aleglitazar and muraglitazar

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

Clinical trials of cardiovascular disease (CVD) prevention in patients with type 2 diabetes mellitus primarily have been directed at the modification of a single major risk factor; however, in trials that enroll patients with and without diabetes, the absolute risk in CVD events remains higher in patients with diabetes. Efforts to reduce the macrovascular and microvascular residual risk have been directed toward a multifactorial CVD risk-factor modification; nonetheless, long-term complications remain high. Dual-peroxisome proliferator-activated receptor (PPAR) α/γ agonists may offer opportunities to lower macrovascular and microvascular complications of type 2 diabetes mellitus beyond the reductions achieved with conventional risk-factor modification. The information presented elucidates the differentiation of compound-specific vs class-effect properties of PPARs as the basis for future development of a new candidate molecule. Prior experience with thiazolidinediones, an approved class of PPARγ agonists, and glitazars, investigational class of dual-PPARα/γ agonists, also provides important lessons about the risks and benefits of targeting a nuclear receptor while revealing some of the future challenges for regulatory approval.

Topics: Alkanesulfonates; Diabetic Angiopathies; Glycine; Humans; Hypoglycemic Agents; Insulin Resistance; Ligands; Oxazines; Oxazoles; Phenylpropionates; Phosphorylation; PPAR alpha; PPAR delta; PPAR gamma; Thiazolidinediones; Thiophenes; United States; United States Food and Drug Administration

Topics: Alkanesulfonates; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Glycine; Humans; Hypoglycemic Agents; Oxazoles; Phenylpropionates; PPAR alpha; PPAR gamma; Thiophenes