A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia

Abstract

Background:Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated.Conclusion:Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

New dual peroxisome proliferator activated receptor agonist—Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence

“…Clinical evidences from Bezafibrate (a pan-PPAR [α, β/δ, γ] activator) studies supported the concept of a pan-PPAR/dual-PPAR therapeutic approach for diabetic dyslipidemia [31,32]. In the past two decades, Glitazars, dual PPAR α/γ agonists, have attracted global attention due to unique lipid and glycemic modifying actions [9,33,36]. Many Glitazars such as Muraglitazar, Ragaglitazar, Tesaglitazar, Naveglitazar, Farglitazar, Aleglitazar were developed but failed during preclinical stage or the clinical development stage due to lack of efficacy or safety issues [9,[36][37][38].…”

“…In the past two decades, Glitazars, dual PPAR α/γ agonists, have attracted global attention due to unique lipid and glycemic modifying actions [9,33,36]. Many Glitazars such as Muraglitazar, Ragaglitazar, Tesaglitazar, Naveglitazar, Farglitazar, Aleglitazar were developed but failed during preclinical stage or the clinical development stage due to lack of efficacy or safety issues [9,[36][37][38]. Clinical development of Muraglitazar was discontinued due to cardiovascular AEs such as myocardial infarction, stroke, heart failure [9].…”

Combination of Peroxisome Proliferator-Activated Receptor (PPAR) Alpha and Gamma Agonists Prevents Corneal Inflammation and Neovascularization in a Rat Alkali Burn Model

“…Therefore, instillation of a drug combination may be more effective than a single PPAR agonist for corneal alkali burn. Recently, a few reports have been published on a PPARα/γ dual agonist [ 38 , 39 ]. Kaur et al reported that trans-acrylic acid derivatives have binding affinity for PPARα and PPARγ and significantly reduce the plasma glucose level and total cholesterol level in diabetic rats compared to pioglitazone [ 39 ].…”

The potential role of sesquiterpene lactones isolated from medicinal plants in the treatment of the metabolic syndrome – A review

“…Activation of PPAR-α by hypolipidemic fibrate class of drugs decreases TG levels and raises HDL-C in dyslipidemic individuals, whereas activation of PPAR-γ by antidiabetic thiazolidinedione agents causes insulin sensitization to enhance glucose metabolism ( Botta et al., 2018 ). Currently, dual PPARα/γ agonists, which stimulate both PPARα and PPAR-γ isoforms to similar extents, are gaining popularity since it is believed that they are able to ameliorate the unwanted side effects of selective PPAR-α and PPAR-γ agonists; and may also be used to treat dyslipidemia and T2DM simultaneously ( Balakumar et al., 2019 ). Tirotundin ( 7 ) and tagitinin A ( 8 ) have been suggested being dual PPARα/γ agonists after the evaluation of their agonistic activity against PPARs employing a transient transfection reporter assay in HepG2 cells ( Lin et al., 2012 ).…”