The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation

Abstract

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.

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

“…Pioglitazone cardioprotection has also been observed in diabetic mice, revealing an alternative mechanism by which PTEN/AKT/FAK modulation reduces collagen deposition and pathological DiCM hypertrophy [51]. In contrast, the tesaglitazar and the glitazar classes of dual PPARα and PPARγ agonists has been shown to worsen cardiac function in type 2 diabetes patients [170,171].…”

Structural Basis for PPARs Activation by The Dual PPARα/γ Agonist Sanguinarine: A Unique Mode of Ligand Recognition

“…Moreover, Saroglitazar has never been associated with cardiovascular complications. Previous studies have presented the high efficiency of dual PPARα/γ agonists against hyperglycemia and hyperlipidemia [ 33 ]. Therefore, we examined the mRNA expression level of PPARα-target genes in hepatocytes and differentiation-dependent PPARγ-target genes in 3T3–L1 preadipocyte cells.…”

Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

“…This strategy's main problem was the inability of the newly designed derivatives to eliminate the TZD-caused risk for heart failure, due to imbalance of activity on PPARα and PPARγ. [40] The only dual PPARα/γ agonist completing clinical trials and entering the market in India was saroglitazar (Scheme 9). This molecule is a potent PPARα and moderate PPARγ agonist that effectively lowered plasma levels of triglycerides, free fatty acids, glucose and insulin in preclinical states (animal models of DT2, obesity and hyperlipidemia), proving its ability to reduce insulin resistance.…”

“…Activating the PPARδ receptor could be beneficial for conditions such as obesity, insulin resistance and atherosclerosis (via reducing triglyceride and increasing HDL levels) [22] . Thus, in an attempt to improve the profile of PPARγ agonists, research interest was directed towards the design of multitarget molecules aiming at more than one PPAR subtype; mixed PPARα/γ, PPARγ/δ, PPARα/δ and triple PPARα/γ/δ agonists could influence a variety of different factors, rendering them an improved approach for the treatment of DT2 in diabetic patients with other common co‐morbidities such as metabolic syndrome [40] …”

“…A list of these derivatives together with their reason for withdrawal is presented in Table 1. This strategy's main problem was the inability of the newly designed derivatives to eliminate the TZD‐caused risk for heart failure, due to imbalance of activity on PPARα and PPARγ [40] …”