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Specifically, orforglipron functions as a potent partial agonist that preferentially activates G-protein signaling over β-arrestin recruitment to the receptor.97 Currently under evaluation for obesity and T2DM treatment, orforglipron may offer an alternative to oral semaglutide with reduced administration constraints, as it does not require fasting prior to dosing.98 In obese subjects, 36 weeks of orforglipron therapy produced a dose-dependent weight loss of up to 14.7%, compared to 2.3% in the placebo group, accompanied by favorable changes in cardiometabolic risk factors.99 Danuglipron represents another oral, non-peptide, G-protein-biased GLP-1RAs.100 A recent Phase 2b trial in obese individuals demonstrated that 32 weeks of treatment with danuglipron at doses ranging from 40 to 200 mg twice daily resulted in an average weight loss of 11.7%, whereas the placebo group exhibited 1.4% weight gain.101 However, treatment discontinuation rates exceeded 50% across all dosing cohorts compared to approximately 40% in the placebo group, with gastrointestinal adverse events being the most frequently reported.101 In patients with T2DM and overweight or obesity, 16 weeks of danuglipron administered twice daily at a maximum dose of 120 mg yielded placebo-adjusted weight loss of up to 4.2 kg and a reduction in mean HbA1c levels of up to 1.2% relative to placebo in the highest dose group.102 Effects of GLP-1RAs on Cardiovascular System Within the cardiovascular system, the GLP-1 receptor is expressed in both cardiac myocytes and endothelial cells,103 indicating that GLP-1 receptor activation exerts both direct and indirect effects on cardiac and vascular functions

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