PPARG and heart failure: However,their initial success was tempered by side effects such as weightgain, fluid retention, and increased risk of heart failure, limitingtheir clinical use.3 To address these issues,researchers are developing second-generation PPARγ ligands withpartial agonist or antagonist properties,4−8 including MCC-555, DRF-2593 (balaglitazone), metaglidasen,and halofenate (Figure 1A), some of which are in Phase II and III clinical trials.9−11 PPARγ ligands not only benefit diabetes treatment but alsoshow promise in other areas.