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Serving as 2nd\u2010line therapeutics, glitazones were the first class, influencing PPAR\u2010\u03b3, yet a range of adverse effects were reported regarding the use of PPAR\u2010\u03b3 full agonists. Agents having partial PPAR\u2010\u03b3 agonistic effect or selectively modulate PPAR\u2010\u03b3 transactivity have been introduced. Nonetheless, most of these agents were abandoned at phase II clinical trials for unbalanced supra\u2010therapeutic activation of the multireceptors. Despite clinical attentions towards advers effects, these clinical failures have defined the pharmacological boundaries for safer drug design. The emerging clinical pathway focuses on bifunctional hybridization to achieve glucose homeostasis through synergistic modulation rather than high\u2010dose single\u2010target activation. It was not until 2003 where G\u2010protein\u2010coupled receptor 40 (GPCR40), currently named as free fatty acid receptor\u2010I (FFAR1), was discovered. A plausible FFAR1\/PPAR\u2010\u03b3 crosstalk has been suggested linking both receptors and insulin secretion. These findings triggered the development of several FFAR1 agonists. Nevertheless, and till the time of writing this review, limited studies proposed the synthesis of such hybrid molecules with only one reaching a regional market. The provided review deals with recent advances of both FFAR1 and PPAR\u2010\u03b3 ligands in managing T2DM. Up\u2010to\u2010date medicinal chemistry description of FFAR1 and PPAR\u2010\u03b3 modulators as well as each dual agonists have been provided with highlighted structural diversity and activity interlink for each main class.<\/jats:p>","DOI":"10.1002\/ardp.70335","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:43:31Z","timestamp":1791225811000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trends in Developing PPAR\u2010Gamma and FFAR1\/GPCR40 Modulators for Managing Type\u2010II Diabetes Mellitus"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1333-980X","authenticated-orcid":false,"given":"Ahmad J.","family":"Almalki","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy King Abdulaziz University Jeddah Saudi Arabia"},{"name":"Center of Excellence for Drug Research and Pharmaceutical Industries King Abdulaziz University Jeddah Saudi Arabia"},{"name":"Toxicology and Forensic Sciences Unit King Fahd Medical Research Center, King Abdulaziz University Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc23-S004"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119"},{"key":"e_1_2_11_4_1","unstructured":"International_Diabetes_Federation \u201cIDF diabetes Atlas. 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