 bpm 1.04, 95% CI 0.98-1.11, p = 0.20). Similar results were observed in subgroups of patients with hypertensive blood pressure at baseline (OR 0.98 per 10 bpm, 95% CI 0.93-1.03, p = 0.42) or patients with a history of hypertension (OR 1.02 per 10 bpm, 95% CI 0.98-1.07, p = 0.31), respectively. Stratification by use of an ACE inhibitor/AT1-receptor blocker did also not change the results. In multivariate analysis, both heart rate and MAU were significantly predictive of a cardiovascular outcome., Conclusion: There was no evidence of an association between heart rate and MAU in diabetic patients with cardiovascular disease, independently of whether hypertension was present or not, but both markers were independently predictive of a cardiovascular outcome. These results do not support a causal link between heart rate and MAU.

Objectives: Low-T3 syndrome is highly prevalent and independently prognostic in cardiovascular patients. The relationship and prognostic impact with the cardiac marker NT-pro-BNP have not been thoroughly investigated., Methods: Thyroid hormone levels and NT-pro-BNP were assessed in 615 consecutive patients hospitalized for cardiovascular disease. Patients with primary overt or latent thyroid disorder, hormone replacement, thyreostatic and amiodarone therapy were excluded. The association with and predictive impact on mortality were examined., Results: 36 (7.1%) patients had low-T3 syndrome. After adjustment for known confounders, NT-pro-BNP was significantly associated with fT3 and low-T3 syndrome. fT3 (HR 0.58, 95%CI 0.34-0.98) and low-T3 syndrome (HR 3.0, 95%CI 1.4-6.3) were predictive for mortality after adjustment for NT-pro-BNP levels and other cardiovascular prognostic variables. In patients with fT3 levels within the normal range, fT3 and NT-pro-BNP stratified by median values showed complementary prognostic information with the highest risk for mortality in patients with low normal fT3 and high NT-pro-BNP (HR 10.5, 95%CI 3.2-34.6)., Conclusions: fT3 and low-T3 syndrome are significantly related to NT-pro-BNP in patients with cardiovascular disease, but are predictors of mortality independently of NT-pro-BNP and other known cardiovascular risk parameters., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: Pioglitazone has diverse multiple effects on metabolic and inflammatory processes that have the potential to influence cardiovascular disease pathophysiology at various points in the disease process, including atherogenesis, plaque inflammation, plaque rupture, haemostatic disturbances and microangiopathy., Results: Linking the many direct and indirect effects on the vasculature to the reduction in key macrovascular outcomes reported with pioglitazone in patients with type 2 diabetes presents a considerable challenge. However, recent large-scale clinical cardiovascular imaging studies are beginning to provide some mechanistic insights, including a potentially important role for improvements in high-density lipoprotein cholesterol with pioglitazone. In addition to a role in prevention, animal studies also suggest that pioglitazone may minimize damage and improve recovery during and after ischaemic cardio- and cerebrovascular events., Design and Methods: In this review, we consider potential cardiovascular protective mechanisms of pioglitazone by linking preclinical data and clinical cardiovascular outcomes guided by insights from recent imaging studies., Conclusion: Pioglitazone may influence CVD pathophysiology at multiple points in the disease process, including atherogenesis, plaque inflammation, plaque rupture and haemostatic disturbances (i.e. thrombus/embolism formation), as well as microangiopathy.

Background: Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes., Methods: PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months., Results: At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points (P < .05) and a trend to benefit in the sixth (P = .052), with hazard ratios of 0.79 to 0.83., Conclusions: In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.

Background: B-type natriuretic peptides are excellent markers of cardiac function and are strong prognostic parameters in patients with coronary heart disease and heart failure. We examined the diagnostic and prognostic value of natriuretic peptides in a heterogeneous group of patients of a cardiological university hospital., Methods: NT-pro-BNP was assessed in 573 inpatients (66 % male, median age 66 years) and association with demographic and cardiological parameters, in-hospital course as well as the combined endpoint of death, heart failure hospitalization and stroke was analyzed during a median follow-up time of 1117 days., Results: NT-pro-BNP was significantly associated with age, diastolic blood pressure, renal function, previous myocardial infarction, arterial occlusive disease, atrial fibrillation, NYHA class and left-ventricular dysfunction. Differentiation of distinct cardiac diseases by NT-pro-BNP was not possible. NT-pro-BNP identified patients with a length of hospital stay of more than 12 days with a sensitivity of 88,2 % and a negative predictive value of 97 %. Supramedian NT-pro-BNP values (> 300 pg/ml) indicated a relative risk for the combined endpoint of 7,5 (95 % CI 4,1 - 13,8) compared to inframedian NT-pro-BNP values. Prognostic value of NT-pro-BNP was independent of and stronger than demographic and cardiological risk markers., Conclusion: NT-pro-BNP is a strong and independent predictor of in-hospital course and long-term outcome in inpatients with cardiovascular disease. NT-pro-BNP assessment allows a risk-adapted patient management for non-cardiologists.

Patients with diabetes and chronic kidney disease (CKD) are at particularly high risk for cardiovascular disease (CVD). This post hoc analysis from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. CKD, defined as an estimated GFR <60 ml/min per 1.73m(2), was present in 597 (11.6%) of 5154 patients. More patients with CKD reached the primary composite end point (all-cause mortality, myocardial infarction (MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle) than patients without CKD (27.5 versus 19.6%; P < 0.0001). Patients with CKD were also more likely to reach a secondary composite end point (all-cause mortality, MI, and stroke). Patients who had CKD and were treated with pioglitazone were less likely to reach the secondary end point (hazard ratio 0.66; 95% confidence interval 0.45 to 0.98), but this association was not observed among those with better renal function. In addition, there was a greater decline in estimated GFR with pioglitazone (between-group difference 0.8 ml/min per 1.73 m(2)/yr) than with placebo. In conclusion, CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and preexisting macrovascular disease. Patients who had CKD and were treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke, independent of the severity of renal impairment.

Introduction: Thiazolidinediones significantly reduce fasting plasma glucose and HbA (1c). These effects are due to improved insulin sensitivity by activating the nuclear PPAR-gamma (peroxisomal proliferator-activated receptors-gamma) and affection of different intracellular functions. The objective of this review was to analyse recently published studies and meta-analyses about thiazolidinediones, which suggested a significant cardiovascular risk associated with rosiglitazone therapy. Therefore clinicians have been left uncertain as to whether rosiglitazone should still be considered for the treatment of type-2-diabetes., Discussion: An important side-effect of thiazolidinediones is fluid retention and edema. Therefore, heart failure NYHA I-IV is a contraindication for treatment with Thiazolidinediones. Pioglitazone shows favourable changes in lipid parameters like decrease of serum-triglycerides and increase of HDL-cholesterol, while Rosiglitazone temporarily increases LDL-cholesterol. In patients with type-2-diabetes mellitus and a high cardiovascular risk the PROactive study did not show a significant effect on the primary endpoint but significantly reduced the predefined secondary combined endpoint of total mortality, nonfatal myocardial infarction and stroke. Conversely, recently published meta-analyses suggested an increased cardiovascular risk and myocardial infarction rate associated with rosiglitazone therapy., Conclusion: Treatment with Rosiglitazone should be reconsidered because of a potential cardiovascular risk. In high risk patients without heart failure pioglitazone may be favoured for treatment of type 2 diabetes mellitus.

Objective: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure., Research Design and Methods: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression., Results: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025)., Conclusions: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

The prognostic value of NT-pro-BNP has not been thoroughly evaluated in diabetic inpatients with manifest cardiovascular disease. NT-pro-BNP was measured in 156 patients with type 2 diabetes mellitus hospitalised due to cardiovascular disease. The association of NT-pro-BNP with mortality and the combined endpoint (CE) of death, heart failure decompensation, stroke and myocardial infarction was analysed during a median follow-up time of 1183 days. Patients who died (1669 IQR 788-5640 vs. 398, IQR 158-990 pg/ml) and patients with CE (1353, IQR 730-4289 vs. 304, IQR 128-784 pg/ml, both p=0.0001) had significantly elevated NT-pro-BNP compared to patients without the corresponding endpoint. Patients with supramedian NT-pro-BNP (>518 pg/ml) had significantly worse outcome regarding mortality (HR 5.5, 95%CI 2.0-14.8) and CE (HR 5.0, 95%CI 2.2-11.2) than patients with inframedian values even after adjustment for age, NYHA class and renal function. At a cut-off of 422 pg/ml, NT-pro-BNP showed a sensitivity of 89.6% and a negative predictive value of 92.8% for detection of patients with future CE. In this sample of diabetic patients with a broad spectrum of cardiovascular disease, NT-pro-BNP was a strong predictor of long-term outcome. NT-pro-BNP measured at discharge identifies high-risk patients independently of the underlying heart disease.

Background and Objective: The expenses of health insurances are continuously raising. With implementation of evidence-based medicine resulting in polypharmacy, compliance is decreasing and patients as well as physicians are facing unintentional drug interactions. Furthermore the arbitrary use of additional drugs apart from prescribed medication has to be considered. The objective of this study was to analyse polypharmacy, compliance and utilisation patterns for non-prescription medications (OTC) in patients with cardiovascular diseases., Methods: 100 patients with cardiovascular diseases (45 women, 55 men, 58 - 87 years) were interviewed using a questionnaire. The compliance was determined by the Morisky-Score., Results: 78 % of the patients received more than four pills every day (median 8.34). Most common products were beta-blockers (89 %), ACE-Inhibitors/Sartans (69 %) and aspirin (65 %). Only 52 % of the patients knew the indications of their medication. Although 83 % of the patients claimed to be absolutely compliant concerning their medication, the Morisky-Score revealed a high compliance only in 52 %. The compliance decreased significantly if the number of prescribed medication increased to more than four pills a day. 48 % of the patients took regularly non-prescription products, 35 % more than three additional products daily. Most commonly multivitamins, minerals, herbals and non-steroidal anti-inflammatory drugs were used. This non-prescription medication did not affect the compliance of the patients., Conclusions: Polypharmacy with more than four pills daily leads to a lower compliance and can therefore influence the implementation of guideline-medicine. Non-prescription medication is widely used and should be considered because of their potential side-effects and drug interactions.

Most cardiovascular disease risk factors are modifiable by lifestyle changes. Nevertheless, the modern lifestyle is associated with increasing cardiovascular risk worldwide, with high prevalence of smoking, physical inactivity and obesity. Obesity is linked with diabetes, which has risen alarmingly, presently affecting 194 million people worldwide. The number of people with diabetes is also expected to double by 2025. Diabetes increases the risk of cardiovascular disease, which is the number one cause of death in industrialized countries. The complications of diabetes also increase disability, reduce life expectancy and create tremendous health costs. There is research available, however, which shows that diabetes can be prevented in the obese through lifestyle intervention. Such interventions are necessary to overcome what may be the most challenging health problem of the 21st century., ((c) 2006 Prous Science. All rights reserved.)

Diabetes is a major risk factor for coronary artery disease and most patients with diabetes die of cardiovascular complications. Reduction of cardiovascular risk is therefore a high priority in the management of patients with diabetes. Microalbuminuria is an important predictor of cardiovascular events and forms one of the components of the insulin resistance/metabolic syndrome, which confers a particularly high risk of cardiovascular death. The currently available glucose-lowering agents vary considerably in their ability to reduce microalbuminuria. The sulfonylureas and metformin appear to have little effect on microalbuminuria expressed as urinary albumin/creatinine ratio, while the thiazolidinediones have unique effects on this risk factor, in parallel with their effects on insulin resistance. In two 1-year European multicenter, randomized, double-blind monotherapy trials (n=2444), pioglitazone produced similar reductions in urinary albumin/creatinine ratio to gliclazide and greater reductions than metformin (P<0.001). Similarly, two further 1-year European multicenter, randomized, double-blind trials assessed the effects of add-on therapy (n=1269) on urinary albumin/creatinine ratio. In the first study, urinary albumin/creatinine ratio was reduced by pioglitazone add-on to sulfonylurea (-15%), but was largely unaffected by metformin add-on to sulfonylurea (2%; P<0.05). In the second, urinary albumin/creatinine ratio was also reduced by pioglitazone add-on to metformin (-10%), but increased by gliclazide add-on to metformin (6%, P<0.05). The results of these studies indicated that compared with metformin or gliclazide, pioglitazone may provide therapeutic benefits, over and above those due to improved glycemic control. These include significant reductions in urinary albumin/creatinine ratio, a known cardiovascular risk marker.

Background: People with type 2 diabetes generally carry an array of risk factors for cardiovascular disease (CVD), including hyperglycaemia, dyslipidaemia, alterations in inflammatory mediators and coagulation/thrombolytic parameters, as well as other 'non-traditional' risk factors, many of which may be closely associated with insulin resistance. Consequently, rates of CVD mortality and morbidity are particularly high in this population. Targeting hyperglycaemia alone does not reduce the excess risk in diabetes, highlighting the need for aggressive treatment of other risk factors., Scope: This is a review of cardiovascular risk markers in diabetes, based on MEDLINE and EMBASE literature searches (1994-2004)., Findings: Although, the current use of statin therapy is effective at reducing low-density lipoprotein (LDL)-cholesterol, residual risk remains from other independent lipid and non-lipid factors. The peroxisome proliferator-activated receptor-gamma(PPARgamma) appears to be intimately involved in regulating risk markers at multiple levels. Ligands that activate PPARgamma, which include the thiazolidinedione (TZD) insulin-sensitizing agents used to manage type 2 diabetes, display a number of potential anti-atherogenic properties, including effects on high-density lipoprotein (HDL) cholesterol and triglycerides, as well as other beneficial non-lipid effects, such as regulating levels of mediators involved in inflammation and endothelial dysfunction. Data from several sources suggest that simple strategies combining TZDs and statins could have complementary effects on CVD risk factors profiles in diabetes, alongside the ability to control glycaemia., Conclusion: It is hoped that studies currently underway will provide insights into the value of such treatment approaches in terms of reducing the excess CVD risk, morbidity and mortality associated with type 2 diabetes.

Besides classical, modifiable risk factors (hypercholesterolemia, hypertension, smoking) abnormalities of the glucose metabolism (diabetes mellitus, impaired glucose tolerance) are strong emerging cardiovascular risk factors. Epidemiological data indicate that 8 % of the population and up to 60 % of patients with coronary artery disease have abnormalities of glucose metabolism. The prevalence of these abnormalities will increase as the population ages and the mean body weight increases. An abnormal glucose concentration damages the endothelium in several ways: increased oxidative stress, inflammatory processes and an activation of procoagulant factors all impair endothelial function. A blood glucose normalising therapy is thought to decrease the incidence of cardiovascular events in these patients. In patients with an acute myocardial infarction and diabetes mellitus an early intensive insulin therapy improves the outcome of these patients. In summary, the early detection and treatment of abnormalities of glucose metabolism reduces cardiac events.

Objective: The PROspective 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 randomized, 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 randomized 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 randomization 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 randomized 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 infarction (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.