aleglitazar and Acute-Coronary-Syndrome

To define the predictors of long-term mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome.. A total of 7226 patients from a randomized trial, testing the effect on cardiovascular outcomes of the dual peroxisome proliferator-activated receptor agonist aleglitazar in patients with type 2 diabetes mellitus and recent acute coronary syndrome (AleCardio trial), were analysed. Median follow-up was 2 years. The independent mortality predictors were defined using Cox regression analysis. The predictive information provided by each variable was calculated as percent of total chi-square of the model. All-cause mortality was 4.0%, with cardiovascular death contributing for 73% of mortality. The mortality prediction model included N-terminal proB-type natriuretic peptide (adjusted hazard ratio = 1.68; 95% confidence interval = 1.51-1.88; 27% of prediction), lack of coronary revascularization (hazard ratio = 2.28; 95% confidence interval = 1.77-2.93; 18% of prediction), age (hazard ratio = 1.04; 95% confidence interval = 1.02-1.05; 15% of prediction), heart rate (hazard ratio = 1.02; 95% confidence interval = 1.01-1.03; 10% of prediction), glycated haemoglobin (hazard ratio = 1.11; 95% confidence interval = 1.03-1.19; 8% of prediction), haemoglobin (hazard ratio = 1.01; 95% confidence interval = 1.00-1.02; 8% of prediction), prior coronary artery bypass (hazard ratio = 1.61; 95% confidence interval = 1.11-2.32; 7% of prediction) and prior myocardial infarction (hazard ratio = 1.40; 95% confidence interval = 1.05-1.87; 6% of prediction).. In patients with type 2 diabetes mellitus and recent acute coronary syndrome, mortality prediction is largely dominated by markers of cardiac, rather than metabolic, dysfunction.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Myocardial Revascularization; Natriuretic Peptide, Brain; Oxazoles; Peptide Fragments; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Risk Factors; Thiophenes; Time Factors; Treatment Outcome

Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain.. The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter.. In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events.. After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.

Topics: Acute Coronary Syndrome; Aged; Diabetes Mellitus, Type 2; Female; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Natriuretic Peptide, Brain; Oxazoles; Peptide Fragments; Proportional Hazards Models; Risk Assessment; Risk Factors; Survival Analysis; Thiophenes

In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus) trial, which compared the PPAR-α/γ agonist aleglitazar with placebo.. Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death.. A twofold higher baseline adiponectin (. In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes.

Topics: Acute Coronary Syndrome; Adiponectin; Aged; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fatty Acids, Nonesterified; Female; Humans; Male; Middle Aged; Myocardial Infarction; Oxazoles; Retrospective Studies; Stroke; Thiophenes; Treatment Outcome

Worsening renal function during hospitalization for an acute coronary syndrome is strongly predictive of in-hospital and long-term outcome. However, the role of post-discharge worsening renal function has never been investigated in this setting.. We considered the placebo cohort of the AleCardio trial comparing aleglitazar with standard medical therapy among patients with type 2 diabetes mellitus and a recent acute coronary syndrome. Patients who had died or had been admitted to hospital for heart failure before the 6-month follow-up, as well as patients without complete renal function data, were excluded, leaving 2776 patients for the analysis. Worsening renal function was defined as a >20% reduction in estimated glomerular filtration rate from discharge to 6 months, or progression to macroalbuminuria. The Cox regression analysis was used to determine the prognostic impact of 6-month renal deterioration on the composite of all-cause death and hospitalization for heart failure.. Worsening renal function occurred in 204 patients (7.34%). At a median follow-up of 2 years the estimated rates of death and hospitalization for heart failure per 100 person-years were 3.45 (95% confidence interval [CI], 2.46-6.36) for those with worsening renal function, versus 1.43 (95% CI, 1.14-1.79) for patients with stable renal function. At the adjusted analysis worsening renal function was associated with the composite endpoint (hazard ratio 2.65; 95% CI, 1.57-4.49; P <.001).. Post-discharge worsening renal function is not infrequent among patients with type 2 diabetes and acute coronary syndromes with normal or mildly depressed renal function, and is a strong predictor of adverse cardiovascular events.

Topics: Acute Coronary Syndrome; Aged; Albuminuria; Analysis of Variance; Biomarkers; Cause of Death; Comorbidity; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Humans; Male; Oxazoles; Patient Discharge; Percutaneous Coronary Intervention; Peroxisome Proliferator-Activated Receptors; Predictive Value of Tests; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Thiophenes

No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles.. To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS).. AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated.. Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily.. The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function.. The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased.. Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk.. clinicaltrials.gov Identifier: NCT01042769.

Topics: Acute Coronary Syndrome; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Myocardial Infarction; Oxazoles; Peroxisome Proliferator-Activated Receptors; Risk; Stroke; Survival Analysis; Thiophenes; Treatment Outcome

Peroxisome proliferator-activated receptors (PPARs) regulate transcription of genes involved in glucose uptake, lipid metabolism, and inflammation. Aleglitazar is a potent dual PPAR agonist with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles and biomarkers of cardiovascular risk. The AleCardio trial examines whether the addition of aleglitazar to standard medical therapy reduces the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome.. AleCardio is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. A total of 7,228 patients were randomized to aleglitazar 150 μg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to the first event of cardiovascular death, myocardial infarction, or stroke. Principal safety end points are hospitalization due to heart failure and changes in renal function. Treatment will continue until 7,000 patients are followed up for at least 2.5 years and 950 primary end point events are adjudicated.. AleCardio will establish whether the PPAR-α/γ agonist aleglitazar improves cardiovascular outcomes in patients with diabetes and high-risk coronary disease.

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Hospitalization; Humans; Male; Middle Aged; Morbidity; Myocardial Infarction; Oxazoles; Peroxisome Proliferator-Activated Receptors; Risk Factors; Stroke; Thiophenes; Treatment Outcome