New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease

Abstract

ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

“…The magnitude of this pleiotropic action of fibrates in comparison to other conventional and novel lipid-modifying treatments [63][64][65][66][67][68], including selective PPAR modulators [69,70], needs to be determined. More data from longitudinal studies are needed to assess whether the improvement in FMD may reflect a true reduction in the cardiovascular risk and if this positive effects are restricted to some particular categories of patients.…”

Treatment options for managing atherogenic dyslipidemia and fatty liver disease

“…As recently discussed [20], therapies for NAFLD should ideally not only reverse the accumulation of TG in hepatocytes (i.e., hepatic steatosis) but also effectively suppress hepatic inflammation, thereby preventing progression of simple steatosis to non-alcoholic steatohepatitis, fibrosis and cirrhosis. Current treatment modalities, including fenofibrate, can target the risk factors of NAFLD, such as dyslipidemia, insulin resistance, oxidative stress and inflammation [21].…”

“…In addition, newer agents are being developed that have less potential for adverse pharmacokinetic interactions with statins as well as greater specificity and balanced activation of PPAR subtypes [20]; such new agents would improve the beneficial lipid-modifying effects of PPAR activation while minimizing off-target adverse effects.…”

Impact of Co-Morbidities in Non Alcoholic Fatty Liver Disease among Type 2 Diabetes Mellitus

“…[15] The most common form of dyslipidemia in NAFLD patients is atherogenic dyslipidemia, which is characterized by hypertriglyceridemia, low HDL-C levels, and high LDL-C levels. [16] Long-term dyslipidemia may increase the expression and activity of sterol regulatory element binding protein-1c, a transcription factor, which adversely affects the profiles of lipid and lipoprotein synthesis in the liver, including increased TG, LDL, and very low-density lipoprotein (VLDL) levels and decreased HDL-C levels. [17,18] There is a strong link between insulin resistance and metabolic dyslipidemia in T2DM.…”