aleglitazar and Cardiovascular-Diseases

This study evaluates the cardiovascular risk and safety of a dual peroxisome proliferator-activated receptor alpha and gamma (PPARα&γ), aleglitazar, for the management of type 2 diabetes mellitus. Studies were identified after a literature search in electronic databases and included in the meta-analysis according to eligibility criteria. Meta-analyses of mean differences in the changes from the baseline or odds ratios of selected indices between the aleglitazar- and the placebo/comparator-treated participants were performed. Seven studies {11,832 individuals; age 59.3 years [95% confidence interval (CI) 56.4-61.9]; body mass index 30.8 kg/m [95% CI 30.1-31.7]; sex, 54% males [44-64]} were included. In comparison with the placebo or pioglitazone, the aleglitazar treatment significantly improved %HbA1c, high-density lipoprotein-cholesterol (HDL-chol), and triglycerides. Aleglitazar also significantly decreased fasting plasma glucose and apolipoprotein B compared with the placebo. However, compared with the placebo or pioglitazone, aleglitazar significantly increased serum creatinine levels and significantly decreased the estimated glomerular filtration rate. In addition, the aleglitazar treatment was associated with a significantly increased body weight. Incidence of hypoglycemia, gastrointestinal hemorrhage, bone fractures, heart failure, cardiovascular death, and malignancy was higher in the aleglitazar group. Despite efficacy in glycemic and lipidic control, the aleglitazar treatment was associated with a poor safety profile.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Lipids; Male; Middle Aged; Oxazoles; PPAR alpha; PPAR gamma; Risk Assessment; Risk Factors; Thiophenes; Treatment Outcome; Weight Gain

The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors superfamily and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.

Topics: Alkanesulfonates; Animals; Cardiotoxicity; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Glycine; Humans; Hypoglycemic Agents; Oxazoles; Phenylpropionates; PPAR alpha; PPAR gamma; Risk Assessment; Risk Factors; Signal Transduction; Thiophenes

Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-α agonists such as fibrates improve dyslipidaemia, while PPAR-γ agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes--in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-α/γ agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-α/γ agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes.

Topics: Blood Glucose; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dyslipidemias; Humans; Hypoglycemic Agents; Oxazoles; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR gamma; Rosiglitazone; Thiazolidinediones; Thiophenes; Treatment Outcome

In preliminary clinical studies, aleglitazar, a new dual PPAR-α-γ agonist, has been demonstrated to improve hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus. This review will provide up-to-date information on the clinical safety and efficacy of aleglitazar, which is currently under Phase III clinical investigation for reduction of cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome.. A PubMed literature search (January 1950 to February 2011) was conducted using the following search terms: aleglitazar, PPAR, PPAR α agonist, PPAR γ agonist and PPAR α/γ agonist. Additional articles were gathered using reference lists from sources obtained from the original literature search. This review summarizes available information pertaining to pharmacodynamics, pharmacokinetics, clinical studies and safety/tolerability of aleglitazar. The effects of this new drug are compared and contrasted with those of fibrates (PPAR-α agonists), thiazolidinediones (PPAR-γ agonists) and other dual PPAR-α-γ agonists.. Preliminary evidence from clinical studies with aleglitazar is promising, with reported improvements in glycemia, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein B and blood pressure. However, PPAR-α- and -γ-associated side effects have been observed and additional large-scale, long-term clinical studies are necessary to better understand the clinical implications of these effects.

Topics: Apolipoproteins B; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Interactions; Fibric Acids; Humans; Hypoglycemic Agents; Oxazoles; PPAR alpha; PPAR gamma; Thiazolidinediones; Thiophenes; Triglycerides

Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis.. This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS).. LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study.. This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; PPAR alpha; PPAR gamma; Risk Factors

The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar.. The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population.. Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

Topics: Aged; Cardiovascular Diseases; Clopidogrel; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Interactions; Female; Heart Disease Risk Factors; Humans; Male; Middle Aged; Oxazoles; PPAR alpha; PPAR gamma; Risk Factors; Thiophenes

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.. 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.. 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).. 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.

Topics: Aged; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Early Termination of Clinical Trials; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Myalgia; Myocardial Infarction; Myositis; Oxazoles; Peripheral Arterial Disease; PPAR alpha; PPAR gamma; Prediabetic State; Stroke; Thiophenes; Treatment Outcome

Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar.. In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with

Topics: Analysis of Variance; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Least-Squares Analysis; Male; Middle Aged; Oxazoles; Pioglitazone; PPAR alpha; PPAR gamma; Safety; Single-Blind Method; Thiazolidinediones; Thiophenes; Treatment Outcome

Preventing morbidity and mortality from diabetes mellitus is of paramount importance as the incidence of this disease is increasing across the world. While microvascular complications of diabetes such as nephropathy, retinopathy, and neuropathy are reduced with intensive glycemic control, treatment of hyperglycemia has not been consistently shown to have effects on the macrovascular complications of diabetes such as coronary artery, cerebrovascular, and peripheral vascular disease. Preventive efforts have accordingly shifted toward the modification of other cardiovascular risk factors in diabetic patients. Agonism of the peroxisome proliferator-activated receptors (PPARs) has long been an attractive target for antidiabetic therapy due to the role of PPARs in glycemic control and lipid metabolism. PPAR-α agonists such as rosiglitazone and pioglitazone are used in clinical practice for the treatment of diabetes, and there is some evidence that pioglitazone may have positive effects on cardiovascular complications by virtue of its favorable effects on lipid profiles. However, they have not been shown to reduce macrovascular events. PPAR-α agonism is the mechanism of action in the fibrate class of medications; these agents have been shown to increase high-density lipoprotein cholesterol (HDL-C) levels, reduce triglyceride levels, and improve cardiovascular outcomes. Given the prevalence of lipid abnormalities in patients with diabetes, dual PPAR-α/γ agonists (glitazars) could potentially benefit patients with diabetes. A phase II trial examining a novel dual PPAR agonist, aleglitazar, showed that therapy with this agent reduced hyperglycemia and favorably modified levels of HDL-C and triglycerides with an acceptable safety profile. Aleglitazar is currently being studied in large-scale clinical trials to assess whether it will reduce the risk of major cardiovascular endpoints (death, myocardial infarction, or stroke) among patients with diabetes and coronary artery disease. If ongoing studies confirm the theoretical benefit and safety of dual PPAR-α/γ agonism, aleglitazar may become the first therapy demonstrated to reduce macrovascular complications in patients with diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Oxazoles; PPAR alpha; PPAR gamma; Risk Factors; Thiophenes