Abstract

Peroxisome proliferator-activated receptor gamma (PPAR-γ) played a central role in regulating glucose and lipid 
metabolism, making it a critical target for combating insulin resistance and type 2 diabetes mellitus. Traditional 
PPAR-γ agonists, notably thiazolidinediones (TZDs), effectively improved insulin sensitivity but were limited by 
adverse effects such as weight gain, edema, and cardiovascular risks. Recent developments focus on synthetic PPAR
γ modulators that selectively activate beneficial pathways while minimizing harmful side effects. This review aimed 
to critically evaluate the molecular mechanisms of selective PPAR-γ modulators (SPARMs), their impact on 
metabolic outcomes, and their potential to overcome adverse effects associated with TZDs. An extensive literature 
search identified preclinical and clinical studies assessing the efficacy and safety profiles of SPARMs, with inclusion 
criteria emphasizing mechanistic insights and metabolic endpoints. Emerging evidence indicated that SPARMs 
induced favorable improvements in insulin sensitivity, lipid profiles, and inflammatory markers comparable to TZDs 
but with reduced or absent adverse effects such as weight gain and edema. Structural modifications that influenced 
coactivator recruitment appeared pivotal for these outcomes. However, variability in clinical responses and limited 
long-term data highlight ongoing challenges. Selective PPAR-γ modulators held promise as therapeutic agents 
capable of delivering metabolic benefits without the adverse effects characteristic of TZDs. Nonetheless, further 
detailed mechanistic studies and extended clinical assessments were required to fully delineate their safety and 
efficacy profiles.