Examining the safety of PPAR agonists – current trends and future prospects

Abstract

The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.

Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells

“…Improved understanding of the cellular and molecular mechanisms underlying these neuronal changes may facilitate better clinical management for patients diagnosed with HD. PPARγ agonizts, like rosiglitazone, have been used for decades to not only successfully treat some patients with Type II diabetes [36], but also shed light on the role of these drugs in cellular and animal models of neurodegenerative diseases [18][19][20][21][37][38][39]. Thus, due to the PPARγ-dependent neuroprotective benefits of rosiglitazone seen here, the extensive knowledge base of their possible side effects and toxicity in humans, and the shortened translation time from the bench to bedside that would be afforded by repurposing these drugs, PPARγ agonizts emerge as an attractive alternative novel therapeutic option that may improve outcomes for some HD patients.…”

Metabolic comorbidities in Cushing's syndrome

“…The effect of metformin (and possibly thiazolidinediones) on fat tissue and other organ AMP-activated protein kinases (AMPK) could be beneficial (44,45). Pioglitazone may have a potential negative effect on heart and bone (46). Thiazolidinediones have been demonstrated to have a direct adrenocorticotropic hormone (ACTH)-lowering effect on corticotrophinomas in vitro, but no convincing results arose from clinical trials on patients with CD (47).…”

Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy

“…PPARα controls the expression of a wide range of proteins involved in both the transport and β oxidation of free FAs in liver, kidney, heart, muscle, and adipose tissue (13,14) and is activated by FA moieties and fibrates (15). In the vasculature, PPARα exerts antiinflammatory effects in addition to having a positive influence on vessel reactivity and remodeling and macrophage lipid handling within the plaque (16)(17)(18).…”